Human Genetics in Nursing Suresh K Sharma
INDEX
×
Chapter Notes

Save Clear


IntroductionChapter 1

In 1865, Gregor Mendal was the first to describe the elements of hereditary genes. His observation and analysis of the observable features of Pea led him to conclude that specific traits particulate factors were passed on unchanged from a parent plant to the next generation. Scientific discoveries during the last several decades have provided more information about how genes function and how they contribute to human health and disease. Currently more than 10,371 identified genetic disorders are known to be inherited in a predictable pattern in families. Nurses are at present in all health care settings and care for individuals who may have genetic conditions or predisposition. They also ensure that these individuals have access to the most current genetic information, genetic diagnosis, treatment and management therapeutics. With this knowledge, nurses can collect appropriate family information; provide current and appropriate information and support patients, families and communities as they integrate this new information and technology into their daily lives.
 
CONCEPT OF GENETICS
The term ‘Genetics’ was introduced by Bateson in 1906. It has been derived from the Greek word ‘gene’, which means ‘to become’ or ‘to grow into’. Therefore, genetics is the science of coming into being.
“Genetics is that branch of biological sciences which deals with the transmission of characteristics from parents to offspring”.
In other words “Genetics is the study of inheritance of disease in families, mapping of disease genes to specific location on chromosomes, analysis of molecular mechanism through which 2genes cause disease and the diagnosis and treatment of genetic diseases”.
Traditionally genetics has been associated with childbearing decision-making and caring for children with genetic disorders. Medical genetics has focused on the inheritance of hereditary disorders affecting only a small portion of the population. Genetic services have been primarily associated with prenatal genetic counseling, identification of pediatric disorders associated with birth defects and dysmorphology, and in some cases rare adult onset single gene disorders. Recent genetic and technological advances are helping us to better understand how genetic changes impact human variation as well as the development of cancer, Alzheimer's disease, diabetes and other multifactorial diseases that are prevalent in adults.
The Human Genome Project, one of the most significant research endeavors of the twentieth century, deserves much of the credit for the discovery of these new applications of genetic information. Specifically, research from the Human Genome Project is providing a new and better understanding of the genetic contribution to disease, the development of targeted drug therapy (pharmacogenetics) and the development of genetic tests that identify those who may have or are at risk of developing genetic diseases. The results of this explosion of knowledge is a rapid paradigm shift from the ‘old genetics’ to the ‘new genetics’. Under the ‘new genetics’ paradigm nearly all diseases have a genetic component. Now recognized is the fact that most common human diseases such as myocardial infarction, cancer, mental illness, diabetes, and Alzheimer's disease are a result of complex interactions between a number of factors including the influence of one or more genes and a variety of environmental exposures.
The influence of recent genetic advances on nursing practice is especially evident in oncology. Oncology nurses practicing in cancer prevention and control apply genetic principles to their daily clinical practice. For example, they assess hereditary and non-hereditary cancer risk factors, take detailed family histories and construct pedigrees, identify individuals and families at risk for hereditary cancer syndromes, make recommendations for cancer 3risk reduction, surveillance, and management, and when appropriate, counsel and educate about the risks and benefits of genetic testing.
This genetic revolution and shift to the ‘new genetics’ has created a demand for health professionals in a number of clinical specialities who understand the genetic contribution to disease risk, the impact on disease management, and the genetic educational needs of patients and families. Nurses have risen to the challenge capitulating genetic nursing practice into a new era.
 
BASIC GENETIC TERMS
  • Genes: Genes are genetic material on a chromosome that code for a trait. For example, one person has a gene for eye color.
  • Alleles: They are variations of genes. Means the two genes, which occur on the same locus in the two homologous chromosomes of an individual and control the expression of a character, are called as alleles. For example, one person has the allele for brown eye color. Note that some alleles are dominant over others. That is, if a person inherits both the dominant and the recessive alleles, the dominant allele will be the one expressed.
  • Gene locus: A particular portion or region of the chromosome representing a single gene is called as locus. The alleles of gene occupy the same gene locus on the two homologous chromosomes.
  • Homologous chromosomes: Members of the chromosome pairs with same gene number and arrangement.
  • Dominant allele: It is one of a pair of alleles, which can express itself whether present in homozygous or heterozygous state, e.g. the gene for tallness Tt and TT, where T is dominate alleles and person will be tall in both conditions.
  • Recessive allele: The allele of an allelic or allelomophic pair, which is unable to express its effect in the presence of its contrasting alleles in a heterozygote is called recessive alleles. For example, one has alleles of eye ‘Bb’ (B-Brown, b-blue) here b is recessive allele therefore person will have brown eye not 4blue. The effect of recessive allele becomes known only when it is present in the homozygous state (bb), in this state person will have blue eye.
  • Codominant alleles: The alleles, which do not show dominance-recessive relationship and are able to express themselves independently when present together are called codominant alleles. Here in heterozygous state both alleles express themselves. As a result, the heterozygous condition has a phenotype different from either homozygous genotypes. The joint character may appear to be intermediate between the ones produced by the two homozygous genotypes.
  • Heterozygous alleles: One allele of the same gene pair differs from the other. For example, for eye color Bb.
  • Homozygous alleles: Alleles that are identical or same in gene pair. For example, for eye color BB.
  • Hemizygous: Having one copy of a particular gene. For example, for eye color only B is present.
  • Genotype: It is the gene complement or genetic constitution of an individual with regard to one character irrespective of whether the genes are expressed or not. For example, one has the genotype Bb since one has the allele for brown eye color (B) and the allele for blue eye color (b). An organism is said to be homozygous for a certain trait if it carries two of the same alleles. It is homozygous dominant if it carries two dominant alleles and homozygous recessive if it carries two recessive alleles. The organism in above said example is heterozygous – it carries two different alleles.
  • Phenotype: It is observable or measurable distinctive structural or functional characteristics of an individual with regard to one or more characters which is a result of gene products brought to expression in a given environment. The characteristics are visible to a person (e.g. height, color of eyes etc.) or require special test for its identification (e.g. serological test for blood group). In other words, it is the expression of a gene.
For example, since one has the genotype Bb with one dominant and one recessive allele, the dominant allele (B) will mask the recessive allele (b) and one will have the phenotype for brown eyes. 5Phenotype can be modified by environment through genotype establishes the boundaries within which the environment can modify the phenotype. For example, a fair colored person can have tanned colored skin due to excessive exposure to skin.
  • A karyotype is a picture showing the arrangement of a full set of human chromsomes
 
PRACTICAL APPLICATIONS OF GENETICS IN NURSING
In last few years genetics gained several major developments and discoveries related to health and disease. Medical and nursing care practices are largely influenced with recent genetic advancements in health care. Recent advances in genetics knowledge and technology have impacted all areas of nursing practices. Application of genetics in nursing is very wide since:
  • All nurses have role in the delivery of genetic services and management of genetic information.
  • Nurses require genetic knowledge to identify, support, refer and care for persons affected by or at risk for genetic disorders.
  • Nurses can offer care that protects patients and families from the risk associated with genetic information, including addressing family issues.
  • Nurses are also needed to refer patients to genetic specialist and assist in making choice of genetic health care.
  • Genetic nursing is practiced in different environment such as maternity, pediatrics, medical-surgical, psychiatric and community health nursing.
  • Genetic nursing is a holistic practice that includes assessing, planning, implementing and evaluating the physical, spiritual, ethical and psychosocial aspects of patients and families who have genetic concerns.
  • Genetic nursing includes following:
    • Client and family assessment to identify genetic risk factors. In assessment takes detailed family history and construct a pedigree, analyze the assessment data. In addition, interpret information collected.
      6
    • Planning and implementation of care during diagnosis and management of genetic disorders. In care, provide genetic education and develop and carry out a plan of care to address genetic concerns.
    • Information, counseling and support services to persons affected by or at risk for genetic disorders.
    • Meeting referral needs.
    • Long-term follow up
  • Advanced practice nurses may play direct roles in genetic counseling and in advanced assessment. They also may work within a particular specialty in which genetics plays a role, such as an oncology or cardiology clinic, as well as in long-term management of specific genetic disorders depending on the speciality area in which they are trained.
The past several years have transformed genetic nursing practice from an all but, hidden practice to a recognized nursing specialty with a visible contribution to the genetic and overall health of individuals and families. Nurses have been involved in managing genetic information since the 1960s, when nurses provided services to children with genetic disorders and their families. Although in some respects the nurse's role today in managing genetic information and caring for individuals and families at risk for or diagnosed with genetic diseases or conditions is similar to this traditional role, the scope of practice is much broader and more encompassing. What has also changed, according to Forsman, is the amount of genetic information available and the population to which this information may be applied. We now know that genetic changes contribute to most, if not all diseases. Consequently, the scope of genetic knowledge application in nursing is limitless. “Nursing can ignore genetics no longer.” Major practical applications of genetics in nursing are as follows:
  1. Understands genetic basis of disease: With knowledge of genetics, nurses well understand that large proportion of total disease have genetic basis. In addition will learn about;
    • Role of different genes in causation of genetic disorders and defects.
      7
    • Good or bad genes for health-illness continuum.
    • Role of gene and chromosomal mutation in health and illness.
    • Normal and abnormal cell division and its genetic regulation.
    • Mechanism of disease inheritance from one generation to next generation.
    • Basic mechanisms of inheritance and transmission of chromosomes and genes, including the concepts of variation and mutation.
    • Genetic factors are playing role in an individual's health.
    • Genetic contribution towards different diseases, disorders and defects.
    • Genetic contributions to common and complex conditions such as breast cancer, colorectal cancer, heart disease and hypercholesterolemia, mental illness, certain behavioral traits, and Alzheimer's disease.
  2. Early and effective diagnosis of genetic disorders: Genetic knowledge of nurses will equip them with;
    • Information about genetic risk, genetic testing and screening, and the implications, both positive and negative results.
    • Interpretations of the results of genetic tests.
    • Interpretation of genetic risks (i.e. how to explain the meaning of a I in 4 risk for having another child with Tay-Sachs’ disease).
    • Awareness of the possibility of an inherited or genetic component for a client's condition and knowledge of cardinal features of familial predisposition such as early age of disease onset, multiple family members with the same diagnosis, predisposing risk factors.
    • What constitutes a proper family history specifically, what key information should be obtained and how to construct and read pedigrees.
  3. Contributes towards health promotion with genetic aspect: By learning about genetics nurses will enhance their understanding about:
    • Relationship of health and disease in relation to genetics, including how genetics and the environment interact and 8how genes interact with genes. This should lead to new ways of thinking about health promotion and disease prevention.
    • Healthy prenatal environment will ensure minimal risk of genetic defects among newborns.
    • Environmental interaction of an individual is an important factor in reference to gene or chromosomal mutation, which may have positive or negative impact on health of an individual.
    • Learn about pharmacogenomics, that every individual has unique genetic make up therefore responds differently to same drug. For example, a drug ‘A’ may be very effective to cure an illness in an individual, but same drug may bring severe hypersensitive reaction for another person.
    • An understanding of genetic contributions to human diversity including concepts such as discrimination and eugenics.
  4. Prevention of genetic conditions: Prevention is major principle of any medical discipline, similarly knowledge of genetics will enhance nurse's understanding that;
    • Several genetic disorders can be prevented with prompt and early diagnosis and treatment. For example, Phenylketo­nuria (PKU) related mental retardation could be prevented with early newborn screening and diagnosis and diet management.
    • The genetic disorders can be prevented by selected inter­ventions. For example, risk of neural tube defect can be minimized with administration of folic acid in first trimester of pregnancy.
  5. Management and care in genetic disorders: Knowledge of genetics will empower the nurses to manage and care for patients with genetic disorders in their routine health care practice by building up their understanding about;
    • Genetic approaches to the therapy of genetic and complex diseases.
    • Care management of adults with childhood genetic disorders.
    • Care management of persons with adult genetic disorders such as Huntington disease.
    • Ways in which genetic knowledge is used in diagnosis and treatment applications.
      9
  6. Genetic information and counseling: Nurses are largely involved in providing genetic information and counseling to patients and families, who are at risk or experiencing genetic disorders. Therefore, knowledge of genetics well help them to;
    • Development of nonjudgmental attitudes about genetics and related disorders.
    • What information needs to be collected before providing genetic counseling.
    • What information needs to be provided to patient and family before offering genetic counseling.
    • Role of nurses in delivering genetic information and counseling.
    • Application of traditional nursing skills such as patient education, confidentiality, and counseling about genetic information. The concept of nondirective counseling can be included.
  7. Referral services: In developing countries, there is less awareness about genetic disorders and health care facilities offering services for testing and management of genetic disorders. Nurses are the primary health care providers who can direct them to right place for their diagnosis and manage­ment. So that, genetic information will equip nurses to provide effective referral services to their genetic clients.
    • Services available to manage the genetic disorders at local or national level.
    • Knowledge about referral possibilities knowing not only who should be referred but also how and to whom it should be done.
    • Ways to access resources relating to genetics for patient and self-education and the need to keep them up-to-date.
  8. Social and ethical issues in genetics: There are several social and ethical issues, which play important role in care of patients with genetic disorders. Therefore, study of genetics will make nurses to build;
    • An awareness of social, legal, and ethical issues related to genetics, including effects on individuals, groups, and societies, some of which are unique to genetic conditions.
      10
    • An understanding of the social and ethical ramifications of possessing a particular genotype or genetic disorder in terms of societal issues, confidentiality, freedom of choice, and risks in terms of insurance and disclosure.
 
