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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 mef2ca 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 mef2ca mutation. Here, we compared gene expression between these strains, which revealed that selective breeding enriched for high and low mef2ca paralog expression in the low- and high-penetrance strains, respectively. We found that mef2ca 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 mef2ca paralogs, mef2aa, mef2b, mef2cb, and mef2d 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.

SUBMITTER: Bailon-Zambrano R

PROVIDER: S-EPMC9555865 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Variable paralog expression underlies phenotype variation.

Bailon-Zambrano Raisa R Sucharov Juliana J Mumme-Monheit Abigail A Murry Matthew M Stenzel Amanda A Pulvino Anthony T AT Mitchell Jennyfer M JM Colborn Kathryn L KL Nichols James T JT

eLife 20220922

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>me ...[more]

PMID: 36134886

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Project description:BackgroundThe degree by which mechanisms underlying phenotypic convergence are similar among taxa depends on the number of evolutionary paths available for selection to act upon. Likelihood of convergence will be influenced by an interplay of factors such as genetic architecture, phylogenetic history and population demography. To determine if there is convergence or divergence in mechanisms underlying phenotypic similarity, we assessed whether gene transcription patterns differed among species with similar levels of hypoxia tolerance.ResultsThree species of marine fish from the superfamily Cottoidea (smoothhead sculpin [Artedius lateralis], sailfin sculpin [Nautichthys oculofasciatus] and Pacific staghorn sculpin [Leptocottus armatus]), all of which have previously been shown to share the same level of hypoxia tolerance, were exposed to short-(8 h) and longer-term (72 h) hypoxia and mRNA transcripts were assessed using a custom microarray. We examined hypoxia-induced transcription patterns in metabolic and protein production pathways and found that a high proportion of genes associated with these biological processes showed significant differences among the species. Specifically, the data suggest that the smoothhead sculpin, unlike the sailfin sculpin and the Pacific staghorn sculpin, relied on amino acid degradation rather than glycolysis or fatty acid oxidation to generate ATP during hypoxia exposure. There was also variation across the species in the transcription of genes involved in protein production (e.g. mRNA processing and protein translation), such that it increased in the smoothhead sculpin, decreased in the sailfin sculpin and was variable in the Pacific staghorn sculpin.ConclusionsChanges in metabolic and protein production pathways are part of the key responses of fishes to exposures to environmental hypoxia. Yet, species with similar overall hypoxia tolerance exhibited different transcriptional responses in these pathways, indicating flexibility and complexity of interactions in the evolution of the mechanisms underlying the hypoxia tolerance phenotype. The variation in the hypoxia-induced transcription of genes across species with similar hypoxia tolerance suggests that similar whole-animal phenotypes can emerge from divergent evolutionary paths that may affect metabolically important functions.

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Variable paralog expression underlies phenotype variation.

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Variable paralog expression underlies phenotype variation.

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