Functional Determinants and Evolutionary Consequences of Pleiotropy in Complex and Mendelian Traits

Area of Science:

• Genetics and Genomics
• Evolutionary Biology
• Systems Biology

Background:

• Pleiotropy, where one gene influences multiple phenotypes, is a fundamental aspect of genotype-to-phenotype networks.
• Understanding pleiotropy's prevalence, mechanisms, and consequences is crucial for deciphering complex biological systems.

Purpose of the Study:

• To investigate cross-species and cross-trait similarities and differences in gene pleiotropy patterns.
• To identify common features and evolutionary pressures associated with highly pleiotropic genes.

Main Methods:

• Utilized genotype-to-phenotype association data from Human Phenotype Ontology and Mouse Genome Database.
• Analyzed genome-wide association data from UK Biobank and FinnGen cohorts for Mendelian and complex traits.
• Compared pleiotropy patterns across species and trait types, examining gene features and selection pressures.

Main Results:

• Gene pleiotropy effects correlate well between species but show weaker correlation across different trait types within a species.
• Highly pleiotropic genes share features like broad tissue expression, involvement in numerous biological processes, and extensive protein interactions.
• Highly pleiotropic genes are under stronger negative selection and show enrichment of recent positive selection signals.

Conclusions:

• A common mechanism underlies pleiotropic effects across different trait domains.
• High pleiotropy plays a significant role in adaptation, despite imposing constraints on genetic variation.