Biology subjects

Smith, M.

Publications and source records attributed to Smith, M..

At least 91 records · Page 5Linked to original sources

bioRxiv2022

Intracellular calcium elevations drive the nucleation of FIP200- and ATG13-containing pre-autophagosomal structures that become omegasomes

Ca2+ modulates autophagy at multiple steps including the induction and maturation of autophagosomes, but the magnitude and spatiotemporal properties of this calcium signal and its ultimate effect on the autophagic machinery are unclear. Focusing on the induction step leading to omegasome formation, we report that low but sustained elevations in cytosolic calcium levels induce omegasome formation but treatments that only transiently elevate calcium do not. The calcium-induced structures are early intermediates that mature into omegasomes but do not constitute full autophagosomes because they are partially devoid of late autophagy proteins ATG16 and LC3. In addition to omegasomes, all four components of the ULK complex (ULK1, FIP200, ATG13, ATG101) respond to calcium modulation: they translocate to early autophagy puncta in complete medium upon calcium elevation, and are inhibited from translocation during starvation by calcium chelation with BAPTA-2 AM. The principal early step affected by calcium lies downstream of mTORC1 inactivation and upstream of VPS34 activation, coinciding biochemically with phosphorylation of ATG13 at serine 318, which is known to require ULK1 activity. However, although the calcium-mediated step requires ATG9, FIP200 and ATG13, it does not require ULK1/2, suggesting that calcium does not directly regulate ULK1 activity but rather it regulates the mechanism by which the ULK complex components ATG13 and FIP200, together with ATG9, nucleate pre-autophagosomal precursors. This calcium-induced nucleation is sufficient to drive autophagy induction up to the omegasome step, but not beyond it.

cell biology↗

bioRxiv2022

Umbilical cord blood-derived cell therapy for perinatal brain injury: A systematic review & meta-analysis of preclinical studies - Part B.

IntroductionWe previously described preclinical literature, which supports umbilical cord blood-derived cell (UCBC) therapy use for perinatal brain injury. However, efficacy of UCBCs may be influenced by different patient populations and intervention characteristics. ObjectivesTo systematically review effects of UCBCs on brain outcomes in animal models of perinatal brain injury across subgroups to better understand contribution of model type (preterm versus term), brain injury type, UCB cell type, route of administration, timing of intervention, cell dosage and number of doses. MethodsA systematic search of MEDLINE and Embase databases was performed to identify studies using UCBC therapy in animal models of perinatal brain injury. Subgroup differences were measured by chi2 test where possible. ResultsDifferential benefits of UCBCs were seen in a number of subgroup analyses including intraventricular haemorrhage (IVH) vs. hypoxia ischaemia (HI) model (apoptosis white matter (WM): chi2=4.07; P=0.04, neuroinflammation-TNF-: chi2=5.99; P=0.01), UCB-derived mesenchymal stromal cells (MSCs) vs. UCB-derived mononuclear cells (MNCs) (oligodendrocyte WM: chi2=5.01; P=0.03, neuroinflammation-TNF-: chi2=3.93; P=0.05, apoptosis grey matter (GM), astrogliosis WM) and intraventricular/intrathecal vs. systemic routes of administration (microglial activation GM: chi2=7.51; P=0.02, astrogliosis WM: chi2=12.44; P=0.002). We identified a serious risk of bias and overall low certainty of evidence. ConclusionsPreclinical evidence suggests greater efficacy for UCBCs in IVH compared to HI injury model, use of UCB-MSCs compared to UCB-MNCs, and use of local administrative routes compared to systemic routes in animal models of perinatal brain injury. Further research is needed to improve certainty of evidence found and address knowledge gaps. SIGNIFICANCE STATEMENTIn neonatal medicine there is a clear need for the development of new therapies that can provide neuroregenerative benefits for infants with brain injuries. This review offers a unique and comprehensive resource to inform the development of future preclinical and clinical studies. In part A of this review, we systematically reviewed the preclinical literature surrounding UCBCs as a therapy for perinatal brain injury. In part B of this review, we investigated the effect variables, such as UCB cell type, timing of administration and dosage, have on the efficacy of UCB-derived cell therapy in animal models of perinatal brain injury. We identified UCBCs to show greater efficacy in the brain injury model of IVH compared to HI, the use of UCB-derived MSCs compared to MNCs and the use of local administrative routes compared to systemic routes. In addition to this, we identified knowledge gaps such as the limited preclinical literature surrounding the effect of dose number and sex.

