Introduction to Medical Genetics

Genetics is playing an increasingly important role in the practice of clinical medicine. Improved hygiene, better health care and awareness of good nutritional standards have resulted in an overall decrease in the incidence of infectious diseases. Additionally the role of genetic factors in the underlying pathology of disease is being better understood, the importance of genetics in medicine has increased.

The lifetime frequency of genetic disorders is estimated to be 7 per thousand, and this number includes cardiovascular diseases, which result from complex interactions of genes and environment and cancers, which result from accumulation of mutations in somatic cells. Genetic diseases are responsible for 10% of adult and 30-40% of pediatric hospital admissions. Congenital malformations when caused by genetic factors constitute a major cause of infant mortality.

Table 1.1 lists the burden of genetic diseases and their frequency in the general population. These figures necessitate today’s physicians and health care professionals to understand the fundamentals and principles of genetic science in order to accurately counsel patients and their families. Patterns of genetic disorders vary in their occurrence, mode of inheritance and recurrence risk estimates. In addition, environmental factors and teratogens tend to mimic genetic disease, making it mandatory to take the role of these factors in human embryonic and adult development into consideration before making a final diagnosis.

WHY IS STUDY OF GENETIC DISORDERS IMPORTANT?

1. Mutations and pathological changes that result as a consequence of these mutations are established for generations and are irreversible.

2. Genetic disorders can manifest in many body systems and expression of the disease can occur any time during the life of individual.

3. Disease in any one individual in the family puts other members living or yet to be born at risk.

4. Genetic diseases have a major psychological and social impact.

5. Treatment for genetic disease is largely experimental and is only available at specialized centers.

Dus to the recent advances in technology and increasing awareness of the patient population, physicians have an added responsibility in patient health care.

MENDEL’S LAWS

The principles of heredity and its understanding owe much to the pioneering work of an Austrian monk Gregor Mendel in 1865. Mendel studied clearly defined pairs of contrasting characters in the offspring of the garden pea (pisum sativum). However his work remained largely unnoticed until 1900. In his breeding experiments Mendel studied contrasting characters in garden peas e.g. tall pea plants were crossed with short pea plants (Fig. 1.1). All the plants in the first generation or F1 were tall. When the plants in this generation were subjected to interbreeding, the resulting plants were tall and short in a ratio of 3:1 [F2]. The characteristics in the F1 hide breeds are referred to as dominant, and those in the F2 are described as recessive. Mendel interpreted his findings suggesting that plant structure was controlled by factors one each from the parent. Wilhelm Johannsen coined these hereditary factors as genes. The first pure breed plants (tall and short) with identical genes used in the initial cross, are referred to as homozygous. The hybrid plants [F1], each of which inherit one gene for tallness and one for shortness are referred to as heterozygous. The combination of genetic material in the progeny is studied by constructing a square called Punnet’s Square. On the basis of his experiments, the famous laws of Mendel were established. These are known as (1) Law of Unit inheritance, (2) Law of Segregation and (3) Law of Independent assortment.

1. Unit Inheritance: This law clearly states that blending of the characters of parents does not occur in the progeny.

2. Segregation: Two members of a gene pair (alleles) always segregate and pass to different gametes. However, if a chromosomal pair fails to segregate, the offspring can inherit a severe abnormality.

3. Independent assortment: Gene pairs / characters assorted to a gamete are independent of each other. However, genes, which are closely linked on the same chromosome, do not assort independently but remain together from one generation to the other. This was not at that particular point of time recognized by Mendel.

Although Mendel presented and published his work in 1865, the significance of his discoveries was not realized until the early 1900 when three plant breeders De Vries, Correns and Tschermak confirmed his findings. It was around the same time that Charles Darwin’s book on “The Origin of species” was published in 1859. Darwin emphasized the hereditary nature of the variability between members of a species, which

is important in evolution. Heredity at the time was thought to involve blending of characters of both the parents. Archibald Garrod in 1902 proposed the idea that alkaptonuria was a recessive genetic disorder, and was the first to recognize the theory of a single gene. In collaboration with William Bateson, Garrod proposed that this was a Mendelian recessive trait with affected persons homozygous for the underactive gene. This was the first disease to be interpreted as a single gene trait. The urine of patients darkens on standing or on exposure to alkali. This is due to an inability on the part of the patient to metabolise homogentisic acid. Garrod also coined the term “Inborn error of metabolism”. Several hundred such disorders have now been identified and this area is known as ’’Biochemical Genetics”. In the 20th century the role of heredity became clearer and could explain different genetic mechanisms. Hereditary conditions are currently grouped as single gens disorders, chromosomal disorders and multifactorial disorders. Two other conditions now being considered are mitochondrial inheritance and somatic genetic diseases. As the understanding of the nature of biological structure and function of the living organism grew, the role of genes in life processes became increasingly recognized. In 1941, Beadle and Tatum formulated a hypothesis of one gene - one enzyme with the discovery that genes are composed of DNA. Since 1940, molecular analysis of genetic material has progressed rapidly. The intense interest in the composition of nucleic acids culminated in the discovery of the double helical structure for deoxyribonucleic acid (DNA) in 1953 by Watson and Crick for which they received the Nobel Prize in 1962.

History of chromosomes and chromosomal techniques

In order to understand and study the developmental process and expression of characters breeding experiments are to be performed. All breeding experiments are performed with looking at naturally existing genetic differences in a species. Mendel’s experiments are well known and are described above. An ideal model for such experiments would be a model in which new generations are rapidly and easily maintained under laboratory conditions, and an organism that has variety in its physical characters with the chromosome number being minimum. In 1910, the American geneticist Thomas Hunt Morgan and his students, Sturtevant, Bridges and Muller, started experiments on a fruitfly, Drosophilia Meianogaster. Drosophilia produces new generation every 14 days, which is 25 times faster than the green pea.

