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融合基因表達(dá)差異的生物代謝變化預(yù)測

Prediction of altered metabolism for expression differencesin fusion genes

作者: 胡聰聰  鄭浩然  馬浩 
單位:中國科學(xué)技術(shù)大學(xué)計算機科學(xué)與技術(shù)學(xué)院(合肥230027)
關(guān)鍵詞: 基于約束;代謝網(wǎng)絡(luò);差異基因表達(dá);多細(xì)胞生物;兩點狀態(tài);代謝流量 
分類號:R318
出版年·卷·期(頁碼):2017·36·2(128-133)
摘要:

目的 當(dāng)前存在許多基于約束的優(yōu)化建模方法利用全基因組的代謝網(wǎng)絡(luò)來預(yù)測生物代謝流量分布,而幾乎所有的這些建模方法都需要代謝物的攝取和分泌速率以及生物先驗知識的信息,比如假設(shè)生物量或者ATP產(chǎn)量最大。但是由于多細(xì)胞生物代謝物的攝取和分泌速率的測量很困難,并且多細(xì)胞高等生物的不同組織通常有不同的代謝目標(biāo),所以很難確定一個合理的代謝目標(biāo)來建模研究高等生物的代謝。本文利用基因表達(dá)的差異信息和代謝網(wǎng)絡(luò),能夠預(yù)測單細(xì)胞或多細(xì)胞生物代謝流量的變化,不需要生物的先驗知識和代謝物分泌或攝取速率的信息。方法 模型假設(shè)在兩點狀態(tài)下,如果編碼酶的基因表達(dá)量存在顯著變化,則酶催化的反應(yīng)的代謝流量也應(yīng)該存在顯著變化。利用微陣列基因組學(xué)數(shù)據(jù)和生物全基因組的代謝網(wǎng)絡(luò),通過使生物代謝流量的變化與基因表達(dá)的變化盡可能一致來建立優(yōu)化模型,預(yù)測生物顯著差異的代謝流量分布。結(jié)果 模型利用在有氧恒化器中以不同稀釋速率生長的大腸桿菌的基因表達(dá)數(shù)據(jù),預(yù)測的代謝流量與實驗中實際測量的代謝流量一致。結(jié)論 本文提出的基于約束的建模方法可以簡單準(zhǔn)確地定性預(yù)測低等生物的代謝流量變化,為研究高等生物的代謝變化提供了有效途徑。

Objective Currently,there are many methods for constraint-based optimization modelling using whole-genome metabolic networks to predict the metabolic flux distribution.Most of these methods require rates of metabolite uptake and secretion,as well as a priori knowledge of biological parameters,including biomass and the highest level of ATP production.However,measuring the rates of metabolite uptake and secretion in complex multicellular organisms is very challenging and is further complicated by different tissues having different metabolic goals.This presents a significant obstacle in modelling the metabolism of higher organisms.This study predicts the changes in metabolic flux in both unicellular and multicellular organisms using differences in gene expression and metabolic networks,a method which does not require a priori knowledge or information on the rate of metabolite uptake or secretion of organisms.Methods The present study hypothesized that in a two-state model,significant changes in the expression of an enzyme-encoding gene should result in a significant change in the metabolic rate of the enzyme-catalysed reaction.Microarray analysis of genomic data and whole-genome metabolic networks was used to construct an optimization model that could predict significant changes in the distribution of metabolic flux by maximizing the consistency between changes in metabolic flux and gene expression.Results The model predicted significant changes in metabolic flux,which were consistent with the experimental measurements of metabolic flux changes in aerobic chemostat cultures of Escherichia coli under different dilution rates.Conclusions The present study proposes a constraint-based modelling method that can accurately predict qualitative changes in flux for lower organisms and provides an effective way to investigate the altered metabolism of higher organisms.

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