A Genetic Basis for a Postmeiotic X Versus Y Chromosome Intragenomic Conflict in the Mouse

Intragenomic conflicts arise when a genetic element favours its own transmission to the detriment of others. Conflicts over sex chromosome transmission are expected to have influenced genome structure, gene regulation, and speciation. In the mouse, the existence of an intragenomic conflict between X- and Y-linked multicopy genes has long been suggested but never demonstrated. The Y-encoded multicopy gene Sly has been shown to have a predominant role in the epigenetic repression of post meiotic sex chromatin (PMSC) and, as such, represses X and Y genes, among which are its X-linked homologs Slx and Slxl1. Here, we produced mice that are deficient for both Sly and Slx/Slxl1 and observed that Slx/Slxl1 has an opposite role to that of Sly, in that it stimulates XY gene expression in spermatids. Slx/Slxl1 deficiency rescues the sperm differentiation defects and near sterility caused by Sly deficiency and vice versa. Slx/Slxl1 deficiency also causes a sex ratio distortion towards the production of male offspring that is corrected by Sly deficiency. All in all, our data show that Slx/Slxl1 and Sly have antagonistic effects during sperm differentiation and are involved in a postmeiotic intragenomic conflict that causes segregation distortion and male sterility. This is undoubtedly what drove the massive gene amplification on the mouse X and Y chromosomes. It may also be at the basis of cases of F1 male hybrid sterility where the balance between Slx/Slxl1 and Sly copy number, and therefore expression, is disrupted. To the best of our knowledge, our work is the first demonstration of a competition occurring between X and Y related genes in mammals. It also provides a biological basis for the concept that intragenomic conflict is an important evolutionary force which impacts on gene expression, genome structure, and speciation.

基因组内冲突（intragenomic conflict）指某一遗传元件为提升自身传递效率而损害其他遗传元件的现象。学界长期推测，性染色体传递相关的冲突可能对基因组结构、基因调控及物种形成产生影响。在小鼠中，X染色体与Y染色体连锁的多拷贝基因之间存在基因组内冲突这一假说虽被提出已久，却从未得到实验证实。Y染色体编码的多拷贝基因Sly已被证实可在表观遗传层面主导调控减数分裂后性染色质（post meiotic sex chromatin, PMSC）的沉默，进而抑制X与Y染色体上的基因表达，其中便包括其X染色体连锁的同源基因Slx与Slxl1。本研究构建了同时缺失Sly与Slx/Slxl1的小鼠模型，观察发现Slx/Slxl1的功能与Sly截然相反：它可促进精子细胞中XY连锁基因的表达。Slx/Slxl1的缺失可挽救Sly缺失导致的精子分化缺陷与近乎不育的表型，反之亦然。此外，Slx/Slxl1缺失会引发性别比例偏向雄性后代的畸变，而该畸变可通过Sly缺失得到纠正。综上，本研究数据表明，Slx/Slxl1与Sly在精子分化过程中发挥拮抗作用，并参与了一场可导致分离畸变与雄性不育的减数分裂后基因组内冲突。这无疑是驱动小鼠X、Y染色体上出现大量基因扩增的关键原因。该冲突也可能是部分F1雄性杂种不育现象的分子基础——此类病例中Slx/Slxl1与Sly的拷贝数（及其表达量）平衡被打破。据我们所知，本研究首次证实了哺乳动物中X与Y连锁相关基因之间存在竞争关系。同时，本研究也为“基因组内冲突是影响基因表达、基因组结构与物种形成的重要进化驱动力”这一理论提供了生物学实验依据。