scholarly journals Sperm DNA methylation epimutation biomarker for paternal offspring autism susceptibility

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicolás Garrido ◽  
Fabio Cruz ◽  
Rocio Rivera Egea ◽  
Carlos Simon ◽  
Ingrid Sadler-Riggleman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Autism Spectrum ◽  
Epigenetic Alterations ◽  
Genome Wide ◽  
Sperm Dna ◽  
A Genome ◽  
Potential Biomarker ◽  
Test Sets ◽  
Autism Susceptibility ◽  
Sperm Dna Methylation

Abstract Background Autism spectrum disorder (ASD) has increased over tenfold over the past several decades and appears predominantly associated with paternal transmission. Although genetics is anticipated to be a component of ASD etiology, environmental epigenetics is now also thought to be an important factor. Epigenetic alterations, such as DNA methylation, have been correlated with ASD. The current study was designed to identify a DNA methylation signature in sperm as a potential biomarker to identify paternal offspring autism susceptibility. Methods and results Sperm samples were obtained from fathers that have children with or without autism, and the sperm then assessed for alterations in DNA methylation. A genome-wide analysis (> 90%) for differential DNA methylation regions (DMRs) was used to identify DMRs in the sperm of fathers (n = 13) with autistic children in comparison with those (n = 13) without ASD children. The 805 DMR genomic features such as chromosomal location, CpG density and length of the DMRs were characterized. Genes associated with the DMRs were identified and found to be linked to previously known ASD genes, as well as other neurobiology-related genes. The potential sperm DMR biomarkers/diagnostic was validated with blinded test sets (n = 8–10) of individuals with an approximately 90% accuracy. Conclusions Observations demonstrate a highly significant set of 805 DMRs in sperm that can potentially act as a biomarker for paternal offspring autism susceptibility. Ancestral or early-life paternal exposures that alter germline epigenetics are anticipated to be a molecular component of ASD etiology.

scholarly journals Integrating Signals from Sperm Methylome Analysis and Genome-Wide Association Study for a Better Understanding of Male Fertility in Cattle

Epigenomes ◽  
2019 ◽  
Vol 3 (2) ◽  
pp. 10 ◽  
Author(s):  
Lingzhao Fang ◽  
Yang Zhou ◽  
Shuli Liu ◽  
Jicai Jiang ◽  
Derek M. Bickhart ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Complex Traits ◽  
Male Fertility ◽  
Genome Wide Association ◽  
Human Society ◽  
Potential Candidate ◽  
Genome Wide ◽  
Sperm Dna ◽  
Genomic Regions ◽  
Sperm Dna Methylation

Decreased male fertility is a big concern in both human society and the livestock industry. Sperm DNA methylation is commonly believed to be associated with male fertility. However, due to the lack of accurate male fertility records (i.e., limited mating times), few studies have investigated the comprehensive impacts of sperm DNA methylation on male fertility in mammals. In this study, we generated 10 sperm DNA methylomes and performed a preliminary correlation analysis between signals from sperm DNA methylation and signals from large-scale (n = 27,214) genome-wide association studies (GWAS) of 35 complex traits (including 12 male fertility-related traits). We detected genomic regions, which experienced DNA methylation alterations in sperm and were associated with aging and extreme fertility phenotypes (e.g., sire-conception rate or SCR). In dynamic hypomethylated regions (HMRs) and partially methylated domains (PMDs), we found genes (e.g., HOX gene clusters and microRNAs) that were involved in the embryonic development. We demonstrated that genomic regions, which gained rather than lost methylations during aging, and in animals with low SCR were significantly and selectively enriched for GWAS signals of male fertility traits. Our study discovered 16 genes as the potential candidate markers for male fertility, including SAMD5 and PDE5A. Collectively, this initial effort supported a hypothesis that sperm DNA methylation may contribute to male fertility in cattle and revealed the usefulness of functional annotations in enhancing biological interpretation and genomic prediction for complex traits and diseases.

scholarly journals High-resolution analyses of human sperm dynamic methylome reveal thousands of novel age-related epigenetic alterations

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Mingju Cao ◽  
Xiaojian Shao ◽  
Peter Chan ◽  
Warren Cheung ◽  
Tony Kwan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Human Sperm ◽  
Distal Region ◽  
Epigenetic Alterations ◽  
Transcription Start Sites ◽  
Neurodevelopmental Disease ◽  
Cpg Sites ◽  
Age Related ◽  
Sperm Dna ◽  
Sperm Dna Methylation

