Copy number variation in Y chromosome multicopy genes is linked to a paternal parent-of-origin effect on CNS autoimmune disease in female offspring
Copy number variation in Y chromosome multicopy genes is linked to a paternal parent-of-origin effect on CNS autoimmune disease in female offspring
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DOI：
10.1186/s13059-015-0591-7
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发表时间：
2015-02-10
期刊：
影响因子：
12.3
通讯作者：
Teuscher, Cory
中科院分区：
文献类型：
--
作者：
Case, Laure K.;Wall, Emma H.;Teuscher, Cory
背景：与男性相比，某些自身免疫性疾病的患病率在女性中更高，尽管男性的疾病严重程度通常更高。这种性二态性的原因尚不清楚，但它可能反映了精子发生过程中携带 Y 染色体的精子或受孕/怀孕早期男性胎儿的负选择。此前，我们发现实验性自身免疫性脑脊髓炎（EAE）的性别二态性与 Y 染色体多拷贝基因的拷贝数变异（CNV）相关。在这里，我们检验了 Y 染色体多拷贝基因中的 CNV 影响雌性小鼠 EAE 易感性的父本亲本效应的假设。结果：我们表明，拥有相同 X 染色体和 Y 染色体多拷贝基因中的 CNV 的 C57BL/6 J 康体品系小鼠表现出精子头异常和性别比例偏雌性。这与同源 X:Y 染色体多拷贝基因之间 CNV 不平衡引起的 X-Y 基因组内冲突是一致的。这些雄性还表现出 EAE 的父系遗传给雌性后代，以及精子核内 microRNA 的差异负载。此外，在人类中，患有多发性硬化症的先证者家族同样表现出女性偏向的性别比例，而患有非性二态性自身免疫性疾病的先证者家族则表现出无偏见的性别比例。结论：这些发现为雄配子水平上的机制提供了证据，该机制导致EAE中的性别二态性和雌性小鼠中的父本亲本效应，这提高了类似机制可能导致多发性硬化症中性别二态性的可能性。硬化。
Background: The prevalence of some autoimmune diseases is greater in females compared with males, although disease severity is often greater in males. The reason for this sexual dimorphism is unknown, but it may reflect negative selection of Y chromosome-bearing sperm during spermatogenesis or male fetuses early in the course of conception/pregnancy. Previously, we showed that the sexual dimorphism in experimental autoimmune encephalomyelitis (EAE) is associated with copy number variation (CNV) in Y chromosome multicopy genes. Here, we test the hypothesis that CNV in Y chromosome multicopy genes influences the paternal parent-of-origin effect on EAE susceptibility in female mice.Results: We show that C57BL/6 J consomic strains of mice possessing an identical X chromosome and CNV in Y chromosome multicopy genes exhibit sperm head abnormalities and female-biased sex ratio. This is consistent with X-Y intragenomic conflict arising from an imbalance in CNV between homologous X: Y chromosome multicopy genes. These males also display paternal transmission of EAE to female offspring and differential loading of microRNAs within the sperm nucleus. Furthermore, in humans, families of probands with multiple sclerosis similarly exhibit a female-biased sex ratio, whereas families of probands affected with non-sexually dimorphic autoimmune diseases exhibit unbiased sex ratios.Conclusions: These findings provide evidence for a mechanism at the level of the male gamete that contributes to the sexual dimorphism in EAE and paternal parent-of-origin effects in female mice, raising the possibility that a similar mechanism may contribute to the sexual dimorphism in multiple sclerosis.