Abstract
Bleomycin is a powerful chemotherapeutic drug used to treat a variety of cancers. However, individual patients vary in their responses to bleomycin. The identification of genetic differences that underlie this response variation could improve treatment outcomes by tailoring bleomycin dosages to each patient. We used the model organism Caenorhabditis elegans to identify genetic determinants of bleomycin-response differences by performing linkage mapping on recombinants derived from a cross between the laboratory strain (N2) and a wild strain (CB4856). This approach identified a small genomic region on chromosome V that underlies bleomycin-response variation. Using near-isogenic lines, and strains with CRISPR-Cas9 mediated deletions and allele replacements, we discovered that a novel nematode-specific gene (scb-1) is required for bleomycin resistance. Although the mechanism by which this gene causes variation in bleomycin responses is unknown, we suggest that a rare variant present in the CB4856 strain might cause differences in the potential stress-response function of scb-1 between the N2 and CB4856 strains, thereby leading to differences in bleomycin resistance.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1453-1468 |
| Number of pages | 16 |
| Journal | Genetics |
| Volume | 212 |
| Issue number | 4 |
| DOIs | |
| State | Published - Aug 1 2019 |
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Keywords
- C. elegans bleomycin
- QTL
- drug-response
- linkage mapping
ASJC Scopus subject areas
- Genetics
Cite this
}
A Novel Gene Underlies Bleomycin-Response Variation in Caenorhabditis elegans. / Brady, Shannon C.; Zdraljevic, Stefan; Bisaga, Karol W.; Tanny, Robyn Elizabeth; Cook, Daniel E.; Lee, Daehan; Wang, Ye; Andersen, Erik Christian.
In: Genetics, Vol. 212, No. 4, 01.08.2019, p. 1453-1468.Research output: Contribution to journal › Article
TY - JOUR
T1 - A Novel Gene Underlies Bleomycin-Response Variation in Caenorhabditis elegans
AU - Brady, Shannon C.
AU - Zdraljevic, Stefan
AU - Bisaga, Karol W.
AU - Tanny, Robyn Elizabeth
AU - Cook, Daniel E.
AU - Lee, Daehan
AU - Wang, Ye
AU - Andersen, Erik Christian
PY - 2019/8/1
Y1 - 2019/8/1
N2 - Bleomycin is a powerful chemotherapeutic drug used to treat a variety of cancers. However, individual patients vary in their responses to bleomycin. The identification of genetic differences that underlie this response variation could improve treatment outcomes by tailoring bleomycin dosages to each patient. We used the model organism Caenorhabditis elegans to identify genetic determinants of bleomycin-response differences by performing linkage mapping on recombinants derived from a cross between the laboratory strain (N2) and a wild strain (CB4856). This approach identified a small genomic region on chromosome V that underlies bleomycin-response variation. Using near-isogenic lines, and strains with CRISPR-Cas9 mediated deletions and allele replacements, we discovered that a novel nematode-specific gene (scb-1) is required for bleomycin resistance. Although the mechanism by which this gene causes variation in bleomycin responses is unknown, we suggest that a rare variant present in the CB4856 strain might cause differences in the potential stress-response function of scb-1 between the N2 and CB4856 strains, thereby leading to differences in bleomycin resistance.
AB - Bleomycin is a powerful chemotherapeutic drug used to treat a variety of cancers. However, individual patients vary in their responses to bleomycin. The identification of genetic differences that underlie this response variation could improve treatment outcomes by tailoring bleomycin dosages to each patient. We used the model organism Caenorhabditis elegans to identify genetic determinants of bleomycin-response differences by performing linkage mapping on recombinants derived from a cross between the laboratory strain (N2) and a wild strain (CB4856). This approach identified a small genomic region on chromosome V that underlies bleomycin-response variation. Using near-isogenic lines, and strains with CRISPR-Cas9 mediated deletions and allele replacements, we discovered that a novel nematode-specific gene (scb-1) is required for bleomycin resistance. Although the mechanism by which this gene causes variation in bleomycin responses is unknown, we suggest that a rare variant present in the CB4856 strain might cause differences in the potential stress-response function of scb-1 between the N2 and CB4856 strains, thereby leading to differences in bleomycin resistance.
KW - C. elegans bleomycin
KW - QTL
KW - drug-response
KW - linkage mapping
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UR - http://www.scopus.com/inward/citedby.url?scp=85071354481&partnerID=8YFLogxK
U2 - 10.1534/genetics.119.302286
DO - 10.1534/genetics.119.302286
M3 - Article
VL - 212
SP - 1453
EP - 1468
JO - Genetics
JF - Genetics
SN - 0016-6731
IS - 4
ER -