Roche Researchers Sequence Complete Genome of Cynomolgus Monkey and Develop Novel Gene Expression Microarray for Drug Safety Assessment
BASEL, Switzerland, September 22, 2011 /PRNewswire/ –
A team of researchers from Roche (SIX: RO, ROG; OTCQX: RHHBY)
[http://www.roche.com/investors.htm ], including scientists from Roche
Pharma Research and Early Development and Roche NimbleGen, reported inGenome
Research (1) that they have generated the first draft genome sequence of the
cynomolgus monkey (Macaca fascicularis) and developed a novel microarray
design for in depth expression profiling for use in preclinical drug safety
The cynomolgus macaque is one of the most important and widely used
non-human primate animal models in basic and applied biomedical research.
Compared to other species, non-human primates have a closer evolutionary
relationship to humans and exhibit high physiological similarity well suited
to serve as translational models for preclinical drug safety assessment.
To improve the predictive power of primate experiments for humans, Prof.
Ulrich Certa, Global Head Molecular Toxicology, and his team first applied a
shotgun sequencing strategy using the Genome Sequencer FLX System from
Roche’s 454 Life Sciences division in combination with other next generation
sequencing technologies to decode the entire genome of a Macaca fascicularis
female of Mauritian origin with 6-fold coverage. In addition, roughly two
million potential single-nucleotide polymorphisms (SNPs) were discovered
which, for the first time, will allow high-resolution genotyping of
individuals in this species.
Using a combination of sequence alignment and exon size conservation,
more than 20,000 transcripts in the cynomolgus monkey genome were predicted
and used to build a M. fascicularis-specific gene expression microarray on
the Roche NimbleGen 12x135K platform, in less than two months enabling
comprehensive yet economical transcriptome analysis. The 12-plex expression
array format contains 135,000 oligonucleotide features per array with six
60-mer probes interrogating each transcript with more probe space available
for either including additional targets of M. fascicularis or other custom
The comparative expression analysis of liver samples from 36 animals of
different geographic origin resulted in the identification of over 700 genes
with highly variable expression while the majority of the transcriptome
showed relatively stable expression with low inter-animal variation.
Interestingly enough, considerable inter-individual as well as inter-species
variability was found in gene expression levels of a number of drug safety
and response related genes. Variation in gene expression among individuals
can be critical for the interpretation of drug safety data and genome-wide
gene expression profiling can now be used to improve drug safety studies and
discover the mode of action of novel drugs in a relevant animal model.
“The flexibility and accuracy of the NimbleGen expression microarray
platform allowed us to develop a novel microarray based on our genome
sequencing effort. For the first time, gene expression can be monitored with
high-specificity in this animal model to answer mechanistic or safety
related questions based on transcriptional responses. Furthermore, we plan
to design additional arrays for copy-number-variation and SNP analysis on
the NimbleGen array platform. These combined efforts will hopefully improve
the translational value of non-human primate experiments for humans. As in
humans, it might become possible in the future to discover polymorphisms in
drug-response genes that differentiate poor and good metabolizers for
instance” explained Prof. Ulrich Certa, principle lead of the project.
“The knowledge we obtained from the cynomolgus genome and gene
expression profiling using NimbleGen microarrays is an important
contribution towards the better use of this species as a drug safety model
for the assessment of novel human drugs. In particular, the published
research data represents a significant contribution to the global “3R”
animal welfare initiative, which has the goal to reduce, refine and replace
animal experiments” stated Thomas Singer, Global Head of Non Clinical Safety
Pharma Research and Early Development (pRED).
Headquartered in Basel, Switzerland, Roche is a leader in
research-focused healthcare with combined strengths in pharmaceuticals and
diagnostics. Roche is the world’s largest biotech company with truly
differentiated medicines in oncology, virology, inflammation, metabolism and
CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based
cancer diagnostics and a pioneer in diabetes management. Roche’s
personalised healthcare strategy aims at providing medicines and diagnostic
tools that enable tangible improvements in the health, quality of life and
survival of patients. In 2009, Roche had over 80,000 employees worldwide and
invested almost 10 billion Swiss francs in R&D. The Group posted sales of
49.1 billion Swiss francs. Genentech, United States, is a wholly owned
member of the Roche Group. Roche has a majority stake in Chugai
Pharmaceutical, Japan. For more information: http://www.roche.com.
(1)Ebeling et al. Genome-based analysis of the nonhuman primate Macaca
fascicularis as a model for drug safety assessment. (2011) Genome Research.
Published in Advance Aug 23, 2011. doi:10.1101/gr.123117.111
For life science research only. Not for use in diagnostic procedures.
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