As above, so below: whole transcriptome profiling demonstrates strong molecular similarities between avian dorsal and ventral pallial subdivisions

Over the last two decades, beginning withthe Avian Brain Nomenclature Forum in2000, major revisions have been made to our understanding of the organization andnomenclature of the avian brain. However, there are still unresolved questions on avianpallial organization, particularly whether the cells above the vestigial ventricle representdistinct populations to those below it or similar populations. To test these two hypothe-ses, we profiled the transcriptomes of the major avian pallial subdivisions dorsal and ven-tral to the vestigial ventricle boundary using RNA sequencing and a new zebra finchgenome assembly containing about 22,000annotated, complete genes. We found thatthe transcriptomes of neural populations above and below the ventricle were remarkablysimilar. Each subdivision in dorsal pallium (Wulst) had a corresponding molecular counter-part in the ventral pallium (dorsal ventricularridge). In turn, each corresponding subdivi-sion exhibited shared gene co-expression modules that contained gene sets enriched infunctional specializations, such as anatomical structure development, synaptic transmis-sion, signaling, and neurogenesis. Thesefindings are more in line with the continuumhypothesis of avian brain subdivision organization above and below the vestigial ventriclespace, with the pallium as a whole consisting offour major cell populations (intercalatedpallium, mesopallium, hyper-nidopallium, andarcopallium) instead of seven (hyperpalliumapicale, interstitial hyperpallium apicale, intercalated hyperpallium, hyperpalliumdensocellare, mesopallium, nidopallium, and arcopallium). We suggest adopting a morestreamlined hierarchical naming system thatreflects the robust similarities in geneexpression, neural connectivity motifs, and function. These findings have important impli-cations for our understanding of overall vertebrate brain evolution

The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL

Incidence of Sports-Related Concussion Among NCAA Women’s Ice Hockey Athletes

Background: There are limited data on the incidence of concussion and concussion symptom nondisclosure among collegiate women’s ice hockey athletes. Purpose: To determine the incidence of sports-related concussion (SRC) in National Collegiate Athletic Association (NCAA) women’s ice hockey athletes. Study Design: Descriptive epidemiology study. Methods: An anonymous online survey was completed by 459 NCAA women’s ice hockey athletes. Players reported diagnosed concussions as well as incidents where they experienced an impact or blow to the head followed by symptoms associated with a concussion; reports spanned the duration of the 2014-2015 season and throughout players’ organized hockey career. Results: About half (n = 219, 47.7%) of respondents reported at least 1 diagnosed concussion over the duration of their entire organized ice hockey career. A total of 13.3% (n = 61) of respondents reported a diagnosed concussion during the 2014-2015 season. The incidence rate was 1.18 (95% CI, 0.92-1.51) per 1000 athlete-exposures to a game or practice and 0.58 (95% CI, 0.45-0.74) per 1000 hours of ice time. One-third (34.2%, n = 157) of players reported at least 1 impact where they experienced concussion-like symptoms during the 2014-2015 season; 82.8% of these players reported that they continued to play after at least 1 of these impacts, and 66.8% of players reported at least 1 impact where they never disclosed any symptoms. Conclusion: There is a high incidence of SRC in collegiate women’s ice hockey and a concerning level of symptom nondisclosure. Additional research is needed to understand the causes of concussion and reasons for the lack of symptom disclosure, including factors specific to female athletes and contextual issues specific to women’s collegiate ice hockey

The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias

Includes 3 unnumbered pages at the end of the article. Published online 2 March 2015Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.Anna K Andersson ... Charles G Mullighan ... et al. for The St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Projec

The genomic landscape of core-binding factor acute myeloid leukemias

Acute myeloid leukemia (AML) comprises a heterogeneous group of leukemias frequently defined by recurrent cytogenetic abnormalities, including rearrangements involving the core-binding factor (CBF) transcriptional complex. To better understand the genomic landscape of CBF-AMLs, we analyzed both pediatric (n = 87) and adult (n = 78) samples, including cases with RUNX1-RUNX1T1 (n = 85) or CBFB-MYH11 (n = 80) rearrangements, by whole-genome or whole-exome sequencing. In addition to known mutations in the Ras pathway, we identified recurrent stabilizing mutations in CCND2, suggesting a previously unappreciated cooperating pathway in CBF-AML. Outside of signaling alterations, RUNX1-RUNX1T1 and CBFB-MYH11 AMLs demonstrated remarkably different spectra of cooperating mutations, as RUNX1-RUNX1T1 cases harbored recurrent mutations in DHX15 and ZBTB7A, as well as an enrichment of mutations in epigenetic regulators, including ASXL2 and the cohesin complex. This detailed analysis provides insights into the pathogenesis and development of CBF-AML, while highlighting dramatic differences in the landscapes of cooperating mutations for these related AML subtypes.Zachary J Faber ... Charles G. Mullighan ... et al

The genomic landscape of core-binding factor acute myeloid leukemias

Acute myeloid leukemia (AML) comprises a heterogeneous group of leukemias frequently defined by recurrent cytogenetic abnormalities, including rearrangements involving the core-binding factor (CBF) transcriptional complex. To better understand the genomic landscape of CBF-AMLs, we analyzed both pediatric (n = 87) and adult (n = 78) samples, including cases with RUNX1-RUNX1T1 (n = 85) or CBFB-MYH11 (n = 80) rearrangements, by whole-genome or whole-exome sequencing. In addition to known mutations in the Ras pathway, we identified recurrent stabilizing mutations in CCND2, suggesting a previously unappreciated cooperating pathway in CBF-AML. Outside of signaling alterations, RUNX1-RUNX1T1 and CBFB-MYH11 AMLs demonstrated remarkably different spectra of cooperating mutations, as RUNX1-RUNX1T1 cases harbored recurrent mutations in DHX15 and ZBTB7A, as well as an enrichment of mutations in epigenetic regulators, including ASXL2 and the cohesin complex. This detailed analysis provides insights into the pathogenesis and development of CBF-AML, while highlighting dramatic differences in the landscapes of cooperating mutations for these related AML subtypes

Towards complete and error-free genome assemblies of all vertebrate species

The Vertebrate Genome Project has used an optimized pipeline to generate high-quality genome assemblies for sixteen species (representing all major vertebrate classes), which have led to new biological insights. High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for only a few non-microbial species(1-4). To address this issue, the international Genome 10K (G10K) consortium(5,6) has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences