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| Open AccessA comparative analysis of planarian genomes reveals regulatory conservation in the face of rapid structural divergence
Planarians are model systems for stem cells and regeneration. This study provides new genome assemblies of the model species S. mediterranea and 3 relatives and uses comparative genomics of planarians to reveal that synteny is not an evolutionary constraint in flatworm genome evolution.
- Mario Ivanković
- , Jeremias N. Brand
- & Jochen C. Rink
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Article
| Open AccessAn elevated rate of whole-genome duplications in cancers from Black patients
In the United States, Black patients have higher rates of cancer mortality, but the sources of such disparities remain poorly understood. Here, the authors analyze genomic data from large-scale patient cohorts and find that cancers from self-reported Black patients are significantly more likely to exhibit whole genome duplications; they also explore a potential link to environmental exposures.
- Leanne M. Brown
- , Ryan A. Hagenson
- & Jason M. Sheltzer
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Article
| Open AccessComplex trait associations in rare diseases and impacts on Mendelian variant interpretation
Polygenic scores aggregate the effects of common genetic variants and have been shown to underly certain rare diseases. Here, the authors conduct a large-scale association analysis of rare disease phenotypes and open-source polygenic scores and apply this information to rare variant interpretation and disease gene discovery
- Craig Smail
- , Bing Ge
- & Tomi Pastinen
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Article
| Open AccessA point mutation in VIG1 boosts development and chilling tolerance in rice
Very few genes are involved in simultaneous regulation of seedling vigor, cold tolerance and grain yield in rice. Here, the authors report OsbZIP01 and OsbZIP18 function cooperatively in determining seedling establishment, chilling tolerance, and grain yield in rice.
- Dunpin Xiong
- , Juan Wang
- & Shanguo Yao
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Article
| Open AccessIdentifying genetic variants associated with chromatin looping and genome function
Here, the authors present an HiChIP dataset on naïve CD4 T cells from 30 donors. They investigate genotype-dependent and allele-specific variation of chromatin loops between active regulatory elements, reporting loop-associated variants linked to dynamic changes in gene expression.
- Sourya Bhattacharyya
- & Ferhat Ay
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Article
| Open AccessGermline variant affecting p53β isoforms predisposes to familial cancer
Pathogenic germline variants in TP53 predispose to a variety of cancers, but variants solely affecting alternatively spliced isoforms of TP53 are understudied. Here, the authors identify a heterozygous stop-lost variant that specifically affects p53β isoforms and predisposes to familial cancer using germline whole-exome sequencing and functional genomics assays.
- Stephanie A. Schubert
- , Dina Ruano
- & Tom van Wezel
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Article
| Open AccessMultiplex, single-cell CRISPRa screening for cell type specific regulatory elements
Scalable CRISPRa screening of cis-regulatory elements in non-cancer cell lines has proved challenging. Here, the authors describe a scalable, CRISPR activation screening framework to identify regulatory element-gene pairs in diverse cell types including cancer cells and neurons.
- Florence M. Chardon
- , Troy A. McDiarmid
- & Jay Shendure
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Article
| Open AccessDNA Methylation signatures underpinning blood neutrophil to lymphocyte ratio during first week of human life
Evaluating the immune status of newborns helps recognition of those who are at higher risk for serious infectious diseases. Here authors identify lower, epigenetically inferred,
neutrophil-to-lymphocyte ratios during the first week of life as risk factor for sepsis and provide insight into the underpinning epigenetic and transcriptional patterns.
- David Martino
- , Nina Kresoje
- & Tobias R. Kollmann
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Article
| Open AccessEngineering TadA ortholog-derived cytosine base editor without motif preference and adenosine activity limitation
Engineered TadA variants in cytosine base editors (CBEs) offer advantages like smaller size and reduced off-target effects. Here, authors develop an advanced CBE (aTdCBE) through ortholog screening and protein engineering, successfully enabling exon skipping in Duchenne muscular dystrophy model.
- Guoling Li
- , Xue Dong
- & Yingsi Zhou
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Article
| Open AccessFundamental equations linking methylation dynamics to maximum lifespan in mammals
The mystery of mammalian lifespan is examined through DNA methylation dynamics, revealing an inverse relationship between lifespan and average methylation rate changes in bivalent promoter regions. Results vary depending on chromatin context.
- Steve Horvath
- , Joshua Zhang
- & Zhe Fei
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Article
| Open AccessTargeted transcriptional downregulation of MYC using epigenomic controllers demonstrates antitumor activity in hepatocellular carcinoma models
Development of targeted MYC inhibitors for cancer therapy remains challenging. Here, the authors design an mRNA medicine which downregulates MYC gene transcription via epigenetic modification of MYC regulatory elements, showing significant antitumor activity in preclinical models of hepatocellular carcinoma.
- William Senapedis
- , Kayleigh M. Gallagher
- & Thomas G. McCauley
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Article
| Open AccessSerotonin deficiency from constitutive SKN-1 activation drives pathogen apathy
Here, Nair et al show that constitutive activation of the cytoprotective transcription factor SKN-1 within the digestive and nervous system of Caenorhabditis elegans impedes serotonin signalling and leads to pathogen-apathy behaviour.
- Tripti Nair
- , Brandy A. Weathers
- & Sean P. Curran
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Article
| Open AccessPost-transcriptional reprogramming by thousands of mRNA untranslated regions in trypanosomes
Cells that transcribe almost ‘everything everywhere all at once’ rely upon alternative expression controls. Here the authors employ massive parallel reporter assays and 3’UTR-seq to profile regulatory untranslated regions (UTRs) in African trypanosome.
- Anna Trenaman
- , Michele Tinti
- & David Horn
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Article
| Open AccessPRDM3/16 regulate chromatin accessibility required for NKX2-1 mediated alveolar epithelial differentiation and function
Growth and differentiation of pulmonary epithelial cells is precisely controlled to form the alveoli that create the gas exchange region of the lung. Here, the authors demonstrate that epigenetic modulation of the genome by PRDM3/16 mediates NKX2-1 activity to control alveolar cell fate and differentiation during embryonic and perinatal lung development.
- Hua He
- , Sheila M. Bell
- & Jeffrey A. Whitsett
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Article
| Open AccessGenome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy
Here the authors use UK Biobank data to identify 251 genetic loci associated with serum triglycerides to HDL-cholesterol ratio, a surrogate marker for insulin resistance. Key genes, including PLA2G12A, PLA2G6, and TNFAIP8, offer potential therapeutic targets for metabolic diseases.
- Natalie DeForest
- , Yuqi Wang
- & Amit R. Majithia
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Article
| Open AccessSequence variants influencing the regulation of serum IgG subclass levels
Immunoglobulin G (IgG) is the main isotype of antibody in human blood. Here the authors describe 14 genetic variants that affect IgG levels in blood. The data provide new insight into the regulation of humoral immunity that could be useful in the development of antibody-based therapeutics.
- Thorunn A. Olafsdottir
- , Gudmar Thorleifsson
- & Kari Stefansson
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Article
| Open AccessPopulation suppression by release of insects carrying a dominant sterile homing gene drive targeting doublesex in Drosophila
CRISPR homing gene drives can suppress pest populations by targeting female fertility genes, converting wild-type alleles into drive alleles in the germline of drive heterozygotes. Here the authors demonstrate a genetic pest suppression system based on dominant female-sterile doublesex alleles and show that releases of transgenic males eliminated Drosophila cage populations, with modelling showing improved performance compared to similar systems.
- Weizhe Chen
- , Jialiang Guo
- & Jackson Champer
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Article
| Open AccessEvaluating the cost-effectiveness of polygenic risk score-stratified screening for abdominal aortic aneurysm
Kelemen et al. find that leveraging related traits improves polygenic score performance for abdominal aortic aneurysm. Health-economic modelling suggests that combining smoking and genetic risk information may improve cost-effectiveness of screening.
- M. Kelemen
- , J. Danesh
- & L. G. Kim
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Article
| Open AccessImpact and characterization of serial structural variations across humans and great apes
Structural variants (SV) can accumulate in repeat-rich parts of the genome and transform them in unexpected ways. Here, with their new assembly-based genotyper (NAHRwhals), the authors verify multi-step SVs in 37 human loci and identify alleles at risk for copy-number variation.
