Sequencing and characterizing short tandem repeats in the human genome

Tanudisastro, Hope A.; Deveson, Ira W.; Dashnow, Harriet; MacArthur, Daniel G.

doi:10.1038/s41576-024-00692-3

Cited by 25 publications

(7 citation statements)

References 157 publications

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“…It is worth noting that humans have over 1 million known STR loci, some of which can give rise to severe genetic disorders upon expansion. As a result, it is crucial to continue conducting research and furthering our understanding of these loci to aid in the prevention of these debilitating illnesses [78].…”

Section: Short Tandem Repeatmentioning

confidence: 99%

Correlations of the CNR1 Gene with Personality Traits in Women with Alcohol Use Disorder

Maciocha,

Suchanecka,

Chmielowiec

et al. 2024

IJMS

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Alcohol use disorder (AUD) is a significant issue affecting women, with severe consequences for society, the economy, and most importantly, health. Both personality and alcohol use disorders are phenotypically very complex, and elucidating their shared heritability is a challenge for medical genetics. Therefore, our study investigated the correlations between the microsatellite polymorphism (AAT)n of the Cannabinoid Receptor 1 (CNR1) gene and personality traits in women with AUD. The study group included 187 female subjects. Of these, 93 were diagnosed with alcohol use disorder, and 94 were controls. Repeat length polymorphism of microsatellite regions (AAT)n in the CNR1 gene was identified with PCR. All participants were assessed with the Mini-International Neuropsychiatric Interview and completed the NEO Five-Factor and State-Trait Anxiety Inventories. In the group of AUD subjects, significantly fewer (AAT)n repeats were present when compared with controls (p = 0.0380). While comparing the alcohol use disorder subjects (AUD) and the controls, we observed significantly higher scores on the STAI trait (p < 0.00001) and state scales (p = 0.0001) and on the NEO Five-Factor Inventory Neuroticism (p < 0.00001) and Openness (p = 0.0237; insignificant after Bonferroni correction) scales. Significantly lower results were obtained on the NEO-FFI Extraversion (p = 0.00003), Agreeability (p < 0.00001) and Conscientiousness (p < 0.00001) scales by the AUD subjects when compared to controls. There was no statistically significant Pearson’s linear correlation between the number of (AAT)n repeats in the CNR1 gene and the STAI and NEO Five-Factor Inventory scores in the group of AUD subjects. In contrast, Pearson’s linear correlation analysis in controls showed a positive correlation between the number of the (AAT)n repeats and the STAI state scale (r = 0.184; p = 0.011; insignificant after Bonferroni correction) and a negative correlation with the NEO-FFI Openness scale (r = −0.241; p = 0.001). Interestingly, our study provided data on two separate complex issues, i.e., (1) the association of (AAT)n CNR1 repeats with the AUD in females; (2) the correlation of (AAT)n CNR1 repeats with anxiety as a state and Openness in non-alcohol dependent subjects. In conclusion, our study provided a plethora of valuable data for improving our understanding of alcohol use disorder and anxiety.

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Section: Short Tandem Repeatmentioning

confidence: 99%

Correlations of the CNR1 Gene with Personality Traits in Women with Alcohol Use Disorder

Maciocha,

Suchanecka,

Chmielowiec

et al. 2024

IJMS

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“…More than a million cataloged STR loci make up ∼3% of the human genome and are scattered throughout (Lander et al 2001; Gymrek 2017). Expansions or contractions of at least 60 of these STRs have been associated with human genetic disorders, concerning predominantly neurogenetic diseases (Depienne and Mandel 2021; Tanudisastro et al 2024). These disorders include, but are not limited to, myotonic dystrophies, Huntington disease, fragile X syndrome, and different forms of spinocerebellar ataxias (van der Sanden et al 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Over the last decade, exome sequencing (ES) has become increasingly important for diagnosing patients (Srivastava et al 2019) and in addition to the targeted repeat expansion assays, it is now also possible to detect specific STR expansions using ES and genome sequencing (GS) (Gymrek et al 2012; Dolzhenko et al 2017; Tang et al 2017; Willems et al 2017; Dashnow et al 2018; Tankard et al 2018; Dolzhenko et al 2019; Mousavi et al 2019; van der Sanden et al 2021). However, dedicated next generation sequencing STR detection tools are limited by the 100-150 bp read length and/or total fragment length of short-read sequencing (Halman and Oshlack 2020; Tanudisastro et al 2024). Altogether, every genetic diagnostic test that is currently performed for patients with a suspected repeat expansion disorder has its own limitations and no generic one-test-fits-all approach is currently available.…”

