Contrasting signals of positive selection in genes involved in human skin-color variation from tests based on SNP scans and resequencing

De, Lao Oscar, Vermeulen Mark, Xue Yali, Woodwark Cara, Gillson, Coffey, Ayub Qasim, Mehdi, Kayser Manfred, Tyler-Smith Chris

Description

Numerous genome-wide scans conducted by genotyping previously ascertained single-nucleotide polymorphisms (SNPs) have provided candidate signatures for positive selection in various regions of the human genome, including in genes involved in pigmentation traits. However, it is unclear how well the signatures discovered by such haplotype-based test statistics can be reproduced in tests based on full resequencing data. Four genes ( oculocutaneous albinism II ( OCA2 ) , tyrosinase-related protein 1 ( TYRP1 ) , dopachrome tautomerase ( DCT ), and KIT ligand ( KITLG )) implicated in human skin-color variation, have shown evidence for positive selection in Europeans and East Asians in previous SNP-scan data. In the current study, we resequenced 4.7 to 6.7 kb of DNA from each of these genes in Africans, Europeans, East Asians, and South Asians. Results Applying all commonly used neutrality-test statistics for allele frequency distribution to the newly generated sequence data provided conflicting results regarding evidence for positive selection. Previous haplotype-based findings could not be clearly confirmed. Although some tests were marginally significant for some populations and genes, none of them were significant after multiple-testing correction. Combined P values for each gene-population pair did not improve these results. Application of Approximate Bayesian Computation Markov chain Monte Carlo based to these sequence data using a simple forward simulator revealed broad posterior distributions of the selective parameters for all four genes, providing no support for positive selection. However, when we applied this approach to published sequence data on SLC45A2 , another human pigmentation candidate gene, we could readily confirm evidence for positive selection, as previously detected with sequence-based and some haplotype-based tests. Conclusions Overall, our data indicate that even genes that are strong biological candidates for positive selection and show reproducible signatures of positive selection in SNP scans do not always show the same replicability of selection signals in other tests, which should be considered in future studies on detecting positive selection in genetic data.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2011
• Nombre de lectures: 24
• Langue: English

Extrait

de Gruijteret al.Investigative Genetics2011,2:24 http://www.investigativegenetics.com/content/2/1/24

R E S E A R C HOpen Access Contrasting signals of positive selection in genes involved in human skincolor variation from tests based on SNP scans and resequencing 1,2†1*†1 33 3 Johanna Maria de Gruijter, Oscar Lao, Mark Vermeulen , Yali Xue , Cara Woodwark , Christopher J Gillson , 3 34 1†3† Alison J Coffey , Qasim Ayub , S Qasim Mehdi , Manfred Kayserand Chris TylerSmith

Abstract Background:Numerous genomewide scans conducted by genotyping previously ascertained singlenucleotide polymorphisms (SNPs) have provided candidate signatures for positive selection in various regions of the human genome, including in genes involved in pigmentation traits. However, it is unclear how well the signatures discovered by such haplotypebased test statistics can be reproduced in tests based on full resequencing data. Four genes (oculocutaneous albinism II(OCA2), tyrosinaserelated protein 1(TYRP1), dopachrome tautomerase(DCT), andKIT ligand(KITLG)) implicated in human skincolor variation, have shown evidence for positive selection in Europeans and East Asians in previous SNPscan data. In the current study, we resequenced 4.7 to 6.7 kb of DNA from each of these genes in Africans, Europeans, East Asians, and South Asians. Results:Applying all commonly used neutralitytest statistics for allele frequency distribution to the newly generated sequence data provided conflicting results regarding evidence for positive selection. Previous haplotype based findings could not be clearly confirmed. Although some tests were marginally significant for some populations and genes, none of them were significant after multipletesting correction. CombinedPvalues for each genepopulation pair did not improve these results. Application of Approximate Bayesian Computation Markov chain Monte Carlo based to these sequence data using a simple forward simulator revealed broad posterior distributions of the selective parameters for all four genes, providing no support for positive selection. However, when we applied this approach to published sequence data onSLC45A2, another human pigmentation candidate gene, we could readily confirm evidence for positive selection, as previously detected with sequence based and some haplotypebased tests. Conclusions:Overall, our data indicate that even genes that are strong biological candidates for positive selection and show reproducible signatures of positive selection in SNP scans do not always show the same replicability of selection signals in other tests, which should be considered in future studies on detecting positive selection in genetic data.

Background Largescale genotyping projects using genomewide sin glenucleotide polymorphisms (SNPs) have provided large amounts of data describing the genetic diversity of human populations [16]. Several statistical methods have been developed and used for detection of signatures

* Correspondence: [e-mail] †Contributed equally 1 Department of Forensic Molecular Biology, Erasmus MC University Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands Full list of author information is available at the end of the article

of selective processes from genomewide SNP data, which we refer to as‘SNP scans’[7]. All these approaches try to recover fingerprints of selective sweeps by detect ing signals in the haplotypic variation of a genomic region and/or the spectrum of the variation of the genetic diversity [815]. However, the results obtained with the different test statistics usually show limited overlap (see results from Voightet al. [12] Wanget al. [14] and Akey [16]), therefore, it would be desirable to compare the results from SNP haplotypebased tests using the‘gold standard’of full resequencing data and suitable statistical

© 2011 de Gruijter et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.