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1. Population-scale proteome variation in human induced pluripotent stem cells

Author

Mirauta, Bogdan Andrei, Seaton, Daniel D, Bensaddek, Dalila, Brenes, Alejandro, Bonder, Marc Jan, Kilpinen, Helena, Agu, Chukwuma A, Alderton, Alex, Danecek, Petr, Denton, Rachel, Durbin, Richard, Gaffney, Daniel J, Goncalves, Angela, Halai, Reena, Harper, Sarah, Kirton, Christopher M, Kolb-Kokocinski, Anja, Leha, Andreas, McCarthy, Shane A, Memari, Yasin, Patel, Minal, Birney, Ewan, Casale, Francesco Paolo, Clarke, Laura, Harrison, Peter W, Streeter, Ian, Denovi, Davide, Stegle, Oliver, Lamond, Angus I, Meleckyte, Ruta, Moens, Natalie, Watt, Fiona M, Ouwehand, Willem H, Beales, Philip, Mirauta, Bogdan Andrei [0000-0002-9733-292X], Bonder, Marc Jan [0000-0002-8431-3180], Kilpinen, Helena [0000-0001-6692-6154], Stegle, Oliver [0000-0002-8818-7193], Lamond, Angus I [0000-0001-6204-6045], Apollo - University of Cambridge Repository, and Helsinki Institute of Life Science HiLIFE

Subjects
Male, Proteomics, Proteome, Genome-wide association study, VARIANTS, Transcriptome, 0302 clinical medicine, SCHIZOPHRENIA, Human proteome project, genetics, Disease, Biology (General), Induced pluripotent stem cell, Child, GENE-EXPRESSION, 0303 health sciences, education.field_of_study, Drug discovery, General Neuroscience, General Medicine, Middle Aged, Phenotype, Child, Preschool, Medicine, ABUNDANCE, Female, Research Article, Adult, Adolescent, Genotype, QH301-705.5, induced pluripotent stem cells, Science, Population, Quantitative Trait Loci, deleterious variants, Genomics, Computational biology, Quantitative trait locus, Biology, General Biochemistry, Genetics and Molecular Biology, DIFFERENTIAL EXPRESSION, 03 medical and health sciences, Young Adult, RESOURCE, REVEALS, genomics, Humans, human, RNA, Messenger, education, 030304 developmental biology, Aged, IDENTIFICATION, General Immunology and Microbiology, Infant, Newborn, Genetic Variation, Infant, Genetics and Genomics, QUANTIFICATION, Genetics, Population, REGULATORY VARIATION, 3111 Biomedicine, 030217 neurology & neurosurgery
Abstract

Human disease phenotypes are driven primarily by alterations in protein expression and/or function. To date, relatively little is known about the variability of the human proteome in populations and how this relates to variability in mRNA expression and to disease loci. Here, we present the first comprehensive proteomic analysis of human induced pluripotent stem cells (iPSC), a key cell type for disease modelling, analysing 202 iPSC lines derived from 151 donors, with integrated transcriptome and genomic sequence data from the same lines. We characterised the major genetic and non-genetic determinants of proteome variation across iPSC lines and assessed key regulatory mechanisms affecting variation in protein abundance. We identified 654 protein quantitative trait loci (pQTLs) in iPSCs, including disease-linked variants in protein-coding sequences and variants with trans regulatory effects. These include pQTL linked to GWAS variants that cannot be detected at the mRNA level, highlighting the utility of dissecting pQTL at peptide level resolution.

