Distinguishing protein-coding and noncoding genes in the human genome Export

by: Michele Clamp, Ben Fry, Mike Kamal, Xiaohui Xie, James Cuff, Michael F. Lin, Manolis Kellis, Kerstin Lindblad-Toh, Eric S. Lander

Proceedings of the National Academy of Sciences In Proceedings of the National Academy of Sciences, Vol. 104, No. 49. (4 December 2007), pp. 19428-19433.

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algorithms amino-acid animals data-mining genetics genome hominidae homology humans mammals methods phylogenomics primates proteins rna sequence vertebrates

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Abstract

10.1073/pnas.0709013104 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 â24,500 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 ORFsâspecifically, 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 â20,500. 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.

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RIS record

TY - JOUR ID - citeulike:1989097 L3 - citeulike-article-id:1989097 N2 - 10.1073/pnas.0709013104 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 â24,500 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 ORFsâspecifically, 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 â20,500. 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. IS - 49 JF - Proceedings of the National Academy of Sciences EP - 19433 TI - Distinguishing protein-coding and noncoding genes in the human genome VL - 104 T2 - Proceedings of the National Academy of Sciences SP - 19428 KW - algorithms KW - amino-acid KW - animals KW - data-mining KW - genetics KW - genome KW - hominidae KW - homology KW - humans KW - mammals KW - methods KW - phylogenomics KW - primates KW - proteins KW - rna KW - sequence KW - vertebrates AU - Clamp, Michele AU - Fry, Ben AU - Kamal, Mike AU - Xie, Xiaohui AU - Cuff, James AU - Lin, Michael AU - Kellis, Manolis AU - Lindblad-Toh, Kerstin AU - Lander, Eric PY - 2007/12/04/ UR - http://dx.doi.org/10.1073/pnas.0709013104 ER -

Distinguishing protein-coding and noncoding genes in the human genome Export

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