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Explore scientific publications featuring PacBio long-read sequencing data

The Journal of Immunology  |  2023

FLAIRR-Seq: A Method for Single-Molecule Resolution of Near Full-Length Antibody H Chain Repertoires

Easton E. Ford, David Tieri, Oscar L. Rodriguez, Nancy J. Francoeur, Juan Soto, Justin T. Kos, Ayelet Peres, William S. Gibson, Catherine A. Silver, Gintaras Deikus, Elizabeth Hudson, Cassandra R. Woolley, Noam Beckmann, Alexander Charney, Thomas C. Mitchell, Gur Yaari, Robert P. Sebra, Corey T. Watson, Melissa L. Smith

Current Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) using short-read sequencing strategies resolve expressed Ab transcripts with limited resolution of the C region. In this article, we present the near-full-length AIRR-seq (FLAIRR-seq) method that uses targeted amplification by 5′ RACE, combined with single-molecule, real-time sequencing to generate highly accurate (99.99%) human Ab H chain transcripts. FLAIRR-seq was benchmarked by comparing H chain V (IGHV), D (IGHD), and J (IGHJ) gene usage, complementarity-determining region 3 length, and somatic hypermutation to matched datasets generated with standard 5′ RACE AIRR-seq using short-read sequencing and full-length isoform sequencing. Together, these data demonstrate robust FLAIRR-seq performance using RNA samples derived from PBMCs, purified B cells, and whole blood, which recapitulated results generated by commonly used methods, while additionally resolving H chain gene features not documented in IMGT at the time of submission. FLAIRR-seq data provide, for the first time, to our knowledge, simultaneous single-molecule characterization of IGHV, IGHD, IGHJ, and IGHC region genes and alleles, allele-resolved subisotype definition, and high-resolution identification of class switch recombination within a clonal lineage. In conjunction with genomic sequencing and genotyping of IGHC genes, FLAIRR-seq of the IgM and IgG repertoires from 10 individuals resulted in the identification of 32 unique IGHC alleles, 28 (87%) of which were previously uncharacterized. Together, these data demonstrate the capabilities of FLAIRR-seq to characterize IGHV, IGHD, IGHJ, and IGHC gene diversity for the most comprehensive view of bulk-expressed Ab repertoires to date.
Biorxiv  |  2023

Utility of long-read sequencing for All of Us

M. Mahmoud, Y. Huang, K. Garimella, P. A. Audano, W. Wan, N. Prasad, R. E. Handsaker, S. Hall, A. Pionzio, M. C. Schatz, M. E. Talkowski, E. E. Eichler, S. E. Levy, F. J. Sedlazeck

The All of Us (AoU) initiative aims to sequence the genomes of over one million Americans from diverse ethnic backgrounds to improve personalized medical care. In a recent technical pilot, we compared the performance of traditional short-read sequencing with long-read sequencing in a small cohort of samples from the HapMap project and two AoU control samples representing eight datasets. Our analysis revealed substantial differences in the ability of these technologies to accurately sequence complex medically relevant genes, particularly in terms of gene coverage and pathogenic variant identification. We also considered the advantages and challenges of using low coverage sequencing to increase sample numbers in large cohort analysis. Our results show that HiFi reads produced the most accurate results for both small and large variants. Further, we present a cloud-based pipeline to optimize SNV, indel and SV calling at scale for long-reads analysis. These results will lead to widespread improvements across AoU.
Nature Communications  |  2022

Transposable element-mediated rearrangements are prevalent in human genomes

Parithi Balachandran, Isha A. Walawalkar, Jacob I. Flores, Jacob N. Dayton, Peter A. Audano, Christine R. Beck

Transposable elements constitute about half of human genomes, and their role in generating human variation through retrotransposition is broadly studied and appreciated. Structural variants mediated by transposons, which we call transposable element-mediated rearrangements (TEMRs), are less well studied, and the mechanisms leading to their formation as well as their broader impact on human diversity are poorly understood. Here, we identify 493 unique TEMRs across the genomes of three individuals. While homology directed repair is the dominant driver of TEMRs, our sequence-resolved TEMR resource allows us to identify complex inversion breakpoints, triplications or other high copy number polymorphisms, and additional complexities. TEMRs are enriched in genic loci and can create potentially important risk alleles such as a deletion in TRIM65, a known cancer biomarker and therapeutic target. These findings expand our understanding of this important class of structural variation, the mechanisms responsible for their formation, and establish them as an important driver of human diversity.
Nature Communications  |  2022

