Nature Genetics ( IF 31.7 ) Pub Date : 2024-06-27 , DOI: 10.1038/s41588-024-01808-5 David Pellerin , Giulia F. Del Gobbo , Madeline Couse , Egor Dolzhenko , Sathiji K. Nageshwaran , Warren A. Cheung , Isaac R. L. Xu , Marie-Josée Dicaire , Guinevere Spurdens , Gabriel Matos-Rodrigues , Igor Stevanovski , Carolin K. Scriba , Adriana Rebelo , Virginie Roth , Marion Wandzel , Céline Bonnet , Catherine Ashton , Aman Agarwal , Cyril Peter , Dan Hasson , Nadejda M. Tsankova , Ken Dewar , Phillipa J. Lamont , Nigel G. Laing , Mathilde Renaud , Henry Houlden , Matthis Synofzik , Karen Usdin , Andre Nussenzweig , Marek Napierala , Zhao Chen , Hong Jiang , Ira W. Deveson , Gianina Ravenscroft , Schahram Akbarian , Michael A. Eberle , Kym M. Boycott , Tomi Pastinen , Emily Bateman , Chelsea Berngruber , Fabio Cunial , Colleen P. Davis , Huyen Dinh , Harsha Doddapaneni , Kim Doheny , Shannon Dugan-Perez , Tara Dutka , Evan E. Eichler , Philip Empey , Sarah Fazal , Chris Frazar , Kiran Garimella , Jessica Gearhart , Richard Gibbs , Jane Grimwood , Namrata Gupta , Salina K. Hall , Yi Han , William T. Harvey , Jess Hosea , PingHsun Hsieh , Jianhong Hu , Yongqing Huang , James Hwang , Michal Izydorczyk , Hyeonsoo Jeong , Ziad Khan , Sarah Kirkpatrick , Michelle Kokosinski , Sam Kovaka , Edibe Nehir Kurtas , Rebecca Lakatos , Emily LaPlante , Samuel K. Lee , Niall Lennon , Shawn Levy , Qiuhui Li , Lee Lichtenstein , Glennis A. Logsdon , Chris Lord , Ryan Lorig-Roach , Medhat Madmoud , Anant Maheshwari , Beth Marosy , Heer Mehta , Ginger Metcalf , David Mohr , Carolina Montano , Luke Morina , Yulia Mostovoy , Anjene Musick , Donna Muzny , Shane Neph , Justin Paschall , Karynne Patterson , Arianna Pionzio , David Porubsky , Nripesh Prasad , Allison N. Rozanski , Alba Sanchis-Juan , Michael C. Schatz , Sophie Schwartz , Alan Scott , Adriana Sedeno-Cortes , Fritz Sedlazeck , Tristan Shaffer , Hua Shen , Beri Shifaw , Joshua D. Smith , Natthapon Soisangwan , Andrew Stergachis , Hang Su , Michael Talkowski , Winston Timp , Vanesa Vee , Evie Wan , Yuanyuan Wang , George Weissenberger , Julie Wertz , Marsha Wheeler , Christopher Whelan , DongAhn Yoo , Shadi Zaheri , Xinchang Zheng , Yiming Zhu , Michelle Zilka , Bernard Brais , Stephan Zuchner , Matt C. Danzi ,
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The factors driving or preventing pathological expansion of tandem repeats remain largely unknown. Here, we assessed the FGF14 (GAA)·(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a common 5′-flanking variant in 70.34% of alleles analyzed (3,463/4,923) that represents the phylogenetically ancestral allele and is present on all major haplotypes. This common sequence variation is present nearly exclusively on nonpathogenic alleles with fewer than 30 GAA-pure triplets and is associated with enhanced stability of the repeat locus upon intergenerational transmission and increased Fiber-seq chromatin accessibility.
中文翻译：
常见的侧翼变异与 FGF14-SCA27B 重复基因座的稳定性增强相关
驱动或阻止串联重复病理性扩张的因素仍然很大程度上未知。在这里，我们通过长读长和桑格测序评估了 2,530 名个体中的 FGF14 (GAA)·(TTC) 重复基因座，并在 70.34% 的分析等位基因 (3,463/4,923) 中鉴定了一个常见的 5' 侧翼变异，该变异代表了系统发育上的祖先等位基因并且存在于所有主要单倍型中。这种常见的序列变异几乎只存在于少于 30 个 GAA 纯三联体的非致病性等位基因上，并且与代际传递时重复位点稳定性的增强以及 Fiber-seq 染色质可及性的增加有关。
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