Reverse Chemical Genetics: Comprehensive Fitness Profiling Reveals the Spectrum of Drug Target Interactions.
The emergence and prevalence of drug resistance demands streamlined strategies to identify drug resistant variants in a fast, systematic and cost-effective way. Methods commonly used to understand and predict drug resistance rely on limited clinical studies from patients who are refractory to drugs...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2016-09-01
|
Series: | PLoS Genetics |
Online Access: | http://europepmc.org/articles/PMC5010250?pdf=render |
id |
doaj-94cea4068c87454f833a2244a4a5b03c |
---|---|
record_format |
Article |
spelling |
doaj-94cea4068c87454f833a2244a4a5b03c2020-11-24T22:04:58ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042016-09-01129e100627510.1371/journal.pgen.1006275Reverse Chemical Genetics: Comprehensive Fitness Profiling Reveals the Spectrum of Drug Target Interactions.Lai H WongSunita SinhaJulien R BergeronJoseph C MellorGuri GiaeverPatrick FlahertyCorey NislowThe emergence and prevalence of drug resistance demands streamlined strategies to identify drug resistant variants in a fast, systematic and cost-effective way. Methods commonly used to understand and predict drug resistance rely on limited clinical studies from patients who are refractory to drugs or on laborious evolution experiments with poor coverage of the gene variants. Here, we report an integrative functional variomics methodology combining deep sequencing and a Bayesian statistical model to provide a comprehensive list of drug resistance alleles from complex variant populations. Dihydrofolate reductase, the target of methotrexate chemotherapy drug, was used as a model to identify functional mutant alleles correlated with methotrexate resistance. This systematic approach identified previously reported resistance mutations, as well as novel point mutations that were validated in vivo. Use of this systematic strategy as a routine diagnostics tool widens the scope of successful drug research and development.http://europepmc.org/articles/PMC5010250?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lai H Wong Sunita Sinha Julien R Bergeron Joseph C Mellor Guri Giaever Patrick Flaherty Corey Nislow |
spellingShingle |
Lai H Wong Sunita Sinha Julien R Bergeron Joseph C Mellor Guri Giaever Patrick Flaherty Corey Nislow Reverse Chemical Genetics: Comprehensive Fitness Profiling Reveals the Spectrum of Drug Target Interactions. PLoS Genetics |
author_facet |
Lai H Wong Sunita Sinha Julien R Bergeron Joseph C Mellor Guri Giaever Patrick Flaherty Corey Nislow |
author_sort |
Lai H Wong |
title |
Reverse Chemical Genetics: Comprehensive Fitness Profiling Reveals the Spectrum of Drug Target Interactions. |
title_short |
Reverse Chemical Genetics: Comprehensive Fitness Profiling Reveals the Spectrum of Drug Target Interactions. |
title_full |
Reverse Chemical Genetics: Comprehensive Fitness Profiling Reveals the Spectrum of Drug Target Interactions. |
title_fullStr |
Reverse Chemical Genetics: Comprehensive Fitness Profiling Reveals the Spectrum of Drug Target Interactions. |
title_full_unstemmed |
Reverse Chemical Genetics: Comprehensive Fitness Profiling Reveals the Spectrum of Drug Target Interactions. |
title_sort |
reverse chemical genetics: comprehensive fitness profiling reveals the spectrum of drug target interactions. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2016-09-01 |
description |
The emergence and prevalence of drug resistance demands streamlined strategies to identify drug resistant variants in a fast, systematic and cost-effective way. Methods commonly used to understand and predict drug resistance rely on limited clinical studies from patients who are refractory to drugs or on laborious evolution experiments with poor coverage of the gene variants. Here, we report an integrative functional variomics methodology combining deep sequencing and a Bayesian statistical model to provide a comprehensive list of drug resistance alleles from complex variant populations. Dihydrofolate reductase, the target of methotrexate chemotherapy drug, was used as a model to identify functional mutant alleles correlated with methotrexate resistance. This systematic approach identified previously reported resistance mutations, as well as novel point mutations that were validated in vivo. Use of this systematic strategy as a routine diagnostics tool widens the scope of successful drug research and development. |
url |
http://europepmc.org/articles/PMC5010250?pdf=render |
work_keys_str_mv |
AT laihwong reversechemicalgeneticscomprehensivefitnessprofilingrevealsthespectrumofdrugtargetinteractions AT sunitasinha reversechemicalgeneticscomprehensivefitnessprofilingrevealsthespectrumofdrugtargetinteractions AT julienrbergeron reversechemicalgeneticscomprehensivefitnessprofilingrevealsthespectrumofdrugtargetinteractions AT josephcmellor reversechemicalgeneticscomprehensivefitnessprofilingrevealsthespectrumofdrugtargetinteractions AT gurigiaever reversechemicalgeneticscomprehensivefitnessprofilingrevealsthespectrumofdrugtargetinteractions AT patrickflaherty reversechemicalgeneticscomprehensivefitnessprofilingrevealsthespectrumofdrugtargetinteractions AT coreynislow reversechemicalgeneticscomprehensivefitnessprofilingrevealsthespectrumofdrugtargetinteractions |
_version_ |
1725827962470662144 |