title: Copy number variation in Y chromosome multicopy genes is linked to a paternal parent-of-origin effect on CNS autoimmune disease in female offspring.
abstract: 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.
authors.affiliation: Department of Medicine, University of Vermont, Given Medical Building C317, Burlington, VT, 05405, USA. lcase@uvm.edu.
authors.forename: Laure K
authors.initials: LK
authors.lastname: Case
authors.affiliation: Department of Medicine, University of Vermont, Given Medical Building C317, Burlington, VT, 05405, USA. ewall@uvm.edu.
authors.forename: Emma H
authors.initials: EH
authors.lastname: Wall
authors.affiliation: Department of Medicine, University of Vermont, Given Medical Building C317, Burlington, VT, 05405, USA. eosmansk@uvm.edu.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Osmanski
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT, 05405, USA. jdragon@uvm.edu.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Dragon
authors.affiliation: Department of Medicine, University of Vermont, Given Medical Building C317, Burlington, VT, 05405, USA. nareshas@stanford.edu.|Current address: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. nareshas@stanford.edu.
authors.forename: Naresha
authors.initials: N
authors.lastname: Saligrama
authors.affiliation: Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61802, USA. zacharyj@illinois.edu.
authors.forename: James F
authors.initials: JF
authors.lastname: Zachary
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, MA, 02115, USA. blemos@hsph.harvard.edu.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Lemos
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, 19129, USA. Libby@DrexelMed.edu.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Blankenhorn
authors.affiliation: Department of Medicine, University of Vermont, Given Medical Building C317, Burlington, VT, 05405, USA. cteusche@uvm.edu.|Department of Pathology, University of Vermont, Burlington, VT, 05405, USA. cteusche@uvm.edu.
authors.forename: Cory
authors.initials: C
authors.lastname: Teuscher
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001327:Autoimmune Diseases / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D056915:DNA Copy Number Variations / Q000235:genetics*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D016014:Linear Models; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012727:Sex Characteristics; D012744:Sex Ratio; D013091:Spermatogenesis / Q000235:genetics; D013094:Spermatozoa / Q000378:metabolism; D014960:X Chromosome / Q000235:genetics; D014998:Y Chromosome / Q000235:genetics*
chemical_list: D016207:Cytokines; D035683:MicroRNAs