Errors in the meiotic recombination process underlie a variety of chromosomal abnormalities, which are associated with spontaneous miscarriages and a wide range of human diseases. In spite of the crucial importance of recombination in meiosis, recent studies have revealed tremendous variation in rates among human females, and a rapid evolution of fine-scale recombination rates in apes. These observations raise important questions about recombination rate variation within and between species and its determinants. Addressing these questions is a key medical challenge, as well as an important step in understanding how natural selection acts on recombination rates. Here, we propose a unique combination of experimental and computational approaches to: i) Quantify variation in recombination rates among human males and females, using dense genotyping data collected in a large pedigree of a founder population (the Hutterites). These data will be used to evaluate the reliability of linkage-disequilibrium based maps, and garner new insights into the genetic basis of recombination rate variation and its possible effects on fertility. ii) Characterize the evolution of broad-scale recombination rates by building a genome-wide genetic map for common chimpanzees, the closest living evolutionary relative of humans. By comparing the map to what is seen in humans, we can assess the evolutionary constraints acting on recombination over different genetic scales, and ask whether the same determinants of recombination are at work in the two species. iii) Test hypotheses about the evolution of recombination hotspots, and delimit the rate at which they evolve, by performing sperm-typing experiments in two human populations and in common chimpanzees. In summary, we propose to combine molecular and population genetics tools to address outstanding questions about selective constraints on human recombination, with important implications for human genetics and evolutionary biology. Project Summary: A substantial fraction of human embryos are aneuploid (i.e., have an abnormal number of chromosomes) and, as a result, do not survive to full term or have severe developmental disabilities. Most cases of aneuploidy are caused by errors in the meiotic recombination process. This work aims to characterize variation in the human recombination process and to understand its determinants, thereby improving our understanding of the susceptibility to aneuploidy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM083098-04
Application #
7928145
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
2007-09-17
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2010
Total Cost
$250,273
Indirect Cost
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Baker, Zachary; Schumer, Molly; Haba, Yuki et al. (2017) Repeated losses of PRDM9-directed recombination despite the conservation of PRDM9 across vertebrates. Elife 6:
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Bradburd, Gideon S; Ralph, Peter L; Coop, Graham M (2016) A Spatial Framework for Understanding Population Structure and Admixture. PLoS Genet 12:e1005703
Wei, Shan; Williams, Zev (2016) Rapid Short-Read Sequencing and Aneuploidy Detection Using MinION Nanopore Technology. Genetics 202:37-44
Elyashiv, Eyal; Sattath, Shmuel; Hu, Tina T et al. (2016) A Genomic Map of the Effects of Linked Selection in Drosophila. PLoS Genet 12:e1006130
Moorjani, Priya; Sankararaman, Sriram; Fu, Qiaomei et al. (2016) A genetic method for dating ancient genomes provides a direct estimate of human generation interval in the last 45,000 years. Proc Natl Acad Sci U S A 113:5652-7
Ralph, Peter L; Coop, Graham (2015) The Role of Standing Variation in Geographic Convergent Adaptation. Am Nat 186 Suppl 1:S5-23

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