Gene content evolution in the arthropods

Arthropods comprise the largest and most diverse phylum on Earth and play vital roles in nearly every ecosystem. Their diversity stems in part from variations on a conserved body plan, resulting from and recorded in adaptive changes in the genome. Dissection of the genomic record of sequence change enables broad questions regarding genome evolution to be addressed, even across hyper-diverse taxa within arthropods. Using 76 whole genome sequences representing 21 orders spanning more than 500 million years of arthropod evolution, we document changes in gene and protein domain content and provide temporal and phylogenetic context for interpreting these innovations. We identify many novel gene families that arose early in the evolution of arthropods and during the diversification of insects into modern orders. We reveal unexpected variation in patterns of DNA methylation across arthropods and examples of gene family and protein domain evolution coincident with the appearance of notable phenotypic and physiological adaptations such as flight, metamorphosis, sociality, and chemoperception. These analyses demonstrate how large-scale comparative genomics can provide broad new insights into the genotype to phenotype map and generate testable hypotheses about the evolution of animal diversity

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Genetic architecture of laterality defects revealed by whole exome sequencing

Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects

Sex differences in oncogenic mutational processes.

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research

The Drosophila melanogaster Genetic Reference Panel

A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype&ndash;phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype&ndash;phenotype mapping using the power of Drosophila genetics

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

Whole Exome Analysis Reveals Key Genomic Differences between Sporadic and Endemic Pediatric Burkitt Lymphoma

Abstract Introduction Burkitt Lymphoma (BL) is a highly aggressive hematological malignancy that originates from germinal center B-cells, is characterized by IG/MYC translocation, and affects both children and adults. Clinical and biological differences have been noted between endemic BL, which occurs in equatorial Africa and is virtually always associated with Epstein-Barr virus (EBV) infection, and sporadic BL that is infrequently associated with EBV. BL is highly curable using an aggressive chemotherapy regimen, but the intensive supportive care required to manage the toxicities of this treatment precludes its use for most patients with endemic BL, resulting in poorer survival for those patients. Although previous genetic studies have identified recurrent mutations in BL (including alterations in ID3 and its downstream targets TCF3 and CCND3), endemic BL has not been as well characterized and the extent of differences between sporadic and endemic BL (and their potential relation to pathogenesis and response to therapy) is not yet clear. Therefore, more extensive genomic characterization of both sporadic and endemic BL is needed to provide insight into tumor biology and to identify novel therapeutic targets that can be utilized to provide less toxic treatments. Methods We interrogated frozen tumor and matched normal blood samples from a cohort of 30 pediatric BL cases, 12 of which were collected from Uganda and 18 from Texas Children's Cancer Center (Houston, TX). Whole exome sequencing (WES) and copy number analysis were performed on the Illumina platform using the OmniExpress array and VCrome 2.1 WES capture reagent and analyzed utilizing the Baylor College of Medicine Human Genome Sequencing Center bioinformatic pipeline. A median of 135x average coverage and &gt;97% of targeted bases with at least 20x coverage was observed for WES. Results WES revealed a median of 46 nonsilent somatic mutations per case for endemic BL (range 19-207), and 32 per case for sporadic BL (range 13-119). Evidence of the EBV genome was detected in all endemic BL samples and 3/18 (17%) of sporadic BL cases. Mutations were found in genes known to be frequently mutated in BL, including MYC in 7/12 (58%) of endemic cases and 12/18 (67%) of sporadic cases and TP53 in 5/12 (42%) and 9/18 (50%), respectively. Of note, mutations in DDX3X (7/12 [58%] endemic, 9/18 [50%] sporadic) and FOXO1 (5/12 [42%] endemic, 7/18 [39%] sporadic) were identified frequently in our cohort. As previously described, the ID3 pathway was more frequently targeted by mutations in sporadic BL: ID3 in 8/18 (44%) sporadic cases vs 3/12 (25%) endemic, TCF3 in 3/18 (17%) vs. 1/12 (8%), and CCND3 in 7/18 (39%) vs 2/12 (17%), respectively. Mutations in the SWI/SNF chromatin-remodeling genes ARID1A and SMARCA4 have been reported to occur in BL in a mutually exclusive fashion. In our cohort, mutations in SMARCA4 were exclusive to sporadic cases (9/18, 50%) and not found in endemic tumors (P = 0.01). Conversely, ARID1A mutations were much more frequent in endemic cases (7/12, 58%) as compared to sporadic ones (3/18, 17%) (P &lt; 0.05). Only one sporadic case was found to have both genes mutated. Copy number analysis did not reveal recurrent focal copy number deletions. Amplification of 13q31.2 - q32.2 was detected in sporadic cases (4/18, 22%) but not in endemic cases, while focal amplification of 7p14.1 (3/10, 30%) and 14q11.2 (4/10, 40%) were exclusive to endemic tumors. Conclusions These findings provide novel insight into the landscapes of genomic alterations in pediatric endemic and sporadic BL. Our data confirm the recurrence of mutated genes previously associated with BL and highlight differences between endemic and sporadic BL, most notably, the exclusivity of SMARCA4 mutations in sporadic BL cases in this cohort. The recurrence of mutations in ARID1A and SMARCA4 emphasizes the critical role of these SWI/SNF proteins in BL. More extensive molecular studies (whole genome and transcriptome sequencing) of this cohort are ongoing and may reveal additional differences between endemic and sporadic BL. Additional studies will be required to more precisely assess the frequency of these alterations in BL and their link to clinical features of the disease, as well as the biological relevance of the BL genes identified through these genomic analyses. Figure. Figure. Disclosures No relevant conflicts of interest to declare. </jats:sec