Andrew J C Russell

Andrew J C Russell

EMBO Postdoctoral Fellow at the Broad Institute of MIT and Harvard in the laboratory of Dr. Fei Chen

Publications

Somatic mutation landscapes at single-molecule resolution

Published in Nature, 2021

Somatic mutations drive the development of cancer and may contribute to ageing and other diseases. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.

Recommended citation: Abascal F, Harvey LMR, Mitchell E, Lawson ARJ, Lensing SV, Ellis P, Russell AJC, Alcantara RE, Baez-Ortega A, Wang Y, Kwa EJ, Lee-Six H, Cagan A, Coorens THH, Chapman MS, Olafsson S, Leonard S, Jones D, Machado HE, Davies M, Øbro NF, Mahubani KT, Allinson K, Gerstung M, Saeb-Parsy K, Kent DG, Laurenti E, Stratton MR, Rahbari R, Campbell PJ, Osborne RJ, Martincorena I. Somatic mutation landscapes at single-molecule resolution. " Nature. 2021 Apr 28. doi: 10.1038/s41586-021-03477-4. Epub ahead of print. PMID: 33911282. https://pubmed.ncbi.nlm.nih.gov/33911282/

The Application of Single-Cell RNA Sequencing in Vaccinology

Published in J Immunol Res., 2020

Single-cell RNA sequencing allows highly detailed profiling of cellular immune responses from limited-volume samples, advancing prospects of a new era of systems immunology. The power of single-cell RNA sequencing offers various opportunities to decipher the immune response to infectious diseases and vaccines. Here, we describe the potential uses of single-cell RNA sequencing methods in prophylactic vaccine development, concentrating on infectious diseases including COVID-19. Using examples from several diseases, we review how single-cell RNA sequencing has been used to evaluate the immunological response to different vaccine platforms and regimens. By highlighting published and unpublished single-cell RNA sequencing studies relevant to vaccinology, we discuss some general considerations how the field could be enriched with the widespread adoption of this technology.

Recommended citation: Andrés Noé, Tamsin N Cargill, Carolyn M Nielsen, Andrew J C Russell, Eleanor Barnes. (2019). "The Application of Single-Cell RNA Sequencing in Vaccinology." J Immunol Res.. 2020:8624963. http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7411487/

The Malaria Cell Atlas: Single parasite transcriptomes across the complete Plasmodium life cycle

Published in Science, 2019

Malaria parasites adopt a remarkable variety of morphological life stages as they transition through multiple mammalian host and mosquito vector environments. We profiled the single-cell transcriptomes of thousands of individual parasites, deriving the first high-resolution transcriptional atlas of the entire Plasmodium berghei life cycle. We then used our atlas to precisely define developmental stages of single cells from three different human malaria parasite species, including parasites isolated directly from infected individuals. The Malaria Cell Atlas provides both a comprehensive view of gene usage in a eukaryotic parasite and an open-access reference dataset for the study of malaria parasites.

Recommended citation: Virginia M Howick, Andrew J C Russell, Tallulah Andrews, Haynes Heaton, Adam J Reid, Kedar Natarajan, Hellen Butungi, Tom Metcalf, Lisa H Verzier, Julian C Rayner, Matthew Berriman, Jeremy K Herren, Oliver Billker, Martin Hemberg, Arthur M Talman, Mara K N Lawniczak (2019). "The Malaria Cell Atlas: Single parasite transcriptomes across the complete Plasmodium life cycle." Science. 365(6455). http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7056351/

Single-Cell (Multi)omics Technologies

Published in Annu Rev Genomics Hum Genet., 2018

Single-cell multiomics technologies typically measure multiple types of molecule from the same individual cell, enabling more profound biological insight than can be inferred by analyzing each molecular layer from separate cells. These single-cell multiomics technologies can reveal cellular heterogeneity at multiple molecular layers within a population of cells and reveal how this variation is coupled or uncoupled between the captured omic layers. The data sets generated by these techniques have the potential to enable a deeper understanding of the key biological processes and mechanisms driving cellular heterogeneity and how they are linked with normal development and aging as well as disease etiology. This review details both established and novel single-cell mono- and multiomics technologies and considers their limitations, applications, and likely future developments.

Recommended citation: Lia Chappell, Andrew J C Russell, Thierry Voet. (2018). "Single-Cell (Multi)omics Technologies." Annu Rev Genomics Hum Genet .. 19:15-41. https://pubmed.ncbi.nlm.nih.gov/29727584/

CRISPRi is not strand-specific at all loci and redefines the transcriptional landscape

Published in Elife, 2017

CRISPRi, an adapted CRISPR-Cas9 system, is proposed to act as a strand-specific roadblock to repress transcription in eukaryotic cells using guide RNAs (sgRNAs) to target catalytically inactive Cas9 (dCas9) and offers an alternative to genetic interventions for studying pervasive antisense transcription. Here, we successfully use click chemistry to construct DNA templates for sgRNA expression and show, rather than acting simply as a roadblock, sgRNA/dCas9 binding creates an environment that is permissive for transcription initiation/termination, thus generating novel sense and antisense transcripts. At HMS2 in Saccharomyces cerevisiae, sgRNA/dCas9 targeting to the non-template strand for antisense transcription results in antisense transcription termination, premature termination of a proportion of sense transcripts and initiation of a novel antisense transcript downstream of the sgRNA/dCas9-binding site. This redefinition of the transcriptional landscape by CRISPRi demonstrates that it is not strand-specific and highlights the controls and locus understanding required to properly interpret results from CRISPRi interventions.

Recommended citation: Françoise S Howe, Andrew Russell, Anna R Lamstaes, Afaf El-Sagheer, Anitha Nair, Tom Brown, Jane Mellor. (2017). "CRISPRi is not strand-specific at all loci and redefines the transcriptional landscape. " Elife. 6. http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5665645/