Published
2020

2. Narrow-sense heritability estimation of complex traits using identity-by-descent information

Author

Evans, Luke M., Tahmasbi, Rasool, Jones, Matthew, Vrieze, Scott I., Abecasis, Gonçalo R., Das, Sayantan, Bjelland, Doug W., deCandia, Teresa R., Abecasis, Gonçalo, Altshuler, David, Anderson, Carl A, Angius, Andrea, Barrett, Jeffrey C, Berndt, Sonja, Boehnke, Michael, Boomsma, Dorrett, Branham, Kari, Breen, Gerome, Brummett, Chad M, Busonero, Fabio, Campbell, Harry, Campbell, Peter, Chan, Andrew, Chen, Sai, Chew, Emily, Cocca, Massimiliano, Collins, Francis S, Corbin, Laura J, Cucca, Francesco, Danecek, Petr, de Bakker, Paul I W, Dedoussis, George, Dekker, Annelot, Delaneau, Olivier, Dorr, Marcus, Durbin, Richard, Farmaki, Aliki-Eleni, Ferrucci, Luigi, Forer, Lukas, Fraser, Ross M, Frayling, Timothy, Fuchsberger, Christian, Gabriel, Stacey, Gandin, Ilaria, Gasparini, Paolo, Gillies, Christopher E, Gilly, Arthur, Groop, Leif, Harrison, Tabitha, Hattersley, Andrew, Holmen, Oddgeir L, Hveem, Kristian, Iacono, William, Joshi, Amit, Kang, Hyun Min, Khalili, Hamed, Kooperberg, Charles, Koskinen, Seppo, Kretzler, Matthias, Kretzschmar, Warren, Kwong, Alan, Lee, James C, Levy, Shawn, Luo, Yang, Mahajan, Anubha, Marchini, Jonathan, McCarroll, Steven, McCarthy, Mark I, McCarthy, Shane, McGue, Matt, McInnis, Melvin, Meitinger, Thomas, Melzer, David, Mezzavilla, Massimo, Min, Josine L, Mohlke, Karen L, Myers, Richard M, Nauck, Matthias, Nickerson, Deborah, Palotie, Aarno, Pato, Carlos, Pato, Michele, Peters, Ulrike, Pirastu, Nicola, Rheenen, Wouter Van, Richards, J Brent, Ripatti, Samuli, Sala, Cinzia, Salomaa, Veikko, Sampson, Matthew G, Schlessinger, David, Schoen, Robert E, Schoenherr, Sebastian, Scott, Laura J, Sharp, Kevin, Sidore, Carlo, Slagboom, P Eline, Small, Kerrin, Smith, George Davey, Soranzo, Nicole, Spector, Timothy, Stambolian, Dwight, Swaroop, Anand, Swertz, Morris A, Teumer, Alexander, Timpson, Nicholas, Toniolo, Daniela, Traglia, Michela, Tuke, Marcus, Tuomilehto, Jaakko, den Berg, Leonard H Van, van Duijn, Cornelia M, Veldink, Jan, Vincent, John B, Volker, Uwe, Vrieze, Scott, Walter, Klaudia, Wijmenga, Cisca, Willer, Cristen, Wilson, James F, Wood, Andrew R, Zeggini, Eleftheria, Zhang, He, Yang, Jian, Goddard, Michael E., Visscher, Peter M., and Keller, Matthew C.

Subjects
0301 basic medicine, Genome-wide association study, Biology, Population stratification, Genetic correlation, Polymorphism, Single Nucleotide, Identity by descent, Article, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Missing heritability problem, Genetic variation, Genetics, Chromosomes, Human, Humans, Human height, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Genome, Human, Heritability, Twin study, Minor allele frequency, Phenotype, 030104 developmental biology, Haplotypes, Evolutionary biology, Trait, 030217 neurology & neurosurgery
Abstract

Heritability is a fundamental parameter in genetics. Traditional estimates based on family or twin studies can be biased due to shared environmental or non-additive genetic variance. Alternatively, those based on genotyped or imputed variants typically underestimate narrow-sense heritability contributed by rare or otherwise poorly tagged causal variants. Identical-by-descent (IBD) segments of the genome share all variants between pairs of chromosomes except new mutations that have arisen since the last common ancestor. Therefore, relating phenotypic similarity to degree of IBD sharing among classically unrelated individuals is an appealing approach to estimating the near full additive genetic variance while possibly avoiding biases that can occur when modeling close relatives. We applied an IBD-based approach (GREML-IBD) to estimate heritability in unrelated individuals using phenotypic simulation with thousands of whole-genome sequences across a range of stratification, polygenicity levels, and the minor allele frequencies of causal variants (CVs). In simulations, the IBD-based approach produced unbiased heritability estimates, even when CVs were extremely rare, although precision was low. However, population stratification and non-genetic familial environmental effects shared across generations led to strong biases in IBD-based heritability. We used data on two traits in ~120,000 people from the UK Biobank to demonstrate that, depending on the trait and possible confounding environmental effects, GREML-IBD can be applied to very large genetic datasets to infer the contribution of very rare variants lost using other methods. However, we observed apparent biases in these real data, suggesting that more work may be required to understand and mitigate factors that influence IBD-based heritability estimates.

