Testis expression in Mus musculus domesticus WSB/EiJ x Mus musculus musculus PWD/PhJ F2 hybrids

To characterize the genetic basis of hybrid male sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven "hotspots," seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL - but not cis eQTL - were substantially lower when mapping was restricted to a "fertile" subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility. Gene expression was measured in whole testis in males aged 70(±5) days. Samples include 294 WSB/EiJ x PWD/PhJ F2s, 11 PWD/PhJ x WSB/EiJ F2s, 8 WSB/EiJ, 8 PWD/PhJ, 6 PWD/PhJ x WSB/EiJ F1s and 4 WSB/EiJ x PWD/PhJ F1s.为详细解析杂交雄性不育的遗传基础，本研究采用系统遗传学研究策略，将基因表达性状定位与不育表型、数量性状基因座（QTL）定位相结合。我们对源于小家鼠指名亚种（M. musculus musculus）与小家鼠家鼠亚种（M. m. domesticus）的野生来源近交系杂交获得的305只雄性F2代个体，开展了全基因组睾丸基因表达量检测。本研究共鉴定出数千个参与表达量变异调控的顺式作用与反式作用表达数量性状基因座（eQTL）。大量反式eQTL聚集形成11个调控热点区域，其中7个与本杂交实验中鉴定到的不育表型QTL共定位。当仅将定位分析限定于“可育”小鼠亚群时，反式eQTL的数量及其聚集程度均显著降低，而顺式eQTL则无此变化，这为反式eQTL调控热点与雄性不育存在关联提供了实验依据。对携带eQTL的转录本进行功能注释，有助于解析不育位点所干扰的生物学过程，并为候选基因的筛选优先级提供指导。通过条件定位策略，我们鉴定出依赖于基因座间互作的eQTL，揭示了一套复杂的上位性调控系统。本研究结果印证了已有研究结论，包括X染色体在杂交不育中发挥的关键作用。本实验以70(±5)日龄的雄性小鼠全睾丸组织为材料开展基因表达量检测。实验样本包含294只WSB/EiJ × PWD/PhJ F2代个体、11只PWD/PhJ × WSB/EiJ F2代个体、8只WSB/EiJ纯系个体、8只PWD/PhJ纯系个体、6只PWD/PhJ × WSB/EiJ F1代个体以及4只WSB/EiJ × PWD/PhJ F1代个体。