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Abstract Single-stranded RNA molecules can form intramolecular bonds between nucleotides to create secondary structures. These structures can have phenotypic effects, meaning mutations that alter secondary structure may be subject to natural selection. Here, we examined the population genetics of these mutations within Arabidopsis thaliana genes. We began by identifying derived SNPs with the potential to alter secondary structures within coding regions, using a combination of computational prediction and empirical data analysis. We identified 8,469 such polymorphisms, representing a small portion (∼0.024%) of sites within transcribed genes. We examined nucleotide diversity and allele frequencies of these “pair-changing mutations” (pcM) in 1,001 A. thaliana genomes. The pcM SNPs at synonymous sites had a 13.4% reduction in nucleotide diversity relative to non-pcM SNPs at synonymous sites and were found at lower allele frequencies. We used demographic modeling to estimate selection coefficients, finding selection against pcMs in 5′ and 3′ untranslated regions. Previous work has shown that some pcMs affect gene expression in a temperature-dependent matter. We explored associations on a genome-wide scale, finding that pcMs existed at higher population frequencies in colder environments, but so did non-PCM alleles. Derived pcM mutations had a small but significant relationship with gene expression; transcript abundance for pcM-containing alleles had an average reduction in expression of ∼4% relative to alleles with conserved ancestral secondary structure. Overall, we document selection against derived pcMs in untranslated regions but find limited evidence for selection against derived pcMs at synonymous sites. 

Abstract Epistasis is caused by genetic interactions among mutations that affect fitness. To characterize properties and potential mechanisms of epistasis, we engineered eight double mutants that combined mutations from the rho and rpoB genes of Escherichia coli. The two genes encode essential functions for transcription, and the mutations in each gene were chosen because they were beneficial for adaptation to thermal stress (42.2 °C). The double mutants exhibited patterns of fitness epistasis that included diminishing returns epistasis at 42.2 °C, stronger diminishing returns between mutations with larger beneficial effects and both negative and positive (sign) epistasis across environments (20.0 °C and 37.0 °C). By assessing gene expression between single and double mutants, we detected hundreds of genes with gene expression epistasis. Previous work postulated that highly connected hub genes in coexpression networks have low epistasis, but we found the opposite: hub genes had high epistasis values in both coexpression and protein–protein interaction networks. We hypothesized that elevated epistasis in hub genes reflected that they were enriched for targets of Rho termination but that was not the case. Altogether, gene expression and coexpression analyses revealed that thermal adaptation occurred in modules, through modulation of ribonucleotide biosynthetic processes and ribosome assembly, the attenuation of expression in genes related to heat shock and stress responses, and with an overall trend toward restoring gene expression toward the unstressed state. 

Summary Genetic load can reduce fitness and hinder adaptation. While its genetic underpinnings are well established, the influence of environmental variation on genetic load is less well characterized, as is the relationship between genetic load and putatively adaptive genetic variation. This study examines the interplay among climate, species range dynamics, adaptive variation, and mutational load – a genomic measure of genetic load – inVitis arizonica, a wild grape native to the American Southwest.We estimated mutational load and identified climate‐associated adaptive genetic variants in 162 individuals across the species' range. Using a random forest model, we analyzed the relationship between mutational load, climate, and range shifts.Our findings linked mutational load to climatic variation, historical dispersion, and heterozygosity. Populations at the leading edge of range expansion harbored higher load and fewer putatively adaptive alleles associated with climate. Climate projections suggest thatV. arizonicawill expand its range by the end of the century, accompanied by a slight increase in mutational load at the population level.This study advances understanding of how environmental and geographic factors shape genetic load and adaptation, highlighting the need to integrate deleterious variation into broader models of species response to climate change.