Publications by year
In Press
Malekizadeh Y, Williams G, Kelson M, Whitfield D, Mill J, Collier D, Ballard C, Jeffries A, Creese B (In Press). Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects. Alzheimer's and Dementia: Translational Research and Clinical Interventions
2021
Weightman Potter PG, Washer SJ, Jeffries AR, Holley JE, Gutowski NJ, Dempster EL, Beall C (2021). Attenuated Induction of the Unfolded Protein Response in Adult Human Primary Astrocytes in Response to Recurrent Low Glucose.
FRONTIERS IN ENDOCRINOLOGY,
12 Author URL.
Davies J, Franklin A, Commin G, Walker E, Policicchio S, Jeffries A, Burrage J, Chioza B, Liu J, Bray N, et al (2021). CELL-TYPE-SPECIFIC PATTERNS OF DNA METHYLATION IN THE DEVELOPING HUMAN BRAIN.
Author URL.
Imm J, Pishva E, Ali M, Kerrigan TL, Jeffries A, Burrage J, Glaab E, Cope EL, Jones KM, Allen ND, et al (2021). Characterization of DNA Methylomic Signatures in Induced Pluripotent Stem Cells During Neuronal Differentiation.
Frontiers in Cell and Developmental Biology,
9Abstract:
Characterization of DNA Methylomic Signatures in Induced Pluripotent Stem Cells During Neuronal Differentiation
In development, differentiation from a pluripotent state results in global epigenetic changes, although the extent to which this occurs in induced pluripotent stem cell-based neuronal models has not been extensively characterized. In the present study, induced pluripotent stem cell colonies (33Qn1 line) were differentiated and collected at four time-points, with DNA methylation assessed using the Illumina Infinium Human Methylation EPIC BeadChip array. Dynamic changes in DNA methylation occurring during differentiation were investigated using a data-driven trajectory inference method. We identified a large number of Bonferroni-significant loci that showed progressive alterations in DNA methylation during neuronal differentiation. A gene–gene interaction network analysis identified 60 densely connected genes that were influential in the differentiation of neurons, with STAT3 being the gene with the highest connectivity.
Abstract.
Steg LC, Shireby GL, Imm J, Davies JP, Franklin A, Flynn R, Namboori SC, Bhinge A, Jeffries AR, Burrage J, et al (2021). Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons.
Mol Brain,
14(1).
Abstract:
Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons.
Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.
Abstract.
Author URL.
Goode O, Smith A, Zarkan A, Cama J, Invergo BM, Belgami D, Caño-Muñiz S, Metz J, O’Neill P, Jeffries A, et al (2021). Persister Escherichia coli Cells Have a Lower Intracellular pH than Susceptible Cells but Maintain Their pH in Response to Antibiotic Treatment.
mBio,
12(4).
Abstract:
Persister Escherichia coli Cells Have a Lower Intracellular pH than Susceptible Cells but Maintain Their pH in Response to Antibiotic Treatment
Persister and VBNC cells can phenotypically survive environmental stressors, such as antibiotic treatment, limitation of nutrients, and acid stress, and have been linked to chronic infections and antimicrobial resistance. It has recently been suggested that pH regulation might play a role in an organism’s phenotypic survival to antibiotics; however, this hypothesis remains to be tested.
Abstract.
Kemp SA, Collier DA, Datir RP, Ferreira IATM, Gayed S, Jahun A, Hosmillo M, Rees-Spear C, Mlcochova P, Lumb IU, et al (2021). SARS-CoV-2 evolution during treatment of chronic infection.
Nature,
592(7853), 277-282.
Abstract:
SARS-CoV-2 evolution during treatment of chronic infection
The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.
Abstract.
Collier DA, De Marco A, Ferreira IATM, Meng B, Datir RP, Walls AC, Kemp SA, Bassi J, Pinto D, Silacci-Fregni C, et al (2021). Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies.
NATURE,
593(7857), 136-+.
Author URL.
Masoli JAH, Jeffries A, Temperton B, Auckland C, Michelsen M, Warwick-Dugdale J, Manley R, Farbos A, Ellard S, Knight B, et al (2021). Viral genetic sequencing identifies staff transmission of COVID-19 is important in a community hospital outbreak.
