Abstract
Comparisons between diverse vertebrate genomes have uncovered thousands of highly conserved non-coding sequences, an increasing number of which have been shown to function as enhancers during early development. Despite their extreme conservation over 500 million years from humans to cartilaginous fish, these elements appear to be largely absent in invertebrates, and, to date, there has been little understanding of their mode of action or the evolutionary processes that have modelled them. We have now exploited emerging genomic sequence data for the sea lamprey, Petromyzon marinus, to explore the depth of conservation of this type of element in the earliest diverging extant vertebrate lineage, the jawless fish (agnathans). We searched for conserved non-coding elements (CNEs) at 13 human gene loci and identified lamprey elements associated with all but two of these gene regions. Although markedly shorter and less well conserved than within jawed vertebrates, identified lamprey CNEs are able to drive specific patterns of expression in zebrafish embryos, which are almost identical to those driven by the equivalent human elements. These CNEs are therefore a unique and defining characteristic of all vertebrates. Furthermore, alignment of lamprey and other vertebrate CNEs should permit the identification of persistent sequence signatures that are responsible for common patterns of expression and contribute to the elucidation of the regulatory language in CNEs. Identifying the core regulatory code for development, common to all vertebrates, provides a foundation upon which regulatory networks can be constructed and might also illuminate how large conserved regulatory sequence blocks evolve and become fixed in genomic DNA.
Highlights
Comparisons between diverse vertebrate genomes have uncovered thousands of very highly conserved sequences that show little or no evidence of coding for proteins [1,2,3]
We searched the lamprey whole genome shotgun sequence with a dataset of 1205 coding elements (CNEs) from 13 gene loci that are distributed across 27Mb of the human genome. These regions include 108 duplicated CNEs, the most ancient CNEs for which we have a date of origin [18] and 46 ultraconserved elements (UCEs), sequences that retain 100% identity over at least 200bp between mouse, rat and human genomes [29]. 73 lamprey CNEs were identified (Table S2), including hits to 38 dCNEs and 14 UCEs, with matches to gnathostome CNEs in all but two of the gene regions (Table 1), implying a widespread distribution of CNEs across developmental regulators in lamprey
The ancestry of vertebrate CNEs is clearly identifiable through their abundance in sharks [3], whereas the identification of duplicated CNEs suggests that some elements were present even earlier [18]
Summary
Comparisons between diverse vertebrate genomes have uncovered thousands of very highly conserved sequences that show little or no evidence of coding for proteins [1,2,3]. Many of these sequences are found in the proximity of genes that co-ordinate early development, and an increasing number have been shown to function as enhancers in both zebrafish [2] and mouse embryos [4,5]. The repertoire of CNEs in the genome of the elephant shark (Callorhinchus milii) generally encompasses those conserved between mammals and teleost fish [3] indicating that these sequences evolved and became fixed very early in the vertebrate lineage. Analyses suggest that urochordates are evolving very rapidly [6,8,9] which may have resulted in loss of CNE-like sequences in this lineage
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