Biology subjects

Coleman, C.

Publications and source records attributed to Coleman, C..

4 recordsLinked to original sources

bioRxiv2023

A genome-wide cytotoxicity screen of Cluster F1 mycobacteriophage Girr reveals novel inhibitors of Mycobacterium smegmatis growth

Over the past decade, thousands of bacteriophage genomes have been sequenced and annotated. A striking observation from this work is that known structural features and functions cannot be assigned for >65% of the encoded proteins. One approach to begin experimentally elucidating the function of these uncharacterized gene products is genome-wide screening to identify phage genes that confer phenotypes of interest like inhibition of host growth. This study describes the results of a screen evaluating the effects of overexpressing each gene encoded by the temperate Cluster F1 mycobacteriophage Girr on the growth of the host bacterium Mycobacterium smegmatis. Overexpression of 29 of the 102 Girr genes ([~]28% of the genome) resulted in mild to severe cytotoxicity. Of the 29 toxic genes described, 12 have no known function (NKF) and are predominately small proteins of <125 amino acids. Overexpression of the majority of these 12 cytotoxic NKF proteins resulted in moderate to severe growth reduction and represent novel antimicrobial products. The remaining 17 toxic genes have predicted functions, encoding products involved in phage structure, DNA replication/modification, DNA binding/gene regulation, or other enzymatic activity. Comparison of this dataset with prior genome-wide cytotoxicity screens of mycobacteriophages Waterfoul and Hammy reveals some common functional themes, though several of the predicted Girr functions associated with cytotoxicity in our report, including genes involved in lysogeny, have not been described previously. This study, completed as part of the HHMI-supported SEA-GENES project, highlights the power of parallel, genome-wide overexpression screens to identify novel interactions between phages and their hosts.

microbiology↗

bioRxiv2023

Surveillance of 16 UK native bat species through conservationist networks uncovers coronaviruses with zoonotic potential

There has been limited characterisation of bat-borne coronaviruses in Europe. Here, we screened for coronaviruses in 48 faecal samples from 16 of the 17 bat species breeding in the UK, collected through a bat rehabilitation and conservationist network. We recovered nine (two novel) complete genomes across six bat species: four alphacoronaviruses, a MERS-related betacoronavirus, and four closely related sarbecoviruses. We demonstrate that at least one of these sarbecoviruses can bind and use the human ACE2 receptor for infecting human cells, albeit suboptimally. Additionally, the spike proteins of these sarbecoviruses possess an R-A-K-Q motif, which lies only one nucleotide mutation away from a furin cleavage site (FCS) that enhances infectivity in other coronaviruses, including SARS-CoV-2. However, mutating this motif to an FCS does not enable spike cleavage. Overall, while UK sarbecoviruses would require further molecular adaptations to infect humans, their zoonotic risk is unknown and warrants closer surveillance.

genomics↗

bioRxiv2022

Transposable elements drive the evolution of metazoan zinc finger genes

Cys2-His2 Zinc finger genes (ZNFs) form the largest family of transcription factors in metazoans. ZNF evolution is highly dynamic and characterized by the rapid expansion and contraction of numerous subfamilies across the animal phylogeny. The forces and mechanisms underlying rapid ZNF evolution remain poorly understood, but there is growing evidence that the targeting and repression of lineage-specific transposable elements (TEs) plays a major role in the diversification of the Kruppel-associated box ZNF (KZNF) subfamily, which predominates in tetrapod genomes. At present, it is unknown whether this function and co-evolutionary relationship is unique to KZNFs, or a broader feature of metazoan ZNFs. Here, we present evidence that genomic conflict with TEs has been a central driver in the diversification of ZNFs in animals. Sampling from more than 4000 animal genome assemblies, we show that the copy number of retroelements correlates with that of ZNFs across at least 750 million years of metazoan evolution, both within and between major taxonomic groups. Using computational predictions, we show that ZNFs preferentially bind TEs in a diverse set of representative animal species. We further investigate one of the most expansive ZNF subfamilies found in cyprinid fish, which are characterized by a conserved domain we dubbed the Fish N-terminal Zinc-finger associated (FiNZ) domain. FiNZ-ZNFs have dramatically expanded in several fish species, including the zebrafish in which we predict ~700 FiNZ-ZNF genes. Almost all are located on the long arm of chromosome 4, and recent duplicates are evolving adaptively under positive selection. Like mammalian KZNFs, the bulk of zebrafish FiNZ-ZNFs are expressed in waves at the onset of zygotic genome activation. Blocking FiNZ-ZNF translation using morpholinos during early zebrafish embryogenesis results in a global de-repression of young, transcriptionally active TEs, likely driven by the failure to establish heterochromatin over these elements. Together, these data suggest that ZNF diversification has been intimately connected to TE expansion throughout animal evolution and that families of ZNFs have been deployed independently in fish and mammals to repress TEs during early embryogenesis.

genomics↗

bioRxiv2022

Multi-omic profiling of the developing human cerebral cortex at the single cell level

The cellular complexity of the human brain is established via dynamic changes in gene expression throughout development that is mediated, in part, by the spatiotemporal activity of cis-regulatory elements. We simultaneously profiled gene expression and chromatin accessibility in 45,549 cortical nuclei across 6 broad developmental time-points from fetus to adult. We identified cell-type specific domains in which chromatin accessibility is highly correlated with gene expression. Differentiation pseudotime trajectory analysis indicates that chromatin accessibility at cis-regulatory elements precedes transcription and that dynamic changes in chromatin structure play a critical role in neuronal lineage commitment. In addition, we mapped cell-type and temporally specific genetic loci implicated in neuropsychiatric traits, including schizophrenia and bipolar disorder. Together, our results describe the complex regulation of cell composition at critical stages in lineage determination, serve as a developmental blueprint of the human brain and shed light on the impact of spatiotemporal alterations in gene expression on neuropsychiatric disease. One-Sentence SummarySimultaneous profiling of gene expression and chromatin accessibility in single nuclei from 6 developmental time-points sheds light on cell fate determination in the human cerebral cortex and on the molecular basis of neuropsychiatric disease.

neuroscience↗