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Institut für Biophysik
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Major Scientific Break-Throughs

  • Mutagenesis in driver genes: We showed with several different molecular assays that the germline of older males is a repository of mutations linked to congenital disorders (Tiemann-Boege et al. PNAS 2002; Wyrobyk et al PNAS 2006; Qin et al. PloS Biol 2007; Shinde et al. Hum Mol Genet 2013). Our work on the paternal age effect was the first to accurately quantify new mutations in human sperm DNA (Tiemann-Boege et al. PNAS 2002). Currently, we are screening the frequency of de novo mutations in sperm of old and young donors with error corrected sequencing in selected driver genes, and have discovered unreported substitutions expanding in the male germline (Salazar et al, 2022). We also observe a high number of de novo events explained by a selective advantage of the driver mutation prior the maturation of the male germline (Moura et al, submitted).
     

  • Sequence-Function characterization of membrane proteins: We have discovered a series of mutations in different receptor tyrosine kinases (RTK). These are of particular importance since they correlate with tumorigenesis, mosaic disease, and congenital disorders. We have focused on FGFR3 and ERBB2 and discovered with deep-sequencing evidence for positive selection in mutations accumulating in the male germline (Salazar et al., 2022). We have characterized the clonal expansion of these mutants in sperm and dissected testis (Moura et al submitted) and are characterizing the function and activation of these receptors with biophysical methods (Hartl et al 2023 JMC). 
     

  • Sequence evolution and recombination hotspots: We demonstrated by pooled-sperm typing that recombination in humans is concentrated in narrow regions, known as hotspots (Tiemann-Boege et al PloS Genetics 2006). As a principal investigator, my group showed in an unconventional work that a high number of de novo mutations accumulate in crossovers, which are counteracted by GC biased gene conversion, explaining the rapid evolution of hotspots (Arbeithuber et al. PNAS 2015). My group also discovered that heterologies in microsatellites affect their transmission and evolution at recombination hotspots, in a process that leads to a genome-wide enrichment of short poly-As in hotspots (Heissl et al. LSA 2019).
     

  • Protein binding: My group has also developed important assays to characterize with diverse biophysical methods the binding of PRDM9. With these assays (e.g. SPR and FCS), my group showed that PRDM9 interacts with the DNA for many hours (Striedner et al. Chromosome Res 2017) and that the PRDM9 Zn finger domain binds to only one DNA target within a trimer (Schwarz et al. LSA. 2019).
     
  • Development of technologies to count rare events: We have developed several single molecule-based approaches to measure mutations at very low levels (Tiemann-Boege et al. PNAS 2002; Boulanger et al. PloS One 2012), such as the digital emulsion PCR technology (Tiemann-Boege et al Anal Chem 2009). My team has explored potential technical caveats and considerable improvements of ultra-sensitive mutation detection methods (Arbeithuber et al. DNA Res 2016), and developed several error-corrected sequencing strategies to detect rare mutations (Salazar et al., 2022), including the bioinformatics tools (Povysil et al NARGB 2021).

 

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Johannes Kepler Universität Linz

Altenberger Straße 69

4040 Linz, Österreich

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