HiFi metagenomic sequencing enables assembly of accurate and complete genomes from human gut microbiota

Kim, Chan Yeong and Ma, Junyeong and Lee, Insuk

complete MAGs, circular contigs, Metagenomics, Microbiology, Microbiome, Microbial community, HiFi

Advances in metagenomic assembly have led to the discovery of genomes belonging to uncultured microorganisms. Metagenome-assembled genomes (MAGs) often suffer from fragmentation and chimerism. Recently, 20 complete MAGs (cMAGs) have been assembled from Oxford Nanopore long-read sequencing of 13 human fecal samples, but with low nucleotide accuracy. Here, we report 102 cMAGs obtained by Pacific Biosciences (PacBio) high-accuracy long-read (HiFi) metagenomic sequencing of five human fecal samples, whose initial circular contigs were selected for complete prokaryotic genomes using our bioinformatics workflow. Nucleotide accuracy of the final cMAGs was as high as that of Illumina sequencing. The cMAGs could exceed 6 Mbp and included complete genomes of diverse taxa, including entirely uncultured RF39 and TANB77 orders. Moreover, cMAGs revealed that regions hard to assemble by short-read sequencing comprised mostly genomic islands and rRNAs. HiFi metagenomic sequencing will facilitate cataloging accurate and complete genomes from complex microbial communities, including uncultured species.
Biorxiv  |  2022

Design and performance of a long-read sequencing panel for pharmacogenomics

Maaike van der Lee, Loes Busscher, Roberta Menafra, Qinglian Zhai, Redmar R. van den Berg, Sarah B Kingan, Nina Gonzaludo, Ting Hon, Ting Han, Leonardo Arbiza, Ibrahim Numanagić, Susan L. Kloet, Jesse J. Swen

Pharmacogenomics (PGx)-guided drug treatment is one of the cornerstones of personalized medicine. However, the genes involved in drug response are highly complex and known to carry many (rare) variants. Current technologies (short-read sequencing and SNP panels) are limited in their ability to resolve these genes and characterize all variants. Moreover, these technologies cannot always phase variants to their allele of origin. Recent advance in long-read sequencing technologies have shown promise in resolving these problems. Here we present a long-read sequencing panel-based approach for PGx using PacBio HiFi sequencing.
Nature Methods  |  2022

Metagenome assembly of high-fidelity long reads with hifiasm-meta

Feng, Xiaowen and Cheng, Haoyu and Portik, Daniel and Li, Heng

assembly, Metagenomics, Microbiology, Microbiome, Microbial community, Metagenome, MAGs

De novo assembly of metagenome samples is a common approach to the study of microbial communities. Current metagenome assemblers developed for short sequence reads or noisy long reads were not optimized for accurate long reads. We thus developed hifiasm-meta, a metagenome assembler that exploits the high accuracy of recent data. Evaluated on seven empirical datasets, hifiasm-meta reconstructed tens to hundreds of complete circular bacterial genomes per dataset, consistently outperforming other metagenome assemblers.
Microbial Genomics  |  2022

Finding the right fit: Evaluation of short-read and long-read sequencing approaches to maximize the utility of clinical microbiome data

Gehrig, Jeanette L and Portik, Daniel M and Driscoll, Mark D and Jackson, Eric and Chakraborty, Shreyasee and Gratalo, Dawn and Ashby, Meredith and Valladares, Ricardo

live biotherapeutic product, shotgun metagenomics, MAGs, Microbiome, Microbial community, 16S rRNA

