Genomic evidence for elevated mutation rates in highly expressed genes

Area of Science:

• Genetics
• Molecular Biology
• Genomics

Background:

• Reporter gene assays suggest transcription-associated mutagenesis (TAM) and transcription-coupled repair.
• The net genomic impact of transcription on mutation rates remains unclear.

Purpose of the Study:

• To determine the overall effect of gene transcription on mutation rates at a genomic scale.
• To investigate the relationship between gene expression levels and mutation rates in yeast and human germlines.

Main Methods:

• Comparative genomics of related yeast species.
• Mutation accumulation experiments in yeast.
• Analysis of human germline mutation rates and gene expression data.

Main Results:

• Gene expression levels positively correlate with point mutation rates in yeast.
• Transcription-induced mutagenesis occurs on both DNA strands, suggesting multiple TAM mechanisms.
• A significant positive correlation exists between human germline mutation rates and gene expression levels.

Conclusions:

• Transcription is an overall mutagenic process.
• Increased gene expression leads to a higher mutation rate.
• Transcription-associated mutagenesis is a significant factor in genomic mutation rates.