Friday, February 19th, 2010
Initially posted 11 September 2009 by evomed
Chapter 3 introduced the concept of positive selection, which refers to the increase in frequency of specific traits that confer a fitness advantage. Table 3.1 also gave examples of several human genes which have been shown to be under recent positive selection (ie, within the last 10,000 years). It is thought that environmental changes act as strong selective pressures for genotypes that enable adaptation to the new local environment. An example of such a change would be the transition from hunter-gatherer to agricultural practices 10–12,000 years ago. The lactase-coding gene LCT, which enables hydrolysis of the predominant milk sugar lactose, provides an illustrative example. Positive selection for this gene, and hence lactase persistence into adulthood, has been shown in Northern European and East African populations and is attributed to the domestication of cattle and subsequent introduction of milk to the diet.
Several genes involved in skin pigmentation have also shown population-specific selective sweeps, suggesting that the evolution of human skin pigmentation is also driven by adaptation to different climates as humans migrated out of Africa towards more temperate regions. KITLG, which codes for a ligand of the tyrosine kinase receptor encoded by the KIT locus, is one such example. Among other biological properties, the Kit ligand plays a critical role in melanocyte development and migration. KITLG has been shown to be under positive selection in Europeans and East-Asians, but not Africans. Genotyping of an ancestral SNP (rs642742), located at a potentially regulatory region upstream of KITLG, demonstrated that Africans possessed the ancestral A allele while European and East Asian populations displayed a significantly higher frequency of the derived G allele that leads to lighter skin, possibly due to lower KITLG expression than that from the A allele (Miller et al. 2008). The selective pressure for lighter skin is not clear, although vitamin D requirements and sexual selection have been proposed.
Recently, Kanetsky et al. (2009) and Rapley et al. (2009) independently conducted genome-wide association studies (GWAS) to determine markers of testicular germ cell tumors (TGCT). TGCTs are the most commonly diagnosed cancer among young to mid-age males. Genotype frequencies for cases and controls of European ancestry were determined and compared. Seven of the eight SNP markers that reached genome-wide statistical significance (P < 5.0 x 10–8) in the study by Kanetsky et al. were located within the KITLG gene region on 12q22. Independent replication was then performed on two of the SNPs (rs3782179 and rs4474514) in another cohort. Using similar methodology, Rapley et al. found strong evidence of association for two SNPs located on chromosome 12 (rs995030 and rs1508595) which held up after replication. The estimated per-allele odds ratios (OR) for the susceptibility loci on chromosome 12 in the two studies ranged from 2.55 to 3.08—ratios that are remarkably high in comparison to the OR for other GWAS-identified cancer susceptibility loci.
The findings from both teams clearly demonstrate that KITLG is a risk factor for the development of TGCT. It is interesting to note, as have Kanetsky et al., that the incidence of TGCT in men of European ancestry is almost fivefold higher than in black men. The findings, coupled with HapMap data showing significantly higher disease allele frequency in European than in African ancestry populations, suggest that the difference may be explained at least partially by inherited variation at the KITLG locus. It is important to bear in mind that GWAS can only reveal associations, not causality; however biochemical studies investigating the mechanisms by which lower KITLG expression affects melanocyte properties, and the role that KITLG plays in the development of TGCT, may provide some clues. The similar results from the two TGCT studies suggest that potentially negative consequences of positive selection cannot be overlooked.