Functional Analysis of Human EED Variants Using Drosophila.

IF 3.3 3区生物学 Q2 GENETICS & HEREDITY

Genetics Pub Date : 2025-06-20 DOI:10.1093/genetics/iyaf120

Sharri S Cyrus, Sònia Medina Giró, Tianshun Lian, Douglas W Allan, William T Gibson

引用次数: 0

Abstract

The Polycomb Repressive Complex 2 is an epigenetic reader/writer that methylates histone H3K27. Rare germline partial loss of function (pLoF) variants in core members of the complex (EZH2, EED, SUZ12) cause overgrowth and intellectual disability syndromes, whereas somatic variants are implicated in cancer. However, up to 1% of the general population will have a rare variant in one of these genes, most of which would be classified as variants of uncertain significance (VUS). Towards screening these VUS for partial LoF alleles that may contribute to disease, here we report functional assays in Drosophila to interrogate Embryonic Ectoderm Development (EED) missense variants. We mimicked the amino acid change(s) of EED variants into its Drosophila ortholog, esc, and tested their function. Known likely benign variants functioned wildtype and known pathogenic variants were LoF. We further demonstrate the utility of this calibrated assay as a scalable approach to assist clinical interpretation of human EED VUS.

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果蝇对人类EED变异的功能分析。

Polycomb suppression Complex 2是一种表观遗传的读取器/写入器，可使组蛋白H3K27甲基化。该复合体核心成员（EZH2， EED, SUZ12）中罕见的种系部分功能丧失（pLoF）变异会导致过度生长和智力残疾综合征，而体细胞变异则与癌症有关。然而，在一般人群中，高达1%的人会在这些基因中有一个罕见的变异，其中大多数将被归类为不确定意义的变异（VUS）。为了筛选这些VUS中可能导致疾病的部分LoF等位基因，我们在果蝇中进行了功能测定，以询问胚胎外胚层发育（EED）错义变异体。我们模拟了果蝇EED变体的氨基酸变化，并测试了它们的功能。已知可能的良性变异为野生型，而已知的致病变异为LoF。我们进一步证明了这种校准分析作为一种可扩展的方法来帮助临床解释人类EED VUS的效用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Genetics GENETICS & HEREDITY-

CiteScore

6.90

自引率

6.10%

发文量

177

审稿时长

1.5 months

期刊介绍： GENETICS is published by the Genetics Society of America, a scholarly society that seeks to deepen our understanding of the living world by advancing our understanding of genetics. Since 1916, GENETICS has published high-quality, original research presenting novel findings bearing on genetics and genomics. The journal publishes empirical studies of organisms ranging from microbes to humans, as well as theoretical work. While it has an illustrious history, GENETICS has changed along with the communities it serves: it is not your mentor''s journal. The editors make decisions quickly – in around 30 days – without sacrificing the excellence and scholarship for which the journal has long been known. GENETICS is a peer reviewed, peer-edited journal, with an international reach and increasing visibility and impact. All editorial decisions are made through collaboration of at least two editors who are practicing scientists. GENETICS is constantly innovating: expanded types of content include Reviews, Commentary (current issues of interest to geneticists), Perspectives (historical), Primers (to introduce primary literature into the classroom), Toolbox Reviews, plus YeastBook, FlyBook, and WormBook (coming spring 2016). For particularly time-sensitive results, we publish Communications. As part of our mission to serve our communities, we''ve published thematic collections, including Genomic Selection, Multiparental Populations, Mouse Collaborative Cross, and the Genetics of Sex.