A long-standing challenge in human microbiome research is achieving the taxonomic and functional resolution needed to generate testable hypotheses about the gut microbiota's impact on health and disease. With a growing number of live microbial interventions in clinical development, this challenge is renewed by a need to understand the pharmacokinetics and pharmacodynamics of therapeutic candidates. While short-read sequencing of the bacterial 16S rRNA gene has been the standard for microbiota profiling, recent improvements in the fidelity of long-read sequencing underscores the need for a re-evaluation of the value of distinct microbiome-sequencing approaches. We leveraged samples from participants enrolled in a phase 1b clinical trial of a novel live biotherapeutic product to perform a comparative analysis of short-read and long-read amplicon and metagenomic sequencing approaches to assess their utility for generating clinical microbiome data. Across all methods, overall community taxonomic profiles were comparable and relationships between samples were conserved. Comparison of ubiquitous short-read 16S rRNA amplicon profiling to long-read profiling of the 16S-ITS-23S rRNA amplicon showed that only the latter provided strain-level community resolution and insight into novel taxa. All methods identified an active ingredient strain in treated study participants, though detection confidence was higher for long-read methods. Read coverage from both metagenomic methods provided evidence of active-ingredient strain replication in some treated participants. Compared to short-read metagenomics, approximately twice the proportion of long reads were assigned functional annotations. Finally, compositionally similar bacterial metagenome-assembled genomes (MAGs) were recovered from short-read and long-read metagenomic methods, although a greater number and more complete MAGs were recovered from long reads. Despite higher costs, both amplicon and metagenomic long-read approaches yielded added microbiome data value in the form of higher confidence taxonomic and functional resolution and improved recovery of microbial genomes compared to traditional short-read methodologies.
AJHG  |  2022

Familial Long-Read Sequencing Increases Yield of De Novo Mutations

Noyes, Michelle D. and Harvey, William T. and Porubsky, David and Sulovari, Arvis and Li, Ruiyang and Rose, Nicholas R. and Audano, Peter A. and Munson, Katherine M. and Lewis, Alexandra P. and Hoekzema, Kendra and Mantere, Tuomo and Graves-Lindsay, Tina A. and Sanders, Ashley D. and Goodwin, Sara and Kramer, Melissa and Mokrab, Younes and Zody, Michael C. and Hoischen, Alexander and Korbel, Jan O. and McCombie, W. Richard and Eichler, Evan E.

Studies of de novo mutation (DNM) have typically excluded some of the most repetitive and complex regions of the genome because these regions cannot be unambiguously mapped with short-read sequencing data. To better understand the genome-wide pattern of DNM, we generated long-read sequence data from an autism parent-child quad with an affected female where no pathogenic variant had been discovered in short-read Illumina sequence data. We deeply sequenced all four individuals by using three sequencing platforms (Illumina, Oxford Nanopore, and Pacific Biosciences) and three complementary technologies (Strand-seq, optical mapping, and 10X Genomics). Using long-read sequencing, we initially discovered and validated 171 DNMs across two children—a 20% increase in the number of de novo single-nucleotide variants (SNVs) and indels when compared to short-read callsets. The number of DNMs further increased by 5% when considering a more complete human reference (T2T-CHM13) because of the recovery of events in regions absent from GRCh38 (e.g., three DNMs in heterochromatic satellites). In total, we validated 195 de novo germline mutations and 23 potential post-zygotic mosaic mutations across both children; the overall true substitution rate based on this integrated callset is at least 1.41 × 10−8 substitutions per nucleotide per generation. We also identified six de novo insertions and deletions in tandem repeats, two of which represent structural variants. We demonstrate that long-read sequencing and assembly, especially when combined with a more complete reference genome, increases the number of DNMs by >25% compared to previous studies, providing a more complete catalog of DNM compared to short-read data alone.
MDPI  |  2022

Complete Genome Sequence of Herpes Simplex Virus 2 Strain G

Chang, Weizhong and Jiao, Xiaoli and Sui, Hongyan and Goswami, Suranjana and Sherman, Brad T. And Fromont, Caroline and Caravaca, Juan Manuel and Tran, Bao and Imamichi, Tomozumi

