Biology subjects

Lu, Z.

Publications and source records attributed to Lu, Z..

At least 181 records · Page 10Linked to original sources

bioRxiv2022

A Novel Sequence Labeling Framework for Extracting Drug-Protein Relations from Biomedical Literature

Automatic extracting interactions between chemical compound/drug and gene/protein is significantly beneficial to drug discovery, drug repurposing, drug design, and biomedical knowledge graph construction. To promote the development of the relation extraction between drug and protein, the BioCreative VII challenge organized the DrugProt track. This paper describes the approach we developed for this task. In addition to the conventional text classification framework that has been widely used in relation extraction tasks, we propose a sequence labeling framework to drug-protein relation extraction. We first comprehensively compared the cutting-edge biomedical pre-trained language models for both frameworks. Then, we explored several ensemble methods to further improve the final performance. In the evaluation of the challenge, our best submission (i.e., the ensemble of models in two frameworks via major voting) achieved the F1-score of 0.795 on the official test set. Further, we realized the sequence labeling framework is more efficient and achieves better performance than the text classification framework. Finally, our ensemble of the sequence labeling models with majority voting achieves the best F1-score of 0.800 on the test set. Database URLhttps://github.com/lingluodlut/BioCreativeVII_DrugProt

bioinformatics↗

bioRxiv2022

3D Organic Bioelectronics for Monitoring In Vitro Stem Cell Cultures

Three-dimensional in vitro stem cell models has enabled a fundamental understanding of cues that direct stem cell fate and be used to develop novel stem cell treatments. While sophisticated 3D tissues can be generated, technology that can accurately monitor these complex models in a high-throughput and non-invasive manner is not well adapted. Here we show the development of 3D bioelectronic devices based on the electroactive polymer poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) - PEDOT:PSS and their use for non-invasive, electrical monitoring of stem cell growth. We show that the electrical, mechanical and wetting properties as well as the pore size/architecture of 3D PEDOT:PSS scaffolds can be fine-tuned simply by changing the processing crosslinker additive. We present a comprehensive characterization of both 2D PEDOT:PSS thin films of controlled thicknesses, and 3D porous PEDOT:PSS structures made by the freeze-drying technique. By slicing the bulky scaffolds we show that homogeneous, porous 250 um thick PEDOT:PSS slices are produced, generating biocompatible 3D constructs able to support stem cell cultures. These multifunctional membranes are attached on Indium-Tin oxide substrates (ITO) with the help of an adhesion layer that is used to minimize the interface charge resistance. The optimum electrical contact result in 3D devices with a characteristic and reproducible, frequency dependent impedance response. This response changes drastically when human adipose derived stem cells grow within the porous PEDOT:PSS network as revealed by fluorescence microscopy. The increase of these stem cell population within the PEDOT:PSS porous network impedes the charge flow at the interface between PEDOT:PSS and ITO, enabling the interface resistance to be extracted by equivalent circuit modelling, used here as a figure of merit to monitor the proliferation of stem cells. The strategy of controlling important properties of 3D PEDOT:PSS structures simply by altering processing parameters can be applied for development of a number of stem cell in vitro models. We believe the results presented here will advance 3D bioelectronic technology for both fundamental understanding of in vitro stem cell cultures as well as the development of personalized therapies.

bioengineering↗

bioRxiv2022

Full-length transcriptome maps of reef-building coral illuminate the molecular basis of calcification, symbiosis, and circadian genes

BackgroundReef-building corals are critical species for sustaining coral reefs and are highly threatened by global climate change. However, relevant transcriptomic data largely rely on short-read sequencing, which severely limits the understanding of coral molecular mechanisms and leaves many important biological questions unresolved. ResultsWe sequenced the full-length transcriptomes of four common and frequently dominant reef-building corals, including two Robusta clade species, Pocillopora damicornis and Pocillopora verrucosa, and two Complexa clade species, Acropora muricata and Montipora foliosa, using the PacBio Sequel II platform. We obtained information on gene functions, structures and expression profiles. Among them, a comparative analysis of biomineralization-related genes provided insights into the molecular basis of coral skeletal density. The gene expression profiles of the symbiote Symbiodiniaceae were also isolated and annotated from the holobiont sequence data; these profiles showed more highly convergent traits related to gene structure and expression level than those of coral hosts. Interestingly, we observed that intracellular algal cells share some evolutionary convergence between intracellular symbiosis in corals and intracellular digestion in amphioxus. Finally, a phylogenetic analysis of key circadian clock genes among 27 evolutionarily representative species indicated that there are four key members in early metazoans, including cry genes; Clock or Npas2; cyc or Arntl; and tim, while per, as the fifth member, occurs in Bilateria. ConclusionsOur work overcomes the incompleteness of short-read sequencing and illuminates the molecular basis of calcification, symbiosis, and circadian genes, thus providing a foundation for further work on the manipulation of skeleton production or symbiosis to promote the survival of these important organisms.

