Understanding signatures of positive natural selection in human zinc transporter genes

Abstract

Zinc is an essential micronutrient with a tightly regulated systemic and cellular homeostasis. In humans, some zinc transporter genes (ZTGs) have been previously reported as candidates for strong geographically restricted selective sweeps. However, since zinc homeostasis is maintained by the joint action of 24 ZTGs, other more subtle modes of selection could have also facilitated human adaptation to zinc availability. Here, we studied whether the complete set of ZTGs are enriched for signals of positive selection in worldwide populations and population groups from South Asia. ZTGs showed higher levels of genetic differentiation between African and non-African populations than would be randomly expected, as well as other signals of polygenic selection outside Africa. Moreover, in several South Asian population groups, ZTGs were significantly enriched for SNPs with unusually extended haplotypes and displayed SNP genotype-environmental correlations when considering zinc deficiency levels in soil in that geographical area. Our study replicated some well-characterized targets for positive selection in East Asia and sub-Saharan Africa, and proposes new candidates for follow-up in South Asia (SLC39A5) and Africa (SLC39A7). Finally, we identified candidate variants for adaptation in ZTGs that could contribute to different disease susceptibilities and zinc-related human health traits.

Human genetic adaptation related to cellular zinc homeostasis

“…This gene encodes the ZnT9 protein, a recently characterized ZT in the mitochondria [ 21 , 22 ]. Moreover, the patterns of genetic variation and population differentiation at SLC30A9 have also been investigated in candidate-based selection studies analyzing human adaptation in relation to zinc homeostasis [ 13 , 23 , 24 ]. In most of these previous studies, the adaptive signals in SLC30A9 have been attributed to a non-synonymous single nucleotide polymorphism (SNP) (rs1047626, A>G at chr4:42001654; GRCh38) resulting in the substitution of a methionine by a valine in the N-terminus of the ZnT9 transporter (Met50Val) [ 13 , 17 , 23 , 24 ].…”

“…Moreover, the patterns of genetic variation and population differentiation at SLC30A9 have also been investigated in candidate-based selection studies analyzing human adaptation in relation to zinc homeostasis [ 13 , 23 , 24 ]. In most of these previous studies, the adaptive signals in SLC30A9 have been attributed to a non-synonymous single nucleotide polymorphism (SNP) (rs1047626, A>G at chr4:42001654; GRCh38) resulting in the substitution of a methionine by a valine in the N-terminus of the ZnT9 transporter (Met50Val) [ 13 , 17 , 23 , 24 ]. In agreement with the strong signatures of recent positive selection detected in East Asia, this non-synonymous SNP presents extremely high levels of population differentiation, where the ancestral A-allele (encoding Met) is at high frequency in African populations, whereas the derived G-allele (encoding Val) is nearly fixed in East Asian populations and at intermediate frequencies in European, South Asian, and American populations.…”

Human genetic adaptation related to cellular zinc homeostasis

“…This gene encodes the ZnT9 protein, a recently characterized ZT in the mitochondria (Deng et al 2021; Ma et al 2021). Moreover, the patterns of genetic variation and population differentiation at SLC30A9 have also been investigated in candidate-based selection studies analyzing human adaptation in relation to zinc homeostasis (Zhang et al 2015; Engelken et al 2016; Roca-Umbert et al 2022). In most of these previous studies, the adaptive signals in SLC30A9 have been attributed to a non-synonymous single nucleotide polymorphism (SNP) (rs1047626; c.148A>G) resulting in the substitution of a methionine by a valine in the N-terminus of the ZnT9 transporter (Met50Val) (Grossman et al 2013; Zhang et al 2015; Engelken et al 2016; Roca-Umbert et al 2022).…”

“…Moreover, the patterns of genetic variation and population differentiation at SLC30A9 have also been investigated in candidate-based selection studies analyzing human adaptation in relation to zinc homeostasis (Zhang et al 2015; Engelken et al 2016; Roca-Umbert et al 2022). In most of these previous studies, the adaptive signals in SLC30A9 have been attributed to a non-synonymous single nucleotide polymorphism (SNP) (rs1047626; c.148A>G) resulting in the substitution of a methionine by a valine in the N-terminus of the ZnT9 transporter (Met50Val) (Grossman et al 2013; Zhang et al 2015; Engelken et al 2016; Roca-Umbert et al 2022). In agreement with the strong signatures of recent positive selection detected in East Asia, this non-synonymous SNP presents extremely high levels of population differentiation, where the ancestral A-allele (encoding Met) is at high frequency in African populations, whereas the derived G-allele (encoding Val) is nearly fixed in East Asian populations and at intermediate frequencies in European, South Asian, and American populations.…”