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  • 1
    Publication Date: 2011-07-22
    Description: Recombination, together with mutation, gives rise to genetic variation in populations. Here 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 value 〈 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 PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154982/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154982/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hinch, Anjali G -- Tandon, Arti -- Patterson, Nick -- Song, Yunli -- Rohland, Nadin -- Palmer, Cameron D -- Chen, Gary K -- Wang, Kai -- Buxbaum, Sarah G -- Akylbekova, Ermeg L -- Aldrich, Melinda C -- Ambrosone, Christine B -- Amos, Christopher -- Bandera, Elisa V -- Berndt, Sonja I -- Bernstein, Leslie -- Blot, William J -- Bock, Cathryn H -- Boerwinkle, Eric -- Cai, Qiuyin -- Caporaso, Neil -- Casey, Graham -- Cupples, L Adrienne -- Deming, Sandra L -- Diver, W Ryan -- Divers, Jasmin -- Fornage, Myriam -- Gillanders, Elizabeth M -- Glessner, Joseph -- Harris, Curtis C -- Hu, Jennifer J -- Ingles, Sue A -- Isaacs, William -- John, Esther M -- Kao, W H Linda -- Keating, Brendan -- Kittles, Rick A -- Kolonel, Laurence N -- Larkin, Emma -- Le Marchand, Loic -- McNeill, Lorna H -- Millikan, Robert C -- Murphy, Adam -- Musani, Solomon -- Neslund-Dudas, Christine -- Nyante, Sarah -- Papanicolaou, George J -- Press, Michael F -- Psaty, Bruce M -- Reiner, Alex P -- Rich, Stephen S -- Rodriguez-Gil, Jorge L -- Rotter, Jerome I -- Rybicki, Benjamin A -- Schwartz, Ann G -- Signorello, Lisa B -- Spitz, Margaret -- Strom, Sara S -- Thun, Michael J -- Tucker, Margaret A -- Wang, Zhaoming -- Wiencke, John K -- Witte, John S -- Wrensch, Margaret -- Wu, Xifeng -- Yamamura, Yuko -- Zanetti, Krista A -- Zheng, Wei -- Ziegler, Regina G -- Zhu, Xiaofeng -- Redline, Susan -- Hirschhorn, Joel N -- Henderson, Brian E -- Taylor, Herman A Jr -- Price, Alkes L -- Hakonarson, Hakon -- Chanock, Stephen J -- Haiman, Christopher A -- Wilson, James G -- Reich, David -- Myers, Simon R -- 090532/Wellcome Trust/United Kingdom -- CA060691/CA/NCI NIH HHS/ -- CA092447/CA/NCI NIH HHS/ -- CA100374/CA/NCI NIH HHS/ -- CA100598/CA/NCI NIH HHS/ -- CA1116460/CA/NCI NIH HHS/ -- CA1116460S1/CA/NCI NIH HHS/ -- CA121197/CA/NCI NIH HHS/ -- CA121197S2/CA/NCI NIH HHS/ -- CA127219/CA/NCI NIH HHS/ -- CA1326792/CA/NCI NIH HHS/ -- CA140388/CA/NCI NIH HHS/ -- CA141716/CA/NCI NIH HHS/ -- CA148085/CA/NCI NIH HHS/ -- CA148127/CA/NCI NIH HHS/ -- CA22453/CA/NCI NIH HHS/ -- CA54281/CA/NCI NIH HHS/ -- CA55769/CA/NCI NIH HHS/ -- CA58223/CA/NCI NIH HHS/ -- CA63464/CA/NCI NIH HHS/ -- CA68485/CA/NCI NIH HHS/ -- CA68578/CA/NCI NIH HHS/ -- CA77305/CA/NCI NIH HHS/ -- CA87895/CA/NCI NIH HHS/ -- CA88164/CA/NCI NIH HHS/ -- ES007784/ES/NIEHS NIH HHS/ -- ES011126/ES/NIEHS NIH HHS/ -- ES06717/ES/NIEHS NIH HHS/ -- ES10126/ES/NIEHS NIH HHS/ -- GM08016/GM/NIGMS NIH HHS/ -- GM091332/GM/NIGMS NIH HHS/ -- HD33175/HD/NICHD NIH HHS/ -- HG004726/HG/NHGRI NIH HHS/ -- HHSN268200960009C/PHS HHS/ -- HL084107/HL/NHLBI NIH HHS/ -- N01-HC-65226/HC/NHLBI NIH HHS/ -- P30 ES010126/ES/NIEHS NIH HHS/ -- R01 CA052689/CA/NCI NIH HHS/ -- R01 CA092447/CA/NCI NIH HHS/ -- R01 HG006399/HG/NHGRI NIH HHS/ -- R01 HL084107-04/HL/NHLBI NIH HHS/ -- R01-CA73629/CA/NCI NIH HHS/ -- U01 HG004168/HG/NHGRI NIH HHS/ -- U01 HG004168-03/HG/NHGRI NIH HHS/ -- Intramural NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2011 Jul 20;476(7359):170-5. doi: 10.1038/nature10336.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21775986" target="_blank"〉PubMed〈/a〉
