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"Annotation-free quantification of RNA splicing using LeafCutter" - a new publication with contributions from UGI's Jack Humphrey

The excision of introns from pre-mRNA is an essential step in mRNA processing. We developed LeafCutter to study sample and population variation in intron splicing. LeafCutter identifies variable splicing events from short-read RNA-seq data and finds events of high complexity. Our approach obviates the need for transcript annotations and circumvents the challenges in estimating relative isoform or exon usage in complex splicing events. LeafCutter can be used both to detect differential splicing between sample groups and to map splicing quantitative trait loci (sQTLs). Compared with contemporary methods, our approach identified 1.4–2.1 times more sQTLs, many of which helped us ascribe molecular effects to disease-associated variants. Transcriptome-wide associations between LeafCutter intron quantifications and 40 complex traits increased the number of associated disease genes at a 5% false discovery rate by an average of 2.1-fold compared with that detected through the use of gene expression levels alone. LeafCutter is fast, scalable, easy to use, and available online.

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"Synima: a Synteny imaging tool for annotated genome assemblies" - new publication from UGI's Rhys Farrer presenting a new tool for visualizing synteny across any number of annotated genomes

Ortholog prediction and synteny visualization across whole genomes are valuable methods for detecting and representing a range of evolutionary processes such as genome expansion, chromosomal rearrangement, and chromosomal translocation. Few standalone methods are currently available to visualize synteny across any number of annotated genomes.

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Congratulations to Juan Camilo Chacón-Duque - the latest Dr in the house

Please join us in congratulating Juan Camilo Chacón-Duque who has successfully defended his thesis on the genetic history of Latin America: fine-scale population structure, sub-continental ancestry and phenotypic diversity supervised by Garrett Hellenthal.

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"The global distribution and spread of the mobilized colistin resistance gene mcr-1" - new preprint from UGI's Francois Balloux, Lucy van Dorp and Liam Shaw

Colistin represents one of the very few available drugs for treating infections caused by carbapenem resistant Enterobacteriaceae (CRE). As such, the recent plasmid-mediated spread of the mobilized colistin resistance gene mcr-1 poses a significant public health threat requiring global monitoring and surveillance. In this work, we characterize the global distribution of mcr-1 using a dataset of 457 mcr-1 positive sequenced isolates consisting of currently publicly available mcr-1 carrying sequences combined with an additional 110 newly sequenced mcr-1 positive isolates from China. We find mcr-1 in a diversity of plasmid backgrounds but identify an immediate background common to all mcr-1 sequences. Our analyses establish that all mcr-1 elements in circulation descend from the same initial mobilization of mcr-1 by an ISApl1 transposon in the mid 2000s (2002-2008; 95% higher posterior density), followed by a dramatic demographic expansion, which led to its current global distribution. Our results provide the first systematic phylogenetic analysis of the origin and spread of mcr-1, and emphasize the importance of understanding the movement of mobile elements carrying antibiotic resistance genes across multiple levels of genomic organization.

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"A perturbation model of the gut microbiome's response to antibiotics" - new preprint from UGI's Liam Shaw, Francois Balloux and colleagues

Even short courses of antibiotics are known to reduce gut microbiome diversity. However, there has been limited mathematical modelling of the associated dynamical time-response. Here, we take inspiration from a 'stability landscape' schematic and develop an impulse-response model of antibiotic perturbation. We fit this model to previously published data where individuals took a ten-day course of antibiotics (clindamycin or ciprofloxacin) and were sampled up to a year afterwards. By fitting an extended model allowing for a transition to an alternative stable state, we find support for a long-term transition to an alternative community state one year after taking antibiotics. This implies that a single treatment of antibiotics not only reduces the diversity of the gut flora for up to a year but also alters its composition, possibly indefinitely. Our results provide quantitative support for a conceptual picture of the gut microbiome and demonstrate that simple models can provide biological insight.

