Sperm miRNA expression data from male C57BL/6J, C57BL/6J-ChrY^SJL, and C57BL/6J-ChrY^RF

The prevalence of some autoimmune diseases (AID) is greater in females compared with males, notwithstanding that disease severity is often greater in males. The reason for this sexual dimorphism (SD) is unknown, but may reflect negative selection of Y chromosome (ChrY) bearing sperm during spermatogenesis or male fetuses early in the course of conception/pregnancy. Previously, we showed that the SD in experimental autoimmune encephalomyelitis (EAE) is associated with copy number variation (CNV) in ChrY multicopy genes. Here, we test the hypothesis that CNV in ChrY multicopy genes influences the paternal parent-of-origin effect on EAE susceptibility in female mice. We show that C57BL/6J consomic strains of mice possessing an identical ChrX and CNV in ChrY multicopy genes exhibit a female biased sex-ratio and sperm head abnormalities, consistent with X-Y intragenomic conflict arising from an imbalance in CNV between homologous ChrX:ChrY multicopy genes. These males also display paternal transmission of EAE to female offspring and differential loading of miRNAs within the sperm nucleus. These findings provide evidence for a genetic mechanism at the level of the male gamete that contributes to the SD in EAE and paternal parent-of-origin effects in female mice, raising the possibility that a similar mechanism may contribute to the SD in MS. miRNA expression was analyzed in epidydimal sperm pooled from 5 mice for each replicate per strain.部分自身免疫性疾病（autoimmune diseases, AID）的患病率在女性中高于男性，尽管男性患者的疾病严重程度往往更高。这种性别二态性（sexual dimorphism, SD）的潜在机制尚未阐明，但其可能与精子发生过程中携带Y染色体（Y chromosome, ChrY）的精子发生负向选择，或是受孕/妊娠早期的男性胎儿相关。此前本团队已证实，实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis, EAE）中的性别二态性与Y染色体多拷贝基因的拷贝数变异（copy number variation, CNV）存在相关性。本研究旨在验证下述假说：Y染色体多拷贝基因的拷贝数变异，会影响父系亲本起源效应对雌性小鼠实验性自身免疫性脑脊髓炎易感性的调控作用。 研究结果显示，携带完全一致的X染色体（ChrX）且Y染色体多拷贝基因存在拷贝数变异的C57BL/6J同源导入系小鼠，会呈现雌性偏向的性别比例与精子头部畸形表型，这与同源X染色体与Y染色体多拷贝基因间拷贝数失衡引发的X-Y染色体内基因组冲突相符。此类雄性小鼠还可通过父系将实验性自身免疫性脑脊髓炎传递给雌性后代，且其精子细胞核内的微小RNA（miRNAs）负载模式存在差异。 上述研究结果为雄性配子层面的遗传机制提供了实验证据，该机制可阐释实验性自身免疫性脑脊髓炎中的性别二态性与雌性小鼠的父系亲本起源效应，同时提示类似机制或同样参与多发性硬化症（multiple sclerosis, MS）的性别二态性形成。本研究针对每个品系的每一次重复实验，均采用混合自5只小鼠的附睾精子进行微小RNA表达分析。