AXDND1 is required to balance spermatogonial commitment and for sperm tail formation in mice and humans.

Dynein complexes are large, multi-unit assemblies involved in many biological processes via their critical roles in protein transport and axoneme motility. Using next-generation sequencing of infertile men presenting with low or no sperm in their ejaculates, we identified damaging variants in the dynein-related gene AXDND1. We thus hypothesised that AXDND1 is a critical regulator of male fertility.

Hispanic Ethnicity and Fertility Outcomes.

Objective: To assess the association between ethnicity and fertility outcomes for men in a statewide cohort.

Methods: We linked data from the Utah Population Database and Subfertility Health Assisted Reproduction and Environment database, to comprise a cohort of sub-fertile men who underwent semen analysis between 1998 and 2017 in Utah. A multivariable Cox proportional hazard model was constructed to understand the impact of ethnicity on fertility outcomes in our cohort.

Undiagnosed RASopathies in infertile men.

RASopathies are syndromes caused by congenital defects in the Ras/mitogen-activated protein kinase (MAPK) pathway genes, with a population prevalence of 1 in 1,000. Patients are typically identified in childhood based on diverse characteristic features, including cryptorchidism (CR) in >50% of affected men. As CR predisposes to spermatogenic failure (SPGF; total sperm count per ejaculate 0-39 million), we hypothesized that men seeking infertility management include cases with undiagnosed RASopathies.

Heterozygous Stop Gain Mice Replicate the Primary Ovarian Insufficiency Phenotype in Women.

We created the c.1286C>G stop-gain mutation found in a family with primary ovarian insufficiency (POI) at age 30 years. The C57/Bl6 transgenic mouse model contained a floxed exon 10-19 cassette with a conditional knock-in cassette containing the c.

Toward clinical exomes in diagnostics and management of male infertility.

Infertility, affecting ∼10% of men, is predominantly caused by primary spermatogenic failure (SPGF). We screened likely pathogenic and pathogenic (LP/P) variants in 638 candidate genes for male infertility in 521 individuals presenting idiopathic SPGF and 323 normozoospermic men in the ESTAND cohort. Molecular diagnosis was reached for 64 men with SPGF (12%), with findings in 39 genes (6%).

The human infertility single-cell testis atlas (HISTA): an interactive molecular scRNA-Seq reference of the human testis.

Background: Single-cell RNA-seq (scRNA-Seq) has been widely adopted to study gene expression of the human testis. Several datasets of scRNA-Seq from human testis have been generated from different groups processed with different informatics pipelines. An integrated atlas of scRNA-Seq expression constructed from multiple donors, developmental ages, and fertility states would be widely useful for the testis research community.

C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line.

In the male mouse germ line, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide DNA methylation of young active transposons through SPOCD1. However, the underlying mechanisms of SPOCD1-mediated piRNA-directed transposon methylation and whether this pathway functions to protect the human germ line remain unknown. We identified loss-of-function variants in human SPOCD1 that cause defective transposon silencing and male infertility.

Resistance and aerobic training increases genome-wide DNA methylation in women with polycystic ovary syndrome.

Physical activity is a first-line treatment for polycystic ovary syndrome (PCOS). Resistance or aerobic exercise improves metabolic complications, reproductive outcomes, and quality of life in PCOS. DNA methylation reprogramming during exercise may be the major modifier behind these changes.

An assessment of alterations to human sperm methylation patterns in coronavirus disease 2019 infected and healthy control males.

Objective: To determine whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects male reproductive health, considering the many potential factors that contribute to declines in male fertility on a semiglobal scale.

Design: In total, 64 human semen samples-32 treatment and 32 control-were laboratory processed and bioinformatically analyzed to assess differences in DNA methylation patterns. Implementing multiple bioinformatic tools, the analyses conducted will elicit between-group differences with respect to epigenetic age, epigenetic instability, semiglobal, and regional methylation, in addition to methylation patterns as a function of time since infection.