Abstract Background Children of aged fathers are at a higher risk of developing mental disorders. Alterations in sperm DNA methylation have been implicated as a potential cause. However, age-dependent modifications of the germ cells’ epigenome remain poorly understood. Our objective was to assess the DNA methylation profile of human spermatozoa during aging. Results We used a high throughput, customized methylC-capture sequencing (MCC-seq) approach to characterize the dynamic DNA methylation in spermatozoa from 94 fertile and infertile men, who were categorized as young, 48 men between 18–38 years or old 46 men between 46–71 years. We identified more than 150,000 age-related CpG sites that are significantly differentially methylated among 2.65 million CpG sites covered. We conducted machine learning using our dataset to predict the methylation age of subjects; the age prediction accuracy based on our assay provided a more accurate prediction than that using the 450 K chip approach. In addition, we found that there are more hypermethylated (62%) than hypomethylated (38%) CpG sites in sperm of aged men, corresponding to 798 of total differential methylated regions (DMRs), of which 483 are hypermethylated regions (HyperDMR), and 315 hypomethylated regions (HypoDMR). Moreover, the distribution of age-related hyper- and hypomethylated CpGs in sperm is not random; the CpG sites that were hypermethylated with advanced age were frequently located in the distal region to genes, whereas hypomethylated sites were near to gene transcription start sites (TSS). We identified a high density of age-associated CpG changes in chromosomes 4 and 16, particularly HyperDMRs with localized clusters, the chr4 DMR cluster overlaps PGC1α locus, a protein involved in metabolic aging and the chr16 DMR cluster overlaps RBFOX1 locus, a gene implicated in neurodevelopmental disease. Gene ontology analysis revealed that the most affected genes by age were associated with development, neuron projection, differentiation and recognition, and behaviour, suggesting a potential link to the higher risk of neurodevelopmental disorders in children of aged fathers. Conclusion We identified thousands of age-related and sperm-specific epigenetic alterations. These findings provide novel insight in understanding human sperm DNA methylation dynamics during paternal aging, and the subsequently affected genes potentially related to diseases in offspring.

scholarly journals Sperm DNA Methylation Epimutation Biomarkers for Male Infertility and FSH Therapeutic Responsiveness

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Saturnino Luján ◽  
Ettore Caroppo ◽  
Craig Niederberger ◽  
Joan-Carles Arce ◽  
Ingrid Sadler-Riggleman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Male Infertility ◽  
Sperm Quality ◽  
Therapeutic Treatment ◽  
Idiopathic Infertility ◽  
Epigenetic Biomarkers ◽  
Genome Wide ◽  
Sperm Dna ◽  
Infertility Patients ◽  
Sperm Dna Methylation

AbstractMale factor infertility is increasing and recognized as playing a key role in reproductive health and disease. The current primary diagnostic approach is to assess sperm quality associated with reduced sperm number and motility, which has been historically of limited success in separating fertile from infertile males. The current study was designed to develop a molecular analysis to identify male idiopathic infertility using genome wide alterations in sperm DNA methylation. A signature of differential DNA methylation regions (DMRs) was identified to be associated with male idiopathic infertility patients. A promising therapeutic treatment of male infertility is the use of follicle stimulating hormone (FSH) analogs which improved sperm numbers and motility in a sub-population of infertility patients. The current study also identified genome-wide DMRs that were associated with the patients that were responsive to FSH therapy versus those that were non-responsive. This novel use of epigenetic biomarkers to identify responsive versus non-responsive patient populations is anticipated to dramatically improve clinical trials and facilitate therapeutic treatment of male infertility patients. The use of epigenetic biomarkers for disease and therapeutic responsiveness is anticipated to be applicable for other medical conditions.

Analysis of Gene-Specific and Genome-Wide Sperm DNA Methylation

2012 ◽  
pp. 451-458 ◽  
Author(s):  
Saher Sue Hammoud ◽  
Bradley R. Cairns ◽  
Douglas T. Carrell
Keyword(s):  
Dna Methylation ◽  
Genome Wide ◽  
Sperm Dna ◽  
Sperm Dna Methylation

55 Peri-conceptional undernourishment perturbs offspring sperm methylome

2019 ◽  
Vol 31 (1) ◽  
pp. 153
Author(s):  
P. Toschi ◽  
E. Capra ◽  
D. Anzalone ◽  
F. Turri ◽  
F. Pizzi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Folic Acid ◽  
Folic Acid Supplementation ◽  
Computer Assisted ◽  
Methyl Donors ◽  
Acid Supplementation ◽  
Maternal Undernutrition ◽  
Sperm Dna ◽  
A Genome ◽  
Sperm Dna Methylation

