At least 5% of the human genome predating the mammalian radiation is thought to have evolved under purifying selection, yet protein-coding and related untranslated exons occupy at most 2% of the genome. Thus, the majority of conserved, and by extension functional sequence in the human genome appears to be non-exonic. This non-exonic sequence is largely thought to control the expression of nearby genes during development. Recent work has highlighted a handful of cases where mobile element insertions have resulted in the introduction of novel conserved non-exonic elements. I detect over 280,000 conserved non-exonic elements (CNEs), totaling approximately 7Mb of sequence, that were co-opted from SINE, LINE, LTR and DNA transposon insertions. I demonstrate that at least 11%, and an estimated 20%, of gene regulatory sequence in the human genome was co-opted from mobile elements. The placement in the genome of CNEs co-opted from mobile elements closely resembles that of CNEs. The co-option events are most often located at the edges of gene deserts and show a strong preference for residing closest to genes involved in development and transcription regulation. In particular, CNEs with clear repetitive origins are located near genes involved in cell adhesion, including all characterized cellular members of the reelin-signaling pathway. I find that particular regions of certain mobile element insertions are more likely to be held under purifying selection. In particular, I show six examples where paralogous instances of a highly exapted mobile element region define a sequence motif that closely matches that of a known transcription factor binding site.
Along with using existing annotation for previously discovered mobile elements, I have discovered a novel family of mobile elements that was active on the human lineage. I report that 18 conserved, and by extension functional, elements in the human genome are the result of retroposon insertions that occurred after the speciation of birds and reptiles from the human lineage and have been evolving under purifying selection in mammals. The retroposon was quickly inactivated in the mammalian ancestor and all traces of it, besides this small group of insertions being held under purifying selection, have been lost after more than 100 million years of neutral decay. However, the tuatara has maintained a near-ancestral version of this retroposon in its extant genome, which allows me to connect the 18 human elements to the evolutionary events that created them. I propose that conservation efforts over the course of more than 100 years may not have only prevented the tuatara from going extinct, but could have preserved our ability to understand the evolutionary history of functional elements in the human genome that would otherwise have been lost with the tuatara's extinction. I argue that species with historically low population sizes are more likely to harbor ancient mobile elements for long periods of time and in near ancestral states, making these species indispensable in understanding the evolutionary origin of functional elements in the human genome.
Overall, I find that mobile elements may have played a larger role than previously recognized in shaping and specializing the landscape of gene regulation during human evolution.
|School:||University of California, Santa Cruz|
|School Location:||United States -- California|
|Source:||DAI-B 71/09, Dissertation Abstracts International|
|Keywords:||Conserved nonexonic elements, Gene regulatory networks, Mobile elements|
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