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A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats

View ORCID ProfileTristan V de Jong, View ORCID ProfileYanchao Pan, View ORCID ProfilePasi Rastas, View ORCID ProfileDaniel Munro, View ORCID ProfileMonika Tutaj, View ORCID ProfileHuda Akil, View ORCID ProfileChris Benner, View ORCID ProfileApurva S Chitre, View ORCID ProfileWilliam Chow, View ORCID ProfileVincenza Colonna, View ORCID ProfileClifton L Dalgard, View ORCID ProfileWendy M Demos, View ORCID ProfilePeter A Doris, View ORCID ProfileErik Garrison, View ORCID ProfileAron Geurts, View ORCID ProfileHakan M Gunturkun, View ORCID ProfileVictor Guryev, Thibaut Hourlier, View ORCID ProfileKerstin Howe, Jun Huang, View ORCID ProfileTed Kalbfleisch, View ORCID ProfilePanjun Kim, Ling Li, View ORCID ProfileSpencer Mahaffey, View ORCID ProfileFergal J Martin, View ORCID ProfilePejman Mohammadi, View ORCID ProfileAyse Bilge Ozel, View ORCID ProfileOksana Polesskaya, View ORCID ProfileMichal Pravenec, View ORCID ProfilePjotr Prins, View ORCID ProfileJonathan Sebat, Jennifer R Smith, View ORCID ProfileLeah C Solberg Woods, Boris Tabakoff, Alan Tracey, Marcela Uliano-Silva, View ORCID ProfileFlavia Villani, Hongyang Wang, Burt M Sharp, View ORCID ProfileFrancesca Telese, View ORCID ProfileZhihua Jiang, View ORCID ProfileLaura Saba, View ORCID ProfileXusheng Wang, View ORCID ProfileTerence D Murphy, View ORCID ProfileAbraham A Palmer, View ORCID ProfileAnne E Kwitek, View ORCID ProfileMelinda (Mindy) R Dwinell, View ORCID ProfileRobert W Williams, View ORCID ProfileJun Z Li, View ORCID ProfileHao Chen
doi: https://doi.org/10.1101/2023.04.13.536694
Tristan V de Jong
1Department of Pharmacology, Addiction Science, and Toxicology, University of Tennessee Health Science Center
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Yanchao Pan
2Department of Human Genetics, University of Michigan
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Pasi Rastas
3Institute of Biotechnology, University of Helsinki
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Daniel Munro
4Department of Psychiatry, University of California San Diego, Scripps Research
5Department of Integrative Structural and Computational Biology, Scripps Research
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Monika Tutaj
6Department of Physiology, Medical College of Wisconsin
7Rat Genome Database, Medical College of Wisconsin
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Huda Akil
8Michigan Neuroscience Institute, University of Michigan
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Chris Benner
9Department of Medicine, University of California San Diego
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Apurva S Chitre
10Department of Psychiatry, University of California San Diego
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William Chow
11Tree of Life, Wellcome Sanger Institute
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Vincenza Colonna
12Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center
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Clifton L Dalgard
13Department of Anatomy, Physiology & Genetics; The American Genome Center, Uniformed Services University of the Health Sciences
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Wendy M Demos
6Department of Physiology, Medical College of Wisconsin
7Rat Genome Database, Medical College of Wisconsin
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Peter A Doris
14The Brown Foundation Institute Of Molecular Medicine, Center For Human Genetics, University of Texas Health Science Center
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Erik Garrison
12Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center
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Aron Geurts
15Rat Genome Database; Department of Physiology, Medical College of Wisconsin
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Hakan M Gunturkun
1Department of Pharmacology, Addiction Science, and Toxicology, University of Tennessee Health Science Center
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Victor Guryev
16Genome Structure and Ageing, University of Groningen, UMC Groningen
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Thibaut Hourlier
17European Molecular Biology Laboratory, European Bioinformatics Institute
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Kerstin Howe
18Tree of Life, Wellcome Sanger Institute, Cambridge, UK, Wellcome Sanger Institute
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Jun Huang
1Department of Pharmacology, Addiction Science, and Toxicology, University of Tennessee Health Science Center
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Ted Kalbfleisch
19Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky
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Panjun Kim
12Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center
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Ling Li
20Department of Biology, University of North Dakota
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Spencer Mahaffey
21Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus
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Fergal J Martin
17European Molecular Biology Laboratory, European Bioinformatics Institute
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Pejman Mohammadi
22Department of Integrative Structural and Computational Biology, Scripps Research Translational Institute, Scripps Research
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Ayse Bilge Ozel
2Department of Human Genetics, University of Michigan
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Oksana Polesskaya
23Department of Psychiatry, University of California San Diego
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Michal Pravenec
24Institute of Physiology, Czech Academy of Sciences
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Pjotr Prins
12Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center
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Jonathan Sebat
23Department of Psychiatry, University of California San Diego
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Jennifer R Smith
6Department of Physiology, Medical College of Wisconsin
7Rat Genome Database, Medical College of Wisconsin
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Leah C Solberg Woods
25Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine
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Boris Tabakoff
26Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado
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Alan Tracey
11Tree of Life, Wellcome Sanger Institute
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Marcela Uliano-Silva
11Tree of Life, Wellcome Sanger Institute
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Flavia Villani
12Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center
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Hongyang Wang
27Department of Animal Sciences, Washington State University
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Burt M Sharp
12Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center
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Francesca Telese
10Department of Psychiatry, University of California San Diego
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Zhihua Jiang
27Department of Animal Sciences, Washington State University
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Laura Saba
21Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus
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Xusheng Wang
12Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center
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Terence D Murphy
28National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health
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Abraham A Palmer
23Department of Psychiatry, University of California San Diego
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Anne E Kwitek
6Department of Physiology, Medical College of Wisconsin
7Rat Genome Database, Medical College of Wisconsin
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Melinda (Mindy) R Dwinell
6Department of Physiology, Medical College of Wisconsin
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Robert W Williams
12Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center
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Jun Z Li
2Department of Human Genetics, University of Michigan
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  • For correspondence: junzli@med.umich.edu hchen@uthsc.edu
Hao Chen
1Department of Pharmacology, Addiction Science, and Toxicology, University of Tennessee Health Science Center
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  • For correspondence: junzli@med.umich.edu hchen@uthsc.edu
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Abstract

