Biology subjects

Evans, K.

Publications and source records attributed to Evans, K..

28 records · Page 2Linked to original sources

bioRxiv2019

Cerebrovascular reactivity assessment with O2-CO2 exchange ratio under brief breath hold challenge

Hypercapnia during breath holding is believed to be the dominant driver behind the modulation of cerebral blood flow (CBF). Here we showed that the cerebrovascular responses to brief breath hold epochs were coupled not only with increased partial pressure of carbon dioxide (PCO2), but also with a decrease in partial pressure of oxygen (PO2). We used transcranial Doppler ultrasound to evaluate the CBF changes during breath holding by measuring the cerebral blood flow velocity (CBFv) in the middle cerebral arteries, a pair of cerebral arteries that supply most parts of the brain. The regional CBF changes during breath hold epochs were mapped with blood oxygenation level dependent (BOLD) signal changes as surrogate of CBF changes using functional magnetic resonance imaging (fMRI) technique. Given the interdependence of the dynamic changes between PCO2 and PO2, we found that the breath-by-breath O2-CO2 exchange ratio (bER), namely the ratio of changes in PO2 ({Delta}PO2) to changes in PCO2 ({Delta}PCO2) between end inspiration and end expiration, was superior to either {Delta}PO2 or {Delta}PCO2 alone in coupling with the changes of CBFv and BOLD signals under breath hold challenge. The regional cerebrovascular reactivity (CVR) results derived by regressing BOLD signal changes on bER under breath hold challenge resembled those derived by regressing BOLD signal changes on end-tidal partial pressure of CO2 (PETCO2) under exogenous CO2 challenge. Our findings provide a novel insight on the potential of using bER to better quantify CVR changes under breath hold challenge, although the physiological mechanisms of cerebrovascular changes underlying breath hold and exogenous CO2 challenges are potentially different.

neuroscience↗

bioRxiv2019

Dynamic Brain-Body Coupling of Breath-by-Breath O2-CO2 Exchange Ratio with Resting State Cerebral Hemodynamic Fluctuations

The origin of low frequency cerebral hemodynamic fluctuations (CHF) in resting state remains unknown. Here we studied the contribution of respiratory gas exchange (RGE) metrics to CHF during spontaneous breathing. RGE metrics include the breath-by-breath changes of partial pressure of oxygen ({Delta}PO2) and carbon dioxide ({Delta}PCO2) between end inspiration and end expiration, and their ratio breath-by-breath O2-CO2 exchange ratio (bER). We used transcranial Doppler sonography to evaluate CHF changes during spontaneous breathing by measuring the cerebral blood flow velocity (CBFv) in the middle cerebral arteries. The regional CHF changes during spontaneous breathing were mapped with blood oxygenation level dependent (BOLD) signal changes using functional magnetic resonance imaging (fMRI) technique. We found that prominent oscillations with periods of 0.5 to 2 minutes characterized {Delta}PO2, {Delta}PCO2 and bER. The oscillations of bER were coherent with CHF during spontaneous breathing at the frequency range of 0.008-0.03Hz which is consistent with the low frequency resting state CHF. CHF had strong correlation with bER, followed by {Delta}PO2 and then by {Delta}PCO2. Brain regions with the strongest bER-CHF coupling overlapped with many areas of default mode network. Although the physiological mechanisms underlying the strong correlation between bER and CHF are not completely understood, our findings suggest the contribution of bER to low frequency resting state CHF. It also provides a novel insight of brain-body interaction via CHF and oscillations of RGE metrics.

neuroscience↗

bioRxiv2019

Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we used single-cell RNAseq to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice to wildtype controls. Our computational analysis of 14,646 single-cell transcriptomes reveals that MDSCs emerge through a previously unrealized aberrant neutrophil maturation trajectory in the spleen giving rise to a unique chemokine-responsive, immunosuppressive cell state that strongly differs from normal myeloid cells. We establish the first MDSC-specific gene signature and identify novel surface markers for improved detection and enrichment of MDSCs in murine and human samples. Our study provides the first single-cell transcriptional map defining the development of MDSCs, which will ultimately enable us to specifically target these cells in cancer patients.\n\nOne Sentence SummaryWe used single cell transcriptomics to identify the unique molecular features distinguishing myeloid-derived suppressor cells (MDSCs) from their normal, myeloid counterparts, which enabled us to reveal distinct transitory gene expression changes during their maturation in the spleen, and to identify novel cell surface markers for improved detection and isolation of MDSCs.

cancer biology↗

bioRxiv2019

A meta-analysis of genome-wide association studies of epigenetic age acceleration

Epigenetic age acceleration is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC, TPMT) and immune system pathways (TRIM59, EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3, MANBA, TRIM46), with metabolic functions (UBE2D3, MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with fathers age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.\n\nAuthor SummaryDNA methylation, a type of epigenetic process, is known to vary with age. Methylation levels at specific sites across the genome can be combined to form estimates of age known as epigenetic age. The difference between epigenetic age and chronological age is referred to as epigenetic age acceleration, with positive values indicating that a person is biologically older than their years. Understanding why some people seem to age faster than others could shed light on the biological processes behind age-related decline; however, the mechanisms underlying differential rates of epigenetic ageing are largely unknown. Here, we investigate genetic determinants of two commonly used epigenetic age acceleration measures, based on the Horvath and Hannum epigenetic clocks. We report novel genetic variants and genes associated with epigenetic age acceleration, and highlight differences in the genetic factors influencing these two measures. We identify ten genetic variants and 21 genes associated with Horvath-based epigenetic age acceleration, and one variant and 12 genes associated with the Hannum-based measure. There were no genome-wide significant variants or genes in common between the Horvath-based and Hannum-based measures, supporting the hypothesis that they represent different aspects of ageing. Our results suggest a partial genetic basis underlying some previously reported phenotypic associations.