Whereas an organism’s genotype is relatively static throughout life, the epigenome is highly dynamic and can adapt, or be altered, in response to the external environment such as diet. Intrauterine exposure to nutrient availability can alter the establishment of epigenetic marks, not only in the exposed individuals, but also in their offspring. Inheritance of such an environmentally acquired phenotype by the subsequent generation occurs through epigenetic modifications in the germline. Here, using a genome-wide approach, we evaluate how modification of the maternal diet pre- (14 days) and post- (28 days) conception can affect methylation status of the sperm of male offspring. Specifically, using a sheep model, we focused on the effect of maternal undernutrition on adult sperm methylation and its long-term consequences on sperm physiology and quality. Moreover, we investigated if supplementation of folic acid, to increase the availability of methyl donors, could prevent or ameliorate the adverse uterine environment caused by maternal undernutrition. Male lambs obtained from mothers subjected to different nutritional regimens (UND: undernutrition; FA: undernutrition and folic acid supplementation) appeared normal at birth, with a comparable body weight until Day 30 postpartum. Sperm DNA methylation, obtained by reduced representation bisulfite sequencing, differed in offspring that experienced in utero undernutrition (UND and FA) compared with the control group (CTR). In particular, the number of differentially methylated regions (DMR) was lower when UND and FA groups were compared, whereas a higher number of DMR was observed by comparison of CTR with both experimental groups. In addition, a high percentage of DMR were shared between UND and FA groups when compared with CTR, clearly indicating a influence of maternal nutrition on the offspring sperm DNA methylation rearrangement. Gene ontology (GO) analysis showed variation in functional categories related to sperm functionality such as chondroitin sulfate synthesis, potassium ion import, and others related to metabolism (biotin and glucagon). Furthermore, using computer-assisted semen analysis and flow cytometric measurement, we observed lower a sperm motility index and higher incidence of chromatin structure alterations in spermatozoa collected from UND and FA groups compared with CTR. Finally, to verify the effect of such reported abnormality on lamb fertility, we used the semen for in vitro embryo production. While we obtained good quality blastocysts from all 3 groups, a reduction in the percentage of embryo development, partially compensated in the FA group, was found using spermatozoa from UND rams. Taken together, our results confirm that a nutritional stress during early mammalian development can lead to epigenetic modification in the offspring. This damage can be partially ameliorated with folic acid supplementation; however, some alteration still persists in the germline and could be passed to the next generation, with as yet unknown consequences.

Genome-wide profiling of sperm DNA methylation in relation to buffalo (Bubalus bubalis) bull fertility

2014 ◽  
Vol 82 (5) ◽  
pp. 750-759.e1 ◽  
Author(s):  
Arpana Verma ◽  
Sandeep Rajput ◽  
Sachinandan De ◽  
Rakesh Kumar ◽  
Atish Kumar Chakravarty ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bubalus Bubalis ◽  
Genome Wide ◽  
Sperm Dna ◽  
Sperm Dna Methylation

scholarly journals Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans

Epigenomics ◽  
2015 ◽  
Vol 7 (5) ◽  
pp. 717-731 ◽  
Author(s):  
Joshua Denham ◽  
Brendan J O'Brien ◽  
Jack T Harvey ◽  
Fadi J Charchar
Keyword(s):  
Dna Methylation ◽  
Exercise Training ◽  
Genome Wide ◽  
Sperm Dna ◽  
Sperm Dna Methylation

scholarly journals Early-Life Exposure to Environmental Contaminants Perturbs the Sperm Epigenome and Induces Negative Pregnancy Outcomes for Three Generations via the Paternal Lineage

Epigenomes ◽  
2021 ◽  
Vol 5 (2) ◽  
pp. 10
Author(s):  
Clotilde Maurice ◽  
Mathieu Dalvai ◽  
Romain Lambrot ◽  
Astrid Deschênes ◽  
Marie-Pier Scott-Boyer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Pregnancy Outcomes ◽  
Sperm Quality ◽  
The Arctic ◽  
Congenital Defects ◽  
Developmental Defects ◽  
Early Life Exposure ◽  
Sperm Dna ◽  
Inuit Population ◽  
Sperm Dna Methylation

Due to the grasshopper effect, the Arctic food chain in Canada is contaminated with persistent organic pollutants (POPs) of industrial origin, including polychlorinated biphenyls and organochlorine pesticides. Exposure to POPs may be a contributor to the greater incidence of poor fetal growth, placental abnormalities, stillbirths, congenital defects and shortened lifespan in the Inuit population compared to non-Aboriginal Canadians. Although maternal exposure to POPs is well established to harm pregnancy outcomes, paternal transmission of the effects of POPs is a possibility that has not been well investigated. We used a rat model to test the hypothesis that exposure to POPs during gestation and suckling leads to developmental defects that are transmitted to subsequent generations via the male lineage. Indeed, developmental exposure to an environmentally relevant Arctic POPs mixture impaired sperm quality and pregnancy outcomes across two subsequent, unexposed generations and altered sperm DNA methylation, some of which are also observed for two additional generations. Genes corresponding to the altered sperm methylome correspond to health problems encountered in the Inuit population. These findings demonstrate that the paternal methylome is sensitive to the environment and that some perturbations persist for at least two subsequent generations. In conclusion, although many factors influence health, paternal exposure to contaminants plays a heretofore-underappreciated role with sperm DNA methylation contributing to the molecular underpinnings involved.

scholarly journals DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 441
Author(s):  
Fanny Pineau ◽  
Davide Caimmi ◽  
Sylvie Taviaux ◽  
Maurane Reveil ◽  
Laura Brosseau ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dna Methylation ◽  
Clinical Trials ◽  
Lung Disease ◽  
Disease Severity ◽  
Genome Wide ◽  
A Genome ◽  
Lung Disease Severity ◽  
Epigenetic Biomarker

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

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