Positive selection in Europeans and East-Asians at the ABCA12 gene

Roberto Sirica,Caterina Missero,Valeria Petrella,Vincenza Colonna,Ombretta Guardiola,Donatella Tramontano,Yali Xue,Heerman Kumar,Qasim Ayub,Dario Antonini,Marco Salvemini,Marianna Buonaiuto,Lucia Sticco,Giovanni D’Angelo,Chris Tyler-Smith,Gennaro Andolfi

doi:10.1038/s41598-019-40360-9

Abstract

Natural selection acts on genetic variants by increasing the frequency of alleles responsible for a cellular function that is favorable in a certain environment. In a previous genome-wide scan for positive selection in contemporary humans, we identified a signal of positive selection in European and Asians at the genetic variant rs10180970. The variant is located in the second intron of the ABCA12 gene, which is implicated in the lipid barrier formation and down-regulated by UVB radiation. We studied the signal of selection in the genomic region surrounding rs10180970 in a larger dataset that includes DNA sequences from ancient samples. We also investigated the functional consequences of gene expression of the alleles of rs10180970 and another genetic variant in its proximity in healthy volunteers exposed to similar UV radiation. We confirmed the selection signal and refine its location that extends over 35 kb and includes the first intron, the first two exons and the transcription starting site of ABCA12. We found no obvious effect of rs10180970 alleles on ABCA12 gene expression. We reconstructed the trajectory of the T allele over the last 80,000 years to discover that it was specific to H. sapiens and present in non-Africans 45,000 years ago.

Highlights

ATP binding cassette (ABC) transporters are trans-membrane ubiquitous proteins, that translocate natural substrates across plasma membranes
In the Complete Genomics dataset (CG)[18], the T/T genotype is significantly more frequent among Asians and Europeans compared to Africans
This is true both when considering samples partially overlapping with Phase I, and samples unique to CG (Table 1, Fisher exact test p-value < 2.2e-16), suggesting that the observed pattern of higher derived allele frequencies in Europeans and Asians compared to Africans was not due to the specific set of sample used but is reproducible

Summary

Introduction

ATP binding cassette (ABC) transporters are trans-membrane ubiquitous proteins, that translocate natural substrates across plasma membranes. ABCA12 is a keratinocyte transmembrane transporter that binds and hydrolyzes ATP to transport lipids in the lamellar granules[3] This activity is required to form the extracellular lipid barrier in the outermost layer of the skin, the stratum corneum of the epidermis[3]. We demonstrated that the derived allele T is highly frequent in Asians and Europeans, compared to Africans, where the ancestral C variant prevails This evidence, together with the identification of patterns typical of positive selection in the genomic region of rs10180970 let us speculate that ancestor of current Europeans and Asians should have had an advantage in carrying the T allele and that it would be interesting to determine the functional consequences and the trajectory of the T allele through time

Methods

Results

Conclusion