Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Whiffin, Nicola ; Groop, Leif LU ; Haiman, C ; Melander, Olle LU
; Nilsson, Peter M
LU
and Ware, James S.
(2020)
In Nature Communications
11(1).
- Abstract
- Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely... (More)
- Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/c9d0f2fd-ff4b-4a8e-ba62-4207da9f7a6c
- author
- Whiffin, Nicola
; Groop, Leif
LU
; Haiman, C
; Melander, Olle
LU
; Nilsson, Peter M
LU
and Ware, James S.
- author collaboration
- organization
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 11
- issue
- 1
- article number
- 2523
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85085581111
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-019-10717-9
- language
- English
- LU publication?
- yes
- id
- c9d0f2fd-ff4b-4a8e-ba62-4207da9f7a6c
- date added to LUP
- 2022-03-29 11:39:06
- date last changed
- 2024-04-10 09:33:26
@article{c9d0f2fd-ff4b-4a8e-ba62-4207da9f7a6c,
abstract = {{Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes.}},
author = {{Whiffin, Nicola and Groop, Leif and Haiman, C and Melander, Olle and Nilsson, Peter M and Ware, James S.}},
issn = {{2041-1723}},
language = {{eng}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Nature Communications}},
title = {{Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals}},
url = {{http://dx.doi.org/10.1038/s41467-019-10717-9}},
doi = {{10.1038/s41467-019-10717-9}},
volume = {{11}},
year = {{2020}},
}