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Abstract BackgroundMouse is probably the most important model organism to study mammal biology and human diseases. A better understanding of the mouse genome will help understand the human genome, biology and diseases. However, despite the recent progress, the characterization of the regulatory sequences in the mouse genome is still far from complete, limiting its use to understand the regulatory sequences in the human genome. ResultsHere, by integrating binding peaks in ~ 9,000 transcription factor (TF) ChIP-seq datasets that cover 79.9% of the mouse mappable genome using an efficient pipeline, we were able to partition these binding peak-covered genome regions into acis-regulatory module (CRM) candidate (CRMC) set and a non-CRMC set. The CRMCs contain 912,197 putative CRMs and 38,554,729 TF binding sites (TFBSs) islands, covering 55.5% and 24.4% of the mappable genome, respectively. The CRMCs tend to be under strong evolutionary constraints, indicating that they are likelycis-regulatory; while the non-CRMCs are largely selectively neutral, indicating that they are unlikelycis-regulatory. Based on evolutionary profiles of the genome positions, we further estimated that 63.8% and 27.4% of the mouse genome might code for CRMs and TFBSs, respectively. ConclusionsValidation using experimental data suggests that at least most of the CRMCs are authentic. Thus, this unprecedentedly comprehensive map of CRMs and TFBSs can be a good resource to guide experimental studies of regulatory genomes in mice and humans.
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Prevalent use and evolution of exonic regulatory sequences in the human genome
Abstract It has long been known that exons can serve ascis‐regulatory sequences, such as enhancers. However, the prevalence of such dual‐use of exons and how they evolve remain elusive. Based on our recently predicted, highly accurate large sets ofcis‐regulatory module candidates (CRMCs) and non‐CRMCs in the human genome, we find that exonic transcription factor binding sites (TFBSs) occupy at least a third of the total exon lengths, and 96.7% of genes have exonic TFBSs. Both A/T and C/G in exonic TFBSs are more likely under evolutionary constraints than those in non‐CRMC exons. Exonic TFBSs in codons tend to encode loops rather than more critical helices and strands in protein structures, while exonic TFBSs in untranslated regions (UTRs) tend to avoid positions where known UTR‐related functions are located. Moreover, active exonic TFBSs tend to be in close physical proximity to distal promoters whose genes have elevated transcription levels. These results suggest that exonic TFBSs might be more prevalent than originally thought and likely in dual‐use. We proposed a parsimonious model that well explains the observed evolutionary behaviors of exonic TFBS as well as how a stretch of codons evolve into a TFBS. Key pointsThere are more exonic regulatory sequences in the human genome than originally thought.Exonic transcription factor binding sites are more likely under negative selection or positive selection than counterpart nonregulatory sequences.Exonic transcription factor binding sites tend to be located in genome sequences that encode less critical loops in protein structures, or in less critical parts in 5′ and 3′ untranslated regions.
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- Award ID(s):
- 2051491
- PAR ID:
- 10406874
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Natural Sciences
- Volume:
- 3
- Issue:
- 2
- ISSN:
- 2698-6248
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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