Biological Sciences Division
Published March 21, 2013 | Version v1
Journal article Open

Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, including the Gene DMRT1

Creators

  • 1. University of Porto
  • 2. University of Utah
  • 3. University of Chicago
  • 4. National Institutes of Health
  • 5. Washington University School in St. Louis
  • 6. University of Santiago de Compostela
  • 7. Nanjing Medical University
  • 8. Wellcome Trust Sanger Institute
  • 9. University of Toronto
  • 10. Cornell University

Description

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.

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Additional details

Identifiers

DOI
10.1371/journal.pgen.1003349
Other
oai:uchicago.tind.io:10894

Funding

Portuguese Foundation for Science and Technology
European funds
COMPETE program
FCT
postdoctoral fellowship
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
National Institute of Diabetes and Digestive and Kidney Diseases
George M. O'Brien Center for Kidney Disease Kidney Translational Research Core grant

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Human Genetics, Obstetrics and Gynecology