Widespread Ultraconservation Divergence in Primates

Ovcharenko, Ivan

doi:10.1093/molbev/msn116

Cited by 19 publications

(20 citation statements)

References 37 publications

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“…Although further study is required to explain the immutability of UCEs after lineage divergence and sequence fixation across a long evolutionary history, we cannot rule out this possibility. It also should be noted that the absence of UCRs in species from the same lineage does not necessarily mean that those UCRs disappeared in those species but rather that they may exist as derivative sequences by mutation [2,15,28,29]. …”

Section: Resultsmentioning

confidence: 99%

“…Large numbers of DNA elements (≥200 bp) exhibiting 100% similarity have been found to be conserved across several mammalian species [1,2]. Shorter ultraconserved elements (UCEs) longer than 50 bp and 100 bp have also been identified in several insect species and plants, respectively [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…UCEs are often located near genes implicated in transcription and developmental processes, splicing, and ion flow control across membranes [1,2,5-7]. In vivo analysis of the embryos of transgenic mice uncovered the transcriptional enhancer activities of UCEs targeting developmental genes and transcription factors (TFs) [8,9].…”

Section: Introductionmentioning

confidence: 99%

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The evolution of ultraconserved elements with different phylogenetic origins

2012

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BackgroundUltraconserved elements of DNA have been identified in vertebrate and invertebrate genomes. These elements have been found to have diverse functions, including enhancer activities in developmental processes. The evolutionary origins and functional roles of these elements in cellular systems, however, have not yet been determined.ResultsHere, we identified a wide range of ultraconserved elements common to distant species, from primitive aquatic organisms to terrestrial species with complicated body systems, including some novel elements conserved in fruit fly and human. In addition to a well-known association with developmental genes, these DNA elements have a strong association with genes implicated in essential cell functions, such as epigenetic regulation, apoptosis, detoxification, innate immunity, and sensory reception. Interestingly, we observed that ultraconserved elements clustered by sequence similarity. Furthermore, species composition and flanking genes of clusters showed lineage-specific patterns. Ultraconserved elements are highly enriched with binding sites to developmental transcription factors regardless of how they cluster.ConclusionWe identified large numbers of ultraconserved elements across distant species. Specific classes of these conserved elements seem to have been generated before the divergence of taxa and fixed during the process of evolution. Our findings indicate that these ultraconserved elements are not the exclusive property of higher modern eukaryotes, but rather transmitted from their metazoan ancestors.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The evolution of ultraconserved elements with different phylogenetic origins

2012

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“…First, we found that similarly to the GC content and divergence, the SNP density in HCTs is roughly constant throughout the HCT, but is strikingly different from the flanking sequences. For example, the overall SNP density in HCTs for E2F1 (0.2 SNPs/kb) is comparable to the SNP density in ultraconserved regions in the human genome (Ovcharenko 2008). This value is fivefold lower than that observed in flanking sequences (Fig.…”

Section: Tfbss In Conserved Hcts Evolve Under Purifying Selectionmentioning

confidence: 94%

Homotypic clusters of transcription factor binding sites are a key component of human promoters and enhancers

Gotea¹,

Visel²,

Westlund³

et al. 2010

Genome Res.

212

206

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Clustering of multiple transcription factor binding sites (TFBSs) for the same transcription factor (TF) is a common feature of cis-regulatory modules in invertebrate animals, but the occurrence of such homotypic clusters of TFBSs (HCTs) in the human genome has remained largely unknown. To explore whether HCTs are also common in human and other vertebrates, we used known binding motifs for vertebrate TFs and a hidden Markov model–based approach to detect HCTs in the human, mouse, chicken, and fugu genomes, and examined their association with cis-regulatory modules. We found that evolutionarily conserved HCTs occupy nearly 2% of the human genome, with experimental evidence for individual TFs supporting their binding to predicted HCTs. More than half of the promoters of human genes contain HCTs, with a distribution around the transcription start site in agreement with the experimental data from the ENCODE project. In addition, almost half of the 487 experimentally validated developmental enhancers contain them as well—a number more than 25-fold larger than expected by chance. We also found evidence of negative selection acting on TFBSs within HCTs, as the conservation of TFBSs is stronger than the conservation of sequences separating them. The important role of HCTs as components of developmental enhancers is additionally supported by a strong correlation between HCTs and the binding of the enhancer-associated coactivator protein Ep300 (also known as p300). Experimental validation of HCT-containing elements in both zebrafish and mouse suggest that HCTs could be used to predict both the presence of enhancers and their tissue specificity, and are thus a feature that can be effectively used in deciphering the gene regulatory code. In conclusion, our results indicate that HCTs are a pervasive feature of human cis-regulatory modules and suggest that they play an important role in gene regulation in the human and other vertebrate genomes.

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“…This rapid burst of base pair substitutions in HAR1 was interpreted as evidence that HAR1 acquired an important new function in humans and in particular may have altered human brain by influencing the activity of a whole network of genes (Pollard et al 2006a). On the other hand, many highly conserved noncoding sequences have been found (Dermitzakis et al 2002;Bejerano et al 2004Bejerano et al , 2006Ovcharenko 2008;Stephen et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Intragene Higher Order Repeats in Neuroblastoma BreakPoint Family Genes Distinguish Humans from Chimpanzees

Paar

Glunčić

Rosandić

et al. 2011

Molecular Biology and Evolution

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Much attention has been devoted to identifying genomic patterns underlying the evolution of the human brain and its emergent advanced cognitive capabilities, which lie at the heart of differences distinguishing humans from chimpanzees, our closest living relatives. Here, we identify two particular intragene repeat structures of noncoding human DNA, spanning as much as a hundred kilobases, that are present in human genome but are absent from the chimpanzee genome and other nonhuman primates. Using our novel computational method Global Repeat Map, we examine tandem repeat structure in human and chimpanzee chromosome 1. In human chromosome 1, we find three higher order repeats (HORs), two of them novel, not reported previously, whereas in chimpanzee chromosome 1, we find only one HOR, a 2mer alphoid HOR instead of human alphoid 11mer HOR. In human chromosome 1, we identify an HOR based on 39-bp primary repeat unit, with secondary, tertiary, and quartic repeat units, fully embedded in human hornerin gene, related to regenerating and psoriatric skin. Such an HOR is not found in chimpanzee chromosome 1. We find a remarkable human 3mer HOR organization based on the ~1.6-kb primary repeat unit, fully embedded within the neuroblastoma breakpoint family genes, which is related to the function of the human brain. Such HORs are not present in chimpanzees. In general, we find that human-chimpanzee differences are much larger for tandem repeats, in particularly for HORs, than for gene sequences. This may be of great significance in light of recent studies that are beginning to reveal the large-scale regulatory architecture of the human genome, in particular the role of noncoding sequences. We hypothesize about the possible importance of human accelerated HOR patterns as components in the gene expression multilayered regulatory network.

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Widespread Ultraconservation Divergence in Primates

Cited by 19 publications

References 37 publications

The evolution of ultraconserved elements with different phylogenetic origins

The evolution of ultraconserved elements with different phylogenetic origins

Homotypic clusters of transcription factor binding sites are a key component of human promoters and enhancers

Intragene Higher Order Repeats in Neuroblastoma BreakPoint Family Genes Distinguish Humans from Chimpanzees

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