(A) GWA output using Slope as a trait value. Significant QTL intervals are IV: 15939340–16613710 and V: 15660911–17615557. (B) GWA output using PC1 as a trait value. Significant QTL intervals are V: 1345848–2764788 and V: 15775895–18065050. (C) WormCat Category 3 enrichments for all genes with variants in the QTL. (D) Fold-enrichment of protein domains significantly enriched among genes with variants in QTL. A hypergeometric p-value was calculated for each of 102 protein domains present, and a Bonferroni-corrected p-value of 0.00049 was used as a threshold to determine significance. Red indicates the receptor L domain, which is found in irld genes. (E) All variants in irld genes that are within significant QTL and their association with the starvation-resistance traits, Slope and PC. Each gene name is shown next to the most significant variant for that gene, but multiple variants are plotted for each gene when present. Red indicates genes selected for functional validation. (F) Slope trait values for strains based on whether they have ALT and REF alleles for specific irld-39 and irld-52 variants predicated to disrupt protein function. The irld-52 variant p-value is p=0.007 for the PC1 trait value (only the Slope trait value is shown here). Significance determined from GWA fine mapping. (G) Slope trait values for strains based on whether they are hyper-divergent or not at irld-11 and irld-57 loci. T-test on trait values between hyper-divergent and non-divergent strains. (F–G) DL238, EG4725, NIC526, and MY2147 are color-coded as indicated. (H) The four irld genes selected for genome editing and the edits generated for each. For irld-39 and irld-52, N2 and MY2147 have the REF allele and were edited to have the ALT allele. irld-11 and irld-57 are hyper-divergent in DL238 and EG2745 backgrounds, so full gene deletions were generated in N2 and MY2147 backgrounds. (I) L1 starvation survival assays on irld-39 and irld-52 ALT alleles in N2 and MY2147 backgrounds. There were no significant differences between strains within a background. (J) L1 starvation survival assays on irld-11 and irld-57 deletions in N2 and MY2147 backgrounds. There were no significant differences between strains within a background. (K–L). Worm length following 48 hr recovery with food after 1 or 8 d of L1 starvation for indicated genotypes. Linear mixed-effects model; one-way p-value for interaction between strain and duration of starvation; 4–5 biological replicates per condition. ΔΔ indicates effect size of interaction between duration of starvation and strain compared to control (the difference in differences between strains’ mean length at days 1 and 8). (F,G,K,L) ***p<0.001, **p<0.01, *p<0.05, n.s. not significant.