TY  - JOUR
A1  - Friedman, Robin C
A1  - Farh, Kyle Kai-How
A1  - Burge, Christopher B
A1  - Bartel, David
T1  - Most mammalian mRNAs are conserved targets of microRNAs
Y1  - 2008/01/01 
JF  - Genome Research 
JO  - Genome Research 
DO  - 10.1101/gr.082701.108 
SP  - gr.082701.108 
UR  - http://genome.cshlp.org/content/early/2008/01/01/gr.082701.108.abstract 
N2  - MicroRNAs (miRNAs) are small endogenous RNAs that bind to short, seed-matched sites in the 3'UTRs of mRNAs to direct the posttranscriptional repression of these messages.  Comparative sequence analyses have shown that, on the whole, a sizable number of these sites are preferentially conserved, but previous analyses were not suitable for measuring the probability of individual sites being selectively maintained and may have substantially underestimated the true scope of conserved targeting.  We have overhauled our comparative genomics tool for finding and analyzing the conservation of 3' UTR motifs and applied it to the analysis of human miRNA sites.  The new tool more completely controls for background conservation by accounting for mutational biases, dinucleotide conservation rates, and the conservation rates of individual UTRs.  These improvements allow statistically powerful analysis of the conservation of individual miRNA target sites - an important criterion for assessing which of the many sites are most promising for experimental follow-up.  Moreover, substantial increases in sensitivity were achieved by more efficiently incorporating new genomes and different seed-match types.  When considering sites matching the 87 mammalian miRNA families conserved to chicken or beyond, over 45,000 sites within human 3'UTRs are conserved above background levels. This number represents a ~3-fold increase over the most sensitive lower-bound reported previously and indicates that more than 60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs.  Mammalian-specific miRNAs have far fewer conserved targets than do the more broadly conserved ones, even when considering only more recently emerged targets.  Several seed-match types contribute similar numbers of targets, indicating that purifying selection acts on weaker but more common target sites roughly as often as on stronger but rarer sites.  Although pairing to the 3' end of miRNAs can compensate for seed mismatches, this class of sites appears to constitute less than 2% of all conserved sites.  We generate scores for the probability of any seed match being selectively maintained due to miRNA targeting, called PCT, which correlate with experimental data on site efficacy.  Our greatly expanded set of target predictions, which now include conserved 3'-compensatory sites, are available at the TargetScan web site, which displays the PCT score for each site and each predicted target. 
ER  -