neuroscience↗

bioRxiv2022

Umbilical cord blood-derived cell therapy for perinatal brain injury: A systematic review & meta-analysis of preclinical studies - Part A

IntroductionPerinatal brain injury is a major contributor to long-term adverse neurodevelopment. There is mounting preclinical evidence for use of umbilical cord blood (UCB)-derived cell therapy as potential treatment. ObjectivesTo systematically review and analyse effects of UCB-derived cell therapy on brain outcomes in preclinical models of perinatal brain injury. MethodsMEDLINE and Embase databases were searched for relevant studies. Brain injury outcomes were extracted for meta-analysis to calculate standard mean difference (SMD) with 95% confidence interval (CI), using an inverse variance, random effects model. Outcomes were separated based on grey matter (GM) and white matter (WM) regions where applicable. Risk of bias was assessed using SYRCLE, and GRADE was used to summarise certainty of evidence. ResultsFifty-five eligible studies were included (7 large, 48 small animal models). UCB-derived cell therapy significantly improved outcomes across multiple domains, including decreased infarct size (SMD 0.53; 95%CI (0.32, 0.74), P<0.00001), apoptosis (WM, SMD 1.59; 95%CI (0.86, 2.32), P<0.0001), astrogliosis (GM, SMD 0.56; 95%CI (0.12, 1.01), P=0.01), microglial activation (WM, SMD 1.03; 95%CI (0.40, 1.66), P=0.001), neuroinflammation (TNF-, SMD 0.84; 95%CI (0.44, 1.25), P<0.0001); as well as improved neuron number (SMD 0.86; 95%CI (0.39, 1.33), P=0.0003), oligodendrocyte number (GM, SMD 3.35; 95%CI (1.00, 5.69), P=0.005) and motor function (cylinder test, SMD 0.49; 95%CI (0.23, 0.76), P=0.0003). Risk of bias was determined as serious, and overall certainty of evidence was low. ConclusionsUCB-derived cell therapy is an efficacious treatment in pre-clinical models of perinatal brain injury, however findings are limited by low certainty of evidence. SIGNIFICANCE STATEMENTPerinatal brain injury can lead to significant long-term neurodevelopmental deficits. There are limited treatment options available, and new interventions are urgently required. Through assessment of preclinical studies, this systematic review and meta-analysis shows that umbilical cord blood-derived cell therapy is an efficacious treatment for perinatal brain injury across a wide range of neuropathological and functional domains, albeit with low certainty of evidence. It also identified knowledge gaps, including that future studies should focus on non-hypoxic ischemic models, preterm models, large animal models and should explore the heterogeneity that exists in treatment protocols.

neuroscience↗

bioRxiv2022

Learning representations for image-based profiling of perturbations

Measuring the phenotypic effect of treatments on cells through imaging assays is an efficient and powerful way of studying cell biology, and requires computational methods for transforming images into quantitative data that highlight phenotypic outcomes. Here, we present an optimized strategy for learning representations of treatment effects from high-throughput imaging data, which follows a causal framework for interpreting results and guiding performance improvements. We use weakly supervised learning (WSL) for modeling associations between images and treatments, and show that it encodes both confounding factors and phenotypic features in the learned representation. To facilitate their separation, we constructed a large training dataset with Cell Painting images from five different studies to maximize experimental diversity, following insights from our causal analysis. Training a WSL model with this dataset successfully improves downstream performance, and produces a reusable convolutional network for image-based profiling, which we call Cell Painting CNN-1. We conducted a comprehensive evaluation of our strategy on three publicly available Cell Painting datasets, discovering that representations obtained by the Cell Painting CNN-1 can improve performance in downstream analysis for biological matching up to 30% with respect to classical features, while also being more computationally efficient.

bioinformatics↗

bioRxiv2022

Characterization of the immunoglobulin lambda chain locus from diverse populations reveals extensive genetic variation

