Biology subjects

Chand, M.

Publications and source records attributed to Chand, M..

3 recordsLinked to original sources

bioRxiv2023

Putative APOBEC3 deaminase editing in MPXV as evidence for sustained human transmission since at least 2016.

Mpox is often described as being endemic in West and Central Africa as a zoonotic disease that transmits through contact with the reservoir rodent host, likely a species of African squirrel. In May 2022, human cases of Mpox were detected spreading internationally beyond countries with known endemic reservoirs. At time of writing, 84,700 confirmed cases have been reported in 110 countries. When the first cases from 2022 were sequenced, it was seen that they shared 42 single nucleotide differences from the closest mpox virus (MPXV) genome sampled in 2018. This number of changes within 3-4 years is unexpectedly large and points to a much greater evolutionary rate than expected for a poxvirus. Strikingly, most nucleotide changes are of a specific type - a dinucleotide change from TC->TT or its reverse complement GA->AA. This mutation type is characteristic of the action of APOBEC3 deaminases; host-enzymes with reported antiviral function. Analysis of MPXV genomes sampled from 2017 to 2022 showed further evidence of TC->TT mutation pattern enrichment, with 93% of transmitted single nucleotide mutations since 2017 consistent with APOBEC3 editing. Assuming APOBEC-editing is characteristic of MPXV infection in human hosts, we propose an APOBEC clock that - at a rate of ~6 APOBEC3 mutations per year - estimates MPXV has been circulating in humans since 2016. This evolutionary pattern of host-enzyme editing has implications for the longer-term fitness of the virus in this epidemic as such mechanisms are primarily antiviral in function, but in the context of a poxvirus also provide a source of variation that may conceivably facilitate adaptation.

evolutionary biology↗

bioRxiv2022

Genome-first detection of emerging resistance to novel therapeutic agents for SARS-CoV-2

Some COVID-19 patients are unable to clear their infection or are at risk of severe disease, requiring treatment with neutralising monoclonal antibodies (nmAb) and/or antivirals. The rapid roll-out of novel therapeutics means there is limited understanding of the likely genetic barrier to drug resistance. Unprecedented genomic surveillance of SARS-CoV-2 in the UK has enabled a genome-first approach to the detection of emerging drug resistance. Here we report the accrual of mutations in Delta and Omicron cases treated with casirivimab+imdevimab and sotrovimab respectively. Mutations occur within the epitopes of the respective nmAbs. For casirivimab+imdevimab these are present on contiguous raw reads, simultaneously affecting both components. Using surface plasmon resonance and pseudoviral neutralisation assays we demonstrate these mutations reduce or completely abrogate antibody affinity and neutralising activity, suggesting they are driven by immune evasion. In addition, we show that some mutations also reduce the neutralising activity of vaccine-induced serum.

genetics↗

bioRxiv2022

The origins and molecular evolution of SARS-CoV-2 lineage B.1.1.7 in the UK

The first SARS-CoV-2 variant of concern (VOC) to be designated was lineage B.1.1.7, later labelled by the World Health Organisation (WHO) as Alpha. Originating in early Autumn but discovered in December 2020, it spread rapidly and caused large waves of infections worldwide. The Alpha variant is notable for being defined by a long ancestral phylogenetic branch with an increased evolutionary rate, along which only two sequences have been sampled. Alpha genomes comprise a well-supported monophyletic clade within which the evolutionary rate is more typical of SARS-CoV-2. The Alpha epidemic continued to grow despite the continued restrictions on social mixing across the UK, and the imposition of new restrictions, in particular the English national lockdown in November 2020. While these interventions succeeded in reducing the absolute number of cases, the impact of these non-pharmaceutical interventions was predominantly to drive the decline of the SARS-CoV-2 lineages which preceded Alpha. We investigate the only two sampled sequences that fall on the branch ancestral to Alpha. We find that one is likely to be a true intermediate sequence, providing information about the order of mutational events that led to Alpha. We explore alternate hypotheses that can explain how Alpha acquired a large number of mutations yet remained largely unobserved in a region of high genomic surveillance: an under-sampled geographical location, a non-human animal population, or a chronically-infected individual. We conclude that the last hypothesis provides the best explanation of the observed behaviour and dynamics of the variant, although we find that the individual need not be immunocompromised, as persistently-infected immunocompetent hosts also display a higher within-host rate of evolution. Finally, we compare the ancestral branches and mutation profiles of other VOCs to each other, and identify that Delta appears to be an outlier both in terms of the genomic locations of its defining mutations, and its lack of rapid evolutionary rate on the ancestral branch. As new variants, such as Omicron, continue to evolve (potentially through similar mechanisms) it remains important to investigate the origins of other variants to identify ways to potentially disrupt their evolution and emergence.

evolutionary biology↗