Worldwide Distribution of the MYH9 Kidney Disease Susceptibility Alleles and Haplotypes: Evidence of Historical Selection in Africa

MYH9 was recently identified as renal susceptibility gene (OR 3–8, p<10−8) for major forms of kidney disease disproportionately affecting individuals of African descent. The risk haplotype (E-1) occurs at much higher frequencies in African Americans (≥60%) than in European Americans (<4%), revealing a genetic basis for a major health disparity. The population distributions of MYH9 risk alleles and the E-1 risk haplotype and the demographic and selective forces acting on the MYH9 region are not well explored. We reconstructed MYH9 haplotypes from 4 tagging single nucleotide polymorphisms (SNPs) spanning introns 12–23 using available data from HapMap Phase II, and by genotyping 938 DNAs from the Human Genome Diversity Panel (HGDP). The E-1 risk haplotype followed a cline, being most frequent within sub-Saharan African populations (range 50–80%), less frequent in populations from the Middle East (9–27%) and Europe (0–9%), and rare or absent in Asia, the Americas, and Oceania. The fixation indexes (FST) for pairwise comparisons between the risk haplotypes for continental populations were calculated for MYH9 haplotypes; FST ranged from 0.27–0.40 for Africa compared to other continental populations, possibly due to selection. Uniquely in Africa, the Yoruba population showed high frequency extended haplotype length around the core risk allele (C) compared to the alternative allele (T) at the same locus (rs4821481, iHs = 2.67), as well as high population differentiation (FST(CEU vs. YRI) = 0.51) in HapMap Phase II data, also observable only in the Yoruba population from HGDP (FST = 0.49), pointing to an instance of recent selection in the genomic region. The population-specific divergence in MYH9 risk allele frequencies among the world's populations may prove important in risk assessment and public health policies to mitigate the burden of kidney disease in vulnerable populations

