Research paperGenetic variation in the Mauritian cynomolgus macaque population reflects variation in the human population
Introduction
Non-human primates are increasingly studied and considered highly relevant animal models for human biomedical disease research. Members of the Macaca genus, represented by rhesus and cynomolgus macaques, are among the most commonly used non-human primates due to their close evolutionary relationship to humans, analogous disease susceptibilities, and wide-spread commercial availability (Carlsson et al. 2004). The cynomolgus macaque has important advantages over the rhesus macaque for use in research that include easier handling based on smaller body size (Rowe, 1996), lower acquisition cost, better availability, and lack of seasonal fertility which may affect experimental outcome (Taylor 2010). These advantages combined with the high level (~93%) of sequence conservation between the cynomolgus macaque and human genome (Ebeling et al. 2011), and physiological similarity with humans, have contributed to the widespread use of cynomolgus macaques for translational studies in research and drug development (Ebeling et al., 2011, Ise et al., 2011). For these studies, cynomolgus macaques are sourced from several different countries including Mauritius, Vietnam, the Philippines, and Indonesia. Recently it was shown that there are biologically relevant genetic differences among cynomolgus macaques linked to geographic origin (Tosi and Coke, 2007, Satkoski Trask et al., 2013). Additionally, it has been reported that the genomic composition of macaques can have considerable influence on the outcome of biomedical experiments (Flynn et al., 2009, de Groot et al., 2011, Kanthaswamy et al., 2013) and drug metabolism (Uno et al., 2014, Utoh et al., 2015).
The first published cynomolgus macaque genome was based on a single female of Mauritian origin (Ebeling et al. 2011). This sequence information was the basis for being able to map the amount and type of genomic variation in cynomolgus macaques. Since then, two additional genome sequences from macaques of Vietnamese and Malaysian origin have been published (Yan et al., 2011, Higashino et al., 2012), and RNA-based next-generation sequencing has been used to better annotate both the rhesus and cynomolgus macaque genomes (Peng et al. 2014). However, wide-scale characterization of genetic variability in the cynomolgus macaque Population has not been conducted.
Exome sequencing has proven to be a powerful and efficient tool in human genetic studies (Metzker, 2010) as it allows an unbiased investigation of almost all protein-coding regions in a large sample of individuals at a fraction of the cost of whole genome sequencing. The method has been successfully applied to identification of genetic signatures in the human population that are associated with drug-induced toxicity, such as paclitaxel dose-limiting neuropathy (Apellaniz-Ruiz et al. 2015), drug-induced long QT interval syndrome (Weeke et al. 2014), and gemcitabine- or carboplatin-induced myelosuppression (Green et al. 2016). In this study, exome sequencing was conducted using genomic DNA collected from 101 cynomolgus macaques of Mauritian origin, with the aim of characterizing genetic composition in a cynomolgus macaque population, and comparing it to genetic variability observed in the human population. Knowledge of genetic variants in cynomolgus macaques offers the potential for advances in understanding phenotypic variability in cynomolgus macaques and improved translation to humans.
Section snippets
Macaque exomes yield high quality sequence data
The complete sequences were submitted to NCBI (Sequence Read Archive accession: SRP139392; Temporary Submission ID: SUB3892628; Release date: 2019–06-01). The latest assembly of the cynomolgus macaque genome published by the University of Washington (Macaca_fascicularis_5.0, http://www.ncbi.nlm.nih.gov/assembly/GCF_000364345.1) was used as the reference sequence genome for alignment of all sequencing reads. Given that the Macaca_fascicularis_5.0 genome is a newer genome build than the sequences
Discussion
Critical to capturing the genetic diversity within a population is the sample size being selected for study. A recent publication showed that the majority of variants identified in immune system genes in cynomolgus macaques of Mauritian origin have a MAF greater than 5% (Wu and Adkins 2012). In addition, it was estimated that a common variant with a MAF greater than 5% has greater than a 99% chance of being detected twice in a population with sample size of 100. Furthermore, Tennessen et al.,
Animals
Blood samples were obtained from 101 naïve cynomolgus macaques (24 female, 77 male) of Mauritian origin (Charles River Laboratories, Houston, TX). All procedures performed were in accordance with established guidelines and approved by an Institutional Animal Care and Use Committee or through an ethical review process.
Genomic DNA isolation
Genomic DNA was extracted from whole blood samples using the QIAamp Blood Kit (Qiagen, Valencia, CA) in accordance with manufacturer instructions. Each DNA sample was quantified
CRediT authorship contribution statement
Hong Wu: Conceptualization, Methodology, Investigation, Visualization, Formal analysis, Writing - original draft. Xinmin Zhang: Data curation, Visualization, Formal analysis. Baohong Zhang: Formal analysis. Karissa Adkins: Conceptualization, Methodology, Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Authors were employed by Pfizer, Drug Safety Research and Development, Groton, CT at the time this research was conducted.