AXDND1 is required to balance spermatogonial commitment and for sperm tail formation in mice and humans.

Dynein complexes are large, multi-unit assemblies involved in many biological processes including male fertility via their critical roles in protein transport and axoneme motility. Previously we identified a pathogenic variant in the dynein gene in an infertile man. Subsequently we identified an additional four potentially compound heterozygous variants of unknown significance in in two additional infertile men.

Epigenetic determinants of reproductive potential augment the predictive ability of the semen analysis.

Objective: To investigate the power of DNA methylation variability in sperm cells in assessing male fertility potential.

Design: Retrospective cohort.

Setting: Fertility care centers.

Global effects of identity and aging on the human sperm methylome.

Background: As the average age of fatherhood increases worldwide, so too does the need for understanding effects of aging in male germline cells. Molecular change, including epigenomic alterations, may impact offspring. Age-associated change to DNA cytosine methylation in the cytosine-guanine (CpG) context is a hallmark of aging tissues, including sperm.

Tissue-specific DNA methylation variability and its potential clinical value.

Complex diseases have multifactorial etiologies making actionable diagnostic biomarkers difficult to identify. Diagnostic research must expand beyond single or a handful of genetic or epigenetic targets for complex disease and explore a broader system of biological pathways. With the objective to develop a diagnostic tool designed to analyze a comprehensive network of epigenetic profiles in complex diseases, we used publicly available DNA methylation data from over 2,400 samples representing 20 cell types and various diseases.

Environmental exposure to industrial air pollution is associated with decreased male fertility.

Objective: To understand how chronic exposure to industrial air pollution is associated with male fertility through semen parameters.

Design: Retrospective cohort study.

Patients: Men in the Subfertility, Health, and Assisted Reproduction cohort who underwent a semen analysis in the two largest healthcare systems in Utah from 2005-2017 with ≥1 measured semen parameter (N = 21,563).

DDX3Y is likely the key spermatogenic factor in the AZFa region that contributes to human non-obstructive azoospermia.

Non-obstructive azoospermia, the absence of sperm in the ejaculate due to disturbed spermatogenesis, represents the most severe form of male infertility. De novo microdeletions of the Y-chromosomal AZFa region are one of few well-established genetic causes for NOA and are routinely analysed in the diagnostic workup of affected men. So far, it is unclear which of the three genes located in the AZFa chromosomal region is indispensible for germ cell maturation.

Diverse monogenic subforms of human spermatogenic failure.

Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%.

Effect of chemotherapy on the uterus of young adult cancer survivors.

Objective: To investigate the impact of chemotherapy on the uterus.

Design: Cross-sectional pilot study.

Setting: Single university fertility clinic.

DDB1- and CUL4-associated factor 12-like protein 1 (Dcaf12l1) is not essential for male fertility in mice.

Male infertility is a common condition affecting at least 7% of men worldwide and is often genetic in origin. Using whole exome sequencing, we recently discovered three hemizygous, likely damaging variants in DDB1- and CUL4-associated factor 12-like protein 1 (DCAF12L1) in men with azoospermia. DCAF12L1 is located on the X-chromosome and as identified by single cell sequencing studies, its expression is enriched in human testes and specifically in Sertoli cells and spermatogonia.

Seasonal variation in semen quality is not associated with fecundity in the Utah Population Database.

We determine whether a suspected seasonal variability in semen quality affect subsequent live birth rates. This is a retrospective, cohort analysis of men who provided semen analyses as part of fertility workup through a large andrology lab between 1996 and 2013 and corresponding birth rates using the Utah Population Database (UPDB). Semen parameters were analysed including total motile count (TMC), total sperm count, sperm concentration and progressive motility.

Zinc finger RNA binding protein 2 (ZFR2) is not required for male fertility in the mouse.

Background: Thousands of genes are expressed during spermatogenesis and male infertility has a strong genetic component. Within this study, we focus on the role of Zfr2 in male fertility, a gene previously implicated in human male fertility. To date, very little is known about the role of ZFR2 in either humans or mice.