High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes
David R Powell,1 Jean-Pierre Revelli,1 Deon D Doree,1 Christopher M DaCosta,1 Urvi Desai,1 Melanie K Shadoan,1 Lawrence Rodriguez,2 Michael Mullens,2 Qi M Yang,1 Zhi-Ming Ding,1 Laura L Kirkpatrick,3 Peter Vogel,1 Brian Zambrowicz,1– 3 Arthur T Sands,1– 3 Kenneth A Platt,3 Gwenn M Hansen,3 Robert Br...
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Dove Medical Press
2021
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oai:doaj.org-article:2d957345ea1944c1964a341d36812b022021-12-02T19:02:38ZHigh-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes1178-7007https://doaj.org/article/2d957345ea1944c1964a341d36812b022021-08-01T00:00:00Zhttps://www.dovepress.com/high-throughput-screening-of-mouse-gene-knockouts-identifies-establish-peer-reviewed-fulltext-article-DMSOhttps://doaj.org/toc/1178-7007David R Powell,1 Jean-Pierre Revelli,1 Deon D Doree,1 Christopher M DaCosta,1 Urvi Desai,1 Melanie K Shadoan,1 Lawrence Rodriguez,2 Michael Mullens,2 Qi M Yang,1 Zhi-Ming Ding,1 Laura L Kirkpatrick,3 Peter Vogel,1 Brian Zambrowicz,1– 3 Arthur T Sands,1– 3 Kenneth A Platt,3 Gwenn M Hansen,3 Robert Brommage1 1Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA; 2Department of Information Technology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USA; 3Department of Molecular Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USACorrespondence: David R PowellDepartment of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, 2445 Technology Forest Boulevard, The Woodlands, Tx, 77381, USATel +1 713 249 3972Fax +1 281 863 8115Email dpowell@lexpharma.comPurpose: Obesity is a major public health problem. Understanding which genes contribute to obesity may better predict individual risk and allow development of new therapies. Because obesity of a mouse gene knockout (KO) line predicts an association of the orthologous human gene with obesity, we reviewed data from the Lexicon Genome5000TM high throughput phenotypic screen (HTS) of mouse gene KOs to identify KO lines with high body fat.Materials and Methods: KO lines were generated using homologous recombination or gene trapping technologies. HTS body composition analyses were performed on adult wild-type and homozygous KO littermate mice from 3758 druggable mouse genes having a human ortholog. Body composition was measured by either DXA or QMR on chow-fed cohorts from all 3758 KO lines and was measured by QMR on independent high fat diet-fed cohorts from 2488 of these KO lines. Where possible, comparisons were made to HTS data from the International Mouse Phenotyping Consortium (IMPC).Results: Body fat data are presented for 75 KO lines. Of 46 KO lines where independent external published and/or IMPC KO lines are reported as obese, 43 had increased body fat. For the remaining 29 novel high body fat KO lines, Ksr2 and G2e3 are supported by data from additional independent KO cohorts, 6 (Asnsd1, Srpk2, Dpp8, Cxxc4, Tenm3 and Kiss1) are supported by data from additional internal cohorts, and the remaining 21 including Tle4, Ak5, Ntm, Tusc3, Ankk1, Mfap3l, Prok2 and Prokr2 were studied with HTS cohorts only.Conclusion: These data support the finding of high body fat in 43 independent external published and/or IMPC KO lines. A novel obese phenotype was identified in 29 additional KO lines, with 27 still lacking the external confirmation now provided for Ksr2 and G2e3 KO mice. Undoubtedly, many mammalian obesity genes remain to be identified and characterized.Keywords: obesity, druggable, homologous recombination, gene trappingPowell DRRevelli JPDoree DDDaCosta CMDesai UShadoan MKRodriguez LMullens MYang QMDing ZMKirkpatrick LLVogel PZambrowicz BSands ATPlatt KAHansen GMBrommage RDove Medical Pressarticleobesitydruggablehomologous recombinationgene trappingSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol Volume 14, Pp 3753-3785 (2021) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
obesity druggable homologous recombination gene trapping Specialties of internal medicine RC581-951 |
| spellingShingle |
