Selective breeding modifies mef2ca mutant incomplete penetrance by tuning the opposing Notch pathway

• DOI: 10.1371/journal.pgen.1008507
• Publication Date: 2019-12-02T19:12:21Z
• Authors: Juliana Sucharov; Kuval Ray; Elliott P. Brooks; James T. Nichols
• Keywords: Penetrance; Genetic screen; Phenocopy

Deleterious genetic mutations allow developmental biologists to understand how genes control development. However, not all loss of function mutants develop phenotypic changes. Many deleterious only produce a phenotype in subset mutant individuals, phenomenon known as incomplete penetrance. Incomplete penetrance can confound analyses gene and our understanding this widespread remains inadequate. To better what controls penetrance, we capitalized on the zebrafish mef2ca which produces craniofacial phenotypes with variable Starting characterized allele, used classical selective breeding methods generate strains mutant-associated consistently appear low or high Strikingly, for converted allele behavior from homozygous lethal viable. Meanwhile, fully recessive partially dominant. Comparing selectively-bred low- high-penetrance revealed that initially respond similarly mutation, but then expression differences between emerge during Thus, altered temporal circuitry manifest through pressure modify Specifically, demonstrate Notch signaling strains, further show experimental manipulation pathway phenocopies changes occurring breeding. This study provides evidence is inherited liability-threshold trait. Our finding vertebrate animals overcome mutation by tuning complements other reported mechanisms overcoming such transcriptional adaptation compensatory genes, alternative mRNA splicing, maternal deposition wild-type transcripts, are observed system. The approach resultant change uncovered advances expands current resilience.