The study by Friedman et al. (2008) investigates the conservation of microRNA (miRNA) target sites in mammalian mRNAs. The authors developed an improved method to quantitatively evaluate site conservation, which was applied to analyze human 3'UTRs. This new method incorporates new genomes and better controls for background conservation by accounting for mutational biases, dinucleotide conservation rates, and individual UTR conservation rates. The improved model enabled the detection of a new site type, the "offset 6mer," and increased the number of preferentially conserved miRNA target sites by nearly threefold. Over 45,000 miRNA target sites within human 3'UTRs are conserved above background levels, and more than 60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. Mammalian-specific miRNAs have fewer conserved targets compared to more broadly conserved miRNAs, even when considering recently emerged targets. The study also found that pairing to the 3' end of miRNAs can compensate for seed mismatches, but this class of sites constitutes less than 2% of all preferentially conserved sites. The improved method enables statistically powerful analysis of individual miRNA target sites, with the probability of preferentially conserved targeting (PCT) correlating with experimental measurements of repression. The expanded set of target predictions, including conserved 3'-compensatory sites, is available at the TargetScan website.The study by Friedman et al. (2008) investigates the conservation of microRNA (miRNA) target sites in mammalian mRNAs. The authors developed an improved method to quantitatively evaluate site conservation, which was applied to analyze human 3'UTRs. This new method incorporates new genomes and better controls for background conservation by accounting for mutational biases, dinucleotide conservation rates, and individual UTR conservation rates. The improved model enabled the detection of a new site type, the "offset 6mer," and increased the number of preferentially conserved miRNA target sites by nearly threefold. Over 45,000 miRNA target sites within human 3'UTRs are conserved above background levels, and more than 60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. Mammalian-specific miRNAs have fewer conserved targets compared to more broadly conserved miRNAs, even when considering recently emerged targets. The study also found that pairing to the 3' end of miRNAs can compensate for seed mismatches, but this class of sites constitutes less than 2% of all preferentially conserved sites. The improved method enables statistically powerful analysis of individual miRNA target sites, with the probability of preferentially conserved targeting (PCT) correlating with experimental measurements of repression. The expanded set of target predictions, including conserved 3'-compensatory sites, is available at the TargetScan website.