Across diverse taxa, selfing species have evolved independently from outcrossing species thousands of times. The transition from outcrossing to selfing significantly decreases the effective population size, effective recombination rate, and heterozygosity within a species. These changes lead to a reduction in genetic diversity, and therefore adaptive potential, by intensifying the effects of random genetic drift and linked selection. Within the nematode genus Caenorhabditis , selfing has evolved at least three times and all three species, including in the model organism Caenorhabditis elegans , show substantially reduced genetic diversity relative to outcrossing species. Selfing and outcrossing Caenorhabditis species are often found in the same niches, but we still do not know how selfing species with limited genetic diversity can adapt to these environments. Here, we examine the whole-genome sequences from 609 wild C. elegans strains isolated worldwide and show that genetic variation is concentrated in punctuated hyper-divergent regions that cover 20% of the C. elegans reference genome. These regions are enriched in environmental response genes that mediate sensory perception, pathogen response, and xenobiotic stress response. Population genomic evidence suggests that genetic diversity in these regions has been maintained by long-term balancing selection. Using long- read genome assemblies for 15 wild strains, we show that hyper-divergent haplotypes contain unique sets of genes and show levels of divergence comparable to levels found between Caenorhabditis species that diverged millions of years ago. These results provide an example for how species can avoid the evolutionary “dead end” associated with selfing.

Hawaiian isolates of the nematode species Caenorhabditis elegans have long been known to harbor genetic diversity greater than the rest of the worldwide population, but this observation was supported by only a small number of wild strains. To better characterize the niche and genetic diversity of Hawaiian C. elegans and other Caenorhabditis species, we sampled different substrates and niches across the Hawaiian islands. We identified hundreds of new Caenorhabditis strains from known species and a new species, Caenorhabditis oiwi. Hawaiian C. elegans are found in cooler climates at high elevations but are not associated with any specific substrate, as compared to other Caenorhabditis species. Surprisingly, admixture analysis revealed evidence of shared ancestry between some Hawaiian and non-Hawaiian C. elegans strains. We suggest that the deep diversity we observed in Hawaii might represent patterns of ancestral genetic diversity in the C. elegans species before human influence.

We find that variation in the dbt-1 gene underlies natural differences in Caenorhabditis elegans responses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of C. elegans natural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

Summary paragraphThe mating system of a species profoundly influences its evolutionary trajectory1–3. Across diverse taxa, selfing species have evolved independently from outcrossing species thousands of times4. The transition from outcrossing to selfing significantly decreases the effective population size, effective recombination rate, and heterozygosity within a species5. These changes lead to a reduction in the genetic diversity, and therefore adaptive potential, by intensifying the effects of random genetic drift and linked selection6,7. Selfing has evolved at least three times independently in the nematode genus Caenorhabditis8, including in the model organism Caenorhabditis elegans, and all three selfing species show substantially reduced genetic diversity relative to outcrossing species8,9. Selfing and outcrossing Caenorhabditis species are often found in the same niches, but we still do not know how selfing species with limited genetic diversity can adapt to and inhabit these same diverse environments. Here, we discovered previously uncharacterized levels and patterns of genetic diversity by examining the whole-genome sequences from 609 wild C. elegans strains isolated worldwide. We found that genetic variation is concentrated in punctuated hyper-divergent regions that cover 20% of the C. elegans reference genome. These regions are enriched in environmental response genes that mediate sensory perception, pathogen response, and xenobiotic stress. Population genomic evidence suggests that these regions have been maintained by balancing selection. Using long-read genome assemblies for 15 wild isolates, we found that hyper-divergent haplotypes contain unique sets of genes and show levels of divergence comparable to that found between Caenorhabditis species that diverged millions of years ago. Taken together, these results suggest that ancient genetic diversity present in the outcrossing ancestor of C. elegans has been maintained by long-term balancing selection since the evolution of selfing. These results provide an example for how species can avoid the evolutionary “dead end” associated with selfing by maintaining ancestral genetic diversity.

There is an accumulating body of evidence suggesting that the subzero Antarctic marine environment places physiological constraints on protein homeostasis. Levels of ubiquitin (Ub)-conjugated proteins,