evolutionary biology↗

bioRxiv2022

Peptidoglycan recognition protein S2 is crucial for activation the Toll pathway against Israeli acute paralysis virus infection in honey bee Apis mellifera

Although honey bee responses to pathogens have been systematically described in the past decades, antiviral signalling pathways mechanisms are not thoroughly characterized. To decipher direct antiviral roles of an immune pathway, we firstly used the infectious clone of Israeli acute paralysis virus (IAPV) to screen 42 immune genes involved in mTOR, MAPK, Toll, Endocytosis, Jak-STAT pathway and homeobox protein, heat shock protein, as well as antimicrobial peptides (AMPs), and found that Toll pathway was a potential predominant immune pathway in Apis mellifera. Consistent with this, only dsRNA-PGRP-S2 treated A. mellifera significantly exhibited impaired activation of Toll pathway, promoting susceptibility to the IAPV infection. Finally, immunofluorescence results confirmed that the Toll pathway was initiated by peptidoglycan recognition protein S2 (PGRP-S2) interacting with Toll protein. Co-immunoprecipitation findings also further preliminarily confirmed PGRP-S2 directly interacting with viral capsid protein IAPV-VP3 to induce the activation of the Toll pathway in A. mellifera. These findings highlight that the Toll pathway is demanded efficient inhibitions of IAPV replication as a specific antiviral pathway in A. mellifera, and PGRP-S2, acting as a pattern recognition receptor, could be a new approach for control of the viral disease. Author summaryHoney bee viruses, particularly IAPV, had been implicated in the colony decline with a global distribution resulting in insufficient pollination services. However, little is known about the antiviral mechanism of honey bee. In this study, we found that the Toll pathway was required for A. mellifera against IAPV infection and initiated by PGRP-S2. We also confirmed that dsRNA-PGRP-S2 treated A. mellifera exhibited impaired Toll pathway activation and promoted susceptibility to the IAPV infection. As a result, we employed co-immunoprecipitation technique to identify the interaction between the PGRP-S2 with Toll. Moreover, it was found the PGRP-S2 directly recognized IAPV-VP3 to activate the immune pathway against IAPV infection. Our work provides novel evidence that honey bees own a specific antiviral immune pathway and suggests that targeting PGRP-S2 could be a new approach for controlling the viral disease.

immunology↗

bioRxiv2022

A high-performance genetically encoded fluorescent indicator for in vivo cAMP imaging

cAMP is a key second messenger that regulates diverse cellular functions including neural plasticity. However, the spatiotemporal dynamics of intracellular cAMP in intact organisms are largely unknown due to low sensitivity and/or brightness of current genetically encoded fluorescent cAMP indicators. Here, we report the development of the new circularly permuted GFP (cpGFP)-based cAMP indicator G-Flamp1, which exhibits a large fluorescence increase (a maximum {Delta}F/F0 of 1100% in HEK293T cells), relatively high brightness, appropriate affinity (a Kd of 2.17 {micro}M) and fast response kinetics (an association and dissociation half-time of 0.20 s and 0.087 s, respectively). Furthermore, the crystal structure of the cAMP-bound G-Flamp1 reveals one linker connecting the cAMP-binding domain to cpGFP adopts a distorted {beta}-strand conformation that may serve as a fluorescence modulation switch. We demonstrate that G-Flamp1 enables sensitive monitoring of endogenous cAMP signals in brain regions that are implicated in learning and motor control in living organisms such as fruit flies and mice.

molecular biology↗

bioRxiv2022

Multi-ancestry fine-mapping improves precision to identify causal genes in transcriptome-wide association studies

