Large-scale appearance of ultraconserved elements in tetrapod genomes and slowdown of the molecular clock

Mammalian genomes contain millions of highly conserved noncoding sequences, many of which are regulatory. The most extreme examples are the 481 ultraconserved elements (UCEs) that are identical over at least 200 bp in human, mouse, and rat and show 96% identity with chicken, which diverged approximately 3 10 MYA. If the substitution rate in UCEs remained constant, these elements should also be present with a high level of identity in fish (similar to 450 Myr), but this is not the case, suggesting that many appeared in the amniotes or tetrapods or that the molecular clock has slowed down in these lineages. or both. Taking advantage of the availability of multiple genomes, we identified 13,736 UCEs in the human genome that are identical over at least 100 bp in at least 3 of 5 placental mammals, including 2,189 sequences over at least 200 bp, thereby greatly expanding, the repertoire of known UCEs, and investigated the evolution of these sequences in opossum, chicken, frog, and fish. We conclude that there was a massive genome-wide acquisition and expansion of UCEs during tetrapod and then amniote evolution, accompanied by a slowdown of the molecular clock, particularly in the amniotes, a process consistent with their functional exaptation in these lineages. The majority of tetrapod-specific UCEs are noncoding and associated with genes involved in regulation of transcription and development. In contrast, fish genomes contain relatively few UCEs, the majority of which are common to all bony vertebrates. These elements are different from other conserved noncoding elements and appear to be important regulatory innovations that became fixed following the emergence of vertebrates from the sea to the land.