Abstract:
Viral genetic sequencing identifies staff transmission of COVID-19 is important in a community hospital outbreak
AbstractBackgroundWe have successfully used whole-genome sequencing to provide additional information for transmission pathways in infectious spread. We report and interpret genomic sequencing results in clinical context from a large outbreak of COVID-19 with 46 cases across staff and patients in a community hospital in the UK.MethodsFollowing multiple symptomatic cases within a two-week period, all staff and patients were screened by RT-PCR and staff subsequently had serology tests.ResultsThirty staff (25%) and 16 patients (62%) tested positive for COVID-19. Genomic sequencing data showed significant overlap of viral haplotypes in staff who had overlapping shift patterns. Patient haplotypes were more distinct from each other but had overlap with staff haplotypes.ConclusionsThis study includes clinical and genomic epidemiological detail that demonstrates the value of a combined approach. Viral genetic sequencing has identified that staff transmission of COVID-19 was important in this community hospital outbreak.Key pointsDetailed analysis of a large community hospital outbreak in older adults and staff with concurrent clinical and genomic data, including working patterns.Staff transmission was important in this community hospital outbreak.We found plausible associations between staff and patient cases.
Abstract.
2020
Potter PGW, Washer S, Jeffries AR, Holley JE, Gutowski NJ, Dempster E, Beall C (2020). Analysis of the transcriptome and DNA methylome in response to acute and recurrent low glucose in human primary astrocytes.
Abstract:
Analysis of the transcriptome and DNA methylome in response to acute and recurrent low glucose in human primary astrocytes
ABSTRACTAims/hypothesisRecurrent hypoglycaemia (RH) is a major side-effect of intensive insulin therapy for people with diabetes. Changes in hypoglycaemia sensing by the brain contribute to the development of impaired counterregulatory responses to and awareness of hypoglycaemia. Little is known about the intrinsic changes in human astrocytes in response to acute and recurrent low glucose (RLG) exposure.MethodsHuman primary astrocytes (HPA) were exposed to zero, one, three or four bouts of low glucose (0.1 mmol/l) for three hours per day for four days to mimic RH. On the fourth day, DNA and RNA were collected. Differential gene expression and ontology analyses were performed using DESeq2 and GOseq respectively. DNA methylation was assessed using the Infinium MethylationEPIC BeadChip platform.Results24 differentially expressed genes (DEGs) were detected (after correction for multiple comparisons). One bout of low glucose exposure had the largest effect on gene expression. Pathway analyses revealed that endoplasmic-reticulum (ER) stress-related genes such as HSPA5, XBP1, and MANF, involved in the unfolded protein response (UPR), were all significantly increased following LG exposure, which was diminished following RLG. There was little correlation between differentially methylated positions and changes in gene expression yet the number of bouts of LG exposure produced distinct methylation signatures.Conclusions/interpretationThese data suggest that exposure of human astrocytes to transient LG triggers activation of genes involved in the UPR linked to endoplasmic reticulum (ER) stress. Following RLG, the activation of UPR related genes was diminished, suggesting attenuated ER stress. This may be mediated by metabolic adaptations to better preserve intracellular and/or ER ATP levels, but this requires further investigation.
Abstract.
Jeffries AR, Leung SK, Castanho I, Moore K, Davies JP, Dempster EL, Bray NJ, O‘Neill P, Tseng E, Ahmed Z, et al (2020). Full-length transcript sequencing of human and mouse identifies widespread isoform diversity and alternative splicing in the cerebral cortex.
Abstract:
Full-length transcript sequencing of human and mouse identifies widespread isoform diversity and alternative splicing in the cerebral cortex
AbstractAlternative splicing is a post-transcriptional regulatory mechanism producing multiple distinct mRNA molecules from a single pre-mRNA. Alternative splicing has a prominent role in the central nervous system, impacting neurodevelopment and various neuronal functions as well as being increasingly implicated in brain disorders including autism, schizophrenia and Alzheimer’s disease. Standard short-read RNA-Seq approaches only sequence fragments of the mRNA molecule, making it difficult to accurately characterize the true nature of RNA isoform diversity. In this study, we used long-read isoform sequencing (Iso-Seq) to generate full-length cDNA sequences and map transcript diversity in the human and mouse cerebral cortex. We identify widespread RNA isoform diversity amongst expressed genes in the cortex, including many novel transcripts not present in existing genome annotations. Alternative splicing events were found to make a major contribution to RNA isoform diversity in the cortex, with intron retention being a relatively common event associated with nonsense-mediated decay and reduced transcript expression. of note, we found evidence for transcription from novel (unannotated genes) and fusion events between neighbouring genes. Although global patterns of RNA isoform diversity were found to be generally similar between human and mouse cortex, we identified some notable exceptions. We also identified striking developmental changes in transcript diversity, with differential transcript usage between human adult and fetal cerebral cortex. Finally, we found evidence for extensive isoform diversity in genes associated with autism, schizophrenia and Alzheimer’s disease. Our data confirm the importance of alternative splicing in the cerebral cortex, dramatically increasing transcriptional diversity and representing an important mechanism underpinning gene regulation in the brain. We provide this transcript level data as a resource to the scientific community.
Abstract.