Transcriptome-wide association studies (TWAS) are a powerful approach to identify genes whose expression associates with complex disease risk. However, non-causal genes can exhibit association signals due to confounding by linkage disequilibrium patterns (LD) and eQTL pleiotropy at genomic risk regions which necessitates fine-mapping of TWAS signals. Here, we present MA-FOCUS, a multi-ancestry framework for the improved identification of genes underlying traits of interest. We demonstrate that by leveraging differences in ancestry-specific patterns of LD and eQTL signals, MA-FOCUS consistently outperforms single-ancestry fine-mapping approaches with equivalent total sample size across multiple metrics. We perform 15 blood trait TWAS using genome-wide summary statistics (average NEA=511k, NAA=13k) and lymphoblastoid cell line eQTL data from cohorts of primarily European and African continental ancestries. We recapitulate evidence demonstrating shared genetic architectures for eQTL and blood traits between the two ancestry groups and observe that gene-level effects correlate 20% more strongly across ancestries compared with SNP-level effects. We perform fine-mapping using MA-FOCUS and find evidence that genes at TWAS risk regions are more likely to be shared across ancestries rather than ancestry-specific. Using multiple lines of evidence to validate our findings, we find gene sets produced by MA-FOCUS are more enriched in hematopoietic categories compared to alternative approaches (P = 1.73 x 10-16). Our work demonstrates that including, and appropriately accounting for, genetic diversity can drive deeper insights into the genetic architecture of complex traits.

genetics↗

bioRxiv2022

Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model

Mutations in the SYNGAP1 gene are one of the common predictors of neurodevelopmental disorders, commonly resulting in individuals developing autism, intellectual disability, epilepsy, and sleep deficits. EEG recordings in neurodevelopmental disorders show potential to identify clinically translatable biomarkers to both diagnose and track the progress of novel therapeutic strategies, as well as providing insight into underlying pathological mechanisms. In a rat model of SYNGAP1 haploinsufficiency in which the exons encoding the calcium/lipid binding and GTPase activating protein (GAP) domains have been deleted (Syngap+/{Delta}-GAP) we analysed the duration and occurrence of wake, non rapid eye movement (NREM) and rapid eye movement (REM) brain states during 6 hour multi-electrode EEG recordings. We find that although Syngap+/{Delta}-GAP animals spend an equivalent percent time in wake and sleep states, they have an abnormal brain state distribution as the number of wake and NREM bouts are reduced and there is an increase in the average duration of both wake and NREM epochs. We perform connectivity analysis by calculating the average imaginary coherence between electrode pairs at varying distance thresholds during these states. In group averages from pairs of electrodes at short distances from each other, a clear reduction in connectivity during NREM is present between 11.5 Hz and 29.5 Hz, a frequency range that overlaps with sleep spindles, oscillatory phenomena thought to be important for normal brain function and memory consolidation. Sleep spindles occurrence, amplitude, power and spread across multiple electrodes were not reduced in Syngap+/{Delta}-GAP rats, with only a small decrease in duration detected. Nonetheless, by analysing the dynamic imaginary coherence during sleep spindles, we found a reduction in high connectivity instances between short-distance electrode pairs. Finally, by comparing the dynamic imaginary coherence during sleep spindles between individual electrode pairs, we identified a group of channels over the right somatosensory, association and visual cortices that have a significant reduction in connectivity during sleep spindles in mutant animals. These data suggest that Syngap+/{Delta}-GAP rats have altered brain state dynamics and EEG connectivity, which may have clinical relevance for SYNGAP haploinsufficiency in humans.

neuroscience↗

bioRxiv2022

Sex-specific transcription and DNA methylation landscapes of the Asian citrus psyllid, a vector of huanglongbing pathogens.

