title: Contrasting signals of positive selection in genes involved in human skin-color variation from tests based on SNP scans and resequencing.
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), 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.
authors: Department of Forensic Molecular Biology, Erasmus MC University Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.|Netherlands Forensic Institute, Postbus 24044, The Hague, 2490 AA, The Netherlands.
authors: Johanna Maria
authors: JM
authors: de Gruijter
authors: Department of Forensic Molecular Biology, Erasmus MC University Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.
authors: Oscar
authors: O
authors: Lao
authors: Department of Forensic Molecular Biology, Erasmus MC University Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.
authors: Mark
authors: M
authors: Vermeulen
authors: Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors: Yali
authors: Y
authors: Xue
authors: Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors: Cara
authors: C
authors: Woodwark
authors: Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors: Christopher J
authors: CJ
authors: Gillson
authors: Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors: Alison J
authors: AJ
authors: Coffey
authors: Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors: Qasim
authors: Q
authors: Ayub
authors: Sindh Institute of Urology and Transplantation (SIUT) Karachi, Civil Hospital Karachi 74200, Pakistan.
authors: S Qasim
authors: SQ
authors: Mehdi
authors: Department of Forensic Molecular Biology, Erasmus MC University Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.
authors: Manfred
authors: M
authors: Kayser
authors: Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors: Chris
authors: C
authors: Tyler-Smith