Understanding signatures of positive natural selection in human zinc transporter genes

Ana Roca-Umbert,Rocio Caro-Consuegra,Ruben Vicente,Gabriel Felipe Rodriguez-Lozano,Elena Bosch,Diego Londono-Correa

doi:10.1038/s41598-022-08439-y

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.

Highlights

Affects multiple physiological and metabolic processes, leading to growth retardation, a dysfunctional immune response, and even cognitive impairment[14,17,18]
The final curated South Asian dataset comprised a total of 1353 individuals (979 of them South Asian) and included four external reference populations (Yoruba in Ibadan, Nigeria (YRI); Utah residents with Northern and Western European ancestry (CEU); Han Chinese in Beijing, China (CHB); and individuals with Mexican Ancestry (MXL)), populations from Pakistan (PAK), Bangladesh (BEB) and Sri Lanka (STU), and five Indian groups: tribal populations speaking Austroasiatic languages (T-AA), Dravidian-speaking tribal populations (T-DR), Tibeto-Burman-speaking tribal populations (T-TB), non-tribal populations speaking Dravidian languages, and non-tribal populations speaking Indo-European languages (Fig. 1, Supplementary Table S3)
We show that the complete set of Zinc Transporter Genes (ZTGs) display higher genetic differentiation than expected in comparisons of African versus non-African populations

Summary

Introduction

Affects multiple physiological and metabolic processes, leading to growth retardation, a dysfunctional immune response, and even cognitive impairment[14,17,18]. We first analyzed global patterns of ZTG variation using whole-genome data from Phase 3 of the 1000 Genomes Project[41], which comprises human populations from the five main continental regions We extended this analysis to different population groups from South Asia using whole-genome data from the Pilot phase of the GenomeAsia 100 K P roject[42] to investigate a specific geographical region with well-recognized zinc d eficiency[22]. Our results show that the complete set of ZTGs presents extreme levels of genetic differentiation between African and non-African populations, as well as unusual patterns of genetic variation arising from different strong geographically restricted selective sweeps across a few ZTGs, and other more subtle forms of adaptation, especially in South Asia. We highlight several candidate variants for selection in the ZTGs, some of them correlating with zinc soil availability, which deserve further functional studies and experimental validation

Methods

Results

Conclusion