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Exome screening to identify loss-of-function mutations in the rhesus macaque for development of preclinical models of human disease

Overview of attention for article published in BMC Genomics, March 2016
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Title
Exome screening to identify loss-of-function mutations in the rhesus macaque for development of preclinical models of human disease
Published in
BMC Genomics, March 2016
DOI 10.1186/s12864-016-2509-5
Pubmed ID
Authors

Adam S. Cornish, Robert M. Gibbs, Robert B. Norgren

Abstract

Exome sequencing has been utilized to identify genetic variants associated with disease in humans. Identification of loss-of-function mutations with exome sequencing in rhesus macaques (Macaca mulatta) could lead to valuable animal models of genetic disease. Attempts have been made to identify variants in rhesus macaques by aligning exome data against the rheMac2 draft genome. However, such efforts have been impaired due to the incompleteness and annotation errors associated with rheMac2. We wished to determine whether aligning exome reads against our new, improved rhesus genome, MacaM, could be used to identify high impact, loss-of-function mutations in rhesus macaques that would be relevant to human disease. We compared alignments of exome reads from four rhesus macaques, the reference animal and three unrelated animals, against rheMac2 and MacaM. Substantially more reads aligned against MacaM than rheMac2. We followed the Broad Institute's Best Practice guidelines for variant discovery which utilizes the Genome Analysis Toolkit to identify high impact mutations. When rheMac2 was used as the reference genome, a large number of apparent false positives were identified. When MacaM was used as the reference genome, the number of false positives was greatly reduced. After examining the variant analyses conducted with MacaM as reference genome, we identified two putative loss-of-function mutations, in the heterozygous state, in genes related to human health. Sanger sequencing confirmed the presence of these mutations. We followed the transmission of one of these mutations (in the butyrylthiocholine gene) through three generations of rhesus macaques. Further, we demonstrated a functional decrease in butyrylthiocholinesterase activity similar to that observed in human heterozygotes with loss-of-function mutations in the same gene. The new MacaM genome can be effectively utilized to identify loss-of-function mutations in rhesus macaques without generating a high level of false positives. In some cases, heterozygotes may be immediately useful as models of human disease. For diseases where homozygous mutants are needed, directed breeding of loss-of-function heterozygous animals could be used to create rhesus macaque models of human genetic disease. The approach we describe here could be applied to other mammals, but only if their genomes have been improved beyond draft status.

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Mendeley readers

The data shown below were compiled from readership statistics for 12 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 1 8%
France 1 8%
Unknown 10 83%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 5 42%
Researcher 2 17%
Lecturer 1 8%
Student > Master 1 8%
Student > Doctoral Student 1 8%
Other 1 8%
Unknown 1 8%
Readers by discipline Count As %
Agricultural and Biological Sciences 7 58%
Social Sciences 1 8%
Biochemistry, Genetics and Molecular Biology 1 8%
Medicine and Dentistry 1 8%
Neuroscience 1 8%
Other 0 0%
Unknown 1 8%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 03 March 2016.
All research outputs
#5,296,896
of 7,346,659 outputs
Outputs from BMC Genomics
#4,026
of 5,412 outputs
Outputs of similar age
#181,619
of 281,318 outputs
Outputs of similar age from BMC Genomics
#181
of 217 outputs
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