Basic principles underlie Hardy-Weinberg equilibrium, and there are explanations for the distribution and frequency of alleles in human populations. Processes such as genetic drift, gene flow, and selection are at work. The HLA system serves as a model for these themes. The important issue of linkage disequilibrium is described and there is discussion of multifactorial inheritance. The chapter closes with a brief examination of the recent evolution of Homo sapiens.
The extent of genetic variability in human populations is enormous. It is reflected outwardly in the unique characteristics of all individuals, other than identical twins who, of course, share a common inheritance. This variability includes differential disease susceptibility for both common and rare diseases, including those with clear-cut recessive or dominant patterns of inheritance, the main concerns of this work.
The first clear-cut Mendelian genetic examples of this human variability were the red cell blood groups, starting with Landsteiner's discovery of the ABO types in 1900, the year of the rediscovery of Mendel's work. The first common disease-related genetic variant was probably the rhesus-negative condition associated with hemolytic disease of the newborn, now a preventable disease. With the development of techniques for identifying protein variability, using starch gel and other types of electrophoresis, it became clear that many proteins including, of course, enzymes, had common genetic variants. The most extreme level of genetic variability is still associated with the major histocompatibility or HLA system, with its many loci and many hundreds of alleles—some of which show striking associations with autoimmune diseases such as ankylosing spondylitis, rheumatoid arthritis, and juvenile onset insulin-dependent diabetes mellitus (IDDM).
In parallel with the discovery of these common genetic variants, generally called polymorphisms as long as an allele has a frequency of more than 1 percent, came the description of rare clear-cut Mendelian inherited diseases, starting with Archibald Garrod's description of alkaptonuria as an “inborn error of metabolism.” Some categories of inherited disease, notably the hemoglobinopathies—starting with the sickle cell trait and anemia, the first disease to be clearly defined at a molecular level—are clearly polymorphic, but only in certain populations, notably in this case those in and originating from West Africa. Gradually, some of the rare inherited diseases were defined in terms of enzyme deficiencies or other protein abnormalities, such as the hemoglobinopathies or collagen abnormalities.
It was recognized many years ago, notably by R.A. Fisher and J.B.S. Haldane in the late 1920s and early 1930s, that linkage analysis using common polymorphisms would be a very powerful tool for the analysis of inherited diseases. The limitation of this method, which Fisher and Haldane then could not easily see being overcome, was the very limited availability of usable genetic polymorphisms, largely at the time restricted to half a dozen or so red cell blood group systems. That limitation has been completely removed by the recombinant DNA revolution.