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SARS-CoV-2 within-host diversity and transmission

Science

A year into the severe acute respiratory syndrome coronavirus 2 pandemic, we are experiencing waves of new variants emerging. Some of these variants have worrying functional implications, such as increased transmissibility or antibody treatment escape. Lythgoe et al. have undertaken in-depth sequencing of more than 1000 hospital patients' isolates to find out how the virus is mutating within individuals. Overall, there seem to be consistent and reproducible patterns of within-host virus diversity. The authors observed only one or two variants in most samples, but a few carried many variants. Although the evidence indicates strong purifying selection, including in the spike protein responsible for viral entry, the authors also saw evidence for transmission clusters associated with households and other possible superspreader events. After transmission, most variants fizzled out, but occasionally some initiated ongoing transmission and wider dissemination. Science , this issue p. [eabg0821][1] ### INTRODUCTION Genome sequencing at an unprecedented scale during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is helping to track spread of the virus and to identify new variants. Most of this work considers a single consensus sequence for each infected person. Here, we looked beneath the consensus to analyze genetic variation within viral populations making up an infection and studied the fate of within-host mutations when an infection is transmitted to a new individual. Within - host diversity offers the means to help confirm direct transmission and identify new variants of concern. ### RATIONALE We sequenced 1313 SARS-CoV-2 samples from the first wave of infection in the United Kingdom. We characterized within-host diversity and dynamics in the context of transmission and ongoing viral evolution. ### RESULTS Within-host diversity can be described by the number of intrahost single nucleotide variants (iSNVs) occurring above a given minor allele frequency (MAF) threshold. We found that in lower-viral-load samples, stochastic sampling effects resulted in a higher variance in MAFs, leading to more iSNVs being detected at any threshold. Based on a subset of 27 pairs of high-viral-load replicate RNA samples (>50,000 uniquely mapped veSEQ reads, corresponding to a cycle threshold of ~22), iSNVs with a minimum 3% MAF were highly reproducible. Comparing samples from two time points from 41 individuals, taken on average 6 days apart (interquartile ratio 2 to 10), we observed a dynamic process of iSNV generation and loss. Comparing iSNVs among 14 household contact pairs, we estimated transmission bottleneck sizes of one to eight viruses. Consensus differences between individuals in the same household, where sample depth allowed iSNV detection, were explained by the presence of an iSNV at the same site in the paired individual, consistent with direct transmission leading to fixation. We next focused on a set of 563 high-confidence iSNV sites that were variant in at least one high-viral-load sample (>50,000 uniquely mapped); low-confidence iSNVs unlikely to represent genomic diversity were excluded. Within-host diversity was limited in high-viral-load samples (mean 1.4 iSNVs per sample). Two exceptions, each with >14 iSNVs, showed variant frequencies consistent with coinfection or contamination. Overall, we estimated that 1 to 2% of samples in our dataset were coinfected and/or contaminated. Additionally, one sample was coinfected with another coronavirus (OC43), with no detectable impact on diversity. The ratio of nonsynonymous to synonymous ( dN/dS ) iSNVs was consistent with within-host purifying selection when estimated across the whole genome [ dN/dS = 0.55, 95% confidence interval (95% CI) = 0.49 to 0.61] and for the Spike gene ( dN/dS = 0.60, 95% CI = 0.45 to 0.82). Nevertheless, we observed Spike variants in multiple samples that have been shown to increase viral infectivity (L5F) or resistance to antibodies (G446V and A879V). We observed a strong association between high-confidence iSNVs and a consensus change on the phylogeny (153 cases), consistent with fixation after transmission or de novo mutations reaching consensus. Shared variants that never reached consensus (261 cases) were not phylogenetically associated. ### CONCLUSION Using robust methods to call within-host variants, we uncovered a consistent pattern of low within-host diversity, purifying selection, and narrow transmission bottlenecks. Within-host emergence of vaccine and therapeutic escape mutations is likely to be relatively rare, at least during early infection, when viral loads are high, but the observation of immune-escape variants in high-viral-load samples underlines the need for continued vigilance. ![Figure][2] Diagram showing low SARS-CoV-2 within-host genetic diversity and narrow transmission bottleneck. Individuals with high viral load typically have few, if any, within-host variants. Narrow transmission bottlenecks mean that the major variant in the source individual was typically transmitted and the minor variants lost. Occasionally, the minor variant was transmitted, leading to a consensus change, or multiple variants were transmitted, resulting in a mixed infection. Credit: FontAwesome, licensed under CC BY 4.0. Extensive global sampling and sequencing of the pandemic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have enabled researchers to monitor its spread and to identify concerning new variants. Two important determinants of variant spread are how frequently they arise within individuals and how likely they are to be transmitted. To characterize within-host diversity and transmission, we deep-sequenced 1313 clinical samples from the United Kingdom. SARS-CoV-2 infections are characterized by low levels of within-host diversity when viral loads are high and by a narrow bottleneck at transmission. Most variants are either lost or occasionally fixed at the point of transmission, with minimal persistence of shared diversity, patterns that are readily observable on the phylogenetic tree. Our results suggest that transmission-enhancing and/or immune-escape SARS-CoV-2 variants are likely to arise infrequently but could spread rapidly if successfully transmitted. [1]: /lookup/doi/10.1126/science.abg0821 [2]: pending:yes