The relationship of DNA methylation and sex-biased gene expression is of high interest, it allows research into mechanisms of sexual dimorphism and the development of potential novel strategies for insect pest control. The Asian citrus psyllid, Diaphorina citri Kuwayama, is a major vector for the causative agents of Huanglongbing (HLB), which presents an unparalleled challenge to citrus production worldwide. Here, we identify the X chromosome of D. citri and investigate differences in the transcription and DNA methylation landscapes between adult virgin males and females. We find a large number of male-biased genes on the autosomes and a depletion of such on the X chromosome. We have also characterised the methylome of D. citri, finding low genome-wide levels, which is unusual for an hemipteran species, as well as evidence for both promoter and TE methylation. Overall, DNA methylation profiles are similar between the sexes but with a small number of differentially methylated genes found to be involved in sex differentiation. There also appears to be no direct relationship between differential DNA methylation and differential gene expression. Our findings lay the groundwork for the development of novel epigenetic-based pest control methods, and given the similarity of the D. citri methylome to other insect species, these methods could be applicable across agricultural insect pests.

evolutionary biology↗

bioRxiv2022

Molecular insights into the MCM8/9 helicase complex in DNA unwinding and translocation

MCM8 and MCM9 form a functional helicase complex (MCM8/9) that plays an essential role in DNA homologous recombination repair for DNA double-strand break. However, the structural characterization of MCM8/9 for DNA binding/unwinding remains unclear. Here, we report structures of the MCM8/9 complex using cryo-electron microscopy single particle analysis. The structures reveal that MCM8/9 is arranged into a heterohexamer through a three-fold symmetry axis, creating a central channel that accommodates DNA. Multiple characteristic hairpins from the N-terminal oligosaccharide/oligonucleotide (OB) domains of MCM8/9 protrude into the central channel and serve to unwind the duplex DNA. When activated by HROB, the structure of MCM8/9s N-tier ring converts its symmetry from C3 to C1 with a conformational change that expands the MCM8/9s trimer interface. Moreover, our structural dynamic analyses revealed that the flexible C-tier ring exhibited rotary motions relative to the N-tier ring, which is required for the unwinding ability of MCM8/9. In summary, our structural and biochemistry study provide a basis for understanding the DNA unwinding mechanism of MCM8/9 helicase in homologous recombination.

biophysics↗

bioRxiv2022

Blocking Kir6.2 channels with SpTx1 potentiates glucose-stimulated insulin secretion from murine pancreatic β cells and lowers blood glucose in diabetic mice

ATP-sensitive K+ (KATP) channels in pancreatic {beta} cells comprise pore-forming subunits (Kir6.2) and modulatory sulfonylurea receptor subunits (SUR1). The ATP sensitivity of these channels enables them to couple metabolic state to insulin secretion in {beta} cells. Antidiabetic sulfonylureas such as glibenclamide target SUR1 and indirectly suppress Kir6.2 activity. Glibenclamide acts as both primary and secondary secretagogues to trigger insulin secretion and potentiate glucose-stimulated insulin secretion, respectively. We tested whether blocking Kir6.2 itself causes the same effects as glibenclamide, and found that the Kir6.2 pore-blocker SpTx1 acts as a strong secondary, but not a primary, secretagogue. SpTx1 triggered a transient rise of plasma insulin and lowered the elevated blood glucose of diabetic mice over-expressing Kir6.2 but did not affect those of non-diabetic mice. This proof-of-concept study suggests that blocking Kir6.2 may serve as an effective treatment for diabetes and other diseases stemming from Kir6.2 hyperactivity that cannot be suppressed with sulfonylureas.

physiology↗

bioRxiv2022

DNA origami as a nanomedicine for targeted rheumatoid arthritis therapy through reactive oxygen species and nitric oxide scavenging

High levels of reactive oxygen species (ROS) and nitric oxide (NO) generated by M1 macrophages induce inflammation in the development of rheumatoid arthritis (RA). The eliminating of ROS and NO therefore represents an alternative strategy for RA treatment. Because DNA molecules possess ROS- and endogenous NO-scavenging capability, herein, we develop a nanomedicine based on triangular DNA origami nanostructures for targeted RA treatment. We showed that folic acid-modified triangular DNA origami nanostructures (FA-tDONs) could reduce ROS and NO simultaneously inside proinflammatory M1 macrophages, leading to their polarization into anti-inflammatory M2 subtype. Further in vivo studies confirmed that FA-tDONs could actively target inflamed joints in collagen-induced arthritis (CIA) mice, attenuate inflammatory cytokines and alleviate disease progression. This work demonstrated that DNA origami itself could act as a potential nanomedicine for targeted RA treatment.

bioengineering↗

bioRxiv2021

Simultaneous Optimization of Excitation Wavelength and Emission Window for Semiconducting Polymer Nanoparticles to Improve Imaging Quality