Immunoglobulins (IGs), crucial components of the adaptive immune system, are encoded by three genomic loci. However, the complexity of the IG loci severely limits the effective use of short read sequencing, limiting our knowledge of population diversity in these loci. We leveraged existing long read whole-genome sequencing (WGS) data, fosmid technology, and IG targeted single-molecule, real-time (SMRT) long-read sequencing (IG-Cap) to create haplotype-resolved assemblies of the IG Lambda (IGL) locus from 6 ethnically diverse individuals. In addition, we generated 10 diploid assemblies of IGL from a diverse cohort of individuals utilizing IG-cap. From these 16 individuals, we identified significant allelic diversity, including 37 novel IGLV alleles. In addition, we observed highly elevated single nucleotide variation (SNV) in IGLV genes relative to IGL intergenic and genomic background SNV density. By comparing SNV calls between our high quality assemblies and existing short read datasets from the same individuals, we show a high propensity for false-positives in the short read datasets. Finally, for the first time, we nucleotide-resolved common 5-10 Kb duplications in the IGLC region that contain functional IGLJ and IGLC genes. Together these data represent a significant advancement in our understanding of genetic variation and population diversity in the IGL locus.

genetics↗

bioRxiv2022

Antibody repertoire gene usage is explained by common genetic variants in the immunoglobulin heavy chain locus

Variation in the antibody response has been linked to differential outcomes in disease, and suboptimal vaccine and therapeutic responsiveness, the determinants of which have not been fully elucidated. Countering models that presume antibodies are generated largely by stochastic processes, we demonstrate that polymorphisms within the immunoglobulin heavy chain locus (IGH) significantly impact the naive and antigen-experienced antibody repertoire, indicating that genetics predisposes individuals to mount qualitatively and quantitatively different antibody responses. We pair recently developed long-read genomic sequencing methods with antibody repertoire profiling to comprehensively resolve IGH genetic variation, including novel structural variants, single nucleotide variants, and genes and alleles. We show that IGH germline variants determine the presence and frequency of antibody genes in the expressed repertoire, including those enriched in functional elements linked to V(D)J recombination, and overlapping disease-associated variants. These results illuminate the power of leveraging IGH genetics to better understand the regulation, function and dynamics of the antibody response in disease.

genomics↗

bioRxiv2022

Non-catastrophic collapse of VEEV by lethal mutagenesis

RNA viruses replicate at a high mutation rate, providing a highly adaptive capacity to the population as well as vulnerability to an extinction due to additional mutations, which is the conceptual basis for lethal mutagenesis. However, the mechanistic understanding of lethal mutagenesis has remained unclear due to the lack of RNA mutagens with potent antiviral activity and the inherent inability to distinguish between infectious and non-infectious sub-populations within a viral population. In our study, we investigated how the replication competency and mutation frequency of Venezuelan Equine Encephalitis Virus (VEEV) change following treatment with the RNA mutagen {beta}-d-N4-hydroxycytidine, a potent antiviral RNA mutagen. By pairing limiting dilution with a long-read sequencing approach, we specifically determined genomic sequences of replication-competent viral clones from the total population. We found that replication-competent VEEV population maintained itself within a narrow mutation spectrum with a significantly lower mutation frequency than the total population. We also found that treatment with an RNA mutagen did not induce catastrophic destruction of the infectious population even at a high exposure, allowing replication-competent subpopulations with increased variability in mutational fitness and enhanced adaptability to new selection pressures, such as antiviral treatment, to continue to propagate. Together our study provides new understanding of viral population landscape and suggests a careful consideration of lethal mutagenesis as an antiviral strategy for high-capacity replicating viruses such as alphaviruses.

microbiology↗

bioRxiv2022

Genomics of cold adaptations in the Antarctic notothenioid fish radiation.

Numerous novel adaptations characterise the radiation of notothenioids, the dominant fish group in the freezing seas of the Southern Ocean. To improve understanding of the evolution of this iconic fish group, we generated and analysed new genome assemblies for 24 species covering all major subgroups of the radiation. We present a new estimate for the onset of the radiation at 10.7 million years ago, based on a time-calibrated phylogeny derived from genome-wide sequence data. We identify a two-fold variation in genome size, driven by expansion of multiple transposable element families, and use long-read sequencing data to reconstruct two evolutionarily important, highly repetitive gene family loci. First, we present the most complete reconstruction to date of the antifreeze glycoprotein gene family, whose emergence enabled survival in sub-zero temperatures, showing the expansion of the antifreeze gene locus from the ancestral to the derived state. Second, we trace the loss of haemoglobin genes in icefishes, the only vertebrates lacking functional haemoglobins, through complete reconstruction of the two haemoglobin gene clusters across notothenioid families. Finally, we show that both the haemoglobin and antifreeze genomic loci are characterised by multiple transposon expansions that may have driven the evolutionary history of these genes.