IMPACT OF GENETIC CONDITIONS ON FAMILIES
Genetic disorders or defects are chronic and long lasting and permanent, even after repair. A person in family with genetic problem can be a terribly very sad experience for every family member. When cause of problem in hereditary, the news can be seriously difficult to accept for parents. In many families, when they learn that family member is suffering from a genetic problem, it may cause a grief reaction, a mourning for the loss of hope and expectations which are part of every family. The grieving, with all its feeling of anger, depression and intense sadness is not an uncommon phenomenon.
It is normal and natural reaction whenever a person experiences a loss, whether it be the any morbidity or mortality of a person in a family. Grieving and emotional impact is one dimension of the impact of genetic conditions on family; there are several other aspects of impact on family like cognitive, social, cultural, and economic impact of genetic conditions on families (Fig. 1.1).
zoom view
Fig. 1.1: Dimensions of impact of genetic conditions on families
11
  1. Social impact: Genetic conditions in a family may lead to mild to serious level of social impact on the family. Some of them are:
    • Social stigma
    • Social discrimination
    • Decreased planned family size
    • Loss of geographical mobility
    • Decreased opportunities for siblings
    • Loss of family integrity
    • Social isolation
    • Lifestyle alterations
    • Reduction in contribution to their community by families
    • Disruption of husband-wife or partner relationship
    • Threatened family self-concept
    • Genetically affected persons are considered less than human being in society.
    • Altered family process
    • Altered marriage and reproductive implications (infertility, abortions, defective child birth)
    • Prenatal conflicts (whether to get pregnant or not, whether to continue pregnancy or not)
    • Disruption in parent-child relationship
    • Marriage partner selection problems
    • Guilt regarding putting child in long-term care facilities
    • Difficult child rearing
    • Housing and living arrangement changes
    • Cultural impact includes that genetic screening is not allowed in certain cultures, people perceive genetic conditions a punishment of good for bad deeds.
  2. Economic impact: The impact of burden of genetic conditions is more than just financial costs. Financial costs to the family may occur in subtle ways. These include costs of special diet, day care, household help, housing adaptations, buying special equipments and clothing and travelling. If the family is not in large city, travel to major medical facilities means more than just expenses of transportation. Major economic impacts are:
    • Cost of genetic testing and screening
    • Cost of long-term genetic therapies and repeated surgeries and transfusions
      12
    • Cost of institutionalization or long-term home of community care
    • Cost of bearing additional burden and needs of other family members
    • Other additional costs of care including travel and stay in city of health care facility. Moreover, job leave of family member accompanying for diagnosis and treatment.
    • Loss of career opportunities and job flexibility
    • In addition non-productive life, job discrimination, insurance discrimination and financial dependence on family.
  3. Psychological impact: Psychological reactions include shock, disbelief, denial, guilt, grieving, mourning, hostility, anger, anxiety, bargaining, resentment, shame, sorrow, self-pity, and eventually adaptation and adjustment are very common psychological responses of a family who is having a person with genetic disorder. As discussed above a family with genetically affected person may experience wide variety of emotional trauma, some of additional are:
    • Loss of self-esteem
    • Altered self-concept
    • Hopelessness
    • Helplessness
    • Stress and emotional threat because of uncertainty of future
    • Loss of dream and aspirations
    • Coping with intolerant public attitudes
  4. Physical and cognitive impact: Genetic disorders are responsible to cause variety of physical and cognitive manifestations; some of important are:
    • Physical health problems
    • Individual's inability to get equal opportunity to learn
    • Mental retardation
    • Misunderstanding regarding implications of carrier state.
      13
 
Factors influencing the Impact of Genetic Conditions on Families
There are various factors which influence the impact of genetic conditions on the families and the way in which they cope with. There are factors for individual families. Some of them are as follows:
  • The size, structure and stage of the development cycle of the family: Families in which there is only one child born with congenital defects after six or seven normal normal ones, may be less disrupted because there are more hands to help with all that needs to be done. In general the most successful in coping are homes in which two parents are present and they have matured in their marriage or relationship. Parents who have an affected first child early in their marriage have not yet developed their own interrelationships before having to cope with additional burden. The age of other children also determines family function. The sex of the affected children is also relevant. There is some evidence to show that father may have more difficulty in coping with severely affected sons.
  • Religious, ethnic and cultural beliefs and practices: Some couples believe that a child who is mentally retarded or physically affected has been sent to them as a special gift from God. Others, on such a discovery curse God and lose faith. If strong faith is present that comforts the family. It is also useful to know the cultural aspect of disease, disability, healing the body and death and how the individual is believed to influence or be influenced by life event.
  • Availability of relationship with extended family members or close friends: Having many relatives available may mean more helping hands and loving support, if the relationships are positive ones. Sometimes friends may fill the gap of relatives.
  • The prior status of the relationship between parents: It appears that those who had a satisfactory relationship prior to the genetic problem have the best chance of remaining intact.
  • Coping resources both tangible and intangibles: Some communities are able to form a network that provides loving support for families. Some individuals learn to draw on deep resources that 14they did not realize they possessed. The nurse should make every effort to identify and mobilize support from parents group, private, public, government agencies and foundations.
  • The visibility and severity of the disorder and its meaning to the family: In certain groups, superstitions associated with particular defect may cause the avoidance and rejection of the individual and family. Certain disorders have become more accepted than others, through the media and through the appearance of the affected person. Family may have more tolerance for a cute little girl with braces on her legs than for an 18 years adolescent who is mentally retarded and cannot control motion or drooling. Hidden disorders such as congenital heart defects may cause burdens in the way of finances, care and concern but not in appearance. Craniofacial anomalies until they can be corrected may cause suffering that is related to the reaction of others. Many societies equate beauty with goodness and ugliness with evil. The meaning of the disorders to each parent should be explored, often separately.
  • Variable relating to individual family members including personalities, past experience, view of roles, attitude towards child rearing, education etc.
  • How the family function together and has dealt with previous crisis: This ability may be assessed by observation, interview or the use of tools such as the family APGAR or Parenting Stress Index.
  • The lifestyle and plans of the family: A family who travels with couple extensively may have to modify which plans. If they have a child who cannot walk or who requires special food that cannot last for a long time on trip. They can be helped to plan and modify activities in a way that may include everyone.
  • Other attributes of the disorders: This includes the severity of the disease, its natural history, age of onset, type and frequency of treatment, the necessity for surgery or repeated hospitalization and the long-term outlook so that future planning can occur.
 
Role of Nurses in Managing the Impact of Genetic Conditions on Families
Nurse need to remember that the discovery of genetic disorder or anomaly is a shattering experience for a family. It can permanently 15and abruptly alter the life plans of a family. Nurses can promote an effective coping among family with following interventions:
  • Recognize that different people cope with such a shock in different ways. Resist labeling parents as non-caring, rejecting etc.
  • Do not inject personal biases.
  • Build a trusting and permissive atmosphere
  • Emphasize the legitimacy of parents feeling.
  • Work with the family in identifying family strength, support, limitations and other concerns, such as time, financial obligations and other children.
  • Build family strength.
  • Raise the issues of pre-birth expectations and how these may be related to present feelings, the mother may need to verbally relive the pregnancy before she can go on.
  • Identify willingness and ability of parents to cope.
  • Special care procedure, such as moving the child with osteogenesis imperfecta or feeding the infant with cleft palate should be taught, helping such situation brings success in such endeavors helps to boost parents self-confidence, shows them that they can cope and gives them same sense of self worth.
  • Recognize that the emotions they are experiencing are exhausting and disorganizing. Decision-making may be difficult and may need to be postponed.
  • Observe and record the interaction of parents with each other and with child, family communication pattern, their concern, their needs, so that nursing plans and interventions are not repeated but are built on what have occurred previously.
  • Help the father and mother to maintain open communication and plan for their role at home. Before discharge help parents, plan for what supplies and equipments will be needed and where they can be obtained.
  • Ascertain the support system available to the family.
  • Contact patient groups of person with similar affected children. These provide various types of assistance, from financial to equipments, to telephone crisis lines, to friendly listening and sharing, to coping measures, to hospital visiting and more.
    16
  • Work with parents to plan a time-table that includes needs of normal sibling and for parents, tension-reducing activities.
  • Often provide opportunities to ask questions and voice concern.
  • Follow-up care and regularly scheduled session with the care coordinator is essential before parents leave the hospital.
  • Obtain information and refer parents to respective advanced care facilities and programs.
  • Plan for follow-up should include counseling for grief resolution, marital and family relationships, reproductive options discussion and genetic counseling.
  • Help parents and family to rebuild self-esteem and feel that they are human beings worthy of being linked.
  • Make it clear to family that you are willing to listen and talk and be sure that you are willing when called on.
  • If the parents have not raised the issue, the nurse should ask the parents, if they have considered discussing the newly diagnosed disorder with others in family and outside.
  • Be aware of some of the signs of successful adjustment, an intact family, the resumption of sexual relationship between partners, appropriate plans for future reproduction in light of genetic counseling and family goal, ability to help other parents, realistic plans for management of the affected child, retention of the family health practitioner and ability to relate to others are some measures that can be used.
  • Remember to ask the parents how are they doing. This will give them feeling of concerned.
 
REVIEW OF CELLULAR DIVISION
Cell division is a process by which a cell, called the parent cell, divides into two or more cells, called daughter cells. Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The primary concern of cell division is the maintenance of the original cell's genome. Before division can occur, the genomic information which is stored in chromosomes must be replicated, and the duplicated genome 17separated cleanly between cells. A great deal of cellular infrastructure is involved in keeping genomic information consistent between “generations”.
In another type of cell division present only in eukaryotes, called meiosis, a cell is permanently transformed into a gamete and cannot divide again until fertilization. As the cell division is the part of the cell cycle; where cell grows and divides. Therefore, it is wise to first understand about the cell cycle.
 
Cell Cycle
The cell cycle consists of four distinct phases: G1 phase, S phase, G2 phase (collectively known as interphase) and M phase. M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis, in which the cell's cytoplasm divides forming distinct cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase (Fig. 1.2).
zoom view
Fig. 1.2: Schematic presentation of the cell cycle
18
 
M phase
The relatively brief M phase consists of nuclear division (mitosis) and cytoplasmic division (cytokinesis). Mitosis divides genetic information during cell division.
 
Interphase
After M phase, the daughter cells begin interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division. Interphase is a phase of the cell cycle, which includes:
G1 Phase The first phase within interphase, from the end of the previous M phase till the beginning of DNA synthesis is called G1 (G indicating gap or growth). During this phase the biosynthetic activities of the cell, which had been considerably slowed down during M phase, resume at a high rate. This phase is marked by synthesis of various enzymes that are required in S phase, mainly those needed for DNA replication. Duration of G1 is highly variable, even among different cells of the same species. The G1 phase is a period in the cell cycle during interphase, after cytokinesis and before the S phase.
S Phase The ensuing S phase starts when DNA synthesis commences; when it is complete, all of the chromosomes have been replicated, i.e. each chromosome has two (sister) chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled, though the ploidy of the cell remains the same. Rates of RNA transcription and protein synthesis are very low during this phase. An exception to this is histone production, most of which occurs during the S phase. The duration of S phase is relatively constant among cells of the same species.
G2 Phase The cell then enters the G2 phase, which lasts until the cell enters mitosis. Again, significant protein synthesis occurs during this phase, mainly involving the production of microtubules, 19which are required during the process of mitosis. Inhibition of protein synthesis during G2 phase prevents the cell from undergoing mitosis. G2 phase is the 3rd and final subphase in interphase of the cell cycle.
 
G0 Phase
The term “post-mitotic” is sometimes used to refer to both quiescent and senescent cells. Nonproliferative cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated. Cellular senescence is a state that occurs in response to DNA damage or degradation that would make a cell's progeny nonviable; it is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis. Some cell types in mature organisms, such as parenchymal cells of the liver and kidney, enter the G0 phase semi-permanently and can only be induced to begin dividing again under very specific circumstances; other types, such as epithelial cells, continue to divide throughout an organism's life.
Considering the cell cycle in its entirely, the sequence of event is (Fig. 1.3):
 
MITOSIS
Mitosis is the process in which a eukaryotic cell separates the chromosomes in its cell nucleus, into two identical sets in two daughter nuclei (Fig. 1.4). It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two daughter cells containing roughly equal shares of these cellular components.
zoom view
Fig. 1.3: Events of cycle in somatic cell
20
zoom view
Fig. 1.4: Mitosis
Mitosis and cytokinesis together define the mitotic (M) phase of the cell cycle – the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell.
Mitosis occurs exclusively in eukaryotic cells, but occurs in different ways in different species. The process of mitosis is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These stages are prophase, prometaphase, metaphase, anaphase and telophase. During the process of mitosis the pairs of chromosomes condense and attach to fibers that pull the sister chromatids to opposite sides of the cell. The cell then divides in cytokinesis, to produce two identical daughter cells.
Because cytokinesis usually occurs in conjunction with mitosis, “mitosis” is often used interchangeably with “mitotic phase”. Errors in mitosis can either kill a cell through apoptosis or cause mutations that may lead to cancer.21
 
Phases of Mitosis
The mitotic phase is a relatively short period of the cell cycle. It alternates with the much longer interphase, where the cell prepares itself for cell division. Interphase is therefore not part of mitosis. Interphase is divided into three phases, G1 (first gap), S (synthesis), and G2 (second gap). During all three phases, the cell grows by producing proteins and cytoplasmic organelles. However, chromosomes are replicated only during the S phase. Thus, a cell grows (G1), continues to grow as it duplicates its chromosomes (S), grows more and prepares for mitosis (G2), and divides (M).
  1. Prophase: It is the first stage of mitosis. During early prophase, the chromatin fibers condense and shortened into chromosome that are visible under the light microscope. The condensation process may prevent entangling of the long DNA strands as they move during mitosis. Because DNA replication took place during the S phase of interphase, each prophase chromosome consists of a pair of identical, double-stranded chromatids. A constricted region called a centromere holds the chromatid pair together. At the outside of each centromere is a protein complex known as the kinetochore. Later in prophase, tubulins in the pericentriolar material of the centrosomes start to form the mitotic spindle, a football-shaped assembly of microtubules lengthen, they push the centrosomes to the poles (end) of the cell so that the spindle extends from pole to pole. The spindle is responsible for the separation of chromatids to opposite poles of the cell. Then, the nucleous disappears and the nuclear envelopes breaks down (Fig. 1.5).
    zoom view
    Fig. 1.5: Schematic diagram and brief description of prophase
    22
  2. Metaphase: During metaphase, the kinetochore microtubules align the centromeres of the chromatid pair at the exact center of the mitotic spindle. This midpoint region is called the metaphase plate (Fig. 1.6).
    zoom view
    Fig. 1.6: Schematic diagram and brief description of metaphase
  3. Anaphase: During anaphase, the centromeres split, separating the two members of each chromatid pair, which move toward opposite poles of the cell (Fig. 1.7). Once separated, the chromatids are termed as chromosomes. As the chromosomes are pulled by the kinetochore microtubules lead the way, dragging the trailing arms of the chromosomes towards the pole.
    zoom view
    Fig. 1.7: Schematic diagram and brief description of anaphase
    23
Telophase: The final stage of mitosis, telophase, begins after chromosomal movement stops (Fig. 1.8). The identical sets of chromosomes now at opposite poles of the cell, unicoil and forms around each chromatin mass, nucleoli reappear in the daughter nuclei and the mitotic spindle disappears.
zoom view
Fig. 1.8: Schematic diagram and brief description of telophase
Cytoplasmic division/Cytokinesis: Division of a parent cell's cytoplasm and organelles into two daughter cells is called cytokinesis. This process begins in late anaphase or early telophase with formation of a cleavage furrow, a slight indention of the plasma membrane. The cleavage furrow usually appears midway because the centrosomes extends around the periphery of the cell (Fig. 1.9). Actin microfilaments that lie just inside the plasma membrane progressively inward. The ring constricts the center of the cell, like tightening a belt around the waist and ultimately pinches it in two. Because the plane of the cleavage furrow is always perpendicular to the mitotic spindle, the two sets of chromosomes end up in separate daughter cells. When cytokinesis is complete, interphase begins.
zoom view
Fig. 1.9: Schematic diagram and brief description of cytokinesis
24
 
MEIOSIS
In biology or life science, meiosis (pronounced my-oh-sis) is a process of reductional division in which the number of chromosomes per cell is cut in half. In animals, meiosis always results in the formation of gametes (Fig. 1.10).
During meiosis, the genome of a diploid germ cell, which is composed of long segments of DNA packaged into chromosomes, undergoes DNA replication followed by two rounds of division, resulting in four haploid cells. Each of these cells contain one complete set of chromosomes, or half of the genetic content of the original cell.
zoom view
Fig. 1.10: Meiosis
25
If meiosis produces gametes, these cells must fuse during fertilization to create a new diploid cell, or zygote before any new growth can occur. Thus, the division mechanism of meiosis is a reciprocal process to the joining of two genomes that occurs at fertilization. Because the chromosomes of each parent undergo genetic recombination during meiosis, each gamete, and thus each zygote, will have a unique genetic blueprint encoded in its DNA. Together, meiosis and fertilization constitute sexuality in the eukaryotes, and generate genetically distinct individuals in populations.
Meiosis uses many of the same biochemical mechanisms employed during mitosis to accomplish the redistribution of chromosomes. There are several features unique to meiosis, most importantly the pairing and genetic recombination between homologous chromosomes.
 