Published
2018

3. A map of human genome variation from population-scale sequencing

Author

Durbin, Richard M., Altshuler, David L., Abecasis, Gonçalo R., Bentley, David R., Chakravarti, Aravinda, Clark, Andrew G., Collins, Francis S., De La Vega, Francisco M., Donnelly, Peter, Egholm, Michael, Flicek, Paul, Gabriel, Stacey B., Gibbs, Richard A., Knoppers, Bartha M., Lander, Eric S., Lehrach, Hans, Mardis, Elaine R., McVean, Gil A., Nickerson, Debbie A., Peltonen, Leena, Schafer, Alan J., Sherry, Stephen T., Wang, Jun, Wilson, Richard K., Deiros, David, Metzker, Mike, Muzny, Donna, Reid, Jeff, Wheeler, David, Li, Jingxiang, Jian, Min, Li, Guoqing, Li, Ruiqiang, Liang, Huiqing, Tian, Geng, Wang, Bo, Wang, Jian, Wang, Wei, Yang, Huanming, Zhang, Xiuqing, Zheng, Huisong, Ambrogio, Lauren, Bloom, Toby, Cibulskis, Kristian, Fennell, Tim J., Jaffe, David B., Shefler, Erica, Sougnez, Carrie L., Gormley, Niall, Humphray, Sean, Kingsbury, Zoya, Koko-Gonzales, Paula, Stone, Jennifer, McKernan, Kevin J., Costa, Gina L., Ichikawa, Jeffry K., Lee, Clarence C., Sudbrak, Ralf, Borodina, Tatiana A., Dahl, Andreas, Davydov, Alexey N., Marquardt, Peter, Mertes, Florian, Nietfeld, Wilfiried, Rosenstiel, Philip, Schreiber, Stefan, Soldatov, Aleksey V., Timmermann, Bernd, Tolzmann, Marius, Affourtit, Jason, Ashworth, Dana, Attiya, Said, Bachorski, Melissa, Buglione, Eli, Burke, Adam, Caprio, Amanda, Celone, Christopher, Clark, Shauna, Conners, David, Desany, Brian, Gu, Lisa, Guccione, Lorri, Kao, Kalvin, Kebbel, Andrew, Knowlton, Jennifer, Labrecque, Matthew, McDade, Louise, Mealmaker, Craig, Minderman, Melissa, Nawrocki, Anne, Niazi, Faheem, Pareja, Kristen, Ramenani, Ravi, Riches, David, Song, Wanmin, Turcotte, Cynthia, Wang, Shally, Dooling, David, Fulton, Lucinda, Fulton, Robert, Weinstock, George, Burton, John, Carter, David M., Churcher, Carol, Coffey, Alison, Cox, Anthony, Palotie, Aarno, Quail, Michael, Skelly, Tom, Stalker, James, Swerdlow, Harold P., Turner, Daniel, De Witte, Anniek, Giles, Shane, Bainbridge, Matthew, Challis, Danny, Sabo, Aniko, Yu, Fuli, Yu, Jin, Fang, Xiaodong, Guo, Xiaosen, Li, Yingrui, Luo, Ruibang, Tai, Shuaishuai, Wu, Honglong, Zheng, Hancheng, Zheng, Xiaole, Zhou, Yan, Marth, Gabor T., Garrison, Erik P., Huang, Weichun, Indap, Amit, Kural, Deniz, Lee, Wan-Ping, Fung Leong, Wen, Quinlan, Aaron R., Stewart, Chip, Stromberg, Michael P., Ward, Alistair N., Wu, Jiantao, Lee, Charles, Mills, Ryan E., Shi, Xinghua, Daly, Mark J., DePristo, Mark A., Ball, Aaron D., Banks, Eric, Browning, Brian L., Garimella, Kiran V., Grossman, Sharon R., Handsaker, Robert E., Hanna, Matt, Hartl, Chris, Kernytsky, Andrew M., Korn, Joshua M., Li, Heng, Maguire, Jared R., McCarroll, Steven A., McKenna, Aaron, Nemesh, James C., Philippakis, Anthony A., Poplin, Ryan E., Price, Alkes, Rivas, Manuel A., Sabeti, Pardis C., Schaffner, Stephen F., Shlyakhter, Ilya A., Cooper, David N., Ball, Edward V., Mort, Matthew, Phillips, Andrew D., Stenson, Peter D., Sebat, Jonathan, Makarov, Vladimir, Ye, Kenny, Yoon, Seungtai C., Bustamante, Carlos D., Boyko, Adam, Degenhardt, Jeremiah, Gravel, Simon, Gutenkunst, Ryan N., Kaganovich, Mark, Keinan, Alon, Lacroute, Phil, Ma, Xin, Reynolds, Andy, Clarke, Laura, Cunningham, Fiona, Herrero, Javier, Keenen, Stephen, Kulesha, Eugene, Leinonen, Rasko, McLaren, William