Journal Articles
Permanent URI for this collectionhttps://mro.massey.ac.nz/handle/10179/7915
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Item SeroBA: rapid high-throughput serotyping of Streptococcus pneumoniae from whole genome sequence data.(Microbiology Society, 2018-06-15) Epping L; van Tonder AJ; Gladstone RA; The Global Pneumococcal Sequencing Consortium; Bentley SD; Page AJ; Keane JAStreptococcus pneumoniae is responsible for 240 000-460 000 deaths in children under 5 years of age each year. Accurate identification of pneumococcal serotypes is important for tracking the distribution and evolution of serotypes following the introduction of effective vaccines. Recent efforts have been made to infer serotypes directly from genomic data but current software approaches are limited and do not scale well. Here, we introduce a novel method, SeroBA, which uses a k-mer approach. We compare SeroBA against real and simulated data and present results on the concordance and computational performance against a validation dataset, the robustness and scalability when analysing a large dataset, and the impact of varying the depth of coverage on sequence-based serotyping. SeroBA can predict serotypes, by identifying the cps locus, directly from raw whole genome sequencing read data with 98 % concordance using a k-mer-based method, can process 10 000 samples in just over 1 day using a standard server and can call serotypes at a coverage as low as 15-21×. SeroBA is implemented in Python3 and is freely available under an open source GPLv3 licence from: https://github.com/sanger-pathogens/seroba.Item Allele-specific binding variants causing ChIP-seq peak height of histone modification are not enriched in expression QTL annotations.(BioMed Central Ltd, 2024-06-27) Ghoreishifar M; Chamberlain AJ; Xiang R; Prowse-Wilkins CP; Lopdell TJ; Littlejohn MD; Pryce JE; Goddard MEBACKGROUND: Genome sequence variants affecting complex traits (quantitative trait loci, QTL) are enriched in functional regions of the genome, such as those marked by certain histone modifications. These variants are believed to influence gene expression. However, due to the linkage disequilibrium among nearby variants, pinpointing the precise location of QTL is challenging. We aimed to identify allele-specific binding (ASB) QTL (asbQTL) that cause variation in the level of histone modification, as measured by the height of peaks assayed by ChIP-seq (chromatin immunoprecipitation sequencing). We identified DNA sequences that predict the difference between alleles in ChIP-seq peak height in H3K4me3 and H3K27ac histone modifications in the mammary glands of cows. RESULTS: We used a gapped k-mer support vector machine, a novel best linear unbiased prediction model, and a multiple linear regression model that combines the other two approaches to predict variant impacts on peak height. For each method, a subset of 1000 sites with the highest magnitude of predicted ASB was considered as candidate asbQTL. The accuracy of this prediction was measured by the proportion where the predicted direction matched the observed direction. Prediction accuracy ranged between 0.59 and 0.74, suggesting that these 1000 sites are enriched for asbQTL. Using independent data, we investigated functional enrichment in the candidate asbQTL set and three control groups, including non-causal ASB sites, non-ASB variants under a peak, and SNPs (single nucleotide polymorphisms) not under a peak. For H3K4me3, a higher proportion of the candidate asbQTL were confirmed as ASB when compared to the non-causal ASB sites (P < 0.01). However, these candidate asbQTL did not enrich for the other annotations, including expression QTL (eQTL), allele-specific expression QTL (aseQTL) and sites conserved across mammals (P > 0.05). CONCLUSIONS: We identified putatively causal sites for asbQTL using the DNA sequence surrounding these sites. Our results suggest that many sites influencing histone modifications may not directly affect gene expression. However, it is important to acknowledge that distinguishing between putative causal ASB sites and other non-causal ASB sites in high linkage disequilibrium with the causal sites regarding their impact on gene expression may be challenging due to limitations in statistical power.Item Mining the 99 Lives Cat Genome Sequencing Consortium database implicates genes and variants for the Ticked locus in domestic cats (Felis catus)(John Wiley and Sons Ltd on behalf of Stichting International Foundation for Animal Genetics, 2021-06) Lyons LA; Buckley RM; Harvey RJ; 99 Lives Cat Genome ConsortiumTabby patterns of fur coats are defining characteristics in wild and domestic felids. Historically, three autosomal alleles at one locus (Tabby): Abyssinian (Ta ; a.k.a. ticked), mackerel (Tm ; a.k.a. striped) and blotched (tb ; a.k.a. classic, blotched) were thought to control these patterns in domestic cats and their breeds. Currently, at least three loci influence cat tabby markings, two of which are designated Tabby and Ticked. The Tabby locus is laeverin (LVRN) and affects the mackerel and blotched patterns. The unidentified gene for the Ticked locus on cat chromosome B1 was suggested to control the presence or absence of the ticked pattern (Tabby - Abyssinian (Ta ; a.k.a. ticked). The cat reference genome (Cinnamon, the Abyssinian) has the ticked phenotype and the variant dataset and coat phenotypes from the 99 Lives Cat Genome Consortium (195 cats) were used to identify candidate genes and variants associated with the Ticked locus. Two strategies were used to find the Ticked allele(s), one considered Cinnamon with the reference allele or heterozygous (Strategy A) and the other considered Cinnamon as having the variant allele or heterozygous (Strategy B). For Strategy A, two variants in Dickkopf Wnt Signaling Pathway Inhibitor 4 (DKK4), a p.Cys63Tyr (B1:41621481, c.188G>A) and a less common p.Ala18Val (B1:42620835, c.53C>T) variant are suggested as two alleles influencing the Ticked phenotype. Bioinformatic and molecular modeling analysis suggests that these changes disrupt a key disulfide bond in the Dkk4 cysteine-rich domain 1 or Dkk4 signal peptide cleavage respectively. All coding variants were excluded as Ticked alleles using Strategy B.Item Werewolf, There Wolf: Variants in Hairless Associated with Hypotrichia and Roaning in the Lykoi Cat Breed.