Process
Because meiosis is a “one-way” process, it cannot be said to engage in a cell cycle as mitosis does. However, the preparatory steps that lead up to meiosis are identical in pattern and name to the interphase of the mitotic cell cycle.
Interphase is divided into three phases:
Gap 1 (G1) phase: This is a very active period, where the cell synthesizes its vast array of proteins, including the enzymes and structural proteins it will need for growth. In G1 stage each of the chromosomes consists of a single (very long) molecule of DNA. In humans, at this point cells are 46 chromosomes, 2N, identical to somatic cells.
Synthesis (S) phase: The genetic material is replicated: each of its chromosomes duplicates, producing 46 chromosomes each made up of two sister chromatids. The cell is still considered diploid because it still contains the same number of chromosome. The identical sister chromatids have not yet condensed into the densely packaged chromosomes visible under the light microscope. This will take place during prophase I in meiosis. 26
Gap 2 (G2) phase: G2 phase is absent in Meiosis
Interphase is followed by meiosis I and then meiosis II.
Meiosis-I consists of separating the pairs of homologous chromosome, each made up of two sister chromatids, into two cells. One entire haploid content of chromosomes is contained in each of the resulting daughter cells; the first meiotic division therefore reduces the ploidy of the original cell by a factor of 2 (Fig. 1.11).
Meiosis-II consists of decoupling each chromosome's sister strands (chromatids), and segregating the individual chromatids into haploid daughter cells. The two cells resulting from meiosis I divide during meiosis II, creating 4 haploid daughter cells. Meiosis I and II are each divided into prophase, metaphase, anaphase, and telophase stages, similar in purpose to their analogous subphases in the mitotic cell cycle. Therefore, meiosis includes the stages of meiosis I (prophase I, metaphase I, anaphase I, telophase I), and meiosis II (prophase II, metaphase II, anaphase II, telophase II).
Meiosis generates genetic diversity in two ways: (1) independent alignment and subsequent separation of homologous chromosome pairs during the first meiotic division allows a random and independent selection of each chromosome segregates into each gamete; and (2) physical exchange of homologous chromosomal regions by recombination during prophase I results in new genetic combinations within chromosomes (Fig. 1.12).
zoom view
Fig. 1.11: Meiosis-I (For color version see plate 1)
27
zoom view
Fig. 1.12: Meiosis-II (For color version see plate 1)
 
Meiosis-phases
 
Meiosis-I
In meiosis-I, the homologous pairs in a diploid cell separate, producing two haploid cells (23 chromosomes, N in humans), so meiosis-I is referred to as a reductional division. A regular diploid human cell contains 46 chromosomes and is considered 2N because it contains 23 pairs of homologous chromosomes. However, after meiosis-I, although the cell contains 46 chromosomes it is only considered N because later in anaphase I the sister chromatids will remain together as the spindle pulls the pair toward the pole of the new cell. In meiosis-II, an equational division similar to mitosis will occur whereby the sister chromatids are finally split, creating a total of 4 haploid cells (23 chromosomes, N) per daughter cell from the first division.28
 
Prophase I
Homologous chromosomes pair (or synapse) and crossing over (or recombination) occurs, a step unique in meiosis. The paired and replicated chromosomes are called bivalents or tetrads, which have two chromosomes and four chromatids, with one chromosome coming from each parent. At this stage, non-sister chromatids may cross-over at points called chiasmata (plural; singular chiasma) (Fig. 1.13).
Leptotene: The first stage of prophase I is the leptotene stage, also known as leptonema, from Greek words meaning “thin threads”. During this stage, individual chromosomes begin to condense into long strands within the nucleus. However, the two sister chromatids are still so tightly bound that they are indistinguishable from one another. The chromosomes in the leptotene stage show a specific arrangement where the telomeres are oriented towards the nuclear membrane. Hence, this stage is called “bouquet stage” (Fig. 1.13)
Zygotene: The zygotene stage, also known as zygonema, from Greek words meaning “paired threads”. We have seen that the 46 chromosomes in each cell consist of 23 pairs (the X and Y chromosomes of the male being taken pair). The two chromosomes of each comes to lie parallel to each other, and are closely apposed. This pairing chromosomes also referred to as synopsis or conjugation. Two chromosomes together constitute a bivalent (Fig. 1.13).
Pachytene: The pachytene stage, also known as pachynema, from Greek words meaning “thick threads”, contains the following chromosomal crossover.
zoom view
Fig. 1.13: Substages of Prophase-I
29
The two chromatids of each chromosomes together become distinct. The biovalent now has four chromatids in it and is called a tetrad. There are two central and two peripheral chromatids, one from each chromosome. An important event now takes place. The two central chromatids (one belonging to each chromosome of the bivalent) become coiled over each other so that they cross at a number of points. This is called crossing over. At the site where the chromatids cross they become adherent; the point of adhesion are called as chiasmata (Fig. 1.13).
Nonsister chromatids of homologous chromosomes randomly exchange segments of genetic information over regions of homology. (Sex chromosomes, however, are not wholly identical, and only exchange information over a small region of homology.) Exchange takes place at sites where recombination nodules (the aforementioned chiasmata) have formed (Fig. 1.14). The exchange of information between the non-sister chromatids results in a recombination of information; each chromosome has the complete set of information it had before, and there are no gaps formed as a result of the process. Because the chromosomes cannot be distinguished in the synaptonemal complex, the actual act of crossing over is not perceivable through the microscope.
Diplotene: During the diplotene stage, also known as diplonema, from Greek words meaning “two threads”, the synaptonemal complex degrades and homologous chromosomes separate from one another a little.
zoom view
Fig. 1.14: Crossing-over (Recombination)
30
The chromosomes themselves uncoil a bit, allowing some transcription of DNA. However, the homologous chromosomes of each bivalent remain tightly bound at chiasmata, the regions where crossing-over occurred. The chiasmata remain on the chromosomes until they are severed in Anaphase-I (Fig. 1.13).
In human fetal oogenesis all developing oocytes develop to this stage and stop before birth. This suspended state is referred to as the dictyotene stage and remains so until puberty. In males, only spermatogonia exist until meiosis begins at puberty.
Diakinesis: Chromosomes condense further during the diakinesis stage, from Greek words meaning “moving through”. This is the first point in meiosis where the four parts of the tetrads are actually visible. Sites of crossing over entangle together, effectively overlapping, making chiasmata clearly visible. Other than this observation, the rest of the stage closely resembles prometaphase of mitosis; the nucleoli disappear, the nuclear membrane disintegrates into vesicles, and the meiotic spindle begins to form (Fig. 1.13).
 
Synchronous Processes
During these stages, two centrosomes, containing a pair of centrioles in animal cells, migrate to the two poles of the cell. These centrosomes, which were duplicated during S-phase, function as microtubule organizing centers nucleating microtubules, which are essentially cellular ropes and poles. The microtubules invade the nuclear region after the nuclear envelope disintegrates, attaching to the chromosomes at the kinetochore. The kinetochore functions as a motor, pulling the chromosome along the attached microtubule toward the originating centriole, like a train on a track. There are four kinetochores on each tetrad, but the pair of kinetochores on each sister chromatid fuses and functions as a unit during meiosis-I.
Microtubules that attach to the kinetochores are known as kinetochore microtubules. Other microtubules will interact with microtubules from the opposite centriole: these are called 31nonkinetochore microtubules or polar microtubules. A third type of microtubules, the aster microtubules, radiates from the centrosome into the cytoplasm or contacts components of the membrane skeleton.
 
Metaphase-I
Homologous pairs move together along the metaphase plate: As kinetochore microtubules from both centrioles attach to their respective kinetochores, the homologous chromosomes align along an equatorial plane that bisects the spindle, due to continuous counterbalancing forces exerted on the bivalents by the microtubules emanating from the two kinetochores of homologous chromosomes. The physical basis of the independent assortment of chromosomes is the random orientation of each bivalent along the metaphase plate, with respect to the orientation of the other bivalents along the same equatorial line.
 
Anaphase-I
Kinetochore microtubules shorten, severing the recombination nodules and pulling homologous chromosomes apart. Since each chromosome has only one functional unit of a pair of kinetochores, whole chromosomes are pulled toward opposing poles, forming two haploid sets. Each chromosome still contains a pair of sister chromatids. Nonkinetochore microtubules lengthen, pushing the centrioles farther apart. The cell elongates in preparation for division down the center.
 
Telophase-I
The last meiotic division effectively ends when the chromosomes arrive at the poles. Each daughter cell now has half the number of chromosomes but each chromosome consists of a pair of chromatids. The microtubules that make up the spindle network disappear, and a new nuclear membrane surrounds each haploid set. The chromosomes uncoil back into chromatin. Cytokinesis, the pinching of the cell membrane in animal cells or the formation of the cell wall in plant cells, occurs, completing the creation of two daughter cells. Sister chromatids remain attached during telophase-I.32
Cells may enter a period of rest known as interkinesis or interphase II. No DNA replication occurs during this stage.
 
Meiosis II
Meiosis II is the second part of the meiotic process. Much of the process is similar to mitosis. The end result is production of four haploid cells (23 chromosomes, 1N in humans) from the two haploid cells (23 chromosomes, 1N, each of the chromosomes consisting of two sister chromatids) produced in meiosis I.
Prophase II takes an inversely proportional time compared to telophase I. In this prophase we see the disappearance of the nucleoli and the nuclear envelope again as well as the shortening and thickening of the chromatids. Centrioles move to the polar regions and arrange spindle fibers for the second meiotic division.
In metaphase II, the centromeres contain two kinetochores, that attach to spindle fibers from the centrosomes (centrioles) at each pole. The new equatorial metaphase plate is rotated by 90 degrees when compared to meiosis I, perpendicular to the previous plate.
This is followed by anaphase II, where the centromeres are cleaved, allowing microtubules attached to the kinetochores to pull the sister chromatids apart. The sister chromatids by convention are now called sister chromosomes as they move toward opposing poles.
The process ends with telophase II, which is similar to telophase I, and is marked by uncoiling and lengthening of the chromosomes and the disappearance of the spindle.
Table 1.1   Comparison of mitosis and meiosis
Mitosis
Meiosis
Function is for growth and repair
Function is for gamete formation
Happens in most somatic cells
Happens in testes and ovary to form gametes
Proceeded by replication of chromosomes
Proceeded by replication of chromosomes
Has one cell division
Has two cell divisions
Result in two diploid daughter cells
Results in four haploid daughter cells
Daughter cells chromosome number is same as parent cell (2N, diploid)
Daughter cells chromosome number is half of the parent cell (N, haploid)
Daughter cells normally genetically identical
Daughter cells are genetically not the same
33
Nuclear envelopes reform and cleavage or cell wall formation eventually produces a total of four daughter cells, each with a haploid set of chromosomes. Meiosis is now complete.
 
Regulation of Cell Division and Growth
A variety of genes are involved in the control of cell growth and division. The cell cycle is the cell's way of replicating itself in an organized, step-by-step fashion. Tight regulation of this process ensures that a dividing cell's DNA is copied properly, any errors in the DNA are repaired, and each daughter cell receives a full set of chromosomes. The cycle has checkpoints (also called restriction points), which allow certain genes to check for mistakes and halt the cycle for repairs if something goes wrong. If a cell has an error in its DNA that cannot be repaired, it may undergo programmed cell death (apoptosis) (Fig. 1.15). Apoptosis is a common process throughout life that helps the body get rid of cells it doesn't need.
zoom view
Fig. 1.15: Apoptosis (For color version see plate 2)
34
zoom view
Fig. 1.16: Macrophage activity (For color version see plate 2)
Cells that undergo apoptosis break apart and are recycled by a type of white blood cell called a macrophage (Fig. 1.16). Apoptosis protects the body by removing genetically damaged cells that could lead to cancer, and it plays an important role in the development of the embryo and the maintenance of adult tissues.
Cancer results from a disruption of the normal regulation of the cell cycle. When the cycle proceeds without control, cells can divide without order and accumulate genetic defects that can lead to a cancerous tumor. In nutshell, we can say cancer results when cells accumulate genetic errors and multiply without control.
 
CHARACTERISTICS AND STRUCTURE OF GENES
The term ‘gene’ was introduced by Johanssen in 1909. Prior to him Mendel had used the word factor for a specific, distinct, particular unit of inheritance that takes part in expression of a trait. Johanssen has defined gene, as an elementary unit of inheritance, which can be assigned to a particular trait. Morgan's work suggested gene to be the shortest segment of chromosome, which can be separated through crossing over, can undergo mutation and influence expression of one or more traits (Fig. 1.17). 35
zoom view
Fig. 1.17: Structure of gene (Genes are made up of DNA. Each chromosome contains many genes)
Presently, a gene is defined as a unit of inheritance composed of a segment of DNA or chromosome situated at a specific locus (Gene locus), which carries coded information associated with a specific function and can undergo crossing over as well as mutation. Some of the specific features of genes are:
  • A specific portion of the DNA code is called a gene, which has genetic information.
  • The term gene is often used to refer genetic material on a chromosome that code for a trait. For example, one person has a gene for hair color.
  • A unit of genetic material, which is able to replicate.
  • It is a unit of recombination or capable of undergoing crossover.
  • A unit of genetic material, which can undergo mutation.
  • A unit of heredity connected with somatic structure or function that leads to a phenotype expression.
  • A gene is the basic physical and functional unit of heredity.
  • Genes, which are made up of DNA, act as RNA instructor to make molecules called proteins.
  • In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 − 25,000 genes.
  • Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small 36number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person's unique physical features.
  • Genes consist of a long strand of DNA that contain promoter, which control the activity of a gene and coding and non-coding sequence.
  • Gene coding sequence determines what will be the product, while non-coding sequence can regulate the conditions of gene expression.
  • When gene is active, the coding and non-coding sequence is copied in a process called as transcription, producing an RNA copy of the gene's information. This RNA can then direct the synthesis of protein via genetic code. These RNA or proteins are known as gene products.
  • Gene is a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory region, transcribed region and/or other functional sequence regions.
  • A gene is a union of genomic sequences encoding a coherent set of potentially overlapping functional products.
  • The physical development and phenotype of a person can be thought of as a product of genes interacting with each other and with environment.
  • Total set of genes in a person are known as genome.
  • Gene is basically an instruction for human body. Each gene has a specific purpose and every single function of the human body is coded in one or more genes.
  • A person's unique genetic constitutes called the genotype are made up of about 30,000 to 40,000 genes.
  • A person's phenotype, the observable characteristics of his or her genotype, includes the physical appearance and other biological, physiological and molecular traits.
 
Type of Genes
  • Constitutive genes: They are those genes, which are constantly expressing themselves in a cell because their products are 37required for the normal cellular activities, e.g. gene for glycolysis, ATP-ase.
  • Non-constitutive genes (Luxury genes): The genes are not always expressing themselves in a cell. They are switched on or off according to the requirement of cellular activities, e.g. genes for lactose system in Escherichia coli. They are further classified as inducible and repressible.
  • Inducible genes: The genes are switched on in response to the presence of a chemical substance or inducer, which is required for functioning of the product of gene activity.
  • Repressive genes: They are those genes which continue to express themselves till a chemical inhibits or represses their activity.
  • Multigenes: It is a group of similar or nearly similar genes for meeting requirements of time and tissue specific products.
  • Repeated genes: The genes are present in multiple copies, e.g. histone genes, tRNA genes, rRNA genes, actin genes.
  • Single copy genes: The genes are present in single copy.
  • Pseudogenes: They are genes, which have homology to functional genes but are unable to produce functional products due to intervening nonsense codons, inactivation of promoter genes, e.g. several SNRNA genes.
  • Split genes: Split genes are those genes, which possess extra or nonessential region interspersed with essential or coding part.
  • Jumping genes (Transposons): They are segments of DNA that can jump or move from one place in the genome to another.
  • Overlapping genes: Genes those overlap other genes.
  • Structural genes: Structural genes are those genes, which have encoded information for the synthesis of chemical substance (polypeptides for synthesis of structural and transport proteins, enzymes, hormones, several other proteins and no translated and noncoding RNAs) required for cellular machinery.
  • Regulatory genes: Regulatory genes do not transcribe RNAs and, therefore, produce no chemicals. They are meant to control the function of structural genes.
  • Mitochondrial genes: The cell nucleus is not the only site where DNA and genes are present. In humans, they are also present in mitochondria. The mitochondria are bodies located in cell 38cytoplasm that are concerned with energy production and metabolism and are thus known as the ‘Power Plant’ of the cell. One of the function of the Mitochondrial Oxidative Phosphorylation System (OXPHOS) is to generate adenosine triphosphate (ATP) for cell energy. Cell contains hundreds of mitochondria (mt) and each mitochondrium can contain upon 10 copies of mtDNA meaning that thousands of copies of mtDNA are present in some cells. The amount of DNA present in mitochondria is far less than in the nucleus. The mitochondrial genes are virtually only maternally transmitted, since sperm does not contain mitochondria. It is known that some genetic disorders are result of mtDNA mutation.
 
