Exploring signatures of positive selection in pigmentation candidate genes in populations of East Asian ancestry

Jessica L Hider,Esteban J Parra,Rachel M Gittelman,Joshua M Akey,Melissa Edwards,Arnold Rosenbloom,Tapan Shah

doi:10.1186/1471-2148-13-150

Jessica L Hider, Esteban J Parra + Show 5 more

Open Access

https://doi.org/10.1186/1471-2148-13-150

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Abstract

BackgroundCurrently, there is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations. We carried out a genome-wide scan of signatures of positive selection using the 1000 Genomes Phase I dataset, in order to identify pigmentation genes showing putative signatures of selective sweeps in East Asia. We applied a broad range of methods to detect signatures of selection including: 1) Tests designed to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima’s D, Fay and Wu’s H and Fu and Li’s D* and F*), 2) Tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb) and 3) Tests based on genetic differentiation between populations (LSBL). Based on the results obtained from a genome wide analysis of 25 kb windows, we constructed an empirical distribution for each statistic across all windows, and identified pigmentation genes that are outliers in the distribution.ResultsOur tests identified twenty genes that are relevant for pigmentation biology. Of these, eight genes (ATRN, EDAR, KLHL7, MITF, OCA2, TH, TMEM33 and TRPM1,) were extreme outliers (top 0.1% of the empirical distribution) for at least one statistic, and twelve genes (ADAM17, BNC2, CTSD, DCT, EGFR, LYST, MC1R, MLPH, OPRM1, PDIA6, PMEL (SILV) and TYRP1) were in the top 1% of the empirical distribution for at least one statistic. Additionally, eight of these genes (BNC2, EGFR, LYST, MC1R, OCA2, OPRM1, PMEL (SILV) and TYRP1) have been associated with pigmentary traits in association studies.ConclusionsWe identified a number of putative pigmentation genes showing extremely unusual patterns of genetic variation in East Asia. Most of these genes are outliers for different tests and/or different populations, and have already been described in previous scans for positive selection, providing strong support to the hypothesis that recent selective sweeps left a signature in these regions. However, it will be necessary to carry out association and functional studies to demonstrate the implication of these genes in normal pigmentation variation.

Highlights

There is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations
We used three types of statistics: Statistics based on the Site Frequency Spectrum (SFS) (D, D*, F* and H), statistics based on genetic differentiation (LSBL) and long-range haplotype tests (See the Materials and Methods section for more details about each statistic)
Database in order to select genes that may potentially be involved in the pigmentation pathway. In addition to these extreme outliers, we explored if a list of genes that have been previously associated with pigmentary traits in association studies or reported as outliers in previous scans of positive selection in human populations were located in the top 1% of the empirical distributions

Summary

Introduction

There is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations. We applied a broad range of methods to detect signatures of selection including: 1) Tests designed to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima’s D, Fay and Wu’s H and Fu and Li’s D* and F*), 2) Tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb) and 3) Tests based on genetic differentiation between populations (LSBL). One of the climatic factors showing clear geographic patterns is ultraviolet (UV) radiation, which is more intense and shows less seasonality genes show signatures of selection that are shared between European and East Asian populations (e.g. KITLG) [12,18] many genes show positive selection signals in only one population (e.g. SLC24A5 and SLC45A2 in Europe, DCT in East Asia) or independent signals in European and East Asian groups (OCA2) These findings support an evolutionary model in which the most important changes in pigmentary traits occurred after the migration out-of-Africa and the separation of the lineages that gave rise to contemporary European and East Asian populations [5,12,22,23,24,25]. By identifying pigmentation genes showing putative signatures of selective sweeps in East Asia, we will be able to prioritize a list of genes for subsequent association studies in East Asian samples characterized with quantitative methods (e.g. skin reflectometry)

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