- Wolfram Höps
- , Tobias Rausch
- & Fritz J. Sedlazeck
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Article
| Open AccessA sex-stratified analysis of the genetic architecture of human brain anatomy
Here, the authors screen for sex differences in the common genetic architecture of over 1000 neuroanatomical phenotypes, showing overall concordance between female and male individuals.
- Rebecca Shafee
- , Dustin Moraczewski
- & Armin Raznahan
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Article
| Open AccessA truncated B-box zinc finger transcription factor confers drought sensitivity in modern cultivated tomatoes
Elucidation of drought tolerance mechanism would help to develop tolerant crops. Here, the authors reveal the interaction between BBX18, a zinc finger transcription factor, and ascorbate peroxidase (APX1) to mediate drought stress resistance in tomato.
- Jinhua Li
- , Guo Ai
- & Junhong Zhang
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Article
| Open AccessPHYTOCHROME-INTERACTING FACTOR 7 and RELATIVE OF EARLY FLOWERING 6 act in shade avoidance memory in Arabidopsis
Cheng et al. find that priming shade treatment can be memorized and triggers faster hypocotyl elongation upon subsequent exposure to shade. During shade memory, PIF7 and REF6 are required to maintain low levels of H3K27me3 and hyper-induction of shade-memory-related genes.
- Qican Cheng
- , Yue Zeng
- & Lin Li
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Article
| Open AccessSimultaneous profiling of RNA isoforms and chromatin accessibility of single cells of human retinal organoids
Here, the authors present scRICA-seq, which is capable of profiling isoforms and chromatin accessibility for up to 10,000 single cells in a single run. By applying this method to human retinal organoids, they construct a multi-omic cell atlas.
- Shuyao Zhang
- , Yuhua Xiao
- & Youjin Hu
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Article
| Open AccessGenome-wide association studies of thyroid-related hormones, dysfunction, and autoimmunity among 85,421 Chinese pregnancies
Normal maternal thyroid function holds significant relevance for pregnancy outcomes and long-term health. Here, the authors detect genetic associations with thyroid related traits in pregnant women.
- Yuandan Wei
- , Jianxin Zhen
- & Siyang Liu
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Article
| Open AccessNOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke
Stroke is a multifactorial disease influenced by genetic and environmental factors. Here, the authors apply exome-wide association analysis to find rare coding variants associated with stroke in a Pakistani cohort, finding a significant association of a variant in NOTCH3 that is highly enriched in South Asians.
- Juan Lorenzo Rodriguez-Flores
- , Shareef Khalid
- & Danish Saleheen
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Article
| Open AccessContext-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes
Multiple genetic loci are associated with lung cancer risk, but the underlying genetic mechanisms remain poorly understood. Here, the authors perform single-cell RNA-seq and ATAC-seq analyses of lung cells from ever- and never-smokers; they report candidate cis-regulatory elements that colocalise with candidate causal variants in lung cancer risk loci and potential susceptibility genes.
- Erping Long
- , Jinhu Yin
- & Jiyeon Choi
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Article
| Open AccessVariation of C-terminal domain governs RNA polymerase II genomic locations and alternative splicing in eukaryotic transcription
The C-terminal domain of the largest subunit of RNA polymerase II (CTD) is phosphorylated and recruits regulators of transcription. Here the authors show that phosphorylated CTD, upon specific binding to transcription regulators, forms distinct condensates from wildtype CTD, impact promoter binding and RNA processing.
- Qian Zhang
- , Wantae Kim
- & Y. Jessie Zhang
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Article
| Open AccessAn observational and genetic investigation into the association between psoriasis and risk of malignancy
The relationship between psoriasis and cancer remains unclear. Here, the authors use PheWAS, polygenic risk scores, and Mendelian randomization analyses to demonstrate that psoriasis is causally associated with lung and breast cancer.
- Ruolin Li
- , Wenjin Luo
- & Aijun Chen
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Article
| Open AccessThe simplicity of protein sequence-function relationships
Understanding protein sequence-function relationships is complicated by high order epistatic interactions among residues, although the extent of these interactions remains uncertain. Here, the authors present a reference-free method which suggests that sequence-function relationships are relatively simple, with little influence from high order epistatic interactions.