Functions of Genes
  • Genes are components of genetic material and are thus unit of inheritance.
  • They control the morphology or phenotype of individual.
  • Replication of genes is essential for cell division.
  • Genes carry the hereditary information from one generation to next.
  • They control the structure and metabolism of the body.
  • Reshuffling of genes at the time of sexual reproduction produce variation.
  • Different linkages are produced due to crossing over.
  • Genes undergo mutation and change their expression.
  • New genes and consequently new traits develop due to reshuffling of different parts of genes.
  • Genes change their expression due to position effect.
  • Differentiation or formation of different type of cells, tissues and organs in various parts of the body is controlled by expression of certain genes and nonexpression of others.
  • Development or production of different stages in the life history is controlled by genes.
 
Nucleic Acid
Any of a group of complex compounds found in all living cells and viruses, composed of purines, pyrimidines, carbohydrates, and phosphoric acid.
39
zoom view
Fig. 1.18: DNA and RNA structure
Nucleic acids in the form of DNA and RNA control cellular function and heredity (Fig. 1.18).
 
Deoxyribonucleic Acid (DNA)
It is a nucleic acid that contains the genetic instructions for the development and function of living things. All known cellular life and some viruses contain DNA. The main role of DNA in the cell is the long-term storage of information. It is often compared to a blueprint, since it contains the instructions to construct other components of the cell, such as proteins and RNA molecules. The DNA segments that carry genetic information are called genes, but other DNA sequences have structural purposes, or are involved in regulating the expression of genetic information.40
In eukaryotes such as animals and plants, DNA is stored inside the cell nucleus, while in prokaryotes such as bacteria, the DNA is in the cell's cytoplasm. Unlike enzymes, DNA does not act directly on other molecules; rather, various enzymes act on DNA and copy its information into either more DNA, in DNA replication, or transcribe it into protein. In chromosomes, chromatin proteins such as histones compact and organize DNA, as well as help in control of its interactions with other proteins in the nucleus.
DNA is a long polymer of simple units called nucleotides, which are held together by a backbone made of sugars and phosphate groups. This backbone carries four types of molecules called bases and it is the sequence of these four bases that encode information. The major function of DNA is to encode the sequence of amino acid residues in proteins, using the genetic code. To read the genetic code, cells make a copy of a stretch of DNA in the nucleic acid RNA. These RNA copies can then be used to direct protein synthesis, but they can also be used directly as parts of ribosomes or spliceosomes.
 
Ribonucleic Acid (RNA)
It is a nucleic acid polymer consisting of nucleotide monomers. RNA nucleotides contain ribose rings and uracil unlike deoxyribonucleic acid (DNA), which contains deoxyribose and thymine. It is transcribed (synthesized) from DNA by enzymes called RNA polymerases and further processed by other enzymes. RNA serves as the template for translation of genes into proteins, transferring amino acids to the ribosome to form proteins, and also translating the transcript into proteins.
RNA is primarily made up of four different bases: adenine, guanine, cytosine, and uracil. The first three are the same as those found in DNA, but in RNA thymine is replaced by uracil as the base complementary to adenine. This base is also a pyrimidine and is very similar to thymine. Uracil is energetically less expensive to produce than thymine, which may account for its use in RNA. In DNA, however, uracil is readily produced by chemical degradation of cytosine, so having thymine as the normal base makes detection 41and repair of such incipient mutations more efficient. Thus, uracil is appropriate for RNA, where quantity is important but lifespan is not, whereas thymine is appropriate for DNA where maintaining sequence with high fidelity is more critical.
There are also numerous modified bases and sugars found in RNA that serve many different roles. Pseudouridine (ψ) and the DNA nucleoside thymidine are found in various places (most notably in the T ψC loop of every tRNA). Another notable modified base is Inosine (a deaminated Guanine base), which allows a “wobble codon” sequence in tRNA. There are nearly 100 other naturally occurring modified bases, of which pseudouridine and 2′-O-methylribose are by far the most common. The specific roles of many of these modifications in RNA are not fully understood. However, it is notable that in ribosomal RNA, many of the post-translational modifications occur in highly functional regions, such as the peptidyl transferase center and the subunit interface, inferring that they are important for normal function. Single stranded RNA exhibits a right handed stacking pattern that is stabilized by base stacking.
The most important structural feature of RNA that distinguishes it from DNA is the presence of a hydroxyl group at the 2′-position of the ribose sugar. The presence of this functional group enforces the C3’-endo sugar conformation (as opposed to the C2’-endo conformation of the deoxyribose sugar in DNA) that causes the helix to adopt the A-form geometry rather than the B-form most commonly observed in DNA. This results in a very deep and narrow major groove and a shallow and wide minor groove. A second consequence of the presence of the 2′-hydroxyl group is that in conformationally flexible regions of an RNA molecule (that is, not involved in formation of a double helix), it can chemically attack the adjacent phosphodiester bond to cleave the backbone.
 
Biological Role of RNA
Messenger RNA (mRNA): Messenger RNA is RNA that carries information from DNA to the ribosome sites of protein synthesis in the cell. Once mRNA has been transcribed from DNA, it is exported from the nucleus into the cytoplasm (in eukaryotes mRNA 42is “processed” before being exported), where it is bound to ribosomes and translated into protein. After a certain amount of time the message degrades into its component nucleotides, usually with the assistance of RNA polymerases.
Transfer RNA (tRNA): Transfer RNA is a small RNA chain of about 74–93 nucleotides that transfers a specific amino acid to a growing polypeptide chain at the ribosomal site of protein synthesis during translation. It has sites for amino acid attachment and an anticodon region for codon recognition that binds to a specific sequence on the messenger RNA chain through hydrogen bonding. It is a type of non-coding RNA.
Ribosomal RNA (rRNA): Ribosomal RNA is a component of the ribosomes, the protein synthetic factories in the cell. Eukaryotic ribosomes contain four different rRNA molecules: 18S, 5.8S, 28S, and 5S rRNA. Three of the rRNA molecules are synthesized in the nucleolus, and one is synthesized elsewhere. rRNA molecules are extremely abundant and make up at least 80% of the RNA molecules found in a typical eukaryotic cell. In the cytoplasm, ribsomal RNA and protein combine to form a nucleoprotein called a ribosome. The ribosome binds mRNA and carries out protein synthesis. Several ribosomes may be attached to a single mRNA at any time.
Non-coding RNA or “RNA genes: RNA genes (sometimes referred to as non-coding RNA or small RNA) are genes that encode RNA that is not translated into a protein. The most prominent examples of RNA genes are transfer RNA (tRNA) and ribosomal RNA (rRNA), both of which are involved in the process of translation. However, since the late 1990s, many new RNA genes have been found, and thus RNA genes may play a much more significant role than previously thought. In the late 1990s and early 2000, there has been persistent evidence of more complex transcription occurring in mammalian cells (and possibly others). This could point towards a more widespread use of RNA in biology, particularly in gene regulation. A particular class of non-coding RNA, micro RNA, has been found in many metazoans (from Caenorhabditis elegans to Homo sapiens) and clearly plays an 43important role in regulating other genes. First proposed in 2004 by Rassoulzadegan and published in Nature 2006, RNA is implicated as being part of the germline. If confirmed, this result would significantly alter the present understanding of genetics and lead to many questions on DNA-RNA roles and interactions.
Catalytic RNA: Although RNA contains only four bases, in comparison to the twenty amino acids commonly found in proteins, some RNAs are still able to catalyse chemical reactions. These include cutting and ligating other RNA molecules and also the catalysis of peptide bond formation in the ribosome.
Double-stranded RNA: Double-stranded RNA (or dsRNA) is RNA with two complementary strands, similar to the DNA found in all “higher” cells. dsRNA forms the genetic material of some viruses. In eukaryotes, it acts as a trigger to initiate the process of RNA interference and is present as an intermediate step in the formation of siRNAs (small interfering RNAs). siRNAs are often confused with miRNAs; siRNAs are double-stranded, whereas miRNAs are single-stranded. Although initially single stranded there are regions of intra-molecular association causing hairpin structures in pre-miRNAs; immature miRNAs.
 
Comparison of RNA and DNA
Unlike DNA, RNA is almost always a single-stranded molecule and has a much shorter chain of nucleotides. RNA contains ribose, rather than the deoxyribose found in DNA (there is a hydroxyl group attached to the pentose ring in the 2′ position whereas RNA has two hydroxyl groups). These hydroxyl groups make RNA less stable than DNA because it is more prone to hydrolysis. Several types of RNA (tRNA, rRNA) contain a great deal of secondary structure, which help to promote stability.
Like DNA, most biologically active RNAs including tRNA, rRNA, snRNAs and other non-coding RNAs (such as the SRP RNAs) are extensively base paired to form double-stranded helix. Structural analysis of these RNAs have revealed that they are not, “single-stranded” but rather highly structured. Unlike DNA, this structure is not just limited to long double-stranded helix but rather 44collections of short helix packed together into structures akin to proteins. In this fashion, RNAs can achieve chemical catalysis, like enzymes. For instance, determination of the structure of the ribosome in 2000 revealed that the active site of this enzyme that catalyzes peptide bond formation is composed entirely of RNA.
 
Synthesis of RNA
Synthesis of RNA is usually catalyzed by an enzyme – RNA polymerase, using DNA as a template. Initiation of synthesis begins with the binding of the enzyme to a promoter sequence in the DNA (usually found “upstream” of a gene). The DNA double helix is unwound by the helicase activity of the enzyme. The enzyme then progresses along the template strand in the 3′ –> 5′ direction, synthesizing a complementary RNA molecule with elongation occurring in the 5′ –> 3′ direction. The DNA sequence also dictates where termination of RNA synthesis will occur.
There are also a number of RNA-dependant RNA polymerases as well that use RNA as their template for synthesis of a new strand of RNA. For instance, a number of RNA viruses (such as poliovirus) use this type of enzyme to replicate their genetic material. Also, it is known that RNA-dependent RNA polymerases are required for the RNA interference pathway in many organisms.
 
DNA Replication
Cell division is essential for an organism to grow, but when a cell divides it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism for DNA replication. Here, the two strands are separated and then each strand's complementary DNA sequence is recreated by an enzyme called DNA polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base pairing, and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix. In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.45
zoom view
Fig. 1.19: DNA replication
In Figure 1.19, the double helix (blue) is unwound by a helicase. Next, DNA polymerase III (green) produces the leading strand copy (red). A DNA polymerase I molecule (green) binds to the lagging strand. This enzyme makes discontinuous segments (called Okazaki fragments) before DNA ligase (violet) joins them together.
 
PROTEIN BIOSYNTHESIS
Protein biosynthesis (Synthesis) is the process in which cells build proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription which are then used for translation. Protein biosynthesis, although very similar, differs between prokaryotes and eukaryotes (Fig. 1.20).
 
 
An Overview of Protein Synthesis
Within the nucleus of the cell (light blue), genes (DNA, dark blue) are transcribed into RNA. This RNA is then subject to post-transcriptional modification and control, resulting in a mature mRNA (red) that is then transported out of the nucleus and into the cytoplasm (peach), where it undergoes translation into a protein. mRNA is translated by ribosomes (purple) that match the three-base codons of the mRNA to the three-base anti-codons of the appropriate tRNA.
46
zoom view
Fig. 1.20: Protein synthesis process
Newly synthesized proteins (black) are often further modified, such as by binding to an effector molecule (orange), to become fully active.
 
Steps of the Protein Synthesis
Amino acid synthesis: Amino acids are the monomers which are polymerized to produce proteins. Amino acid synthesis is the set of biochemical processes (metabolic pathways) which build the amino acids from carbon sources like glucose. Not all amino acids 47may be synthesized by every organism, for example, adult humans have to obtain 8 of the 20 amino acids from their diet. The amino acids are then loaded onto tRNA molecules for use in the process of translation
Transcription: Transcription is the process by which an mRNA template, carrying the sequence of the protein, is produced for the translation step from the genome. Transcription makes the template from one strand of the DNA double helix, called the template strand. Transcription takes place in 3 stages.
  1. Transcription starts with the process of initiation. RNA polymerase, the enzyme which produces RNA from a DNA template, binds to a specific region on DNA that designates the starting point of transcription. This binding region is called the promoter. As the RNA polymerase binds on to the promoter, the DNA strands begin to unwind.
  2. The second process is elongation. RNA polymerase travels along the template (noncoding) strand, synthesizing a ribonucleotide polymer. RNA polymerase does not use the coding strand as a template because a copy of any strand produces a base sequence complementary to the strand which is being copied. Therefore, DNA from the noncoding strand is used as a template to copy the coding strand.
  3. The third stage is termination. As the polymerase reaches the termination stage, modifications are required for the newly transcribed mRNA to be able to travel to the other parts of the cell, including cytoplasm and endoplasmic reticulum for translation. A 5′ cap is added to the mRNA to protect it from degradation. In eukaryotes a poly-A tail is added on the 3′ end for protection and as a template for further process. Also in eukaryotes (higher organisms) the vital process of splicing occurs at this stage.
Translation: During translation, mRNA previously transcribed from DNA is decoded by specialized cellular structures called ribosomes to make proteins.
The ribosome has sites, which allow another specialized RNA molecule, known as tRNA, to bind to the mRNA. Binding of the correct tRNA to the mRNA on the ribosome is accomplished by an 48“anticodon” that is part of the tRNA. Thus, the correct tRNA, chemically linked to a specific amino acid, is directed to the ribosome to be added to a growing (nascent) polypeptide. The chemical process of connecting two amino acids is shown in the picture below.
zoom view
(The chemical process of connecting two amino acids resulting in a dipeptide and a water molecule)
As the ribosome travels down the mRNA one codon at a time, another tRNA is attached to the mRNA at one of the ribosome sites. The first tRNA is released, but the amino acid that is attached to the first tRNA is now moved to the second tRNA, and binds to its amino acid. This translocation continues on, and a long chain of amino acid (protein), is formed. When the entire unit reaches the stop codon on the mRNA, it falls apart and a newly formed protein is released. This is termination. It is important to know that during this process, many enzymes are used to either assist or facilitate the whole procedure.
The events following biosynthesis (Protein Synthesis) include post-translational modification and protein folding. During and after synthesis, polypeptide chains often fold to assume, so called, native secondary and tertiary structures. This is known as protein folding. Many proteins undergo post-translational modification. This may include the formation of disulfide bridges or attachment of any of a number of biochemical functional groups, such as acetate, phosphate, various lipids and carbohydrates. Enzymes may also remove one or more amino acids from the leading (amino) end of the polypeptide chain, leaving a protein consisting of two polypeptide chains connected by disulfide bonds.
 
