Genetic Database Maps Hidden Mutations That Could Solve Rare Disease Cases
Swedish researchers created the first large-scale map of transposable elements—DNA sequences that make up half the human genome—across 1,000 individuals, aiming to boost diagnosis rates for rare genetic diseases. The work could help clinical labs better identify disease-causing mutations, potentially improving outcomes for the 60% of rare disease patients who currently go undiagnosed despite genetic testing.
Originaltitel: Transposable element insertions in 1000 Swedish individuals
<p>The majority of rare diseases are genetic, and regardless of advanced high-throughput genomics-based investigations, 60% of patients remain undiagnosed. A major factor limiting our ability to identify disease-causing alterations is a poor understanding of the morbid and normal human genome. A major genomic contributor of which function and distribution remain largely unstudied are the transposable elements (TE), which constitute 50% of our genome. Here we aim to resolve this knowledge gap and increase the diagnostic yield of rare disease patients investigated with clinical genome sequencing. To this end we characterized TE insertions in 1000 Swedish individuals from the SweGen dataset and 2504 individuals from the 1000 Genomes Project (1KGP), creating seven population-specific TE insertion databases. Of note, 66% of TE insertions in SweGen were present at > 1% in the 1KGP databases, proving that most insertions are common across populations. Focusing on the rare TE insertions, we show that even though similar to 0.7% of those insertions affect protein coding genes, they rarely affect known disease casing genes (< 0.1%). Finally, we applied a TE insertion identification workflow on two clinical cases where disease causing TE insertions were suspected and could verify the presence of pathogenic TE insertions in both. Altogether we demonstrate the importance of TE insertion detection and highlight possible clinical implications in rare disease diagnostics.</p>