Advancing evolutionary medicine with complete primate genomes and advanced biotechnologies

Trends in Genetics, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Язык: Английский

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Long-read sequencing of hundreds of diverse brains provides insight into the impact of structural variation on gene expression and DNA methylation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 18, 2024

Structural variants (SVs) drive gene expression in the human brain and are causative of many neurological conditions. However, most existing genetic studies have been based on short-read sequencing methods, which capture fewer than half SVs present any one individual. Long-read (LRS) enhances our ability to detect disease-associated functionally relevant structural (SVs); however, its application large-scale genomic has limited by challenges sample preparation high costs. Here, we leverage a new scalable wet-lab protocol computational pipeline for whole-genome Oxford Nanopore Technologies apply it neurologically normal control samples from North American Brain Expression Consortium (NABEC) (European ancestry) Human Collection Core (HBCC) (African or African admixed cohorts. Through this work, publicly available long-read resource 351 (median N50: 27 Kbp at an average depth ~40x genome coverage). We discover approximately 234,905 produce locally phased assemblies that cover 95% all protein-coding genes GRCh38. Utilizing matched datasets these samples, quantitative trait locus (QTL) analyses identify impact post-mortem frontal cortex tissue. Further, determine haplotype-specific methylation signatures millions CpGs and, with data, cis-acting SVs. In summary, results highlight LRS can complex regulatory mechanisms were inaccessible using previous approaches. believe provides critical step toward understanding biological effects variation brain.

Язык: Английский

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Applications of advanced technologies for detecting genomic structural variation

Mutation Research/Reviews in Mutation Research, Год журнала: 2023, Номер 792, С. 108475 - 108475

Опубликована: Июль 1, 2023

Язык: Английский

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Long-read sequencing and optical mapping generates near T2T assemblies that resolves a centromeric translocation

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Апрель 18, 2024

Long-read genome sequencing (lrGS) is a promising method in genetic diagnostics. Here we investigate the potential of lrGS to detect disease-associated chromosomal translocation between 17p13 and 19 centromere. We constructed two sets phased non-phased de novo assemblies; (i) based on only (ii) hybrid assemblies combining with optical mapping using reads median coverage 34X. Variant calling detected both structural variants (SVs) small accuracy variant was compared those called short-read (srGS). The had high quality contiguity N50 62.85 Mb, enabling near telomere assembly less than 100 contigs per haplotype. Notably, successfully identified centromeric breakpoint translocation. A concordance 92% observed when comparing srGS lrGS. In summary, our findings underscore remarkable as comprehensive accurate solution for analysis SVs variants. Thus, could replace large battery tests that were used diagnosis single symptomatic carrier, highlighting realm digital karyotyping.

Язык: Английский

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Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 22, 2024

Abstract More than 50% of families with suspected rare monogenic diseases remain unsolved after whole genome analysis by short read sequencing (SRS). Long-read (LRS) could help bridge this diagnostic gap capturing variants inaccessible to SRS, facilitating long-range mapping and phasing, providing haplotype-resolved methylation profiling. To evaluate LRS’s additional yield, we sequenced a disease cohort 98 samples, including 41 probands some family members, using nanopore sequencing, achieving per sample ∼36x average coverage 32 kilobase (kb) N50 from single flow cell. Our Napu pipeline generated assemblies, phased variants, calls. LRS covered, on average, coding exons in ∼280 genes ∼5 known Mendelian that were not covered SRS. In comparison detected rare, functionally annotated SVs tandem repeats, completely 87% protein-coding genes. de novo be used distinguish postzygotic mosaic prezygotic novos . Eleven solved, diverse underlying genetic causes compound heterozygous large-scale SVs, epigenetic modifications. study demonstrates potential enhance yield for diseases, implying utility future clinical genomics workflows.

Язык: Английский

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