Population Genomics of Premature Termination Codons in Cavefish With Substantial Trait Loss

Area of Science:

• Evolutionary genetics
• Genomics
• Molecular biology

Background:

• Loss-of-function alleles, particularly premature termination codons (PTCs), are key drivers of evolutionary adaptation.
• Cave-adapted organisms often display significant loss of ancestral traits, suggesting a role for loss-of-function mutations.
• Mexican tetra provide a model system to study genetic adaptation in subterranean environments.

Purpose of the Study:

• To investigate the evolutionary history and adaptive potential of PTCs in Mexican tetra populations.
• To determine the role of genetic drift versus positive selection in the accumulation of PTCs in cave populations.
• To identify specific PTCs that may contribute to cave-specific adaptations.

Main Methods:

• Whole genome sequencing of 141 Mexican tetra individuals (cave and surface populations).
• Analysis of PTC frequency and distribution across the genome, correlating with evolutionary constraint.
• Population genetics simulations using SLiM to model PTC evolution under different demographic scenarios.
• CRISPR-Cas9 gene editing to assess the phenotypic effects of specific PTCs (e.g., pde6c).

Main Results:

• Cave populations exhibit significantly higher frequencies of PTCs compared to surface populations.
• PTCs are enriched in genes with relaxed evolutionary constraint.
• Simulations indicate that genetic drift, exacerbated by smaller population sizes in caves, sufficiently explains increased PTC frequency.
• Experimental mutation of pde6c in surface tetra recapitulates cave-associated traits.
• A subset of high-frequency PTCs in cave populations overlaps with selective sweeps, suggesting potential adaptive roles.

Conclusions:

• PTCs play a significant role in generating loss-of-function phenotypes and driving adaptation in cave-dwelling Mexican tetra.
• Relaxed evolutionary constraint and genetic drift are major factors contributing to PTC accumulation in cave populations.
• While drift is a primary driver, specific PTCs may confer adaptive advantages, contributing to the unique biology of subterranean organisms.