Structural diversity and evolutionary constraints of oxidative phosphorylation

Area of Science:

• Biochemistry
• Genetics
• Evolutionary Biology

Background:

• The oxidative phosphorylation (OxPhos) system, essential for cellular energy production, comprises over 90 subunits encoded by nuclear and mitochondrial DNA.
• It is traditionally viewed as a highly conserved system, invariant across cells and individuals.

Purpose of the Study:

• To comprehensively analyze genetic variability within the OxPhos system across evolutionary and population levels.
• To develop a tool for predicting the impact of genetic variants on OxPhos proteins.

Main Methods:

• Analysis of the 1,000 Genomes Project data to assess genetic variation in OxPhos subunits.
• Development and validation of ConScore, a conservation-based predictor for variant impact in OxPhos proteins (ROC-AUC = 0.97, PR-AUC = 0.94).
• Characterization of structural constraints and variability at individual and population levels.

Main Results:

• Unexpected intra-individual genetic variability was identified, primarily from autosomal gene heterozygosity and mitochondrial DNA (mtDNA) diversity.
• Mechanisms such as allelic imbalance and homozygosity bias were found to limit variability in nuclear-encoded OxPhos subunits.
• ConScore effectively predicts the impact of variants within OxPhos proteins.

Conclusions:

• The OxPhos system exhibits significant genetic variability, challenging the notion of invariant structure.
• Understanding protein position significance is crucial for insights into speciation and disease.
• ConScore provides a valuable tool for studying OxPhos protein variation and its functional consequences.