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Genome-wide epigenetic and genetic investigation of male infertility Louie, Kenny


Genetic causes have been known to be involved in up to one-third of male infertility cases. Studies on the sperm and testis from infertile men have suggested that this population may also have higher rates of altered epigenetic modifications, particularly DNA methylation. Thus, we hypothesized that genetic and epigenetic causes may play a role together in male infertility. We used Sanger sequencing to observe the DNA methylation at imprinted differentially methylated regions– H19, IG-GTL2, and MEST – in the sperm of infertile men with oligozoospermia to assess the occurrence of alterations. We analyzed semen samples from fifty-three men (9 fertile and 44 infertile – stratified by sperm concentration). Although we observed altered cases in 13% (3/23) of men with severe oligozoospermia and none among controls, this finding was not significant. We genotyped the same men at the MTHFR C677T single nucleotide polymorphism (SNP) to determine whether this methyl supply gene is associated with DNA methylation in the sperm. We observed a trend that all altered cases had the CT genotype at this SNP and in the severe oligozoospermic subgroup, suggesting a combinatorial effect. Motivated from these findings, we conducted two genome-wide investigations to identify novel genes with DNA methylation alterations and/or SNPs relating to male infertility. We evaluated the genome-wide DNA methylation in the testis of twenty-four men (8 fertile and 16 infertile). Using predictive models, we identified 359 CpGs with altered DNA methylation among the infertile men. Of these loci and using functional analyses, we identified NDE1 which is a gene involved with cell cycle progression and centrosome formation. In the genome-wide SNP analysis of twenty men (13 fertile and 7 infertile), we identified 39 SNPs using machine learning models. Of these SNPs, candidates included MTR – a gene involved with the same folate pathway as MTHFR – and NIN which is a gene involved with proper chromosome segregation during cell division. In summary, we observed altered DNA methylation and SNPs in infertile men. We presented evidence that altered DNA methylation and changes in genetic sequence in genes involved with cell division and progression may impair spermatogenesis leading to male infertility.

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