Analysis of 1,000+ Type-Strain Genomes Substantially Improves Taxonomic Classification of Alphaproteobacteria.

The class Alphaproteobacteria is comprised of a diverse assemblage of Gram-negative bacteria that includes organisms of varying morphologies, physiologies and habitat preferences many of which are of clinical and ecological importance. Alphaproteobacteria classification has proved to be difficult, not least when taxonomic decisions rested heavily on a limited number of phenotypic features and interpretation of poorly resolved 16S rRNA gene trees. Despite progress in recent years regarding the classification of bacteria assigned to the class, there remains a need to further clarify taxonomic relationships. Here, draft genome sequences of a collection of genomes of more than 1000 Alphaproteobacteria and outgroup type strains were used to infer phylogenetic trees from genome-scale data using the principles drawn from phylogenetic systematics. The majority of taxa were found to be monophyletic but several orders, families and genera, including taxa recognized as problematic long ago but also quite recent taxa, as well as a few species were shown to be in need of revision. According proposals are made for the recognition of new orders, families and genera, as well as the transfer of a variety of species to other genera and of a variety of genera to other families. In addition, emended descriptions are given for many species mainly involving information on DNA G+C content and (approximate) genome size, both of which are confirmed as valuable taxonomic markers. Similarly, analysis of the gene content was shown to provide valuable taxonomic insights in the class. Significant incongruities between 16S rRNA gene and whole genome trees were not found in the class. The incongruities that became obvious when comparing the results of the present study with existing classifications appeared to be caused mainly by insufficiently resolved 16S rRNA gene trees or incomplete taxon sampling. Another probable cause of misclassifications in the past is the partially low overall fit of phenotypic characters to the sequence-based tree. Even though a significant degree of phylogenetic conservation was detected in all characters investigated, the overall fit to the tree varied considerably

Analysis of 1,000+ Type-Strain Genomes Substantially Improves Taxonomic Classification of Alphaproteobacteria.

The class Alphaproteobacteria is comprised of a diverse assemblage of Gram-negative bacteria that includes organisms of varying morphologies, physiologies and habitat preferences many of which are of clinical and ecological importance. Alphaproteobacteria classification has proved to be difficult, not least when taxonomic decisions rested heavily on a limited number of phenotypic features and interpretation of poorly resolved 16S rRNA gene trees. Despite progress in recent years regarding the classification of bacteria assigned to the class, there remains a need to further clarify taxonomic relationships. Here, draft genome sequences of a collection of genomes of more than 1000 Alphaproteobacteria and outgroup type strains were used to infer phylogenetic trees from genome-scale data using the principles drawn from phylogenetic systematics. The majority of taxa were found to be monophyletic but several orders, families and genera, including taxa recognized as problematic long ago but also quite recent taxa, as well as a few species were shown to be in need of revision. According proposals are made for the recognition of new orders, families and genera, as well as the transfer of a variety of species to other genera and of a variety of genera to other families. In addition, emended descriptions are given for many species mainly involving information on DNA G+C content and (approximate) genome size, both of which are confirmed as valuable taxonomic markers. Similarly, analysis of the gene content was shown to provide valuable taxonomic insights in the class. Significant incongruities between 16S rRNA gene and whole genome trees were not found in the class. The incongruities that became obvious when comparing the results of the present study with existing classifications appeared to be caused mainly by insufficiently resolved 16S rRNA gene trees or incomplete taxon sampling. Another probable cause of misclassifications in the past is the partially low overall fit of phenotypic characters to the sequence-based tree. Even though a significant degree of phylogenetic conservation was detected in all characters investigated, the overall fit to the tree varied considerably

Genomic Classification of Cutaneous Melanoma

We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four sub-types based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multidimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-makingclose3

The Molecular Taxonomy of Primary Prostate Cancer

There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defectsclose

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele