Discovery of new mutations in meiotic crossover products

Description

Current theories of evolution assume that heritable mutations arise spontaneously across our genome. Yet, this view might not be fully accurate and mechanisms, such as meiotic recombination, might drive the local increase of mutations in regions with high recombination activity. Meiotic recombination is highly localized in small regions that are recurrently targeted for double strand breaks (DSB). If and how mutations are introduced during meiosis is not known, but the steps involved in the repair of DSB could be mutagenic. Intra- and interspecies sequence comparisons have observed an increased diversity at recombination hotspots; however, biased gene conversion could also explain this diversity instead of mutagenic recombination. We have developed a highly sensitive methodology to measure experimentally new mutations introduced at recombination hotspots in human sperm. The analysis of crossover products in one sperm donor showed a significant higher number of transitions compared to non-recombinants; but for two other donors no difference was observed. The mutations were equally distributed in both crossover products and were of the type G>A or C>T suggesting that these are likely deamination events with ~42% occurring at CpG sites. Additionally, we have identified a series of G>T and C>A transversions in genomic and plasmid DNA that are likely false mutations arising as artifacts from the oxidation of guanine (8-oxoguanine). We also observed a high transmission distortion at a SNP located 500bp from the hotspot centre with the C-allele being transmitted 5x more often than the T-allele. Moreover, rare crossover with conversion products were identified, with conversion tracks of less than 30bp biased (4x) towards the homologue not targeted for a double strand break. Our data show that changes in allele frequencies at hotspots are subjected to biased gene conversions, but might also be influenced by new mutations.

Period	19 Sept 2013
Event title	EMBO Meiosis
Event type	Conference
Location	GermanyShow on map