小柯机器人

串联DNA重复的扩增与自闭症发病相关
2020-07-29 21:46
来源：小柯机器人

近日，加拿大病童医院Ryan K. C. Yuen团队发现，串联DNA重复的扩增与自闭症发病相关。相关论文于2020年7月27日在线发表于《自然》。

研究人员探索了自闭症家庭和人群对照中17231个基因组里具有2–20 bp基序的串联重复序列的全基因组特征。研究人员发现了基序大小和序列广泛的多态性。许多与细胞遗传易碎位点相关。在2588个基因座处，自闭症患者中基因相关的串联重复扩增在患病个体中比未受影响的兄弟姐妹明显更为普遍，特别是在外显子和剪接点附近以及与神经系统发育、心血管系统或肌肉相关的基因中。
 
自闭症患儿的罕见串联重复扩增患病率为23.3％，而在未受影响者中为20.7％，这表明自闭症风险的总体贡献为2.6％。它们包括了以神经肌肉疾病而闻名的DMPK和FXN，以及诸如FGF14和CACNB1新基因座中的新型自闭症相关串联重复序列扩增。这些与较低的智商和适应能力有关。这些研究结果表明，串联DNA重复序列扩增对自闭症的遗传病因和表型复杂性有重要贡献。
 
据了解，串联DNA重复序列因每个单位（基序）的大小和序列而异。当扩增后，它们与40多种单基因疾病相关联。它们与复杂疾病的关系以及异质性的程度在很大程度上是未知的。
 
附：英文原文

Title: Genome-wide detection of tandem DNA repeats that are expanded in autism

Author: Brett Trost, Worrawat Engchuan, Charlotte M. Nguyen, Bhooma Thiruvahindrapuram, Egor Dolzhenko, Ian Backstrom, Mila Mirceta, Bahareh A. Mojarad, Yue Yin, Alona Dov, Induja Chandrakumar, Tanya Prasolava, Natalie Shum, Omar Hamdan, Giovanna Pellecchia, Jennifer L. Howe, Joseph Whitney, Eric W. Klee, Saurabh Baheti, David G. Amaral, Evdokia Anagnostou, Mayada Elsabbagh, Bridget A. Fernandez, Ny Hoang, M. E. Suzanne Lewis, Xudong Liu, Calvin Sjaarda, Isabel M. Smith, Peter Szatmari, Lonnie Zwaigenbaum, David Glazer, Dean Hartley, A. Keith Stewart, Michael A. Eberle, Nozomu Sato, Christopher E. Pearson, Stephen W. Scherer, Ryan K. C. Yuen

Issue&Volume: 2020-07-27

Abstract: Tandem DNA repeats vary by the size and sequence of each unit (motif). When expanded, they have been associated with more than 40 monogenic disorders1. Their involvement in complex disorders is largely unknown, as is the extent of their heterogeneity. Here, we interrogated genome-wide characteristics of tandem repeats with 2–20-bp motifs in 17,231 genomes of families with autism2,3 and population controls4. We found extensive polymorphism in motif size and sequence. Many correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated tandem repeat expansions that were rare among population controls were significantly more prevalent among individuals with autism than their unaffected siblings, particularly in exons and near splice junctions and in genes related to nervous system development and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in autism-affected children versus 20.7% in unaffected children, suggesting a collective contribution to autism risk of 2.6%. They included novel autism-linked tandem repeat expansions in DMPK and FXN, known for neuromuscular conditions, and in novel loci such as FGF14 and CACNB1. These were associated with lower IQ and adaptive ability. Our results revealed a strong contribution of tandem DNA repeat expansions to the genetic etiology and phenotypic complexity of autism.

DOI: 10.1038/s41586-020-2579-z

Source: https://www.nature.com/articles/s41586-020-2579-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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