"Analysis of non-coding regions [...] demonstrates that cis-acting regulatory elements with important functions are evolutionarily conserved. Even when such elements are of quite short length, they are distinguishable from the more rapidly evolving non-coding DNA that they are embeded in, provided the number of aligned homologous sequences represents enough evolutionary time for the accumulation of mutations at the less constrained (presumably selectively neutral) base positions. An evolutionary conserved element presents itself as a set of contiguous base positions that appear invariant among the aligned sequences." (Tagle et al. 1988).
By analogy with the DNase footprinting experiments, Tagle et al. proposed the term "phylogenetic footprinting" to describe the phylogenetic comparisons that reveal conserved cis-elements in the non-coding regions of homologous genes. For a good example of phylogenetic footprints, look at the beta-actin gene.
Homologous untranslated sequences were then aligned with CLUSTALW (Thompson et al. 1994). Multiple alignments were manually edited with the SeaView program (Galtier et al. 1996).
Studying HCRs distribution within genes showed that functional constraints are generally much stronger in 3'-non-coding regions than in promoters or introns. The 3'-HCRs are particularly A+T-rich and are always located in the transcribed untranslated regions of genes, which suggest that they are involved in post-transcriptional processes (mRNA export, localisation, translation, or degradation). Functional and structural analysis of HCRs is in under progress. The surprising result of this analysis is that there are very few conserved elements for which a function has been proposed. In most cases the function of conserved elements is absolutely not known.
Information on HCRs (sequences, alignments, annotations, bibliographic references) are compiled in a database (ACUTS: compilation of Ancient Conserved UnTranslated Sequences). Currently 176 out of 326 detected HCRs have been analysed and incorporated in the database.
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Duret L., Dorkeld, F., Gautier, C. (1993) Strong conservation of non-coding sequences during vertebrates evolution: potential involvement in post-transcriptional regulation of gene expression. Nucleic Acids Res., 21, 2315-2322. [ Abstract ]
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