For over a decade, a large research community has relied on a flawed reference assembly of the genome of Rattus norvegicus known as Rnor_6.0. The seventh assembly of the rat reference genome4mRatBN7.2, based on the inbred Brown Norway rat, corrects numerous misplaced segments, reduces base-level errors by approximately 9-fold, and increases contiguity by 290-fold, despite some remaining regions of potential misassembly. Gene annotations are now more complete, significantly improving the mapping precision of genomic, transcriptomic, and proteomics data sets. Simple LiftOver from Rnor_6.0 to mRatBN7.2 misses ∼12% of variants. To facilitate the transition to mRatBN7.2, we performed a joint analysis of 163 whole genomes representing 120 strains/substrains. We defined 20.0 million sequence variations, of which 18.7 thousand are predicted to potentially impact the function of 6,677 genes. Phylogenetic analysis confirmed historical records and prior results and refined the ancestral relationship of these strains. Sixteen million polymorphisms segregate in the widely studied heterogeneous stock rat population, and 11313 million variants segregate collectively in the HXB/BXH and FXLE/LEXF strain families. Some inbred strains differ by only 132 M variants, and closely related substrains segregate by even fewer variants. We generated a new rat genetic map based on data from 1,893 heterogeneous stock rats and annotated transcription start sites and alternative polyadenylation sites.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 14, 2023.
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A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats
Tristan V de Jong, Yanchao Pan, Pasi Rastas, Daniel Munro, Monika Tutaj, Huda Akil, Chris Benner, Apurva S Chitre, William Chow, Vincenza Colonna, Clifton L Dalgard, Wendy M Demos, Peter A Doris, Erik Garrison, Aron Geurts, Hakan M Gunturkun, Victor Guryev, Thibaut Hourlier, Kerstin Howe, Jun Huang, Ted Kalbfleisch, Panjun Kim, Ling Li, Spencer Mahaffey, Fergal J Martin, Pejman Mohammadi, Ayse Bilge Ozel, Oksana Polesskaya, Michal Pravenec, Pjotr Prins, Jonathan Sebat, Jennifer R Smith, Leah C Solberg Woods, Boris Tabakoff, Alan Tracey, Marcela Uliano-Silva, Flavia Villani, Hongyang Wang, Burt M Sharp, Francesca Telese, Zhihua Jiang, Laura Saba, Xusheng Wang, Terence D Murphy, Abraham A Palmer, Anne E Kwitek, Melinda (Mindy) R Dwinell, Robert W Williams, Jun Z Li, Hao Chen
bioRxiv 2023.04.13.536694; doi: https://doi.org/10.1101/2023.04.13.536694
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A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats
Tristan V de Jong, Yanchao Pan, Pasi Rastas, Daniel Munro, Monika Tutaj, Huda Akil, Chris Benner, Apurva S Chitre, William Chow, Vincenza Colonna, Clifton L Dalgard, Wendy M Demos, Peter A Doris, Erik Garrison, Aron Geurts, Hakan M Gunturkun, Victor Guryev, Thibaut Hourlier, Kerstin Howe, Jun Huang, Ted Kalbfleisch, Panjun Kim, Ling Li, Spencer Mahaffey, Fergal J Martin, Pejman Mohammadi, Ayse Bilge Ozel, Oksana Polesskaya, Michal Pravenec, Pjotr Prins, Jonathan Sebat, Jennifer R Smith, Leah C Solberg Woods, Boris Tabakoff, Alan Tracey, Marcela Uliano-Silva, Flavia Villani, Hongyang Wang, Burt M Sharp, Francesca Telese, Zhihua Jiang, Laura Saba, Xusheng Wang, Terence D Murphy, Abraham A Palmer, Anne E Kwitek, Melinda (Mindy) R Dwinell, Robert W Williams, Jun Z Li, Hao Chen
bioRxiv 2023.04.13.536694; doi: https://doi.org/10.1101/2023.04.13.536694

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