In humans, recombination plays a critical role in meiosis. Errors in the recombination process lead to aneuploidy, the leading cause of spontaneous miscarriages and of severe developmental disabilities, as well as to deleterious genome rearrangements and possibly to mutations. Yet in spite of its highly constrained roles, recombination is tremendously variable among humans, at every scale examined. Our long-term research interests lie in characterizing this variation, identifying its determinants and understanding its biomedical and evolutionary implications. In particular, our work revealed heritable variation in the set of recombination hotspots used by different individuals, contributing to the discovery of PRDM9 (a gene of central importance in specifying hotspot locations in mice and humans). This case demonstrates how studies of variation in recombination can yield insight into mechanism. We also documented an effect of recombination rates on female fertility, notably in older mothers. Together, our findings and those from other groups underscore the biomedical importance of understanding the determinants of recombination rate variation and their effects. In this competitive renewal, we propose to analyze a huge set of human pedigrees in order to examine the basis for differences in recombination rates among individuals and the consequences for aneuploidy risk and mutagenesis.
In Aim 1, we focus on differences between sexes. We propose to build a fine-scale, sex-specific genetic map at unprecedented resolution and characterize sex-specific hotspots, by analyzing over 3000 nuclear families that have already been genotyped.
In Aim 2, we will conduct a well-powered genome-wide association study to identify new loci that contribute to variation in recombination phenotypes, using the same set of nuclear families.
In Aim 3, we plan to examine how variation in recombination rates and maternal age influence the risk of aneuploidy.
In Aim 3. i, we will assess the evidence for proper segregation of tetrads without a crossover, i.e., for the presence of a back-up mechanism for achiasmatic chromosomes.
In Aim 3. ii, we will characterize the recombination patterns that endanger proper disjunction. To this end, we will collect and analyze samples from women and their trisomic products of conception, contrasting patterns of recombination in this set to age-matched transmissions to viable, non-trisomic offspring. Finally, in Aim 4, we will test whether recombination introduces germline mutations at non-negligible rates, by collecting and analyzing genome sequences for two large nuclear families. This work will yield important new insights into the determinants of recombination rate variation and the implications for human reproductive health and genome evolution.

Public Health Relevance

Errors in the human recombination process lead to aneuploidy, the foremost cause of spontaneous miscarriage and of severe developmental disabilities. Yet recombination varies tremendously among individuals, for reasons that remain poorly understood. This grant aims to identify determinants of recombination rate variation in humans and assess the impact of recombination on mutagenesis and aneuploidy risk.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
7R01GM083098-06
Application #
8652470
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Janes, Daniel E
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biology
Type
Graduate Schools
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10027
Buffalo, Vince; Mount, Stephen M; Coop, Graham (2016) A Genealogical Look at Shared Ancestry on the X Chromosome. Genetics 204:57-75
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
Bradburd, Gideon S; Ralph, Peter L; Coop, Graham M (2016) A Spatial Framework for Understanding Population Structure and Admixture. PLoS Genet 12:e1005703
Brandvain, Yaniv; Coop, Graham (2015) Sperm should evolve to make female meiosis fair. Evolution 69:1004-14
Ralph, Peter L; Coop, Graham (2015) Convergent Evolution During Local Adaptation to Patchy Landscapes. PLoS Genet 11:e1005630
Sedghifar, Alisa; Brandvain, Yaniv; Ralph, Peter et al. (2015) The Spatial Mixing of Genomes in Secondary Contact Zones. Genetics 201:243-61
Ralph, Peter L; Coop, Graham (2015) The Role of Standing Variation in Geographic Convergent Adaptation. Am Nat 186 Suppl 1:S5-23
Berg, Jeremy J; Coop, Graham (2015) A Coalescent Model for a Sweep of a Unique Standing Variant. Genetics 201:707-25
Muñoz-Fuentes, Violeta; Marcet-Ortega, Marina; Alkorta-Aranburu, Gorka et al. (2015) Strong artificial selection in domestic mammals did not result in an increased recombination rate. Mol Biol Evol 32:510-23
Williams, Amy L; Genovese, Giulio; Dyer, Thomas et al. (2015) Non-crossover gene conversions show strong GC bias and unexpected clustering in humans. Elife 4:

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