16 - Allelic sequence diversity at the human β-globin locus

Summary

Despite nearly 20 years of molecular genetic investigation of human polymorphism, relatively little is known about the nature of variation in the human genome. Only a handful of loci have been investigated in any detail, and most studies have relied on indirect methods for the detection of DNA-level variation, most notably surveys using infrequently-cutting restriction enzymes. DNA sequence analysis (Sanger, Nicklen & Coulson, 1977), the only method with the potential for identifying all nucleotide and length variation present in a given genomic region has been applied to the analysis of the maternally inherited, haploid mitochondrial (mt) DNA genome (e.g. Vigilant et al., 1991; Ruvolo et al., 1993) but not nuclear DNA loci. As a consequence, high resolution investigation of genetic variation has been confined to a small, and largely atypical, portion of the human genome.

There are many reasons why DNA sequence investigation of human nuclear loci has lagged behind equivalent analysis of mtDNA. Mitochondrial DNA is far easier to isolate and analyse than nuclear DNA and phylogenetic interpretation of the allelic variation found there is simplified by the absence of interallelic recombination and gene conversion. Nuclear DNA is not only subject to the (potentially confounding) effects of recombination, it also contains fewer variable nucleotide sites than mtDNA due to its approximately ten-fold lower rate of point mutation (Cann, Stoneking & Wilson, 1987).