A deep population reference panel of tandem repeat variation

jam, Helyaneh Ziaei; Li, Yang; DeVito, Ross; Mousavi, Nima; Ma, Nichole; Lujumba, Ibra; Adam, Yagoub; Maksimov, Mikhail O.; Huang, Bonnie; Dolzhenko, Egor; Qiu, Yunjiang; Kakembo, Fredrick Elishama; Joseph, Habi; Onyido, Blessing; Adeyemi, Jumoke; Bakhtiari, Mehrdad; Park, Jonghun; Javadzadeh, Sara; Jjingo, Daudi; Adebiyi, Ezekiel; Bafna, Vineet; Gymrek, Melissa

doi:10.1101/2023.03.09.531600

Cited by 12 publications

(9 citation statements)

References 83 publications

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“…In fact, a CAG repeat in ZFHX3 was already investigated within the German SCA4 family 20 years ago 8 . As the genome harbors approximately 1.7 million polymorphic STR loci, 28 using even more recent bioinformatic tools such as ExpansionHunter 17 requires filtering of variants by type before outlier detection analysis to simplify and manage the number of STR loci reviewed. Thus, adaptive sampling allows for a flexible, computationally directed, variant agnostic approach to target candidate regions of high linkage and represents an exciting and important method in the discovery of unsolved causes of inherited neurological disorders.…”

Section: Discussionmentioning

confidence: 99%

Adaptive Long‐Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4

Chen,

Gustavsson,

Macpherson

et al. 2024

Movement Disorders

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BackgroundSpinocerebellar ataxia type 4 (SCA4) is an autosomal dominant ataxia with invariable sensory neuropathy originally described in a family with Swedish ancestry residing in Utah more than 25 years ago. Despite tight linkage to the 16q22 region, the molecular diagnosis has since remained elusive.ObjectivesInspired by pathogenic structural variation implicated in other 16q‐ataxias with linkage to the same locus, we revisited the index SCA4 cases from the Utah family using novel technologies to investigate structural variation within the candidate region.MethodsWe adopted a targeted long‐read sequencing approach with adaptive sampling on the Oxford Nanopore Technologies (ONT) platform that enables the detection of segregating structural variants within a genomic region without a priori assumptions about any variant features.ResultsUsing this approach, we found a heterozygous (GGC)n repeat expansion in the last coding exon of the zinc finger homeobox 3 (ZFHX3) gene that segregates with disease, ranging between 48 and 57 GGC repeats in affected probands. This finding was replicated in a separate family with SCA4. Furthermore, the estimation of this GGC repeat size in short‐read whole genome sequencing (WGS) data of 21,836 individuals recruited to the 100,000 Genomes Project in the UK and our in‐house dataset of 11,258 exomes did not reveal any pathogenic repeats, indicating that the variant is ultrarare.ConclusionsThese findings support the utility of adaptive long‐read sequencing as a powerful tool to decipher causative structural variation in unsolved cases of inherited neurological disease. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussionmentioning

confidence: 99%

Adaptive Long‐Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4

Chen,

Gustavsson,

Macpherson

et al. 2024

Movement Disorders

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“…For example, many non-coding variants located in and around the oculocutaneous albinism II (OCA2) gene contribute to hair pigmentation variation, and cannot be identified in the sole study of coding regions (41). Finally, TR variant calling is challenging, with the dozens of available methods yielding unique benefits and drawbacks (42)(43)(44). For example, the GangSTR method used herein has an elevated error rate in the context of AC/TG dinucleotide motifs that is not present in other methods that have different shortcomings.…”

Section: Discussionmentioning

confidence: 99%

Multi-ancestry tandem repeat association study of hair colour using exome-wide sequencing

Fazzari,

Moo-Choy,

Panoyan

et al. 2024

Preprint

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Hair colour variation is influenced by hundreds of positions across the human genome but this genetic contribution has only been narrowly explored. Genome-wide association studies identified single nucleotide polymorphisms (SNPs) influencing hair colour but the biology underlying these associations is challenging to interpret. We report 16 tandem repeats (TRs) with effects on different models of hair colour plus two TRs associated with hair colour in diverse ancestry groups. Several of these TRs expand or contract amino acid coding regions of their localized protein such that structure, and by extension function, may be altered. We also demonstrate that independent of SNP variation, these TRs can be used to great an additive polygenic score that predicts darker hair colour. This work adds to the growing body of evidence regarding TR influence on human traits with relatively large and independent effects relative to surrounding SNP variation.

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“…Several studies have demonstrated that while overall patterns of repeat variations are highly similar across populations, there are notable exceptions with population-specific patterns (Ziaei Jam et al 2023). For instance, common "CAG" expansions in an intronic repeat within the gene CA10 were found predominantly in African individuals, and the motif usage of an intronic repeat in gene PCBP3 showed substantial differences across modern superpopulations (Ziaei Jam et al 2023;Course et al 2021). Another example is the BEAN1 repeat, which showed population-specific pathogenic expansions (Figure 5) (Ishikawa and Nagai 2019).…”

Section: Discussionmentioning

confidence: 99%

MotifScope: a multi-sample motif discovery and visualization tool for tandem repeats

Zhang,

Hulsman,

Salazar

et al. 2024

Preprint

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Tandem repeats (TRs) constitute a significant portion of the human genome, exhibiting high levels of polymorphism due to variations in size and motif composition. These variations have been associated with various neuropathological disorders, underscoring the clinical importance of TRs. Furthermore, the motif structure of these repeats can offer valuable insights into evolutionary dynamics and population structure. However, analysis of TRs has been hampered by the limitations of short-read sequencing technology, which lacks the ability to fully capture the complexity of these sequences. With long-read data becoming more accessible, there is now also a need for tools to explore and characterize these TRs. In this study, we introduce MotifScope, a novel algorithm for visualization of TRs in their population context based on a de novo k-mer approach for motif discovery. Comparative analysis against three established tools, uTR, TRF, and vamos, reveals that MotifScope can identify a greater number of motifs and more accurately represent the actual repeat sequence. Additionally, MotifScope enables comparison of sequencing reads within an individual and assemblies across different individuals, showing its applicability in diverse genomic contexts. We demonstrate potential applications of MotifScope in diverse fields, including population genetics, clinical settings, and forensic analyses.

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A deep population reference panel of tandem repeat variation

Cited by 12 publications

References 83 publications

Adaptive Long‐Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4

Adaptive Long‐Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4

Multi-ancestry tandem repeat association study of hair colour using exome-wide sequencing

MotifScope: a multi-sample motif discovery and visualization tool for tandem repeats

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