ENU-induced phenovariance in mice: inferences from 587 mutations
<p>Abstract</p> <p>Background</p> <p>We present a compendium of <it>N</it>-ethyl-<it>N</it>-nitrosourea (ENU)-induced mouse mutations, identified in our laboratory over a period of 10 years either on the basis of phenotype or whole genome and/or...
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BMC
2012-10-01
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| Series: | BMC Research Notes |
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| Online Access: | http://www.biomedcentral.com/1756-0500/5/577 |
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| author | Arnold Carrie N Barnes Michael J Berger Michael Blasius Amanda L Brandl Katharina Croker Ben Crozat Karine Du Xin Eidenschenk Celine Georgel Philippe Hoebe Kasper Huang Hua Jiang Zhengfan Krebs Philippe La Vine Diantha Li Xiaohong Lyon Stephen Moresco Eva Marie Y Murray Anne R Popkin Daniel L Rutschmann Sophie Siggs Owen M Smart Nora G Sun Lei Tabeta Koichi Webster Victoria Tomisato Wataru Won Sungyong Xia Yu Xiao Nengming Beutler Bruce |
| author_facet | Arnold Carrie N Barnes Michael J Berger Michael Blasius Amanda L Brandl Katharina Croker Ben Crozat Karine Du Xin Eidenschenk Celine Georgel Philippe Hoebe Kasper Huang Hua Jiang Zhengfan Krebs Philippe La Vine Diantha Li Xiaohong Lyon Stephen Moresco Eva Marie Y Murray Anne R Popkin Daniel L Rutschmann Sophie Siggs Owen M Smart Nora G Sun Lei Tabeta Koichi Webster Victoria Tomisato Wataru Won Sungyong Xia Yu Xiao Nengming Beutler Bruce |
| author_sort | Arnold Carrie N |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>We present a compendium of <it>N</it>-ethyl-<it>N</it>-nitrosourea (ENU)-induced mouse mutations, identified in our laboratory over a period of 10 years either on the basis of phenotype or whole genome and/or whole exome sequencing, and archived in the Mutagenetix database. Our purpose is threefold: 1) to formally describe many point mutations, including those that were not previously disclosed in peer-reviewed publications; 2) to assess the characteristics of these mutations; and 3) to estimate the likelihood that a missense mutation induced by ENU will create a detectable phenotype.</p> <p>Findings</p> <p>In the context of an ENU mutagenesis program for C57BL/6J mice, a total of 185 phenotypes were tracked to mutations in 129 genes. In addition, 402 incidental mutations were identified and predicted to affect 390 genes. As previously reported, ENU shows strand asymmetry in its induction of mutations, particularly favoring T to A rather than A to T in the sense strand of coding regions and splice junctions. Some amino acid substitutions are far more likely to be damaging than others, and some are far more likely to be observed. Indeed, from among a total of 494 non-synonymous coding mutations, ENU was observed to create only 114 of the 182 possible amino acid substitutions that single base changes can achieve. Based on differences in overt null allele frequencies observed in phenotypic vs. non-phenotypic mutation sets, we infer that ENU-induced missense mutations create detectable phenotype only about 1 in 4.7 times. While the remaining mutations may not be functionally neutral, they are, on average, beneath the limits of detection of the phenotypic assays we applied.</p> <p>Conclusions</p> <p>Collectively, these mutations add to our understanding of the chemical specificity of ENU, the types of amino acid substitutions it creates, and its efficiency in causing phenovariance. Our data support the validity of computational algorithms for the prediction of damage caused by amino acid substitutions, and may lead to refined predictions as to whether specific amino acid changes are responsible for observed phenotypes. These data form the basis for closer in silico estimations of the number of genes mutated to a state of phenovariance by ENU within a population of G3 mice.</p> |