Castanho I, Murray TK, Leung SK, Hannon E, Jeffries A, Lunnon K, Ahmed Z, Mill J (2020). Genome‐wide DNA methylation signatures of tau and amyloid neuropathology. Alzheimer's & Dementia, 16(S3).
Mizuno K, Jeffries AR, Abel T, Giese KP (2020). Long-lasting transcription in hippocampal area CA1 after contextual fear conditioning.
Neurobiol Learn Mem,
172Abstract:
Long-lasting transcription in hippocampal area CA1 after contextual fear conditioning.
A fundamental question is how memory is stored for several weeks and even longer. A long-lasting increase in gene transcription has been suggested to mediate such long-term memory storage. Here, we used contextual fear conditioning in mice to search for lasting transcription that may contribute to long-term memory storage. Our study focussed on hippocampal area CA1, which has been suggested to have a role for at least one week in contextual fear memory. Using an unbiased microarray analysis followed by confirmatory quantitative real-time PCR, we identified an upregulation of two transcription factors, Fosl2 and Nfil3, which lasted for seven days after conditioning. To our knowledge these are the longest transcriptional changes ever detected in the hippocampus after contextual fear conditioning. Thus, our findings suggest novel transcriptional candidates for long-term memory storage.
Abstract.
Author URL.
Steg LC, Shireby GL, Imm J, Davies JP, Flynn R, Namboori SC, Bhinge A, Jeffries AR, Burrage J, Neilson GWA, et al (2020). Novel Epigenetic Clock for Fetal Brain Development Predicts Fetal Epigenetic Age for iPSCs and iPSC-Derived Neurons.
Steg LC, Shireby GL, Imm J, Davies JP, Franklin A, Flynn R, Namboori SC, Bhinge A, Jeffries AR, Burrage J, et al (2020). Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons.
Abstract:
Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons
AbstractInduced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and iPSC-derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.
Abstract.
Borsini A, Stangl D, Jeffries AR, Pariante CM, Thuret S (2020). The role of omega-3 fatty acids in preventing glucocorticoid-induced reduction in human hippocampal neurogenesis and increase in apoptosis.
Transl Psychiatry,
10(1).
Abstract:
The role of omega-3 fatty acids in preventing glucocorticoid-induced reduction in human hippocampal neurogenesis and increase in apoptosis.
Glucocorticoids have been suggested to be involved in several neuropsychiatric disorders, including depression. One of the possible mechanisms through which glucocorticoids contribute to the development of the depressive symptomatology is via regulation of distinct neurogenic mechanisms in the brain. A preventive or protective approach for these patients might be the use of omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are known for they neuroprotective properties. We used the human hippocampal progenitor cell line HPC0A07/03C and pre-treated cells with either EPA or DHA, followed by treatment with the glucocorticoid cortisol either alone, or in co-treatment with the same n-3 PUFA during subsequent 3 days of proliferation and 7 days of differentiation. During proliferation, both EPA and DHA were able to prevent cortisol-induced reduction in proliferation and increase in apoptosis, when used in pre-treatment, and both pre- and co-treatment. During differentiation, EPA was able to prevent cortisol-induced reduction in neurogenesis and increase in apoptosis, when used in pre-treatment, and both pre- and co-treatment only during the proliferation stage; however, DHA required continuous treatment also during the differentiation stage to prevent cortisol-induced reduction in neurogenesis. Using transcriptomic analyses, we showed that both EPA and DHA regulated pathways involved in oxidative stress and immune response [e.g. nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Signal transducer and activator of transcription 3 (STAT3), Interferon (IFN) and Interleukin (IL)-1 signaling], whereas DHA also regulated pathways involved in cell development and neuronal formation [e.g. cAMP-response element binding protein (CREB) signaling]. We provide the first evidence for treatment with both EPA and DHA to prevent cortisol-induced reduction in human hippocampal neurogenesis, and identify novel molecular mechanisms underlying these effects.
Abstract.
Author URL.
Tovy A, Reyes JM, Gundry MC, Brunetti L, Lee-Six H, Petljak M, Park HJ, Guzman AG, Rosas C, Jeffries AR, et al (2020). Tissue-Biased Expansion of DNMT3A-Mutant Clones in a Mosaic Individual is Associated with Conserved Epigenetic Erosion.
Cell Stem Cell,
27(2), 326-335.e4.
Abstract:
Tissue-Biased Expansion of DNMT3A-Mutant Clones in a Mosaic Individual is Associated with Conserved Epigenetic Erosion.
