RAxML Grove: an empirical phylogenetic tree database.

SUMMARY: The assessment of novel phylogenetic models and inference methods is routinely being conducted via experiments on simulated as well as empirical data. When generating synthetic data it is often unclear how to set simulation parameters for the models and generate trees that appropriately reflect empirical model parameter distributions and tree shapes. As a solution, we present and make available a new database called 'RAxML Grove' currently comprising more than 60 000 inferred trees and respective model parameter estimates from fully anonymized empirical datasets that were analyzed using RAxML and RAxML-NG on two web servers. We also describe and make available two simple applications of RAxML Grove to exemplify its usage and highlight its utility for designing realistic simulation studies and analyzing empirical model parameter and tree shape distributions. AVAILABILITY AND IMPLEMENTATION: RAxML Grove is freely available at https://github.com/angtft/RAxMLGrove. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Social network analysis and whole-genome sequencing to evaluate disease transmission in a large, dynamic population: A study of avian mycobacteriosis in zoo birds.

This study combined a social network analysis and whole-genome sequencing (WGS) to test for general patterns of contagious spread of a mycobacterial infection for which pathways of disease acquisition are not well understood. Our population included 275 cases diagnosed with avian mycobacteriosis that were nested in a source population of 16,430 birds at San Diego Zoo Wildlife Alliance facilities from 1992 through mid-2014. Mycobacteria species were determined using conventional methods and whole genome sequencing (WGS). Mycobacterium avium avium (MAA) and Mycobacterium genavense were the most common species of mycobacteria identified and were present in different proportions across bird taxa. A social network for the birds was constructed from the source population to identify directly and indirectly connected cases during time periods relevant to disease transmission. Associations between network connectivity and genetic similarity of mycobacteria (as determined by clusters of genotypes separated by few single nucleotide polymorphisms, or SNPs) were then evaluated in observed and randomly generated network permutations. Findings showed that some genotypes clustered along pathways of bird connectivity, while others were dispersed throughout the network. The proportion of directly connected birds having a similar mycobacterial genotype was 0.36 and significant (p<0.05). This proportion was higher (0.58) and significant for MAA but not for M. genavense. Evaluations of SNP distributions also showed genotypes of MAA were more related in connected birds than expected by chance; however, no significant patterns of genetic relatedness were identified for M. genavense, although data were sparse. Integrating the WGS analysis of mycobacteria with a social network analysis of their host birds revealed significant genetic clustering along pathways of connectivity, namely for MAA. These findings are consistent with a contagious process occurring in some, but not all, case clusters.

Identification of an N-acetylneuraminic acid-presenting bacteria isolated from a human microbiome.

N-Acetylneuraminic acid is the most abundant sialic acid (SA) in humans and is expressed as the terminal sugar on intestinal mucus glycans. Several pathogenic bacteria harvest and display host SA on their own surfaces to evade Siglec-mediated host immunity. While previous studies have identified bacterial enzymes associated with SA catabolism, no reported methods permit the selective labeling, tracking, and quantitation of SA-presenting microbes within complex multi-microbial systems. We combined metabolic labeling, click chemistry, 16S rRNA gene, and whole-genome sequencing to track and identify SA-presenting microbes from a cultured human fecal microbiome. We isolated a new strain of Escherichia coli that incorporates SA onto its own surface and encodes for the nanT, neuA, and neuS genes necessary for harvesting and presenting SA. Our method is applicable to the identification of SA-presenting bacteria from human, animal, and environmental microbiomes, as well as providing an entry point for the investigation of surface-expressed SA-associated structures.

Phylogenomics of 10,575 genomes reveals evolutionary proximity between domains Bacteria and Archaea.

Rapid growth of genome data provides opportunities for updating microbial evolutionary relationships, but this is challenged by the discordant evolution of individual genes. Here we build a reference phylogeny of 10,575 evenly-sampled bacterial and archaeal genomes, based on a comprehensive set of 381 markers, using multiple strategies. Our trees indicate remarkably closer evolutionary proximity between Archaea and Bacteria than previous estimates that were limited to fewer "core" genes, such as the ribosomal proteins. The robustness of the results was tested with respect to several variables, including taxon and site sampling, amino acid substitution heterogeneity and saturation, non-vertical evolution, and the impact of exclusion of candidate phyla radiation (CPR) taxa. Our results provide an updated view of domain-level relationships.