M., Radhakrishnan, Rajesh, Smith, Richard E., Zalunin, Vadim, Zheng-Bradley, Xiangqun, Korbel, Jan O., Stütz, Adrian M., Bauer, Markus, Keira Cheetham, R., Cox, Tony, Eberle, Michael, James, Terena, Kahn, Scott, Murray, Lisa, Ye, Kai, Fu, Yutao, Hyland, Fiona C. L., Manning, Jonathan M., McLaughlin, Stephen F., Peckham, Heather E., Sakarya, Onur, Sun, Yongming A., Tsung, Eric F., Batzer, Mark A., Konkel, Miriam K., Walker, Jerilyn A., Albrecht, Marcus W., Amstislavskiy, Vyacheslav S., Herwig, Ralf, Parkhomchuk, Dimitri V., Agarwala, Richa, Khouri, Hoda M., Morgulis, Aleksandr O., Paschall, Justin E., Phan, Lon D., Rotmistrovsky, Kirill E., Sanders, Robert D., Shumway, Martin F., Xiao, Chunlin, Auton, Adam, Iqbal, Zamin, Lunter, Gerton, Marchini, Jonathan L., Moutsianas, Loukas, Myers, Simon, Tumian, Afidalina, Knight, James, Winer, Roger, Craig, David W., Beckstrom-Sternberg, Steve M., Christoforides, Alexis, Kurdoglu, Ahmet A., Pearson, John V., Sinari, Shripad A., Tembe, Waibhav D., Haussler, David, Hinrichs, Angie S., Katzman, Sol J., Kern, Andrew, Kuhn, Robert M., Przeworski, Molly, Hernandez, Ryan D., Howie, Bryan, Kelley, Joanna L., Cord Melton, S., Li, Yun, Anderson, Paul, Blackwell, Tom, Chen, Wei, Cookson, William O., Ding, Jun, Min Kang, Hyun, Lathrop, Mark, Liang, Liming, Moffatt, Miriam F., Scheet, Paul, Sidore, Carlo, Snyder, Matthew, Zhan, Xiaowei, Zöllner, Sebastian, Awadalla, Philip, Casals, Ferran, Idaghdour, Youssef, Keebler, John, Stone, Eric A., Zilversmit, Martine, Jorde, Lynn, Xing, Jinchuan, Eichler, Evan E., Aksay, Gozde, Alkan, Can, Hajirasouliha, Iman, Hormozdiari, Fereydoun, Kidd, Jeffrey M., Cenk Sahinalp, S., Sudmant, Peter H., Chen, Ken, Chinwalla, Asif, Ding, Li, Koboldt, Daniel C., McLellan, Mike D., Wallis, John W., Wendl, Michael C., Zhang, Qunyuan, Albers, Cornelis A., Ayub, Qasim, Balasubramaniam, Senduran, Barrett, Jeffrey C., Chen, Yuan, Conrad, Donald F., Danecek, Petr, Dermitzakis, Emmanouil T., Hu, Min, Huang, Ni, Hurles, Matt E., Jin, Hanjun, Jostins, Luke, Keane, Thomas M., Quang Le, Si, Lindsay, Sarah, Long, Quan, MacArthur, Daniel G., Montgomery, Stephen B., Parts, Leopold, Tyler-Smith, Chris, Walter, Klaudia, Zhang, Yujun, Gerstein, Mark B., Snyder, Michael, Abyzov, Alexej, Balasubramanian, Suganthi, Bjornson, Robert, Du, Jiang, Grubert, Fabian, Habegger, Lukas, Haraksingh, Rajini, Jee, Justin, Khurana, Ekta, Lam, Hugo Y. K., Leng, Jing, Jasmine Mu, Xinmeng, Urban, Alexander E., Zhang, Zhengdong, Coafra, Cristian, Dinh, Huyen, Kovar, Christie, Lee, Sandy, Nazareth, Lynne, Wilkinson, Jane, Coffey, Allison, Scott, Carol, Gharani, Neda, Kaye, Jane S., Kent, Alastair, Li, Taosha, McGuire, Amy L., Ossorio, Pilar N., Rotimi, Charles N., Su, Yeyang, Toji, Lorraine H., Brooks, Lisa D., Felsenfeld, Adam L., McEwen, Jean E., Abdallah, Assya, Juenger, Christopher R., Clemm, Nicholas C., Duncanson, Audrey, Green, Eric D., Guyer, Mark S., Peterson, Jane L., The Wellcome Trust Sanger Institute [Cambridge], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Michigan [Ann Arbor], University of Michigan System, The 1000 Genomes Project Consortium, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Altshuler, David, Daly, Mark J., Grossman, Sharon Rachel, Jaffe, David B., Korn, Joshua M., and Dermitzakis, Emmanouil

