Understanding and modeling human traits and diseases: Insights from the comparative genomics resources of Zoonomia

Comparative genomics-based understanding and modeling of human traits and diseases

Understanding the genetic architecture of complex human traits and diseases is one of the major aims of biomedical research. Genetic research, such as genome-wide association studies (GWASs) of large-scale, well-phenotyped cohorts, has identified tens of thousands of genomic variants associated with human traits and diseases. The remaining challenge is how to translate the statistical association of genomic loci to biological mechanisms and clinical strategies. Knowledge of human and mammalian evolution should help in the interpretation, modeling, and targeting of disease-relevant variants. The hypothesis is simple: more conserved genome sequences are more likely to be of greater biological importance. Such sequence conservation across species is defined as evolutionary constraint.

Recently, a special issue of Science1 published a collection of studies from the Zoonomia Project (https://zoonomiaproject.org/), which focused on mammalian evolution. By comparing whole-genome sequences of the 240 placental mammals, researchers identified those genetic elements most constrained along the phylogenic tree or those most rapidly changed among certain evolutionary lineages, both of which are potential indicators of functional importance.1 These large-scale genomes from hundreds of species not only improve our understanding of evolutionary adaptation and innovation but also contribute to our understanding of human diseases and traits.