- Yeonwoo Park
- , Brian P. H. Metzger
- & Joseph W. Thornton
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Article
| Open AccessRNA-mediated double-strand break repair by end-joining mechanisms
Double-strand breaks (DSBs) in DNA are challenging to repair. Here, the authors show that transcript RNAs impact the DSB repair outcomes in human and yeast cells by promoting NHEJ or MMEJ in a sequence-specific manner, suggesting a direct role for RNA in modulating genome stability and evolution.
- Youngkyu Jeon
- , Yilin Lu
- & Francesca Storici
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Article
| Open AccessRING1 missense variants reveal sensitivity of DNA damage repair to H2A monoubiquitination dosage during neurogenesis
Here, the authors establish a human in vitro model of neurodevelopment to investigate an allelic series of clinically relevant RING1 and RNF2 missense variants. The observations reveal that missense variants function according to a dominant-negative genetic mechanism.
- C. W. Ryan
- , S. L. Regan
- & S. L. Bielas
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Article
| Open AccessVariants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behaviors
Here the authors identify 33 individuals with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in the gene encoding Densin-180, a scaffold protein present at postsynaptic sites in neurons of the central nervous system.
- Jana Willim
- , Daniel Woike
- & Hans-Jürgen Kreienkamp
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Article
| Open AccessLong-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis
Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases but the underlying factors driving its development are largely unknown. Here, longitudinal assessment of 4,187 participants over 21 years provides insights into cell-intrinsic and -extrinsic factors contributing to the development and progression of CHIP clones in older adults.
- Md Mesbah Uddin
- , Seyedmohammad Saadatagah
- & Pradeep Natarajan
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Article
| Open AccessGenetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes
The authors present the largest genome-wide association study to date for a rare Parkinsonian disorder, progressive supranuclear palsy (PSP). They include follow-up investigations of the identified susceptibility loci, functional consequences, and cell-specific pathologies, providing insights into genetic and molecular mechanisms underlying PSP.
- Kurt Farrell
- , Jack Humphrey
- & Adam Naj
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Article
| Open AccessGlioblastoma cells increase expression of notch signaling and synaptic genes within infiltrated brain tissue
In glioblastoma, malignant cells can escape surgical resection by migrating into the surrounding healthy brain tissue. Here, the authors use spatial transcriptomics to characterise the tumour core and infiltrated brain regions in glioblastoma, and show shifts in malignant cell composition and molecular pathways with potential clinical implications.
- Dylan Scott Lykke Harwood
- , Vilde Pedersen
- & Bjarne Winther Kristensen
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Article
| Open AccessSystematic identification of post-transcriptional regulatory modules
RNA binding proteins (RBPs) regulate various RNA processes, yet their interactions remain poorly understood. Here, authors generate a comprehensive map of RBP interactions using multimodal data, uncovering context-specific functions and revealing complex post-transcriptional regulatory networks.
- Matvei Khoroshkin
- , Andrey Buyan
- & Hani Goodarzi
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Article
| Open AccessEvolutionary dynamics of the successful expansion of pandemic Vibrio parahaemolyticus ST3 in Latin America
Vibrio parahaemolyticus Sequence Type 3 was first reported in India and expanded globally to areas with distinct climates including Latin America. In this study, the authors investigate the evolutionary mechanisms driving emergence of the strain in Latin America using 280 publicly available genomes and 32 samples newly sequenced in this study.
- Amy Marie Campbell
- , Ronnie G. Gavilan
- & Jaime Martinez-Urtaza
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Article
| Open AccessHuman Smc5/6 recognises transcription-generated positive DNA supercoils
The study reveals a novel relationship between the human Smc5/6 complex and DNA topology during transcription and emphasizes the importance of DNA topology sensing in the defense against extrachromosomal genetic threats.
- Aurélie Diman
- , Gaël Panis
- & Michel Strubin
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Article
| Open AccessCognitive processing speed and accuracy are intrinsically different in genetic architecture and brain phenotypes
Here, the authors investigate the genetic architecture and neuroimaging signatures of cognitive processing speed and accuracy, two fundamental dimensions underlying cognitive abilities. They also identify links between these two factors and lifestyle, mental health and cognitive development.
