Population variation for genome interpretation

General Background
The widespread application of genome-wide next generation sequencing (NGS) methodologies, and especially exome sequencing has rapidly lead to the identification of many new Mendelian disease genes. Interpretation of the more than 20,000 coding variants identified in a single individual remains a daunting challenge, and more difficult the interpretation of non-coding variation will be. Based on my preliminary work I hypothesize that variant interpretation can be greatly improved by studying patterns of neutral genomic variation in the extant human population.

My main objective is to establish the methodology for the interpretation of genomic variation based on human population variation. My second objective is the application of this novel methodology. I will use intellectual disability (ID) as a model disease since it is a relatively common disease associated with reduced fecundity such that selective constraint of variation is important. I will apply my methodology in three distinct ways:
  • The identification of new ID genes.
  • Improving interpretation of variants in known ID disease genes for routine diagnostics.
  • The identification of non-coding elements involved in ID.

Project description
By careful analysis of large collections of published and private variant datasets I will establish detailed maps of population-wide genetic variation and use machine learning approaches to classify variants based on the amount, type and distribution of neutral variants in the same gene. I will expand this approach to the entire genome for the interpretation of non-coding variation. The advantages of this novel approach are A) It exploits the enormous amount of human genome data that is now being generated, allowing for a much more fine-grained and sophisticated map of variation than one based on evolution alone. B) Since, this approach is not dependent on genetic information from other species, it allows the identification of genes and functional elements that are specifically important in humans.

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