Haplotype-resolved diverse human genomes and integrated analysis of structural variation

Science, Journal Year: 2021, Volume and Issue: 372(6537)

Published: Feb. 25, 2021

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% genome: 26 million base pairs) integrate all forms genetic variation, even across complex loci. identified 107,590 structural variants (SVs), which 68% were not discovered with short-read sequencing, 278 SV hotspots (spanning megabases gene-rich sequence). characterized 130 most active mobile element source elements found that 63% SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping short reads up 50,340 SVs, resulting in identification 1526 expression quantitative trait loci as well candidates for adaptive selection within population.

Language: Английский

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TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Nature, Journal Year: 2022, Volume and Issue: 603(7899), P. 131 - 137

Published: Feb. 23, 2022

Variants of UNC13A, a critical gene for synapse function, increase the risk amyotrophic lateral sclerosis and frontotemporal dementia

Language: Английский

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Regional Heterogeneity in Gene Expression, Regulation, and Coherence in the Frontal Cortex and Hippocampus across Development and Schizophrenia

Neuron, Journal Year: 2019, Volume and Issue: 103(2), P. 203 - 216.e8

Published: June 4, 2019

Language: Английский

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Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: 130(11), P. 6080 - 6092

Published: Aug. 13, 2020

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials hampered by our inability distinguish between patients FTLD-TDP FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy pathology, given reports that dysfunction causes STMN2 accumulation. Truncated accumulated human induced pluripotent stem cell-derived neurons depleted TDP-43, not those pathogenic TARDBP mutations absence aggregation or loss nuclear protein. In RNA-Seq analyses brain samples from NYGC ALS cohort, RNA was confined tissues disease subtypes marked inclusions. Last, validated elevated frontal cortex cohort controls progressive supranuclear palsy, Further, FTLD-TDP, observed significant associations phosphorylated levels an earlier age onset. Overall, data uncovered marker FTD.

Language: Английский

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Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(1), P. 4 - 17

Published: Jan. 1, 2022

Language: Английский

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Direct RNA sequencing reveals m6A modifications on adenovirus RNA are necessary for efficient splicing

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Nov. 26, 2020

Adenovirus is a nuclear replicating DNA virus reliant on host RNA processing machinery. Processing and metabolism of cellular RNAs can be regulated by METTL3, which catalyzes the addition N6-methyladenosine (m6A) to mRNAs. While m6A-modified adenoviral have been previously detected, location function this mark within infectious cycle unknown. Since complex adenovirus transcriptome includes overlapping spliced units that would impede accurate m6A mapping using short-read sequencing, here we profile combination meRIP-seq direct long-read sequencing yield both nucleotide transcript-resolved detection. Although early late viral transcripts contain m6A, depletion writer METTL3 specifically impacts reducing their splicing efficiency. These data showcase new technique for discovery individual at resolution, highlight role in regulating pathogen.

Language: Английский

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Transcriptomic organization of the human brain in post-traumatic stress disorder

Nature Neuroscience, Journal Year: 2020, Volume and Issue: 24(1), P. 24 - 33

Published: Dec. 21, 2020

Language: Английский

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Profiling gene expression in the human dentate gyrus granule cell layer reveals insights into schizophrenia and its genetic risk

Nature Neuroscience, Journal Year: 2020, Volume and Issue: 23(4), P. 510 - 519

Published: March 16, 2020

Language: Английский

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Sierra: discovery of differential transcript usage from polyA-captured single-cell RNA-seq data

Genome biology, Journal Year: 2020, Volume and Issue: 21(1)

Published: July 8, 2020

High-throughput single-cell RNA-seq (scRNA-seq) is a powerful tool for studying gene expression in single cells. Most current scRNA-seq bioinformatics tools focus on analysing overall levels, largely ignoring alternative mRNA isoform expression. We present computational pipeline, Sierra, that readily detects differential transcript usage from data generated by commonly used polyA-captured technology. validate Sierra comparing cardiac cell types to bulk of matched populations, finding significant overlap transcripts. across human peripheral blood mononuclear cells and the Tabula Muris, 3 'UTR shortening fibroblasts. available at https://github.com/VCCRI/Sierra .

Language: Английский

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A compromised specific humoral immune response against the SARS-CoV-2 receptor-binding domain is related to viral persistence and periodic shedding in the gastrointestinal tract

Cellular and Molecular Immunology, Journal Year: 2020, Volume and Issue: 17(11), P. 1119 - 1125

Published: Oct. 9, 2020

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been redetected after discharge in some disease 2019 (COVID-19) patients. The reason for the recurrent positivity of test and potential public health concern due to this occurrence are still unknown. Here, we analyzed viral data clinical manifestations 289 domestic Chinese COVID-19 patients found that 21 individuals (7.3%) were readmitted hospitalization detection SARS-CoV-2 discharge. First, experimentally confirmed virus was involved initial infection not a secondary infection. In positive retests, usually anal samples (15 21, 71.4%). Through analysis intracellular subgenomic messenger RNA (sgmRNA), verified retest had active replication their gastrointestinal tracts (3 16 patients, 18.7%) but tracts. Then, persistence associated with high titers, delayed clearance, old age, or more severe symptoms during first hospitalization. contrast, rebound significantly lower levels slower generation receptor-binding domain (RBD)-specific IgA IgG antibodies. Our study demonstrated failed create robust protective humoral immune response, which might result tract possibly shedding. Further exploration mechanism underlying population will be crucial preventing spread developing effective vaccines.

Language: Английский

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