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      The landscape of recombination in African Americans

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          Abstract

          Recombination, together with mutation, is the ultimate source of genetic variation in populations. We leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing-over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P<10 −245). We identify a 17 base pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of African-enriched alleles of PRDM9.

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          A high-resolution recombination map of the human genome.

          Determination of recombination rates across the human genome has been constrained by the limited resolution and accuracy of existing genetic maps and the draft genome sequence. We have genotyped 5,136 microsatellite markers for 146 families, with a total of 1,257 meiotic events, to build a high-resolution genetic map meant to: (i) improve the genetic order of polymorphic markers; (ii) improve the precision of estimates of genetic distances; (iii) correct portions of the sequence assembly and SNP map of the human genome; and (iv) build a map of recombination rates. Recombination rates are significantly correlated with both cytogenetic structures (staining intensity of G bands) and sequence (GC content, CpG motifs and poly(A)/poly(T) stretches). Maternal and paternal chromosomes show many differences in locations of recombination maxima. We detected systematic differences in recombination rates between mothers and between gametes from the same mother, suggesting that there is some underlying component determined by both genetic and environmental factors that affects maternal recombination rates.
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            The fine-scale structure of recombination rate variation in the human genome.

            The nature and scale of recombination rate variation are largely unknown for most species. In humans, pedigree analysis has documented variation at the chromosomal level, and sperm studies have identified specific hotspots in which crossing-over events cluster. To address whether this picture is representative of the genome as a whole, we have developed and validated a method for estimating recombination rates from patterns of genetic variation. From extensive single-nucleotide polymorphism surveys in European and African populations, we find evidence for extreme local rate variation spanning four orders in magnitude, in which 50% of all recombination events take place in less than 10% of the sequence. We demonstrate that recombination hotspots are a ubiquitous feature of the human genome, occurring on average every 200 kilobases or less, but recombination occurs preferentially outside genes.
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              Linkage disequilibrium in the human genome.