Herpes simplex virus type 2 (HSV-2) is a common causative agent of genital tract infections. Moreover, HSV-2 and HIV infection can mutually increase the risk of acquiring another virus infection. Due to the high GC content and highly repetitive regions in HSV-2 genomes, only the genomes of four strains have been completely sequenced (HG52, 333, SD90e, and MS). Strain G is commonly used for HSV-2 research, but only a partial genome sequence has been assembled with Illumina sequencing reads. In the current study, we de novo assembled and annotated the complete genome of strain G using PacBio long sequencing reads, which can span the repetitive regions, analyzed the ‘α’ sequence, which plays key roles in HSV-2 genome circulation, replication, cleavage, and packaging of progeny viral DNA, identified the packaging signals homologous to HSV-1 within the ‘α’ sequence, and determined both termini of the linear genome and cleavage site for the process of concatemeric HSV-2 DNA produced via rolling-circle replication. In addition, using Oxford Nanopore Technology sequencing reads, we visualized four HSV-2 genome isomers at the nucleotide level for the first time. Furthermore, the coding sequences of HSV-2 strain G have been compared with those of HG52, 333, and MS. Moreover, phylogenetic analysis of strain G and other diverse HSV-2 strains has been conducted to determine their evolutionary relationship. The results will aid clinical research and treatment development of HSV-2.
Nature Biotechnology  |  2022

Curated variation benchmarks for challenging medically relevant autosomal genes

Wagner, Justin and Olson, Nathan D. and Harris, Lindsay and McDaniel, Jennifer and Cheng, Haoyu and Fungtammasan, Arkarachai and Hwang, Yih-Chii and Gupta, Richa and Wenger, Aaron M. and Rowell, William J. and Khan, Ziad M. and Farek, Jesse and Zhu, Yiming and Pisupati, Aishwarya and Mahmoud, Medhat and Xiao, Chunlin and Yoo, Byunggil and Sahraeian, Sayed Mohammad Ebrahim and Miller, Danny E. and Jáspez, David and Lorenzo-Salazar, José M. and Muñoz-Barrera, Adrián and Rubio-Rodríguez, Luis A. and Flores, Carlos and Narzisi, Giuseppe and Evani, Uday Shanker and Clarke, Wayne E. and Lee, Joyce and Mason, Christopher E. and Lincoln, Stephen E. and Miga, Karen H. and Ebbert, Mark T. W. and Shumate, Alaina and Li, Heng and Chin, Chen-Shan and Zook, Justin M. and Sedlazeck, Fritz J.

The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes, including CBS, CRYAA and KCNE1. When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome.
Nature Biotechnology  |  2022

Generating lineage-resolved, complete metagenome-assembled genomes from complex microbial communities

Bickhart, Derek M. and Kolmogorov, Mikhail and Tseng, Elizabeth and Portik, Daniel M. And Korobeynikov, Anton and Tolstoganov, Ivan and Uritskiy, Gherman and Liachko, Ivan and Sullivan, Shawn T. and Shin, Sung Bong and Zorea, Alvah and Andreu, Victoria Pascal and Panke-Buisse, Kevin and Medema, Marnix H. and Mizrahi, Itzhak and Pevzner, Pavel A. and Smith, Timothy P.

Metagenomics, Microbiology, Microbiome

Microbial communities might include distinct lineages of closely related organisms that complicate metagenomic assembly and prevent the generation of complete metagenome-assembled genomes (MAGs). Here we show that deep sequencing using long (HiFi) reads combined with Hi-C binning can address this challenge even for complex microbial communities. Using existing methods, we sequenced the sheep fecal metagenome and identified 428 MAGs with more than 90% completeness, including 44 MAGs in single circular contigs. To resolve closely related strains (lineages), we developed MAGPhase, which separates lineages of related organisms by discriminating variant haplotypes across hundreds of kilobases of genomic sequence. MAGPhase identified 220 lineage-resolved MAGs in our dataset. The ability to resolve closely related microbes in complex microbial communities improves the identification of biosynthetic gene clusters and the precision of assigning mobile genetic elements to host genomes. We identified 1,400 complete and 350 partial biosynthetic gene clusters, most of which are novel, as well as 424 (298) potential host–viral (host–plasmid) associations using Hi-C data.
medRxiv  |  2021

Germline mosaicism of a missense variant in KCNC2 in a multiplex family with autism and epilepsy

Mehinovic, Elvisa and Gray, Teddi and Campbell, Meghan and Ekholm, Jenny and Wenger, Aaron and Rowell, William and Grudo, Ari and Grimwood, Jane and Korlach, Jonas and Gurnett, Christina and Constantino, John N. and Turner, Tychele N.

