close
Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Nov 11;368(1632):20130021.
doi: 10.1098/rstb.2013.0021. Print 2013 Dec 19.

The mystery of extreme non-coding conservation

Nathan Harmston  1 , Anja Baresic, Boris Lenhard
Affiliations
Review

The mystery of extreme non-coding conservation

Nathan Harmston et al. Philos Trans R Soc Lond B Biol Sci. .

Erratum in

Abstract

Regions of several dozen to several hundred base pairs of extreme conservation have been found in non-coding regions in all metazoan genomes. The distribution of these elements within and across genomes has suggested that many have roles as transcriptional regulatory elements in multi-cellular organization, differentiation and development. Currently, there is no known mechanism or function that would account for this level of conservation at the observed evolutionary distances. Previous studies have found that, while these regions are under strong purifying selection, and not mutational coldspots, deletion of entire regions in mice does not necessarily lead to identifiable changes in phenotype during development. These opposing findings lead to several questions regarding their functional importance and why they are under strong selection in the first place. In this perspective, we discuss the methods and techniques used in identifying and dissecting these regions, their observed patterns of conservation, and review the current hypotheses on their functional significance.

Keywords: cis-regulatory; conserved non-coding elements; evolution; genome evolution; vertebrate cis-regulation.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Multiple sequence alignments (Multiz alignment of 46 vertebrate genomes) of a set of sequences that are highly conserved over vertebrates. Dots represent bases that are identical to the human GRCh37/hg19 assembly and orange lines represent gaps. (a) Alignments for a CNE near the SOX2 locus, chr3: 180 462 261–180 462 515 and (b) a CNE located at chr3: 177 077 799–177 077 901, which is missing in dog and chicken.
Figure 2.
Figure 2.
Overview of the SOX2 locus, its associated gene desert and its local neighbourhood, specifically the 2.4 Mb region on human chr3 centred around the SOX2 gene. (a) Location of CNEs flanking human SOX2, present between human (Hg) and mouse (Mm) (90% identity over 50 base pairs—shown in dark green), human and chicken (Gg; 90% identity over 50 base pairs—shown in yellow) and human and tetraodon (Tn; 70% identity over 50 base pairs—shown in light green). (b) As the distance increases from SOX2, the density of HCNEs decreases dramatically.
Figure 3.
Figure 3.
Schema of our proposed model of CNE turnover. In the common ancestor of two lineages, cis-regulatory elements (shown in light blue) were recruited within the proximity of a gene which was required to be under a specific form of regulation. Over time, other elements were sequentially recruited in both lineages (shown in green and red) and the corresponding ancestral elements were lost. This process continued until all of the elements in the extant set of CNEs no longer contain any of the set of ancestral elements, and these elements are no longer recognizable between lineages. This results in CNEs changing in position and arrangement within the locus, as well as gaining lineage-specific elements.
See this image and copyright information in PMC

References

    1. Siepel A, et al. 2005. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034–1050 (doi:10.1101/gr.3715005) - DOI - PMC - PubMed
    1. Meader S, Ponting CP, Lunter G. 2010. Massive turnover of functional sequence in human and other mammalian genomes. Genome Res. 20, 1335–1343 (doi:10.1101/gr.108795.110) - DOI - PMC - PubMed
    1. Pennacchio LA, et al. 2006. In vivo enhancer analysis of human conserved non-coding sequences. Nature 444, 499–502 (doi:10.1038/nature05295) - DOI - PubMed
    1. Taher L, McGaughey DM, Maragh S, Aneas I, Bessling SL, Miller W, Nobrega MA, McCallion AS, Ovcharenko I. 2011. Genome-wide identification of conserved regulatory function in diverged sequences. Genome Res. 21, 1139–1149 (doi:10.1101/gr.119016.110) - DOI - PMC - PubMed
    1. Sandelin A, Bailey P, Bruce S, Engström PG, Klos JM, Wasserman WW, Ericson J, Lenhard B. 2004. Arrays of ultraconserved non-coding regions span the loci of key developmental genes in vertebrate genomes. BMC Genomics 5, 99 (doi:10.1186/1471-2164-5-99) - DOI - PMC - PubMed

Publication types

Substances

LinkOut - more resources