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Genome-wide analysis of chemically induced mutations in mouse in phenotype-driven screens

Bauer, Denis C.; McMorran, Brendan J.; Foote, Simon J.; Burgio, Gaetan

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BACKGROUND: N-ethyl-N-nitrosourea (ENU) mutagen has become the method of choice for inducing random mutations for forward genetics applications. However, distinguishing induced mutations from sequencing errors or sporadic mutations is difficult, which has hampered surveys of potential biases in the methodology in the past. Addressing this issue, we created a large cohort of mice with biological replicates enabling the confident calling of induced mutations, which in turn...[Show more]

dc.contributor.authorBauer, Denis C.
dc.contributor.authorMcMorran, Brendan J.
dc.contributor.authorFoote, Simon J.
dc.contributor.authorBurgio, Gaetan
dc.date.accessioned2015-10-26T22:40:04Z
dc.date.available2015-10-26T22:40:04Z
dc.identifier.citationBMC Genomics. 2015 Oct 26;16(1):866
dc.identifier.issn1471-2164
dc.identifier.urihttp://hdl.handle.net/1885/16087
dc.description.abstractBACKGROUND: N-ethyl-N-nitrosourea (ENU) mutagen has become the method of choice for inducing random mutations for forward genetics applications. However, distinguishing induced mutations from sequencing errors or sporadic mutations is difficult, which has hampered surveys of potential biases in the methodology in the past. Addressing this issue, we created a large cohort of mice with biological replicates enabling the confident calling of induced mutations, which in turn allowed us to conduct a comprehensive analysis of potential biases in mutation properties and genomic location. RESULTS: In the exome sequencing data we observe the known preference of ENU to cause A:T⇒G:C transitions in longer genes. Mutations were frequently clustered and inherited in blocks hampering attempts to pinpoint individual causative mutations by genome analysis only. Furthermore, ENU mutations were biased towards areas in the genome that are accessible in testis, potentially limiting the scope of forward genetic approaches to only 1–10 % of the genome. CONCLUSION: ENU provides a powerful tool for exploring the genome-phenome relationship, however forward genetic applications that require the mutation to be passed on through the germ line may be limited to explore only genes that are accessible in testis.
dc.description.sponsorshipThis work was supported by the National Health and Medical Research Council (grant APP 605524, 490037 and 1047082), the Australian Research Council (grant 12010061), the National Collaborative Research Infrastructure Strategy of Australia, and the Education investment fund from the Department of Innovation, Industry, Science and Research.
dc.publisherBioMed Central
dc.rights© 2015 Bauer et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
dc.sourceBMC Genomics
dc.subjectENU
dc.subjectNGS
dc.subjectVariants
dc.subjectForward genetics
dc.titleGenome-wide analysis of chemically induced mutations in mouse in phenotype-driven screens
dc.typeJournal article
dc.language.rfc3066en
dc.rights.holderBauer et al.
local.identifier.citationvolume16
dc.date.issued2015-10-26
local.identifier.absfor060499 - Genetics not elsewhere classified
local.identifier.absfor110803 - Medical Parasitology
local.identifier.absfor111203 - Cancer Genetics
local.identifier.ariespublicationU3488905xPUB6612
local.publisher.urlhttp://www.biomedcentral.com/
local.type.statusPublished Version
local.contributor.affiliationMcMorran, B. J., John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationFoote, S. J., John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationBurgio, G., John Curtin School of Medical Research, The Australian National University
dc.relationhttp://purl.org/au-research/grants/nhmrc/605524
dc.relationhttp://purl.org/au-research/grants/nhmrc/490037
dc.relationhttp://purl.org/au-research/grants/nhmrc/1047082
local.identifier.essn1471-2164
local.bibliographicCitation.issue1
local.bibliographicCitation.startpage866
local.identifier.doi10.1186/s12864-015-2073-4
dc.date.updated2016-02-24T10:11:05Z
local.identifier.scopusID2-s2.0-84945312655
CollectionsANU Research Publications

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