Analysis and benchmarking of small and large genomic variants across tandem repeats

Nature Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: April 26, 2024

Language: Английский

---

Comprehensive genome analysis and variant detection at scale using DRAGEN

Nature Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 25, 2024

Research and medical genomics require comprehensive, scalable methods for the discovery of novel disease targets, evolutionary drivers genetic markers with clinical significance. This necessitates a framework to identify all types variants independent their size or location. Here we present DRAGEN, which uses multigenome mapping pangenome references, hardware acceleration machine learning-based variant detection provide insights into individual genomes, ~30 min computation time from raw reads detection. DRAGEN outperforms current state-of-the-art in speed accuracy across (single-nucleotide variations, insertions deletions, short tandem repeats, structural variations copy number variations) incorporates specialized analysis medically relevant genes. We demonstrate performance 3,202 whole-genome sequencing datasets by generating fully genotyped multisample call format files its scalability, innovation further advance integration comprehensive genomics. Overall, marks major milestone data will various diseases, including Mendelian rare highly platform.

Language: Английский

---

Comprehensive and accurate genome analysis at scale using DRAGEN accelerated algorithms

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 2, 2024

Research and medical genomics require comprehensive scalable solutions to drive the discovery of novel disease targets, evolutionary drivers, genetic markers with clinical significance. This necessitates a framework identify all types variants independent their size (e.g., SNV/SV) or location repeats). Here we present DRAGEN that utilizes methods based on multigenomes, hardware acceleration, machine learning variant detection provide insights into individual genomes ~30min computation time (from raw reads detection). outperforms other state-of-the-art in speed accuracy across (SNV, indel, STR, SV, CNV) further incorporates specialized obtain key medically relevant genes HLA, SMN, GBA). We showcase 3,202 demonstrate its scalability, accuracy, innovations advance integration for research applications.

Language: Английский

---

Assessing Human Ribosomal DNA Variation and Its Association With Phenotypic Outcomes

BioEssays, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 20, 2025

ABSTRACT Although genome‐scale analyses have provided insights into the connection between genetic variability and complex human phenotypes, much trait variation is still not fully understood. Genetic within repetitive elements, such as multi‐copy, multi‐locus ribosomal DNA (rDNA), has emerged a potential contributor to variation. Whereas rDNA was long believed be largely uniform species, recent studies revealed substantial in locus, both across individuals. This variation, which takes form of copy number, structural arrangement, sequence differences, been found associated with phenotypes. review summarizes what currently known about its causes, association phenotypic outcomes, highlighting technical challenges field faces solutions proposed address them. Finally, we suggest experimental approaches that can help clarify elusive mechanisms underlying consequences

Language: Английский

---

Benchmarking of small and large variants across tandem repeats

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 1, 2023

Tandem repeats (TRs) are highly polymorphic in the human genome, have thousands of associated molecular traits, and linked to over 60 disease phenotypes. However, their complexity often excludes them from at-scale studies due challenges with variant calling, representation, lack a genome-wide standard. To promote TR methods development, we create comprehensive catalog regions explore its properties across 86 samples. We then curate variants GIAB HG002 individual tandem repeat benchmark. also present comparison method that handles small large alleles varying allelic representation. The 8.1% genome covered by holds ∼24.9% per individual, including 124,728 17,988 for work community demonstrate utility this benchmark short long read technologies.

Language: Английский

---

C9orf72 expansion creates the unstable folate-sensitive fragile site FRA9A

Deleted Journal, Journal Year: 2024, Volume and Issue: 1(4)

Published: Oct. 1, 2024

Abstract The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked immune DNA damage responses, but source of immunostimulatory or damaged unknown. Here, we show in pre-symptomatic sclerosis-frontotemporal patient cells brains cause folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33 kb as highly compacted chromatin embedded an 8.2 Mb fragility zone spanning 9p21, encompassing 46 genes, making one largest sites. instability, heightened global- Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s Chr9-containing micronuclei, providing endogenous sources DNA. Cells from contained a rearranged FRA9A-expressing Chr9 Chr9-wide dysregulated expression. Somatic repeat instability sensitive folate deficiency. Age-dependent can be transferred CNS peripheral tissues transgenic mice, implicating source. Our results highlight unappreciated effects that trigger vitamin-sensitive chromosome fragility, adding structural variations disease-enriched 9p21 likely elsewhere.

Language: Английский

---

Centromeres in cancer: Unraveling the link between chromosomal instability and tumorigenesis

Medical Oncology, Journal Year: 2024, Volume and Issue: 41(11)

Published: Oct. 1, 2024

Language: Английский

---

Role of fragile sites FATS and FMR1 in tumor progression and their potential clinical significance

International Journal of Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Abstract The fragile sites are defined as specific segments of genes that particularly susceptible to breakage under conditions accelerated replication stress or certain external influences. It has been demonstrated can influence the progression various tumors. However, majority existing studies have focused on functions well‐characterized common sites, such FHIT , WWOX and PARK2 in different oncogenic processes, with insufficient attention directed towards other sites. This article presents an analysis recent investigations into site‐associated tumor suppressor ( FATS ) X mental retardation 1 FMR1 ), across types. discusses mechanisms signaling pathways regulated by these a range cancers, well their clinical implications for treatment. review highlights significance cancers relevance.

Language: Английский

---

Centromere: A Trojan horse for genome stability

DNA repair, Journal Year: 2023, Volume and Issue: 130, P. 103569 - 103569

Published: Sept. 7, 2023

Language: Английский

---

RNA Gain-of-Function Mechanisms in Short Tandem Repeat Diseases

RNA, Journal Year: 2024, Volume and Issue: unknown, P. rna.080277.124 - rna.080277.124

Published: Dec. 26, 2024

As adaptors, catalysts, guides, messengers, scaffolds and structural components, RNAs perform an impressive array of cellular regulatory functions often by recruiting RNA-binding proteins (RBPs) to form ribonucleoprotein complexes (RNPs). While this RNA-RBP interaction network allows precise RNP assembly the subsequent dynamics required for normal functions, RNA motif mutations may trigger formation aberrant structures that lead cell dysfunction disease. Here, we provide our perspective on one type mutation, gain-of-function associated with abnormal expansion short tandem repeats (STRs) underlie multiple developmental degenerative diseases. We first discuss current understanding polymorphic STR in processing localization followed assessment pathogenic roles expansions neuromuscular disease myotonic dystrophy. also highlight ongoing questions controversies focused STR-based insights into regulation nuclear export as well relevance pathomechanism other disorders both coding non-coding genes.

Language: Английский

---