A nematode-specific gene underlies bleomycin-response variation in Caenorhabditis elegans

Shannon C. Brady; Stefan Zdraljevic; Karol W. Bisaga; Robyn E. Tanny; Daniel E. Cook; Daehan Lee; Ye Wang; Erik C. Andersen

Because none of the genes with a non-synonymous variant between the N2 and CB4856 strains 575 explained the QTL, we explored other ways in which natural variation could impact bleomycin 576 responses. We used the 13,001 SNPs to perform linkage mapping on the gene expression data of 577 the RIAILs and identified 4,326 expression QTL (eQTL) across the genome (Rockman et al. 578 2010, File S12, File S13, Materials and Methods). Of the 118 genes in the 187 kb surrounding 579 the bleomycin-response QTL, expression for 50 genes were measured in the previous microarray 580 study. We identified a significant eQTL for eight of these 50 genes, four of which mapped to 581 chromosome V (File S13). eQTL for two of those four genes, H19N07.3 and cnc-10, mapped to 582 the center of chromosome V and overlapped with the bleomycin-response QTL. Because cnc-10 583 did not underlie bleomycin response variation (Figure 3B) (Figure 4A and B, File S14) . The length 586 of animals and expression of scb-1 was correlated in the RIAIL strains ( Figure 4C , File S15, 587 r 2 = 0.61, p < 9.5e-13 Spearman's correlation). Although this gene does not have a non-588 synonymous variant between the N2 and CB4856 strains, natural variation in gene expression 589 could impact bleomycin responses. 1.4e-14, ECA1132 vs. N2, p = 6.9e-5, ECA1135 vs. N2, p = 0.006, Tukey HSD). These results 597 suggest that H19N07.3 function is required for resistance to bleomycin. Therefore, we renamed 598 this gene scb-1 for sensitivity to the chemotherapeutic bleomycin. Unlike with the jmjd-5 599 deletion strains, the scb-1 deletion strains had no significant differences in the control condition 600 (File S7). Therefore, the bleomycin sensitivity of the scb-1 deletion strains were not caused by 601 control-condition phenotypes. 602 603 Because an scb-1 non-synonymous variant has not been identified between the N2 and CB4856 604 strains, changes to protein function likely do not cause bleomycin response differences. RIAILs 605 with the CB4856 allele at the QTL peak marker have increased expression of scb-1 and 606 increased bleomycin resistance compared to RIAILs with the N2 allele (Figure 1, Figure 4) . 607