(MDPI (Basel, Switzerland), 2020-06-22) Buckley RM; Gandolfi B; Creighton EK; Pyne CA; Bouhan DM; LeRoy ML; Senter DA; Gobble JR; Abitbol M; Lyons LA; 99 Lives ConsortiumA variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi (a.k.a. werewolf cat), was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as a significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non-lykoi cats suggested two variants in the cat homolog for Hairless (HR) (HR lysine demethylase and nuclear receptor corepressor) as candidate causal gene variants. The lykoi cat was a compound heterozygote for two loss of function variants in HR, an exon 3 c.1255_1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of function HR variants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants in HR for cat hypotrichia can now be established between minor differences in the phenotypic presentations.Item Whole-genome sequencing and ad hoc shared genome analysis of Staphylococcus aureus isolates from a New Zealand primary school(Springer Nature Limited, 2021-10-13) Scott P; Zhang J; Anderson T; Priest PC; Chambers S; Smith H; Murdoch DR; French N; Biggs PJEpidemiological studies of communicable diseases increasingly use large whole-genome sequencing (WGS) datasets to explore the transmission of pathogens. It is important to obtain an initial overview of datasets and identify closely related isolates, but this can be challenging with large numbers of isolates and imperfect sequencing. We used an ad hoc whole-genome multi locus sequence typing method to summarise data from a longitudinal study of Staphylococcus aureus in a primary school in New Zealand. Each pair of isolates was compared and the number of genes where alleles differed between isolates was tallied to produce a matrix of "allelic differences". We plotted histograms of the number of allelic differences between isolates for: all isolate pairs; pairs of isolates from different individuals; and pairs of isolates from the same individual. 340 sequenced isolates were included, and the ad hoc shared genome contained 445 genes. There were between 0 and 420 allelic differences between isolate pairs and the majority of pairs had more than 260 allelic differences. We found many genetically closely related S. aureus isolates from single individuals and a smaller number of closely-related isolates from separate individuals. Multiple S. aureus isolates from the same individual were usually very closely related or identical over the ad hoc shared genome. Siblings carried genetically similar, but not identical isolates. An ad hoc shared genome approach to WGS analysis can accommodate imperfect sequencing of the included isolates, and can provide insights into relationships between isolates in epidemiological studies with large WGS datasets containing diverse isolates.Item Effects of APOE e4-allele and mental work demands on cognitive decline in old age: Results from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe)(John Wiley and Sons Ltd, 2021-01) Rodriguez FS; Roehr S; Pabst A; Kleineidam L; Fuchs A; Wiese B; Lühmann D; Brettschneider C; Wolfsgruber S; Pentzek M; van den Bussche H; König H-H; Weyerer S; Werle J; Bickel H; Weeg D; Maier W; Scherer M; Wagner M; Riedel-Heller SGObjectives Previous studies have observed protective effects of high mental demands at work on cognitive functioning and dementia risk. However, it is unclear what types of demands drive this effect and whether this effect is subject to a person's genetic risk. We investigated to what extent eight different types of mental demands at work together with the APOE e4 allele, a major risk gene for late-onset Alzheimer's disease, affect cognitive functioning in late life. Methods/Design The population-based German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe, n = 2 154) followed cognitively healthy individuals aged 75 years and older in seven assessment waves. Cognitive functioning was assessed via the mini-mental status examination. Results Mixed-effects modeling (adjusted for education, gender, marital status, stroke, depression, and diabetes) indicated that participants who had an occupational history of working in jobs with high compared to low demands in “Language & Knowledge”, “Pattern detection”, “Information processing”, and “Service” had a slower cognitive decline. APOE e4-allele carriers had an accelerated cognitive decline, but this decline was significantly smaller if they had a medium compared to a low level of demands in contrast to non-carriers. Conclusions Our longitudinal observations suggest that cognitive decline could be slowed by an intellectually enriched lifestyle even in risk gene carriers. Fostering intellectual engagement throughout the life-course could be a key prevention initiative to promote better cognitive health in old age.