DNA methyltransferase 3A (DNMT3A) is the most commonly mutated gene in clonal hematopoiesis (CH). Somatic DNMT3A mutations arise in hematopoietic stem cells (HSCs) many years before malignancies develop, but difficulties in comparing their impact before malignancy with wild-type cells have limited the understanding of their contributions to transformation. To circumvent this limitation, we derived normal and DNMT3A mutant lymphoblastoid cell lines from a germline mosaic individual in whom these cells co-existed for nearly 6 decades. Mutant cells dominated the blood system, but not other tissues. Deep sequencing revealed similar mutational burdens and signatures in normal and mutant clones, while epigenetic profiling uncovered the focal erosion of DNA methylation at oncogenic regulatory regions in mutant clones. These regions overlapped with those sensitive to DNMT3A loss after DNMT3A ablation in HSCs and in leukemia samples. These results suggest that DNMT3A maintains a conserved DNA methylation pattern, the erosion of which provides a distinct competitive advantage to hematopoietic cells.
Abstract.
Author URL.
Castanho I, Murray TK, Hannon E, Jeffries A, Walker E, Laing E, Baulf H, Harvey J, Bradshaw L, Randall A, et al (2020). Transcriptional Signatures of Tau and Amyloid Neuropathology.
Cell Rep,
30(6), 2040-2054.e5.
Abstract:
Transcriptional Signatures of Tau and Amyloid Neuropathology.
Alzheimer's disease (AD) is associated with the intracellular aggregation of hyperphosphorylated tau and the accumulation of β-amyloid in the neocortex. We use transgenic mice harboring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the progression of tau and amyloid pathology. rTg4510 mice are characterized by widespread transcriptional differences in the entorhinal cortex with changes paralleling neuropathological burden across multiple brain regions. Differentially expressed transcripts overlap with genes identified in genetic studies of familial and sporadic AD. Systems-level analyses identify discrete co-expression networks associated with the progressive accumulation of tau that are enriched for genes and pathways previously implicated in AD pathology and overlap with co-expression networks identified in human AD cortex. Our data provide further evidence for an immune-response component in the accumulation of tau and reveal molecular pathways associated with the progression of AD neuropathology.
Abstract.
Author URL.
Malekizadeh Y, Williams G, Kelson M, Whitfield D, Mill J, Collier DA, Ballard C, Jeffries AR, Creese B (2020). Whole transcriptome <i>in-silico</i> screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects.
Abstract:
Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects
AbstractINTRODUCTIONStroke/thromboembolic events, infections and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events.METHODWhole transcriptome signatures were generated for SH-SY5Y cells treated with amisulpride, risperidone and volinanserin using RNA-sequencing. Bioinformatic analysis was performed which scored the association between antipsychotic signatures and expression data from 415,252 samples in the NCBI GEO repository.RESULTSAtherosclerosis, venous thromboembolism and influenza NCBI GEO-derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (e.g. BDNF, PDGFR-beta, TNF, TGF-beta, selenoamino acid metabolism and influenza infection).CONCLUSIONThese findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events.COMPETING INTERESTSCB has received grants and personal fees from ACADIA Pharmaceuticals and Lundbeck, and personal fees from Heptares, Roche, Lilly, Otsuka, Orion, GlaxoSmithKline and Pfizer. DAC is an employee of Eli Lilly and Company Ltd.
Abstract.
Malekizadeh Y, Williams G, Kelson M, Whitfield DR, Mill J, Collier DA, Ballard C, Jeffries AR, Creese B (2020). Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects.
Abstract:
Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects
Abstract
. BACKGROUND
Stroke/thromboembolic events, infections and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events.
METHODS
Whole transcriptome signatures were generated for SH-SY5Y cells treated with amisulpride, risperidone and volinanserin using RNA-sequencing. Bioinformatic analysis was performed which scored the association between antipsychotic signatures and expression data from 415,252 samples in the NCBI GEO repository.
RESULTS
Atherosclerosis, venous thromboembolism and influenza NCBI GEO-derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (e.g. BDNF, PDGFR-beta, TNF, TGF-beta, selenoamino acid metabolism and influenza infection).
CONCLUSIONS
These findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events.
Abstract.
2019
Jeffries A, Bray N, O'Neill P, Poschmann J, Hannon E, Mill J (2019). ALTERNATIVE SPLICING AND ISOFOROM DIVERSITY IN THE DEVELOPING BRAIN: RELEVANCE FOR NEUROPSYCHIATRIC DISEASE.
Author URL.
Washer S, Burrage J, Mill J, Jeffries A, Dempster E (2019). FUNCTIONAL ANALYSIS OF THE SCHIZOPHRENIA ASSOCIATED GENE AS3MT IN SH-SY5Y NEUROBLASTOMA CELLS.
Author URL.
Washer S, Oguro-Ando A, Burrage J, Mill J, Jeffries A, Dempster E (2019). FUNCTIONAL ANALYSIS OF THE SCHIZOPHRENIA ASSOCIATED GENE AS3MT IN SH-SY5Y NEUROBLASTOMA CELLS.
