Sex-Specific Regulation of Meiotic Recombination Hotspots

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DESCRIPTION (provided by applicant): 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.