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Efficient analysis of mouse genome sequences reveal many nonsense variants

Sophie Steeland (UGent) , Steven Timmermans (UGent) , Sara Van Ryckeghem (UGent) , Paco Hulpiau (UGent) , Yvan Saeys (UGent) , Marc Van Montagu (UGent) , Roosmarijn Vandenbroucke (UGent) and Claude Libert (UGent)
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Abstract
Genetic polymorphisms in coding genes play an important role when using mouse inbred strains as research models. They have been shown to influence research results, explain phenotypical differences between inbred strains, and increase the amount of interesting gene variants present in the many available inbred lines. SPRET/Ei is an inbred strain derived from Mus spretus that has similar to 1% sequence difference with the C57BL/6J reference genome. We obtained a listing of all SNPs and insertions/deletions (indels) present in SPRET/Ei from the Mouse Genomes Project (Wellcome Trust Sanger Institute) and processed these data to obtain an overview of all transcripts having nonsynonymous coding sequence variants. We identified 8,883 unique variants affecting 10,096 different transcripts from 6,328 protein-coding genes, which is about 28% of all coding genes. Because only a subset of these variants results in drastic changes in proteins, we focused on variations that are nonsense mutations that ultimately resulted in a gain of a stop codon. These genes were identified by in silico changing the C57BL/6J coding sequences to the SPRET/Ei sequences, converting them to amino acid (AA) sequences, and comparing the AA sequences. All variants and transcripts affected were also stored in a database, which can be browsed using a SPRET/Ei M. spretus variants web tool (www.spretus.org), including a manual. We validated the tool by demonstrating the loss of function of three proteins predicted to be severely truncated, namely Fas, IRAK2, and IFN gamma R1.
Keywords
mouse, mutations, genomics, bioinformatics, inflammation, INTERFERON-GAMMA, IMMUNE FUNCTION, MICE, RECEPTOR, GENE, LPS, CRISPR-CAS9, PHENOTYPES, ACTIVATION, PROTEINS

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Chicago
Steeland, Sophie, Steven Timmermans, Sara Van Ryckeghem, Paco Hulpiau, Yvan Saeys, Marc Van Montagu, Roosmarijn Vandenbroucke, and Claude Libert. 2016. “Efficient Analysis of Mouse Genome Sequences Reveal Many Nonsense Variants.” Proceedings of the National Academy of Sciences of the United States of America 113 (20): 5670–5675.
APA
Steeland, S., Timmermans, S., Van Ryckeghem, S., Hulpiau, P., Saeys, Y., Van Montagu, M., Vandenbroucke, R., et al. (2016). Efficient analysis of mouse genome sequences reveal many nonsense variants. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 113(20), 5670–5675.
Vancouver
1.
Steeland S, Timmermans S, Van Ryckeghem S, Hulpiau P, Saeys Y, Van Montagu M, et al. Efficient analysis of mouse genome sequences reveal many nonsense variants. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2016;113(20):5670–5.
MLA
Steeland, Sophie, Steven Timmermans, Sara Van Ryckeghem, et al. “Efficient Analysis of Mouse Genome Sequences Reveal Many Nonsense Variants.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 113.20 (2016): 5670–5675. Print.
@article{7250141,
  abstract     = {Genetic polymorphisms in coding genes play an important role when using mouse inbred strains as research models. They have been shown to influence research results, explain phenotypical differences between inbred strains, and increase the amount of interesting gene variants present in the many available inbred lines. SPRET/Ei is an inbred strain derived from Mus spretus that has similar to 1\% sequence difference with the C57BL/6J reference genome. We obtained a listing of all SNPs and insertions/deletions (indels) present in SPRET/Ei from the Mouse Genomes Project (Wellcome Trust Sanger Institute) and processed these data to obtain an overview of all transcripts having nonsynonymous coding sequence variants. We identified 8,883 unique variants affecting 10,096 different transcripts from 6,328 protein-coding genes, which is about 28\% of all coding genes. Because only a subset of these variants results in drastic changes in proteins, we focused on variations that are nonsense mutations that ultimately resulted in a gain of a stop codon. These genes were identified by in silico changing the C57BL/6J coding sequences to the SPRET/Ei sequences, converting them to amino acid (AA) sequences, and comparing the AA sequences. All variants and transcripts affected were also stored in a database, which can be browsed using a SPRET/Ei M. spretus variants web tool (www.spretus.org), including a manual. We validated the tool by demonstrating the loss of function of three proteins predicted to be severely truncated, namely Fas, IRAK2, and IFN gamma R1.},
  author       = {Steeland, Sophie and Timmermans, Steven and Van Ryckeghem, Sara and Hulpiau, Paco and Saeys, Yvan and Van Montagu, Marc and Vandenbroucke, Roosmarijn and Libert, Claude},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  language     = {eng},
  number       = {20},
  pages        = {5670--5675},
  title        = {Efficient analysis of mouse genome sequences reveal many nonsense variants},
  url          = {http://dx.doi.org/10.1073/pnas.1605076113},
  volume       = {113},
  year         = {2016},
}

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