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PloS one
2014;9 (8): e104858.

Genome-wide association analysis of radiation resistance in Drosophila melanogaster.

Mahesh Vaisnav, Chao Xing, Hung-Chih Ku, Daniel Hwang, Strahinja Stojadinovic, Alexander Pertsemlidis, John M Abrams
Author Information
  1. Mahesh Vaisnav: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas, United States of America.
  2. Chao Xing: McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas, United States of America.
  3. Hung-Chih Ku: McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas, United States of America.
  4. Daniel Hwang: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas, United States of America.
  5. Strahinja Stojadinovic: Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas, United States of America.
  6. Alexander Pertsemlidis: Greehey Children's Cancer Research Institute, Departments of Pediatrics and Cellular & Structural Biology, UT Health Science Center at San Antonio, San Antonio, Texas, United States of America.
  7. John M Abrams: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas, United States of America.
PMID: 25121966 DOI: 10.1371/journal.pone.0104858

Abstract

BACKGROUND: Ionizing radiation is genotoxic to cells. Healthy tissue toxicity in patients and radiation resistance in tumors present common clinical challenges in delivering effective radiation therapies. Radiation response is a complex, polygenic trait with unknown genetic determinants. The Drosophila Genetic Reference Panel (DGRP) provides a model to investigate the genetics of natural variation for sensitivity to radiation.
METHODS AND FINDINGS: Radiation response was quantified in 154 inbred DGRP lines, among which 92 radiosensitive lines and 62 radioresistant lines were classified as controls and cases, respectively. A case-control genome-wide association screen for radioresistance was performed. There are 32 single nucleotide polymorphisms (SNPs) associated with radio resistance at a nominal p<10(-5); all had modest effect sizes and were common variants with the minor allele frequency >5%. All the genes implicated by those SNP hits were novel, many without a known role in radiation resistance and some with unknown function. Variants in known DNA damage and repair genes associated with radiation response were below the significance threshold of p<10(-5) and were not present among the significant hits. No SNP met the genome-wide significance threshold (p = 1.49 × 10(-7)), indicating a necessity for a larger sample size.
CONCLUSIONS: Several genes not previously associated with variation in radiation resistance were identified. These genes, especially the ones with human homologs, form the basis for exploring new pathways involved in radiation resistance in novel functional studies. An improved DGRP model with a sample size of at least 265 lines and ideally up to 793 lines is recommended for future studies of complex traits.

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Grants

  1. C06 RR030414/NCRR NIH HHS
  2. R01 GM072124/NIGMS NIH HHS
  3. C06 RR30414/NCRR NIH HHS
  4. NIH R01GM072124/NIGMS NIH HHS

MeSH Term

Animals
Drosophila melanogaster
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Radiation Tolerance
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Word Cloud

Created with Highcharts 10.0.0radiationresistancelinesgenesresponseDGRPassociatedpresentcommonRadiationcomplexunknownDrosophilamodelvariationamonggenome-wideassociationp<10-5SNPhitsnovelknownsignificancethresholdsamplesizestudiesBACKGROUND:IonizinggenotoxiccellsHealthytissuetoxicitypatientstumorsclinicalchallengesdeliveringeffectivetherapiespolygenictraitgeneticdeterminantsGeneticReferencePanelprovidesinvestigategeneticsnaturalsensitivityMETHODSANDFINDINGS:quantified154inbred92radiosensitive62radioresistantclassifiedcontrolscasesrespectivelycase-controlscreenradioresistanceperformed32singlenucleotidepolymorphismsSNPsradionominalmodesteffectsizesvariantsminorallelefrequency>5%implicatedmanywithoutrolefunctionVariantsDNAdamagerepairsignificantmetp=149×10-7indicatingnecessitylargerCONCLUSIONS:Severalpreviouslyidentifiedespeciallyoneshumanhomologsformbasisexploringnewpathwaysinvolvedfunctionalimprovedleast265ideally793recommendedfuturetraitsGenome-wideanalysismelanogaster

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