Loss-of-function tolerance of enhancers in the human genome.
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 vari...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-04-01
|
| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1008663 |
| _version_ | 1829502313679552512 |
|---|---|
| author | Duo Xu Omer Gokcumen Ekta Khurana |
| author_facet | Duo Xu Omer Gokcumen Ekta Khurana |
| author_sort | Duo Xu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T09:35:59Z |
| format | Article |
| id | doaj.art-9baa6c64ecb8406294a7719256cf3fcc |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-16T09:35:59Z |
| publishDate | 2020-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-9baa6c64ecb8406294a7719256cf3fcc2022-12-21T22:36:25ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042020-04-01164e100866310.1371/journal.pgen.1008663Loss-of-function tolerance of enhancers in the human genome.Duo XuOmer GokcumenEkta KhuranaPrevious 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.https://doi.org/10.1371/journal.pgen.1008663 |
| spellingShingle | Duo Xu Omer Gokcumen Ekta Khurana Loss-of-function tolerance of enhancers in the human genome. PLoS Genetics |
| title | Loss-of-function tolerance of enhancers in the human genome. |
| title_full | Loss-of-function tolerance of enhancers in the human genome. |
| title_fullStr | Loss-of-function tolerance of enhancers in the human genome. |
| title_full_unstemmed | Loss-of-function tolerance of enhancers in the human genome. |
| title_short | Loss-of-function tolerance of enhancers in the human genome. |
| title_sort | loss of function tolerance of enhancers in the human genome |
| url | https://doi.org/10.1371/journal.pgen.1008663 |
| work_keys_str_mv | AT duoxu lossoffunctiontoleranceofenhancersinthehumangenome AT omergokcumen lossoffunctiontoleranceofenhancersinthehumangenome AT ektakhurana lossoffunctiontoleranceofenhancersinthehumangenome |