TY - JOUR
T1 - A screen for genomic disorders of infertility identifies MAST2 duplications associated with nonobstructive azoospermia in humans
AU - Huang, Ni
AU - Wen, Yang
AU - Guo, Xuejiang
AU - Li, Zheng
AU - Dai, Juncheng
AU - Ni, Bixian
AU - Yu, Jun
AU - Lin, Yuan
AU - Zhou, Wen
AU - Yao, Bing
AU - Jiang, Yue
AU - Sha, Jiahao
AU - Conrad, Donald F.
AU - Hu, Zhibin
N1 - Publisher Copyright:
© 2015 by the Society for the Study of Reproduction, Inc.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - Since the cytogenetic identification of azoospermia factor regions 40 years ago, the Y chromosome has dominated research on the genetics of male infertility. We hypothesized that hotspots of structural rearrangement, which are dispersed across the genome, may mediate rare, recurrent copy number variations (CNVs), leading to severe infertility. We tested this hypothesis by contrasting patterns of rare CNVs in 970 Han Chinese men with idiopathic nonobstructive azoospermia and 1661 ethnicity-matched controls. Our results strongly support our previous claim that sperm production is modulated by genetic variation across the entire genome. The X chromosome in particular was enriched for loci modulating spermatogenesis - rare X-linked deletions larger than 100 kb were twice as common in patients compared with controls (odds ratio [OR] = 2.05, P = 0.01). At rearrangement hotspots across the genome, we observed a 2.4-fold enrichment of singleton CNVs in patients (P < 0.02), and we identified 117 testis genes, such as SYCE1 , contained within 47 hotspots that may plausibly mediate genomic disorders of fertility. In our discovery sample we observed 3 case-specific duplications of the autosomal gene MAST2 , and in a replication phase we found another 11 duplications in 1457 patients and 1 duplication in 1590 controls ( P < 5 × 10-5, combined data). With a large, polygenic genetic basis, new ways of establishing the pathogenicity of rare, large-effect mutations will be needed to fully reap the benefit of genome data in the management of azoospermia.
AB - Since the cytogenetic identification of azoospermia factor regions 40 years ago, the Y chromosome has dominated research on the genetics of male infertility. We hypothesized that hotspots of structural rearrangement, which are dispersed across the genome, may mediate rare, recurrent copy number variations (CNVs), leading to severe infertility. We tested this hypothesis by contrasting patterns of rare CNVs in 970 Han Chinese men with idiopathic nonobstructive azoospermia and 1661 ethnicity-matched controls. Our results strongly support our previous claim that sperm production is modulated by genetic variation across the entire genome. The X chromosome in particular was enriched for loci modulating spermatogenesis - rare X-linked deletions larger than 100 kb were twice as common in patients compared with controls (odds ratio [OR] = 2.05, P = 0.01). At rearrangement hotspots across the genome, we observed a 2.4-fold enrichment of singleton CNVs in patients (P < 0.02), and we identified 117 testis genes, such as SYCE1 , contained within 47 hotspots that may plausibly mediate genomic disorders of fertility. In our discovery sample we observed 3 case-specific duplications of the autosomal gene MAST2 , and in a replication phase we found another 11 duplications in 1457 patients and 1 duplication in 1590 controls ( P < 5 × 10-5, combined data). With a large, polygenic genetic basis, new ways of establishing the pathogenicity of rare, large-effect mutations will be needed to fully reap the benefit of genome data in the management of azoospermia.
KW - Aneuploidy
KW - Genetics
KW - Genomics
KW - Male infertility
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U2 - 10.1095/biolreprod.115.131185
DO - 10.1095/biolreprod.115.131185
M3 - Article
C2 - 26203179
AN - SCOPUS:84943247304
SN - 0006-3363
VL - 93
JO - Biology of reproduction
JF - Biology of reproduction
IS - 3
M1 - 61
ER -