Author URL.
Jones SE, Lane JM, Wood AR, van Hees VT, Tyrrell J, Beaumont RN, Jeffries AR, Dashti HS, Hillsdon M, Ruth KS, et al (2019). Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms.
Nature CommunicationsAbstract:
Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms
Using genome-wide data from 697,828 UK Biobank and 23andMe participants, we increase the number of identified loci associated with being a morning person, a behavioural indicator of a person’s underlying circadian rhythm, from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we demonstrate that the chronotype loci influence sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 minutes earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans.
Abstract.
Jeffries AR, Maroofian R, Salter CG, Chioza BA, Cross HE, Patton MA, Dempster E, Temple IK, Mackay DJG, Rezwan FI, et al (2019). Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.
Genome Res,
29(7), 1057-1066.
Abstract:
Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.
Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.
Abstract.
Author URL.
Warmington RJ, Kay W, Jeffries A, O'Neill P, Farbos A, Moore K, Bebber DP, Studholme DJ (2019). High-Quality Draft Genome Sequence of the Causal Agent of the Current Panama Disease Epidemic.
Microbiol Resour Announc,
8(36).
Abstract:
High-Quality Draft Genome Sequence of the Causal Agent of the Current Panama Disease Epidemic.
We present a high-quality draft genome assembly for Fusarium oxysporum f. sp. cubense tropical race 4 (Fusarium odoratissimum), assembled from PacBio reads and consisting of 15 contigs with a total assembly size of 48.59 Mb. This strain appears to belong to vegetative compatibility group complex 01213/16.
Abstract.
Author URL.
Toste CC, Duarte RRR, Jeffries AR, Selvackadunco S, Troakes C, O'Donovan MC, Hill MJ, Bray NJ (2019). No Effect of Genome-Wide Significant Schizophrenia Risk Variation at the DRD2 Locus on the Allelic Expression of DRD2 in Postmortem Striatum.
Mol Neuropsychiatry,
5(4), 212-217.
Abstract:
No Effect of Genome-Wide Significant Schizophrenia Risk Variation at the DRD2 Locus on the Allelic Expression of DRD2 in Postmortem Striatum.
A genome-wide significant association has been reported between non-coding variants at the dopamine D2 receptor (DRD2) gene locus and schizophrenia. However, effects of identified schizophrenia risk alleles on DRD2 function are yet to be demonstrated. Using highly sensitive measures of allele-specific expression, we have assessed cis-regulatory effects associated with genotype at lead SNP rs2514218 on DRD2expression in the adult human striatum. No significant differences were observed in the extent of allelic expression imbalance between samples that were genomic heterozygotes for rs2514218 (where cis-regulatory effects of the risk allele are compared with those of the non-risk allele within individual subjects) and samples that were homozygous for rs2514218 (where cis-regulatory effects of this SNP on each expressed DRD2 allele will be equal). We therefore conclude that rs2514218 genotype is not associated with large effects on overall DRD2 RNA expression, at least in postmortem adult striatum. Alternative explanations for the genetic association between this variant and schizophrenia include effects on DRD2 that are transcript specific, restricted to minor DRD2-expressing cell populations or elicited only under certain physiological circumstances, or mediation through effects on another gene (or genes) at the locus.
Abstract.
Author URL.
O'Brien H, Hannon E, Spiers H, Jeffries A, McLaughlin G, Davies W, Anney R, Hill M, O'Donovan M, Mill J, et al (2019). TRANSCRIPTOMIC STUDIES OF THE HUMAN PRENATAL BRAIN.
Author URL.
Castanho I, Murray T, Hannon E, Jeffries A, Walker E, Laing E, Baulf H, Harvey J, Randall A, Moore K, et al (2019). Transcriptional Signatures of Progressive Neuropathology in Transgenic Models of Tau and Amyloid Pathology.
2018
Muto V, Flex E, Kupchinsky Z, Primiano G, Galehdari H, Dehghani M, Cecchetti S, Carpentieri G, Rizza T, Mazaheri N, et al (2018). Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration.
Neurology,
91(4), e319-e330.
Abstract:
Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration.
OBJECTIVE: to characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families. METHODS: We used whole-exome sequencing (WES) (families 1 and 2) and a combined approach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating SQSTM1 mutation on protein function and the effect of impaired SQSTM1 function on autophagy. We analyzed the consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in vivo using zebrafish as a model. RESULTS: We identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875_876insT and c.934_936delinsTGA). We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux. The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have been followed up for >20 years. CONCLUSIONS: This study offers an accurate clinical characterization of this recently recognized neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy.
Abstract.
Author URL.
