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Comparative Study
. 2006 Jun;16(6):713-22.
doi: 10.1101/gr.5031006. Epub 2006 May 10.

Evolutionary turnover of mammalian transcription start sites

Martin C Frith  1 , Jasmina Ponjavic, David Fredman, Chikatoshi Kai, Jun Kawai, Piero Carninci, Yoshihide Hayashizaki, Albin Sandelin
Affiliations
Comparative Study

Evolutionary turnover of mammalian transcription start sites

Martin C Frith et al. Genome Res. 2006 Jun.

Erratum in

  • Genome Res. 2006 Jul;16(7):947. Hayshizaki, Yoshihide [corrected to Hayashizaki, Yoshihide]

Abstract

Alignments of homologous genomic sequences are widely used to identify functional genetic elements and study their evolution. Most studies tacitly equate homology of functional elements with sequence homology. This assumption is violated by the phenomenon of turnover, in which functionally equivalent elements reside at locations that are nonorthologous at the sequence level. Turnover has been demonstrated previously for transcription-factor-binding sites. Here, we show that transcription start sites of equivalent genes do not always reside at equivalent locations in the human and mouse genomes. We also identify two types of partial turnover, illustrating evolutionary pathways that could lead to complete turnover. These findings suggest that the signals encoding transcription start sites are highly flexible and evolvable, and have cautionary implications for the use of sequence-level conservation to detect gene regulatory elements.

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Figures

Figure 1.
Figure 1.
Histogram of distances between transcription start sites of homologous transcripts. The x-axis indicates the distance between the human TSS and the human position aligned to the mouse TSS.
Figure 2.
Figure 2.
Examples of TSS usage and TSS turnover in promoters of homologous genes. Each histogram subplot is divided into two parts, displaying on the y-axis the CAGE tag distribution of the transcription start sites (TSSs) in the mouse genome (upper part) and of the homologous TSSs in the human genome (lower part). The number of CAGE tags originating from each analyzed tissue is indicated by the color legend (separate for mouse and human). The x-axis displays positions in the alignment between mouse and human; the line between the mouse and human TSS regions represents either aligned nucleotides (thick line) or insertions/deletions (thin line) in the BLASTZ promoter alignment. The homologous mRNAs used for defining the TSS pair (see text) are shown as black arrows with corresponding GenBank accession numbers, where the arrow indicates transcript direction. Full-size images with alignments are available in Supplemental Figure S1. The histograms illustrate different cases of TSS turnover. (A) No turnover (PURA/Pura gene). In most cases, homologous promoter regions have nearly identical TSS usage in the mouse and human genomes. (B) Complete TSS turnover (BCAP29/Bcap29 gene). The TSSs are separated by >100 nt and have zero CAGE tags proximal to the aligned regions in the other species. (C) Shift in alternate TSS usage (HIRIP3/C86302 gene). Similar to case B, but the aligned regions have retained a limited level of transcription initiation activity. (D) TSS sliding (WDR39/Wdr39 gene). The homologous TSS regions overlap, but the flanking regions have no TSSs at the aligned position in the other species.
Figure 3.
Figure 3.
Changes in usage of alternative promoters between human and mouse. We analyzed 1263 pairs of human and mouse TSSs of homologous transcripts. The x-axis indicates the number of CAGE tags at the human TSS region divided by the number of CAGE tags at the human position aligned to the mouse TSS region. The y-axis indicates the number of CAGE tags at the mouse TSS region divided by the number of CAGE tags at the mouse position aligned to the human TSS region. (Black line) No change in usage; (dashed line) twofold change in usage; (dotted line) 10-fold change in usage.
Figure 4.
Figure 4.
Sequence conservation is significantly lower in TSS regions with high levels of turnover. The degree of conservation in the genomic regions surrounding TSS (±50 bp) with high levels of turnover was investigated by using mouse/human BLASTZ NET alignments. Boxplots representing the (A) number of identical aligned nucleotides, (B) number of aligned nonidentical bases, and (C) number of deletions in the human genome using the mouse sequence as reference are shown for TSS regions exhibiting turnover and TSS regions from the reference set. (D) Distribution of lengths of deletions in the alignments. P-values resulting from a Wilcoxon two-tailed rank test between the sample and reference vectors are shown for each case.
Figure 5.
Figure 5.
Schematic view of pairs of TSSs undergoing turnover. This generalized representation of the panels in Figure 2 provides a reference for method descriptions. Labels A–D correspond to the four different promoters in the two species. The vertical bars indicate supporting CAGE tags.
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References

    1. Antequera F., Bird A., Bird A. Number of CpG islands and genes in human and mouse. Proc. Natl. Acad. Sci. 1993;90:11995–11999. - PMC - PubMed
    1. Anusaksathien O., Laplace C., Li X., Ren Y., Peng L., Goldring S.R., Galson D.L., Laplace C., Li X., Ren Y., Peng L., Goldring S.R., Galson D.L., Li X., Ren Y., Peng L., Goldring S.R., Galson D.L., Ren Y., Peng L., Goldring S.R., Galson D.L., Peng L., Goldring S.R., Galson D.L., Goldring S.R., Galson D.L., Galson D.L. Tissue-specific and ubiquitous promoters direct the expression of alternatively spliced transcripts from the calcitonin receptor gene. J. Biol. Chem. 2001;276:22663–22674. - PubMed
    1. Atanasova E., Chiappa S., Wieben E., Brimijoin S., Chiappa S., Wieben E., Brimijoin S., Wieben E., Brimijoin S., Brimijoin S. Novel messenger RNA and alternative promoter for murine acetylcholinesterase. J. Biol. Chem. 1999;274:21078–21084. - PubMed
    1. Burke T.W., Kadonaga J.T., Kadonaga J.T. The downstream core promoter element, DPE, is conserved from Drosophila to humans and is recognized by TAFII60 of. Drosophila. Genes & Dev. 1997;11:3020–3031. - PMC - PubMed
    1. Bush E.C., Lahn B.T., Lahn B.T. Selective constraint on noncoding regions of hominid genomes. PLoS Comput. Biol. 2005;1:e73. - PMC - PubMed

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