Abstract
BackgroundThe 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.ResultsWe 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0591-7) contains supplementary material, which is available to authorized users.
Highlights
The prevalence of some autoimmune diseases is greater in females compared with males, disease severity is often greater in males
For most autoimmune diseases (AIDs) there is a clear sexual dimorphism (SD) in prevalence, in that females are more frequently affected than males, despite the fact that disease severity is often greater in males [1]
We show that families of probands with AIDs displaying a female-biased SD for prevalence, including multiple sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and pauciarticular onset juvenile rheumatoid arthritis (PaJRA), exhibit a female-biased sex ratio, whereas families of probands affected with non-SD AIDs, including systemic onset juvenile rheumatoid arthiritis (SoJRA) and type 1 diabetes (T1D), exhibit an unbiased sex ratio
Summary
The prevalence of some autoimmune diseases is greater in females compared with males, disease severity is often greater in males. Consistent with this observation, Aggarwal et al [5] subsequently reported, using pregnancy histories of both SLE affected and unaffected individuals within SLE families, that there was an excess of male fetal loss in SLE families compared with controls. These findings suggest that genetic risk factors for AIDs may play a role in reproduction, a concept that is consistent with the Red Queen Hypothesis model of sexual reproduction and sex chromosome co-adaptation [6]. The female-biased SD in prevalence observed in many AIDs may reflect negative selection of male fetuses early in the course of conception/pregnancy, and negative selection on Y-bearing sperm during spermatogenesis
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