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Human spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1

2013-03-21Journal article Open access
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dc.contributor.authorLopes, Alexandra
dc.contributor.authorAston, Kenneth I.
dc.contributor.authorThompson, Emma E
dc.contributor.authorCarvalho, Filipa
dc.contributor.authorGonçalves, João
dc.contributor.authorHuang, N.
dc.contributor.authorMatthiesen, Rune
dc.contributor.authorNoordam, Michiel J.
dc.contributor.authorQuintela, Ines
dc.contributor.authorRamu, Avinash
dc.contributor.authorSeabra, Catarina
dc.contributor.authorWilfert, Amy B.
dc.contributor.authorDai, Juncheng
dc.contributor.authorDownie, Jonathan
dc.contributor.authorFernandes, Susana
dc.contributor.authorGuo, Xuejiang
dc.contributor.authorShah, Jiahao
dc.contributor.authorAmorim, Antonio
dc.contributor.authorBarros, Alberto
dc.contributor.authorCarracedo, A.
dc.contributor.authorHu, Z.
dc.contributor.authorHurles, M.E.
dc.contributor.authorMoskovtsev, S.
dc.contributor.authorOber, C.
dc.contributor.authorPaduch, D.A.
dc.contributor.authorSchiffman, J.D.
dc.contributor.authorSchlegel, P.N.
dc.contributor.authorSousa, M.
dc.contributor.authorCarrell, D.T.
dc.contributor.authorConrad, D.F.
dc.date.accessioned2014-03-17T17:12:33Z
dc.date.available2014-03-17T17:12:33Z
dc.date.issued2013-03-21
dc.description.abstractGonadal 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,261023), rare X-linked CNVs by 29%, (OR 1.29 [1.11–1.50], p,161023), 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 = 6.261025). 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.por
dc.description.sponsorshipThis work was partially funded by the Portuguese Foundation for Science and Technology FCT/MCTES (PIDDAC) and co-financed by European funds (FEDER) through the COMPETE program, research grant PTDC/SAU-GMG/101229/2008. IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology, and Higher Education and is partially supported by FCT. AML is the recipient of a postdoctoral fellowship from FCT (SFRH/BPD/73366/2010). CO is supported by a grant from the United States National Institutes of Health (R01 HD21244), JDS is supported by Damon Runyon Clinical Investigator Award, Alex's Lemonade Stand Foundation Epidemiology Award, and the Eunice Kennedy Shriver Children's Health Research Career Development Award NICHD 5K12HD001410. Support for humans studies and specimens were provided by the NIH/NIDDK George M. O'Brien Center for Kidney Disease Kidney Translational Research Core (P30DK079333) grant to Washington University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.por
dc.identifier.citationPLoS Genet. 2013 Mar;9(3):e1003349. doi: 10.1371/journal.pgen.1003349. Epub 2013 Mar 21por
dc.identifier.issn1553-7390
dc.identifier.otherdoi:10.1371/journal.pgen.1003349
dc.identifier.urihttp://hdl.handle.net/10400.18/2157
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherPublic Library of Sciencepor
dc.relation.publisherversionhttp://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003349por
dc.subjectHuman Infertilitypor
dc.subjectHuman Spermatogenesispor
dc.subjectMale Infertilitypor
dc.subjectDMRT1por
dc.subjectCNVpor
dc.subjectAzoospermiapor
dc.subjectOligozoospermiapor
dc.subjectArraypor
dc.subjectDoenças Genéticaspor
dc.titleHuman spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1por
dc.typejournal article
dspace.entity.typePublication
oaire.citation.startPagee1003349por
oaire.citation.titlePLoS Geneticspor
oaire.citation.volume9(3)por
rcaap.rightsopenAccesspor
rcaap.typearticlepor

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