Optimized excitation wavelength and emission window are essential for fluorescence imaging with high quality. Semiconducting polymer nanoparticles (SPNs) as fluorescent contrast agents have been extensively studied, but their imaging abilities in the second near-infrared IIb window (NIR-IIb, 1500-1700 nm) with long excitation wavelength have not been reported yet. Herein, as a proof-of-concept, we demonstrate for the first time that an SPN named L1057 nanoparticles (NPs) exhibit intense NIR-IIb signal due to its ultra-high brightness and broad emission spectrum. After screening 915 nm as an optimal excitation wavelength, we applied L1057 NPs to visualize the whole-body vessels, cerebral vessels, gastrointestinal tract, and tumor progression in different stages, achieving superior spatial resolution and signal to background ratio in the NIR-IIb window with respect to NIR-II window (1000-1700 nm). This study reveals that simultaneous optimization of excitation wavelength and emission window is an efficient strategy to enhance imaging quality and that L1057 NPs can serve as a promising NIR-IIb contrast agent for high-resolution and deep-tissue imaging.

bioengineering↗

bioRxiv2021

Enhancer RNA-based modeling of adverse events and objective responses of immunotherapy

Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 or CTLA-4 are emerging and effective immunotherapy strategies. However, ICI treated patients present heterogeneous responses and adverse events, thus demanding effective ways to assess benefit over risk before treatment. Here, by integrating pan-cancer clinical and molecular data, we tried to predict immune-related adverse events (irAEs, risk) and objective response rates (ORRs, benefit) based on enhancer RNAs (eRNAs) expression among patients receiving anti-PD-1/PD-L1 therapy. We built two effective regression models, explaining 71% variance (R=0.84) of irAEs with three eRNAs and 79% (R=0.89) of ORRs with five eRNAs. Interestingly, target genes of irAE-related enhancers, including upstream regulators of MYC, were involved in metabolism, inflammation, and immune activation, while ORR-related enhancers target PAK2 and DLG1 which directly participate in T cell activation. Our study provides references for the identification of immunotherapy-related biomarkers and potential therapeutic targets during immunotherapy.

bioinformatics↗

bioRxiv2021

Chemical Reversible Crosslinking Enables Measurement of RNA 3D Distances and Alternative Conformations in Cells

Three-dimensional (3D) structures dictate the functions of RNA molecules in a wide variety of biological processes. However, direct determination of RNA 3D structures in vivo is difficult due to their large sizes, conformational heterogeneity, and dynamics. Here we present a new method, Spatial 2-Hydroxyl Acylation Reversible Crosslinking (SHARC), which uses chemical crosslinkers of defined lengths to measure distances between nucleotides in cellular RNA. Integrating crosslinking, exonuclease (exo) trimming, proximity ligation, and high throughput sequencing, SHARC enables transcriptome-wide tertiary structure contact maps at high accuracy and precision, revealing heterogeneous RNA structures and interactions. SHARC data provide constraints that improves Rosetta-based RNA 3D structure modeling at near-nanometer resolution. Integrating SHARC-exo with other crosslinking-based methods, we discover compact folding of the 7SK RNA, a critical regulator of transcriptional elongation. These results establish a new strategy for measuring RNA 3D distances and alternative conformations in their native cellular context.

biochemistry↗

bioRxiv2021

A live attenuated influenza virus-vectored intranasal COVID-19 vaccine provides rapid, prolonged, and broad protection against SARS-CoV-2 infection

Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they are limited with respect to eliciting local immunity in the respiratory tract, which is the primary infection site for SARS-CoV-2. To overcome the limitations of intramuscular vaccines, we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, named CA4-dNS1-nCoV-RBD (dNS1-RBD). A preclinical study showed that in hamsters challenged 1 day and 7 days after single-dose vaccination or 6 months after booster vaccination, dNS1-RBD largely mitigated lung pathology, with no loss of body weight, caused by either the prototype-like strain or beta variant of SARS-CoV-2. Lasted data showed that the animals could be well protected against beta variant challenge 9 months after vaccination. Notably, the weight loss and lung pathological changes of hamsters could still be significantly reduced when the hamster was vaccinated 24 h after challenge. Moreover, such cellular immunity is relatively unimpaired for the most concerning SARS-CoV-2 variants. The protective immune mechanism of dNS1-RBD could be attributed to the innate immune response in the nasal epithelium, local RBD-specific T cell response in the lung, and RBD-specific IgA and IgG response. Thus, this study demonstrates that the intranasally delivered dNS1-RBD vaccine candidate may offer an important addition to fight against the ongoing COVID-19 pandemic, compensating limitations of current intramuscular vaccines, particularly at the start of an outbreak.