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| spelling | doaj.art-111cb65d7d664211b71c04f934f15c412022-12-21T23:13:11ZengBMCBMC Research Notes1756-05002012-10-015157710.1186/1756-0500-5-577ENU-induced phenovariance in mice: inferences from 587 mutationsArnold Carrie NBarnes Michael JBerger MichaelBlasius Amanda LBrandl KatharinaCroker BenCrozat KarineDu XinEidenschenk CelineGeorgel PhilippeHoebe KasperHuang HuaJiang ZhengfanKrebs PhilippeLa Vine DianthaLi XiaohongLyon StephenMoresco Eva Marie YMurray Anne RPopkin Daniel LRutschmann SophieSiggs Owen MSmart Nora GSun LeiTabeta KoichiWebster VictoriaTomisato WataruWon SungyongXia YuXiao NengmingBeutler Bruce<p>Abstract</p> <p>Background</p> <p>We present a compendium of <it>N</it>-ethyl-<it>N</it>-nitrosourea (ENU)-induced mouse mutations, identified in our laboratory over a period of 10 years either on the basis of phenotype or whole genome and/or whole exome sequencing, and archived in the Mutagenetix database. Our purpose is threefold: 1) to formally describe many point mutations, including those that were not previously disclosed in peer-reviewed publications; 2) to assess the characteristics of these mutations; and 3) to estimate the likelihood that a missense mutation induced by ENU will create a detectable phenotype.</p> <p>Findings</p> <p>In the context of an ENU mutagenesis program for C57BL/6J mice, a total of 185 phenotypes were tracked to mutations in 129 genes. In addition, 402 incidental mutations were identified and predicted to affect 390 genes. As previously reported, ENU shows strand asymmetry in its induction of mutations, particularly favoring T to A rather than A to T in the sense strand of coding regions and splice junctions. Some amino acid substitutions are far more likely to be damaging than others, and some are far more likely to be observed. Indeed, from among a total of 494 non-synonymous coding mutations, ENU was observed to create only 114 of the 182 possible amino acid substitutions that single base changes can achieve. Based on differences in overt null allele frequencies observed in phenotypic vs. non-phenotypic mutation sets, we infer that ENU-induced missense mutations create detectable phenotype only about 1 in 4.7 times. While the remaining mutations may not be functionally neutral, they are, on average, beneath the limits of detection of the phenotypic assays we applied.</p> <p>Conclusions</p> <p>Collectively, these mutations add to our understanding of the chemical specificity of ENU, the types of amino acid substitutions it creates, and its efficiency in causing phenovariance. Our data support the validity of computational algorithms for the prediction of damage caused by amino acid substitutions, and may lead to refined predictions as to whether specific amino acid changes are responsible for observed phenotypes. These data form the basis for closer in silico estimations of the number of genes mutated to a state of phenovariance by ENU within a population of G3 mice.</p>http://www.biomedcentral.com/1756-0500/5/577N-ethyl-N-nitrosoureaMouseC57BL/6JMutagenesisGenetic screenPolyPhen-2Strand asymmetryPhenotype |
| spellingShingle | Arnold Carrie N Barnes Michael J Berger Michael Blasius Amanda L Brandl Katharina Croker Ben Crozat Karine Du Xin Eidenschenk Celine Georgel Philippe Hoebe Kasper Huang Hua Jiang Zhengfan Krebs Philippe La Vine Diantha Li Xiaohong Lyon Stephen Moresco Eva Marie Y Murray Anne R Popkin Daniel L Rutschmann Sophie Siggs Owen M Smart Nora G Sun Lei Tabeta Koichi Webster Victoria Tomisato Wataru Won Sungyong Xia Yu Xiao Nengming Beutler Bruce ENU-induced phenovariance in mice: inferences from 587 mutations BMC Research Notes N-ethyl-N-nitrosourea Mouse C57BL/6J Mutagenesis Genetic screen PolyPhen-2 Strand asymmetry Phenotype |
| title | ENU-induced phenovariance in mice: inferences from 587 mutations |
| title_full | ENU-induced phenovariance in mice: inferences from 587 mutations |
| title_fullStr | ENU-induced phenovariance in mice: inferences from 587 mutations |
| title_full_unstemmed | ENU-induced phenovariance in mice: inferences from 587 mutations |
| title_short | ENU-induced phenovariance in mice: inferences from 587 mutations |
| title_sort | enu induced phenovariance in mice inferences from 587 mutations |
| topic | N-ethyl-N-nitrosourea Mouse C57BL/6J Mutagenesis Genetic screen PolyPhen-2 Strand asymmetry Phenotype |
| url | http://www.biomedcentral.com/1756-0500/5/577 |
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