Mutations in selfish genes expanding sub-clonally in the male germline also have elevated de novo mutation rates
Sprache des Vortragstitels:
Englisch
Original Kurzfassung:
Some de novo mutations (DNMs) have been observed to expand in the male germline and thus become more frequent with age. These DNMs often occur in genes that modify the protein signaling and confer a selective advantage to the mutant cell. Of particular interest are mutations in genes of the receptor tyrosine kinase (RTK) pathway observed to expand sub-clonally in the aging testis. To further explore this type of mutagenesis, we adapted duplex sequencing, an ultra-deep and highly accurate sequencing method to screen driver mutations in selected genes in sperm DNA. We identified novel mutations that are found at increased frequencies in some sperm donors. Some of these mutations also occur in a larger number of different donors suggesting that these variants not only expand sub-clonally in the germline, but also originated independently quite often. This frequent origin translates into a very high mutation rate that might be explained by a mutation hotspot model. Alternatively, the origin of these germline DNMs might also be the result of mutations with a selective advantage arising during development (post-zygotic mutations) that are then enriched in the mature germline. Our deep-sequencing approach examining mutation rates at single-mutation resolution might provide some insights into the molecular mechanism behind this particular mutagenic mechanism.
Sprache der Kurzfassung:
Englisch
Englische Kurzfassung:
Some de novo mutations (DNMs) have been observed to expand in the male germline and thus become more frequent with age. These DNMs often occur in genes that modify the protein signaling and confer a selective advantage to the mutant cell. Of particular interest are mutations in genes of the receptor tyrosine kinase (RTK) pathway observed to expand sub-clonally in the aging testis. To further explore this type of mutagenesis, we adapted duplex sequencing, an ultra-deep and highly accurate sequencing method to screen driver mutations in selected genes in sperm DNA. We identified novel mutations that are found at increased frequencies in some sperm donors. Some of these mutations also occur in a larger number of different donors suggesting that these variants not only expand sub-clonally in the germline, but also originated independently quite often. This frequent origin translates into a very high mutation rate that might be explained by a mutation hotspot model. Alternatively, the origin of these germline DNMs might also be the result of mutations with a selective advantage arising during development (post-zygotic mutations) that are then enriched in the mature germline. Our deep-sequencing approach examining mutation rates at single-mutation resolution might provide some insights into the molecular mechanism behind this particular mutagenic mechanism.