Genetic and epigenetic profiling of the infertile male

Abstract

Evaluation of reproductive quality of spermatozoa by standard semen analysis is often inadequate to predict ART outcome. Men may be prone to meiotic error and have higher proportion of spermatozoa with fragmented chromatin, capable of affecting the conceptus' health. In men with unexplained infertility, supplementary tests may be pivotal to gain insight into the paternal contribution to the zygotic genome. A total of 113 consenting men were included in the study, with an additional 5 donor specimens used as control. Among study participants, 87 were screened for sperm aneuploidy by fluorescent in situ hybridization (FISH) and ranked according to their increasing age. A total of 18 men were assessed by whole exome sequencing and categorized according to their reproductive outcome as either fertile or infertile. Another set of men (n = 13) had their gene expression analyzed by RNA-seq and were profiled according to their reproductive capacity. FISH revealed that the average aneuploidy rate was highest for men over-55 age group (9.6%), while men >55 had the highest average disomy for chromosomes 17(1.2%) and 18(1.3%). ART results for the entire cohort comprised 157 cycles, stratified by paternal age. The youngest age group (25–30 years) had a fertilization rate of 87.7% which decreased to 46.0% in the >55 age group. Clinical pregnancy rate was highest in the 25-30yr group (80.0%) while no pregnancies were attained in the >55 age groups. Pregnancy loss was characterized by a steadily increasing trend, highest in the 51–55 age group (50.0%). NGS was performed on a cohort of patients classified as having recurrent pregnancy loss. This cohort was classified as the infertile group (n = 10) and was compared to a control group (n = 8) consisting of patients successfully treated by ART. Eight couples in 17 ICSI cycles achieved a clinical pregnancy rate of 82.4% while 10 infertile couples treated in 21 cycles achieved a pregnancy rate of 23.8%, all resulting in pregnancy loss. DNA-sequencing on spermatozoa from these patients yielded overall aneuploidy of 4.0% for fertile and 8.6% for the infertile group (P<0.00001). In the infertile cohort, we identified 17 genes with the highest mutation rate, engaged in key roles of gametogenesis, fertilization and embryo development. RNA-seq was performed on patients (n = 13) with normal semen analyses. Five men unable to attain a pregnancy after ART were categorized as the infertile group, while 8 men who successfully sustained a pregnancy were established as the fertile control. Analysis resulted in 86 differentially expressed genes (P<0.001). Of them, 24 genes were overexpressed and 62 were under-expressed in the infertile cohort. DNA repair genes (APLF, CYB5R4, ERCC4 and TNRFSF21) and apoptosis-modulating genes (MORC1, PIWIL1 and ZFAND6) were remarkably under-expressed (P<0.001). Sperm aneuploidy assessment supported by information on gene mutations may indicate subtle dysfunctions of the spermatozoon. Furthermore, by querying noncoding RNA we may gather knowledge on embryo developmen...

Litter Size of Sheep (Ovis aries): Inbreeding Depression and Homozygous Regions

“…Health is an important reproductive content. Of interest, some candidates related to sperm and infertility were identified, containing MORC1 [ 46 ], TDRD9 [ 47 ], ZFYVE21 [ 48 ], ADGRB3 [ 49 ], SPAG17 [ 50 , 51 ], CKB [ 52 ], and WDR3 [ 53 ], which may have effects on sperm motility and fertilization. Additionally, we identified some candidate genes linked to reproductive diseases, such as NRG3 [ 54 ] and XRCC3 [ 55 ] for ovarian cancer, and BAG5 [ 56 ], CKB [ 57 ] and XRCC3 [ 55 ] for endometriosis.…”

Assessing the cognitive and behavioral development of 3-year-old children born from fathers with severe male infertility

“…One of the most recognized genetic variations associated with autism is on chromosome 15, 46 which has been shown to have higher aneuploidy with advancing paternal age. 47 These incidences of autistic children, although scarce, may possibly be attributed to chromosome 15 aberrations in these older patients. Therefore, cases with Original Research GYNECOLOGY ajog.org advanced paternal age may benefit from a genetic assessment.…”

Fertility Relevance Probability Analysis Shortlists Genetic Markers for Male Fertility Impairment

“…In fact, HORMAD1 (HORMA domain containing 1), participates in DSB repair [Carofiglio et al, 2018], and SMC1B (structural maintenance of chromosomes 1B) engages in chromosome segregation, chromatid cohesion, and the maintenance of genome stability [Revenkova et al, 2001;Mannini et al, 2015]. Thus, candidate markers SPO11, HORMAD1, and SMC1B corroborate that genome and chromosome integrity are essential for normal spermiogenesis and male fertility [Ferlin et al, 2007;Poongothai et al, 2009;Zorrilla and Yatsenko, 2013;Bracke et al, 2018;Cariati et al, 2019;Cheung et al, 2019]. Actually, this is also true for DAZL, through its regulatory effect on the gene coding for synaptonemal complex protein 3 (SYCP3) [Aarabi et al, 2006;Reynolds et al, 2007;see also Miyamoto et al, 2003].…”