Dataset Information

A genome-wide screen for noncoding elements important in primate evolution.

ABSTRACT:

Background

A major goal in the study of human evolution is to identify key genetic changes which occurred over the course of primate evolution. According to one school of thought, many such changes are likely to be found in noncoding sequence. An approach to identifying these involves comparing multiple genomes to identify conserved regions with an accelerated substitution rate in a particular lineage. Such acceleration could be the result of positive selection.

Results

Here we develop a likelihood ratio test method to identify such regions. We apply it not only to the human terminal lineage, as has been done in previous studies, but also to a number of other branches in the primate tree. We present the top scoring elements, and compare our results with previous studies. We also present resequencing data from one particular element accelerated on the human lineage. These data indicate that the element lies in a region of low polymorphism in humans, consistent with the possibility of a recent selective sweep. They also show that the AT to GC bias for polymorphism in this region differs dramatically from that for substitutions.

Conclusion

Our results suggest that screens of this type will be helpful in unraveling the complex set of changes which occurred during primate evolution.

SUBMITTER: Bush EC

PROVIDER: S-EPMC2242780 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Publications

A genome-wide screen for noncoding elements important in primate evolution.

Bush Eliot C EC Lahn Bruce T BT

BMC evolutionary biology 20080123

<h4>Background</h4>A major goal in the study of human evolution is to identify key genetic changes which occurred over the course of primate evolution. According to one school of thought, many such changes are likely to be found in noncoding sequence. An approach to identifying these involves comparing multiple genomes to identify conserved regions with an accelerated substitution rate in a particular lineage. Such acceleration could be the result of positive selection.<h4>Results</h4>Here we de ...[more]

PMID: 18215302

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Project description:Background & aimsLong noncoding RNAs (lncRNAs) are found to have profound impacts on diverse cellular processes. Although high-throughput sequencing studies have shown the differential lncRNA expression profiles between hepatocellular carcinoma (HCC) and nontumor livers, the functional impacts of lncRNAs on HCC development await further investigation. Herein, we sought to address the functional roles of lncRNAs in HCC pathogenesis by in vivo functional screening.MethodsWe performed genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/dead CRISPR-associated protein 9 (dCas9) lncRNA activation screening in HCC xenografts. We characterized the clinical relevance of positively selected lncRNAs using transcriptomic data sets. We used CRISPR-based gene activation and knockdown approaches to show the functional roles of positively selected lncRNAs including Cancer Susceptibility 11 (CASC11) in HCC. RNA sequencing and chromatin isolation by RNA purification sequencing were used to investigate the molecular mechanisms of CASC11 in HCC progression.ResultsThe in vivo functional screening identified 1603 positively selected lncRNAs, 538 of which were overexpressed in HCC patients. Systematic transcriptomic data analysis and clinical investigation showed that patients with high expression of these lncRNA candidates correlated with aggressive tumor behaviors. Overexpression of these lncRNAs aggravated HCC cell growth. Detailed characterization of a lncRNA candidate, CASC11, showed its pivotal role in cell proliferation and tumor growth. Mechanistically, chromatin isolation by RNA purification sequencing showed that CASC11 was bound to the CASC11/MYC proto-oncogene shared promoter region on chromosome 8q24. CASC11 modulated the transcriptional activity of MYC in a cis-regulatory manner, which affected the expression of MYC downstream target genes, consequently promoting G1/S progression.ConclusionsOur study showed the power of in vivo CRISPR screening, which comprehensively investigated the functionality of lncRNAs in HCC progression, providing a rationale for targeting these lncRNAs clinically.

Project description:BackgroundIdentification and mapping of repetitive elements is a key step for accurate gene prediction and overall structural annotation of genomes. During the assembly and annotation of three highly repetitive amoeba genomes, Entamoeba histolytica, Entamoeba dispar, and Entamoeba invadens, we performed comparative sequence analysis to identify and map all class I and class II transposable elements in their sequences.ResultsHere, we report the identification of two novel Entamoeba-specific repeats: ERE1 and ERE2; ERE1 is spread across the three genomes and associated with different repeats in a species-specific manner, while ERE2 is unique to E. histolytica. We also report the identification of two novel subfamilies of LINE and SINE retrotransposons in E. dispar and provide evidence for how the different LINE and SINE subfamilies evolved in these species. Additionally, we found a putative transposase-coding gene in E. histolytica and E. dispar related to the mariner transposon Hydargos from E. invadens. The distribution of transposable elements in these genomes is markedly skewed with a tendency of forming clusters. More than 70% of the three genomes have a repeat density below their corresponding average value indicating that transposable elements are not evenly distributed. We show that repeats and repeat-clusters are found at syntenic break points between E. histolytica and E. dispar and hence, could work as recombination hot spots promoting genome rearrangements.ConclusionThe mapping of all transposable elements found in these parasites shows that repeat coverage is up to three times higher than previously reported. LINE, ERE1 and mariner elements were present in the common ancestor to the three Entamoeba species while ERE2 was likely acquired by E. histolytica after its separation from E. dispar. We demonstrate that E. histolytica and E. dispar share their entire repertoire of LINE and SINE retrotransposons and that Eh_SINE3/Ed_SINE1 originated as a chimeric SINE from Eh/Ed_SINE2 and Eh_SINE1/Ed_SINE3. Our work shows that transposable elements are organized in clusters, frequently found at syntenic break points providing insights into their contribution to chromosome instability and therefore, to genomic variation and speciation in these parasites.

Dataset Information

A genome-wide screen for noncoding elements important in primate evolution.

Background

Results

Conclusion

Publications

A genome-wide screen for noncoding elements important in primate evolution.

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