obesity druggable homologous recombination gene trapping Specialties of internal medicine RC581-951 Powell DR Revelli JP Doree DD DaCosta CM Desai U Shadoan MK Rodriguez L Mullens M Yang QM Ding ZM Kirkpatrick LL Vogel P Zambrowicz B Sands AT Platt KA Hansen GM Brommage R High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes |
| description |
David R Powell,1 Jean-Pierre Revelli,1 Deon D Doree,1 Christopher M DaCosta,1 Urvi Desai,1 Melanie K Shadoan,1 Lawrence Rodriguez,2 Michael Mullens,2 Qi M Yang,1 Zhi-Ming Ding,1 Laura L Kirkpatrick,3 Peter Vogel,1 Brian Zambrowicz,1– 3 Arthur T Sands,1– 3 Kenneth A Platt,3 Gwenn M Hansen,3 Robert Brommage1 1Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA; 2Department of Information Technology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USA; 3Department of Molecular Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USACorrespondence: David R PowellDepartment of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, 2445 Technology Forest Boulevard, The Woodlands, Tx, 77381, USATel +1 713 249 3972Fax +1 281 863 8115Email dpowell@lexpharma.comPurpose: Obesity is a major public health problem. Understanding which genes contribute to obesity may better predict individual risk and allow development of new therapies. Because obesity of a mouse gene knockout (KO) line predicts an association of the orthologous human gene with obesity, we reviewed data from the Lexicon Genome5000TM high throughput phenotypic screen (HTS) of mouse gene KOs to identify KO lines with high body fat.Materials and Methods: KO lines were generated using homologous recombination or gene trapping technologies. HTS body composition analyses were performed on adult wild-type and homozygous KO littermate mice from 3758 druggable mouse genes having a human ortholog. Body composition was measured by either DXA or QMR on chow-fed cohorts from all 3758 KO lines and was measured by QMR on independent high fat diet-fed cohorts from 2488 of these KO lines. Where possible, comparisons were made to HTS data from the International Mouse Phenotyping Consortium (IMPC).Results: Body fat data are presented for 75 KO lines. Of 46 KO lines where independent external published and/or IMPC KO lines are reported as obese, 43 had increased body fat. For the remaining 29 novel high body fat KO lines, Ksr2 and G2e3 are supported by data from additional independent KO cohorts, 6 (Asnsd1, Srpk2, Dpp8, Cxxc4, Tenm3 and Kiss1) are supported by data from additional internal cohorts, and the remaining 21 including Tle4, Ak5, Ntm, Tusc3, Ankk1, Mfap3l, Prok2 and Prokr2 were studied with HTS cohorts only.Conclusion: These data support the finding of high body fat in 43 independent external published and/or IMPC KO lines. A novel obese phenotype was identified in 29 additional KO lines, with 27 still lacking the external confirmation now provided for Ksr2 and G2e3 KO mice. Undoubtedly, many mammalian obesity genes remain to be identified and characterized.Keywords: obesity, druggable, homologous recombination, gene trapping |
| format |
article |
| author |
Powell DR Revelli JP Doree DD DaCosta CM Desai U Shadoan MK Rodriguez L Mullens M Yang QM Ding ZM Kirkpatrick LL Vogel P Zambrowicz B Sands AT Platt KA Hansen GM Brommage R |
| author_facet |
Powell DR Revelli JP Doree DD DaCosta CM Desai U Shadoan MK Rodriguez L Mullens M Yang QM Ding ZM Kirkpatrick LL Vogel P Zambrowicz B Sands AT Platt KA Hansen GM Brommage R |
| author_sort |
Powell DR |
| title |
High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes |
| title_short |
High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes |
| title_full |
High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes |
| title_fullStr |
High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes |
| title_full_unstemmed |
High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes |
| title_sort |
high-throughput screening of mouse gene knockouts identifies established and novel high body fat phenotypes |
| publisher |
Dove Medical Press |
| publishDate |
2021 |
| url |
https://doaj.org/article/2d957345ea1944c1964a341d36812b02 |
| work_keys_str_mv |
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