Discovery of new mutations in meiotic crossover products
Sprache des Vortragstitels:
Englisch
Original Tagungtitel:
EMBO Meiosis
Sprache des Tagungstitel:
Englisch
Original Kurzfassung:
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.
Forschungs-