The strange bedfellows of AI and ethics

#artificialintelligence

Over the last decade, we have heard a lot of doom-saying about how artificial intelligence (AI) would result in the loss of huge numbers of jobs However, the picture (across both public and private sectors) is now starting to look not only more nuanced but also more positive. A 2017 report from consultancy PWC suggested that embedding AI across all sectors is likely to create thousands of jobs. In the UK, one estimate suggests that it could contribute as much as 5% of GDP within 10 years. That’s not to say that we won’t lose jobs, because we undoubtedly will. However, they will be


Run out of milk? Robots on call for Singapore home deliveries

#artificialintelligence

The World Economic Forum's Centre for the Fourth Industrial Revolution, in partnership with the UK government, has developed guidelines for more ethical and efficient government procurement of artificial intelligence (AI) technology. Governments across Europe, Latin America and the Middle East are piloting these guidelines to improve their AI procurement processes.


AI technology used to track asbestos cancer tumours

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He said: "Mesothelioma is almost like the peel of an orange, it forms like a rind around the lung and if you take a scan of that tumour, it is a very complex shape. To measure changes in that shape is very difficult."


The key to stopping procrastination? Compassion.

Christian Science Monitor | Science

One of the most amazing things about the human mind is its ability to imagine events that haven't happened yet. To make a decision about something new – trying a new dish, picking a show to watch, and choosing a career – you have to mentally construct the experience and then predict how pleasant or unpleasant it will be. But this simulation, say psychologists, is often distorted. Our predictions tend to exaggerate how happy or sad we'll feel, and for how long. "No doubt good things make us happy and bad things make us sad," says Tim Wilson, a social psychologist at the University of Virginia. "But as a rule, not as long as we think they will." In the final episode of the Monitor's six-part series "It's About Time," hosts Rebecca Asoulin and Eoin O'Carroll explore how thinking about our future selves can help us make better decisions in the present. "We are always making trade-offs about things happening now versus later," says Dorsa Amir, an evolutionary anthropologist at Boston College. One of the most common ways that our present selves trip up our future selves is by procrastinating. But there are many ways for us to overcome the tendency to put things off, says Fuschia Sirois, a psychologist at the University of Sheffield in England. So the next time you notice yourself about to procrastinate, remind yourself that it's OK to struggle. This is the final episode of a six-part series that's part of the Monitor's "Rethinking the News" podcast. To listen to the other episodes on our site or on your favorite podcast player, please visit the "It's About Time" series page. This audio story was designed to be heard. We strongly encourage you to experience it with your ears, but we understand that is not an option for everybody. You can find the audio player above.


