The Genetic Basis of Lethal Mutations and How They Persist in Nature

Abstract

Recessive lethal mutations are widespread across studied species, with estimates suggesting that each individual carries at least one. Mysteriously, some lethal alleles appear to be at higher frequencies than expected given their extreme deleterious nature. These findings gave rise to debate in the 1930s-1970s on whether classical balancing selection may influence some lethal allele frequencies (on top of mutation-selection balance). We suggest that mutation–selection balance alone based on current genome-wide mutation rate estimates cannot explain lethal variation in nature and investigate other forces outside of classical balancing selection. We discuss the potential that linked selection may drive maintenance of lethal alleles through associative overdominance or linkage to beneficial mutations. We then investigate via simulation the possibility that lethal mutations could accumulation in genomic regions impacted by associative overdominance. Findings suggest that while it is possible that associative overdominance can impact lethal genetic diversity under unique circumstances, it likely does not explain most lethal polymorphisms present in nature. To uncover the genetic basis of lethality in nature and provide insight on the possible evolutionary forces allowing some to persist at higher frequencies, we locate hundreds of recessive lethal mutations in D. melanogaster via complementation testing. By fine-mapping and sequencing a subset of these lethal mutations, we determine candidate lethal mutations in specific genes and discover that many lethal disruptions are caused by transposable element insertions. The most common transposable element in our data is estimated to have recently invaded D. melanogaster (between 2013-2016). The ubiquity of lethal alleles in natural populations is a classic conundrum for evolutionary geneticists – we return to this question from the over 50 years ago utilizing modern tools and sequencing technology to that provide novel insight into this age-old mystery.