Section: Introductionmentioning

confidence: 99%

“…The introduction of long-read technologies has allowed the detection of large repeat expansions and determining the exact repeat size because long reads can entirely span (very long) repeat loci, which improves mapping quality and reduces mapping bias (Mantere et al 2019; Tanudisastro et al 2024). Recently, long-read sequencing technologies, such as HiFi (PacBio) and nanopore (ONT) sequencing, have proven the benefit of long reads for STR detection (Giesselmann et al 2019; Mitsuhashi et al 2019; Sone et al 2019; Chiu et al 2021; Dolzhenko et al 2024).…”

Section: Introductionmentioning

confidence: 99%

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Optical genome mapping enables accurate repeat expansion testing

van der Sanden,

Neveling,

Shukor

et al. 2024

Preprint

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Short tandem repeats (STRs) are amongst the most abundant class of variations in human genomes and are meiotically and mitotically unstable which leads to expansions and contractions. STR expansions are frequently associated with genetic disorders, with the size of expansions often correlating with the severity and age of onset. Therefore, being able to accurately detect the total repeat expansion length and to identify potential somatic repeat instability is important. Current standard of care (SOC) diagnostic assays include laborious repeat-primed PCR-based tests as well as Southern blotting, which are unable to precisely determine long repeat expansions and/or require a separate set-up for each locus. Sequencing-based assays have proven their potential for the genome-wide detection of repeat expansions but have not yet replaced these diagnostic assays due to their inaccuracy to detect long repeat expansions (short-read sequencing) and their costs (long-read sequencing). Here, we tested whether optical genome mapping (OGM) can efficiently and accurately identify the STR length and assess the stability of known repeat expansions. We performed OGM for 85 samples with known clinically relevant repeat expansions in DMPK, CNBP and RFC1, causing myotonic dystrophy type 1 and 2 and cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), respectively. After performing OGM, we applied three different repeat expansion detection workflows, i.e. manual de novo assembly, local guided assembly (local-GA) and molecule distance script of which the latter two were developed as part of this study. The first two workflows estimated the repeat size for each of the two alleles, while the third workflow was used to detect potential somatic instability. The estimated repeat sizes were compared to the repeat sizes reported after the SOC and concordance between the results was determined. All except one known repeat expansions above the pathogenic repeat size threshold were detected by OGM, and allelic differences were distinguishable, either between wildtype and expanded alleles, or two expanded alleles for recessive cases. An apparent strength of OGM over current SOC methods was the more accurate length measurement, especially for very long repeat expansion alleles, with no upper size limit. In addition, OGM enabled the detection of somatic repeat instability, which was detected in 9/30 DMPK, 23/25 CNBP and 4/30 RFC1 samples, leveraging the analysis of intact, native DNA molecules. In conclusion, for tandem repeat expansions larger than ~300 bp, OGM provides an efficient method to identify exact repeat lengths and somatic repeat instability with high confidence across multiple loci simultaneously, enabling the potential to provide a significantly improved and generic genome-wide assay for repeat expansion disorders.

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“…Over 2 million TRs have been reported to occur in the human genome 17,18 , residing within both coding and non-coding regions and playing a crucial role in regulating gene expression, genome stability, and chromatin structure [19][20][21] . Yet, TR expansions have long been disregarded as a possible explanation of unexplained genetic disorders that are not neurological, largely due to the challenges in profiling them in high-throughput genomic sequencing datasets and in interpreting their clinical relevance 22 . Consequently, our understanding of the extent of variability within these loci and their contribution to disease, beyond the catalog of known disease-associated TRs 8,9,23 , are quite limited.…”

Section: Introductionmentioning

confidence: 99%

A comprehensive tandem repeat catalog of the human genome

Chiu,

Rajan Babu,

Friedman

et al. 2024

Preprint

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With the increasing availability of long-read sequencing data, high-quality human genome assemblies, and software for fully characterizing tandem repeats, genome-wide genotyping of tandem repeat loci on a population scale becomes more feasible. Such efforts not only expand our knowledge of the tandem repeat landscape in the human genome but also enhance our ability to differentiate pathogenic tandem repeat mutations from benign polymorphisms. To this end, we analyzed 272 genomes assembled using datasets from three public initiatives that employed different long-read sequencing technologies. Here, we report a catalog of over 18 million tandem repeat loci, many of which were previously unannotated. Some of these loci are highly polymorphic, and many of them reside within coding sequences.

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Sequencing and characterizing short tandem repeats in the human genome

Cited by 25 publications

References 157 publications

Correlations of the CNR1 Gene with Personality Traits in Women with Alcohol Use Disorder

Correlations of the CNR1 Gene with Personality Traits in Women with Alcohol Use Disorder

Optical genome mapping enables accurate repeat expansion testing

A comprehensive tandem repeat catalog of the human genome

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