title: Human spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1.
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.
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Lopes
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Aston
authors.forename: Emma
authors.initials: E
authors.lastname: Thompson
authors.forename: Filipa
authors.initials: F
authors.lastname: Carvalho
authors.forename: João
authors.initials: J
authors.lastname: Gonçalves
authors.forename: Ni
authors.initials: N
authors.lastname: Huang
authors.forename: Rune
authors.initials: R
authors.lastname: Matthiesen
authors.forename: Michiel J
authors.initials: MJ
authors.lastname: Noordam
authors.forename: Inés
authors.initials: I
authors.lastname: Quintela
authors.forename: Avinash
authors.initials: A
authors.lastname: Ramu
authors.forename: Catarina
authors.initials: C
authors.lastname: Seabra
authors.forename: Amy B
authors.initials: AB
authors.lastname: Wilfert
authors.forename: Juncheng
authors.initials: J
authors.lastname: Dai
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Downie
authors.forename: Susana
authors.initials: S
authors.lastname: Fernandes
authors.forename: Xuejiang
authors.initials: X
authors.lastname: Guo
authors.forename: Jiahao
authors.initials: J
authors.lastname: Sha
authors.forename: António
authors.initials: A
authors.lastname: Amorim
authors.forename: Alberto
authors.initials: A
authors.lastname: Barros
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Sergey
authors.initials: S
authors.lastname: Moskovtsev
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
authors.forename: Darius A
authors.initials: DA
authors.lastname: Paduch
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Schiffman
authors.forename: Peter N
authors.initials: PN
authors.lastname: Schlegel
authors.forename: Mário
authors.initials: M
authors.lastname: Sousa
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Carrell
authors.forename: Donald F
authors.initials: DF
authors.lastname: Conrad
mesh_terms: D044466:Asian People / Q000235:genetics; D053713:Azoospermia / Q000235:genetics / Q000503:physiopathology; D041321:Chromosomes, Human, X; D041322:Chromosomes, Human, Y; D056915:DNA Copy Number Variations; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D011247:Pregnancy; D029589:Seminal Plasma Proteins; D017384:Sequence Deletion; D013091:Spermatogenesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C110547:DMRT1 protein; D029589:Seminal Plasma Proteins; D014157:Transcription Factors
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