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INTRODUCTION One of the central applications of the human reference genome has been to serve as a baseline for comparison in nearly all human genomic studies. Unfortunately, many difficult regions of the reference genome have remained unresolved for decades and are affected by collapsed duplications, missing sequences, and other issues. Relative to the current human reference genome, GRCh38, the Telomere-to-Telomere CHM13 (T2T-CHM13) genome closes all remaining gaps, adds nearly 200 million base pairs (Mbp) of sequence, corrects thousands of structural errors, and unlocks the most complex regions of the human genome for scientific inquiry. RATIONALE We demonstrate how the T2T-CHM13 reference genome universally improves read mapping and variant identification in a globally diverse cohort. This cohort includes all 3202 samples from the expanded 1000 Genomes Project (1KGP), sequenced with short reads, as well as 17 globally diverse samples sequenced with long reads. By applying state-of-the-art methods for calling single-nucleotide variants (SNVs) and structural variants (SVs), we document the strengths and limitations of T2T-CHM13 relative to its predecessors and highlight its promise for revealing new biological insights within technically challenging regions of the genome. RESULTS Across the 1KGP samples, we found more than 1 million additional high-quality variants genome-wide using T2T-CHM13more »Free, publicly-accessible full text available April 1, 2023
Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion–base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.Free, publicly-accessible full text available April 1, 2023
Shotgun transcriptome, spatial omics, and isothermal profiling of SARS-CoV-2 infection reveals unique host responses, viral diversification, and drug interactionsAbstract In less than nine months, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) killed over a million people, including >25,000 in New York City (NYC) alone. The COVID-19 pandemic caused by SARS-CoV-2 highlights clinical needs to detect infection, track strain evolution, and identify biomarkers of disease course. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs and a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, viral, and microbial profiling. We applied these methods to clinical specimens gathered from 669 patients in New York City during the first two months of the outbreak, yielding a broad molecular portrait of the emerging COVID-19 disease. We find significant enrichment of a NYC-distinctive clade of the virus (20C), as well as host responses in interferon, ACE, hematological, and olfaction pathways. In addition, we use 50,821 patient records to find that renin–angiotensin–aldosterone system inhibitors have a protective effect for severe COVID-19 outcomes, unlike similar drugs. Finally, spatial transcriptomic data from COVID-19 patient autopsy tissues reveal distinct ACE2 expression loci, with macrophage and neutrophil infiltration in the lungs. These findings can inform public health and may help develop and drive SARS-CoV-2 diagnostic, prevention, and treatment strategies.Free, publicly-accessible full text available December 1, 2022