genomics↗

bioRxiv2022

Activation of targetable inflammatory immune signaling is seen in Myelodysplastic Syndromes with SF3B1 mutations

BackgroundMutations in the SF3B1 splicing factor are commonly seen in Myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML), yet the specific oncogenic pathways activated by missplicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood. MethodsRNA-seq data from SF3B1 mutant samples was analyzed and functional roles of IRAK4 isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in pre-clinical models of MDS/AML ResultsRNA-seq splicing analysis of innate immune mediators in SF3B1 mutant MDS samples revealed retention of full-length exon 6 of interleukin-1 receptor-associated kinase 4 (IRAK4), a critical downstream mediator that links the Myddosome to inflammatory NF-kB activation. Exon 6 retention leads to a longer isoform, encoding a protein (IRAK4-Long) that contains the entire death domain and kinase domain, leading to maximal activation of NF-kB. Cells with wild-type SF3B1 contain smaller IRAK4 isoforms that are targeted for proteosomal degradation. Expression of IRAK4-Long in SF3B1 mutant cells induces TRAF6 activation leading to K63-linked ubiquitination of CDK2, associated with a block in hematopoietic differentiation. Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models. ConclusionsSF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models.

cancer biology↗

bioRxiv2022

Caecilian genomes reveal molecular basis of adaptation and convergent evolution of limblessness in snakes and caecilians.

We present genome sequences for the caecilians Geotrypetes seraphini (3.8Gb) and Microcaecilia unicolor (4.7Gb), representatives of a limbless, mostly soil-dwelling amphibian clade with reduced eyes, and unique putatively chemosensory tentacles. More than 69% of both genomes are composed of repeats, with retrotransposons the most abundant. We identify 1,150 orthogroups which are unique to caecilians and enriched for functions in olfaction and detection of chemical signals. There are 379 orthogroups with signatures of positive selection on caecilian lineages with roles in organ development and morphogenesis, sensory perception and immunity amongst others. We discover that caecilian genomes are missing the ZRS enhancer of Sonic Hedgehog which is also mutated in snakes. In vivo deletions have shown ZRS is required for limb development in mice, thus revealing a shared molecular target implicated in the independent evolution of limblessness in snakes and caecilians.

evolutionary biology↗

bioRxiv2022

Directed differentiation of EA/TEF patient-derived induced pluripotent stem cells into esophageal epithelial organoids reveal SOX2 dysregulation at the anterior foregut stage

A series of well-regulated cellular and molecular events result in the compartmentalization of the anterior foregut into the esophagus and trachea. Disruption of the compartmentalization process leads to esophageal atresia/tracheoesophageal fistula (EA/TEF). Therefore, the objective is to differentiate pluripotent stem cells (PSCs), namely, embryonic stem cells and iPSCs from healthy individuals and iPSCs from EA/TEF type C patients, into mature 3-dimensional esophageal organoids expressing Involucrin, Keratin-4, -13, and p63. CXCR4, SOX17, and GATA4 expression was similar in both patient and healthy endodermal cells. Key transcription factor SOX2 was significantly lower in patient-derived anterior foregut. RNA sequencing revealed critical genes GSTM1 and RAB37 to be significantly lower in patient-derived anterior foregut. Furthermore, we observed an abnormal expression of NKX2.1 in the patient-derived mature esophageal organoids. We therefore hypothesize that a transient dysregulation of SOX2 and the abnormal expression of NKX2.1 in patient-derived cells could be responsible for the abnormal foregut compartmentalization.

developmental biology↗

bioRxiv2022

Spindle reorientation in response to mechanical stress is an emergent property of the spindle positioning mechanisms

Proper orientation of the mitotic spindle plays a crucial role in embryos, during tissue development, and in adults, where it functions to dissipate mechanical stress to maintain tissue integrity and homeostasis. While mitotic spindles have been shown to reorient in response to external mechanical stresses, the subcellular cues that mediate spindle reorientation remain unclear. Here, we have used a combination of optogenetics and computational modelling to better understand how mitotic spindles respond to inhomogeneous tension within the actomyosin cortex. Strikingly, we find that the optogenetic activation of RhoA only influences spindle orientation when it is induced at both poles of the cell. Under these conditions, the sudden local increase in cortical tension induced by RhoA activation reduces pulling forces exerted by cortical regulators on astral microtubules. This leads to a perturbation of the torque balance exerted on the spindle, which causes it to rotate. Thus, spindle rotation in response to mechanical stress is an emergent phenomenon arising from the interaction between the spindle positioning machinery and the cell cortex.

