Clusters of nucleotide substitutions and insertion/deletion mutations are associated with repeat sequences

Area of Science:

• Genomics
• Molecular Biology
• Evolutionary Biology

Background:

• Comparative genomics reveals patterns of genome evolution, but causal mechanisms are often unclear.
• A common observation is the link between insertion/deletion mutations (indels) and elevated nucleotide substitution rates.

Purpose of the Study:

• To investigate the causal mechanisms underlying the association between indels and increased substitution rates.
• To determine if sequence context, rather than indels themselves, drives these mutation rate increases.

Main Methods:

• Analysis of population genomics data from Escherichia coli, Saccharomyces paradoxus, and Drosophila.
• Examination of the association between indels and repeat sequences.
• Analysis of mutational signatures and experimental validation of mutation rates.

Main Results:

• Approximately two-thirds of indels are closely linked to repeat sequences.
• Repeat sequence abundance predicts regions of high sequence diversity, independent of indels.
• The mutational signature near indels aligns with error-prone DNA polymerase activity.

Conclusions:

• Repeat sequences, not indels, are the primary drivers of increased mutation rates by promoting replication fork arrest.
• This mechanism leads to the recruitment of error-prone polymerases, influencing genome evolution.
• Sequence context plays a crucial role in modulating mutation rates and evolutionary trajectories.