Loss-of-function tolerance of enhancers in the human genome

English version

Autoři: Duo Xu ^aff001; Omer Gokcumen ^aff005; Ekta Khurana ^aff001
Působiště autorů: Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, United States of America ^aff001; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, United States of America ^aff002; Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, United States of America ^aff003; Meyer Cancer Center, Weill Cornell Medicine, New York, New York, United States of America ^aff004; Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, New York, United States of America ^aff005
Vyšlo v časopise: Loss-of-function tolerance of enhancers in the human genome. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008663
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008663

Souhrn

Previous studies have surveyed the potential impact of loss-of-function (LoF) variants and identified LoF-tolerant protein-coding genes. However, the tolerance of human genomes to losing enhancers has not yet been evaluated. Here we present the catalog of LoF-tolerant enhancers using structural variants from whole-genome sequences. Using a conservative approach, we estimate that individual human genomes possess at least 28 LoF-tolerant enhancers on average. We assessed the properties of LoF-tolerant enhancers in a unified regulatory network constructed by integrating tissue-specific enhancers and gene-gene interactions. We find that LoF-tolerant enhancers tend to be more tissue-specific and regulate fewer and more dispensable genes relative to other enhancers. They are enriched in immune-related cells while enhancers with low LoF-tolerance are enriched in kidney and brain/neuronal stem cells. We developed a supervised learning approach to predict the LoF-tolerance of all enhancers, which achieved an area under the receiver operating characteristics curve (AUROC) of 98%. We predict 3,519 more enhancers would be likely tolerant to LoF and 129 enhancers that would have low LoF-tolerance. Our predictions are supported by a known set of disease enhancers and novel deletions from PacBio sequencing. The LoF-tolerance scores provided here will serve as an important reference for disease studies.

Klíčová slova:

Centrality – Gene expression – Gene regulation – Gene regulatory networks – Genetic networks – Human genomics – Network analysis – Protein-protein interactions

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