Anticipate the emergence of genetic defects from genomics data

With the recent development of approaches using high throughput genotyping and sequencing, identifying the causal mutation underlying a genetic defect from several cases has become much simpler. However, cases, or their corresponding biological material, are not always available. This article presents two approaches relying on high throughput data analysis to identify recessive lethal mutations or to efficiently orient their research from genome sequence. The first approach uses genotyping data to look for genomic regions presenting a deficit in homozygotes. This method has proven to be efficient with several mutations already characterized in each analyzed bovine breed. In the second approach, DNA variants are searched in the available whole genome sequences, with strong annotations suggesting that they are not tolerated in the homozygous state. The number of false positives is relatively high but these variants can orient the observation step toward mating at risk or homozygous animals and, in the most favorable cases, to anticipate the outbreak of the defect. Examples are provided with the RP1 gene responsible for retina degeneration or the EDAR gene responsible for the ectodermal anhidrotic syndrome.