Subjects
Male, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Pilot Projects, Chromosomes, Human, Y/genetics, DNA, Mitochondrial/genetics, 0302 clinical medicine, ddc:576.5, 2. Zero hunger, Genetics, Recombination, Genetic, 0303 health sciences, Multidisciplinary, Genetics, Population/methods, Genomics, Polymorphism, Single Nucleotide/genetics, Recombination, Genetic/genetics, 3. Good health, Genetic Variation/genetics, Sequence Analysis, DNA/methods, Calibration, Female, Mutation/genetics, Genotype, Haplotypes/genetics, Biology, Instability, DNA, Mitochondrial, Polymorphism, Single Nucleotide, Article, Selection, Genetic/genetics, Factor (chord), Evolution, Molecular, 03 medical and health sciences, Table (landform), Humans, Selection, Genetic, Genetic Association Studies, 030304 developmental biology, Genotype imputation, Chromosomes, Human, Y, Genome, Human, Computational Biology, Genetic Variation, Sequence Analysis, DNA, Genomics/methods, Genetics, Population, Haplotypes, Sample Size, wide association gene-expression recombination hotspots meiotic recombination genotype imputation rare variants haplotype map nucleotide diseases common, Mutation, Genome, Human/genetics, Trinucleotide repeat expansion, Sequence Alignment, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

April 1, 2011, The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother–father–child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10[superscript −8] per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research., Ministry of Science and Technology of the People's Republic of China (973 program no. 2011CB809200), National Natural Science Foundation (China) (30725008), National Natural Science Foundation (China) (30890032), National Natural Science Foundation (China) (30811130531), National Natural Science Foundation (China) (30221004), China (Chinese 863 program 2006AA02Z177), China (Chinese 863 program 2006AA02Z334), China (Chinese 863 program 2006AA02A302), China (Chinese 863 program 2009AA022707), National Institutes of Health (U.S.) (Grant U54HG2750), National Institutes of Health (U.S.) (Grant U01HG5208), National Institutes of Health (U.S.) (Grant U54HG3067)

Published
2010

4. Insights into human genetic variation and population history from 929 diverse genomes

Author

Howard M. Cann, Shane A. McCarthy, Chris Tyler-Smith, David Reich, Aylwyn Scally, Qasim Ayub, Pontus Skoglund, Petr Danecek, Jean-François Deleuze, Manjinder S. Sandhu, Pille Hallast, Ruoyun Hui, Yuan Chen, Swapan Mallick, Yali Xue, Sabine Felkel, Anders Bergström, Hélène Blanché, Mohamed A. Almarri, Jack Kamm, Richard Durbin, Bergström, Anders [0000-0002-4096-9268], McCarthy, Shane A [0000-0002-2715-4187], Hui, Ruoyun [0000-0002-5689-7131], Almarri, Mohamed A [0000-0003-1255-0918], Ayub, Qasim [0000-0003-3291-0917], Danecek, Petr [0000-0002-4159-1666], Felkel, Sabine [0000-0001-8935-8305], Hallast, Pille [0000-0002-0588-3987], Kamm, Jack [0000-0003-2412-756X], Blanché, Hélène [0000-0003-2115-575X], Deleuze, Jean-François [0000-0002-5358-4463], Mallick, Swapan [0000-0002-4531-4439], Reich, David [0000-0002-7037-5292], Skoglund, Pontus [0000-0002-3021-5913], Scally, Aylwyn [0000-0002-0807-1167], Durbin, Richard [0000-0002-9130-1006], Tyler-Smith, Chris [0000-0002-6492-5403], and Apollo - University of Cambridge Repository

