Distinguishing protein-coding and noncoding genes in the human genome
Distinguishing protein-coding and noncoding genes in the human genome
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DOI：
10.1073/pnas.0709013104
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发表时间：
2007-12-04
影响因子：
11.1
通讯作者：
Lander, Eric S.
中科院分区：
文献类型：
--
作者：
Clamp, Michele;Fry, Ben;Lander, Eric S.
虽然人类基因组计划在4年前就完成了，但人类蛋白质编码基因的目录仍然是一个有争议的问题。目前的目录总共列出了大约24，500个推定的蛋白质编码基因。人们普遍怀疑这些条目中的很大一部分是随机存在于RNA转录本中的功能上无意义的ORF，因为它们没有显示出与小鼠或狗进化保守的证据。然而，目前还没有科学的理由来排除ORF，仅仅因为它们没有表现出进化保守性：另一种假设是，这些ORF中的大多数实际上是有效的人类基因，反映了灵长类谱系中的基因创新或其他谱系中的基因丢失。在这里，我们拒绝这个假设，通过仔细分析非保守的ORF，特别是，他们在其他灵长类动物的属性。我们发现，这些ORF的绝大多数是随机发生的。作为一个副产品，这项分析产生了对当前人类目录的重大修订，将蛋白质编码基因的数量削减到大约20，500个。具体来说，它表明，只有在有明确证据表明编码蛋白质的情况下，才应该将非保守的ORF添加到人类基因目录中。它还提供了一个原则性的方法来评估未来提出的人类基因目录。最后，研究结果表明，哺乳动物蛋白质编码基因的真正创新相对较少。
Although the Human Genome Project was completed 4 years ago, the catalog of human protein-coding genes remains a matter of controversy. Current catalogs list a total of approximate to 24,500 putative protein-coding genes. It is broadly suspected that a large fraction of these entries are functionally meaningless ORFs present by chance in RNA transcripts, because they show no evidence of evolutionary conservation with mouse or dog. However, there is currently no scientific justification for excluding ORFs simply because they fail to show evolutionary conservation: the alternative hypothesis is that most of these ORFs are actually valid human genes that reflect gene innovation in the primate lineage or gene loss in the other lineages. Here, we reject this hypothesis by carefully analyzing the nonconserved ORFs-specifically, their properties in other primates. We show that the vast majority of these ORFs are random occurrences. The analysis yields, as a by-product, a major revision of the current human catalogs, cutting the number of protein-coding genes to approximate to 20,500. Specifically, it suggests that nonconserved ORFs should be added to the human gene catalog only if there is clear evidence of an encoded protein. It also provides a principled methodology for evaluating future proposed additions to the human gene catalog. Finally, the results indicate that there has been relatively little true innovation in mammalian protein-coding genes.