Paralog dependency indirectly affects the robustness of human cells

Area of Science:

• Genetics and Genomics
• Molecular Biology
• Systems Biology

Background:

• Paralogous genes provide protective redundancy, but some form functionally dependent protein complexes (heteromers).
• The functional dependency of heteromeric paralogs might reduce their protective capacity against deleterious mutations.

Purpose of the Study:

• To investigate the robustness of gene loss-of-function by examining the impact of paralog properties on deleteriousness.
• To determine if functionally dependent paralogs are less protective against gene inactivation.

Main Methods:

• Utilized CRISPR-Cas9 gene editing in over 450 human cell lines to create gene loss-of-function mutations.
• Analyzed the "robustness landscape" of gene inactivation, correlating deleteriousness with paralog characteristics.
• Investigated protein-protein interactions and gene dosage balance for heteromeric paralogs.

Main Results:

• Identified specific regions in the "robustness landscape" where gene inactivation is more deleterious, influenced by paralog properties.
• Heteromeric paralogs, characterized by high expression and numerous protein interactions, are more prone to these deleterious regions.
• Stricter gene dosage balance in heteromers and the strength of their physical interactions correlate with increased deleteriousness upon loss-of-function.

Conclusions:

• Functionally dependent paralogs, especially heteromers, exhibit reduced robustness to gene loss-of-function.
• Physical dependency and dosage sensitivity contribute to the higher deleteriousness observed in heteromeric paralogs.
• Understanding these dependencies is crucial for predicting the impact of genetic variations and designing gene therapies.