Subjects
Neanderthal, Population structure, Human genetic variation, Genome, 0302 clinical medicine, INDEL Mutation, Genetics (clinical), health care economics and organizations, Phylogeny, Neanderthals, 0303 health sciences, education.field_of_study, Multidisciplinary, Population size, 030305 genetics & heredity, Hominidae, 3. Good health, Asia, DNA Copy Number Variations, Population, education, Oceania, Genome, Viral, Biology, Polymorphism, Single Nucleotide, DNA sequencing, Article, 03 medical and health sciences, biology.animal, Genetic variation, Genetics, Population growth, Animals, Humans, Molecular Biology, Denisovan, 030304 developmental biology, Whole genome sequencing, Population Density, Whole Genome Sequencing, Genome, Human, Racial Groups, Central africa, Genetic Variation, 15. Life on land, biology.organism_classification, Genetics, Population, Haplotypes, Evolutionary biology, Africa, Human genome, Americas, Genome, Bacterial, 030217 neurology & neurosurgery
Abstract

INTRODUCTION: Large-scale human genome sequencing studies to date have been limited to large, metropolitan populations or to small numbers of genomes from each group. Much remains to be understood about the extent and structure of genetic variation in our species and how it was shaped by past population separations, admixture, adaptation, size changes, and gene flow from archaic human groups. Larger numbers of genome sequences from more diverse populations are needed to illuminate these questions. RATIONALE: We sequence 929 genomes from 54 geographically, linguistically and culturally diverse human populations to an average of 35x coverage, and analyze the variation among them. We also physically resolve the haplotype phase of 26 of these genomes using linked-read sequencing. RESULTS: We identify 67.3 million single-nucleotide polymorphisms (SNPs), 8.8 million small insertions or deletions (indels) and 40,736 copy number variants (CNVs). This includes hundreds of thousands of variants that had not been discovered by previous sequencing efforts but which are common in one or more population. We demonstrate benefits to the study of population relationships of genome sequences over ascertained array genotypes, particularly when involving African populations. Populations in central and southern Africa, the Americas and Oceania each harbour tens to hundreds of thousands of private, common genetic variants. The majority of these variants arose as novel mutations rather than through archaic introgression, except in Oceanian populations where many private variants derive from Denisovan admixture. While some reach high frequencies, no variants are fixed between major geographical regions. We estimate that the genetic separation between present-day human populations occurred mostly within the last 250,000 years. However, these early separations were gradual in nature and shaped by protracted gene flow. All populations thus still had some genetic contact more recently than this, but there is also evidence that a small fraction of present-day structure might be hundreds of thousands of years older. Most populations expanded in size over the last 10,000 years, but hunter-gatherer groups did not. The low diversity among the Neanderthal haplotypes segregating in present-day populations indicates that, while more than one Neanderthal individual must have contributed genetic material to modern humans, there was likely only one major episode of admixture. In contrast, Denisovan haplotype diversity reflects a more complex history involving more than one episode of admixture. We find small amounts of Neanderthal ancestry in West African genomes, most likely reflecting Eurasian admixture. Despite their very low levels or absence of archaic ancestry, African populations share many Neanderthal and Denisovan variants that are absent from Eurasia, reflecting how a larger proportion of the ancestral human variation has been maintained in Africa. CONCLUSION: The discovery of substantial amounts of common genetic variation that was previously undocumented, and is geographically restricted, highlights the continued value of anthropologically informed study designs for understanding human diversity. The genome sequences presented here are a freely available resource with relevance to population history, medical genetics, anthropology and linguistics. [Figure: see text]

