Somatic mutation and selection at population scale

Area of Science:

• Genomics
• Molecular Biology
• Cancer Research

Background:

• Aging tissues accumulate microscopic clones with somatic driver mutations, potentially initiating cancer or contributing to aging.
• Detecting mutations in small clones is challenging, limiting our understanding of this phenomenon.
• Somatic mutations play a role in aging and disease, but their precise mechanisms and selection pressures are not fully understood.

Purpose of the Study:

• To introduce an advanced version of nanorate sequencing (NanoSeq) for sensitive detection of somatic mutations in small clones.
• To profile large numbers of clones in polyclonal samples with single-molecule sensitivity.
• To accurately determine mutation rates, signatures, and driver frequencies across various tissues.

Main Methods:

• Utilized a novel duplex sequencing method (NanoSeq) with an ultra-low error rate (<5 errors/billion base pairs).
• Applied targeted NanoSeq to 1,042 oral epithelium and 371 blood samples from a twin cohort.
• Employed multivariate regression models to study the impact of exposures and risk factors on somatic mutation acquisition and selection.

Main Results:

• Revealed a rich selection landscape in oral epithelium, with 46 genes under positive selection and over 62,000 driver mutations identified.
• Observed evidence of negative selection in essential genes, indicating constraints on mutation accumulation.
• Generated high-resolution maps of selection across coding and non-coding sites, akin to in vivo saturation mutagenesis.
• Demonstrated how factors like age, tobacco, and alcohol influence somatic mutation patterns.

Conclusions:

• Accurate single-molecule sequencing with NanoSeq is a powerful tool for studying early carcinogenesis and cancer prevention.
• This technology enables detailed investigation into the role of somatic mutations in aging and disease.
• The findings provide insights into mutational epidemiology and the selection pressures acting on somatic mutations in vivo.