Evidence of positive selection in ERBB2 detected by errorcorrected sequencing in the male germline

Description

Mutations in the male germline are a driving force behind rare genetic diseases. The epidermal growth factor family of receptor tyrosine kinases (ERBB2) is an important oncogene with a crucial role in cell proliferation and survival and high expression levels in the mature male germline. Given the replicative nature of spermatogenesis, de novo mutations (DNMs) in this gene could increase in frequency in the aging testis posing important consequences for the transmission and recurrence of associated disorders. Here we examined the accumulation of DNMs in sperm DNA of different aged donors using duplex sequencing. We implemented different fragmentation strategies and DNA treatments prior to library preparation, as well as bioinformatic tools to reduce the number of artefacts. This resulted in a very powerful data set comprising 458 mutations with a strong signature of positive selection for exonic mutations in ERBB2 measured by a dN/dS ratio larger than the neutral expectation. Mutations were mainly missense substitutions enriched in the tyrosine kinase domain. Our functional assessment of selected mutation with biophysical approaches verified that the DNM also resulted in a functional change with an increased signaling activity of the ERBB2 pathway. Our method can be easily applied to other genes and provides important information about the opportunities and limitations of error-corrected sequencing.

Period	10 Sept 2023
Event title	Environmental Mutagenesis & Genomics Society 54th Annual Meeting
Event type	Conference
Location	United StatesShow on map