Population Genetics. Individual Variation

Surveys of the genotypes of individuals within human populations have shown an immense variation at the level of individual nucleotide positions, genes, gene complexes, whole chromosomes, and genomes of cell organelles (e.g., mitochondria). No two individuals, even identical twins, are genetically identical because mutational errors in DNA replication are sufficiently frequent to guarantee that base pair differences will exist between the genomes of daughter cells of a single cell division.

For example, if two genomes are surveyed for nucleotide differences by restriction endonucleases, which cut DNA at specific well-defined sequences, they will differ from each other at about one in every 200 base pairs. The functional significance of these differences is unknown because the restriction sites are not localized to particular genes or to particular base positions within codons.

Much more revealing surveys of genetic variation come from studies of particular genes and gene complexes such as those specifying enzymes, blood group antigens, histocompatibility systems, and specific developmental features.

Surveys of more than 100 enzyme-coding loci, using gel electrophoresis to detect amino acid substitutions caused by mutations, have shown that approximately one-quarter are polymorphic within a major racial group and one-third are polymorphic within the species as a whole. A locus is classified as polymorphic if the most common allele at the locus has a frequency of 0.99 or less.

Another measure of genetic diversity of a population is the proportion of heterozygotes (i.e., in which the two genes of a pair are not identical) averaged over loci. For a typical human population, this proportion is roughly 0.065 for enzyme-coding loci. Both in the proportion of loci polymorphic and average heterozygosity, humans are typical of vertebrates in general.

In some cases one allele at a polymorphic locus is frequent, but in others there are two or more allelic forms with roughly equal frequencies. Table I shows the frequencies of the homozygotes (in which the two genes of the same pair are identical) and of the heterozygotes for the 15 most polymorphic enzymes in the English population.

TABLE I. Frequencies of Various Enzyme Variants Found in the English Population

Polymorphisms of a similar degree are found for red cell antigens. Of 33 known red cell antigen genes, about one-third are polymorphic with an average heterozygosity of 0.16. Table II shows the allelic frequencies at the polymorphic blood group loci in the English population.

TABLE II. Blood Type Frequencies in the English White Population

By far the most extraordinary polymorphism in human populations is for the HLA gene complex of tightly linked loci specifying histocompatability proteins. In Caucasians, for example, there are 14 alternate alleles at the A locus, 17 alleles at the В locus, 6 at the C, and 8 at the locus. The alleles at all the loci are generally in intermediate to low frequency, and none of the loci has a very common form (usually referred to as “wild type”).

The consequence of the large amount of genic polymorphism is that the probability that two individuals chosen from a European population are genetically identical, considering only the 35 most polymorphic loci, is about 8 X 10^-14. Nor do these highly polymorphic loci exhaust the known variation.

About 2 per 1000 individuals carry a rare variant, recognizable electrophoretic allele for some enzyme-coding locus. “Inborn errors of metabolism,” in which some enzymatic function is deficient or absent, are usually the consequence of homozygosity for a low-frequency mutant allele at a locus and thus are individually rare. Heterozygotes for these alleles are much more common, however.

In a sample from the United States examined for 14 inherited disorders, it was estimated that 13% of newborns were heterozygous for a mutant allele. It is clear that all human individuals are heterozygous for scores of mutations that would be deleterious in the homozygous condition.