- Mingyang Li
- , Xixi Dang
- & Dan Wu
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Article
| Open AccessRAD52 resolves transcription-replication conflicts to mitigate R-loop induced genome instability
Collisions of transcription and replication machineries on the same DNA strand threaten genomic stability. Here, the authors show that RAD52 prevents these collisions by regulating R-loop formation and resolution. RAD52 deficiency leads to increased R-loops, exacerbated collisions, DNA damage, and higher mutational burden in tumors.
- Manisha Jalan
- , Aman Sharma
- & Simon N. Powell
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Article
| Open AccessscConfluence: single-cell diagonal integration with regularized Inverse Optimal Transport on weakly connected features
The abundance of unpaired multimodal single-cell data drives the need for improved integration methods. Here, authors introduce scConfluence, a method combining uncoupled autoencoders with regularized Inverse Optimal Transport to tackle robustly diverse integration scenarios.
- Jules Samaran
- , Gabriel Peyré
- & Laura Cantini
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Article
| Open AccessNanodynamo quantifies subcellular RNA dynamics revealing extensive coupling between steps of the RNA life cycle
The life of RNAs is governed by a series of transcriptional and post-transcriptional steps. Here, authors developed Nanodynamo, an experimental and computational workflow for studying how the coordinated action of these steps shapes breast cancer gene expression programs at the subcellular level.
- Lucia Coscujuela Tarrero
- , Valeria Famà
- & Mattia Pelizzola
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Article
| Open AccessIdentification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions
Repeat expansions in the FGF14 gene can cause late-onset cerebellar ataxia (SCA27B), however the defining features of pathogenic expansions remain uncertain. Here, the authors compare the sequence and structure of FGF14 repeat expansions in patients and controls, leading them to suggest a lower pathogenic threshold and emphasizing the importance of sequencing the full expansion for accurate interpretation.
- Lars Mohren
- , Friedrich Erdlenbruch
- & Christel Depienne
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Article
| Open AccessPMEL is involved in snake colour pattern transition from blotches to stripes
Corn snakes are a useful model organism for studying skin pigmentation. Here they characterize the Terrazzo morph and identify the role of PMEL in the patterning of pigmented cells in the skin, explaining how the wild-type blotches change to stripes in Terrazzo.
- Athanasia C. Tzika
- , Asier Ullate-Agote
- & Maya Kummrow
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Article
| Open AccessYeast EndoG prevents genome instability by degrading extranuclear DNA species
Mitochondrial DNA or retrotransposon cDNA released into the cytoplasm is degraded to prevent sterile inflammation. In this study, the authors demonstrate that nucleolytic degradation of these DNA species in a yeast model organism prevents their transfer to the nucleus and genome instability.
- Yang Yu
- , Xin Wang
- & Grzegorz Ira
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Article
| Open AccessInvestigating the shared genetic architecture between depression and subcortical volumes
Depression affects millions of people worldwide. Here, the authors show a substantial polygenic overlap between depression and brain subcortical volumes, identifying 44 shared loci.
- Mengge Liu
- , Lu Wang
- & Feng Liu
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Article
| Open AccessAsexuality shapes traits in a hybrid fish
Morphology associated with reproductive strategy in animals can be difficult to isolate. Here, the authors use geometric morphometrics to study triploid hybrid Chrosomus fish that reproduce sexually and asexually, identifying morphological differences associated with reproductive strategy.
- Joëlle Lafond
- , Christelle Leung
- & Bernard Angers
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Article
| Open AccessSingle-cell analyses of polyclonal Plasmodium vivax infections and their consequences on parasite transmission
Single cell analyses of non-human primates infected with one or two strains of Plasmodium vivax provide insights on the origin of polyclonality in patients and reveal an important population bottleneck occurring during pre-erythrocytic development.
- Brittany Hazzard
- , Juliana M. Sá
- & David Serre
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Article
| Open AccessClinical-grade whole genome sequencing-based haplarithmisis enables all forms of preimplantation genetic testing
This work demonstrates a novel preimplantation genetic testing (PGT) method that detects aberrations in both the nuclear and mitochondrial genomes of IVF embryos. The technology traces the origin of chromosomal aberrations to before or after fertilisation.
- Anouk E. J. Janssen
- , Rebekka M. Koeck
- & Masoud Zamani Esteki
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