Gonadal failure, along with early pregnancy loss and perinatal death, may be an important filter that limits the propagation of harmful mutations in the human population. We hypothesized that men with spermatogenic impairment, a disease with unknown genetic architecture and a common cause of male infertility, are enriched for rare deleterious mutations compared to men with normal spermatogenesis. After assaying genomewide SNPs and CNVs in 323 Caucasian men with idiopathic spermatogenic impairment and more than 1,100 controls, we estimate that each rare autosomal deletion detected in our study multiplicatively changes a man's risk of disease by 10% (OR 1.10 [1.04-1.16], p<2×10-3), rare X-linked CNVs by 29%, (OR 1.29 [1.11-1.50], p<1×10-3), and rare Y-linked duplications by 88% (OR 1.88 [1.13-3.13], p<0.03). By contrasting the properties of our case-specific CNVs with those of CNV callsets from cases of autism, schizophrenia, bipolar disorder, and intellectual disability, we propose that the CNV burden in spermatogenic impairment is distinct from the burden of large, dominant mutations described for neurodevelopmental disorders. We identified two patients with deletions of DMRT1, a gene on chromosome 9p24.3 orthologous to the putative sex determination locus of the avian ZW chromosome system. In an independent sample of Han Chinese men, we identified 3 more DMRT1 deletions in 979 cases of idiopathic azoospermia and none in 1,734 controls, and found none in an additional 4,519 controls from public databases. The combined results indicate that DMRT1 loss-of-function mutations are a risk factor and potential genetic cause of human spermatogenic failure (frequency of 0.38% in 1306 cases and 0% in 7,754 controls, p = 6.2×10-5). Our study identifies other recurrent CNVs as potential causes of idiopathic azoospermia and generates hypotheses for directing future studies on the genetic basis of male infertility and IVF outcomes.
Details
Title
Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, including the Gene DMRT1
Author
Lopes, Alexandra M. : University of Porto Aston, Kenneth I. : University of Utah Thompson, Emma : University of Chicago Carvalho, Filipa : University of Porto Gonçalves, João : National Institutes of Health Huang, Ni : Washington University School in St. Louis Matthiesen, Rune : University of Porto Noordam, Michiel J. : Washington University School in St. Louis Quintela, Inés : University of Santiago de Compostela Ramu, Avinash : Washington University School in St. Louis Seabra, Catarina : University of Porto Wilfert, Amy B. : Washington University School in St. Louis Dai, Juncheng : Nanjing Medical University Downie, Jonathan M. : University of Utah Fernandes, Susana : University of Porto Guo, Xuejiang : Nanjing Medical University Sha, Jiahao : Nanjing Medical University Amorim, António : University of Porto Barros, Alberto : University of Porto Carracedo, Angel : University of Santiago de Compostela Hu, Zhibin : Nanjing Medical University Hurles, Matthew E. : Wellcome Trust Sanger Institute Moskovtsev, Sergey : University of Toronto Ober, Carole : University of Chicago Paduch, Darius A. : Cornell University Schiffman, Joshua D. : University of Utah Schlegel, Peter N. : Cornell University Sousa, Mário : University of Porto Carrell, Douglas T. : University of Utah Conrad, Donald F. : Washington University School in St. Louis
Funding Information
Portuguese Foundation for Science and Technology European funds, COMPETE program, PTDC/SAU-GMG/101229/2008 FCT, postdoctoral fellowship, SFRH/BPD/73366/2010 United States National Institutes of Health, R01 HD21244 Damon Runyon, Clinical Investigator Award Alex's Lemonade Stand Foundation, Epidemiology Award Eunice Kennedy Shriver National Institute of Child Health and Human Development, Children's Health Research Career Development Award, 5K12HD001410 National Institute of Diabetes and Digestive and Kidney Diseases, George M. O'Brien Center for Kidney Disease Kidney Translational Research Core grant, P30DK079333
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