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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PROVIDER: PRJNA272796 | ENA |
REPOSITORIES: ENA
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Project description: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.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.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.
| S-EPMC4396973 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE29454: Effect of Advanced Paternal Age on Copy Number Variation in Offspring (custom array) GSE29455: Effect of Advanced Paternal Age on Copy Number Variation in Offspring (commercial array) Refer to individual Series
2011-07-12 | E-GEOD-29456 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2015-01-16 | GSE65048 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-01-16 | E-GEOD-65048 | biostudies-arrayexpress
Project description: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. Three biological replicates for each strain were pooled from the axillary, brachial, and inguinal lymph nodes from 5 mice for each replicate. RNA was isolated from CD4+TCRB+ FAC sorted cells.
2015-01-16 | E-GEOD-65038 | biostudies-arrayexpress
Project description: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.
2015-01-16 | GSE65038 | GEO
Project description:MotivationWhole genome sequencing (WGS) of parent-offspring trios is a powerful approach for identifying disease-associated genes via detecting copy number variations (CNVs). Existing approaches, which detect CNVs for each individual in a trio independently, usually yield low-detection accuracy. Joint modeling approaches leveraging Mendelian transmission within the parent-offspring trio can be an efficient strategy to improve CNV detection accuracy.ResultsIn this study, we developed TrioCNV, a novel approach for jointly detecting CNVs in parent-offspring trios from WGS data. Using negative binomial regression, we modeled the read depth signal while considering both GC content bias and mappability bias. Moreover, we incorporated the family relationship and used a hidden Markov model to jointly infer CNVs for three samples of a parent-offspring trio. Through application to both simulated data and a trio from 1000 Genomes Project, we showed that TrioCNV achieved superior performance than existing approaches.Availability and implementationThe software TrioCNV implemented using a combination of Java and R is freely available from the website at https://github.com/yongzhuang/TrioCNV CONTACT: ydwang@hit.edu.cnSupplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC4907378 | biostudies-literature
Project description:The offspring of older fathers have an increased risk of neurodevelopmental disorders such as schizophrenia and autism. It has been proposed that de novo point mutations and copy number variants (CNVs) in the continually dividing spermatogonia underlie this association. In light of the evidence implicating CNVs with schizophrenia and autism, here we use a mouse model to test the hypothesis that the offspring of older males have an increased risk of de novo CNVs. Three-month-old and fourteen- to sixteen-month-old C57BL/6J sires were mated with three-month-old dams to create control offspring and offspring of old sires, respectively. Applying genome-wide microarray screening technology, seven distinct CNVs were identified in a discovery set of twelve offspring and their parents. Competitive quantitative PCR was employed to confirm the variants and establish their frequency in a replication set of 77 offspring and their parents. Six de novo CNVs were detected in the offspring of older sires, while none were detected in the control group. One of the de novo CNVs involved Auts2 (autism susceptibility candidate 2), and other CNVs included genes linked to schizophrenia, autism and brain development. Two of the CNVs were associated with behavioural and/or neuroanatomical phenotypic features. This is the first experimental demonstration that the offspring of older males have more de novo CNVs. The results suggest that offspring of older fathers may be at increased risk of neurodevelopmental disorders such as schizophrenia and autism via the generation of de novo CNV in the male germline. In light of the trends for delayed parenthood in many societies, and in light of the potential for these CNVs to accumulate over subsequent generations, the impact of these mechanisms on the health of future generations warrants closer scrutiny. 2 sires of advanced paternal age (12-16 months of age) and 2 control (3 months of age) sires were mated to dams (3 months of age) to create 6 offspring of advanced paternal age (APA) and 6 control offspring (C), respectively, with an even number of sexes within each group of offspring. A commerical aCGH and a custom CNV array (both supplied by Agilent) were used in combination to detect copy number variations in the genomes of the offspring and their parents. DNA from all male animals was hybridized against a male reference animal and that from all female animals against a female reference animal.
2011-07-12 | E-GEOD-29454 | biostudies-arrayexpress
Project description:The offspring of older fathers have an increased risk of neurodevelopmental disorders such as schizophrenia and autism. It has been proposed that de novo point mutations and copy number variants (CNVs) in the continually dividing spermatogonia underlie this association. In light of the evidence implicating CNVs with schizophrenia and autism, here we use a mouse model to test the hypothesis that the offspring of older males have an increased risk of de novo CNVs. Three-month-old and fourteen- to sixteen-month-old C57BL/6J sires were mated with three-month-old dams to create control offspring and offspring of old sires, respectively. Applying genome-wide microarray screening technology, seven distinct CNVs were identified in a discovery set of twelve offspring and their parents. Competitive quantitative PCR was employed to confirm the variants and establish their frequency in a replication set of 77 offspring and their parents. Six de novo CNVs were detected in the offspring of older sires, while none were detected in the control group. One of the de novo CNVs involved Auts2 (autism susceptibility candidate 2), and other CNVs included genes linked to schizophrenia, autism and brain development. Two of the CNVs were associated with behavioural and/or neuroanatomical phenotypic features. This is the first experimental demonstration that the offspring of older males have more de novo CNVs. The results suggest that offspring of older fathers may be at increased risk of neurodevelopmental disorders such as schizophrenia and autism via the generation of de novo CNV in the male germline. In light of the trends for delayed parenthood in many societies, and in light of the potential for these CNVs to accumulate over subsequent generations, the impact of these mechanisms on the health of future generations warrants closer scrutiny. 2 sires of advanced paternal age (12-16 months of age) and 2 control (3 months of age) sires were mated to dams (3 months of age) to create 6 offspring of advanced paternal age (APA) and 6 control offspring (C), respectively, with an even number of sexes within each group of offspring. A commerical aCGH and a custom CNV array (both supplied by Agilent) were used in combination to detect copy number variations in the genomes of the offspring and their parents. DNA from all male animals was hybridized against a male reference animal and that from all female animals against a female reference animal.
2011-07-12 | E-GEOD-29455 | biostudies-arrayexpress
Project description:<p>The gut microbiota operates at the interface of host-environment interactions to influence human homeostasis and metabolic networks. Environmental factors that unbalance gut microbial ecosystems can therefore elicit physiological and disease-associated responses across somatic tissues. However, the systemic impact of the gut microbiome on the germline - and consequently on the F1 offspring it gives rise to - is unexplored. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory ‘gut-germline axis’ in males, which is sensitive to environmental exposures and programs offspring fitness through impacting placental function.</p>
2024-02-12 | MTBLS1629 | MetaboLights