Darwinian Positive Selection on the Pleiotropic Effects of KITLG Explain Skin Pigmentation and Winter Temperature Adaptation in Eurasians

Abstract

Human skin color diversity is considered an adaptation to environmental conditions such as UV radiation. Investigations into the genetic bases of such adaptation have identified a group of pigmentation genes contributing to skin color diversity in African and non-African populations. Here we present a population analysis of the pigmentation gene KITLG with previously reported signal of Darwinian positive selection in both European and East Asian populations. We demonstrated that there had been recurrent selective events in the upstream and the downstream regions of KITLG in Eurasian populations. More importantly, besides the expected selection on the KITLG variants favoring light skin in coping with the weak UV radiation at high latitude, we observed a KITLG variant showing adaptation to winter temperature. In particular, compared to UV radiation, winter temperature showed a much stronger correlation with the prevalence of the presumably adaptive KITLG allele in Asian populations. This observation was further supported by the in vitro functional test at low temperature. Consequently, the pleiotropic effects of KITLG, i.e. pigmentation and thermogenesis were both targeted by natural selection that acted on different KITLG sequence variants, contributing to the adaptation of Eurasians to both UV radiation and winter temperature at high latitude areas.

Pigment Intensity in Dogs is Associated with a Copy Number Variant Upstream of KITLG

“…Sulem et al (2007) found that a variant upstream of KITLG was associated with hair color in a genome-wide association scan in Icelanders and Dutch [46]. This variant likely lies in linkage disequilibrium, with an extended haplotype upstream of KITLG showing a strong signature of selection in humans [46][47][48]. Guenther et al (2014) found that this region drove expression exclusively in hair follicles using reporter constructs in mice [49].…”

Postadmixture Selection on Chileans Targets Haplotype Involved in Pigmentation, Thermogenesis and Immune Defense against Pathogens

“…We found that the strongest signals are associated with genes previously involved in pigmentation, thermogenesis, and immune defense against pathogens ( Guenther et al. 2014 ; Yang et al. 2018 ), all of them phenotypes under strong selection in diverse human populations ( Karlsson et al.…”

“…Although rs12821256 is a causative variant of lighter hair color in northern Europeans ( Guenther et al. 2014 ), KITLG regulates the amount of melanin pigments in hair follicles as well as in the skin and is also involved in thermogenesis ( Yang et al. 2018 ).…”

“…KITLG variants, including rs12821256 , have undergone strong positive selection in Europeans ( Grossman et al. 2010 ; Yang et al. 2018 ).…”

Genome-Wide Changes in Genetic Diversity in a Population of Myotis lucifugus Affected by White-Nose Syndrome

“…Finally, KITLG produces a protein involved in mast cell development, migration and function, and melanogenesis. KITLG has been documented as a target of evolution in recent studies and in humans it has been linked with thermoregulation (Yang et al 2018), which is a critical component of bat life history (Studier and O'Farrell 1972). In fact, upregulation of KITLG at low temperature helps promote the production of brown fat for heat generation (Huang et al 2014).…”