Dr. Moran Gershoni, Volcani Center
Title: Sex specific genetics and the paradox of common inherited infertility
The prevalence of several human morbid phenotypes is sometimes much higher than intuitively expected. This can directly arise from the presence of two sexes, male and female, in one species. Male and female have almost identical genomes but are typically distinctly dimorphic, including dissimilar disease susceptibilities. Sexually dimorphic traits mainly result from differential expression of genes present in both sexes. Such genes can be subject to different, and even opposing, selection constraints in the two sexes. This can impact the species evolution by differential selection on mutations with dissimilar effects on the two sexes. One of the most common health conditions in human and other mammals is infertility. This is surprising since infertility causing mutations directly suppress their own propagation and are expected to remain extremely rare. We thus proposed that high incidence of “unfit traits” such as infertility, could be partially explained by sex-differential selection.
By comprehensively mapping human sex-differential genetic architecture across 53 tissues we revealed thousands of genes with sex differential expression. We showed that sex-differential genes are related to various biological systems, and suggested new insights into the pathophysiology of diverse human diseases. We also identified a significant association between sex-specific gene transcription and propagation of deleterious mutations, which might affect the prevalence of different traits and diseases. Interestingly, most of the sex-specific genes that undergo reduced selection efficiency are essential for
successful reproduction. Thus, numerous deleterious mutations in hundreds of reproduction genes suggest that infertility is highly complex, caused by multiple genetic etiologies. To untangle the genetic complexity of infertility we took a lineage-based phenotype-clustering approach to uncover genetic causes of sub- and infertility in human and cattle. Our initial cohorts were divided into groups according to their precise phenotypes. Applying whole exome/genome sequencing and
genome-wide genotyping we then carried out kinship analyses to determine the lineage based subclusters. The cases in each sub-cluster were considered to be derived from the same etiology and were further analyzed to identify their genetic causes.
Using this approach, we have identified novel genes, mutations and genetic markers for human and cattle infertility.