Mis MA, Rogers MF, Jeffries AR, Wilbrey AL, Chen L, Yang Y, Dib-Hajj S, Waxman SG, Stevens EB, Randall AD, et al (2018). Differential aging-related changes in neurophysiology and gene expression in IB4-positive and IB4-negative nociceptive neurons.
Aging Cell,
17(4).
Abstract:
Differential aging-related changes in neurophysiology and gene expression in IB4-positive and IB4-negative nociceptive neurons.
Despite pain prevalence altering with age, the effects of aging on the properties of nociceptors are not well understood. Nociceptors, whose somas are located in dorsal root ganglia, are frequently divided into two groups based on their ability to bind isolectin B4 (IB4). Here, using cultured neurons from 1-, 3-, 5-, 8-, 12-, and 18-month-old mice, we investigate age-dependent changes in IB4-positive and IB4-negative neurons. Current-clamp experiments at physiological temperature revealed nonlinear changes in firing frequency of IB4-positive, but not IB4-negative neurons, with a peak at 8 months. This was likely due to the presence of proexcitatory conductances activated at depolarized membrane potentials and significantly higher input resistances found in IB4-positive neurons from 8-month-old mice. Repetitive firing in nociceptors is driven primarily by the TTX-resistant sodium current, and indeed, IB4-positive neurons from 8-month-old mice were found to receive larger contributions from the TTX-resistant window current around the resting membrane potential. To further address the mechanisms behind these differences, we performed RNA-seq experiments on IB4-positive and IB4-negative neurons from 1-, 8-, and 18-month-old mice. We found a larger number of genes significantly affected by age within the IB4-positive than IB4-negative neurons from 8-month-old mice, including known determinants of nociceptor excitability. The above pronounced age-dependent changes at the cellular and molecular levels in IB4-positive neurons point to potential mechanisms behind the reported increase in pain sensitivity in middle-aged rodents and humans, and highlight the possibility of targeting a particular group of neurons in the development of age-tailored pain treatments.
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Jeffries AR, Maroofian R, Salter CG, Chioza BA, Cross HE, Patton MA, Temple IK, Mackay D, Rezwan FI, Aksglæde L, et al (2018). Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.
Abstract:
Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging
AbstractGermline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3A (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated to genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. Notably, these findings were most striking in a carrier of the AML associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders; NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders.
Abstract.
Tovy A, Park HJ, Reyes JM, Guzman A, Rau RE, Jeffries A, Jonnathan M, Baple E, Crosby A, Petljak M, et al (2018). Mosaic DNMT3A Germline Mutation As a Model for Mutant DNMT3A Competitive Advantage in the Blood Lineage.
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O’Brien HE, Hannon E, Jeffries AR, Davies W, Hill MJ, Anney RJ, O’Donovan MC, Mill J, Bray NJ (2018). Sex differences in gene expression in the human fetal brain.
Abstract:
Sex differences in gene expression in the human fetal brain
ABSTRACTWidespread structural, chemical and molecular differences have been reported between the male and female human brain. Although several neurodevelopmental disorders are more commonly diagnosed in males, little is known regarding sex differences in early human brain development. Here, we used RNA sequencing data from a large collection of human brain samples from the second trimester of gestation (N = 120) to assess sex biases in gene expression within the human fetal brain. In addition to 43 genes (102 Ensembl transcripts) transcribed from the Y-chromosome in males, we detected sex differences in the expression of 2558 autosomal genes (2723 Ensembl transcripts) and 155 genes on the X-chromosome (207 Ensembl transcripts) at a false discovery rate (FDR) < 0.1. Genes exhibiting sex-biased expression in human fetal brain are enriched for high-confidence risk genes for autism and other developmental disorders. Male-biased genes are enriched for expression in neural progenitor cells, whereas female-biased genes are enriched for expression in Cajal-Retzius cells and glia. All gene- and transcript-level data are provided as an online resource (available at http://fgen.psycm.cf.ac.uk/FBSeq1) through which researchers can search, download and visualize data pertaining to sex biases in gene expression during early human brain development.
Abstract.
2017
Jeffries AR, Mill J (2017). Profiling Regulatory Variation in the Brain: Methods for Exploring the Neuronal Epigenome.
Biol Psychiatry,
81(2), 90-91.
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Devall M, Smith RG, Jeffries A, Hannon E, Davies MN, Schalkwyk L, Mill J, Weedon M, Lunnon K (2017). Regional differences in mitochondrial DNA methylation in human post-mortem brain tissue.
Clin Epigenetics,
9Abstract:
Regional differences in mitochondrial DNA methylation in human post-mortem brain tissue.