cell biology↗

bioRxiv2022

Genetic load in incomplete lupus erythematosus

Incomplete lupus erythematosus (ILE) patients have lupus features but insufficient criteria for systemic lupus erythematosus (SLE) classification. Some ILE patients transition to SLE, but most avoid major organ involvement. This study tested whether the milder disease course in ILE is influenced by reduced SLE-risk allele genetic load. We calculated the genetic load based on 99 SLE-associated risk alleles in European American SLE patients (>4 ACR-1997 criteria, n=171), ILE patients (3 ACR-1997 criteria; n=174), a subset of ILE patients not meeting SLICC classification (ILESLICC, n=119), and healthy controls (n=133). ILE and SLE patients had significantly greater SLE-risk allele genetic load compared to healthy controls, while ILESLICC patients had a trend toward an increased genetic load, although not statistically significant. However, the genetic load did not differ between ILE and SLE. In conclusion, ILE and SLE patients have comparable genetic loads of SLE risk loci, suggesting similar genetic predisposition between these conditions. Phenotypic differences between SLE and ILE may instead be influenced by ILE-specific variants and gene-environment interactions.

immunology↗

bioRxiv2021

Amplification and attenuation of noisy expression by export processes

Inside mammalian cells, single genes are known to be transcribed in stochastic bursts leading to the synthesis of nuclear RNAs that are subsequently exported to the cytoplasm to create mRNAs. We systematically characterize the role of export processes in shaping the extent of random fluctuations (i.e. noise) in the mRNA level of a given gene. Using the method of Partitioning of Poisson arrivals, we derive an exact analytical expression for the noise in mRNA level assuming that the nuclear retention time of each RNA is an independent and identically distributed random variable following an arbitrary distribution. These results confirm recent experimental/theoretical findings that decreasing the nuclear export rate buffers the noise in mRNA level, and counterintuitively, decreasing the noise in the nuclear retention time enhances the noise in the mRNA level. Next, we further generalize the model to consider a dynamic extrinsic disturbance that affects the nuclear-to-cytoplasm export. Our results show that noise in the mRNA level varies non-monotonically with the disturbance timescale. More specifically, high- and low-frequency external disturbances have little impact on the mRNA noise level, while noise is amplified at intermediate frequencies. In summary, our results systematically uncover how the coupling of bursty transcription with nuclear export can both attenuate or amplify noise in mRNA levels depending on the nuclear retention time distribution and the presence of extrinsic fluctuations.

systems biology↗

bioRxiv2021

Data-driven approaches for genetic characterization of SARS-CoV-2 lineages

The genome of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), has been sequenced at an unprecedented scale, leading to a tremendous amount of viral genome sequencing data. To understand the evolution of this virus in humans, and to assist in tracing infection pathways and designing preventive strategies, we present a set of computational tools that span phylogenomics, population genetics and machine learning approaches. To illustrate the utility of this toolbox, we detail an in depth analysis of the genetic diversity of SARS-CoV-2 in first year of the COVID-19 pandemic, using 329,854 high-quality consensus sequences published in the GISAID database during the pre-vaccination phase. We demonstrate that, compared to standard phylogenetic approaches, haplotype networks can be computed efficiently on much larger datasets, enabling real-time analyses. Furthermore, time series change of Tajimas D provides a powerful metric of population expansion. Unsupervised learning techniques further highlight key steps in variant detection and facilitate the study of the role of this genomic variation in the context of SARS-CoV-2 infection, with Multiscale PHATE methodology identifying fine-scale structure in the SARS-CoV-2 genetic data that underlies the emergence of key lineages. The computational framework presented here is useful for real-time genomic surveillance of SARS-CoV-2 and could be applied to any pathogen that threatens the health of worldwide populations of humans and other organisms.

bioinformatics↗

bioRxiv2021

Benchmarking ultra-high molecular weight DNA preservation methods for long-read and long-range sequencing

