Biology subjects

Jolly, C. J.

Publications and source records attributed to Jolly, C. J..

15 recordsLinked to original sources

bioRxiv2026

Azacitidine Response in Myelodysplastic Syndromes is Marked by NK-like CD8 T-Cell Expansion and CXCL12+ Reticular Cell Remodeling

Myelodysplastic syndromes (MDS) are driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs), leading to clonal expansion and ineffective hematopoiesis. Hypomethylating agents (HMAs; azacitidine or decitabine) are the standard of care for higher-risk MDS. However, their effects on the bone marrow (BM) microenvironment, and the extent to which these changes correlate with clinical response, remain poorly understood. We performed longitudinal analyses of BM aspirates, trephine biopsies, and peripheral blood samples from MDS patients treated with azacitidine in a clinical trial (NCT03493646), integrating CyTOF, 5' single-cell RNA and TCR sequencing, plasma proteomics, and multiplex immunofluorescence microscopy to characterize changes associated with azacitidine response. Clinical responders showed expansion of GzmBCD56CD8 T cells together with increased type I and type II interferon signaling within the T-cell compartment. Responders also exhibited marked alterations in circulating platelet- and myeloid-derived factors with the potential to remodel the BM niche. Spatial analyses revealed expansion of "neighborhoods" enriched for CXCL12-abundant reticular cells and CD8 T cells in responders, whereas HSPC-enriched neighborhoods were largely unchanged. In contrast, several HSPC-enriched neighborhoods expanded in non-responders. These microenvironmental changes were accompanied by evidence of enhanced myelopoiesis in clinical responders. Our findings support a model in which azacitidine response extends beyond direct effects on malignant hematopoietic cells to involve coordinated remodeling of the BM microenvironment which may be reinforced by platelet- and myeloid-derived signals that establish a feed-forward circuit promoting productive hematopoiesis. One Sentence SummaryLongitudinal bone marrow profiling reveals stromal and immune correlates of azacitidine response in myelodysplastic syndrome.

cancer biology↗

bioRxiv2026

SCIMETAR-seq tracks immunophenotype, demethylation, mutations, and transcriptomes in single cells undergoing HMA therapy

5-azacytidine improves haematopoiesis and delays leukaemic progression in myelodysplastic neoplasms, but responses vary and are complicated by clonal mosaicism and heterogenous demethylation. Using a novel single-cell pipeline ("SCIMETAR-seq"), we found 5-azacytidine induced clonally distinct differentiation responses, with nuclear DNA demethylation occurring primarily in cycling progenitors. Despite the absence of significant nuclear DNA demethylation, quiescent stem cells underwent transcriptional remodelling in vivo, accompanied by 5-azacytidine-induced C*G-to-G*C mutations in mitochondria.

cancer biology↗

bioRxiv2026

Single cell multiomics reveal clonal and functional dynamics of MDS stem/progenitor cells during hypomethylating therapy

Progressive somatic mutations in hematopoietic stem cells (HSCs) drive the development of myelodysplastic neoplasms (MDS). Hypomethylating agents such as azacitidine (AZA) can improve blood counts and reduce blasts, although responses are rarely durable. Determinants of AZA response are complex and incompletely understood, although accumulating evidence suggests that epigenetic rewiring of mutated HSCs underlies improved hematopoietic output. Using single cell multiomics on longitudinal bone marrow samples, we show that AZA responsiveness involves expansion of cells with transcriptomic profiles shared with hematopoietic stem and progenitor cells (HSPCs) from healthy donors. These regenerating cells are depleted of copy number variations and of TP53 mutations. We also identify patient-restricted cell populations, some of which recede through transcriptional restoration or AZA cytotoxicity, and others which expand, regardless of initial clinical response, and dominate at progression. Individual patients carried multiple patient-restricted populations which had unique surface immunophenotypes and were genetically distinct. Strikingly, sorted cells from in vivo progression clones that were AZA-refractive in patients regained AZA-sensitivity when cultured in vitro, suggesting that lack of AZA response at the cellular level can be modulated by cell-extrinsic factors in vivo. Overall, we find that AZA response involves partial hematopoietic regeneration via functional differentiation of mutated, but not cytogenetically abnormal HSPCs, and that persistence of AZA-refractive sub-populations contributes to eventual disease progression.

cancer biology↗

bioRxiv2025

Efficient CRISPR-Cas9-mediated genome editing of the cane toad (Rhinella marina)

Invasive species inflict major ecological, economic, social, and cultural harm worldwide, highlighting the urgent need for innovative and effective control strategies. Genome editing offers exciting possibilities for creating highly targeted control methods for invasive species. Here, we demonstrate CRISPR-Cas9 genome editing in the cane toad (Rhinella marina), one of Australias most notorious invasive species, by targeting the tyrosinase gene to produce albino phenotypes that provide clear visual markers for assessing editing efficiency. Microinjection of Cas9 protein and guide RNAs into one-cell zygotes resulted in 87.6% of mosaic larvae displaying nearly complete albinism, with 2.3% exhibiting complete albinism. For completely albino individuals, genomic analysis confirmed predominantly frameshift mutations or large deletions at the target site, with no wild-type alleles detected. Germline transmission rates reflected the extent of albinism in the mosaic adult, where we achieved maternal germline transmission rates of almost 100%. This technology, representing the first application of CRISPR-Cas9 in the Bufonidae family, opens possibilities for exploring both basic research questions and strategies for population control.

synthetic biology↗

bioRxiv2024

Genome-Wide CRISPR-Cas9 Screening Identifies a Synergy between Hypomethylating Agents and SUMOylation Blockade in MDS/AML

Hypomethylating agents (HMAs) are frontline therapies effective at altering the natural course of Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are hallmarks of HMA therapy. To address this clinical need, we performed a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identified TOPORS as a highly ranked loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that the depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. Importantly, the combination of HMAs with targeting of TOPORS did not functionally impair healthy hematopoiesis. While inhibitors of TOPORS are currently unavailable, we show that inhibition of protein SUMOylation (upstream of TOPORS functions) with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with the inhibition of SUMOylation or TOPORS demonstrates a favourable therapeutic index and is a rational treatment framework for High-Risk MDS (HR-MDS) or AML.

molecular biology↗

bioRxiv2023

A global catalog of whole-genome diversity from 233 primate species

The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology, and is urgent given severe threats these species are facing. Here, we present high coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human-specific. This study will open a wide range of research avenues for future primate genomic research. One-Sentence SummaryThe whole genome sequences of 233 primate species provide insight into the determinants of genetic diversity, phylogenomics, and human uniqueness.

genomics↗

bioRxiv2023

Genome-wide coancestry reveals details of ancient and recent male-driven reticulation in baboons

Baboons (genus Papio) are a morphologically and behaviorally diverse clade of catarrhine monkeys that have experienced hybridization between phenotypically and genetically distinct phylogenetic species. We used high coverage whole genome sequences from 225 wild baboons representing 19 geographic localities to investigate population genomics and inter-species gene flow. Our analyses provide an expanded picture of evolutionary reticulation among species and reveal novel patterns of population structure within and among species, including differential admixture among conspecific populations. We describe the first example of a baboon population with a genetic composition that is derived from three distinct lineages. The results reveal processes, both ancient and recent, that produced the observed mismatch between phylogenetic relationships based on matrilineal, patrilineal, and biparental inheritance. We also identified several candidate genes that may contribute to species-specific phenotypes. One-Sentence SummaryGenomic data for 225 baboons reveal novel sites of inter-species gene flow and local effects due to differences in admixture.

evolutionary biology↗

bioRxiv2022

Single cell genotyping of matched bone marrow and peripheral blood cells in treatment naive and AZA-treated MDS and CMML

Progressively acquired somatic mutations in hematopoietic stem cells are central to pathogenesis in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). They can lead to proliferative advantages, impaired differentiation and progressive cytopenias. MDS or CMML patients with high-risk disease are treated with hypomethylating agents including 5-azacytidine (AZA). Clinical improvement does not require eradication of mutated cells and may be related to improved differentiation capacity of mutated hematopoietic stem and progenitor cells (HSPCs). However, the contribution of mutated HSPCs to steadystate hematopoiesis in MDS and CMML is unclear. To address this, we characterised the somatic mutations of individual stem, progenitor (common myeloid progenitor, granulocyte monocyte progenitor, megakaryocyte erythroid progenitor), and matched circulating (monocyte, neutrophil, naive B cell) haematopoietic cells in treatment naive and AZA-treated MDS and CMML via high-throughput single cell genotyping. The mutational burden was similar across multiple hematopoietic cell types, and even the most mutated stem and progenitor clones maintained their capacity to differentiate to mature myeloid and, in some cases, lymphoid cell types in vivo. Our data show that even highly mutated HSPCs contribute significantly to circulating blood cells in MDS and CMML, prior to and following AZA treatment. Key points* Highly mutated HSPCs contribute significantly to circulating blood cells in MDS and CMML, prior to and following AZA treatment. * The mutational burden in matched bone marrow and peripheral blood cells in MDS and CMML was similar throughout myelopoiesis.

cancer biology↗

bioRxiv2021

High-altitude adaptation and incipient speciation in geladas

Survival at high altitude requires adapting to extreme conditions such as environmental hypoxia. To understand high-altitude adaptations in a primate, we assembled the genome of the gelada (Theropithecus gelada), an endemic Ethiopian monkey, and complemented it with population resequencing, hematological, and morphometric data. Unexpectedly, we identified a novel karyotype that may contribute to reproductive isolation between gelada populations. We also identified genomic elements including protein-coding sequences and gene families that exhibit accelerated changes in geladas and may contribute to high-altitude adaptation. Our findings lend insight into mechanisms of speciation and adaptation while providing promising avenues for functional hypoxia research.

genomics↗

bioRxiv2021

Chaphamaparvovirus Antigen and Nucleic Acids are not Detected in Kidney Tissues from Cats with Chronic Renal Disease or Immunosuppressive Diseases

Mouse Kidney Parvovirus (MKPV) was recently recognized as the cause of murine inclusion body nephropathy, a disease reported for over 40 years in laboratory mice. Immunodeficient mice are persistently infected with MKPV, leading to chronic renal disease, morbidity and mortality whereas immunocompetent mice seroconvert with mild renal pathology. Given the high incidence of MKPV infection in wild mice in the New York City area, the first goal of this study was to evaluate the possibility of MKPV involvement in feline chronic kidney disease (CKD) from the same geographic region. As MKPV and related parvoviruses recently described in other animal species appear to have a tropism for kidney tissue, the second goal was to investigate the possible role of a virus of this group, other than MKPV, in the development of feline CKD, Presence of MKPV and related viruses was investigated in feline renal samples using PCR, RNA in situ hybridization (ISH) and immunohistochemistry (IHC). Cats were divided into three groups: normal (N=25), CKD (N=25) and immune suppressed (N=25). None of the kidney tissues from any of the 75 cats revealed the presence of MKPV DNA, RNA or antigen expression. Nor was "fechavirus" detected using PCR in renal tissue from cats with chronic kidney disease. We conclude that MKPV is an unlikely cause or contributor to feline CKD.

pathology↗

bioRxiv2019

Trophic cascade driven by behavioural fine-tuning as naive prey rapidly adjust to a novel predator

AO_SCPLOWBSTRACTC_SCPLOWThe arrival of novel predators can trigger trophic cascades driven by shifts in prey numbers. Predators also elicit behavioural change in prey populations, via phenotypic plasticity and/or rapid evolution, and such changes may also contribute to trophic cascades. Here we document rapid demographic and behavioural changes in populations of a prey species (grassland melomys Melomys burtoni, a granivorous rodent) following the introduction of a novel marsupial predator (northern quoll Dasyurus hallucatus). Within months of quolls appearing, populations of melomys exhibited reduced survival and population declines relative to control populations. Quoll-invaded populations (n = 4) were also significantly shyer than nearby, quoll-free populations (n = 3) of conspecifics. This rapid but generalised response to a novel threat was replaced over the following two years with more threat-specific antipredator behaviours (i.e. predator-scent aversion). Predator-exposed populations, however, remained more neophobic than predator-free populations throughout the study. These behavioural responses manifested rapidly in avoidance of seeds associated with quoll scent, with discrimination playing out over a spatial scale of tens of metres. Presumably the significant and novel predation pressure induced by quolls drove melomys populations to fine-tune behavioural responses to be more predator-specific through time. These behavioural shifts could reflect individual plasticity (phenotypic flexibility) in behaviour or may be adaptive shifts from natural selection imposed by quoll predation. Our study provides a rare insight into the rapid ecological and behavioural shifts enacted by prey to mitigate the impacts of a novel predator and shows that trophic cascades can be strongly influenced by behavioural changed rates of seed predation by melomys across treatments. Quoll-invaded melomys populations exhibited lower per-capita seed take rates, and rapidly developed an as well as numerical responses.

ecology↗

bioRxiv2019

MKPV (aka MuCPV) and related chapparvoviruses are nephro-tropic and encode novel accessory proteins p15 and NS2

Mouse kidney parvovirus (MKPV) is a member of the provisional Chapparvovirus genus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four MKPV transcripts, created by alternative splicing, to a common transcription initiation region, and use mass spectrometry to identify \"p10\" and \"p15\" as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and a splicing-dependent putative accessory protein NS2 are conserved in all near-complete tetrapod chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that chapparvoviruses with >60% VP1 amino acid identity to MKPV be classified into a genus dubbed Nephroparvovirus, which is consistent with nomenclature for the genus Erythroparvovirus.

microbiology↗

bioRxiv2019

Genomic signatures of extreme body size divergence in baboons

Kinda and gray-footed chacma baboons occupy opposite extremes of the body size distribution in extant baboons (genus Papio). In order to detect signatures of natural selection in these two species, we genotyped 24,790 genome-wide autosomal SNPs from populations of Zambian baboons using double digest RADseq. We scanned the genome for evidence of selection by identifying regions with extreme differentiation between populations. We find evidence of selection on body size influencing multiple genes in one or both species, including FGF1, ATXN2, and PRKCE. We also find an enriched signal of selection associated with biological processes involved in multicellular organism growth and development, cell proliferation and cell growth, nutrient metabolism, and chondrocyte differentiation. Finally, we find that selection has impacted components of the CCKR signaling pathway, which regulates food intake and metabolism, and the JAK/STAT signaling pathway, which mediates the effect of cytokine signals on processes including epiphyseal chondrocyte proliferation essential for longitudinal bone growth. Our findings highlight promising avenues for future studies disentangling the genetic architecture of body size in primates including humans.

evolutionary biology↗

bioRxiv2019

Genome-wide ancestry and introgression in a Zambian baboon hybrid zone

Hybridization in nature offers unique insights into the process of natural selection in incipient species and their hybrids. In order to evaluate the patterns and targets of selection, we examine a recently discovered ba-boon hybrid zone in the Kafue River valley of Zambia, where Kinda baboons (Papio kindae) and gray-footed chacma baboons (P. ursinus griseipes) coexist with hybridization. We genotyped baboons at 14,962 variable genome-wide autosomal markers using double-digest RADseq. We compare ancestry patterns from this genome-wide dataset to previously reported ancestry from mitochondrial-DNA and Y-chromosome sources. We also fit a Bayesian genomic cline model to scan for genes with extreme patterns of introgression. We show that the Kinda baboon Y chromosome has penetrated the species boundary to a greater extent than either mitochondrial DNA or the autosomal chromosomes. We also find evidence for overall restricted introgression in the JAK/STAT signaling pathway. Echoing results in other species including humans, we find evidence for enhanced and/or directional introgression of immune-related genes or pathways including the toll-like receptor pathway, the blood coagulation pathway, and the LY96 gene. Finally we show enhanced introgression and excess chacma baboon ancestry in the sperm tail gene ODF2. Together, our results eluci-date the dynamics of introgressive hybridization in a primate system while highlighting genes and pathways under selection.

evolutionary biology↗

bioRxiv2018

Immune regeneration in irradiated mice is not impaired by the absence of DPP9 enzymatic activity

The ubiquitous intracellular protease dipeptidyl peptidase 9 (DPP9) has roles in antigen presentation and B cell signaling. To investigate the importance of DPP9 in immune regeneration, primary and secondary chimeric mice were created in irradiated recipients using fetal liver cells and adult bone marrow cells, respectively, using wild-type (WT) and DPP9 gene-knockin (DPP9S729A) enzyme-inactive mice. Immune cell reconstitution was assessed at 6 and 16 weeks post-transplant. Primary chimeric mice successfully regenerated neutrophils, natural killer, T and B cells, irrespective of donor cell genotype. There were no significant differences in total myeloid cell or neutrophil numbers between DPP9-WT and DPP9S729A-reconstituted mice. There were fewer B cells in the DPP9S729A-origin compared to DPP9 WT-origin mice in primary chimeric mice. In secondary chimeric mice, cells of DPP9S729A-origin cells displayed enhanced engraftment compared to WT. However, we observed no differences in myeloid or lymphoid lineage reconstitution between WT and DPP9S729A donors, indicating that hematopoietic stem cell (HSC) engraftment and self-renewal is not diminished by the absence of DPP9 enzymatic activity. This is the first report on transplantation of bone marrow cells that lack DPP9 enzymatic activity.

immunology↗