BACKGROUND: DNA methylation is an important epigenetic mechanism involved in gene regulation, with alterations in DNA methylation in the nuclear genome being linked to numerous complex diseases. Mitochondrial DNA methylation is a phenomenon that is receiving ever-increasing interest, particularly in diseases characterized by mitochondrial dysfunction; however, most studies have been limited to the investigation of specific target regions. Analyses spanning the entire mitochondrial genome have been limited, potentially due to the amount of input DNA required. Further, mitochondrial genetic studies have been previously confounded by nuclear-mitochondrial pseudogenes. Methylated DNA Immunoprecipitation Sequencing is a technique widely used to profile DNA methylation across the nuclear genome; however, reads mapped to mitochondrial DNA are often discarded. Here, we have developed an approach to control for nuclear-mitochondrial pseudogenes within Methylated DNA Immunoprecipitation Sequencing data. We highlight the utility of this approach in identifying differences in mitochondrial DNA methylation across regions of the human brain and pre-mortem blood. RESULTS: We were able to correlate mitochondrial DNA methylation patterns between the cortex, cerebellum and blood. We identified 74 nominally significant differentially methylated regions (p
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Imm J, Kerrigan TL, Jeffries A, Lunnon K (2017). Using induced pluripotent stem cells to explore genetic and epigenetic variation associated with Alzheimer's disease.
Epigenomics,
9(11), 1455-1468.
Abstract:
Using induced pluripotent stem cells to explore genetic and epigenetic variation associated with Alzheimer's disease.
It is thought that both genetic and epigenetic variation play a role in Alzheimer's disease initiation and progression. With the advent of somatic cell reprogramming into induced pluripotent stem cells it is now possible to generate patient-derived cells that are able to more accurately model and recapitulate disease. Furthermore, by combining this with recent advances in (epi)genome editing technologies, it is possible to begin to examine the functional consequence of previously nominated genetic variants and infer epigenetic causality from recently identified epigenetic variants. In this review, we explore the role of genetic and epigenetic variation in Alzheimer's disease and how the functional relevance of nominated loci can be investigated using induced pluripotent stem cells and (epi)genome editing techniques.
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2016
Jeffries AR, Uwanogho DA, Cocks G, Perfect LW, Dempster E, Mill J, Price J (2016). Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming.
RNA,
22(10), 1620-1630.
Abstract:
Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming.
Clonal level random allelic expression imbalance and random monoallelic expression provides cellular heterogeneity within tissues by modulating allelic dosage. Although such expression patterns have been observed in multiple cell types, little is known about when in development these stochastic allelic choices are made. We examine allelic expression patterns in human neural progenitor cells before and after epigenetic reprogramming to induced pluripotency, observing that loci previously characterized by random allelic expression imbalance (0.63% of expressed genes) are generally reset to a biallelic state in induced pluripotent stem cells (iPSCs). We subsequently neuralized the iPSCs and profiled isolated clonal neural stem cells, observing that significant random allelic expression imbalance is reestablished at 0.65% of expressed genes, including novel loci not found to show allelic expression imbalance in the original parental neural progenitor cells. Allelic expression imbalance was associated with altered DNA methylation across promoter regulatory regions, with clones characterized by skewed allelic expression being hypermethylated compared to their biallelic sister clones. Our results suggest that random allelic expression imbalance is established during lineage commitment and is associated with increased DNA methylation at the gene promoter.
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2015
Devall M, Burrage J, Caswell R, Johnson M, Troakes C, Al-Sarraj S, Jeffries AR, Mill J, Lunnon K (2015). A comparison of mitochondrial DNA isolation methods in frozen post-mortem human brain tissue--applications for studies of mitochondrial genetics in brain disorders.
Biotechniques,
59(4), 241-246.
Abstract:
A comparison of mitochondrial DNA isolation methods in frozen post-mortem human brain tissue--applications for studies of mitochondrial genetics in brain disorders.
Given that many brain disorders are characterized by mitochondrial dysfunction, there is a growing interest in investigating genetic and epigenetic variation in mitochondrial DNA (mtDNA). One major caveat for such studies is the presence of nuclear-mitochondrial pseudogenes (NUMTs), which are regions of the mitochondrial genome that have been inserted into the nuclear genome over evolution and, if not accounted for, can confound genetic studies of mtDNA. Here we provide the first systematic comparison of methods for isolating mtDNA from frozen post-mortem human brain tissue. Our data show that a commercial method from Miltenyi Biotec, which magnetically isolates mitochondria using antibodies raised against the mitochondrial import receptor subunit TOM22, gives significant mtDNA enrichment and should be considered the method of choice for mtDNA studies in frozen brain tissue.
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2014
Wong CCY, Meaburn EL, Ronald A, Price TS, Jeffries AR, Schalkwyk LC, Plomin R, Mill J (2014). Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits.
Mol Psychiatry,
19(4), 495-503.
Abstract:
Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits.
Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.
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2012
Jeffries AR, Perfect LW, Ledderose J, Schalkwyk LC, Bray NJ, Mill J, Price J (2012). Stochastic choice of allelic expression in human neural stem cells.
Stem Cells,
30(9), 1938-1947.
Abstract:
Stochastic choice of allelic expression in human neural stem cells.
Monoallelic gene expression, such as genomic imprinting, is well described. Less well-characterized are genes undergoing stochastic monoallelic expression (MA), where specific clones of cells express just one allele at a given locus. We performed genome-wide allelic expression assessment of human clonal neural stem cells derived from cerebral cortex, striatum, and spinal cord, each with differing genotypes. We assayed three separate clonal lines from each donor, distinguishing stochastic MA from genotypic effects. Roughly 2% of genes showed evidence for autosomal MA, and in about half of these, allelic expression was stochastic between different clones. Many of these loci were known neurodevelopmental genes, such as OTX2 and OLIG2. Monoallelic genes also showed increased levels of DNA methylation compared to hypomethylated biallelic loci. Identified monoallelic gene loci showed altered chromatin signatures in fetal brain, suggesting an in vivo correlate of this phenomenon. We conclude that stochastic allelic expression is prevalent in neural stem cells, providing clonal diversity to developing tissues such as the human brain.
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2010
Schalkwyk LC, Meaburn EL, Smith R, Dempster EL, Jeffries AR, Davies MN, Plomin R, Mill J (2010). Allelic skewing of DNA methylation is widespread across the genome.
Am J Hum Genet,
86(2), 196-212.
Abstract:
Allelic skewing of DNA methylation is widespread across the genome.
DNA methylation is assumed to be complementary on both alleles across the genome, although there are exceptions, notably in regions subject to genomic imprinting. We present a genome-wide survey of the degree of allelic skewing of DNA methylation with the aim of identifying previously unreported differentially methylated regions (DMRs) associated primarily with genomic imprinting or DNA sequence variation acting in cis. We used SNP microarrays to quantitatively assess allele-specific DNA methylation (ASM) in amplicons covering 7.6% of the human genome following cleavage with a cocktail of methylation-sensitive restriction enzymes (MSREs). Selected findings were verified using bisulfite-mapping and gene-expression analyses, subsequently tested in a second tissue from the same individuals, and replicated in DNA obtained from 30 parent-child trios. Our approach detected clear examples of ASM in the vicinity of known imprinted loci, highlighting the validity of the method. In total, 2,704 (1.5%) of our 183,605 informative and stringently filtered SNPs demonstrate an average relative allele score (RAS) change > or =0.10 following MSRE digestion. In agreement with previous reports, the majority of ASM ( approximately 90%) appears to be cis in nature, and several examples of tissue-specific ASM were identified. Our data show that ASM is a widespread phenomenon, with >35,000 such sites potentially occurring across the genome, and that a spectrum of ASM is likely, with heterogeneity between individuals and across tissues. These findings impact our understanding about the origin of individual phenotypic differences and have implications for genetic studies of complex disease.
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2003
Jeffries AR, Mungall AJ, Dawson E, Halls K, Langford CF, Murray RM, Dunham I, Powell JF (2003). beta-1,3-Glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation.
Mol Psychiatry,
8(7), 654-663.
Abstract:
beta-1,3-Glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation.
We have mapped and sequenced both chromosome breakpoints of a balanced t(6;11)(q14.2;q25) chromosome translocation that segregates with a schizophrenia-like psychosis. Bioinformatics analysis of the regions revealed a number of confirmed and predicted transcripts. No confirmed transcripts are disrupted by either breakpoint. The chromosome 6 breakpoint region is gene poor, the closest transcript being the serotonin receptor 1E (HTR1E) at 625 kb telomeric to the breakpoint. The chromosome 11 breakpoint is situated close to the telomere. The closest gene, beta-1,3-glucuronyltransferase (B3GAT1 or GlcAT-P), is 299 kb centromeric to the breakpoint. B3GAT1 is the key enzyme during the biosynthesis of the carbohydrate epitope HNK-1, which is present on a number of cell adhesion molecules important in neurodevelopment. Mice deleted for the B3GAT1 gene show defects in hippocampal long-term potentiation and in spatial memory formation. We propose that the translocation causes a positional effect on B3GAT1, affecting expression levels and making it a plausible candidate for the psychosis found in this family. More generally, regions close to telomeres are highly polymorphic in both sequence and length in the general population and several studies have implicated subtelomeric deletions as a common cause of idiopathic mental retardation. This leads us to the hypothesis that polymorphic or other variation of the 11q telomere may affect the activity of B3GAT1 and be a risk factor for schizophrenia and related psychoses in the general population.
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