Quantifying functional constraints in the mammalian genome

The two principal aims of the research were:
1. To quantify and compare selective constraints in conserved noncoding elements in mammals.
2. To estimate the distribution of effects of new mutations in coding and noncoding sequences in wild mice.
The main results and achievements of the project were:
1. We developed a new method to infer the distribution of effects of new mutations and the fraction of adaptive substitutions based on within-species nucleotide polymorphism data and between-species divergence data, and applied this to data sets of coding and noncoding DNA in humans, Drosophila and wild mice.
2. We have set up a web server that runs software we have written to allow evolutionary biologists to analyse nucleotide polymorphism and divergence data in order to make inferences on the nature of selection operating in the genome.
3. We showed that in wild mice, about 50% of amino acid substitutions have been driven to fixation between species by positive selection.
4. We showed that ultra-conserved noncoding elements and their flanking regions are subject to substantially higher selective constraints in murid rodents than hominids, presumably due to differences in effective population size.
5. We have shown that most mutation occurring in noncoding DNA flanking protein-coding genes are either weakly deleterious or selectively neutral, and that only a small proportion of differences between species in these regions have been fixed by positive natural selection.
6. We have collected a data set of polymorphisms in conserved noncoding elements in wild mice The low level of polymorphisms and the distribution of allele frequencies indicates that most new mutations are strongly deleterious.