GENETIC CODE
The genetic code is the set of rules by which information encoded in genetic material (DNA or RNA sequences) is translated into proteins (amino acid sequences) by living cells (Fig. 1.21).
49
zoom view
Fig. 1.21: Genetic code
Specifically, the code defines a mapping between tri-nucleotide sequences called codons and amino acids; every triplet of nucleotides in a nucleic acid sequence specifies a single amino acid. Most organisms use a nearly universal code that is referred to as the standard genetic code. Even viruses, which are not cellular and do not synthesize proteins themselves, have proteins made using this standard code. For a time, therefore, the code was thought to be universal. However, there are notable exceptions. It is also possible for a single organism to translate different parts of the genome in different ways. For example, in humans, protein synthesis in mitochondria relies on a modified genetic code that varies from the standard one.
The position or sequence of the bases in DNA ultimately determines the position of the amino acids in the polypeptide chain whose synthesis is directed by the DNA. Therefore, the structure and properties of body proteins are determined by the DNA base sequence of a person's gene. It does this by means of a code.
50
zoom view
Fig. 1.22: Relationship among the nucleotide base sequence of DNA, mRNA, tRNA and amino acids in the polypeptide chain production
Each amino acid is specified by a sequence of three bases called a codon. There are 20 major amino acids and 64 codons or code words. Sixty-one of the codon specify amino acids and 3 are “stop” single that terminate the genetic message. One codon that specifies an amino acid usually begins the message. More than one code word may specify a given amino acid, but only one amino acid is specified by any one codon; thus the code is said to be degenerated. For example, the codons that code for the amino acid leucine are UAG, UUG, CUU, CUC, CUA and CUG, but none of these codes for any other amino acid. The relationship between the base sequence in DNA, mRNA, the anticodon in tRNA and the translation into any amino acid is shown in Figure 1.22.
The code is non-overlapping. Therefore, CACUUUAGA is read as CAC, UUU, AGA, and specifies histidine, Phenylalanine, and arginine, respectively. A shorthand way of returning to specific amino acid is to use either specific group of three letters or a single letter to denote specific amino acid. To this system, for example, arginine may be referred to as ‘arg’ or as simply ‘R’ while the symbols for phenylalanine are either ‘Phe’ or ‘F’. General genetics referred to in the reference provide more information about the code.
 
NAMING GENES
The HUGO Gene Nomenclature Committee designates an official name and symbol (an abbreviation of the name) for each known human gene. Some official gene names include additional 51information in parentheses, such as related genetic conditions, subtypes of a condition, or inheritance pattern. The HGNC (Human Genomic Naming Committee) is a non-profit organization funded by the U.K. Medical Research Council and the U.S. National Institutes of Health. The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome. During the research process, genes often acquire several alternate names and symbols. Different researchers investigating the same gene may each give the gene a different name, which can cause confusion. The HGNC assigns a unique name and symbol to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research. Genetics Home Reference describes genes using the HGNC's official gene names and gene symbols. Genetics Home Reference frequently presents the symbol and name separated with a colon (for example, FGFR4: Fibroblast Growth Factor Receptor 4).
 
CHROMOSOME
In the nucleus of each cell, the DNA molecule is packed into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure. Chromosomes are organized structures of DNA and proteins that are found in cells. A chromosome is a singular piece of DNA, which contains many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions. The word chromosome comes from the Greek (chroma, color) and (soma, body) due to their property of being stained very strongly by some dyes. Chromosomes vary extensively between different organisms. Chromosomes are packaged by proteins into a condensed structure called chromatin.
Chromosomes are not visible in the cell's nucleus not even under a microscope when the cell is not dividing. However, the DNA that makes up chromosomes becomes more tightly packed during cell division and is then visible under a microscope. Most of what researchers know today about chromosomes was learned by observing chromosomes during cell division.
52
zoom view
Fig. 1.23: Structure of chromosome
zoom view
Fig. 1.24: Structure of 23 pairs of human chromosomes
Each chromosome has a constriction point called the centromere, which divides the chromosome into two sections, or “arms.” The short arm of the chromosome is labeled the “p arm.” The long arm of the chromosome is labeled the “q arm.” The location of the centromere on each chromosome gives the chromosome its characteristic shape, and can be used to describe the location of specific genes (Fig. 1.23).
In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46. Twenty-two of these pairs, called 53autosomes, look the same in both males and females. The 23rd pair, the sex chromosomes, differs between males and females. Females have two copies of the X chromosome while males have one X and one Y chromosome (Fig. 1.24).
 
Functions of Chromosome
  • Chromosomes contain genes. All the hereditary information is located in the genes.
  • Chromosomes control the synthesis of structural proteins and thus help in cell division and cell growth.
  • They control cellular differentiation.
  • By directing the synthesis of particular enzymes, chromosome control cell metabolism.
  • Chromosomes can replicate themselves or produce their carbon copies for passage to daughter cells and next generation.
  • Chromosomes produce nucleoli for synthesis of ribosomes.
  • Their haploid or diploid number respectively brings about gametophytic and sporophytic characteristics to the individual.
  • Chromosomes form a link between the offspring and the parents.
  • Some chromosomes called sex chromosomes (e.g. X and Y) determine the sex of the individual.
  • Through the process of crossing over, chromosomes introduce variations.
  • Mutations are produced due to change in gene chemistry.
 
CHROMOSOMES—SEX DETERMINATION
A sex-determination system is a biological system that determines the development of sexual characteristics in an organism. Most sexual organisms have two sexes. In many cases, sex determination is genetic: males and females have different alleles or even different genes that specify their sexual morphology. In human being, this is often accompanied by chromosomal differences. In some species of reptiles, including alligators and the tuatara, sex is determined by the temperature at which the egg is incubated or social variables (the size of an organism relative to other members of its population). Sex-determination systems are not yet fully understood in all the 54species. However, it is very clear in human being, which is very well explained by XX/XY chromosomes sex determination theory.
 
Chromosomal Determination of Sex
Henking (1891) discovered an X-body in the reproductive cell of firefly. Y-body was discovered by Stevens (1902). Wilson and Stevens (1905) put forward chromosome theory of sex and named the X and Y-bodies on heterogamesis or occurrence of two types of gametes in one of the two sexes. It is of the following types.
  • XX-XY Type
  • XX-X0 Type
  • ZX-ZZ Type
  • ZO – ZZ Type
  • Haplodiploidy
However, in human being XX-XY Type of heterogamesis theory is applicable. In human beings the female possess two homomorphic (isomorphic) sex chromosomes, named XX. The males contain two heteromorphic sex chromosome, i.e. XY. The Y-chromosome is often shorter and heterochromatic (made of heterochromatin). Despite of difference in morphology, the XY chromosomes are homologous and synapse during zygotene phase of meiosis. It is because they have two parts, homologous and differential. Homologous region of the two help in pairing. They carry same genes which may have different alleles. Such genes present on both X and Y chromosomes are XY-linked genes. They are inherited like autosomal genes, e.g. xeroderma pigmentation, epidermolysis bullosa. The differential region of Y-chromosome carries only Y-linked or holandric genes, e.g. testis determining factor (TDF). It is perhaps the smallest gene occupying only 14 base pairs. Other holandric genes are hypertrichosis (excessive hairness) on pinna, porcupine skin, keratoderma dissipatum (thickening of skin of hands and feet) and webbed toes. Holandric genes are directly inherited by son from his father. Genes present on the differential region of X-chromosome also find expression in male whether they are dominant or recessive, e.g. color blindness, hemophilia. It is because the males are hemizygous for these genes. 55
Human being have 22 pairs of autosomes and one pair of sex chromosomes. All the ova formed by female are similar in their chromosome type (22 + X). Therefore, females are homogametic. The male gametes or sperms produced by human male are of two types, (22 + X) and (22 + Y). Human males are therefore heterogametic (Male digamety).
 
Sex of Offspring (Fig. 1.25)
Sex of the offspring is determined at the time of fertilization. It cannot be changed later on. It does not depend on any characteristic of the female parent because they are homogametic and produce only one type of eggs (22 + X). The male gametes are of two types, androsperms (22 + Y) and gynosperms (22 + X). They are produced in equal proportion. Fertilization of the egg (22 + X) with gynosperm (22 + X) will produce female child (44 + XX), while fertilization of egg (22 + X) with androsperm (22 +Y) gives rise to male child (44 + XY). As the two types of sperms are produced in equal proportion, there are chances of getting a male or female child in a particular mating. As Y-chromosome determines the male sex of the individual, it is also called as androsome.
zoom view
Fig. 1.25: Sex-determination schematic presentation
56
 
CHROMOSOMAL ABERRATIONS (CHROMOSOMAL MUTATION)
  • Chromosomal aberrations are disruptions in the normal chromosomal content of a cell, and are a major cause of genetic conditions in humans, such as Down syndrome.
  • In other words, they are changes in the number and or arrangement of genes in the chromosomes.
  • Change in number of chromosomes is known as aneuploidy or numerical aberration.
  • Change in arrangement of genes in the chromosomes is known as structural aberration.
  • Chromosomal aberrations may involve changes in single chromosome, known as intrachromosomal aberrations.
  • Chromosomal aberrations may involve changes in two chromosomes, known as interchromosomal aberrations.
  • They are also termed as chromosomal abnormalities. Some chromosome abnormalities do not cause disease in carriers, such as translocations, or chromosomal inversions, although they may lead to a higher chance of having a child with a chromosome disorder. Abnormal numbers of chromosomes or chromosome sets, aneuploidy, may be lethal or give rise to genetic disorders.
  • Chromosomal abnormalities result in a proportion of congenital anomalies, developmental and intellectual disabilities and behavioral difficulties. The majority of spontaneous abortions (about 50–60%) are the result of chromosomal abnormalities, particularly, if they occur early, numerical changes in chromosomes are summarized in Table 1.2, structural changes are summarized in Table 1.3 and illustration 1.26.
Chromosomal aberrations can lead to a variety of genetic disorders. Human examples include: some of genetic disorder, or genetic disease are:
  • Cri du chat, which is caused by the deletion of part of the short arm of chromosome 5. “Cri du chat” means “cry of the cat” in French, and the condition was so-named because affected babies make high-pitched cries that sound like a cat.
    57
    Table 1.2   Change in chromosomal number (aneuploidy) (Numerical aberration)
    Change
    Description
    Example
    Monosomy
    One chromosome is missing
    Turner syndrome (Cells in female contain 45 chromosomes with one X chromosome rather than two)
    Trisomy
    One extra chromosome is present
    Trisomy 21 chromosome (Down syndrome) Cells contain 47 chromosomes
    Tetrasomy
    Two extra chromosomes are present
    Cells contain 48 chromosomes (Not compatible with life)
    Triploidy
    One extra chromosome set of haploid genome is present
    Cells contain 69 chromosomes (Not compatible with life)
    Tetraploidy
    Two extra chromosome sets of haploid genome are present
    Cells contain 92 chromosomes (Not compatible with life)
    zoom view
    Fig. 1.26: Chromosomal aberrations
    Affected individuals have wide-set eyes, a small head and jaw and are moderately to severely mentally retarded and very short.
    58
    Table 1.3   Major changes in chromosome structure (Structural aberration)
    Chatige
    Description
    Deletion (del)
    Part of a chromosome is missing with the accompanying DNA, can be at the end (terminal) or in the middle (interstitial). For example, del 5 p, cri-du-chat syndrome
    Duplication (liup)
    Part of a chromosome is duplicated along with the accompanying DNA, so that an extra piece of chromosomal material is present. For example, in cat eye syndrome, there is duplication of a certain segment of chromosome 22 resulting in iris coloboma. anal atresia and various congenital malformations.
    Inversion (tnv)
    Alteration in which a portion of die chromosome is rearranged by two breaks occurring 180 degree rotation of the chromosome piece between them and its reinsertion. For example, about 40% are chromosome 9. May or may not result in visible effects
    Ring chromosome (r)
    Formed when a segment at die end(s) of one of a pair of chromosome is lost and fuse to form a circular structure. For example, Ring chromosome 14 is associated with psychomotor delav, mental retardation and dysmorphic craniofacial features. It is very rare
    Translocation (t)
    Transfer of a chromosome segment to another chromosome after breakage has occurred. In reciprocal translocation two chromosomes exchange piece. A Robertsonism translocation usually involve two acrocentric chromosomes whose long arms fuse. Often small fragments are lost. In a balanced translocation no genetic material added or lost. Balanced reciprocal translocations usually do not cause problems. For example, translocation trisomy 21 or Down syndrome may result from the presence of 46 chromosomes that include a translocation chromosome such as 114 t21 or 114q 21 c so that the genetic material of 47 chromosomes with genetic material of 3 chromosome 21. is present. There is a normal chromosome 14, two normal 21 and translocation chromosome consisting of the second chromosome 14 and extra chromosome 21q.
    59
  • Wolf-Hirschhorn syndrome, which is caused by partial deletion of the short arm of chromosome 4. It is characterized by severe growth retardation and severe to profound mental retardation.
  • Down's syndrome, usually is caused by an extra copy of chromosome 21 (trisomy 21). Characteristics include decreased muscle tone, stockier build, asymmetrical skull, slanting eyes and mild to moderate mental retardation.
  • Edwards syndrome, which is the second most common trisomy after Down syndrome. It is a trisomy of chromosome 18. Symptoms include mental and motor retardation and numerous congenital anomalies causing serious health problems. Ninety percent die in infancy; however, those who live past their first birthday usually are quite healthy thereafter. They have a characteristic hand appearance with clenched hands and overlapping fingers.
  • Patau syndrome, also called D-Syndrome or trisomy-13. Symptoms are somewhat similar to those of trisomy-18, but they do not have the characteristic hand shape.
  • IDIC15, abbreviation for Isodicentric 15 on chromosome 15; also called the following names due to various researches, but they all mean the same; IDIC (15), Inverted dupliction 15, extra Marker, Inv dup 15, partial tetrasomy 15.
  • Jacobsen syndrome, also called the terminal 11q deletion disorder. This is a very rare disorder. Those affected have normal intelligence or mild mental retardation, with poor expressive language skills. Most have a bleeding disorder called Paris-Trousseau syndrome.
  • Klinefelter's syndrome (XXY). Men with Klinefelter syndrome are usually sterile, and tend to have longer arms and legs and to be taller than their peers. Boys with the syndrome are often shy and quiet, and have a higher incidence of speech delay and dyslexia. During puberty, without testosterone treatment, some of them may develop gynecomastia.
  • Turner syndrome (X instead of XX or XY). In Turner syndrome, female sexual characteristics are present but underdeveloped. People with Turner syndrome often have a short stature, low hairline, abnormal eye features and bone development and a “caved-in” appearance to the chest.
    60
  • XYY syndrome. XYY boys are usually taller than their siblings. Like XXY boys and XXX girls, they are somewhat more likely to have learning difficulties.
  • Triple-X syndrome (XXX). XXX girls tend to be tall and thin. They have a higher incidence of dyslexia.
  • Small supernumerary marker chromosome. This means there is an extra, abnormal chromosome. Features depend on the origin of the extra genetic material. Cat-eye syndrome and isodicentric chromosome 15 syndrome (or Idic15) are both caused by a supernumerary marker chromosome, as is Pallister-Killian syndrome.
 