AI technology used to track asbestos cancer tumours

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Patients receiving treatment for a rare cancer linked to asbestos exposure are being assessed with artificial intelligence in a pilot project.


Is a Jaffa Cake a biscuit? Physicist uses AI to solve debate

Daily Mail - Science & tech

A physicist has used the power of artificial intelligence (AI) to solve the age-old debate about whether Jaffa Cakes are biscuits or cakes. Dr. Héloïse Stevance, an astrophysicist at the University of Auckland in New Zealand, trained algorithms with nearly 100 recipes of traditional cakes and biscuits. She then ran two Jaffa Cakes recipes through the algorithms, which recognised them unambiguously as cakes'without a doubt'. Jaffa Cakes, which are made by Edinburgh-based manufacturer McVitie's, consist of a disc of orange-flavoured jelly, milk chocolate and a mysterious spongy base. But fans of the popular British snack have passionately debated whether they're biscuits or cakes due to their unique texture and appearance.


Algorithms similar to what Netflix and Facebook use can 'predict' the biological language of cancer

Daily Mail - Science & tech

Algorithms similar to those used by Netflix, Amazon and Facebook have shown the ability to decipher the'biological language' of cancer, Alzheimer's and other neurodegenerative diseases. Researchers trained a large-scale language model with a recommendation AI to look at what happens when something goes wrong with proteins that leads to the development of a disease. The work, conducted by St. John's College and the University of Cambridge, programed the algorithm to learn the language of shapeshifting droplets of proteins found in cells in order to understand their function and malfunction. By learning these protein droplets' language, the team can then'correct the grammatical mistakes inside cells that cause disease.'' Professor Tuomas Knowles, a Fellow at St John's College, said: 'Any defects connected with these protein droplets can lead to diseases such as cancer. 'This is why bringing natural language processing technology into research into the molecular origins of protein malfunction is vital if we want to be able to correct the grammatical mistakes inside cells that cause disease.' Machine learning technology has made waves in the tech industry – Netflix uses it to recommend series, Facebook's suggest someone to friend and Amazon's Alexa has an algorithm to recognize people based on their voice.


Artificial Intelligence could 'crack the language of cancer and Alzheimer's'

#artificialintelligence

Powerful algorithms used by Netflix, Amazon and Facebook can'predict' the biological language of cancer and neurodegenerative diseases like Alzheimer's, scientists have found. Big data produced during decades of research was fed into a computer language model to see if artificial intelligence can make more advanced discoveries than humans. Academics based at St John's College, University of Cambridge, found the machine-learning technology could decipher the'biological language' of cancer, Alzheimer's, and other neurodegenerative diseases. Their ground-breaking study has been published in the scientific journal PNAS today and could be used in the future to'correct the grammatical mistakes inside cells that cause disease'. Professor Tuomas Knowles, lead author of the paper and a Fellow at St John's College, said: "Bringing machine-learning technology into research into neurodegenerative diseases and cancer is an absolute game-changer. Ultimately, the aim will be to use artificial intelligence to develop targeted drugs to dramatically ease symptoms or to prevent dementia happening at all."


National Artificial Intelligence Strategy Announced in United Kingdom

#artificialintelligence

Having recently announced the launch of the new UK Cyber Security Council, the UK government has followed up by announcing its plans to publish a new National Artificial Intelligence Strategy (the AI Strategy) later this year. The aim of the AI Strategy is to build on the United Kingdom's position as a global center for the development, commercialization, and adoption of responsible AI. Digital Secretary Oliver Dowden announced the strategy, commenting, "Unleashing the power of AI is a top priority in our plan to be the most pro-tech government ever. The UK is already a world leader in this revolutionary technology and the new AI Strategy will help us seize its full potential--from creating new jobs and improving productivity to tackling climate change and delivering better public services." The intention is for the AI Strategy to align with the UK government's overall plans to support jobs and economic growth through increased investment in infrastructure, skills, and innovation.