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Institut für Biophysik
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Discovery of New mutations using ultra-sensitive sequencing

Linz Institute of Technology (LIT) - Seed research grant


Project start: 2017

New mutations in the germline are directly transmitted to our children and have therefore profound consequences in future generations. In males, the frequency of new mutations in the germline increases with age, thus the delayed parenthood in our society with an older conception age of the father could be an important health risk for our children. In the past, my research showed that special types of mutations causing skeletal dysplasias (also known as “selfish” or “driver” mutations) cause the expansion of mutant spermatogonial stem cells leading to clusters of mutant cells that grow with age, explaining the higher incidence of affected children with paternal age. In parallel to this research, I have developed ultrasensitive technologies to measure rare mutations. One method, called bead-emulsion amplification (BEA), counts rare known mutations at a very high sensitivity by amplifying millions of single DNA molecules in an emulsion on microscopic beads.

In my next research direction, I want to develop an ultra-sensitive sequencing (USS) protocol based on next-generation sequencing to complement the existing BEA technology for analyzing rare mutations. The two methods would provide a very powerful combination to assess the mutation expansion patterns in the male germline: first, unknown driver mutations can be discovered with USS; then, the expansion patterns of these candidate driver mutations can be analyzed in detail with BEA, which allows a high sample throughput that is prohibitive for USS. Proof of principle of a working USS assay would allow aiming for research proposals that address high impact research questions pertaining how new mutations expand in the aging male germline and if these mutations are a health risk for our children. Specifically, the aims of this proposal are:

  1. establish an ultrasensitive sequencing technology based on next generation sequencing with a detection limit of less than one mutation in 105-106 of wild type DNA molecules;
  2. develop a pipeline for the sequence analysis and characterization of mutations,
  3. sequence a well-characterized driver gene to determine the robustness of the technology.