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The genus Serratia has been studied for over a century and includes clinically-important and diverse environmental members. Despite this, there is a paucity of genomic information across the genus and a robust whole genome-based phylogenetic framework is lacking. Here, we have assembled and analysed a representative set of 664 genomes from across the genus, including 215 historic isolates originally used in defining the genus. Phylogenomic analysis of the genus reveals a clearly-defined population structure which displays deep divisions and aligns with ecological niche, as well as striking congruence between historical biochemical phenotyping data and contemporary genomics data. We highlight the genomic, phenotypic and plasmid diversity of Serratia , and provide evidence of different patterns of gene flow across the genus. Our work provides a framework for understanding the emergence of clinical and other lineages of Serratia . The genus Serratia includes clinically-important and diverse environmental bacteria. Here, Williams et al. assemble and analyse a representative set of 664 genomes from across the genus, including historic isolates, to provide a genome-based phylogenetic framework for a better understanding of the emergence of clinical and environmental lineages of Serratia .

A significant proportion of children (up to 7% in the UK) present with pronounced language difficulties that cannot be explained by obvious causes like other neurological and medical conditions. A substantial genetic component is predicted to underlie such language problems. Copy number variants (CNVs) have been implicated in neurodevelopmental and psychiatric conditions, such as autism and schizophrenia, but it is not fully established to what extent they might contribute to language disorders. We conducted a CNV screen in a longitudinal cohort of young children with language-related difficulties (n = 85), focusing on single events at candidate loci. We detected a de novo deletion on chromosome 15q13.1-13.3. The adjacent 15q11-13.1 locus is disrupted in Prader-Willi and Angelman syndromes, while disruptions across the breakpoints (BP1-BP6) have previously been implicated in different neurodevelopmental phenotypes including autism, intellectual disability (ID), seizures and developmental delay (DD). This is the first report of a deletion at BP3-BP5 being linked to a deficit confined to language impairment, in the absence of ID, expanding the range of phenotypes that implicate the chromosome 15q13 locus.

Background Specific language impairment (SLI) is a common neurodevelopmental disorder, observed in 5–10 % of children. Family and twin studies suggest a strong genetic component, but relatively few candidate genes have been reported to date. A recent genome-wide association study (GWAS) described the first statistically significant association specifically for a SLI cohort between a missense variant (rs4280164) in the NOP9 gene and language-related phenotypes under a parent-of-origin model. Replications of these findings are particularly challenging because the availability of parental DNA is required. Methods We used two independent family-based cohorts characterised with reading- and language-related traits: a longitudinal cohort ( n  = 106 informative families) including children with language and reading difficulties and a nuclear family cohort ( n  = 264 families) selected for dyslexia. Results We observed association with language-related measures when modelling for parent-of-origin effects at the NOP9 locus in both cohorts: minimum P  = 0.001 for phonological awareness with a paternal effect in the first cohort and minimum P  = 0.0004 for irregular word reading with a maternal effect in the second cohort. Allelic and parental trends were not consistent when compared to the original study. Conclusions A parent-of-origin effect at this locus was detected in both cohorts, albeit with different trends. These findings contribute in interpreting the original GWAS report and support further investigations of the NOP9 locus and its role in language-related traits. A systematic evaluation of parent-of-origin effects in genetic association studies has the potential to reveal novel mechanisms underlying complex traits.

Chemokine (C–C motif) ligand 5 ( CCL5 ) and chemokine (C–C motif) receptor 5 are implicated in the pathogenesis of diabetic nephropathy (DN). We hypothesize that variants in these genes may be associated with DN. The CCL5 and chemokine receptor type 5 ( CCR5 ) genes were resequenced, variants identified ( n =58), allele frequencies determined in 46 individuals (92 chromosomes) and efficient haplotype tag single-nucleotide polymorphisms (htSNPs) selected to effectively evaluate the common variation in these genes. One reportedly functional gene variant and eight htSNPs were genotyped in a case–control association study involving Caucasian individuals with type 1 diabetes (267 cases with DN and 442 non-nephropathic diabetic controls). Genotyping was performed using MassARRAY iPLEX, TaqMan, gel electrophoresis and direct capillary sequencing. After correction for multiple testing, there were no statistically significant associations between variants in the CCL5 and CCR5 genes and DN.

Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein ( KLK3 ) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56 kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case–control studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P  = 0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [ P  = 3.41 × 10 −4 , per-allele trend odds ratio (OR) = 0.77, 95% CI = 0.67–0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage 8 or stage ≥III ( P  = 0.31, per-allele trend OR = 1.12, 95% CI = 0.90–1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61 ng/ml, 95% CI = 1.49–1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12 ng/ml, 95% CI = 0.96–1.28) ( P  = 9.70 × 10 −5 ). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy.

Genetic distances between bacterial DNA sequences can be used to cluster populations into closely related subpopulations, and as an additional source of information when detecting possible transmission events. Due to their variable gene content and order, reference-free methods offer more sensitive detection of genetic differences, especially among closely related samples found in outbreaks. However, across longer genetic distances, frequent recombination can make calculation and interpretation of these differences more challenging, requiring significant bioinformatic expertise and manual intervention during the analysis process. Here we present a Population analysis PIPEline (PopPIPE) which combines rapid reference-free genome analysis methods to analyse bacterial genomes across these two scales, splitting whole populations into subclusters and detecting plausible transmission events within closely related clusters. We use k-mer sketching to split populations into strains, followed by split k-mer analysis and recombination removal to create alignments and subclusters within these strains. We first show that this approach creates high quality subclusters on a population-wide dataset of Streptococcus pneumoniae. When applied to nosocomial vancomycin resistant Enterococcus faecium samples, PopPIPE finds transmission clusters which are more epidemiologically plausible than core genome or MLST-based approaches. Our pipeline is rapid and reproducible, creates interactive visualisations, and can easily be reconfigured and re-run on new datasets. Therefore PopPIPE provides a user-friendly pipeline for analyses spanning species-wide clustering to outbreak investigations.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://github.com/bacpop/PopPIPE

