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. ; This work was supported by Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (project Grants BFU2016-77961-P, PID2019-110933GB-I00/AEI/10.13039/501100011033, PID2019-106755RB-I00/AEI/10.13039/501100011033); Unidad de Excelencia María de Maeztu funded by the MCIN and the AEI (https://doi.org/10.13039/501100011033, Ref: CEX2018-000792-M); and by Direcció General de Recerca, Generalitat de Catalunya (2017SGR00702).
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