The age-independent accumulation of selfish mutations in the male gonad measured with duplex sequencing
Sprache des Vortragstitels:
Englisch
Original Tagungtitel:
Probabilistic Modeling in Genomics 2024
Sprache des Tagungstitel:
Englisch
Original Kurzfassung:
Selfish or driver genes, typically associated with somatic tumors, also accumulate mutations in the aging male germline. While long-standing hypotheses suggested that driver mutations originate exclusively in the sexually mature male germline?explaining larger mutation pockets in aged testes and absence in young donors' gametes?our highly sensitive sequencing approach (duplex sequencing) detected a strong positive selection signature in both young and aged sperm donors. Further analysis of mutation distribution in dissected testes revealed no evidence of large expansion events, indicating relative stability in mutant sub-clones. Predominantly, mutations were missense substitutions enriched in the tyrosine kinase domain, likely carrying functional consequences as shown for a handful of mutations with biophysical methods. We propose that selfish mutations accumulate in the male germline in two ways: those increasing with age in testis and sperm, and those arising before sexual maturity, and likely remain constant in numbers with age?a novel finding in this type of mutagenesis.
Sprache der Kurzfassung:
Englisch
Englische Kurzfassung:
Selfish or driver genes, typically associated with somatic tumors, also accumulate mutations in the aging male germline. While long-standing hypotheses suggested that driver mutations originate exclusively in the sexually mature male germline?explaining larger mutation pockets in aged testes and absence in young donors' gametes?our highly sensitive sequencing approach (duplex sequencing) detected a strong positive selection signature in both young and aged sperm donors. Further analysis of mutation distribution in dissected testes revealed no evidence of large expansion events, indicating relative stability in mutant sub-clones. Predominantly, mutations were missense substitutions enriched in the tyrosine kinase domain, likely carrying functional consequences as shown for a handful of mutations with biophysical methods. We propose that selfish mutations accumulate in the male germline in two ways: those increasing with age in testis and sperm, and those arising before sexual maturity, and likely remain constant in numbers with age?a novel finding in this type of mutagenesis.
Forschungs-