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

Alexandra M. Lopes, Kenneth I. Aston, Emma Thompson, Filipa Carvalho, João Gonçalves, Ni Huang, Rune Matthiesen, Michiel J. Noordam, Inés Quintela, Avinash Ramu, Catarina Seabra, Amy B. Wilfert, Juncheng Dai, Jonathan M. Downie, Susana Fernandes, Xuejiang Guo, Jiahao Sha, António Amorim, Alberto Barros, Angel CarracedoZhibin Hu, Matthew E. Hurles, Sergey Moskovtsev, Carole Ober, Darius A. Paduch, Joshua D. Schiffman, Peter N. Schlegel, Mário Sousa, Douglas T. Carrell, Don Conrad

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numbere1003349
JournalPLoS genetics
Volume9
Issue number3
DOIs
StatePublished - Apr 15 2013
Externally publishedYes

Fingerprint

Sex Chromosomes
autosomes
sex chromosomes
chromosome
mutation
infertility
Mutation
gene
male fertility
Azoospermia
Genes
Male Infertility
genes
chromosomes
Chromosomes
sex determination
gene deletion
disability
spermatogenesis
risk factor

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, including the Gene DMRT1. / Lopes, Alexandra M.; Aston, Kenneth I.; Thompson, Emma; Carvalho, Filipa; Gonçalves, João; Huang, Ni; Matthiesen, Rune; Noordam, Michiel J.; Quintela, Inés; Ramu, Avinash; Seabra, Catarina; Wilfert, Amy B.; Dai, Juncheng; Downie, Jonathan M.; Fernandes, Susana; Guo, Xuejiang; Sha, Jiahao; Amorim, António; Barros, Alberto; Carracedo, Angel; Hu, Zhibin; Hurles, Matthew E.; Moskovtsev, Sergey; Ober, Carole; Paduch, Darius A.; Schiffman, Joshua D.; Schlegel, Peter N.; Sousa, Mário; Carrell, Douglas T.; Conrad, Don.

In: PLoS genetics, Vol. 9, No. 3, e1003349, 15.04.2013.

Research output: Contribution to journalArticle

Lopes, AM, Aston, KI, Thompson, E, Carvalho, F, Gonçalves, J, Huang, N, Matthiesen, R, Noordam, MJ, Quintela, I, Ramu, A, Seabra, C, Wilfert, AB, Dai, J, Downie, JM, Fernandes, S, Guo, X, Sha, J, Amorim, A, Barros, A, Carracedo, A, Hu, Z, Hurles, ME, Moskovtsev, S, Ober, C, Paduch, DA, Schiffman, JD, Schlegel, PN, Sousa, M, Carrell, DT & Conrad, D 2013, 'Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, including the Gene DMRT1', PLoS genetics, vol. 9, no. 3, e1003349. https://doi.org/10.1371/journal.pgen.1003349
Lopes, Alexandra M. ; Aston, Kenneth I. ; Thompson, Emma ; Carvalho, Filipa ; Gonçalves, João ; Huang, Ni ; Matthiesen, Rune ; Noordam, Michiel J. ; Quintela, Inés ; Ramu, Avinash ; Seabra, Catarina ; Wilfert, Amy B. ; Dai, Juncheng ; Downie, Jonathan M. ; Fernandes, Susana ; Guo, Xuejiang ; Sha, Jiahao ; Amorim, António ; Barros, Alberto ; Carracedo, Angel ; Hu, Zhibin ; Hurles, Matthew E. ; Moskovtsev, Sergey ; Ober, Carole ; Paduch, Darius A. ; Schiffman, Joshua D. ; Schlegel, Peter N. ; Sousa, Mário ; Carrell, Douglas T. ; Conrad, Don. / Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, including the Gene DMRT1. In: PLoS genetics. 2013 ; Vol. 9, No. 3.
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abstract = "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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AU - Lopes, Alexandra M.

AU - Aston, Kenneth I.

AU - Thompson, Emma

AU - Carvalho, Filipa

AU - Gonçalves, João

AU - Huang, Ni

AU - Matthiesen, Rune

AU - Noordam, Michiel J.

AU - Quintela, Inés

AU - Ramu, Avinash

AU - Seabra, Catarina

AU - Wilfert, Amy B.

AU - Dai, Juncheng

AU - Downie, Jonathan M.

AU - Fernandes, Susana

AU - Guo, Xuejiang

AU - Sha, Jiahao

AU - Amorim, António

AU - Barros, Alberto

AU - Carracedo, Angel

AU - Hu, Zhibin

AU - Hurles, Matthew E.

AU - Moskovtsev, Sergey

AU - Ober, Carole

AU - Paduch, Darius A.

AU - Schiffman, Joshua D.

AU - Schlegel, Peter N.

AU - Sousa, Mário

AU - Carrell, Douglas T.

AU - Conrad, Don

PY - 2013/4/15

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N2 - 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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