Human,, Autism, epilepsy, germline, mosaicism, KCNC2, de novo missense variant, Variant detection

Currently, protein-coding de novo variants and large copy number variants have been identified as important for ∼30% of individuals with autism. One approach to identify relevant variation in individuals who lack these types of events is by utilizing newer genomic technologies. In this study, highly accurate PacBio HiFi long-read sequencing was applied to a family with autism, treatment-refractory epilepsy, cognitive impairment, and mild dysmorphic features (two affected female full siblings, parents, and one unaffected sibling) with no known clinical variant. From our long-read sequencing data, a de novo missense variant in the KCNC2 gene (encodes Kv3.2 protein) was identified in both affected children. This variant was phased to the paternal chromosome of origin and is likely a germline mosaic. In silico assessment of the variant revealed it was in the top 0.05% of all conserved bases in the genome, and was predicted damaging by Polyphen2, MutationTaster, and SIFT. It was not present in any controls from public genome databases nor in a joint-call set we generated across 49 individuals with publicly available PacBio HiFi data. This specific missense mutation (Val473Ala) has been shown in both an ortholog and paralog of Kv3.2 to accelerate current decay, shift the voltage dependence of activation, and prevent the channel from entering a long-lasting open state. Seven additional missense mutations have been identified in other individuals with neurodevelopmental disorders (p = 1.03 × 10−5). KCNC2 is most highly expressed in the brain; in particular, in the thalamus and is enriched in GABAergic neurons. Long-read sequencing was useful in discovering the relevant variant in this family with autism that had remained a mystery for several years and will potentially have great benefits in the clinic once it is widely available.
Wiley  |  2021

Long-read whole genome sequencing reveals HOXD13 alterations in synpolydactyly

Melas, Marilena and Kautto, Esko A. and Franklin, Samuel J. and Mori, Mari and McBride, Kim L. and Mosher, Theresa Mihalic and Pfau, Ruthann B. and Hernandez-Gonzalez, Maria Elena and McGrath, Sean D. and Magrini, Vincent J. and White, Peter and Samora, Julie Balch and Koboldt, Daniel C. and Wilson, Richard K.

Whole genome sequencing, Rare disease, HOXD13, long-read, synpolydactyly 1, SDTY2

Synpolydactyly 1 (SPD; MIM# 186000), also called syndactyly type II (SDTY2), is a genetic limb malformation characterized by polydactyly with syndactyly involving the webbing of the third and fourth fingers, and the fourth and fifth toes. It is caused by heterozygous alterations in HOXD13 with incomplete penetrance and phenotypic variability. In our study, a five-generation family with an SPD phenotype was enrolled in our Rare Disease Genomics Protocol. A comprehensive examination of three generations using Illumina short-read whole-genome sequencing (WGS) did not identify any causative variants. Subsequent WGS using Pacific Biosciences (PacBio) long-read HiFi Circular Consensus Sequencing (CCS) revealed a heterozygous 27-bp duplication in the polyalanine tract of HOXD13. Sanger sequencing of all available family members confirmed that the variant segregates with affected individuals. Re-analysis of an unrelated family with a similar SPD phenotype uncovered a 21-bp (7-alanine) duplication in the same region of HOXD13. Although ExpansionHunter identified these events in most individuals in a retrospective analysis, low sequence coverage due to high GC content in the HOXD13 polyalanine tract makes detection of these events challenging. Our findings highlight the value of long-read WGS in elucidating the molecular etiology of congenital limb malformation disorders.
Microbiology Spectrum  |  2021

Greenhead (Tabanus nigrovittatus) Wolbachia and Its Microbiome: A Preliminary Study

Lefoulon, Emilie and Truchon, Alex and Clark, Travis and Long, Courtney and Frey, Daniel and Slatko, Barton E.

