Mutational constraint analysis workflow for overlapping short open reading frames and genomic neighbors

BMC Genomics, vol. 26, pp. 254

Abstract

Understanding the dark genome is a priority task following the complete sequencing of the human genome. Short open reading frames (sORFs) are a group of largely unexplored elements of the dark genome with the potential for being translated into microproteins. The definitive number of coding and regulatory sORFs is not known, however they could account for up to 1-2% of the human genome. This corresponds to an order of magnitude in the range of canonical coding genes. For a few sORFs a clinical relevance has already been demonstrated, but for the majority of potential sORFs the biological function remains unclear. A major limitation in predicting their disease relevance using large-scale genomic data is the fact that no population-level constraint metrics for genetic variants in sORFs are yet available. To overcome this, we used the recently released gnomAD 4.0 dataset and analyzed the constraint of a consensus set of sORFs and their genomic neighbors. We demonstrate that sORFs are mostly embedded into a moderately constrained genomic context, but within the gencode dataset we identified a subset of highly constrained sORFs comparable to highly constrained canonical genes.

Authors 6

1. Martin Danner Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany

   scieneers GmbH, Karlsruhe, Germany

   Institute for Human Genetics and Genomic Medicine Medical Faculty, RWTH Aachen University Hospital, Pauwelsstrasse 30, D-52074, Aachen, North-Rhine-Westphalia, Germany

   Scieneers GmbH, Kantstraße 1a, 76137, Karlsruhe, Baden-Wuerttemberg, Germany

2. Matthias Begemann Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany

   Institute for Human Genetics and Genomic Medicine Medical Faculty, RWTH Aachen University Hospital, Pauwelsstrasse 30, D-52074, Aachen, North-Rhine-Westphalia, Germany

3. Florian Kraft Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany

   Institute for Human Genetics and Genomic Medicine Medical Faculty, RWTH Aachen University Hospital, Pauwelsstrasse 30, D-52074, Aachen, North-Rhine-Westphalia, Germany

4. Miriam Elbracht Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany

   Institute for Human Genetics and Genomic Medicine Medical Faculty, RWTH Aachen University Hospital, Pauwelsstrasse 30, D-52074, Aachen, North-Rhine-Westphalia, Germany

5. Ingo Kurth Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany

   Institute for Human Genetics and Genomic Medicine Medical Faculty, RWTH Aachen University Hospital, Pauwelsstrasse 30, D-52074, Aachen, North-Rhine-Westphalia, Germany

6. Jeremias Krause corresponding Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany

   Institute for Human Genetics and Genomic Medicine Medical Faculty, RWTH Aachen University Hospital, Pauwelsstrasse 30, D-52074, Aachen, North-Rhine-Westphalia, Germany