Rate volatility and asymmetric segregation diversify mutation burden in cells with mutator alleles

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• Mutations in mismatch repair (MMR) or DNA polymerase exonuclease domains cause mutator phenotypes.
• These phenotypes are crucial for cancer evolution by increasing genetic heterogeneity.

Purpose of the Study:

• To investigate how combined MMR and DNA polymerase defects expand genetic heterogeneity.
• To analyze mutation patterns at single-cell resolution in Saccharomyces cerevisiae.

Main Methods:

• Utilized a single-cell resolution approach to track mutations across cell divisions.
• Analyzed replication errors and their segregation during cell division in yeast.

Main Results:

• Observed a broader-than-expected distribution of replication errors, indicating a volatile mutator phenotype.
• Found that mutation rates varied between cell divisions, with co-varying mismatches segregating to mother and daughter cells.
• Demonstrated that semiconservative replication and mitotic segregation further broaden mutation distribution.

Conclusions:

• Asymmetric segregation of mutations during cell division contributes to diverse mutation burdens in tumors.
• Combined defects in DNA repair pathways significantly increase genetic heterogeneity, impacting cancer evolution.