The 200 Mammals Genome Project: Understanding Evolutionary Conservation at the Single Base Level

To determine the effect of genetic variation on the health of individuals and species, there is a pressing need to assess variants emerging from genomewide studies for their likely functional importance. Reliable methods exist for prioritizing coding variants, but these methods fail when coding regions are poorly annotated. Furthermore, the large majority of candidate variants reside in non-coding sequence, and it remains extremely difficult to accurately determine the significance or function of non-coding variation. Recently, it has been shown that mammalian conservation is the genome annotation that enriches most highly for functional variants. Previous work has used 29 mammalian genomes to detect statistically significant levels of sequence conservation at a 12 base pair resolution. By taking advantage of improvements in sequencing and assembly technology, we will achieve roughly single base pair resolution of constraint.

We have sequenced 145 new placental mammalian genomes, including two species from Rhinocerotidae, using the new, cost effective DISCOVAR de novo genome assembly method. We are combining those with 55 existing high quality mammalian genomes. We will then align all 200 genomes and create a single base pair resolution placental mammalian conservation track, as well as lineage specific tracks for smaller clades within the mammalian tree. These data sets will allow comparisons across lineages, analyses of the evolutionary history of different variants or binding motifs, and correlations between candidate functional variants and different constraint patterns and elements. Our analyses will throw new light onto mammalian evolution, and will greatly inform our understanding of how genomic variation impacts the health of populations.