Role of Genetics in Medicine

Impact of genes on health and disease

Some internet resources

    Human Genome Project

    Human Molecular Genetics List-serv

M.R. Seashore, M.D.

Textbook

Gelehrter, Collins, and Ginsburg, Chapter 1

SUMMARY

There are many important genetic concepts and terms whose definitions must be understood to comprehend modern genetics. Review the terms in the textbook and become familiar with their use.

Many concepts of genetics are familiar to students who have had a basic biology course. Since this course focuses on human genetics, the ways in which they apply to man will be most closely examined. The major concepts are reviewed in text books. Of particular importance are those noted below.

The genetic constitution of the individual, the genotype, is not always obvious, and without the molecular genetic tools which are the subject of later lectures, must be inferred from the pedigree. The phenotype can be observed in the individual. In many conditions caused by the same genotype, the phenotype may vary from one individual to another, giving rise to the concept of variable expression. Occasionally the individual carrying an abnormal gene at the locus of interest may have a completely normal phenotype; this phenomenon is known as variable penetrance. These two features lead to difficulties in identifying individuals carrying a mutant gene, and the tools of modern molecular genetics are brought into play to solve the question.

The three major Mendelian patterns of inheritance are: autosomal dominant, autosomal recessive, and x-linked. Autosomal refers to the location of the mutation on one of the 22 pairs of autosomes; x-linked refers to the location of the mutation on the X chromosome. A mutation is said to be dominant if it is expressed as a definable phenotype when there is only one copy of the mutation. It is termed recessive if it is only expressed in individuals with two copies of the mutant gene. If the alleles at a particular locus are the same, the individual is said to be homozygous for that gene; if they are different, the individual is said to be heterozygous.

Similar phenotypes can be the result of different mutations, whether at the same locus or at a completely separate locus. Recognition of this genetic heterogeneity is crucial to accurate genetic diagnosis and thus to accurate counseling and correct medical management of genetic disorders. No medical specialty will escape the need for this knowledge in the decade to come.

Descriptive and inferential approaches have had heavy emphasis in the past in the study of human genetics. Today modern technology has advanced our understanding of the chromosomal basis for Mendelian inheritance by expanding our knowledge of chromosomal structure and function. The analysis of pedigrees to determine mode of inheritance includes sophisticated mathematical approaches to non-obvious pedigrees and computer modeling of multifactorial hypotheses. New molecular tools have vastly increased the power to analyze human genetic pathology. The study of mutations has been greatly advanced the understanding of normal processes. Mapping of human genetic mutations to specific chromosomal locations has gone on very rapidly over the last five years (see Figure 1). These advances, especially those using recombinant DNA, will make it feasible to map the entire human genome. The Human Genome Project currently underway seeks to map expressed genes, sequence the genome, and discover the significance of unexpressed regions of DNA.

The relevance of human genetic concepts to general medical practice will increase over the coming decades. Advances in clinical genetics have led to diagnosis of rare inherited disorders such as inborn errors of metabolism, many of which are identified in the newborn infant by screening programs. Screening for the heterozygous states for recessively inherited disorders such as Tay-Sachs disease has created new options such a prenatal diagnosis. The lessons learned from these programs will be important when screening for more common heterozygous states becomes feasible. New techniques using gene probes, chromosome walking, and recombinant DNA have refined genetic diagnosis. The possibility of gene transfer has expanded the theoretical possibilities for innovative and perhaps even curative therapy for inherited disorders.

The overall incidence of single gene disorders approaches 1/100 births. This list of some of the more common ones demonstrates how these conditions cross medical specialties and will be seen by many different kinds of physicians.

Hypercholesterolemia 1/500

Sickle cell anemia 1/600 Blacks

Cystic fibrosis 1/1600 Whites

Tay-Sachs disease 1/3500 Ashkenazi Jews

Huntington disease 1/5000

Phenylketonuria 1/10,000

The overall incidence of chromosome abnormalities is 1/150 at birth, with Down syndrome (trisomy 21) the most common at about 1/800.

Both genetic and other factors, presumably environmental, play a role a role in the development of a large group of common conditions, including the congenital malformations spina bifida, cleft lip and palate, congenital heart disease. Common chronic disorders which affect adults are included in this category as well: coronary artery disease, diabetes mellitus, schizophrenia, hypertension, cancer.

McKusick compiled a list of medical journal citations referring to published papers about conditions with a genetic component. Of some 26,546 papers, 45.7% were published in journals related to nine fields of medical practice. The other half were scattered in various general and scientific journals, such as the Journal of the American Medical Association, the New England Journal of Medicine, Nature, Science, and Lancet. While genetics, pediatrics, and neurology top the list of specific specialty journals, note how diverse the other specialties represented are.