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"Association study of schizophrenia with variants in miR-137 binding sites" - new paper by UGI's Dave Curtis and Warren Emmett

There is strong cumulative evidence for the involvement of miR-137 and its targets in the aetiology of schizophrenia. Here we test whether variants, especially rare variants, in miR-137 binding sites are associated with schizophrenia in an exome-sequenced sample of 4225 cases and 5834 controls. Only a small proportion of binding sites were covered by the capture system which had been used. A weighted burden test using the 372 detected variants demonstrated an excess among cases significant at p = 0.024. The sample size is too small to implicate individual variants or genes but overall this finding does provide some further support for the hypothesis that disruption of miR-137 binding sites can increase the risk of schizophrenia, perhaps by leading to over-expression of the target gene. We recommend that future exome sequencing studies should cover the untranscribed regions of genes, which contain the microRNA binding sites, in order that this potentially important pathogenic mechanism can be adequately investigated.

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"Oral microbiomes from hunter-gatherers and traditional farmers reveal shifts in commensal balance and pathogen load linked to diet." - new paper by Dr Florent Lassalle et al 2017

Maladaptation to modern diets has been implicated in several chronic disorders. Given the higher prevalence of disease such as dental caries and chronic gum diseases in industrialized societies, we sought to investigate the impact of different subsistence strategies on oral health and physiology, as documented by the oral microbiome. To control for confounding variables such as environment and host genetics, we sampled saliva from three pairs of populations of hunter-gatherers and traditional farmers living in close proximity in the Philippines. Deep shotgun sequencing of salivary DNA generated high-coverage microbiomes along with human genomes. Comparing these microbiomes with publicly available data from individuals living on a Western diet revealed that abundance ratios of core species were significantly correlated with subsistence strategy, with hunter-gatherers and Westerners occupying either end of a gradient of Neisseria against Haemophilus, and traditional farmers falling in between. Species found preferentially in hunter-gatherers included microbes often considered as oral pathogens, despite their hosts’ apparent good oral health. Discriminant analysis of gene functions revealed vitamin B5 autotrophy and urease-mediated pH regulation as candidate adaptations of the microbiome to the hunter-gatherer and Western diets, respectively. These results suggest that major transitions in diet selected for different communities of commensals and likely played a role in the emergence of modern oral pathogens.

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UGI welcomes Dr Maria Secrier

UCL Genetics Institute is delighted to welcome Dr Maria Secrier, the new Lecturer in Computational Biology.

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The relentless rise of migration in Europe over last 10,000 years - a new study led by researchers from GEE, University of Cambridge and King’s College London

Three major pulses of increased mobility in Europe over the last 10,000 years and a general upward trend in migration have been uncovered in a new study led by researchers from UCL, University of Cambridge and King’s College London.
The new method, published in PNAS, allows, for the first time, to directly quantify changes in prehistoric migration rates using ancient genetic data over the last 30,000 years.

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"How convincing is a matching Y-chromosome profile?" - new paper co-authored by David Balding published in PLoS Genetics

Y-chromosome DNA profiles are important in forensic science, particularly when a male has been accused of assaulting a female.
However, unlike for autosomal profiles, the problem of evaluating weight-of-evidence for Y profiles has not been satisfactorily resolved despite many attempts. The key idea missing from current approaches is that Y-profile matches are due to patrilineal relatedness that is typically too remote to be recognized, but close compared with the relatedness of random pairs from the population. We focus on approximating the number of males with matching Y profiles, rather than a population fraction or match probability. We describe a simulation model of Y profile evolution, implemented in open-source software, for approximating the number of males sharing a Y profile. We extend our simulation method to also model database selection. Even under the optimistic assumption that the database has been sampled randomly in the relevant population, we show that database counts don’t help much. The reason is that modern profiling kits with high profile mutation rates imply that almost all profiles are rare relative to typical database sizes. We discuss how to use our approach to present evidence in court in a way that is both fair and easy to understand.

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