Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The circadian clock improves fitness in the fruit fly, Drosophila melanogaster

It is assumed that a properly timed circadian clock enhances fitness, but only few studies have truly demonstrated this in animals. We raised each of the three classical Drosophila period mutants for >50 generations in the laboratory in competition with wildtype flies. The populations were either kept under a conventional 24-h day or under cycles that matched the mutant’s natural cycle, i.e., a 19-h day in the case of pers mutants and a 29-h day for perl mutants. The arrhythmic per0 mutants were grown together with wildtype flies under constant light that renders wildtype flies similar arrhythmic as the mutants. In addition, the mutants had to compete with wildtype flies for two summers in two consecutive years under outdoor conditions. We found that wildtype flies quickly outcompeted the mutant flies under the 24-h laboratory day and under outdoor conditions, but perl mutants persisted and even outnumbered the wildtype flies under the 29-h day in the laboratory. In contrast, pers and per0 mutants did not win against wildtype flies under the 19-h day and constant light, respectively. Our results demonstrate that wildtype flies have a clear fitness advantage in terms of fertility and offspring survival over the period mutants and – as revealed for perl mutants – this advantage appears maximal when the endogenous period resonates with the period of the environment. However, the experiments indicate that perl and pers persist at low frequencies in the population even under the 24-h day. This may be a consequence of a certain mating preference of wildtype and heterozygous females for mutant males and time differences in activity patterns between wildtype and mutants

New information on the Devonian shark Mcmurdodus, based on material from Western Queensland, Australia

Histological structure of the type and newly collected teeth of the shark Mcmurdodus whitei Turner & Young, 1987, from a Devonian (?late Emsian-early Eifelian) limestone outcrop in the Cravens Peak Beds of western Queensland, was determined by immersion in anise oil, thin sectioning, and acid etching of fractured surfaces. The morphology and vascularization of the teeth are comparable to those of modern hexanchiform and echinorhinid squaliform sharks, being most similar to those of Echinorhinus. A multilayered enameloid layer is not discernible in Mcmurdodus teeth, but a parallel-fibred layer is possibly present. Prismatic calcified cartilage, presumed to be from M. whitei, appears identical to that of all elasmobranchs. Scales and spines and distinctive ring-like elements occur in the same horizon, the latter comparable with elements that encircle the lateral line in Echinorhinus, and which are found in no other Recent elasmobranchs

Need for a Smart Solution: Developing a Sourcing Strategy for a Policy System at a German Insurance Company

The direct insurer Gothaer Insurance Group is among the largest insurance companies in Germany. A project started during the 1990s is still facing the task to introduce a policy system for the commercial sector. The project had its origin in a merger with another German insurer and the system has since evolved over about 18 years. The project team encounters manifold technical and organisational issues as well as external factors which have led the project to a state which requires a decision about its continuance. Driven by a new political agenda that fosters the replacement of mainframe solutions and the use of standard rather than in-house solutions, decisions needed to be made concerning the sourcing strategy: should the system be implemented in-house or with the help of an external partner? Should it be realised by standard software or custom development? A steering committee meeting is set up to decide how to proceed. This case chronicles the series of events leading to that upcoming steering committee and the status quo of the system

The Neogene fossil record of Aetomylaeus (Elasmobranchii, Myliobatidae) from the south-eastern Pacific

The presence of eagle rays of the genus Aetomylaeus in the Neogene of the Temperate Pacific coast of South America (TPSA) still is ambiguous, although the fossil record of elasmobranch fishes (sharks, rays, and skates) from this area is quite good. Here, we present the first unmistakable fossil remains of Aetomylaeus from the Neogene of the TPSA. The material comprises 13 dental plates from one site in Peru and six localities in Chile ranging in age from Miocene to Pliocene and was compared with dental plates of extant species. Our study reveals that the number of tooth rows and the shape of lateral teeth in extant species are seemingly very variable and need to be established before fossil specimens can be confidently identified. Consequently, we do not assign the fossil specimens from the Neogene of the TPSA to any species but leave them as Aetomylaeus. Moreover, we recognized that only the shape of medial teeth provides reliable diagnostic characters in our material, whereas the shape and number of lateral teeth are highly variable, similar to the condition seen in extant species

Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing

Burkitt lymphoma is a mature aggressive B-cell lymphoma derived from germinal center B cells. Its cytogenetic hallmark is the Burkitt translocation t(8;14)(q24;q32) and its variants, which juxtapose the MYC oncogene with one of the three immunoglobulin loci. Consequently, MYC is deregulated, resulting in massive perturbation of gene expression. Nevertheless, MYC deregulation alone seems not to be sufficient to drive Burkitt lymphomagenesis. By whole-genome, whole-exome and transcriptome sequencing of four prototypical Burkitt lymphomas with immunoglobulin gene (IG)-MYC translocation, we identified seven recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma. In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. These findings suggest that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis