Biology subjects

Campbell, P.

Publications and source records attributed to Campbell, P..

At least 19 recordsLinked to original sources

bioRxiv2026

Ex vivo Infrared Nerve Stimulation on the Rat Sciatic Nerve: Challenges and Pitfalls

Infrared nerve stimulation (INS) offers millisecond-scale, electrical artifact-free activation of peripheral nerves, yet rat ex vivo studies remain scarce. We present an INS setup utilizing a lens system for free-beam focus for rat sciatic nerves partially submerged in a nerve bath, making re-wetting of the tissue in existing ex vivo INS setups redundant. Excised sciatic nerve preparations were illuminated at 1470 nm, delivering pulse trains from 100 - 2000 s at 5 Hz with radiant exposures up to 25.7 J/cm2. Compound action potentials (CAPs) were recorded with tungsten hook electrodes. Nerve activity could be recorded up to 200 minutes after excision, though persistent nerve excitability remained comparable to existing ex vivo studies as a yet to be optimized parameter. Peak CAP amplitudes ranged from 3.9 - 36.9 {micro}V with latencies averaged at 3.4 ms. Activation thresholds spanned 1.75 - 13.05 J/cm2. Additionally, potential pitfalls for INS setups and ways to resolve them were investigated, with two artifact types highly relevant to ex vivo INS being identified: A photo-thermal expansion artifact and a photovoltaic artifact with thermo-capacitive coupling. The observations confirm that CAPs can be evoked via INS in an ex vivo preparation of the rat sciatic nerve. The presented platform supports 3R principles and offers a robust basis for introduction of pharmacological investigations with INS.

neuroscience↗

bioRxiv2025

Somatic and germline mutational processes across the tree of life

The characterisation of mutational processes active in somatic and germline cells in vivo has predominantly focused on human cancers1,2, normal tissues3-5 and model organisms6-8. Beyond mammals9, little is known about mutational processes across the tree of life. We developed himut (high-fidelity mutation), an algorithm to identify somatic mutations from circular consensus long-read sequencing data, deploying it on 708 samples from 661 species from Britain and Ireland10. The spectra of somatic mutations, categorised by mutation type and local sequence context, showed considerable between-species divergence but within-species similarity. From normalised spectra across the dataset, we extracted 95 distinct patterns, or signatures, of somatic mutations, together with 18 signatures of germline mutational processes. Only two of the somatic signatures resembled mutational signatures extracted from human cancers1,2. Of the somatic signatures, 22 had significant clustering within the taxonomic classification, with some distributed across an entire kingdom or phylum, while others were restricted to a single family or species. Three somatic signatures were found only in water-dwelling species, with one distributed across multiple clades that might suggest it derives from a water-borne mutagen. Of germline signatures, eight were found in multiple species, showed significant clustering by taxonomic classification and had counterpart somatic signatures with matching mutational spectrum and species distribution. Thus, there is considerably greater diversity of mutational processes across the tree of life than found in human samples, likely reflecting either cell-intrinsic biological processes or environmental exposures (or both) operative within distinct clades.

genomics↗

bioRxiv2025

Neo-sex chromosomes are not correlated with ecology or environment in eutherian mammals

The XX/XY chromosome system is highly conserved in therian mammals. Despite this evolutionary persistence, multiple variant sex chromosome systems exist in mammals. The potential contribution of genomic conflict to the evolution of neo-sex chromosomes has been studied extensively, while the influence of climate and ecology on the emergence and persistence of neo-sex chromosomes is less well understood. Building on previous literature that suggests that ecoclimatic factors can influence intralocus sexual conflict and other forms of genome evolution, we tested whether neo-sex chromosomes in mammals are associated with these factors. We conducted a phylogenetic logistic regression in three representative mammal families using a dataset of variant mammalian sex chromosomes and a database of tetrapod traits and environmental associations. We also incorporated a dataset of mammal karyotypes to test for potential signatures of meiotic drive. When using a single phylogeny, none of the seven ecoclimatic variables tested nor chromosome morphology were significantly correlated with neo-sex chromosomes. However, correlations between neo-sex chromosomes and both range size and mean annual temperature were data-dependent and sensitive to differences in tree topology, demonstrating the importance of accounting for alternative evolutionary hypotheses in comparative methods.

evolutionary biology↗

bioRxiv2025

DNMT3A-R882 mutations intrinsically drive dysfunctional neutropoiesis from human haematopoietic stem cells

Clonal haematopoiesis (CH) arises from the expansion of hematopoietic stem cells (HSCs) carrying leukaemia-associated somatic mutations. CH is linked to pathological immune dysregulation and a greater risk of age-related inflammatory diseases. Yet, how CH mutations impact HSC differentiation into immune effector cells remains understudied. Here, we report a single-cell resolution functional and multi-omic investigation of HSC clonal and differentiation dynamics in individuals with DNMT3A-R882 CH. DNMT3A-R882 reshapes the clonal architecture of haematopoiesis towards an aged phylogenetic structure. Functionally, DNMT3A-R882 HSCs produce decreased monocytic output but more abundant and mature neutrophil progeny compared to WT HSCs in the same individual. Whereas DNMT3A-R882 myeloid progenitors display attenuated inflammatory transcriptional programmes, DNMT3A- R882 mature neutrophils acquire proinflammatory and immunomodulatory features typical of maladaptive immunity and CH co-morbidities. Our findings, validated in humanised mice, identify aberrant DNMT3A-R882 HSC-driven neutropoiesis as a key link between CH, immune dysregulation and risk of inflammatory disease.

cell biology↗

bioRxiv2025

Characterising anthelmintic resistance against benzimidazoles and macrocyclic lactones in gastrointestinal nematode populations of dairy cattle

Anthelmintic resistance in gastrointestinal nematode populations is endemic across all grazing livestock production systems, particularly in small ruminants, but also in cattle. In this study resistance in Cooperia oncophora and Ostertagia ostertagi to macrocyclic lactones and benzimidazoles (BZ) in Scotland was assessed. The faecal egg count reduction test (FECRT) remains the primary tool for assessing anthelmintic resistance in the field; however, differing methodologies and recent guideline updates complicate the interpretation of results across studies. Statistical approaches, such as Bayesian methods used by eggCounts and bayescount, produce varying confidence intervals, which further influence conclusions. The ability of the egg hatch test to detect anthelmintic resistance was evaluated under field conditions, and the EC50 values obtained enabled assessment of the BZ efficacy at both the farm and GIN species levels, without the need for treatment. Mixed amplicon sequencing was applied, and nemabiome analysis confirmed that C. oncophora and Os. ostertagi were the predominant species. Sequencing of the beta-tubulin isotype-1 gene in strongyle communities identified resistance alleles in multiple species. The high EC values and elevated frequencies of BZ-resistance alleles on some farms emphasise the importance of in vitro assays and molecular diagnostics for farm-level resistance management. The detection of resistance against both benzimidazoles and macrocyclic lactones on certain farms highlights the urgency of implementing sustainable control strategies. Although the data presented here are from Scotland, given the high rate of animal movement and similar patterns of anthelmintic usage in the UK, these findings are likely to be relevant across much of the UK. Highlights- Resistance to MLs and BZs was detected in GIN populations of cattle - Multidrug resistance found in Scottish GIN populations of cattle - Egg hatch test results suggest, and sequencing confirms high BZ-resistance allele frequencies

microbiology↗

bioRxiv2025

JAK2 signalling to HNRNPA1 represses retrotransposon activity in haematopoietic stem cells

Retrotransposon expression must be tightly controlled, particularly in long-lived multipotent stem cells, to prevent deleterious consequences including insertional mutations. Several mechanisms are known to repress retrotransposon transcription during development which are generally thought to persist thereafter. However, integration of retrotransposable elements into host genomes has also provided a major source of genetic variation across evolution. This has generated many sequences that have acquired advantageous host functions, but little is known about retrotransposon expression and mobility in adult stem cells or about how these processes might be dynamically regulated. Here we describe the landscape of somatic retrotransposition in haematopoietic stem cells and identify a previously unrecognised pathway which links cytokine signalling, RNA-modulating HNRNP complexes and repression of retrotransposon activity. Activation of JAK2, by thrombopoietin or gain-of-function JAK2 mutations, triggers tyrosine phosphorylation of HNRNPA1 that represses expression of ERVs, LINEs and SINEs and reduces insertional mutagenesis. This pathway coordinates retrotransposon activity with cellular context and state and provides a mechanism for protecting the haematopoietic stem cell genome.

cell biology↗

bioRxiv2025

Mechanistic basis for protection against fatty liver disease by CIDEB loss-of-function mutations

Background & AimsSomatic and germline CIDEB mutations are associated with protection from chronic liver diseases. The mechanistic basis and whether CIDEB suppression would be an effective therapy against fatty liver disease remain unclear. Methods21 CIDEB somatic mutations were introduced into cells to assess functionality. In vivo screening was used to trace Cideb mutant clones in mice fed normal chow, western (WD), and choline-deficient, L-amino acid-defined, high-fat (CDA-HFD) diets. Constitutive and conditional Cideb knockout mice were generated to study Cideb in liver disease. Isotope tracing was used to evaluate fatty acid oxidation and de novo lipogenesis. Transcriptomics, lipidomics, and metabolic analyses were utilized to explore molecular mechanisms. Double knockout models (Cideb/Atgl and Cideb/Ppara) tested mechanisms underlying Cideb loss. ResultsMost CIDEB mutations showed that they impair function, and lineage-tracing showed that loss-of-function clones were positively selected with some, but not all fatty liver inducing diets. Cideb KO mice were protected from WD, CDA-HFD, and alcohol diets, but had the greatest impact on CDA-HFD induced liver disease. Hepatocyte-specific Cideb deletion could ameliorate disease after MASLD establishment, modeling the impact of therapeutic siRNAs. Cideb loss protected livers via increased {beta}-oxidation, specifically through ATGL and PPARa activation. ConclusionsCideb deletion is more protective in some types of fatty liver disease. {beta}-oxidation is an important component of the Cideb protective mechanism. CIDEB inhibition represents a promising approach, and somatic mutations in CIDEB might predict the patient populations that might benefit the most.

physiology↗

bioRxiv2025

Epigenetically dynamic human centromeres are maintained within a stable DNA methylation signature

Centromere location is specified by CENP-A, a centromere-specific histone that epigenetically defines centromere identity. How CENP-A is maintained at one location in rapidly evolving centromeric DNA is unknown. Using single-cell-derived clones of human cell lines, we demonstrate single-cell heterogeneity in CENP-A position within cell populations at neocentromeres and a native centromere. CENP-A heterogeneity is accompanied by unique DNA methylation and H3K9me3 patterns, with DNA methylation shifting according to CENP-A position. We further demonstrate centromere epigenetic evolution over prolonged proliferation, with native centromeres maintaining stable heterochromatin boundaries, but neocentromeres exhibiting DNA methylation instability, H3K9me3 gain, boundary loss and fragility. Lastly, prolonged CENP-A and HJURP overexpression leads to centromere and neocentromere expansion, gradual CENP-A depletion, neocentromere destabilization and CENP-A re-localization that is accompanied by local heterochromatin remodeling. This study reveals the naturally evolving epigenetic plasticity of human centromeres and neocentromeres and highlights the importance of repressive chromatin boundaries in maintaining centromere stability.

cell biology↗

bioRxiv2024

One for the road: Bumble bees consume pollen at flowers

Bees are the primary consumers of pollen in many ecosystems, but pollen consumption by adult bees is rarely studied, leaving a gap in our understanding of the nutritional ecology of collective foraging and pollination biology more generally. For example, while eusocial bees feed upon pollen from colony stores, whether they also consume pollen directly from flowers to meet their own needs or to assess its quality for the broader collective is unknown. We therefore captured wild bumble bee colonies (B. bimaculatus and B. griseocollis) and tested whether individual workers consumed pollen directly from flowers in a lab-based foraging assay. After confirming presence of floral pollen in worker crops (i.e., consumption at flowers), in a field setting we tested alternative hypotheses for the function of this behavior using information about the composition, abundance, and diversity of pollen found in the crops vs. pollen baskets of three species of pollen- and nectar-foraging bumble bees (Bombus bimaculatus, B. griseocollis, and B. impatiens). Consistent with the hypothesis that consuming pollen at flowers reflects sampling, total pollen quantity in crops was consistently smaller than in pollen baskets, and basket pollen tended to be a subset of that found in crops. Further, pollen foragers consumed more and different kinds of pollen than nectar foragers. Pollen consumption at flowers is thus unlikely to be purely incidental, or to substantially benefit workers nutritionally. Instead, consuming pollen directly from flowers likely allows foragers to quickly assess pollen quality before collecting it to feed the colony as whole. SIGNIFICANCE STATEMENTWhile nectar-collecting bees are classic models for the study of foraging behavior and plant-pollinator interactions, little is known about how bees assess pollen while foraging. Pollen is a critical source of protein and lipids, offered by many plant species alongside or instead of nectar. Though variation in pollen macronutrient content and secondary chemistry affect bee reproductive performance and health, whether and how foragers evaluate pollen quality is not known. We show that foraging worker bumble bees consume pollen at flowers and suggest this behavior may allow them to sample its nutritional quality. This sheds new light on the nutritional basis of plant-pollinator interactions and adds to our understanding of how bees regulate their collection of this critical resource.

animal behavior and cognition↗

bioRxiv2024

Maintenance of haematopoietic stem cells by JAK inhibition and increased tyrosine-unphosphorylated STAT5

Normal and malignant hematopoietic stem cells (HSCs) are controlled by extracellular cues including cytokine signalling through the JAK/STAT pathway. Here, we show that STAT5-deficient HSCs exhibit an unusual phenotype: while reduced multi-lineage repopulation and reduced self-renewal are commonly associated with overproliferation and exhaustion, they are instead associated with reduced cell-cycle progression and increased differentiation in STAT5-deficient HSCs. Mechanistic studies show that unphosphorylated-STAT5 (uSTAT5) contributes to this phenotype by constraining HSC differentiation, promoting HSC maintenance and upregulating transcriptional programs associated with stemness. The JAK1/2 inhibitor ruxolitinib increases levels of uSTAT5, constrains differentiation and proliferation of murine HSCs, promotes their maintenance and upregulates transcriptional programs associated with stemness. Ruxolitinib also enhances clonogenicity of normal human HSPCs, CALR-mutant murine HSCs and HSPCs from patients with myelofibrosis. Our results therefore reveal a previously unrecognized role for uSTAT5 in controlling HSC function, highlight JAK inhibition as a strategy for enhancing HSC function and provide insights into the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.

cell biology↗

bioRxiv2024

Deciphering the role of germline complex de novo structural variations in rare disorders

De novo structural variants (dnSVs) have emerged as crucial genetic factors in the context of rare disorders. However, these variations often go undiagnosed in routine genetic screening practices. To shed light on their significance in rare disease, we conducted a comprehensive analysis of the largest cohort of parent-offspring whole-genome sequencing data from the UK 100,000 Genomes Project. Our study encompassed a vast cohort of 12,568 families, including 13,702 offspring affected by rare genetic diseases. We identified a total of 1,872 dnSVs, revealing that approximately 12% of the probands harboured at least one dnSV, of which 9% were identified as likely pathogenic in affected probands (151/1696). Advanced parents age was found to be associated with an increased chance of having dnSVs in probands. We discovered 148 clustered breakpoints resulting from a single event. 60% of these complex dnSVs were classified into 9 major SV types, and could be observed in multiple individuals, while the remaining 40% were private events and had not been previously reported. We found 12% of pathogenic dnSVs are complex SVs, emphasising the critical importance of thoroughly examining and considering complex dnSVs in the context of rare disorders. Furthermore, we discovered an enrichment of maternal dnSVs at subtelometric, early-replicating regions of chromosome 16, suggesting possible sex-specific mechanisms in generation of dnSVs. This study sheds light on the extent of diversity of dnSVs in the germline and their contribution to rare genetic disorders.

genomics↗

bioRxiv2024

Transcription Factors with Broad Expression in the Zebrafish Spinal Cord

BackgroundThe spinal cord is a crucial part of the vertebrate CNS, controlling movements and receiving and processing sensory information from the trunk and limbs. However, there is much we do not know about how this essential organ develops. Here, we describe expression of 21 transcription factors and one transcriptional regulator in zebrafish spinal cord. ResultsWe analyzed the expression of aurkb, foxb1a, foxb1b, her8a, homeza, ivns1abpb, mybl2b, myt1a, nr2f1b, onecut1, sall1a, sall3a, sall3b, sall4, sox2, sox19b, sp8b, tsc22d1, wdhd1, zfhx3b, znf804a, and znf1032 in wild-type and MIB E3 ubiquitin protein ligase 1 zebrafish embryos. While all of these genes are broadly expressed in spinal cord, they have distinct expression patterns from one another. Some are predominantly expressed in progenitor domains, and others in subsets of post-mitotic cells. Given the conservation of spinal cord development, and the transcription factors and transcriptional regulators that orchestrate it, we expect that these genes will have similar spinal cord expression patterns in other vertebrates, including mammals and humans. ConclusionsOur data identify 22 different transcriptional regulators that are strong candidates for playing different roles in spinal cord development. For several of these genes, this is the first published description of their spinal cord expression.

developmental biology↗

bioRxiv2023

Pneumococcal Extracellular Vesicles Mediate Horizontal Gene Transfer via the Transformation Machinery

Bacterial cells secrete extracellular vesicles (EVs), the function of which is a matter of intense investigation. Here, we show that the EVs secreted by the human pathogen Streptococcus pneumoniae (pneumococcus) are associated with bacterial DNA on their surface and can deliver this DNA to the transformation machinery of competent cells. These findings suggest that EVs contribute to gene transfer in Gram-positive bacteria, and in doing so, may promote the spread of drug resistance genes in the population. SignificanceThis work extends our understanding of horizontal gene transfer and the roles of extracellular vesicles in pneumococcus. This bacterium serves as the model for transformation, a process by which bacteria can take up naked DNA from the environment. Here we show that extracellular vesicles secreted by the pneumococcus have DNA on their surface, and that this DNA can be imported by the transformation machinery facilitating gene transfer. Understanding EV-mediated gene transfer may provide new avenues to manage the spread of antibiotic drug resistance.

microbiology↗

bioRxiv2023

Geographic variation in the songs of two closely related song-learning species, Anna's and Costa's hummingbird (Calypte anna, C. costae)

In species that learn their song, cultural transmission of song components can lead to the accumulation of variants that differ among populations, resulting in the formation of dialects. Three avian clades are thought to have independently evolved song learning - parrots, oscine passerines, and hummingbirds. Dialects have mainly been studied in passerines. We extend the study of dialects to the bee hummingbird clade, focusing on Annas and Costas hummingbirds (Calypte anna and C. costae). Both species are vocal learners. Annas produces complex, three phrase, multi-syllable songs and Costas produces simple, one phrase songs. We recorded 5-24 males per population (5 Costas and 6 Annas populations) across the species ranges in the Western United States and tested for evidence of geographic variation in song. We found minor population differences in frequency measures of Costas song, but song form was invariant across populations. Annas song was contrastingly variable with population differences in both syllable use and multiple spectral and temporal measures. The most strongly differentiated Annas population in our study, Seattle (Washington State), is the product of a recent northward range expansion facilitated by human activities that provide additional food sources for hummingbirds. The loss and modification of syllables in this population is suggestive of a founder effect on song. This study provides insight into song evolution in non-passerine vocal learners and contributes to understanding of how complex signals evolve.

animal behavior and cognition↗

bioRxiv2023

Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease

Somatic mutations in non-malignant tissues accumulate with age and insult, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate mutations found in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to non-alcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side-by-side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes identified in human NASH. To prioritize new genes, additional screening of 472 candidates identified 23 somatic perturbations that promoted clonal expansion. In validation studies, liver-wide deletion of Bcl6, Tbx3, or Smyd2 resulted in protection against NASH. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease. HighlightsO_LIMosaic Mboat7 mutations that increase lipotoxicity lead to clonal disappearance in NASH. C_LIO_LIIn vivo screening can identify genes that alter hepatocyte fitness in NASH. C_LIO_LIMosaic Gpam mutations are positively selected due to reduced lipogenesis. C_LIO_LIIn vivo screening of transcription factors and epifactors identified new therapeutic targets in NASH. C_LI

cell biology↗

bioRxiv2021

Fanconi Anemia Pathway Deficiency Drives Copy Number Variation in Squamous Cell Carcinomas

Fanconi anemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink (ICL) repair resulting in chromosome breakage1-3. The FA repair pathway comprises at least 22 FANC proteins including BRCA1 and BRCA24-6, and protects against carcinogenic endogenous and exogenous aldehydes7-10. Individuals with FA are hundreds to thousands-fold more likely to develop head and neck (HNSCC), esophageal and anogenital squamous cell carcinomas (SCCs) with a median onset age of 31 years11. The aggressive nature of these tumors and poor patient tolerance of platinum and radiation-based therapy have been associated with short survival in FA11-16. Molecular studies of SCCs from individuals with FA (FA SCCs) have been limited, and it is unclear how they relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or human papillomavirus (HPV) infection17. Here, by sequencing FA SCCs, we demonstrate that the primary genomic signature of FA-deficiency is the presence of a high number of structural variants (SVs). SVs are enriched for small deletions, unbalanced translocations, and fold-back inversions that arise in the context of TP53 loss. The SV breakpoints preferentially localize to early replicating regions, common fragile sites, tandem repeats, and SINE elements. SVs are often connected forming complex rearrangements. Resultant genomic instability underlies elevated copy number alteration (CNA) rates of key HNSCC-associated genes, including PIK3CA, MYC, CSMD1, PTPRD, YAP1, MXD4, and EGFR. In contrast to sporadic HNSCC, we find no evidence of HPV infection in FA HNSCC, although positive cases were identified in gynecologic tumors. A murine allograft model of FA pathway-deficient SCC was enriched in SVs, exhibited dramatic tumor growth advantage, more rapid epithelial-to-mesenchymal transition (EMT), and enhanced autonomous inflammatory signaling when compared to an FA pathway-proficient model. In light of the protective role of the FA pathway against SV formation uncovered here, and recent findings of FA pathway insufficiency in the setting of increased formaldehyde load resulting in hematopoietic stem cell failure and carcinogenesis18-20, we propose that high copy-number instability in sporadic HNSCC may result from functional overload of the FA pathway by endogenous and exogenous DNA crosslinking agents. Our work lays the foundation for improved FA patient treatment and demonstrates that FA SCC is a powerful model to study tumorigenesis resulting from DNA crosslinking damage.

cancer biology↗

bioRxiv2021

Clonal dynamics of haematopoiesis across the human lifespan

Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer. The cellular alterations that underpin the abruptness of this functional decline after the age of 70 years remain elusive. We sequenced 3579 genomes from single-cell-derived colonies of haematopoietic stem cell/multipotent progenitors (HSC/MPPs) across 10 haematologically normal subjects aged 0-81 years. HSC/MPPs accumulated 17 mutations/year after birth and lost 30bp/year of telomere length. Haematopoiesis in adults aged <65 was massively polyclonal, with high indices of clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. In contrast, haematopoiesis in individuals aged >75 showed profoundly decreased clonal diversity. In each elderly subject, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before age 40, but only 22% had known driver mutations. Genome-wide selection analysis estimated that 1/34 to 1/12 non-synonymous mutations were drivers, occurring at a constant rate throughout life, affecting a wider pool of genes than identified in blood cancers. Loss of Y chromosome conferred selective benefits on HSC/MPPs in males. Simulations from a simple model of haematopoiesis, with constant HSC population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

genomics↗

bioRxiv2021

The longitudinal dynamics and natural history of clonal haematopoiesis

Human cells acquire somatic mutations throughout life, some of which can drive clonal expansion. Such expansions are frequent in the haematopoietic system of healthy individuals and have been termed clonal haematopoiesis (CH). While CH predisposes to myeloid neoplasia and other diseases, we have limited understanding of how and when CH develops, what factors govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression. Here, we track 697 CH clones from 385 individuals aged 55 or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A, TP53) to over 50%/yr (SRSF2-P95H). Growth rates of clones with the same mutation differed by approximately +/-5%/yr, proportionately impacting "slow" drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole genome-sequenced haematopoietic colonies from 7 older individuals, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations only drove expansion later in life, while growth of TET2-mutant clones showed minimal age-dependency. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterise the lifelong natural history of CH and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

cancer biology↗