pathology↗

bioRxiv2021

Transcriptomics analysis reveals intracellular mutual regulation of coral-zooxanthella holobionts

Corals should make excellent models for cross-kingdom regulation research because of their natural animal-photobiont holobiont composition, yet a lack of studies and experimental data restricts their use. Here we integrate new full-length transcriptomes and small RNAs of four common reef-building corals with the published Symbiodinium C1 genome to gain deeper insight into mutual gene regulation in coral-zooxanthella holobionts. We show that zooxanthellae secrete miRNA to downregulate rejection from host coral cells, and that a potential correlation exists between miRNA diversity and physiological activity. Convergence of these holobionts biological functions in different species is also revealed, which implies the low gene impact on bottom ecological niche organisms. This work provides evidence for the early origin of cross-kingdom regulation as a mechanism of self-defense autotrophs can use against heterotrophs, sheds more light on coral-zooxanthella holobionts, and contributes valuable data for further coral research.

ecology↗

bioRxiv2021

Maternal Ezh1/2 deficiency in oocyte delays H3K27me2/3 restoration and impairs epiblast development responsible for embryonic sub-lethality in mouse

Mammalian embryonic development is a complex process regulated by various epigenetic modifications. Recently, maternal histone H3 methylations were found to be inherited and reprogrammed in early embryos to regulate embryonic development. The enhancer of zest homolog 1 and 2 (Ezh1 and Ezh2) belong to the core components of Polycomb repressive complex 2 (PRC2) and are the histone methyltransferase of histone 3 lysine 27 (H3K27). How maternal Ezh1 and Ezh2 function on H3K27 methylation in in vivo preimplantation embryos and embryonic development are not clear. Here, we deleted Ezh1 or/and Ezh2 in growing oocytes using gene knockout mouse models, and found that H3K27me3 in oocytes was disappeared by loss of Ezh2 alone while H3K27me2 was absent upon deletion of both Ezh1 and Ezh2. The effects of Ezh1/2 were inherited in maternal knockout zygotes and early embryos, in which restoration of H3K27me3 was delayed until late blastocyte by loss of Ezh2 alone and H3K27me2 was reestablished until morulae by deletion of Ezh1 and Ezh2. However, the ablation of both Ezh1 and Ezh2, but not single Ezh1 or Ezh2, led to significantly decreased litter size due to growth retardation during post-implantation. Furthermore, maternal Ezh1/2 deficiency caused compromised H3K27me3 and pluripotent epiblast cells in late blastocyst, followed by defective development of epiblast. These results demonstrate that in oocytes, Ezh2 is indispensable for H3K27me3 while Ezh1 complements Ezh2 in H3K27me2. Also, maternal Ezh1/2-H3K27 methylation is inherited in descendant embryos and has a critical effect on fetus and placenta development. Thus, this work sheds light on maternal epigenetic modifications during embryonic development.

developmental biology↗

bioRxiv2021

A genetic bottleneck of mitochondrial DNA during human lymphocyte development

Mitochondria are essential organelles in eukaryotic cells that provide critical support for energetic and metabolic homeostasis. Mutations that accumulate in mitochondrial DNA (mtDNA) in somatic cells have been implicated in cancer, degenerative diseases, and the aging process. However, the mechanisms used by somatic cells to maintain proper functions despite their mtDNA mutation load are poorly understood. Here, we analyzed somatic mtDNA mutations in more than 30,000 human single peripheral and bone marrow mononuclear cells and observed a significant overrepresentation of homoplastic mtDNA mutations in B, T and NK lymphocytes despite their lower mutational burden than other hematopoietic cells. The characteristic mutational landscape of mtDNA in lymphocytes were validated with data from multiple platforms and individuals. Single-cell RNA-seq and computational modeling demonstrated a stringent mitochondrial bottleneck during lymphocyte development likely caused by lagging mtDNA replication relative to cell proliferation. These results illuminate a potential mechanism used by highly metabolically active immune cells for quality control of their mitochondrial genomes.

genetics↗