Meiotic recombination events are distributed unevenly along the chromosomes and are regulated by genetic background and sex. The goal of this project is to determine the factors regulating sex specificity of meiotic recombination, boh its regional distribution along the chromosomes and the activity of sex-specific recombination hotspots. We will search for both dominant and recessive trans-acting genes that differ between two mouse strains and affect sex specificity of hotspots Esrrg-1 and Tmem182. Hotspot Esrrg-1 has the same activity in females, but is two-fold more active in male B6xCAST than in WSBxCAST. Hotspot Tmem182 is dependent on PWD genetic background and is two-fold more active in female B6xPWD compared to WSBxPWD, but the reverse is true in males. We will use genetic crosses that will allow us to assess dominance issues and dosage effects separately, for which we will create new genetic resources by developing two new mouse strains on a B6 genetic background combining knockin alleles of the recombination positioning gene Prdm9 created for this study with CAST or PWD sequences on Chr1. We will test for hotspot activity in sperm and eggs of individual animals using a newly developed massive parallel sequencing assay. We will also characterize in detail the sex-specific effect of mTert(-/-) telomere shortenin on genome-wide, regional and local recombination rates by comparing two genetic crosses on the same genetic background but differing in their telomeric lengths.

Public Health Relevance

In humans, changes in regional patterns of recombination influence susceptibility to aneuploidy in a sex- specific manner and are major causes for sterility miscarriage and birth defects, and improper recombination can cause genome instability and chromosome rearrangements leading to genetic disorders. The proposed work will have significant, immediate applications in mapping genes underlying any disease with a significant genetic component, both in humans and experimental animals, and will help to improve our understanding of processes leading to development of genetically influenced human diseases, such as cancer and infertility.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078452-07
Application #
8518372
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Janes, Daniel E
Project Start
2007-03-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
7
Fiscal Year
2013
Total Cost
$341,972
Indirect Cost
$146,559
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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Baker, Christopher L; Petkova, Pavlina; Walker, Michael et al. (2015) Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots. PLoS Genet 11:e1005512
Baker, Christopher L; Kajita, Shimpei; Walker, Michael et al. (2015) PRDM9 drives evolutionary erosion of hotspots in Mus musculus through haplotype-specific initiation of meiotic recombination. PLoS Genet 11:e1004916
Walker, Michael; Billings, Timothy; Baker, Christopher L et al. (2015) Affinity-seq detects genome-wide PRDM9 binding sites and reveals the impact of prior chromatin modifications on mammalian recombination hotspot usage. Epigenetics Chromatin 8:31
Baker, Christopher L; Walker, Michael; Kajita, Shimpei et al. (2014) PRDM9 binding organizes hotspot nucleosomes and limits Holliday junction migration. Genome Res 24:724-32
Billings, Timothy; Parvanov, Emil D; Baker, Christopher L et al. (2013) DNA binding specificities of the long zinc-finger recombination protein PRDM9. Genome Biol 14:R35
Billings, Timothy; Sargent, Evelyn E; Szatkiewicz, Jin P et al. (2010) Patterns of recombination activity on mouse chromosome 11 revealed by high resolution mapping. PLoS One 5:e15340
Paigen, Kenneth; Petkov, Petko (2010) Mammalian recombination hot spots: properties, control and evolution. Nat Rev Genet 11:221-33
Parvanov, Emil D; Petkov, Petko M; Paigen, Kenneth (2010) Prdm9 controls activation of mammalian recombination hotspots. Science 327:835
Parvanov, Emil D; Ng, Siemon H S; Petkov, Petko M et al. (2009) Trans-regulation of mouse meiotic recombination hotspots by Rcr1. PLoS Biol 7:e36

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