The first mutant observed in the Drosophilia was colour of the eyes. Morgan once observed that in a culture bottle containing flies with red eyes, a male with white eyes was identified. This mutant male was crossed with red-eyed flies. In his experiment he crossed the white-eyed mutant male with red-eyed wild type female. In the F1 generation, both male and female were found to have red eyes. However in the F2 generation, half of the males were white eyed and other half of the males and females had red eyes. These experiments provided evidence that supported the hypothesis, that chromosomes are physical basis of inheritance.

By the late 1950’s, human chromosome studies were developed and their role in sexual development, mental development and reproductive functions were understood. It was in 1956, Tjio and Levan established that normal diploid chromosome number in humans as 46. Various syndromes related to chromosomes were later identified. By 1970, with the combination of cytogenetics and molecular genetics, a new area of molecular cytogenetics emerged. Molecular cytogenetics techniques have opened a new vista in cytogenetic syndromes and many microdeletion syndromes are now identified with the use of fluorescent in-situ hybridization (FISH) technique.

Some commonly used terms in genetics

Human genetics: Human genetics is the scientific study of variation and heredity in human beings.

Medical genetics: Medical genetics is the application of the principles of human genetics to the practice of medicine. Medical genetics is the branch of medicine dealing with the inheritance, diagnosis and treatment of diseases caused by a single gene, chromosomal or multifactorial factors. This science also includes genetic counselling and screening.

Clinical genetics: The term Clinical Genetics is used in medical genetics and deals with the application of genetics to clinical problems in individual families.

Molecular genetics: Molecular genetics involves the interrelationship between DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) and how these molecules are used to synthesize polypeptides, which are the basic component of all proteins.

Incidence: This refers to the rate of at which a disease occurs e.g., 1:1000 means in every 1000 individuals, one will have the disease.

Prevalence: Means proportion of a population affected at any one time. Prevalence of genetic disease is not as high as other disorders as the incidence and life expectancy is less, and the disorder may have a late age of onset.

Frequency: This is synonymous with incidence.

Classification of genetic diseases

Genetic disorders may be classified into single gene, multifactorial, chromosomal, somatic genetic disorders and mitochondrial disorders. Detailed description of these disorders is provided in the chapters on Patterns of Inheritance and Polygenic and Multifactorial Inheritance.

Single Gene Disorders

Single gene disorders are due to deficiency or alteration in the structure of a single gene in an individual. Single gene disorders are further classified into autosomal dominant, autosomal recessive, X-linked traits.

Autosomal dominant traits—these traits are transmitted through the autosomes, and expressed when only a single copy of an abnormal gene is present. The transmission is vertical, from an affected individual to the progeny. Some examples of autosomal dominant disorders are Huntington’s disease, Neurofibromatosis type-1, Marfa's syndrome, and Osteogenesis imperfecta.

Autosomal recessive traits—these are transmitted through autosomes, but expressed only when both the copies of mutant gene are inherited. Some examples of autosomal recessive disorder are cystic fibrosis, Sickle cell anaemia, (3-thalassaemia, Galactosaemia, Phenylketonuria, Tay Sach’s disease and Freidreich ataxia.

X-linked traits—These are transmitted due to mutant genes on the X chromosomes. The definition of dominant or recessive in these conditions is complicated by the inactivation of one of the X chromosomes in the cells of females during early development. Some examples of X-linked disorders are Duchenne Muscular Dystrophy, and Haemophilia A and B.

Multifactorial Disorders

There are many disorders, which have a familial clustering, but they do not follow any Mendelian pattern of inheritance. These disorders are due to an interaction between genes and environment.

Chromosomal Disorders

Mutations of genetic material sometimes involve large parts of the chromosome. When these are large enough to be visible under light microscopy these are termed as chromosomal aberrations. Chromosome aberrations affect 7.5% of conceptuses and have a live birth frequency of 0.6%. Abnormalities of the chromosomes may be classified as numerical aberrations, or structural aberrations. In numerical aberrations, somatic cells contain an abnormal number of normal chromosomes. Examples of these are aneuploidy and polyploidy. In structural aberrations, somatic cells contain one or more abnormal chromosomes. Examples of these include translocations, deletions, ring chromosomes, duplications, inversions and isochromosomes. Chromosomal abnormalities may occur in the sex chromosomes or the autosomes. They may occur in the germline of the parent or an ancestor, or may occur as the result of a somatic mutation, where only a proportion of cells are affected (see below).

Somatic Genetic Disorders

Genetic disorders may not originate at conception (in the germline) but can occur during the process of cell division (mitosis), which is a continuous process occurring throughout life for growth and repair of the body. During these mitotic divisions, there is a chance of error leading to single gene mutations or chromosomal aberrations. Such abnormalities can lead to malignancies thus giving rise to the term acquired or somatic genetic disease.

Mitochondrial Disorders

Disorders of mitochondrial function may involve genes encoded in the nuclear DNA or the mitochondrial DNA. Mitochondria are transmitted from a mother to all her offspring, while the sperm only contributes the nuclear DNA. Therefore mutations in the mitochondrial DNA are inherited maternally that is, females potentially pass the trait to all offspring and males do not transmit the trait. Some examples of these disorders include Leber hereditary optic neuropathy and mitochondrial myopathies.

References

Purandarey , H. (2009) . Essentials of Human Genetics. Second Edition. Jaypee Brothers Medical Publishers (P) Ltd.