Published
2020

5. A reference panel of 64,976 haplotypes for genotype imputation

Author

Steven A. McCarroll, Gerome Breen, Nicole Soranzo, Sayantan Das, Ilaria Gandin, Lukas Forer, David Schlessinger, Jonathan Marchini, Francesco Cucca, Anand Swaroop, Seppo Koskinen, Aliki-Eleni Farmaki, Alan Kwong, Gonçalo R. Abecasis, Marcus Dörr, Yang Luo, Andrew T. Chan, Andrea Angius, P. Eline Slagboom, Petr Danecek, Cinzia Sala, Ulrike Peters, Marcus A. Tuke, D.I. Boomsma, Jan H. Veldink, Nicholas J. Timpson, Scott I. Vrieze, Aarno Palotie, Matt McGue, Wouter van Rheenen, Melvin G. McInnis, Shawn Levy, George Dedoussis, Richard Durbin, Matthias Kretzler, Ross M. Fraser, C Sidore, David Melzer, Eleftheria Zeggini, Andrew R. Wood, Veikko Salomaa, Oddgeir L. Holmen, Alexander Teumer, Hyun Min Kang, James F. Wilson, Cristen J. Willer, Laura J. Scott, Richard M. Myers, George Davey Smith, Andrew T. Hattersley, Matthias Nauck, Matthew G. Sampson, Christian Fuchsberger, Josine L. Min, Leonard H. van den Berg, Thomas Meitinger, David Altshuler, John B. Vincent, Kevin Sharp, Jaakko Tuomilehto, Daniela Toniolo, Cornelia M. van Duijn, Samuli Ripatti, Stacey Gabriel, Michael Boehnke, Annelot M. Dekker, Francis S. Collins, He Zhang, Klaudia Walter, Deborah A. Nickerson, Nicola Pirastu, Morris A. Swertz, Kari Branham, Luigi Ferrucci, Sai Chen, Fabio Busonero, Paul I.W. de Bakker, Kristian Hveem, Charles Kooperberg, Michela Traglia, Warren W. Kretzschmar, Leif Groop, Tabitha A. Harrison, Sebastian Schoenherr, J. Brent Richards, Uwe Völker, Shane A. McCarthy, Harry Campbell, Massimo Mezzavilla, Chad M. Brummett, Mark I. McCarthy, Tim D. Spector, Dwight Stambolian, Massimiliano Cocca, Emily Y. Chew, Carlos N. Pato, Jeffrey C. Barrett, Christopher E. Gillies, William G. Iacono, Karen L. Mohlke, Olivier Delaneau, Laura J Corbin, Cisca Wijmenga, Anubha Mahajan, Timothy M. Frayling, James Lee, Michele T. Pato, Carl A. Anderson, Arthur Gilly, Kerrin S. Small, Paolo Gasparini, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, McCarthy, Shane [0000-0002-2715-4187], Das, Sayantan [0000-0001-6346-1590], Kretzschmar, Warren [0000-0002-2575-0807], Durbin, Richard [0000-0002-9130-1006], Apollo - University of Cambridge Repository, Epidemiology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Mccarthy, Shane, Das, Sayantan, Kretzschmar, Warren, Delaneau, Olivier, Wood, Andrew R, Teumer, Alexander, Kang, Hyun Min, Fuchsberger, Christian, Danecek, Petr, Sharp, Kevin, Luo, Yang, Sidore, Carlo, Kwong, Alan, Timpson, Nichola, Koskinen, Seppo, Vrieze, Scott, Scott, Laura J, Zhang, He, Mahajan, Anubha, Veldink, Jan, Peters, Ulrike, Pato, Carlo, van Duijn, Cornelia M, Gillies, Christopher E, Gandin, Ilaria, Mezzavilla, Massimo, Gilly, Arthur, Cocca, Massimiliano, Traglia, Michela, Angius, Andrea, Barrett, Jeffrey C, Boomsma, Dorrett, Branham, Kari, Breen, Gerome, Brummett, Chad M, Busonero, Fabio, Campbell, Harry, Chan, Andrew, Chen, Sai, Chew, Emily, Collins, Francis S, Corbin, Laura J, Smith, George Davey, Dedoussis, George, Dorr, Marcu, Farmaki, Aliki Eleni, Ferrucci, Luigi, Forer, Luka, Fraser, Ross M, Gabriel, Stacey, Levy, Shawn, Groop, Leif, Harrison, Tabitha, Hattersley, Andrew, Holmen, Oddgeir L, Hveem, Kristian, Kretzler, Matthia, Lee, James C, Mcgue, Matt, Meitinger, Thoma, Melzer, David, Min, Josine L, Mohlke, Karen L, Vincent, John B, Nauck, Matthia, Nickerson, Deborah, Palotie, Aarno, Pato, Michele, Pirastu, Nicola, Mcinnis, Melvin, Richards, J. Brent, Sala, Cinzia, Salomaa, Veikko, Schlessinger, David, Schoenherr, Sebastian, Slagboom, P. Eline, Small, Kerrin, Spector, Timothy, Stambolian, Dwight, Tuke, Marcu, Tuomilehto, Jaakko, van den Berg, Leonard H, van Rheenen, Wouter, Volker, Uwe, Wijmenga, Cisca, Toniolo, Daniela, Zeggini, Eleftheria, Gasparini, Paolo, Sampson, Matthew G, Wilson, James F, Frayling, Timothy, de Bakker, Paul I. W, Swertz, Morris A, Mccarroll, Steven, Kooperberg, Charle, Dekker, Annelot, Altshuler, David, Willer, Cristen, Iacono, William, Ripatti, Samuli, Soranzo, Nicole, Walter, Klaudia, Swaroop, Anand, Cucca, Francesco, Anderson, Carl A, Myers, Richard M, Boehnke, Michael, Mccarthy, Mark I, and Durbin, Richard