The genus Serratia has been studied for over a century and includes clinically-important and diverse environmental members. Despite this, there is a paucity of genomic information across the genus and a robust whole genome-based phylogenetic framework is lacking. Here, we have assembled and analysed a representative set of 664 genomes from across the genus, including 215 historic isolates originally used in defining the genus. Phylogenomic analysis of the genus reveals a clearly-defined population structure which displays deep divisions and aligns with ecological niche, as well as striking congruence between historical biochemical phenotyping data and contemporary genomics data. We show that Serratia is a diverse genus which displays striking plasticity and ability to adapt to its environment, including a highly-varied portfolio of plasmids, and provide evidence of different patterns of gene flow across the genus. This work provides an essential platform for understanding the emergence of clinical and other lineages of Serratia. Competing Interest Statement The authors have declared no competing interest.

A significant proportion of children (up to 7% in the UK) present with pronounced language difficulties that cannot be explained by obvious causes like other neurological and medical conditions. A substantial genetic component is predicted to underlie such language problems. Copy number variants (CNVs) have been implicated in neurodevelopmental and psychiatric conditions, such as autism and schizophrenia, but it is not fully established to what extent they might contribute to language disorders. We conducted a CNV screen in a longitudinal cohort of young children with language-related difficulties (n = 85), focusing on single events at candidate loci. We detected a de novo deletion on chromosome 15q13.1-13.3. The adjacent 15q11-13.1 locus is disrupted in Prader-Willi and Angelman syndromes, while disruptions across the breakpoints (BP1-BP6) have previously been implicated in different neurodevelopmental phenotypes including autism, intellectual disability (ID), seizures and developmental delay (DD). This is the first report of a deletion at BP3-BP5 being linked to a deficit confined to language impairment, in the absence of ID, expanding the range of phenotypes that implicate the chromosome 15q13 locus.

Objectives: To characterise the genetic environment of optrA in linezolid-resistant Enterococcus faecalis isolates from Scotland. Methods: Linezolid-resistant E. faecalis were identified in three Scottish Health Boards and confirmed to carry the optrA gene at the national reference laboratory. WGS was performed with short read (Illumina MiSeq) and long read (Oxford Nanopore MinION) technologies to generate complete genome assemblies. Illumina reads for 94 E. faecalis bloodstream isolates were used to place the optrA-positive isolates in a larger UK phylogeny. Results: Six optrA-positive linezolid-resistant E. faecalis were isolated from urogenital samples in three Scottish Health Boards (2014-2017). No epidemiological links were identified between the patients, four were community-based, and only one had recent linezolid exposure. Reference-based mapping confirmed the isolates were genetically distinct (>13,900 core SNPs). optrA was located on a plasmid in each isolate and these plasmids showed limited nucleotide similarity. There was variable presence of transposable elements surrounding optrA, (including IS1216, IS3, and Tn3) and not always as a recognisable gene cassette. OptrA amino acid sequences were also divergent, resulting in four protein variants differing in 1-20 residues. One isolate belonged to ST16 and clustered with three other isolates in the UK collection (76-182 SNPs), otherwise the optrA-positive isolates were genetically distinct from the bloodstream isolates (>6,000 SNPs). Conclusions: We report multiple variants of the linezolid resistance gene optrA in diverse E. faecalis strain and plasmid backgrounds, suggesting multiple introductions of the gene into the E. faecalis population and selection driving recent emergence.

Background Exposure to alcohol advertising and sponsorship through elite sport is associated with harmful use of alcohol. Owing to strong financial and cultural ties between alcohol and sport in Australia, policy action to restrict alcohol sport sponsorship is unlikely to occur without strong public support for change. This study tested whether exposure to counter-advertising exposing industry marketing of harmful products—a technique shown to be effective in tobacco control—promotes higher support for policy change and less favourable beliefs about the alcohol industry among sport spectators. Methods A sample of 1,075 Australian adults aged 18–49 years who planned to watch an National Rugby League (NRL) State of Origin series game, featuring prominent alcohol sponsorship, was recruited through an online panel and randomly assigned to one of three conditions: control (neutral advertisement); counter-advertisement exposing alcohol harms; counter-advertisement exposing alcohol sponsorship and harms. Participants completed a pre-test questionnaire and viewed their assigned counter-advertisement multiple times in the 5–7 days before the NRL game. Within four days of watching the game, participants completed post-test measures. Results Compared to both the control advertisement and the counter-advertisement exposing alcohol harms, participants who viewed the counter-advertisement exposing alcohol sponsorship and harms were significantly more likely to indicate support for each of four policies aimed at restricting sports-related alcohol marketing, including the complete removal of alcohol sponsorship from sport (51% vs. 32% and 37%). They were also significantly less likely to agree with statements such as “alcohol companies should be allowed to sponsor sport since their products are legal” (39% vs. 63% and 60%) and significantly less likely to report liking alcohol companies in general (38% vs. 59% and 54%). There were no significant differences in policy support or industry beliefs between participants who saw the counter-advertisement exposing alcohol harms and those who saw the control advertisement. Conclusion Counter-advertising employing messages that expose and critique the intent and impact of pervasive alcohol sponsorship in sport has potential to bolster public support for policies targeting alcohol sport sponsorship, diminish beliefs supportive of alcohol industry marketing strategies and enhance negative views of alcohol companies and their marketing practices.