Written by Kaila Honaker (Undergraduate Researcher)
Week 19 (6/20/21) – We discussed the 2020 Nature paper “The Mutational Constraint Spectrum Quantified from Variation in 141,456 Humans” by Karczewski, et al and including authors from the GnomAD consortium, Neale, Daly and MacArthur laboratories . In this manuscript, the authors wanted to form a catalogue/library of rare loss of function variants in humans that can be used to influence medical protocols/knowledge. They defined these variants as those that cause a premature stop codon, frameshift mutation, or change the necessary splice-site nucleotides of exons in the protein transcript. The sample pool that they drew their data from was very filtered so as not to allow for false positive pLoF variants. The data was filtered using the LOFTEE (loss-of-function transcript effect estimator) package which they created. The data mainly came from studies completed on common adult-onset diseases. One issue with this sample pool was that they needed more ancestral diversity, so in the future it might be beneficial to increase their range. It was discovered that known haploinsufficient genes seem to be very strongly depleted of pLoF variation, which is something that one would think to be the opposite. Constraint on genes and the prevalence of those genes in disease were found to be positively correlated. The data from this paper will be very beneficial in the future as a basis for further research on human diseases. The next step for this specific area of the research could be to perform mouse knockout experiments to determine the specific functions of each of these rare variants in a gene.