A haplotype-resolved genome assembly of the Nile rat facilitates exploration of the genetic basis of diabetes

Huishi Toh; Chentao Yang; Giulio Formenti; Kalpana Raja; Lily Yan; Alan Tracey; William Chow; Kerstin Howe; Lucie A Bergeron; Guojie Zhang; Bettina Haase; Jacquelyn Mountcastle; Olivier Fedrigo; John Fogg; Bogdan Kirilenko; Chetan Munegowda; Michael Hiller; Aashish Jain; Daisuke Kihara; Arang Rhie; Adam M Phillippy; Scott A Swanson; Peng Jiang; Dennis O Clegg; Erich D Jarvis; James A Thomson; Ron Stewart; Mark J P Chaisson; Yury V Bukhman

doi:10.1186/s12915-022-01427-8

A haplotype-resolved genome assembly of the Nile rat facilitates exploration of the genetic basis of diabetes

BMC Biol. 2022 Nov 8;20(1):245. doi: 10.1186/s12915-022-01427-8.

Authors

Huishi Toh¹, Chentao Yang², Giulio Formenti³, Kalpana Raja^{4

5}, Lily Yan⁶, Alan Tracey⁷, William Chow⁷, Kerstin Howe⁷, Lucie A Bergeron⁸, Guojie Zhang^{2

8

9

10}, Bettina Haase¹¹, Jacquelyn Mountcastle¹¹, Olivier Fedrigo¹¹, John Fogg¹², Bogdan Kirilenko^{13

14

15}, Chetan Munegowda^{13

14

15}, Michael Hiller^{13

14

15}, Aashish Jain¹⁶, Daisuke Kihara^{16

17}, Arang Rhie¹⁸, Adam M Phillippy¹⁸, Scott A Swanson⁴, Peng Jiang^{19

20

21}, Dennis O Clegg²², Erich D Jarvis²³, James A Thomson^{24

25

26}, Ron Stewart²⁷, Mark J P Chaisson²⁸, Yury V Bukhman²⁹

Affiliations

¹ Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, 93117, USA.
² BGI-Shenzhen, Shenzhen, 518083, China.
³ Laboratory of Neurogenetics of Language, The Rockefeller University/HHMI, New York, NY, USA.
⁴ Bioinformatics and Regenerative Biology, Morgridge Institute for Research, Madison, WI, USA.
⁵ Current address: Sema4, Stamford, CT, USA.
⁶ Department of Psychology & Neuroscience Program, Michigan State University, East Lansing, MI, USA.
⁷ Tree of Life, Wellcome Sanger Institute, Cambridge, CB10 1SA, UK.
⁸ Villum Centre for Biodiversity Genomics, Section for Ecology and Evolution, Department of Biology, University of Copenhagen, DK-2100, Copenhagen, Denmark.
⁹ State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
¹⁰ Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
¹¹ Vertebrate Genome Lab, The Rockefeller University, New York, NY, USA.
¹² Department of Statistics, University of Wisconsin - Madison, Madison, WI, USA.
¹³ LOEWE Centre for Translational Biodiversity Genomics, Senckenberganlage 25, 60325, Frankfurt, Germany.
¹⁴ Senckenberg Research Institute, Senckenberganlage 25, 60325, Frankfurt, Germany.
¹⁵ Goethe-University, Faculty of Biosciences, Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
¹⁶ Department of Computer Science, Purdue University, West Lafayette, IN, USA.
¹⁷ Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
¹⁸ Genome Informatics Section, National Human Genome Research Institute, Bethesda, MD, USA.
¹⁹ Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, OH, USA.
²⁰ Department of Biological, Geological and Environmental Sciences (BGES), Cleveland State University, 2121 Euclid Ave, Cleveland, OH, 44115, USA.
²¹ Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
²² Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, Mail Code 5060, University of California, Santa Barbara, CA, 93016, USA.
²³ The Rockefeller University, Box 54, 1230 York Avenue, New York, NY, 10065, USA.
²⁴ Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, 93106, USA. jthomson@morgridge.org.
²⁵ Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53726, USA. jthomson@morgridge.org.
²⁶ Regenerative Biology Laboratory, Morgridge Institute for Research, Madison, WI, 53715, USA. jthomson@morgridge.org.
²⁷ Bioinformatics and Regenerative Biology, Morgridge Institute for Research, Madison, WI, USA. rstewart@morgridge.org.
²⁸ Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA. mchaisso@usc.edu.
²⁹ Bioinformatics and Regenerative Biology, Morgridge Institute for Research, Madison, WI, USA. ybukhman@morgridge.org.

Abstract

Background: The Nile rat (Avicanthis niloticus) is an important animal model because of its robust diurnal rhythm, a cone-rich retina, and a propensity to develop diet-induced diabetes without chemical or genetic modifications. A closer similarity to humans in these aspects, compared to the widely used Mus musculus and Rattus norvegicus models, holds the promise of better translation of research findings to the clinic.

Results: We report a 2.5 Gb, chromosome-level reference genome assembly with fully resolved parental haplotypes, generated with the Vertebrate Genomes Project (VGP). The assembly is highly contiguous, with contig N50 of 11.1 Mb, scaffold N50 of 83 Mb, and 95.2% of the sequence assigned to chromosomes. We used a novel workflow to identify 3613 segmental duplications and quantify duplicated genes. Comparative analyses revealed unique genomic features of the Nile rat, including some that affect genes associated with type 2 diabetes and metabolic dysfunctions. We discuss 14 genes that are heterozygous in the Nile rat or highly diverged from the house mouse.

Conclusions: Our findings reflect the exceptional level of genomic resolution present in this assembly, which will greatly expand the potential of the Nile rat as a model organism.

Keywords: Arvicanthis niloticus; Diabetes; Diurnal; Genome; Germline mutation rate; Heterozygosity; Long-read genome assembly; Orthology; Positive selection; Retrogenes; Segmental duplications.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Type 2* / genetics
Genome
Genomics
Haplotypes
Humans
Murinae