biostudies-literaturePellerin DOntario Genomics Institute (OGI)U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)NCATS NIH HHSNIDA NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)U.S. Department of Health & Human Services | National Institutes of Health (NIH)Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)Deutsche Forschungsgemeinschaft (German Research Foundation)U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)NHGRI NIH HHSNCI NIH HHSNINDS NIH HHSWellcome TrustNIH HHS1366-1370https://www.ebi.ac.uk/biostudies/studies/S-EPMC11440897biostudies-literatureUnknown56(7)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.Nature geneticsA common flanking variant is associated with enhanced stability of the FGF14-SCA27B repeat locus.PMC11440897R01NS106229S10 OD0304632R01NS072248-11A1S10 OD026880DP1 DA056018UL1 TR004419189963RF1DA048810S10OD030463R01 NS072248RF1 DA048810P30 CA196521S10OD026880DP1DA056018R01 NS106229OGI-147GP1-155867R21HG013397HHSN261201500003UL1TR004419R21 HG013397P30CA196521441409627Del Gobbo GFMetcalf GPatterson KAll of Us Research Program Long Read Working GroupKovaka SMorina LLaing NGCunial FAkbarian SShen HSu HDutka TLogsdon GALorig-Roach RHall SKUsdin KWan EDeveson IWJeong HSedlazeck FZheng XDewar KScriba CKShaffer TDavis CPPellerin DMuzny DPastinen THu JNussenzweig AWeissenberger GMostovoy YLevy SFrazar CBateman EFazal SSoisangwan NLennon NHsieh PLakatos RZhu YRebelo AHan YSchatz MCMatos-Rodrigues GDugan-Perez SBrais BBerngruber CWheeler MHosea JGrimwood JNeph SSmith JDWertz JWandzel MLee SKDolzhenko EXu IRLRavenscroft GIzydorczyk MKokosinski MKurtas ENHuang YGibbs RRenaud MTimp WStevanovski IMusick ARozanski ANDinh HKirkpatrick SAshton CPrasad NMehta HTalkowski MZaheri SSpurdens GMaheshwari AEberle MAAgarwal AChen ZPaschall JSynofzik MGupta NWang YNapierala MCheung WAHoulden HStergachis APionzio AMarosy BLamont PJLi QBonnet CHasson DShifaw BLaPlante ESanchis-Juan ARoth VCouse MZuchner SSedeno-Cortes ADoheny KZilka MMohr DKhan ZJiang HScott AVee VYoo DPeter CMontano CSchwartz SDoddapaneni HDicaire MJLichtenstein LTsankova NMEmpey PPorubsky DMadmoud MHwang JGearhart JWhelan CHarvey WTEichler EEGarimella KLord CNageshwaran SKBoycott KMDanzi MCfalseA common flanking variant is associated with enhanced stability of the FGF14-SCA27B repeat locus.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.2024-01-01T00:00:00Z2024 Jul2026-06-01T05:59:09.965Z2026-04-08T09:48:53.496ZS-EPMC114408973893760610.1038/s41588-024-01808-5