RRC ID 32513
Author Yu J, Wu H, Wen Y, Liu Y, Zhou T, Ni B, Lin Y, Dong J, Zhou Z, Hu Z, Guo X, Sha J, Tong C.
Title Identification of seven genes essential for male fertility through a genome-wide association study of non-obstructive azoospermia and RNA interference-mediated large-scale functional screening in Drosophila.
Journal Hum Mol Genet
Abstract Non-obstructive azoospermia (NOA) is a complex and severe condition whose etiology remains largely unknown. In a genome-wide association study (GWAS) of NOA in Chinese men, few loci reached genome-wide significance, although this might be a result of genetic heterogeneity. Single nucleotide polymorphisms (SNPs) without genome-wide significance may also indicate genes that are essential for fertility, and multiple stage validation can lead to false-negative results. To perform large-scale functional screening of the genes surrounding these SNPs, we used in vivo RNA interference (RNAi) in Drosophila, which has a short maturation cycle and is suitable for high-throughput analysis. The analysis found that 7 (31.8%) of the 22 analyzed orthologous Drosophila genes were essential for male fertility. These genes corresponded to nine loci. Of these genes, leukocyte-antigen-related-like (Lar) is primarily required in germ cells to sustain spermatogenesis, whereas CG12404, doublesex-Mab-related 11E (dmrt11E), CG6769, estrogen-related receptor (ERR) and sulfateless (sfl) function in somatic cells. Interestingly, ERR and sfl are also required for testis morphogenesis. Our study thus demonstrates that SNPs without genome-wide significance in GWAS may also provide clues to disease-related genes and therefore warrant functional analysis.
Volume 24(5)
Pages 1493-503
Published 2015-3-1
DOI 10.1093/hmg/ddu557
PII ddu557
PMID 25361961
MeSH Animals Asian Continental Ancestry Group / genetics Azoospermia / genetics* Disease Models, Animal Drosophila / genetics* Drosophila Proteins / genetics Drosophila Proteins / metabolism Fertility / genetics* Genetic Association Studies Genetic Loci Genetic Predisposition to Disease Humans Male Polymorphism, Single Nucleotide RNA Interference Receptors, Estrogen / genetics Receptors, Estrogen / metabolism Spermatogenesis / genetics Sulfotransferases / genetics Sulfotransferases / metabolism Testis / metabolism
IF 5.101
Times Cited 20