Modern Human Genetics in the Etiology of Disease

Before Mendel described the principles of genetics on the basis of his plant studies, it was recognized that a wide variety of diseases were familial. Although not the first, Sir William Osler is the most recognized modern physician to propose that familial clusterings of diseases were linked to specific gene abnormalities. Medical genetics became a specialty with the recognition that a detailed pedigree made it possible to understand the genetic basis of a given familial disease. However, in the mid-twentieth century, genetic screening was only a concept, and no quantitative tools existed for it. Biochemical screening tests, reflecting the downstream effects of a genetic abnormality, were the first “genetic tests” developed. Population-wide screening for Tay-Sachs disease, a disease with autosomal-recessive inheritance found predominantly in Ashkenazi Jews, was one of the first successful applications of such a test. A combination of biochemical screening and genetic counseling has resulted in a greater than 90% decrease in the occurrence of the disease over the past 2 decades, underlining the importance of this type of screening.

In the late twentieth century, with the advent of reliable DNA sequencing, it became possible to demonstrate that diseases could be assigned to a single-nucleotide change in a specific, important gene. This development led to the idea that single mutations “caused” disease, extending the principles of Osler: one abnormality, one disease.

With the advent of high-speed DNA sequencing, it has become clear that the genetic basis of human disease is much more complex than was formerly recognized. There are several reasons for this greater complexity. First, mutations in specific genes are rarely unique; the same phenotype can result from any of a number of mutations in the same gene. Second, nearly identical phenotypes can result from a mutation in more than one gene. Third, just as genes do not act in isolation, mutations often do not have a strict cause-and-effect relationship with disease (Fig. 72-2). Often an interaction of a mutation with a broad array of environmental factors leads to a given phenotype. Finally, humans are not a product of changes in single genes in isolation but of many, perhaps hundreds, of polymorphisms (Fig. 72-3, upper). Commonly, susceptibility to environmental effects depends not on a single gene but on the interactions of many genes—often genes for nuclear factors that regulate the expression of entire classes of genes. Practical examples are discussed in the following section.

Figure 72-2 Normal, mutant, and polymorphic gene expression.

A, adenine; C, cytosine; G, guanine; T, thymine.

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