Divergent somatic mutation patterns among human cerebellar neuron types

Area of Science:

• Neuroscience
• Genetics
• Genomics

Background:

• Neurons accumulate somatic mutations throughout life.
• Understanding neuronal mutation variability is key to brain function, disease, and aging.

Purpose of the Study:

• To investigate how somatic mutation processes differ between human cerebellar Purkinje and granule neurons.
• To identify factors influencing mutation rates and patterns in aging neurons.

Main Methods:

• High-fidelity duplex DNA sequencing was used to profile somatic mutations.
• Analysis was performed on neurons across the lifespan and in cerebellar ataxias.

Main Results:

• Purkinje and granule neurons showed similar substitution rates, including for the SBS5 mutational signature.
• Substitution patterns and insertion/deletion profiles differed, associated with transcription.
• Cerebellar ataxias had a minimal impact on neuronal mutation profiles.

Conclusions:

• Neuronal types exhibit distinct aging-related mutagenesis.
• Neuron-specific features are unlikely major drivers of SBS5 activity.
• Transcription influences mutation patterns in aging neurons.