Studies in vertebrate genomics require sampling from a broad range of tissue types, taxa, and localities. Recent advancements in long-read and long-range genome sequencing have made it possible to produce high-quality chromosome-level genome assemblies for almost any organism. However, adequate tissue preservation for the requisite ultra-high molecular weight DNA (uHMW DNA) remains a major challenge. Here we present a comparative study of preservation methods for field and laboratory tissue sampling, across vertebrate classes and different tissue types. We find that no single method is best for all cases. Instead, the optimal storage and extraction methods vary by taxa, by tissue, and by down-stream application. Therefore, we provide sample preservation guidelines that ensure sufficient DNA integrity and amount required for use with long-read and long-range sequencing technologies across vertebrates. Our best practices generated the uHMW DNA needed for the high-quality reference genomes for Phase 1 of the Vertebrate Genomes Project (VGP), whose ultimate mission is to generate chromosome-level reference genome assemblies of all [~]70,000 extant vertebrate species.

genomics↗

bioRxiv2021

Effects of High-Volume versus High-Load Resistance Training on Skeletal Muscle Growth and Molecular Adaptations

AimWe evaluated the effects of higher-load (HL) versus (lower-load) higher-volume (HV) resistance training on skeletal muscle hypertrophy, strength, and muscle-level molecular markers. MethodsTrained men (n=15, age: 23{+/-}3 y; training experience: 7{+/-}3 y) performed unilateral lower body training for 6 weeks (3x weekly), where single legs were assigned to HV and HL paradigms. Vastus lateralis (VL) biopsies were obtained prior to study initiation (PRE) as well as 3 days (POST) and 10 days following the last bout (POSTPR). Body composition and strength tests were performed at each testing session, and biochemical assays were performed on muscle tissue after study completion. Two-way within subjects repeated measures ANOVAs were performed on all dependent variables except tracer data, which was compared using dependent samples t-tests. ResultsA significant (p<0.05) interaction existed for unilateral leg extension 1RM (HV<HL at POST and POSTPR). Six-week integrated sarcoplasmic protein synthesis (iSarcoPS) rates were higher in the HV versus HL leg, while no difference between legs existed for integrated myofibrillar protein synthesis rates. Main time effects existed for unilateral leg press strength (PRE<POST and POSTPR), knee extensor peak torque (PRE and POST<POSTPR), dual-energy x-ray absorptiometry (DXA)-derived upper leg lean mass (PRE<POST and POSTPR), ultrasound-derived VL thickness (PRE and POSTPR<POST), sarcoplasmic protein concentrations (POST and POSTPR<PRE), and tropomyosin and troponin protein abundances (POST and POSTPR<PRE). ConclusionsWith the exception of differences in leg extensor strength and iSarcoPS between legs, our data suggest that short-term (6 weeks) HV and HL training elicit similar hypertrophic, strength, and molecular-level adaptations.

physiology↗

bioRxiv2021

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

The rapid, global dispersion of SARS-CoV-2 since its initial identification in December 2019 has led to the emergence of a diverse range of variants. The initial concerns regarding the virus were quickly compounded with concerns relating to the impact of its mutated forms on viral infectivity, pathogenicity and immunogenicity. To address the latter, we seek to understand how the mutational landscape of SARS-CoV-2 has shaped HLA-restricted T cell immunity at the population level during the first year of the pandemic, before mass vaccination. We analyzed a total of 330,246 high quality SARS-CoV-2 genome assemblies sampled across 143 countries and all major continents. Strikingly, we found that specific mutational patterns in SARS-CoV-2 diversify T cell epitopes in an HLA supertype-dependent manner. In fact, we observed that proline residues are preferentially removed from the proteome of prevalent mutants, leading to a predicted global loss of SARS-CoV-2 T cell epitopes in individuals expressing HLA-B alleles of the B7 supertype family. In addition, we show that this predicted global loss of epitopes is largely driven by a dominant C-to-U mutation type at the RNA level. These results indicate that B7 supertype-associated epitopes, including the most immunodominant ones, were more likely to escape CD8+ T cell immunosurveillance during the first year of the pandemic. Together, our study lays the foundation to help understand how SARS-CoV-2 mutants shape the repertoire of T cell targets and T cell immunity across human populations. The proposed theoretical framework has implications in viral evolution, disease severity, vaccine resistance and herd immunity.

immunology↗