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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. Hum Mol Genet 2015 Mar 01;24(5):1493-503

Date

11/02/2014

Pubmed ID

25361961

DOI

10.1093/hmg/ddu557

Scopus ID

2-s2.0-84924455057 (requires institutional sign-in at Scopus site)   40 Citations

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.

Author List

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

Author

Jing Dong PhD Assistant Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Azoospermia
Disease Models, Animal
Drosophila
Drosophila Proteins
Fertility
Genetic Association Studies
Genetic Loci
Genetic Predisposition to Disease
Humans
Male
Polymorphism, Single Nucleotide
RNA Interference
Receptors, Estrogen
Spermatogenesis
Sulfotransferases
Testis