Sex-Specific Regulation of Meiotic Recombination Hotspots

描述（由申请方提供）：减数分裂重组事件沿染色体沿着不均匀分布，并受遗传背景和性别调节。本项目的目的是确定减数分裂重组的性别特异性调控因素，以及它在染色体上的沿着区域分布和性别特异性重组热点的活性。我们将寻找两种小鼠品系之间不同的显性和隐性反式作用基因，并影响热点Esrrg-1和Tmem 182的性别特异性。热点Esrrg-1在雌性中具有相同的活性，但在雄性B6 xCAST中的活性是WSBxCAST的两倍。热点Tmem 182依赖于PWD遗传背景，并且与WSBxPWD相比，在女性B6 xPWD中的活性高两倍，但在男性中则相反。我们将使用遗传杂交，这将使我们能够分别评估优势问题和剂量效应，为此，我们将通过在B6遗传背景上开发两种新的小鼠品系，将为本研究创建的重组定位基因Prdm 9的敲入等位基因与Chr 1上的CAST或PWD序列相结合，来创建新的遗传资源。我们将使用一种新开发的大规模平行测序检测方法检测个体动物精子和卵子中的热点活性。我们还将详细描述mTert（-/-）端粒缩短蛋白对全基因组，区域和局部重组率的性别特异性影响，通过比较两个遗传杂交在相同的遗传背景下，但不同的端粒长度。

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.