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 1;24(5):1493-503. doi: 10.1093/hmg/ddu557. Epub 2014 Oct 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asian People / 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

Substances

  • Drosophila Proteins
  • ERR protein, Drosophila
  • Receptors, Estrogen
  • Sulfotransferases
  • sfl protein, Drosophila

Supplementary concepts

  • Azoospermia, Nonobstructive