Mutation is associated with developmental and hereditary disorders, aging, and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. We used Caenorhabditis elegans whole-genome sequencing to model mutational signatures, analyzing 183 worm populations across 17 DNA repair-deficient backgrounds propagated for 20 generations or exposed to carcinogens. The baseline mutation rate in C. elegans was approximately one per genome per generation, not overtly altered across several DNA repair deficiencies over 20 generations. Telomere erosion led to complex chromosomal rearrangements initiated by breakage–fusion–bridge cycles and completed by simultaneously acquired, localized clusters of breakpoints. Aflatoxin B1 induced substitutions of guanines in a GpC context, as observed in aflatoxin-induced liver cancers. Mutational burden increased with impaired nucleotide excision repair. Cisplatin and mechlorethamine, DNA crosslinking agents, caused dose- and genotype-dependent signatures among indels, substitutions, and rearrangements. Strikingly, both agents induced clustered rearrangements resembling “chromoanasynthesis,” a replication-based mutational signature seen in constitutional genomic disorders, suggesting that interstrand crosslinks may play a pathogenic role in such events. Cisplatin mutagenicity was most pronounced in xpf-1 mutants, suggesting that this gene critically protects cells against platinum chemotherapy. Thus, experimental model systems combined with genome sequencing can recapture and mechanistically explain mutational signatures associated with human disease.

BackgroundThe thrifty gene hypothesis posits that, in populations that experienced periods of feast and famine, natural selection favoured individuals carrying thrifty alleles that promote the storage of fat and energy. Polynesians likely experienced long periods of cold stress and starvation during their settlement of the Pacific and today have high rates of obesity and type 2 diabetes (T2DM), possibly due to past positive selection for thrifty alleles. Alternatively, T2DM risk alleles may simply have drifted to high frequency in Polynesians. To identify thrifty alleles in Polynesians, we previously examined evidence of positive selection on T2DM-associated SNPs and identified a T2DM risk allele at unusually high frequency in Polynesians. We suggested that the risk allele of the Gly482Ser variant in the PPARGC1A gene was driven to high frequency in Polynesians by positive selection and therefore possibly represented a thrifty allele in the Pacific.MethodsHere we examine whether PPARGC1A is a thrifty gene in Pacific populations by testing for an association between Gly482Ser genotypes and BMI in two Pacific populations (Maori and Tongans) and by evaluating the frequency of the risk allele of the Gly482Ser variant in a sample of worldwide populations.ResultsWe find that the Gly482Ser variant is associated with BMI in Tongans but not in Maori. In a sample of 58 populations worldwide, we also show that the 482Ser risk allele reaches its highest frequency in the Pacific.ConclusionThe association between Gly482Ser genotypes and BMI in Tongans together with the worldwide frequency distribution of the Gly482Ser risk allele suggests that PPARGC1A remains a candidate thrifty gene in Pacific populations.

10Understanding the plasticity, robustness, and modularity of transcriptome expression to genetic 11 and environmental conditions is crucial to deciphering how organisms adapt in nature. To test 12 how genome architecture influences transcriptome profiles, we quantified expression responses 13 for distinct temperature-adapted genotypes of the nematode Caenorhabditis briggsae when 14 exposed to chronic temperature stresses throughout development. We found that 56% of the 15 8795 differentially-expressed genes show genotype-specific changes in expression in response 16to temperature (genotype-by-environment interactions, GxE). Most genotype-specific responses 17 occur under heat stress, indicating that cold versus heat stress responses involve distinct 18 genomic architectures. The 22 co-expression modules that we identified differ in their 19 enrichment of genes with genetic versus environmental versus interaction effects, as well as 20 their genomic spatial distributions, functional attributes, and rates of molecular evolution at the 21 sequence level. Genes in modules enriched for simple effects of either genotype or temperature 22 alone tend to evolve especially rapidly, consistent with disproportionate influence of adaptation 23 or weaker constraint on these subsets of loci. Chromosome scale heterogeneity in nucleotide 24 polymorphism, however, rather than the scale of individual genes, predominate as the source of 25 genetic differences among expression profiles, and natural selection regimes are largely 26 decoupled between coding sequences and non-coding flanking sequences that contain cis-27 regulatory elements. These results illustrate how the form of transcriptome modularity and 28 genome structure contribute to predictable profiles of evolutionary change. 29 30

Understanding the plasticity, robustness and modularity of transcriptome expression to genetic and environmental conditions is crucial to deciphering how organisms adapt in nature. To test how genome architecture influences transcriptome profiles, we quantified expression responses for distinct temperature‐adapted genotypes of the nematode Caenorhabditis briggsae when exposed to chronic temperature stresses throughout development. We found that 56% of the 8,795 differentially expressed genes show genotype‐specific changes in expression in response to temperature (genotype‐by‐environment interactions, GxE). Most genotype‐specific responses occur under heat stress, indicating that cold vs. heat stress responses involve distinct genomic architectures. The 22 co‐expression modules that we identified differ in their enrichment of genes with genetic vs. environmental vs. interaction effects, as well as their genomic spatial distributions, functional attributes and rates of molecular evolution at the sequence level. Genes in modules enriched for simple effects of either genotype or temperature alone tend to evolve especially rapidly, consistent with disproportionate influence of adaptation or weaker constraint on these subsets of loci. Chromosome‐scale heterogeneity in nucleotide polymorphism, however, rather than the scale of individual genes predominates as the source of genetic differences among expression profiles, and natural selection regimes are largely decoupled between coding sequences and noncoding flanking sequences that contain cis‐regulatory elements. These results illustrate how the form of transcriptome modularity and genome structure contribute to predictable profiles of evolutionary change.