Whole-genome analysis of mycobacteria from birds at the San Diego Zoo.

METHODS: Mycobacteria isolated from more than 100 birds diagnosed with avian mycobacteriosis at the San Diego Zoo and its Safari Park were cultured postmortem and had their whole genomes sequenced. Computational workflows were developed and applied to identify the mycobacterial species in each DNA sample, to find single-nucleotide polymorphisms (SNPs) between samples of the same species, to further differentiate SNPs between as many as three different genotypes within a single sample, and to identify which samples are closely clustered genomically. RESULTS: Nine species of mycobacteria were found in 123 samples from 105 birds. The most common species were Mycobacterium avium and Mycobacterium genavense, which were in 49 and 48 birds, respectively. Most birds contained only a single mycobacterial species, but two birds contained a mixture of two species. The M. avium samples represent diverse strains of M. avium avium and M. avium hominissuis, with many pairs of samples differing by hundreds or thousands of SNPs across their common genome. By contrast, the M. genavense samples are much closer genomically; samples from 46 of 48 birds differ from each other by less than 110 SNPs. Some birds contained two, three, or even four genotypes of the same bacterial species. Such infections were found in 4 of 49 birds (8%) with M. avium and in 11 of 48 birds (23%) with M. genavense. Most were mixed infections, in which the bird was infected by multiple mycobacterial strains, but three infections with two genotypes differing by ≤ 10 SNPs were likely the result of within-host evolution. The samples from 31 birds with M. avium can be grouped into nine clusters within which any sample is ≤ 12 SNPs from at least one other sample in the cluster. Similarly, the samples from 40 birds with M. genavense can be grouped into ten such clusters. Information about these genomic clusters is being used in an ongoing, companion study of mycobacterial transmission to help inform management of bird collections.

Group-based variant calling leveraging next-generation supercomputing for large-scale whole-genome sequencing studies.

MOTIVATION: Next-generation sequencing (NGS) technologies have become much more efficient, allowing whole human genomes to be sequenced faster and cheaper than ever before. However, processing the raw sequence reads associated with NGS technologies requires care and sophistication in order to draw compelling inferences about phenotypic consequences of variation in human genomes. It has been shown that different approaches to variant calling from NGS data can lead to different conclusions. Ensuring appropriate accuracy and quality in variant calling can come at a computational cost. RESULTS: We describe our experience implementing and evaluating a group-based approach to calling variants on large numbers of whole human genomes. We explore the influence of many factors that may impact the accuracy and efficiency of group-based variant calling, including group size, the biogeographical backgrounds of the individuals who have been sequenced, and the computing environment used. We make efficient use of the Gordon supercomputer cluster at the San Diego Supercomputer Center by incorporating job-packing and parallelization considerations into our workflow while calling variants on 437 whole human genomes generated as part of large association study. CONCLUSIONS: We ultimately find that our workflow resulted in high-quality variant calls in a computationally efficient manner. We argue that studies like ours should motivate further investigations combining hardware-oriented advances in computing systems with algorithmic developments to tackle emerging 'big data' problems in biomedical research brought on by the expansion of NGS technologies.

Choice and control: how involved are people with epilepsy and their families in the management of their epilepsy? Results from an Australian survey in the disability sector.

This study explored the extent to which people with epilepsy and their families have choice and control over the management of their epilepsy and the support provided in the Australian disability sector. It measured the level of direct involvement in planning and recording of their epilepsy health-care needs and support required through the use of epilepsy management plans. An Australian online survey was completed by 118 adults with epilepsy and 171 family members of children and adults with epilepsy, providing demographic and diagnostic data and details of their epilepsy management plan, whether they were involved in writing the plan and the extent to which it included their views on how they want to be supported. Results indicate that just over half of all respondents had an epilepsy management plan, with 83% revised within the past 12 months. Although the majority of respondents were directly involved in writing their plan (87%), only two-thirds (66%) felt that their plan included their views on how they wanted to be supported. Open-ended comments from 111 respondents indicated their desire to be actively involved in this process, as either collaborative team members or 'in charge' of the process. In spite of a move towards person-centered approaches and greater choice and control, further emphasis must be placed on actively involving the person with epilepsy and their family in writing and incorporating their views on support within their epilepsy management plans. This research was undertaken by the Epilepsy Foundation to inform the development of epilepsy support resources for the newly introduced Australian National Disability Insurance Scheme.

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis.

The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.