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Genotype, Population, Genome-wide association study, Single-nucleotide polymorphism, Computational biology, Biology, Polymorphism, Single Nucleotide, SEQUENCE, Article, 03 medical and health sciences, 0302 clinical medicine, Reference Values, Journal Article, Genetics, Humans, GENOME-WIDE ASSOCIATION, education, Alleles, POPULATION, 030304 developmental biology, Genetic association, Whole genome sequencing, education.field_of_study, Internet, 0303 health sciences, Genotype imputation, Medicine (all), Haplotype, ALSPAC, Minor allele frequency, 030104 developmental biology, Genetic Techniques, Haplotypes, RARE VARIANTS, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study
Abstract

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1%, a large increase in the number of SNPs tested in association studies and can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.

Published
2015

6. Tracing the route of modern humans out of Africa by using 225 human genome sequences from Ethiopians and Egyptians

Author

Yuan Chen, Toomas Kivisild, Stephan Schiffels, Ephrem Mekonnen, Petr Danecek, Luca Pagani, Tamiru Oljira, Deepti Gurdasani, Donata Luiselli, Chris Tyler-Smith, Neil Bradman, Marc Haber, Richard Durbin, Rosemary Ekong, Pierre Zalloua, Aylwyn Scally, Endashaw Bekele, Yali Xue, Pagani, Luca, Schiffels, Stephan, Gurdasani, Deepti, Danecek, Petr, Scally, Aylwyn, Chen, Yuan, Xue, Yali, Haber, Marc, Ekong, Rosemary, Oljira, Tamiru, Mekonnen, Ephrem, Luiselli, Donata, Bradman, Neil, Bekele, Endashaw, Zalloua, Pierre, Durbin, Richard, Kivisild, Tooma, and Tyler-Smith, Chris

Subjects
Human Migration, Population, Egypt, Ancient, Molecular Sequence Data, Black People, Biology, Coalescent theory, 03 medical and health sciences, Genetic, Principal Component Analysi, Out of africa, Report, Genetics, Haplotype, Humans, Genetics(clinical), education, Genetics (clinical), History, Ancient, 030304 developmental biology, African Continental Ancestry Group, 0303 health sciences, education.field_of_study, Genetic diversity, Principal Component Analysis, Base Sequence, Geography, Models, Genetic, Human migration, business.industry, Genome, Human, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, Markov Chain, Biological Evolution, Markov Chains, Haplotypes, Evolutionary biology, Homo sapiens, Human genome, Egypt, Ethiopia, business, Human
Abstract

The predominantly African origin of all modern human populations is well established, but the route taken out of Africa is still unclear. Two alternative routes, via Egypt and Sinai or across the Bab el Mandeb strait into Arabia, have traditionally been proposed as feasible gateways in light of geographic, paleoclimatic, archaeological, and genetic evidence. Distinguishing among these alternatives has been difficult. We generated 225 whole-genome sequences (225 at 8× depth, of which 8 were increased to 30×; Illumina HiSeq 2000) from six modern Northeast African populations (100 Egyptians and five Ethiopian populations each represented by 25 individuals). West Eurasian components were masked out, and the remaining African haplotypes were compared with a panel of sub-Saharan African and non-African genomes. We showed that masked Northeast African haplotypes overall were more similar to non-African haplotypes and more frequently present outside Africa than were any sets of haplotypes derived from a West African population. Furthermore, the masked Egyptian haplotypes showed these properties more markedly than the masked Ethiopian haplotypes, pointing to Egypt as the more likely gateway in the exodus to the rest of the world. Using five Ethiopian and three Egyptian high-coverage masked genomes and the multiple sequentially Markovian coalescent (MSMC) approach, we estimated the genetic split times of Egyptians and Ethiopians from non-African populations at 55,000 and 65,000 years ago, respectively, whereas that of West Africans was estimated to be 75,000 years ago. Both the haplotype and MSMC analyses thus suggest a predominant northern route out of Africa via Egypt.

Published
2015

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