Trends in Genetics
Volume 19, Issue 2, February 2003, Pages 68-72
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Genome Analysis
Origin of a substantial fraction of human regulatory sequences from transposable elements

https://doi.org/10.1016/S0168-9525(02)00006-9Get rights and content

Abstract

Transposable elements (TEs) are abundant in mammalian genomes and have potentially contributed to their hosts’ evolution by providing novel regulatory or coding sequences. We surveyed different classes of regulatory region in the human genome to assess systematically the potential contribution of TEs to gene regulation. Almost 25% of the analyzed promoter regions contain TE-derived sequences, including many experimentally characterized cis-regulatory elements. Scaffold/matrix attachment regions (S/MARs) and locus control regions (LCRs) that are involved in the simultaneous regulation of multiple genes also contain numerous TE-derived sequences. Thus, TEs have probably contributed substantially to the evolution of both gene-specific and global patterns of human gene regulation.

Section snippets

5′ promoter regions

Promoters can be defined as the sequence regions that are located directly 5′ of transcription initiation sites and that regulate their 3′ adjacent genes. The Human Promoter Database (HPD; http://zlab.bu.edu/~mfrith/HPD.html) is a repository of >2000 such human promoter sequences, each of ∼500 bp, that were identified by their location 5′ of experimentally characterized transcription initiation sites [11]. We analyzed these promoters to assess the extent to which they are derived from TEs. Of

cis-regulatory elements

To demonstrate unequivocally an effect of TEs on the regulation of host genes, it is necessary to show that experimentally characterized cis-regulatory elements that bind nuclear transcription factors have been derived from TE sequences. We searched systematically for such cases using the Transcription Factor Database (TRANSFAC; http://transfac.gbf.de/TRANSFAC/) [12]. A total of 846 experimentally characterized human cis-regulatory sites from 288 genes, along with their coordinates in GenBank

Untranslated regions of mRNA

Both 5′ and 3′ untranslated regions (UTRs) of mRNA sequences often encode important cis-elements that function to regulate either transcription or translation. Human mRNA sequences taken from the Mammalian Gene Collection (http://mgc.nci.nih.gov/) [16], a database of experimentally characterized full-length mRNA sequences, were surveyed for the presence of TE-derived sequences. mRNA sequences were partitioned into 5′UTRs, protein-coding sequences (CDSs) and 3′UTRs for comparison. Not

Scaffold/matrix attachment regions (S/MARs)

Another mode of transcription regulation in eukaryotes involves the formation of distinct chromatin loops mediated by attachment of specific DNA regions to the nuclear scaffold or matrix [17]. The S/MAR transaction database (S/MARt DB, http://transfac.gbf.de/SMARtDB/) includes a collection of experimentally characterized S/MAR sequences compiled from original publications [18]. We surveyed these sequences for the presence of TEs, and found they are enriched in TE-derived sequences (Table 1).

Conclusion

In addition to their well-documented parasitic properties, TE insertions could result in evolutionary changes that are beneficial to the host, particularly by the donation of regulatory sequences. Here, we demonstrate the potential of TEs to affect substantially the regulation of thousands of human genes by donating cis-regulatory sites. In addition to these gene-specific regulatory effects, TEs appear to affect regulation of the human genome in a more global manner by creating S/MARs that form

Acknowledgements

Galina V. Glazko was supported by research grants from NIH (GM-20293) and NASA (NCC2-1057) awarded to Masatoshi Nei. We thank Nathan J. Bowen and Wolfgang J. Miller for discussions on the relationship between TEs and S/MARs.

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