Incidence
The incidence of the specific chromosomal abnormalities found is summarized in Table 1.4. Autosomal trisomies account for about 25%, sex chromosome abnormalities for about 35% and structural rearrangement for about 40%. These figures represent only a small fraction of chromosomally abnormal conception. Nature exercises considerable selection, as only small percentage of these abnormal conceptions survive to term. Between 10% and 20% of all recognized conception end in spontaneous abortions.
Table 1.4   Incidence of selected chromosomal abnormalities in live born child
Abnormality
Incidence
Autosomal trisomies
  • Trisomy 21 (Down syndrome)
1: 650 − 1: 1,000*
  • Trisomy 13 (Patau syndrome)
1: 4000 − 1: 10,000*
  • Trisomy 18 (Edwards syndrome)
1: 3,500 − 1: 7,500*
Sex-chromosome disorders
  • 45, X (Turner syndrome)
1: 2,500 − 1: 8000#
  • 47, XXX (triple X)
1: 850 − 1: 1,250#
  • 47, XXY (Klinefelter syndrome)
1: 500 − 1: 1,000$
Other Sex-chromosome abnormalities
  • Male
˜1: 1,300$
  • Female
˜1: 1,300#
Structural abnormalities
  • Rearrangement (e.g. translocation, duplications)
˜ 1: 440*
* Live births, # live female birth, $ live male birth
61
Studies of the products of spontaneous abortion have detectable chromosomal abnormalities. Approximately 95–99% of all Turner syndrome embryos are spontaneously aborted, as are about 95% of those with available data, it appears that chromosome abnormalities are present in 10–20% of all recognized conception. This may eventually be higher as techniques for determining cytogenic causes improve, more than 1000 chromosome abnormalities have been described in live births.
 
MECHANISM OF INHERITANCE
Heredity is the transmission of genetic character from parents to the offspring (Fig. 1.27). Gregor Johann Mendal (1866) proposed that inheritance is controlled by paired germinal units or factors, now called as genes. They are present in all cells of the body and are transferred to the next generation through gametes. Factors or genes are thus physical basis of heredity. They represent small segment of chromosomes. Genes are passed from one generation to the next generation or from one cell to its daughter cell as components of chromosome (chromosomal basis of heredity). The genetic material present in chromosomes is DNA. Genes are the segment of DNA called citrons. Therefore, DNA is the chemical basis of heredity.
Inheritance refers to how genetic information is passed down from one generation to next generation. The basic features of mechanism of inheritance are as follows:
  • Genes or chromosomes are physical basis of inheritance.
  • Person inherits half of the genetic information from each parent.
  • Every gene has two copies of genes; and each parent contributes for one copy of gene to their offspring.
  • Genes for different traits are inherited separately from one another. For example, the gene for hair color is not linked with the gene for height. A child may have his mothers’ hair color but may not her height. For the most part, each trait is inherited separately.
    62
zoom view
Fig. 1.27: Mechanism of inheritance
A particular disorder might be described as “running in a family” if more than one person in the family has the condition. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited (passed down from parent to child). Other conditions that appear to run in families are not inherited. Instead, environmental factors such as dietary habits or a combination of genetic and environmental factors are responsible for these disorders.63
 
LAWS OF INHERITANCE
Mendel has given following four laws of inheritance:
  • Law of unit inheritance (paired factors/genes): A character is represented in an organism or person by at least two factors. The two factors lie on the two homologous chromosomes at the same locus. They may represent the same (homozygous, e.g., TT in case of pure tall, tt in case of dwarf) or alternate expression (heterozygous, e.g. Tt in case of heterozygous tall) of the same character. Factors representing the alternate or same form of a character are called as alleles.
  • Law of dominance: In heterozygous individual, a character is represented by two contrasting factor called alleles. Out of the two alleles, only one is able to express its effect in the individual. It is called as dominant allele. The other allele, which does not show its effect in the heterozygous individual is called recessive allele.
  • Law of segregation: The two factors of a characteristic which remain together in an individual do not get mixed up but keep their identity distinct, separate at the time of gametogenesis or sporogenesis, get randomly distributed to different gametes and then get paired again in different offspring as per the principle of probability.
  • Law of independent assortment: According to this principle or law, the two factors of each character assort or separate independent of the factors of other characters at the time of gamete formation and get randomly re-arranged in the offspring.
 
MENDELIAN THEORY OF INHERITANCE
Genes provide the information for the growth, development and function of our bodies. When a gene is changed, there is a different message sent to the cells. A gene change that makes the genes faulty is called a mutation. A mutated (faulty) gene may cause a problem with the development and functioning of different body systems or organs. However, some faulty genes may be beneficial. Our genes are inherited from our parents, who have inherited theirs from their parents and so on. The great majority of genes come in 64pairs, the exceptions being the genes on the sex chromosomes (X and Y) of a male. The term Mendelian inheritance applies when a characteristic or set of characteristics is due to the information contained in a single gene pair. The characteristic may be “usual” or it may not: it could be a genetic condition.
Mendelian Inheritance is so called because our understanding of it started with the observations of an Augustinian monk named Gregor Mendel in the 19th century. The inheritance pattern depends on whether the faulty gene is part of one of the numbered chromosomes called an autosome or on the X chromosome, which is one of the sex chromosomes. It also depends on whether the mutation that makes the gene faulty is “recessive” or “dominant”.
When the inheritance pattern is known it is possible to provide families and individuals with information regarding the chance (or risk) that the condition will affect themselves and other family members of future generations. Autosomal recessive inheritance, autosomal dominant inheritance, X-linked recessive inheritance and X-linked dominant inheritance are the some Mendelian patterns of inheritance.
 
PATTERNS OF INHERITANCE
Some genetic conditions are caused by mutations in a single gene. These conditions are usually inherited in one of several straightforward patterns, depending on the gene involved. Following are the main patterns of inheritance.
  • Mendelian patterns of inheritance: this includes.
    • Autosomal dominant
    • Autosomal recessive
    • Sex-linked inheritance
      1. X-linked dominant
      2. X-linked recessive
      3. Y-linked (Holandric) inheritance
  • Non-mendelian patterns of inheritance
    • Codominant pattern of inheritance
    • Mitochondrial pattern of inheritance
    • Multifactororial pattern of inheritance
      65
 
AUTOSOMAL DOMINANT
One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent (Fig. 1.28). Autosomal dominant disorders tend to occur in every generation of an affected family.
Main characteristics of autosomal dominant inheritance and disorders:
  • Gene is on autosome
  • One copy of the mutant gene is needed for effects
  • Males and females are affected in equal number on average
  • No sex difference in clinical manifestations
    zoom view
    Fig. 1.28: Autosomal dominant pattern of inheritance
    66
  • Vertical family history through several generations may be seen
  • There is wide variation in expression
  • Penetrance may be incomplete (gene can appear or skip a generation)
  • Increase paternal age effect may be seen
  • Fresh gene mutation is frequent
  • Later age of onset is frequent
  • Male-to-male transmission is possible
  • Normal offspring of an affected person will have normal children and grandchildren
  • Least negative effect on reproductive fitness
  • Structural protein defect is often involved
  • In general these disorders tend to be less severe than the recessive disorders
  • Men and woman equally affected, variable expression, reduced penetrance (in some disorders), and advanced paternal age associated with sporadic cases.
Common examples of the autosomal dominant disorders
– Huntington disease
– Neurofibromatosis type 1
– Marfan syndrome
– Colon cancer
– Hereditary breast/and ovarian cancer
Details of the genetic disorders showing autosomal dominant inheritance may be perused from Table 1.5.
In this example, a man with an autosomal dominant disorder has two affected children and two unaffected children (Fig. 1.28).
 
AUTOSOMAL RECESSIVE
Two mutated copies of the genes are present in each cell when a person has an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers) (Fig. 1.29). Autosomal recessive disorders are typically not seen in every generation of an affected family.
Main characteristics of autosomal recessive inheritance and disorders:
  • Gene is located on autosome
  • Horizontal occurrence seen in families.
    67
    Table 1.5   Selective genetic disorders showing autosomal dominant inheritance
    Disorder
    Occurrence
    Brief description
    Aniridia
    1:100,000–1:200,000
    Absence of the iris of the eye to varying degree, glaucoma may develop, may be associated with other abnormalities in different syndrome
    Achondroplasia
    1: 10,000–1: 12,000
    Short limbed type of dwarfism with large hands
    Adult polycystic kidney disease
    1: 250–1: 1250 Enlarged kidney, hematuria, proteinuria, renal cysts, abdominal mass, eventually renal failure, may be associated with hypertension hepatic cyst, diverticular, cerebral hemorrhage may occur, cystic kidney seen on X-ray films.
    Facioscapulohumeral muscular dystrophy-IA
    1: 100,000–3: 100,000
    Facial weakness, atrophy in face, upper limb and shoulder girdle and pelvic girdle muscles, speech may become indistinct: much variability in progression and age of onset.
    Familial hyper-cholesterolemia (type-IIA)
    1:200–1:500
    Low-density lipoprotein receptor mutation resulting in deviated LDL, xanthomas, archs lipoidy, corneal and coronary disease.
    Hereditary sphenxytosis
    1:4500–1: 5000 Red cell membrane defect leading to abnormal shape, impaired survival and hemolytic anemia.
    Huntington disease
    1:1800-1:25000
    Progressive neurological disease due to urinucleotide repeat expansion of CAG, involuntary muscle movements with jerkiness, gait changes, lack of coordination, mental retardation with memory loss, speech problems, personality changes, confusion and decreased mental capacity usually begin in mid-adulthood.
    Nail-patella syndrome
    1: 50,00
    Nail abnormalities, hypoplasia or absent patella and iliac horns, elbow dysplasia, renal lesions and disease, iris and other eye
    68
    abnormalities, glaucoma, gastrointestinal problems.
    Neurofibromatosis-1
    1:3000-1:3,300
    Café-an-lait spots, neurofibromas and malignant progression are common, complications include hypertension, variable expression.
    Osteogenesis
    1: 30,000
    Fragile bones with multiple imperfecta type-1 fractures, mitral valve prolapse, short stature in some cases, progressive hearing loss, and wornian bones.
    Polydactyly
    1:100–1:300
    Extra (supernumerary) digit on hand and feet.
    Tuberous sclerosis-I
    About 1: 10,000
    White leaf shaped macules, seizures, intellectual delay, facial angiofibromas, erythemic nodular rash in butterfly pattern on face, learning and behavioral disorder, shagreen patches may develop retinal pathology and rhebdomyoma of the heart.
    Van-der-woude syndrome
    1: 80,000–1: 100,000
    Cleft lip pits, missing premolars.
    Van Willebrand disease
    1: 1000–30: 1000
    Deficiency or defect in plasma protein called van Willebrand factor, leading to prolonged bleeding time, bleeding from mucous membranes
  • Two copies of the mutated gene are needed for phenotypic manifestations
  • Male and females are affected in equal number on average
  • No sex difference in clinical manifestations
  • Family history is usually negative especially for vertical transmission (in more than one generation)
  • Other affected individual in family in same generation (Horizontal transmission) may be seen.
  • Consanguinity or relatedness is more often present than in other type of inherited conditions
  • Fresh gene mutation is rare
    69
    zoom view
    Fig. 1.29: Autosomal recessive pattern of inheritance
  • Age of disease onset is usually early newborn, infancy, early childhood
  • Greater negative effect on reproductive fitness.
  • Associated with particular ethnic groups.
Common examples of the autosomal recessive disorders
– Cystic fibrosis
– Sickle cell anemia
– Tay-Sachs disease
– Phyenylketonuria
– Thalassemia
Details of genetic disorders showing autosomal recessive inheritance may be perused from Table 1.6.
In this example, two unaffected parents each carry one copy of a gene mutation for an autosomal recessive disorder. They have one affected child and three unaffected children, two of which carry one copy of the gene mutation (Fig. 1.29).70
Table 1.6   Selective genetic disorders showing autosomal recessive inheritance
Disorder
Occurrence
Brief description
Albinism (tyrosinase negative)
1: 15,000-1:40,000 1: 85–1:630 (in Americans)
Melanin lacking in skin hair and eyes, nystagmus, photophobia, susceptible to neoplasm, strabismus, impaired vision
Argininosuccinic aciduria (ASA)
1: 60,000-1: 70, 000
Urea cycle disorder, hyperammonemia, mild mental retardation, vomiting, seizures, coma, abnormal hair shaft
Cystic-fibrosis
1: 2000–1:2500
Pancreatic insufficiency and malabsorption, abnormal exocrine gland, chronic pulmonary disease.
Ellis-van creveld syndrome
Rare
Short-limbed dwarfisms, polydactyly, congenital heart disease, nail anomalies
Glycogen storage disease-Ia (von Gierke disease)
1:20,000
Glucose-6 phosphatase deficiency, bruising, hypoglycemia, enlarged liver, hyperlipidemia, hypertension, short stature
Glycogen storage disease-II (Pompe's disease)
3: 100, 000–4.5: 100, 000
Infant, juvenile and adult form acid maltage deficiency. In infant form cardiac enlargement, cardiomyopathy, hypotonia respiratory insufficiency, developmental delay, macroglossia, death from cardio-respiratory failure by about 2 years of age
Hemochromatosis
1: 3000
Iron storage and tissue damage can result in cirrhosis, diabetes, pancreatitis and other disease, skin pigmentation.
Homocystinuria
1: 40,000-1: 1,40,000
Mental retardation, skeletal defects, lens displacement, tall risk for myocardial infarction, caused by cystathlonine beta-synthase deficiency
Metachromatic leukodystrophy
1: 40,000
Arylsofatase-A deficiency leading to disintegration of myelin and accumulation of lipids in white matter of brain, psychomotor degeneration, hypotonia, adult, juvenile and infantile form
Sickle cell disease
1: 400–1: 600
Hemoglobinopathy with chronic hemolytic anemia, growth retardation, susceptibility to infection, painful crisis, leg ulcers, dectylitis
Tay-Sachs disease
1: 3600
Progressive mental and motor retardation with onset at about 6 months, poor muscle tone, deafness, blindness, convulsions, decelerate rigidity, death usually by 3 to 5 years of age
71
Usher syndrome
Rare
A group of syndrome characterized by congenital sensorineural deafness, visual loss due to retain-iris pigmentations, vestibular ataxia, occasionally mental retardation, speech problems
Xeroderma pigmentosa (Complementation group A-G)
1: 60,000–1: 100,000
Defective DNA repair, sun sensitivity, freckling, atrophic skin lesions, skin cancer develops, photophobia and keratosis, death usually by adulthood
 
