羅氏454完成食蟹猴基因組測(cè)序并研發(fā)其新的表達(dá)譜芯片

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羅氏454完成食蟹猴基因組測(cè)序并研發(fā)其表達(dá)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(gè)由來(lái)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(bào)道他們已經(jīng)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(gè)新的食蟹猴表達(dá)芯片設(shè)計(jì)，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(chǔ)醫(yī)學(xué)和應(yīng)用生物醫(yī)學(xué)研究中最重要和最廣泛使用的非人類靈長(zhǎng)類動(dòng)物模型之一。與其他物種相比，非人類靈長(zhǎng)類動(dòng)物與人類有更密切的進(jìn)化關(guān)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(píng)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(zhǎng)類動(dòng)物實(shí)驗(yàn)結(jié)果轉(zhuǎn)化到人類應(yīng)用的能力，羅氏分子毒理學(xué)全球負(fù)責(zé)人Ulrich Certa先生和他的團(tuán)隊(duì)使用羅氏454公司的基因組測(cè)序FLX系統(tǒng)以及其他二代測(cè)序技術(shù)，應(yīng)用shotgun法解碼一個(gè)來(lái)自毛里求斯的雌性食蟹猴基因組，測(cè)序深度達(dá)到6倍基因組。此外，他們發(fā)現(xiàn)了約200萬(wàn)潛在的單核苷酸多態(tài)性(SNP)，這將使得這個(gè)物種的高分辨率個(gè)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(jié)合序列比對(duì)和外顯子片段大小保守估計(jì)方法，對(duì)超過(guò)兩萬(wàn)個(gè)食蟹猴基因組轉(zhuǎn)錄子進(jìn)行了預(yù)測(cè)，并使用羅氏NimbleGen的12x135K芯片格式設(shè)計(jì)了一個(gè)食蟹猴特異性基因表達(dá)芯片，在不到兩個(gè)月的時(shí)間實(shí)現(xiàn)了經(jīng)濟(jì)且全面的食蟹猴轉(zhuǎn)錄組分析。這種同時(shí)可以測(cè)試12個(gè)樣本的芯片，每個(gè)樣本有13萬(wàn)5000個(gè)長(zhǎng)度為60個(gè)堿基的寡核苷酸探針，每個(gè)轉(zhuǎn)錄子通過(guò)6個(gè)探針進(jìn)行檢測(cè)。此外，芯片上還有剩余探針可以設(shè)計(jì)其他食蟹猴的基因組區(qū)域，或者其他客戶定制的內(nèi)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(duì)來(lái)自不同地區(qū)的36個(gè)食蟹猴肝臟樣本的表達(dá)譜進(jìn)行了比較分析，結(jié)果表明有超過(guò)700個(gè)表達(dá)高度可變，而大多數(shù)轉(zhuǎn)錄子在個(gè)體間的表達(dá)量相對(duì)穩(wěn)定。有趣的是，許多藥品安全及藥物作用的相關(guān)基因的表達(dá)水平在實(shí)驗(yàn)中顯示出存在相當(dāng)?shù)膫€(gè)體間以及種間差異。在個(gè)體之間的基因表達(dá)的差異對(duì)于分析藥物安全至關(guān)重要。全基因組基因表達(dá)分析亦可以提高藥物安全性研究的質(zhì)量，并發(fā)現(xiàn)新藥在相關(guān)的動(dòng)物模型中的代謝及作用機(jī)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(fù)責(zé)該項(xiàng)目的 Ulrich Certa先生說(shuō)：“NimbleGen的表達(dá)微陣列平臺(tái)的靈活性和準(zhǔn)確性，使我們能夠根據(jù)我們的基因組測(cè)序工作結(jié)果開發(fā)一種新基因芯片設(shè)計(jì)。食蟹猴的基因表達(dá)首次可以進(jìn)行高特異性的監(jiān)測(cè)，通過(guò)藥物引起的基因轉(zhuǎn)錄水平的改變來(lái)解答藥物作用機(jī)制或藥物安全的問(wèn)題。此外，我們計(jì)劃設(shè)計(jì)監(jiān)測(cè)拷貝數(shù)改變和SNP分析的NimbleGen芯片。這些方法相結(jié)合將有望提高非人類靈長(zhǎng)類動(dòng)物實(shí)驗(yàn)結(jié)果用于預(yù)測(cè)人類實(shí)驗(yàn)結(jié)果的可參考性。例如，在未來(lái)，在人類研究中同樣可能發(fā)現(xiàn)基因多態(tài)性引起的對(duì)同一藥物不同的代謝反應(yīng)。”

“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(fù)責(zé)人Thomas Singer說(shuō)：“利用食蟹基因組以及NimbleGen基因芯片的表達(dá)譜分析數(shù)據(jù)，我們?cè)鰪?qiáng)動(dòng)物模型用于人類藥物安全實(shí)驗(yàn)的作用與意義。尤其是，所發(fā)表的研究數(shù)據(jù)有助推動(dòng)全球的實(shí)驗(yàn)動(dòng)物的"3R"倡議，即對(duì)減少動(dòng)物實(shí)驗(yàn)（reduce）、改善動(dòng)物實(shí)驗(yàn)條件質(zhì)量（refine）、替代動(dòng)物實(shí)驗(yàn)（replace）有顯著貢獻(xiàn)�！�

“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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