              With the availability of a dense genome-wide map of single nucleotide polymorphisms (SNPs), a central issue in human genetics is whether it is now possible to use linkage disequilibrium (LD) to map genes that cause disease. LD refers to correlations among neighbouring alleles, reflecting 'haplotypes' descended from single, ancestral chromosomes. The size of LD blocks has been the subject of considerable debate. Computer simulations and empirical data have suggested that LD extends only a few kilobases (kb) around common SNPs, whereas other data have suggested that it can extend much further, in some cases greater than 100 kb. It has been difficult to obtain a systematic picture of LD because past studies have been based on only a few (1-3) loci and different populations. Here, we report a large-scale experiment using a uniform protocol to examine 19 randomly selected genomic regions. LD in a United States population of north-European descent typically extends 60 kb from common alleles, implying that LD mapping is likely to be practical in this population. By contrast, LD in a Nigerian population extends markedly less far. The results illuminate human history, suggesting that LD in northern Europeans is shaped by a marked demographic event about 27,000-53,000 years ago.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                21 July 2011
                20 July 2011
                11 February 2012
                : 476
                : 7359
                : 170-175
                Affiliations
                [1 ]Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK
                [2 ]Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA
                [3 ]Dept. of Genetics, Harvard Medical School, New Research Bldg., 77 Ave. Louis Pasteur, Boston, MA 02115, USA
                [4 ]Department of Statistics, Oxford University, 1 South Parks Road, Oxford OX1 3TG, UK
                [5 ]Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
                [6 ]Div. of Genetics & Endocrinology and Program in Genomics, Childrens Hospital Boston, MA 02115, USA
                [7 ]Department of Preventive Medicine and Department of Pathology, Keck School of Medicine, University of Southern California/ Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
                [8 ]Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90089
                [9 ]Center for Applied Genomics, The Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
                [10 ]Jackson Heart Study Coordinating Center, Jackson State University, 350 W. Woodrow Wilson Ave., Suite 701, Jackson, MS 39213, USA
                [11 ]Department of Medicine, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216, USA
                [12 ]Department of Thoracic Surgery, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
                [13 ]Division of Epidemiology in the Department of Medicine, Vanderbilt Epidemiology Center; and the Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
                [14 ]Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
                [15 ]Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 7703
                [16 ]The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
                [17 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
                [18 ]Division of Cancer Etiology, Dept. of Population Science, Beckman Research Inst., City of Hope, CA 91010, USA
                [19 ]International Epidemiology Institute, Rockville, MD 20850, USA
                [20 ]Karmanos Cancer Institute and Dept. of Oncology, Wayne State University of Medicine, Detroit, MI USA 48201
                [21 ]Human Genetics Center and Division of Epidemiology, University of Texas at Houston, 1200 Herman Pressler St., Houston, Texas 77030, USA
                [22 ]Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA 02118 and Framingham Heart Study, Framingham, MA 01702, USA
                [23 ]Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA
                [24 ]Department of Biostatistical Sciences, Wake Forest University School of Medicine WC-2326, Medical Center Blvd., Winston Salem, NC 27157, USA
                [25 ]Institute of Molecular Medicine and Division of Epidemiology, School of Public Health, University of Texas Health Sciences Center at Houston, 1825 Pressler Street, Houston, TX 77030, USA
                [26 ]Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD 20892, USA
                [27 ]Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
                [28 ]Sylvester Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, FL 33136, USA
                [29 ]James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institutions, Baltimore, MD 21287, USA
                [30 ]Cancer Prevention Institute of California, Fremont, CA 94538; and Stanford University School of Medicine and Stanford Cancer Center, Stanford, CA 94305, USA
                [31 ]Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205, USA
                [32 ]Department of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA
                [33 ]Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
                [34 ]Department of Medicine, Division of Allergy, Pulmonary and Critical Care, 6100 Medical Center East, Vanderbilt University Medical Center, Nashville, TN 37232-8300, USA
                [35 ]Department of Health Disparities Research, Division of OVP, Cancer Prevention and Population Sciences, and Center for Community Implementation and Dissemination Research, Duncan Family Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
                [36 ]Department of Epidemiology, Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
                [37 ]Department of Urology, Northwestern University, Chicago, IL 60611, USA
                [38 ]Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI USA
                [39 ]Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, 6701 Rockledge Drive, Bethesda, MD 20892, USA
                [40 ]Cardiovascular Health Research Unit, Depts. of Medicine, Epidemiology & Health Services, Univ. of Washington; Group Health Research Institute; Group Health Cooperative; 1730 Minor Ave., Seattle, WA 98101, USA
                [41 ]Department of Epidemiology, University of Washington, Box 357236 Seattle, WA 98195, USA
                [42 ]Center for Public Health Genomics, University of Virginia, West Complex Room 6111, Charlottesville, VA 22908, USA
                [43 ]Medical Genetics Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
                [44 ]Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
                [45 ]Core Genotype Facility, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland, USA 20877, USA
                [46 ]University of California San Francisco, San Francisco CA 94158, USA
                [47 ]Institute for Human Genetics, Departments of Epidemiology and Biostatistics and Urology, University of California, San Francisco, San Francisco, CA 94158, USA
                [48 ]Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Wolstein Research Building, Cleveland, Ohio 44106, USA
                [49 ]Brigham and Women’s Hospital, Dept. of Medicine, Sleep Medicine, 75 Francis Street, Boston, MA 02115, USA
                [50 ]Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
                [51 ]Jackson State University, 1400 Lynch Street, Jackson, MS 39217, USA
                [52 ]Tougaloo College, 500 West County Line Road, Tougaloo, MS 39174, USA
                [53 ]Departments of Epidemiology and Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA
                [54 ]Dept. of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
                [55 ]Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216, USA
                Author notes
                Correspondence should be addressed to: Anjali G. Hinch ( anjali@ 123456well.ox.ac.uk ); David Reich ( reich@ 123456genetics.med.harvard.edu ) or Simon R. Myers ( myers@ 123456stats.ox.ac.uk )
                [*]

                These authors equally directed the research

                Article
                nihpa313104
                10.1038/nature10336
                3154982
                21775986

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                Funding
                Funded by: National Human Genome Research Institute : NHGRI
                Award ID: U01 HG004168-03 || HG
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