Diversification of the ADH1B gene during expansion of modern humans

Abstract

A variant allele, ADH1B*48His, also known as ADH1B*2, at the human Alcohol Dehydrogenase 1B gene (ADH1B) is strongly associated with alcoholism in some populations and has an unusual geographic distribution. Strong evidence implies selection has increased the frequency of this allele in some East Asian populations but does not fully explain its geographic pattern. We have studied haplotypes of 10 single nucleotide polymorphisms (SNPs) and two short tandem repeat polymorphisms (STRPs) in the ADH1B region in 2,206 individuals from a worldwide set of populations. These SNPs and STRPs define nine common haplogroups most of which have distinct geographic patterns. The haplogroups H5 and H6, both with the derived ADH1B*48His allele, appear restricted to the Middle East and East Asia, respectively. The positively selected H7 is derived from H6 by a new regulatory region variant defining SNP rs3811801 restricted to East Asia. Age estimates of the haplogroups based on the STRPs also agree with the time of the migration events estimated by other studies. H7 is estimated to have expanded recently, around 2,800 years ago, and ancient DNA samples from North China confirm its presence about that time. The dating of the H7 expansion may help understand the selective force on the ADH1B gene.

Figure 1

Markers typed in this paper. The centromere is to the left (downstream) and the telomere is to the right. The SNPs are numbered as represented in haplotypes going from the 5′ to 3′ of the gene, cf. Tables 1 and 2.

Figure 2

Evolutionary schema for the thirteen globally most common haplotypes. While the circle sizes are not strictly proportional to overall frequency, the shadings within each circle represent the proportion of that haplotype occurring in each geographic region by the colors corresponding to regions in the map. H1b, the 14^th haplotype, is very rare but does complete the evolutionary connections. H1c and H5b are not rare but cannot be explained by a single event (crossover or mutation) but have a more complex evolutionary background; the fine dotted lines indicate some of the allelic relationships.

Figure 3

The overall distribution of repeat sizes for the downstream STRP by geographic region. Variances are given for each of the peaks in each region except for the apparent absorbing boundary at 11 repeats.

Figure 4

The STRP size distributions associated with each of the seven major SNP-based haplotypes. Compared to Figure 2, H1 here also includes H1b; H2 here also includes H2b; H4 here also includes H4b. H3 and H5 are not pooled with the minor haplotypes shown in Figure 2. Shadings of each bar in the histograms represent the proportion of that haplotype occurring in each geographic region by the coloring of regions in the map.

Figure 5

Migration routes of the ADH1B haplogroups