羅氏454完成食蟹猴基因組測序并研發(fā)其新的表達譜芯片

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羅氏454完成食蟹猴基因組測序并研發(fā)其表達譜芯片用于藥物安全性研究

Roche Researchers Sequence Complete Genome of Cynomolgus Monkey and Develop Novel Gene Expression Microarray for Drug Safety Assessment

一個由來自羅氏制藥早期研發(fā)部和羅氏子公司NimbleGen科研人員組成的研究小組，最近在Genome Research雜志上報道他們已經獲得了第一稿的食蟹猴（Macaca fascicularis）的基因組序列草圖，并開發(fā)了一個新的食蟹猴表達芯片設計，用于臨床前藥物安全研究。

Ateam of researchers from Roche 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 research.

食蟹獼猴是基礎醫(yī)學和應用生物醫(yī)學研究中最重要和最廣泛使用的非人類靈長類動物模型之一。與其他物種相比，非人類靈長類動物與人類有更密切的進化關系，并具有較高的生理相似性，非常適合作為臨床前藥物安全性評估的模型。

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.

要提高靈長類動物實驗結果轉化到人類應用的能力，羅氏分子毒理學全球負責人Ulrich Certa先生和他的團隊使用羅氏454公司的基因組測序FLX系統(tǒng)以及其他二代測序技術，應用shotgun法解碼一個來自毛里求斯的雌性食蟹猴基因組，測序深度達到6倍基因組。此外，他們發(fā)現了約200萬潛在的單核苷酸多態(tài)性(SNP)，這將使得這個物種的高分辨率個體基因分型成為可能。

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.

結合序列比對和外顯子片段大小保守估計方法，對超過兩萬個食蟹猴基因組轉錄子進行了預測，并使用羅氏NimbleGen的12x135K芯片格式設計了一個食蟹猴特異性基因表達芯片，在不到兩個月的時間實現了經濟且全面的食蟹猴轉錄組分析。這種同時可以測試12個樣本的芯片，每個樣本有13萬5000個長度為60個堿基的寡核苷酸探針，每個轉錄子通過6個探針進行檢測。此外，芯片上還有剩余探針可以設計其他食蟹猴的基因組區(qū)域，或者其他客戶定制的內容。

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 desired content.

研究人員對來自不同地區(qū)的36個食蟹猴肝臟樣本的表達譜進行了比較分析，結果表明有超過700個表達高度可變，而大多數轉錄子在個體間的表達量相對穩(wěn)定。有趣的是，許多藥品安全及藥物作用的相關基因的表達水平在實驗中顯示出存在相當的個體間以及種間差異。在個體之間的基因表達的差異對于分析藥物安全至關重要。全基因組基因表達分析亦可以提高藥物安全性研究的質量，并發(fā)現新藥在相關的動物模型中的代謝及作用機理。

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.

羅氏負責該項目的 Ulrich Certa先生說：“NimbleGen的表達微陣列平臺的靈活性和準確性，使我們能夠根據我們的基因組測序工作結果開發(fā)一種新基因芯片設計。食蟹猴的基因表達首次可以進行高特異性的監(jiān)測，通過藥物引起的基因轉錄水平的改變來解答藥物作用機制或藥物安全的問題。此外，我們計劃設計監(jiān)測拷貝數改變和SNP分析的NimbleGen芯片。這些方法相結合將有望提高非人類靈長類動物實驗結果用于預測人類實驗結果的可參考性。例如，在未來，在人類研究中同樣可能發(fā)現基因多態(tài)性引起的對同一藥物不同的代謝反應�！�

“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.

羅氏非臨床藥物安全早期研發(fā)(pRED)的全球負責人Thomas Singer說：“利用食蟹基因組以及NimbleGen基因芯片的表達譜分析數據，我們增強動物模型用于人類藥物安全實驗的作用與意義。尤其是，所發(fā)表的研究數據有助推動全球的實驗動物的"3R"倡議，即對減少動物實驗（reduce）、改善動物實驗條件質量（refine）、替代動物實驗（replace）有顯著貢獻。”

“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).

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羅氏454完成食蟹猴基因組測序并研發(fā)其新的表達譜芯片