SEX-LINKED INHERITANCE
a. X-linked dominant: X-linked dominant disorders are caused by mutations in genes on the X chrosome. Females are more frequently affected than males, and the chance of passing on an X-linked dominant disorder differs between men (Fig. 1.30) and women (Fig. 1.31). Families with an X-linked dominant disorder often have both affected males and affected females in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).
Major characteristics of X-linked Dominant inheritance and disorders:
  • Mutant gene is located on X-chromosome
  • One copy of the mutant gene is needed for phenotypic manifestations.
  • X-inactivation modifies the gene effect in females
  • Often lethal in males and so many see transmission only in the female line
  • Affected families usually show excess of female offspring (2:1).
  • Affected male have affected mother (unless new mutation).
  • There is no male to male transmission
  • There is no carrier state
  • Disorders are relatively uncommon.
    72
zoom view
Fig. 1.30: X-linked dominant pattern of inheritance: affected father
Common example of the X-linked dominant disorders:
  • Fragile X syndrome
Details of genetic disorders showing X-linked dominant inheritance is depicted in Table 1.7.
In this example, a man with an X-linked dominant condition has two affected daughters and two unaffected sons (Fig. 1.30).
In this example, a woman with an X-linked dominant condition has an affected daughter, an affected son, an unaffected daughter, and an unaffected son (Fig. 1.31).
b. X-linked recessive: X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men (Fig. 1.32) and women (Fig. 1.33). Families with an X-linked recessive disorder often have affected males, but rarely affected females, in each generation.
73
zoom view
Fig. 1.31: X-linked dominant pattern of inheritance: affected mother
A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).
Major characteristics of X-linked recessive inheritance and disorders:
  • Mutant gene is located on X-chromosome
  • One copy of the mutant gene is needed for phenotypic effect in male (hemizygous).
    74
    Table 1.7   Selective genetic disorders showing X-linked dominant inheritance
    Disorder
    Occurrence
    Brief description
    Albright osteodystrophy
    Rare
    Short stature, delayed dentition, brachydactyly, hereditary hypocalcemia pseudohypoparathyroidism, many endocrine problems, muscular atrophy, mineralization of skeleton; round faces, possible intellectual disability, hypertension
    Focal dermal hypoplasia
    Very rare, exactly, unknown
    Atrophy, linear hypoplasia pigmentation, papillomas of skin on lips, axilla and umbilicus, digital anomalies, hypoplastic teeth, ocular anomalies (oloboma, microphthalmia)
    Lucontincotia pigmenti
    Very rare
    Irregular swirling pigmentation of skin lesion, dental anomalies, alopecia, intellectual disability common, seizures, uveitis, retinal abnormalities
    Ornlthine transcarbamylase (OTC) deficiency
    1:80,000 in Japan, rare among others
    Inborn error in urea cycle metabolism, failure to thrive, hyperammonemia, vomiting, headache, confusion, rigidity, lethargy, seizure, coma, many males die in neonatal period
    Orofaciodigital syndrome type-I
    1:50,000
    Cleft palate, tongue, jaw and/or lip, facial hypoplasia, intellectual disability, syndactyly, short digits, polycystic kidney with renal failure
    X-linked hypophosphatemia or vitamin D resistant
    1:25,000
    Disorder of tubular phosphate transport, bowed legs, growth deficiency, rickets with ultimate short stature, possible hearing loss
  • All daughters of affected males will be carriers, if the mother is normal.
  • All sons of affected males will be normal, if the mother is normal.
  • Males are more frequently affected than females.
  • There are some fresh gene mutations
  • There is no male to male transmission
  • Transmission is often through heterozygous (carrier) females
  • Two copies of the mutant genes are usually needed for phenotypic effect in females.
  • Unequal X-inactivation can lead to heterozygotic state in female carriers.
    75
zoom view
Fig. 1.32: X-linked recessive pattern of inheritance: affected father
Common examples of the X-linked recessive disorders:
  • Hemophilia–Fabry disease
  • Duchenne muscular dystrophy
  • Protan and deutan form of color blindness
  • Hunter syndrome
Details of the genetic disorders showing X-linked recessive inheritance is depicted in Table 1.8.
In this example, a man with an X-linked recessive condition has two unaffected daughters who each carry one copy of the gene mutation, and two unaffected sons who do not have the mutation. (Fig. 1.32). 76
zoom view
Fig. 1.33: X-linked recessive pattern of inheritance: carrier mother
In this example, an unaffected woman carries one copy of a gene mutation for an X-linked recessive disorder. She has an affected son, an unaffected daughter who carries one copy of the mutation, and two unaffected children who do not have the mutation (Fig. 1.33).
  1. Y-linked (Holandric) Inheritance: Few genes are known to be located on the Y-chromosome and so this type of inheritance has little clinical significance. Most Y-linked genes manifest their effect with one copy and show male-to-male transmission exclusively. All sons of an affected male would eventually develop trait. Although the age at which they develop disorders do varies. None of the affected male's daughter would inherit the trait. It can be hard to distinguish Y-linked inheritance from autosomal dominant disorders that are male sex limited. Some genes on the Y-chromosome are to determine height, male sex determination such as the ‘SRY’ gene for the testis determining factor, tooth enamel and size, hairy, ear and finger protein.
    77
    Table 1.8   Selective genetic disorders showing X-linked recessive inheritance
    Disorder
    Occurrence
    Brief description
    Color blindness (dentan)
    8: 100
    Normal vision actually, defective color vision with green series defect.
    Duchenne muscular dystrophy
    1: 3000–1: 5000
    Eventual respiratory insufficiency and death
    Fabry disease (diffuse angiokeratoma)
    1:40,000
    Lipid storage disorder ceramide trihexosidase deficiency, a-galactosidase deficiency, onset in adolescence to adulthood, angina, pain attacks, autonomic dysfunction, angiokeratoma.
    G6 PD deficiency
    1:10-1:50
    Enzyme deficiency with subtype shows effect in RBC, usually asymptomatic unless under stress or exposed to certain drugs or infection.
    Hemophilia-A
    1″250-1:4000
    Coagulation disorder due to coagulation factor X deficiency
    Hemophilia-B (Christmas disease)
    1: 4000–1: 7000
    Coagulation disorder due to coagulation factor X deficiency
    Hunter syndrome
    1: 100,000
    Mucopolysaccharide storage disorder with iduronote 2 sulfate deficiency, intellectual disability usual hepatomegaly, splenomegaly, dwarfism, stiff joints, mild and severe form, hearing loss
    Lesch-Nyhan syndrome
    Rare
    Deficiency of purine metabolism enzyme HPRT; hyperuremia, spasticity, athetosis, self-mutilation, developmental delay
    X-linked ichthyosis
    1: 5000–1: 6000
    Symptoms usual by 3 months may be born with sheets of scales (collodion babies) dry scaling skin often appears as it unwashed, developmental delay, bone changes, vascular complications, corneal opacities, steroid sulfatase deficiency.
    Menkes disease
    1: 200,000
    Copper deficiency caused by defective transportation, short stature, seizure, spasticity, hypothermia, kinky, sparse hair (pili torti); intellectual disability
    Male infertility disorder with genetic component can be inherited through this pattern of inheritance.
    78
 
CODOMINANT PATTERN OF INHERITANCE
In codominant inheritance, two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein (Fig. 1.34). Both alleles influence the genetic trait or determine the characteristics of the genetic condition.
Example:
  • ABO blood group,
  • Alpha-1 antitrypsin deficiency
The ABO blood group is a major system for classifying blood types in humans. Blood type AB is inherited in a codominant pattern.
zoom view
Fig. 1.34: Codominant pattern of inheritance
79
In this example, a father with blood type A and a mother with blood type B have four children, each with a different blood type: A, AB, B, and O.
 
MITOCHONDRIAL PATTERN OF INHERITANCE
This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children (Fig. 1.35). Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children.
zoom view
Fig. 1.35: Mitochondrial pattern of inheritance
80
 
Example
Leber's hereditary optic neuropathy (LHON)
In one family, a woman with a mitochondrial disorder and her unaffected husband have only affected children. In another family, a man with a mitochondrial condition and his unaffected wife have no affected children.
 
MULTIFACTORIAL PATTERN OF INHERITANCE
This is a common cause of many birth defects as well as common adult onset conditions such as diabetes, heart disease and cancer. Multifactorial inheritance conditions are believed to be the result of multiple mutations and environmental influence that combine to cause birth defects or disease. Genetic conditions with a multifactorial cause tend to cluster in families but do not follow the characteristic pattern of inheritance seen with single gene disorder (Fig. 1.36).
 
Examples
  • Congenital heart disease
  • Cleft lip/palate
  • Neural tube defect
  • Congenital hip dislocation
  • Diabetes
  • High blood pressure
zoom view
Fig. 1.36: Genetic conditions inherited in a multifactorial manner tend to cluster in families but do not follow the characteristic pattern of inheritance seen with single gene disorders
81
 
FACTS ABOUT TRANSMISSION OF GENETIC DISORDERS
When a genetic disorder is diagnosed in a family, family members often want to know the likelihood that they or their children will develop the condition. This can be difficult to predict in some cases because many factors influence a person's chances of developing a genetic condition. One important factor is how the condition is inherited. For example:
  • Autosomal dominant inheritance: A person affected by an autosomal dominant disorder has a 50 percent chance of passing the mutated gene to each child. The chance that a child will not inherit the mutated gene is also 50 percent.
  • Autosomal recessive inheritance: Two unaffected people who each carry one copy of the mutated gene for an autosomal recessive disorder (carriers) have a 25 percent chance with each pregnancy of having a child affected by the disorder. The chance with each pregnancy of having an unaffected child who is a carrier of the disorder is 50 percent, and the chance that a child will not have the disorder and will not be a carrier is 25 percent.
  • X-linked dominant inheritance: The chance of passing on an X-linked dominant condition differs between men and women because men have one X chromosome and one Y chromosome, while women have two X chromosomes. A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. Therefore, the sons of a man with an X-linked dominant disorder will not be affected, but all of his daughters will inherit the condition. A woman passes on one or the other of her X chromosomes to each child. Therefore, a woman with an X-linked dominant disorder has a 50 percent chance of having an affected daughter or son with each pregnancy.
  • X-linked recessive inheritance: Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. With each pregnancy, a woman who carries an X-linked recessive disorder has a 50 percent chance of having sons who 82are affected and a 50 percent chance of having daughters who carry one copy of the mutated gene.
  • Codominant inheritance: In codominant inheritance, each parent contributes a different version of a particular gene, and both versions influence the resulting genetic trait. The chance of developing a genetic condition with codominant inheritance, and the characteristic features of that condition, depend on which versions of the genes are passed from parents to their child.
  • Mitochondrial inheritance: Mitochondria, which are the energy-producing centers inside cells, each contain a small amount of DNA. Disorders with mitochondrial inheritance result from mutations in mitochondrial DNA. Although mitochondrial disorders can affect both males and females, only females can pass mutations in mitochondrial DNA to their children. A woman with a disorder caused by changes in mitochondrial DNA will pass the mutation to all of her daughters and sons, but the children of a man with such a disorder will not inherit the mutation.
It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4). Having one child with a disorder does not “protect” future children from inheriting the condition. Conversely, having a child without the condition does not mean that future children will definitely be affected.
Although the chances of inheriting a genetic condition appear straightforward, factors such as a person's family history and the results of genetic testing can sometimes modify those chances. In addition, some people with a disease causing mutation never develop any health problems or may experience only mild symptoms of the disorder. If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult.
Estimating the chance of developing or passing on a genetic disorder can be complex. Genetics professionals can help people 83understand these chances and help them make informed decisions about their health.
 
MULTIPLE ALLELES AND BLOOD GROUPS
 
Multiple Alleles
More than two alternative forms of a gene present on the same locus are called multiple alleles. They are produced due to repeated mutation of the same gene but in different directions. Thus, the wild type of allele for red eye colour (w+ or W) in Drosophila melanogster mutated to form allele for white eye (w), further mutation in both have incomplete intermediate dominance over one another. Some of these alleles are wine (ww), coral (wco), blood (wbl), cherry (wc), apricot (wa), eosine (we), buff (wb), tinged (wt), honey (wh), ecru (wec), pearl (wp) and ivory (wi). Despite the presence of several alleles of the same gene in a population, an individual can have only two alleles.
Characteristics includes
  • There are more than two alleles of the same gene, e.g., 15 alleles for eye for eye color in Drosophila, 3 alleles for blood group in human, 4 alleles for coat color in Rabbit.
  • All the multiple alleles occur on the same gene locus of the same chromosome or its homologue.
  • Chromosome contains only one alleles of the group.
  • An individual possesses only two alleles while the gametes carry single allele.
  • Multiple alleles express different alternatives of the same character.
  • Different alleles show codominance-recessive or intermediate dominance amongst themselves. They however, follow mendelian pattern of inheritance.
 
Blood Group System
Immunogenetics began in 900 when Landsteiner discovered the ABO blood group system. At this time 26 such systems, plus 5 collections and 2 series are known in humans, but all are not 84necessarily clinically significant. A six-digit number is given to every blood group antigen, in which the first three digits represent the system, collection or series and the second three digit represent the antigen. The systems that are best characterized and most important are ABO, Rhesus, Kell Lewis, Duffy, MNSs, Lutheran, P, Kidd, Diego, Yt, Xg, Domfrock, childol Rogers and Scianna.
 
ABO Blood Group System
ABO blood group system in human beings is an example of multiple alleles. Humans have four blood groups or blood group phenotypes; A, B, AB, and O. The ABO system is the most clinically important, the major alleles present at the ABO locus chromosomes are A, B, and O. Both A and B alleles are dominant to the O but codominant to each other. The A and B alleles code for certain enzymes and glycosyltransferanses and add sugar to the H substrate precursor to form the A and B glycoprotein antigen. The O allele does not produce an enzyme. These A and B antigens are not confined to the red cell but are widely distributed through the body. There are various subtype of the A, B and O alleles with more polymorphisms being revealed by newer DNA technique, but only A1 and A2 appear to have any antigenic importance. The relationship between genotype and blood group is shown in Table 1.9 and example of the inheritance of the ABO blood group are illustrated in Tables 1.10 and 1.11.
Persons with blood group O are sometimes said to have a “null” phenotype. Independent of the ABO system are the H and secretor systems. Person with the genotype HH or Hh produce the H substrate, which is the precursor for the A and B antigen and is modified by the enzymes produced by the A and B allele does not produce a transferase, it exerts no effect on this pathway, the H substrate is unmodifiable and more H antigen remains present.
Table 1.9   Relationship in ABO blood group system
Blood group (Phenotype)
Genotype(s)
Red cell antigen(s)
Antibodies in serum
A
AO, AA
A (+H)
Anti-B
B
BO, BB
B (+H)
Anti-A
AB
AB
A,B (+H)
None
O
OO
H
Anti-A, Anti-B
85
Table 1.10   Chart showing inheritance of blood groups by children of various parentages
Blood group of mother
Blood group of father
O
A
B
AB
Blood group allele in sperm
O
O
A
O
B
O
A
B
Blood group allele in ova
O
O
OO
(O)
OO
(O)
AO
(A)
OO
(O)
BO
(B)
OO
(O)
AO
(A)
BO
(B)
O
OO
(O)
OO
(O)
AO
(A)
OO
(O)
BO
(B)
OO
(O)
AO
(A)
BO
(B)
A
A
AO
(A)
AO
(A)
AA
(A)
AO
(A)
AB
(AB)
AO
(A)
AA
(A)
AB
(AB)
O
OO
(O)
OO
(O)
AO
(A)
OO
(O)
BO
(B)
OO
(O)
AO
(A)
BO
(B)
B
B
BO
(B)
BO
(B)
AB
(AB)
BO
(B)
BB
(B)
BO
(B)
AB
(AB)
BB
(B)
O
OO
(O)
OO
(O)
AO
(A)
OO
(O)
BO
(B)
OO
(O)
AO
(A)
BO
(B)
AB
A
AO
(A)
AO
(A)
AA
(A)
AO
(A)
AB
(AB)
AO
(A)
AA
(A)
AB
(AB)
B
BO
(B)
BO
(B)
AB
(AB)
BO
(B)
BB
(B)
BO
(B)
AB
(AB)
BB
(B)
* Every column presents offspring genotype of blood group and letters in parentheses are possible blood group phenotype of offspring
The allele h is a rare silent allele recessive to H. Person with hh who have the A and B allele do not express them due to the absence of the H substrate.
86
Table 1.11   Example of transmission of blood group genes (ABO system*)
Parents
AO × BO
AB × OO
AA × BB
AA × BO
AB × BB
BB × OO
Offspring genotype
AB, AO, BO, OO
AO, BO
AB
AB, AO
AB, BB
BO
Theoretical proposition of each pregnancy
¼, ¼, ¼, ¼
½, ½
All
½, ½
½, ½
All
Blood group phenotype
AB, A, B, O
A, B
AB
AB, A
AB, B
B
* Not all possible combinations are shown
The secretor (Se, se) locus determines whether the ABH antigen will be secreted in body fluids such as saliva, individuals who are nonsecretors (se, se) do not secrete ABH antigens. Approximately 80 percent of the white population is secretors. The secretor gene appears to have a regulatory function on the ‘H’ gene.
The clinical significance of this relationship is illustrated by the case of women who contacted the genetic counseling center at Chandigarh. She was believed to have blood group O, her husband was A and her child was AB, she had been told by the local health professionals that this was not possible unless her husband was not the child's father. The situation was causing considerable stress in their married relationship. Investigation demonstrated that she in fact had the B allele, but was homozygous for the rare Bombay phenotype known as hh. B antigen production was blocked by the two h alleles, even though she had one B gene. This client had contacted the genetic counseling center on her own. The health professionals involved in this case had simply accepted what they considered to be the most likely explanation, without further investigation or consultation. Rare cases of other variance are known. This is an example of why it is necessary to recognize the limits of one's own knowledge. Another approach would have been to do DNA testing to establish parentage. 87
A human being carries two of the three alleles, one from each parent. The maximum number of possible genotype is six for the four phenotypes. The phenotypes are tested by two antisera, anti-A and anti-B.
 