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

A global reference for human genetic variation

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.We thank the many people who were generous with contributing their samples to the project: the African Caribbean in Barbados; Bengali in Bangladesh; British in England and Scotland; Chinese Dai in Xishuangbanna, China; Colombians in Medellin, Colombia; Esan in Nigeria; Finnish in Finland; Gambian in Western Division – Mandinka; Gujarati Indians in Houston, Texas, USA; Han Chinese in Beijing, China; Iberian populations in Spain; Indian Telugu in the UK; Japanese in Tokyo, Japan; Kinh in Ho Chi Minh City, Vietnam; Luhya in Webuye, Kenya; Mende in Sierra Leone; people with African ancestry in the southwest USA; people with Mexican ancestry in Los Angeles, California, USA; Peruvians in Lima, Peru; Puerto Ricans in Puerto Rico; Punjabi in Lahore, Pakistan; southern Han Chinese; Sri Lankan Tamil in the UK; Toscani in Italia; Utah residents (CEPH) with northern and western European ancestry; and Yoruba in Ibadan, Nigeria. Many thanks to the people who contributed to this project: P. Maul, T. Maul, and C. Foster; Z. Chong, X. Fan, W. Zhou, and T. Chen; N. Sengamalay, S. Ott, L. Sadzewicz, J. Liu, and L. Tallon; L. Merson; O. Folarin, D. Asogun, O. Ikpwonmosa, E. Philomena, G. Akpede, S. Okhobgenin, and O. Omoniwa; the staff of the Institute of Lassa Fever Research and Control (ILFRC), Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria; A. Schlattl and T. Zichner; S. Lewis, E. Appelbaum, and L. Fulton; A. Yurovsky and I. Padioleau; N. Kaelin and F. Laplace; E. Drury and H. Arbery; A. Naranjo, M. Victoria Parra, and C. Duque; S. Däkel, B. Lenz, and S. Schrinner; S. Bumpstead; and C. Fletcher-Hoppe. Funding for this work was from the Wellcome Trust Core Award 090532/Z/09/Z and Senior Investigator Award 095552/Z/11/Z (P.D.), and grants WT098051 (R.D.), WT095908 and WT109497 (P.F.), WT086084/Z/08/Z and WT100956/Z/13/Z (G.M.), WT097307 (W.K.), WT0855322/Z/08/Z (R.L.), WT090770/Z/09/Z (D.K.), the Wellcome Trust Major Overseas program in Vietnam grant 089276/Z.09/Z (S.D.), the Medical Research Council UK grant G0801823 (J.L.M.), the UK Biotechnology and Biological Sciences Research Council grants BB/I02593X/1 (G.M.) and BB/I021213/1 (A.R.L.), the British Heart Foundation (C.A.A.), the Monument Trust (J.H.), the European Molecular Biology Laboratory (P.F.), the European Research Council grant 617306 (J.L.M.), the Chinese 863 Program 2012AA02A201, the National Basic Research program of China 973 program no. 2011CB809201, 2011CB809202 and 2011CB809203, Natural Science Foundation of China 31161130357, the Shenzhen Municipal Government of China grant ZYC201105170397A (J.W.), the Canadian Institutes of Health Research Operating grant 136855 and Canada Research Chair (S.G.), Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research (M.K.D.), a Le Fonds de Recherche duQuébec-Santé (FRQS) research fellowship (A.H.), Genome Quebec (P.A.), the Ontario Ministry of Research and Innovation – Ontario Institute for Cancer Research Investigator Award (P.A., J.S.), the Quebec Ministry of Economic Development, Innovation, and Exports grant PSR-SIIRI-195 (P.A.), the German Federal Ministry of Education and Research (BMBF) grants 0315428A and 01GS08201 (R.H.), the Max Planck Society (H.L., G.M., R.S.), BMBF-EPITREAT grant 0316190A (R.H., M.L.), the German Research Foundation (Deutsche Forschungsgemeinschaft) Emmy Noether Grant KO4037/1-1 (J.O.K.), the Beatriu de Pinos Program grants 2006 BP-A 10144 and 2009 BP-B 00274 (M.V.), the Spanish National Institute for Health Research grant PRB2 IPT13/0001-ISCIII-SGEFI/FEDER (A.O.), Ewha Womans University (C.L.), the Japan Society for the Promotion of Science Fellowship number PE13075 (N.P.), the Louis Jeantet Foundation (E.T.D.), the Marie Curie Actions Career Integration grant 303772 (C.A.), the Swiss National Science Foundation 31003A_130342 and NCCR “Frontiers in Genetics” (E.T.D.), the University of Geneva (E.T.D., T.L., G.M.), the US National Institutes of Health National Center for Biotechnology Information (S.S.) and grants U54HG3067 (E.S.L.), U54HG3273 and U01HG5211 (R.A.G.), U54HG3079 (R.K.W., E.R.M.), R01HG2898 (S.E.D.), R01HG2385 (E.E.E.), RC2HG5552 and U01HG6513 (G.T.M., G.R.A.), U01HG5214 (A.C.), U01HG5715 (C.D.B.), U01HG5718 (M.G.), U01HG5728 (Y.X.F.), U41HG7635 (R.K.W., E.E.E., P.H.S.), U41HG7497 (C.L., M.A.B., K.C., L.D., E.E.E., M.G., J.O.K., G.T.M., S.A.M., R.E.M., J.L.S., K.Y.), R01HG4960 and R01HG5701 (B.L.B.), R01HG5214 (G.A.), R01HG6855 (S.M.), R01HG7068 (R.E.M.), R01HG7644 (R.D.H.), DP2OD6514 (P.S.), DP5OD9154 (J.K.), R01CA166661 (S.E.D.), R01CA172652 (K.C.), P01GM99568 (S.R.B.), R01GM59290 (L.B.J., M.A.B.), R01GM104390 (L.B.J., M.Y.Y.), T32GM7790 (C.D.B., A.R.M.), P01GM99568 (S.R.B.), R01HL87699 and R01HL104608 (K.C.B.), T32HL94284 (J.L.R.F.), and contracts HHSN268201100040C (A.M.R.) and HHSN272201000025C (P.S.), Harvard Medical School Eleanor and Miles Shore Fellowship (K.L.), Lundbeck Foundation Grant R170-2014-1039 (K.L.), NIJ Grant 2014-DN-BX-K089 (Y.E.), the Mary Beryl Patch Turnbull Scholar Program (K.C.B.), NSF Graduate Research Fellowship DGE-1147470 (G.D.P.), the Simons Foundation SFARI award SF51 (M.W.), and a Sloan Foundation Fellowship (R.D.H.). E.E.E. is an investigator of the Howard Hughes Medical Institute

Private sector engagement in refugee education

The involvement of the private sector in providing education for Syrian refugees has much to commend it but greater consideration needs to be paid to the ethical and practical concerns that may arise