genetics↗

bioRxiv2019

Genomic landscape of 261 childhood cancer patient-derived xenograft models

Accelerating cures for children with cancer remains an immediate challenge due to extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs) from high-risk childhood cancers, many refractory to current standard-of-care treatments. Here, we genomically characterize 261 PDX models from 29 unique pediatric cancer malignancies and demonstrate faithful recapitulation of histologies, subtypes, and refine our understanding of relapsed disease. Expression and mutational signatures are used to classify tumors for TP53 and NF1 inactivation, as well as impaired DNA repair. We anticipate that these data will serve as a resource for pediatric oncology drug development and guide rational clinical trial design for children with cancer.\n\nHighlightsO_LIMultiplatform genomic analysis defines landscape of 261 pediatric cancer patient derived xenograft (PDX) models\nC_LIO_LIPediatric patient derived xenografts faithfully recapitulate relapsed disease\nC_LIO_LIInferred TP53 pathway inactivation correlates with pediatric cancer copy number burden\nC_LIO_LISomatic mutational signatures predict impaired DNA repair across multiple histologies\nC_LI

genomics↗

bioRxiv2018

Drought adaptation in nature by extensive genetic loss-of-function

Visions of a second green revolution empowered by emerging technologies have called for interdisciplinary syntheses to scale up the discovery of functionally definitive gene variants responsible for climate adaptation in plants. We integrated novel approaches using whole genome sequences and satellite remote sensing to identify natural knockout alleles associated with drought histories in wild Arabidopsis thaliana. Genes identified exhibit signatures of parallel molecular evolution, selection for loss-of-function alleles, and shared associations with flowering time phenotypes in directions consistent with longstanding adaptive hypotheses 7 times more often than expected by chance. Artificial knockout lines then confirmed predicted phenotypes experimentally. These findings further challenge popular assumptions about the adaptive value of genetic loss-of-function in nature and inspire new opportunities for engineering climate resilience in crops.\n\nOne sentence summaryWhole genome sequences and satellite-detected droughts point to gene knockouts as valuable genetic fuel for climate adaptation.

evolutionary biology↗

bioRxiv2018

DISC1 regulates N-Methyl-D-Aspartate receptor dynamics: Abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness

The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-Methyl-D-Aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers.

neuroscience↗

bioRxiv2018

Improved prediction of chronological age from DNA methylation limits it as a biomarker of ageing

DNA methylation is associated with age. The deviation of age predicted from DNA methylation from actual age has been proposed as a biomarker for ageing. However, a better prediction of chronological age implies less opportunity for biological age. Here we used 13,661 samples (from blood and saliva) in the age range of 2 to 104 years from 14 cohorts measured on Illumina HumanMethylation450/EPIC arrays to perform prediction analyses. We show that increasing the sample size achieves a smaller prediction error and higher correlations in test datasets. We demonstrate that smaller prediction errors provide a limit to how much variation in biological ageing can be captured by methylation and provide evidence that age predictors from small samples are prone to confounding by cell composition. Our predictor shows a similar or better performance in non-blood tissues including saliva, endometrium, breast, liver, adipose and muscle, compared with Horvaths across-tissue age predictor.

bioinformatics↗

bioRxiv2018

Common loci underlie natural variation in diverse toxin responses

Phenotypic complexity is caused by the contributions of environmental factors and multiple genetic loci, interacting or acting independently. Studies of yeast and Arabidopsis found that the majority of natural variation across phenotypes is attributable to independent additive quantitative trait loci (QTL). Detected loci in these organisms explain most of the estimated heritable variation. By contrast, many heritable components underlying phenotypic variation in metazoan models remain undetected. Before the relative impacts of additive and interactive variance components on metazoan phenotypic variation can be dissected, high replication and precise phenotypic measurements are required to obtain sufficient statistical power to detect loci contributing to this missing heritability. Here, we used a panel of 296 recombinant inbred advanced intercross lines of Caenorhabditis elegans and a high-throughput fitness assay to detect loci underlying responses to 16 different toxins, including heavy metals, chemotherapeutic drugs, pesticides, and neuropharmaceuticals. Using linkage mapping, we identified 82 QTL that underlie variation in responses to these toxins and predicted the relative contributions of additive loci and genetic interactions across various growth parameters. Additionally, we identified three genomic regions that impact responses to multiple classes of toxins. These QTL hotspots could represent common factors impacting toxin responses. We went further to generate near-isogenic lines and chromosome-substitution strains and then experimentally validated these QTL hotspots, implicating additive and interactive loci that underlie toxin-response variation.

genetics↗

bioRxiv2016

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here, we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results suggest that variants in the DISC1 Interactome effect the risk of psychiatric illness through altered expression of schizophrenia-associated genes. The biological impact of rare variants highlighted here merit further study.

genetics↗