Yury Barbitoff1*, Nadezhda Pavlova1, Polina Bogaichuk1 and Alexander Predeus1
1 Institute of Bioinformatics Research and Education, Belgrade, Serbia
barbitoff [at] bioinf.institute
Abstract
Reconstruction of the genotype-to-phenotype relationship network is one of the major goals of modern genomics. Development of ontologies for accurate and formal phenotype description enables a systematic comparison of these relationships between species. In this work, we employed data on genotype-to-phenotype associations from the Human Phenotype Ontology (HPO) and Mouse Genome Informatics (MGI), as well as genome-wide associations from the UK Biobank (UKB) cohort to investigate the similarities and dissimilarities in the architecture of genotype-to-phenotype associations in mice and humans.
Comparison of the sets of upper-level Mammalian Phenotype Ontology (MP) terms for 16,985 orthologous gene pairs showed that only 24.6% (4,184) of all gene pairs were annotated with phenotype terms in both species. Even more surprisingly, only a handful of 15 gene pairs were annotated with exactly identical terms in human and mouse. Of the remaining ones, as many as 385 genes were associated with non-overlapping sets of phenotypes in humans and mice, and as many as 3,784 genes had both concordant and discordant gene-trait associations.
Despite such large differences in genotype-to-phenotype relationships for individual genes, we found that the overall architecture of the genotype-to-phenotype network was similar for the two species. For instance, the pleiotropic effects of orthologous genes were well correlated (Spearman’s p = 0.28) when using upper-level phenotype term count as a measure of pleiotropy. In both species, higher degree of pleiotropy also correlated with various gene-level properties, such as greater evolutionary constraint of a gene and its broader expression across tissues. Similar trends were observed when using UKB genome-wide associations to estimate the degree of pleiotropy for human genes.
Taken together, our observations highlight important discrepancies between phenotype description in humans and mice. At the same time, our analysis suggests that the organization of genotype-to-phenotype networks is largely similar for highly related species.
Keywords: genotype-to-phenotype; complex traits; phenotype ontology; HPO; MPO
Acknowledgement: We thank JetBrains Ltd. for providing support and computational resources for the project.