cis-regulatory evolution

ChIP-Seq identification of weakly conserved hear enhancers (Blow et. al 2010)

1. ChIP-seq on P300 (a transcriptional coactivator)
2. Identified over 3000 genomic regions enriched for P300 binding in heart tissue (E11.5)
   
3. 84% of the peaks do not overlap p300 peaks found in any of the other tissues tested
   
4. 130 of the putative heart enhancers tested in vivo, 97 (75%) functioned as tissue-specific enhancers
   
5. “Notably, we found no significant difference in the frequency of positive heart enhancers among the highly conserved sequences (19/31, or 61%) compared with the sequences that overlapped no conservation (16/30, or 53%; P > 0.1 according to Fisher’s exact test). These results suggest that p300 is an accurate predictor of enhancer activity independent of sequence conservation, and they confirm the in vivo activity of weakly and apparently non-constrained heart enhancers”
6. “Notably, the enhancers identified in these studies exhibited highly restricted expression patterns, with 51/81 (63%) of enhancers driving reproducible reporter gene expression exclusively in the developing heart”
7. Overall, only 6% of candidate heart enhancer overlapped genome regions that were under extremely high constraint

This paper highlights that sequence conservation alone cannot be used as a sole indicator of functionality. Conservation-based methods severely underestimate the number of cis-regulatory elements. Furthermore, from an evolutionary standpoint, lineage specific enhancers (particularly those undergoing positive selection) are where the adaptive action may be taking place!

Another interesting point is the concept of tissue-specific patterns of evolution. This is a concept that has been knocking around for quite some time and is now gaining traction through experimental evidence (Wang 2007, Blekhman 2008).