The Rhesus (Rh) System
It was not until 1940 that Landsteiner and Wiener discovered the rhesus (Rh) system. This system has become increasingly more complex. Many variants and about 45 antigens are known and various symbols have been used to describe the major components. The most common the one proposed by Fisher, Race and Sanger, reflected the existence of three very closely linked lock C, D or d (ho d) antiserum for the ‘d’ antigen has been found and those who are RhD negative actually lack the gene; however ‘d’ is used here for convenience and E or C and E alleles are much less antigenic than D. The D alleles are considered responsible for determining Rh positivity (+) in a dominant relationship to ‘d’. This inheritance pattern is illustrated in Table 1.12; the percentage of Rh negative individuals in the white population is approximately 15 percent, few native Americans or Asians are Rh negative. In the black population approximately 7 percent are Rh negative.
Table 1.12   Example of transmission of blood group genes (Rh system)
Parents
DD × dd
Dd × dd
Dd × Dd
Offspring genotype
DD
Dd, dd
DD, Dd, dd
Theoretical proposition of each pregnancy
All
½, ½
¼, ½, ¼
Blood group phenotype
Rh (+)
Rh (+), Rh (-)
Rh (+), Rh (+), Rh (-)
 
GENE MUTATION (ERRORS OF TRANSMISSION)
They are new sudden inheritable discontinuous variations, which are caused by a change in the nucleotide type and sequence of a DNA segment representing a gene. In other words a gene mutation is a permanent change in the DNA base sequence that makes up a gene. 88Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome. The first recorded gene mutations are Ancon Sheep (1791) and hornless (polled) cattle (1889). Following are the main features of the gene mutation:
  • All genes can mutate. However, mutability differs from gene to gene.
  • The direction of gene mutation cannot be predictable. It can occur in any possible direction to any possible degree.
  • A mutated gene can mutate back to its premutation state.
  • Gene mutation can be lethal, harmful, neutral or advantageous.
  • Most of the mutations are recessive and involve loss of function. A few are dominant ones.
  • The gene mutation may occur naturally and automatically due to several reasons, termed as spontaneous mutation and others are produced by external factors or chemicals, they are termed as induced mutations.
  • Individuals also possess mutator genes (cause mutations through altering polymerase activity) and antimutator genes (Check alteration in nucleotide through sequence during replication).
  • A spontaneous mutation happens through mechanisms of tautomerism (a base change by the repositioning of a hydrogen atom), depurination (loss of purine base-A or G), deamination (change a normal base to an atypical base), transition (a purine change to another purine or a pyrimidine to another pyrimidine) and transversion (a purine become a pyrimidine or vice versa).
  • Mutation can occur in somatic or germinal cells.
Gene mutations occur in two ways:
  • Germline or inherited mutation: Mutations that are passed from parent to child are called inherited mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person's life in virtually every cell in the body. Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in 89which an affected child has a mutation in every cell, but has no family history of the disorder.
  • Somatic or acquired mutation: Acquired during a person's lifetime. Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person's life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than germ cells) cannot be passed on to the next generation. Mutations may also occur in a single cell within an early embryo. As all the cells divide during growth and development, the individual will have some cells with the mutation and some cells without the genetic change. This situation is called mosaicism.
Some genetic changes are very rare; others are common in the population. Genetic changes that occur in more than 1 percent of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although polymorphisms generally have no negative effects on a person's health, some of these variations may influence the risk of developing certain disorders.
 
Causes of Gene Mutation
Any extracellular physical or chemical factor, which can cause mutation, or increase the frequency of mutation in an individual is called as mutagen.
  1. Physical factors: They are two types—temperatures and high-energy radiations.
    • Temperature: Increase in temperature, increase the rate of mutations. Rise in temperature breaks the hydrogen bonding between the two strands of DNA and hence denatures the letters.
    • High energy radiations: They include neutrons, alpha particles, cosmic rays, gamma particles, beta rays, X-rays, ultraviolet rays, 90etc. Ultraviolet rays are nonionizing radiations, which affect DNA by forming thymine dimers. It causes bends in DNA duplex that bring about misreplication. Other high-energy radiations are ionizing radiations. They ionize DNA constituents that can react with several biochemicals, X-rays are known to deaminate and dehydroxylate nitrogen bases, form peroxides and oxidize deoxyribose.
  2. Chemical factors: They are of several types. The common ones are nitrogen acid, alkylating agents, base analogues and acridines. Even some of drugs are known to cause gene mutation, like chemotherapeutic drugs for cancer.
 
Types or Mechanism of Gene Mutation
The smallest part of a gene that undergoes mutation is known as muton. It can be as small as a single nucleotide. Most of the gene mutations involve a change in only a single nucleotide or nitrogen base. These gene mutations are called point mutations. A mutation involving more than one base pair is termed as gross mutation. Gene mutation usually occurs during replication of DNA. It is therefore, also called as copy error mutation. During gene mutation a gene may undergo several point mutations. This produces multiple alleles. Gene mutations have varying effects on health, depending on where they occur and whether they alter the function of essential proteins. The DNA sequence of a gene can be altered in a number of ways. The main types or methods of gene mutations are as follows:
  1. Inversion mutation: A distortion of DNA by mutagen can change the base sequence of a gene in the reverse order. The process is called inversion. The new sequence will naturally have different codones. In example, there is reverse order of DNA base after mutation (Fig. 1.37).
  2. Substitution mutation (replacement): In substitution a nitrogen base is changed with another. It is of two types, transition and transversion.
    1. Transition mutation: A nitrogen base is replaced by another of its type, that is one purine is replaced by another purine (Adenine ↔ guanine), while one pyrimidine by another pyrimidine (cytosine ↔ thymine or uracil).
      91
      zoom view
      Fig. 1.37: Inversion mutation
      zoom view
      Fig. 1.38: Transition mutation
      In example, a purine (guanine) is replaced by another purine (adenine) (Fig. 1.38).
    2. Transversion mutation: Hence a purine base is replaced or substituted by a pyrimidine base and vice versa, e.g. Uracil or thymine with adenine and cytosine with guanine In example, cytosine replaced guanine (Fig. 1.39) and in Figure 1.40 thymine replaced adenine.
  3. Frame-shift mutation: They are those mutations in which the reading of the frame of base sequence shift laterally either in the forward direction due to insertion (addition) of one or more nucleotides or in the backward direction due to deletion of one or more nucleotides.
    92
    zoom view
    Fig. 1.39: Transversion mutation (cytosine replaces guanine)
    zoom view
    Fig. 1.40: Transversion mutation (Thymine replaces adenine)
    Therefore, frame-shift mutations are of two kinds insertion and deletion. A frameshift mutation changes the amino acid sequence from the site of the mutation.
    1. Insertion mutation: An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly. In this example, one nucleotide (adenine) is added in the DNA code, changing the amino acid sequence that follows (Fig. 1.41).
    2. Deletion mutation: A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).
      93
      zoom view
      Fig. 1.41: Insertion mutation
      zoom view
      Fig. 1.42: Deletion mutation
      In this example, one nucleotide (adenine) is deleted from the DNA code, changing the amino acid sequence that follows (Fig. 1.42).
  4. Missense mutation: This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene. In this example, the nucleotide adenine is replaced by cytosine in the genetic code, introducing an incorrect amino acid into the protein sequence (Fig. 1.43).
  5. Nonsense mutation: A nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein.
    94
    zoom view
    Fig. 1.43: Missense mutation
    zoom view
    Fig. 1.44: Nonsense mutation
    This type of mutation results in a shortened protein that may function improperly or not at all. In this example, the nucleotide cytosine is replaced by thymine in the DNA code, signaling the cell to shorten the protein (Fig. 1.44).
  6. Repeat expansion: Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated.
    95
    zoom view
    Fig. 1.45: Repeat expansion
    This type of mutation can cause the resulting protein to function improperly. In this example, a repeated trinucleotide sequence (CAG) adds a series of the amino acid glutamine to the resulting protein (Fig. 1.45).
 
EFFECT OF GENE MUTATIONS ON HEALTH AND DEVELOPMENT
To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the right times. Sometimes, gene mutations prevent one or more of these proteins from working properly. By changing a gene's instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder.
In some cases, gene mutations are so severe that they prevent an embryo from surviving until birth. These changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stages. Because these 96mutations have very serious effects, they are incompatible with life. It is important to note that genes themselves do not cause disease. Genetic disorders are caused by mutations that make a gene function improperly. For example, when people say that someone has “the cystic fibrosis gene,” they are usually referring to a mutated version of the CFTR gene, which causes the disease. All people, including those without cystic fibrosis, have a version of the CFTR gene.
Only a small percentage of mutations cause genetic disorders; most have no impact on health or development. For example, some mutations alter a gene's DNA base sequence but do not change the function of the protein made by the gene. Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed (makes a protein). Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, DNA repair is an important process by which the body protects itself from disease. A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. For example, a beneficial mutation could result in a protein that protects the organism from a new strain of bacteria.
 
REDUCED PENETRANCE AND VARIABLE EXPRESSIVITY
Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern.
Reduced penetrance: Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer 97syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop.
Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetic professionals to interpret a person's family medical history and predict the risk of passing a genetic condition to future generations.
Variable expressivity: Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely; some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience life-threatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1). As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose.
 
ANTICIPATION
The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This phenomenon is called anticipation. Anticipation is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) 98that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation.
Most genetic disorders have signs and symptoms that differ among affected individuals, including affected people in the same family. Not all of these differences can be explained by anticipation. A combination of genetic, environmental, and lifestyle factors is probably responsible for the variability, although many of these factors have not been identified. Researchers study multiple generations of affected family members and consider the genetic cause of a disorder before determining that it shows anticipation.
FURTHER READING
  1. American Society of Human Genetics/American College of Medical Genetics: Points to consider: Ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet 1995;57:1223–41.
  1. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. Oxford University Press,  New York,  1994.
  1. Billings PR, Kohn MA, de Cuevas M, et al. Discrimination as a consequence of genetic testing. Am J Hum Genet 1992;50:476–82.
  1. Bove C, Fry ST, MacDonald DJ. Presymptomatic and predisposition genetic testing: Ethical and social considerations. Semin Oncol Nurs 1997;13:135–40.
  1. Clayton, Julie (Ed). 50 Years of DNA, Palgrave MacMillan Press,  2003. ISBN 978-1-40-391479-8.
  1. Enkins J. Educational issues related to cancer genetics. Semin Oncol Nurs 1997;13:141–44.
  1. Fiers W et al. Complete nucleotide-sequence of bacteriophage MS2-RNA—primary and secondary structure of replicase gene, Nature, 1976;260:500–07.
  1. Havens DMH, Kovner R. Genetic testing: How it is transforming the role of health professionals and the implications for pediatric nurse practitioners. Journal of Pediatric Health Care 1997;11:193–97.
  1. Holtzman NA, Watson MS. Promoting Safe and Effective Genetic 99Testing in the United States: Final Report of the Task Force on Genetic Testing. http://www.nhgri.nih.gov/ELSI/TFGT_final. Accessed September, 1997.
  1. Judson, Horace Freeland. The Eighth Day of Creation: Makers of the Revolution in Biology, Cold Spring Harbor Laboratory Press,  1996. ISBN 978-0-87-969478.
  1. Lippman-Hand A, Fraser FC. Genetic counseling: Provision and reception of information. Am J Hum Genet 1979;3:113–27.
  1. Love RR. The accuracy of patient reports of a family history of cancer. Journal of Chronic Disease 1985;38:289–93.
  1. MacDonald DJ. The oncology nurse's role in cancer risk assessment and counseling. Semin Oncol Nurs 1997;13:123–28.
  1. Matloff ET, Peshkin BN. Complexities in cancer genetic counseling: Breast and ovarian cancer. Principles and Practice of Oncology Updates 1998;12:1–11.
  1. Michie 5, Bron F, Bobrow M, et al. Nondirectiveness in genetic counseling: An empirical study. Am J Hum Genet 1997;60:40–47.
  1. National Society of Genetic Counselors: Code of Ethics, 1992.
  1. National Society of Genetic Counselors: Position Statements, 1991.
  1. Offit K: Clinical Cancer Genetics: Risk Counseling and Management. WileyLiss,  New York,  1998;249.
  1. Olby, Robert. The Path to The Double Helix: Discovery of DNA, first published in October 1974 by MacMillan, with foreword by Francis Crick; ISBN 978-0-48-668117-7; the definitive DNA textbook, revised in 1994, with a 9 page postscript.
  1. Peters J, Stopfer J. Role of the genetic counselor in familial cancer. Oncology 1996;10:159–75.
  1. Rassoulzadegan M, et al. Nature, doi:10.1038/nature04674, 2006.
  1. Reilly PR, Boshar MF, Holzman SH. Ethical issues in genetic research: Disclosure and informed consent. Nat Genet 1997;15:16–20.
  1. Ridley, Matt. Francis Crick. Discoverer of the Genetic Code (Eminent Lives) first published in June 2006 in the USA and then to be in the UK September 2006, by HarperCollins Publishers;  192, ISBN 978-0-06-082333-7.
  1. Rieger PT. Overview of cancer and genetics: Implications for nurse practitioners. Nurse Practitioner Forum 1998;9:122–33.
  1. Rothenberg K, Fuller B, Rothstein M, et al. Genetic information and the workplace: Legislative approaches and policy changes. Science 1997;275:1755–57.
  1. Rothenberg KH. Genetic discrimination and health insurance: A call for legislative action. J Am Med Womens Assoc 1997;52:43–44.
  1. Rowland LP. Molecular basis of genetic heterogeneity: Role of the clinical neurologist. J Child Neurol 1998;13:122–32.
  1. Savage R, Armstrong D. Effect of a general practitioner's consulting style on patients’ satisfaction: A controlled study 1990;BMJ 301:968–70.

  1. 100 Scanlon C, Fibison W. Managing genetic information: Implications for nursing practice. American Nurses Association,  Washington,  DC, 1995.
  1. Schneider KA. Counseling About Cancer: Strategies for Genetic Counselors. Graphic Illusions,  Dennisport,  MA, 1994.
  1. Shiloh S, Saxe L. Perception of risk in genetic counseling. Psychological Health 1989;3:45–61.
  1. Walker AP. Historical perspective and philosophical perspective of genetic counseling. In Emery AEH, Rimoin DL, Connor JM, et al (Eds): Principles and Practice of Medical Genetics, (3rd ed). Churchill-Livingstone,  New York:  1996.
  1. Wertz DC, Fanos JH, Reilly PR. Genetic testing for children and adolescents. Who decides? JAMA 1994;272:875–81.