Human Infertility Genetics

It is thought that nearly half of infertility cases have a genetic basis. Despite extensive knowledge gained from gene knockouts in mice, the genetic causes for the vast majority of idiopathic human infertilities are unknown. Traditional methods for studying inheritance, such as GWAS or linkage analysis, have been confounded by heterogeneity of infertility phenotypes and hundreds of genes involved in reproduction. Finally, we do not know the proportion of cases in which genetically-based infertilities are caused by de novo mutations vs. inheritance of alleles segregating in the human population. This NICHD-funded project (R01HD082568), entitled Identification and validation of human infertility alleles) employs a en entirely different approach to this problem.  The Schimenti lab, in collaboration with the lab of Haiyuan Yu at Cornell, are identifying nonsynonymous single nucleotide polymorphisms (nsSNPs) that functionally disrupt gametogenesis. The complementary expertise of these two laboratories are being brought to bear on the problem - Dr. Yu’s, which has developed massively parallel in silico and in vitro methods to predict and validate disease-causing nsSNPs, and Dr. Schimenti’s which is proficient in the generation and characterization of infertility genes using mouse mutant models. 

The Specific Aims are to: 1) Use computational approaches and high-throughput in vitro assays to identify nsSNPs in human infertility genes that are likely to disrupt protein function. These alleles will be precisely modeled in mice using CRISPR/Cas genome editing. 2) Phenotype the mouse models to identify those SNPs which impact gametogenesis and fertility. Overall, ~100 mouse models corresponding to nsSNPs in  known reproduction genes will be made.  We are maintaining a database (see links below) of experimentally-validated benign and deleterious SNPs in reproduction genes that should be useful to the human reproductive genetics field in the era of personalized medicine.

List of SNPs modeled in mice

List of SNPs tested via in vitro assays

Questions?  Contact John at