| 1. |
- Clamp, Michele, et al.
(författare)
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Distinguishing protein-coding and noncoding genes in the human genome
- 2007
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:49, s. 19428-19433
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Tidskriftsartikel (refereegranskat)abstract
- 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 ≈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 ≈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.
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| 2. |
- Mikkelsen, Tarjei S, et al.
(författare)
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Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7141, s. 167-177
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Tidskriftsartikel (refereegranskat)abstract
- We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation.
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| 3. |
- Xie, Xiaohui, et al.
(författare)
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Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites
- 2007
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:17, s. 7145-7150
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Tidskriftsartikel (refereegranskat)abstract
- Conserved noncoding elements (CNEs) constitute the majority of sequences under purifying selection in the human genome, yet their function remains largely unknown. Experimental evidence suggests that many of these elements play regulatory roles, but little is known about regulatory motifs contained within them. Here we describe a systematic approach to discover and characterize regulatory motifs within mammalian CNEs by searching for long motifs (12-22 nt) with significant enrichment in CNEs and studying their biochemical and genomic properties. Our analysis identifies 233 long motifs (LMs), matching a total of approximately 60,000 conserved instances across the human genome. These motifs include 16 previously known regulatory elements, such as the histone 3'-UTR motif and the neuron-restrictive silencer element, as well as striking examples of novel functional elements. The most highly enriched motif (LM1) corresponds to the X-box motif known from yeast and nematode. We show that it is bound by the RFX1 protein and identify thousands of conserved motif instances, suggesting a broad role for the RFX family in gene regulation. A second group of motifs (LM2*) does not match any previously known motif. We demonstrate by biochemical and computational methods that it defines a binding site for the CTCF protein, which is involved in insulator function to limit the spread of gene activation. We identify nearly 15,000 conserved sites that likely serve as insulators, and we show that nearby genes separated by predicted CTCF sites show markedly reduced correlation in gene expression. These sites may thus partition the human genome into domains of expression.
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