The ortholog conjecture is untestable by the current gene ontology but is supported by RNA sequencing data.
The ortholog conjecture is untestable by the current gene ontology but is supported by RNA sequencing data.
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DOI：
10.1371/journal.pcbi.1002784
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发表时间：
2012
影响因子：
4.3
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Chen X;Zhang J
直系同源猜想假设直系同源基因在功能上比旁系同源基因更相似。这一猜想是系统基因组学的基石，每天被计算和实验生物学家用于预测、解释和理解基因功能。然而，最近的一项研究基于实验得出的基因本体（GO）注释和人类和小鼠的微阵列基因表达数据，对直系同源猜想提出了挑战。相反，它提出同源基因的功能相似性主要由基因作用的细胞环境决定，这解释了为什么观察到（物种内）旁系同源物比（物种间）直系同源物具有更大的功能相似性。在这里，我们表明，相对于旁系同源物之间的功能相似性，人类和小鼠直系同源物之间基于 GO 的功能相似性在过去五年中一直在增加。此外，与旁系同源物相比，直向同源物不太可能被纳入同一研究中，从而导致低估了它们的功能相似性。对具有相同蛋白质序列的同源物的功能研究的仔细检查揭示了实验偏差、注释错误以及在 GO 中标记为实验的基于同源性的功能推论。这些问题以及基于 GO 的发现的临时性使得当前的 GO 不适合检验直系同源猜想。众所周知，RNA 测序 (RNA-Seq) 在比较不同基因或不同物种的表达方面优于微阵列。我们对来自八种哺乳动物和鸡的多个组织的大型 RNA-Seq 数据集的分析表明，直向同源物之间的表达相似性显着高于物种内旁系同源物之间的表达相似性，支持了直向同源物猜想并反驳了基因表达的细胞背景假设。我们的结论是，直系同源猜想在经过测试的范围内仍然基本上有效，但需要使用更多更好的功能数据进行进一步审查。与普遍缓慢的功能测定相比，当今基因组测序的速度非常快，这意味着从基因组序列中识别出的大多数基因的功能只能通过计算预测来注释。这一预测的主要信息来源是模型生物中直系同源基因的功能，因为人们普遍认为直系同源基因在功能上相似，特别是与旁系同源基因相比。这种被称为直向同源物猜想的信念最近在实验得出的基因本体（GO）注释和微阵列基因表达数据的基础上受到了挑战，因为这些数据揭示了旁系同源物比直向同源物具有更大的功能和表达相似性。在这里，我们表明，由于实验偏差、注释错误和基于同源性的功能推断（在 GO 中被错误地标记为实验性的），基于 GO 的功能相似性估计是临时且不可靠的。 RNA测序（RNA-Seq）在比较不同基因或不同物种的表达方面优于微阵列，我们对大型RNA-Seq数据集的分析为基因表达的直系同源猜想提供了强有力的支持。我们的结论是，直系同源猜想在经过测试的范围内仍然基本上有效，但需要使用更多更好的功能数据进行进一步审查。
The ortholog conjecture posits that orthologous genes are functionally more similar than paralogous genes. This conjecture is a cornerstone of phylogenomics and is used daily by both computational and experimental biologists in predicting, interpreting, and understanding gene functions. A recent study, however, challenged the ortholog conjecture on the basis of experimentally derived Gene Ontology (GO) annotations and microarray gene expression data in human and mouse. It instead proposed that the functional similarity of homologous genes is primarily determined by the cellular context in which the genes act, explaining why a greater functional similarity of (within-species) paralogs than (between-species) orthologs was observed. Here we show that GO-based functional similarity between human and mouse orthologs, relative to that between paralogs, has been increasing in the last five years. Further, compared with paralogs, orthologs are less likely to be included in the same study, causing an underestimation in their functional similarity. A close examination of functional studies of homologs with identical protein sequences reveals experimental biases, annotation errors, and homology-based functional inferences that are labeled in GO as experimental. These problems and the temporary nature of the GO-based finding make the current GO inappropriate for testing the ortholog conjecture. RNA sequencing (RNA-Seq) is known to be superior to microarray for comparing the expressions of different genes or in different species. Our analysis of a large RNA-Seq dataset of multiple tissues from eight mammals and the chicken shows that the expression similarity between orthologs is significantly higher than that between within-species paralogs, supporting the ortholog conjecture and refuting the cellular context hypothesis for gene expression. We conclude that the ortholog conjecture remains largely valid to the extent that it has been tested, but further scrutiny using more and better functional data is needed. Today's exceedingly high speed of genome sequencing, compared with the generally slow pace of functional assay, means that the functions of most genes identified from genome sequences will be annotated only through computational prediction. The primary source of information for this prediction is the functions of orthologous genes in model organisms, because orthologs are widely believed to be functionally similar, especially when compared with paralogs. This belief, known as the ortholog conjecture, was recently challenged on the basis of experimentally derived Gene Ontology (GO) annotations and microarray gene expression data, because these data revealed greater functional and expressional similarities of paralogs than orthologs. Here we show that GO-based estimates of functional similarities are temporary and unreliable, due to experimental biases, annotation errors, and homology-based functional inferences that are incorrectly labeled as experimental in GO. RNA sequencing (RNA-Seq) is superior to microarray for comparing the expressions of different genes or in different species, and our analysis of a large RNA-Seq dataset provides strong support to the ortholog conjecture for gene expression. We conclude that the ortholog conjecture remains largely valid to the extent that it has been tested, but further scrutiny using more and better functional data is needed.
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基因本体论：2011年的增强。
影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
影响因子：
4.3
作者：
Engelhardt BE;Jordan MI;Muratore KE;Brenner SE
通讯作者：
Brenner SE
影响因子：
4.3
作者：
Mika, Sven;Rost, Burkhard
通讯作者：
Rost, Burkhard
影响因子：
9.5
作者：
Gharib WH;Robinson-Rechavi M
通讯作者：
Robinson-Rechavi M
DOI：
10.2307/2412448
发表时间：
1970-01-01
期刊：
SYSTEMATIC ZOOLOGY
影响因子：
--
作者：
FITCH, WM
通讯作者：
FITCH, WM