Bacteria, Full-length 16S, greenhead, rRNA, Wolbachia, Metagenomics, Microbiology, Microbiome, 16S, Amplicon

Endosymbiotic Wolbachia bacteria are known to influence the host physiology, microbiota composition, and dissemination of pathogens. We surveyed a population of Tabanus nigrovittatus, commonly referred to as "greenheads," from Crane Beach (Ipswich, MA, USA) for the presence of the alphaproteobacterial symbiont Wolbachia. We studied the COI (mitochondrial cytochrome oxidase) marker gene to evaluate the phylogenetic diversity of the studied specimens. The DNA sequences show strong similarity (between 99.9 and 98%) among the collected specimens but lower similarity to closely related entries in the NCBI database (only between 96.3 and 94.7%), suggesting a more distant relatedness. Low levels of Wolbachia presence necessitated a nested PCR approach, and using 5 markers (ftsZ, fbpA, dnaA, coxA, and gatB), we determined that two recognized "supergroups" of Wolbachia species were represented in the studied specimens, members of clades A and B. Using next-generation sequencing, we also surveyed the insect gut microbiomes of a subset of flies, using Illumina and PacBio 16S rRNA gene sequencing with barcoded primers. The composition of Proteobacteria also varied from fly to fly, with components belonging to Gammaproteobacteria making up the largest percentage of organisms (30 to 70%) among the microbiome samples. Most of the samples showed the presence of Spiroplasma, a member of the phylum Mollicutes, although the frequency of its presence was variable, ranging from 2 to 57%. Another noteworthy bacterial phylum consistently identified was Firmicutes, though the read abundances were typically below 10%. Of interest is an association between Wolbachia presence and higher Alphaproteobacteria representation in the microbiomes, suggesting that the presence of Wolbachia affects the host microbiome. IMPORTANCE Tabanus nigrovittatus greenhead populations contain two supergroups of Wolbachia endosymbionts, members of supergroups A and B. Analysis of the greenhead microbiome using next-generation sequencing revealed that the majority of bacterial species detected belonged to Gammaproteobacteria, with most of the samples also showing the presence of Spiroplasma, a member of the Mollicutes phylum also known to infect insects. An association between Wolbachia presence and higher Alphaproteobacteria representation in the microbiomes suggests that Wolbachia presence affects the host microbiome composition.
PLOS Pathogens  |  2021

High-throughput, single-copy sequencing reveals SARS-CoV-2 spike variants coincident with mounting humoral immunity during acute COVID-19

Ko, Sung Hee and Mokhtari, Elham Bayat and Mudvari, Prakriti and Stein, Sydney and Stringham, Christopher D. and Wagner, Danielle and Ramelli, Sabrina and Ramos-Benitez, Marcos J. and Strich, Jeffrey R. and Davey Jr., Richard T. and Zhou, Tongquing and Misasi, John and Kwong, Peter D. and Chertow, Daniel S. and Sullivan, Nancy J. and Boritz, Eli A.

respiratory virus, SARS-CoV-2, Virus, coronavirus, COVID-19, HiFiViral, pathogen surveillance

Tracking evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within infected individuals will help elucidate coronavirus disease 2019 (COVID-19) pathogenesis and inform use of antiviral interventions. In this study, we developed an approach for sequencing the region encoding the SARS-CoV-2 virion surface proteins from large numbers of individual virus RNA genomes per sample. We applied this approach to the WA-1 reference clinical isolate of SARS-CoV-2 passaged in vitro and to upper respiratory samples from 7 study participants with COVID-19. SARS-CoV-2 genomes from cell culture were diverse, including 18 haplotypes with non-synonymous mutations clustered in the spike NH2-terminal domain (NTD) and furin cleavage site regions. By contrast, cross-sectional analysis of samples from participants with COVID-19 showed fewer virus variants, without structural clustering of mutations. However, longitudinal analysis in one individual revealed 4 virus haplotypes bearing 3 independent mutations in a spike NTD epitope targeted by autologous antibodies. These mutations arose coincident with a 6.2-fold rise in serum binding to spike and a transient increase in virus burden. We conclude that SARS-CoV-2 exhibits a capacity for rapid genetic adaptation that becomes detectable in vivo with the onset of humoral immunity, with the potential to contribute to delayed virologic clearance in the acute setting.
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