Mammalian evolution and human mutation burden in Rab GTPases.

Area of Science:

• Molecular Biology
• Evolutionary Biology
• Genetics

Background:

• Rab GTPases regulate membrane trafficking and are implicated in neurodegeneration and cancer.
• Previous studies focused on individual Rabs, leaving family-level evolutionary and mutation patterns underexplored.

Purpose of the Study:

• To investigate the evolutionary patterns of Rab GTPases across mammalian evolution.
• To integrate evolutionary findings with human disease-related mutations in Rabs.
• To evaluate variation tolerance in Rab protein domains at the population level.

Main Methods:

• Analyzed 54 Rab proteins across 62 placental mammals using branch-site models for sequence evolution.
• Combined evolutionary data with human Rab mutation data from UniProt.
• Defined domain-level metrics: constraint score, damage tolerance, and mutation burden.

Main Results:

• Rabs evolving across more mammalian species showed increased accumulation of damaging mutations in humans.
• The Switch I domain exhibited significant cross-species variation and accommodated disease-relevant mutations.
• Domain-level metrics revealed varying tolerance to variation across Rab proteins and domains.

Conclusions:

• Evolutionary divergence in Rabs correlates with human mutation burden, particularly in functionally critical domains like Switch I.
• The Switch I domain is a key region for understanding Rab function, evolution, and disease association.
• The integrated framework can be applied to other protein families involved in human diseases.