    Keywords: Africa, Western/ethnology ; African Americans/*genetics ; Alleles ; Amino Acid Motifs ; Base Sequence ; Chromosome Mapping ; Crossing Over, Genetic/*genetics ; Europe/ethnology ; European Continental Ancestry Group/genetics ; Evolution, Molecular ; Female ; Gene Frequency ; Genetics, Population ; Genome, Human/*genetics ; Genomics ; Haplotypes/genetics ; Histone-Lysine N-Methyltransferase/chemistry/genetics/metabolism ; Humans ; Male ; Molecular Sequence Data ; Pedigree ; Polymorphism, Single Nucleotide/genetics ; Probability
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-02-04
    Description: The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate meiotic recombination in mice and humans. Prdm9 is the only mammalian speciation gene yet identified and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here we show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such 'symmetric' PRDM9 binding associate with increasing fertility measures, and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in the early stages of speciation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756437/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davies, Benjamin -- Hatton, Edouard -- Altemose, Nicolas -- Hussin, Julie G -- Pratto, Florencia -- Zhang, Gang -- Hinch, Anjali Gupta -- Moralli, Daniela -- Biggs, Daniel -- Diaz, Rebeca -- Preece, Chris -- Li, Ran -- Bitoun, Emmanuelle -- Brick, Kevin -- Green, Catherine M -- Camerini-Otero, R Daniel -- Myers, Simon R -- Donnelly, Peter -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 095552/Z/11/Z/Wellcome Trust/United Kingdom -- 098387/Z/12/Z/Wellcome Trust/United Kingdom -- Intramural NIH HHS/ -- England -- Nature. 2016 Feb 11;530(7589):171-6. doi: 10.1038/nature16931. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK. ; Department of Statistics, University of Oxford, 24-29 St. Giles', Oxford OX1 3LB, UK. ; Genetics and Biochemistry Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840484" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Binding Sites ; Chromosome Pairing/genetics ; Chromosomes, Mammalian/genetics/metabolism ; DNA Breaks, Double-Stranded ; Female ; *Genetic Speciation ; Histone-Lysine N-Methyltransferase/*chemistry/genetics/*metabolism ; Humans ; Hybridization, Genetic/*genetics ; Infertility/*genetics ; Male ; Meiosis/genetics ; Mice ; Mice, Inbred C57BL ; Protein Binding ; *Protein Engineering ; Protein Structure, Tertiary/genetics ; Recombination, Genetic/genetics ; Zinc Fingers/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2019
    Description: 〈p〉Recombination is critical to meiosis and evolution, yet many aspects of the physical exchange of DNA via crossovers remain poorly understood. We report an approach for single-cell whole-genome DNA sequencing by which we sequenced 217 individual hybrid mouse sperm, providing a kilobase-resolution genome-wide map of crossovers. Combining this map with molecular assays measuring stages of recombination, we identified factors that affect crossover probability, including PRDM9 binding on the non-initiating template homolog and telomere proximity. These factors also influence the time for sites of recombination-initiating DNA double-strand breaks to find and engage their homologs, with rapidly engaging sites more likely to form crossovers. We show that chromatin environment on the template homolog affects positioning of crossover breakpoints. Our results also offer insights into recombination in the pseudoautosomal region.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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