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. 2015 Feb 14;16(1):87.
doi: 10.1186/s12864-015-1245-6.

Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution

Affiliations

Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution

Olgert Denas et al. BMC Genomics. .

Abstract

Background: Because species-specific gene expression is driven by species-specific regulation, understanding the relationship between sequence and function of the regulatory regions in different species will help elucidate how differences among species arise. Despite active experimental and computational research, relationships among sequence, conservation, and function are still poorly understood.

Results: We compared transcription factor occupied segments (TFos) for 116 human and 35 mouse TFs in 546 human and 125 mouse cell types and tissues from the Human and the Mouse ENCODE projects. We based the map between human and mouse TFos on a one-to-one nucleotide cross-species mapper, bnMapper, that utilizes whole genome alignments (WGA). Our analysis shows that TFos are under evolutionary constraint, but a substantial portion (25.1% of mouse and 25.85% of human on average) of the TFos does not have a homologous sequence on the other species; this portion varies among cell types and TFs. Furthermore, 47.67% and 57.01% of the homologous TFos sequence shows binding activity on the other species for human and mouse respectively. However, 79.87% and 69.22% is repurposed such that it binds the same TF in different cells or different TFs in the same cells. Remarkably, within the set of repurposed TFos, the corresponding genome regions in the other species are preferred locations of novel TFos. These events suggest exaptation of some functional regulatory sequences into new function. Despite TFos repurposing, we did not find substantial changes in their predicted target genes, suggesting that CRMs buffer evolutionary events allowing little or no change in the TFos - target gene associations. Thus, the small portion of TFos with strictly conserved occupancy underestimates the degree of conservation of regulatory interactions.

Conclusion: We mapped regulatory sequences from an extensive number of TFs and cell types between human and mouse using WGA. A comparative analysis of this correspondence unveiled the extent of the shared regulatory sequence across TFs and cell types under study. Importantly, a large part of the shared regulatory sequence is repurposed on the other species. This sequence, fueled by turnover events, provides a strong case for exaptation in regulatory elements.

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Figures

Figure 1
Figure 1
We built a one to one map between the human and mouse genomes from their WGA. (A) The track diagram shows TFos (unfilled features on outer tracks) and how they map to the other species (middle track). The thick part of the middle track is the mappable DNA. The features on the middle track can be mapped on the other species and are: SeqCons if not overlapping features from the other species (respective color), or FuncCons or FunctActive otherwise (green). The Venn diagrams use the same color code to show the amount (rounded to the closest Mb) of mappable material from one species to the other for DNA sequence, TFos, and DHS. For example, human TFos cover 121 Mb of the human genome. When mapped to mouse, these TFos cover 83 Mb of the mouse genome and 12 Mb of the sequence covered also by mouse TFos. The diagram for DHS is labeled in a similar fashion. (B) The distribution of mappable TFos nucleotides across cell types. The box-plot for each cell type summarizes the distribution of values for the fraction of nucleotides covered by TFos that can be mapped on the other species.
Figure 2
Figure 2
Conservation and re-use of TFos. (A) The distribution of SeqCons, FunctActive, and FunctCons regulatory elements summarized for all human mouse analogous cell lines (Additional file 1: Table S2). In both cell lines, a small fraction of mappable regulatory elements is FunctCons (33% and 15% cell average for human and mouse respectively). A larger fraction (46% and 50% cell average for human and mouse respectively) is FunctActive (plots for each cell are in Additional file 1: Figures S15, S16). (B) Loss and gain of TF binding sites. We used TFos in our data to discover TF binding sites (TFBS) on both species. We mapped human (respectively mouse) TFBS to mouse (respectively human) and computed their distance to the closest mouse (respectively human) TFBS of the same TF on an analogous cell. Among these TFBS those with a positive distance but less than 150 bp contribute to the corresponding bar in the human (respectively mouse) subplot. In other words, each bar is the count of TFBS that were lost and gained within a 150 bp window of the original site. (C) Reuse of FunctActive TFos between different cells and factors. A point on the scatterplot indicates the number of TFos of the corresponding assay in the reference species that can be classified as FunctCons or FunctActive when considering a fixed size set of randomly chosen assays in the comparison species. We performed multiple computations for each chosen size of such sets. Lines indicate the accumulated number of FunctCons, FunctActive, and Seqcons TFos. In this figure, about 93% of the (Mel, Max) assay is covered by TFos from just 35% of the query assays (plots for other cells/TFs in Additional file 1: Figures S17, S18).
Figure 3
Figure 3
Conservation of presumptive gene targets for a repurposed TFos. We combined cross-species gene-gene and TFos-TFos associations and gene-TFos associations to determine whether the sets of target genes of FunctCons and FunctActive TFos differ significantly. Gene-gene association data are based on a set of orthologous genes between human and mouse produced by the mouse ENCODE consortium, gene-TFos data are based on synchronized DHS activity during gene transcription [35], and TFos-TFos associations are based on our cross-species map. In the figure, we show a human TFos of Mxi on K562 (empty oval) associated with PUSL1 and ACAP3. This TFos is FunctActive, since its analogous location (broken oval linked by the dashed line with spaces between ovals indicating insertions in mouse) in mouse is bound by other TFs on other cell types (not shown). However, its analogous site in mouse is linked to gene Acap3. Incidentally, ACAP3 and Acap3 are orthologous and in our gene-gene association set. The human TFos and its analogous site in mouse bind different TFs and are active in different cell types, but they share a target gene.

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