5' splice site GC>GT and GT>GC variants differ markedly in terms of their functionality and pathogenicity.,Human Mutation

当前位置： X-MOL 学术 › Hum. Mutat. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

5' splice site GC>GT and GT>GC variants differ markedly in terms of their functionality and pathogenicity.
Human Mutation ( IF 3.3 ) Pub Date : 2020-05-05 , DOI: 10.1002/humu.24029
Jin-Huan Lin _{1,

2,

3} , Emmanuelle Masson _{1,

4} , Arnaud Boulling ₁ , Matthew Hayden ₅ , David N Cooper ₅ , Claude Férec _{1,

4} , Zhuan Liao _{2,

3} , Jian-Min Chen ₁

Affiliation

In the human genome, most 5′ splice sites (~99%) employ the canonical GT dinucleotide whereas a small minority (~1%) use the noncanonical GC dinucleotide. The functionality and pathogenicity of 5′ splice site GT>GC (+2T>C) variants have been extensively studied but we know very little about 5′ splice site GC>GT (+2C>T) variants. Herein, we have addressed this deficiency by performing a meta‐analysis of reported +2C>T “pathogenic” variants together with a functional analysis of engineered +2C>T substitutions using a cell culture‐based full‐length gene splicing assay. Our results establish proof of concept that +2C>T variants are qualitatively different from +2T>C variants in terms of their functionality and suggest that, in sharp contrast to +2T>C variants, most if not all +2C>T variants have no pathological relevance. Our findings have important implications for interpreting the clinical relevance of +2C>T variants and understanding the evolutionary switching between GT and GC 5′ splice sites in mammalian genomes.

中文翻译：

5' 剪接位点 GC>GT 和 GT>GC 变体在功能和致病性方面存在显着差异。

在人类基因组中，大多数 5' 剪接位点 (~99%) 使用规范的 GT 二核苷酸，而少数 (~1%) 使用非规范的 GC 二核苷酸。5' 剪接位点 GT>GC (+2T>C) 变体的功能和致病性已被广泛研究，但我们对 5' 剪接位点 GC>GT (+2C>T) 变体知之甚少。在此，我们通过对报道的 +2C>T“致病性”变异进行荟萃分析，并使用基于细胞培养的全长基因剪接分析对工程化的 +2C>T 替代进行功能分析，从而解决了这一缺陷。我们的结果证明了 +2C>T 变体在功能方面与 +2T>C 变体在性质上不同的概念，并表明，与 +2T>C 变体形成鲜明对比的是，如果不是所有 +2C>T 变体，大多数无病理相关性。

更新日期：2020-05-05

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11