Variable paralog expression underlies phenotype variation.

Abstract

Human faces are variable; we look different from one another. Craniofacial disorders further increase facial variation. To understand craniofacial variation and how it can be buffered, we analyzed the zebrafish <i>mef2ca</i> mutant. When this transcription factor encoding gene is mutated, zebrafish develop dramatically variable craniofacial phenotypes. Years of selective breeding for low and high penetrance of mutant phenotypes produced strains that are either resilient or sensitive to the <i>mef2ca</i> mutation. Here, we compared gene expression between these strains, which revealed that selective breeding enriched for high and low <i>mef2ca</i> paralog expression in the low- and high-penetrance strains, respectively. We found that <i>mef2ca</i> paralog expression is variable in unselected wild-type zebrafish, motivating the hypothesis that heritable variation in paralog expression underlies mutant phenotype severity and variation. In support, mutagenizing the <i>mef2ca</i> paralogs, <i>mef2aa</i>, <i>mef2b</i>, <i>mef2cb</i>, and <i>mef2d</i> demonstrated modular buffering by paralogs. Specifically, some paralogs buffer severity while others buffer variability. We present a novel, mechanistic model for phenotypic variation where variable, vestigial paralog expression buffers development. These studies are a major step forward in understanding the mechanisms of facial variation, including how some genetically resilient individuals can overcome a deleterious mutation.