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We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

Abstract Background Quantitative trait locus (QTL) studies show that variation in salinity tolerance in Arctic charr and rainbow trout has a genetic basis, even though both these species have low to moderate salinity tolerance capacities. QTL were observed to localize to homologous linkage group segments within putative chromosomal regions possessing multiple candidate genes. We compared salinity tolerance QTL in rainbow trout and Arctic charr to those detected in a higher salinity tolerant species, Atlantic salmon. The highly derived karyotype of Atlantic salmon allows for the assessment of whether disparity in salinity tolerance in salmonids is associated with differences in genetic architecture. To facilitate these comparisons, we examined the genomic synteny patterns of key candidate genes in the other model teleost fishes that have experienced three whole-genome duplication (3R) events which preceded a fourth (4R) whole genome duplication event common to all salmonid species. Results Nine linkage groups contained chromosome-wide significant QTL (AS-2, -4p, -4q, -5, -9, -12p, -12q, -14q -17q, -22, and −23), while a single genome-wide significant QTL was located on AS-4q. Salmonid genomes shared the greatest marker homology with the genome of three-spined stickleback. All linkage group arms in Atlantic salmon were syntenic with at least one stickleback chromosome, while 18 arms had multiple affinities. Arm fusions in Atlantic salmon were often between multiple regions bearing salinity tolerance QTL. Nine linkage groups in Arctic charr and six linkage group arms in rainbow trout currently have no synteny alignments with stickleback chromosomes, while eight rainbow trout linkage group arms were syntenic with multiple stickleback chromosomes. Rearrangements in the stickleback lineage involving fusions of ancestral arm segments could account for the 21 chromosome pairs observed in the stickleback karyotype. Conclusions Salinity tolerance in salmonids from three genera is to some extent controlled by the same loci. Synteny between QTL in salmonids and candidate genes in stickleback suggests genetic variation at candidate gene loci could affect salinity tolerance in all three salmonids investigated. Candidate genes often occur in pairs on chromosomes, and synteny patterns indicate these pairs are generally conserved in 2R, 3R, and 4R genomes. Synteny maps also suggest that the Atlantic salmon genome contains three larger syntenic combinations of candidate genes that are not evident in any of the other 2R, 3R, or 4R genomes examined. These larger synteny tracts appear to have resulted from ancestral arm fusions that occurred in the Atlantic salmon ancestor. We hypothesize that the superior hypo-osmoregulatory efficiency that is characteristic of Atlantic salmon may be related to these clusters.

Abstract Background The capacity to maintain internal ion homeostasis amidst changing conditions is particularly important for teleost fishes whose reproductive cycle is dependent upon movement from freshwater to seawater. Although the physiology of seawater osmoregulation in mitochondria-rich cells of fish gill epithelium is well understood, less is known about the underlying causes of inter- and intraspecific variation in salinity tolerance. We used a genome-scan approach in Arctic charr (Salvelinus alpinus) to map quantitative trait loci (QTL) correlated with variation in four salinity tolerance performance traits and six body size traits. Comparative genomics approaches allowed us to infer whether allelic variation at candidate gene loci (e.g., ATP1α1b, NKCC1, CFTR, and cldn10e) could have underlain observed variation. Results Combined parental analyses yielded genome-wide significant QTL on linkage groups 8, 14 and 20 for salinity tolerance performance traits, and on 1, 19, 20 and 28 for body size traits. Several QTL exhibited chromosome-wide significance. Among the salinity tolerance performance QTL, trait co-localizations occurred on chromosomes 1, 4, 7, 18 and 20, while the greatest experimental variation was explained by QTL on chromosomes 20 (19.9%), 19 (14.2%), 4 (14.1%) and 12 (13.1%). Several QTL localized to linkage groups exhibiting homeologous affinities, and multiple QTL mapped to regions homologous with the positions of candidate gene loci in other teleosts. There was no gene × environment interaction among body size QTL and ambient salinity. Conclusions Variation in salinity tolerance capacity can be mapped to a subset of Arctic charr genomic regions that significantly influence performance in a seawater environment. The detection of QTL on linkage group 12 was consistent with the hypothesis that variation in salinity tolerance may be affected by allelic variation at the ATP1α1b locus. IGF2 may also affect salinity tolerance capacity as suggested by a genome-wide QTL on linkage group 19. The detection of salinity tolerance QTL in homeologous regions suggests that candidate loci duplicated from the salmonid-specific whole-genome duplication may have retained their function on both sets of homeologous chromosomes. Homologous affinities suggest that loci affecting salinity tolerance in Arctic charr may coincide with QTL for smoltification and salinity tolerance traits in rainbow trout. The effects of body size QTL appear to be independent of changes in ambient salinity.

Abstract Background Salmonids are regarded as 4R derivative species, having experienced 4 whole genome duplication events in their ancestry. Many duplicated chromosome regions still share extensive homology with one another which is maintained primarily through male-based homeologous chromosome pairings during meiosis. The formation of quadrivalents during meiosis leads to pseudolinkage. This phenomenon is more prevalent within 5 of the 12 ancestral teleost linkage groups in salmonids. Results We constructed a genetic linkage map for brook charr and used this in combination with the genetic map from Arctic charr, to make comparisons with the genetic map of rainbow trout. Although not all chromosome arms are currently mapped, some homologous chromosome rearrangements were evident between Arctic charr and brook charr. Notably, 10 chromosome arms in brook charr representing 5 metacentric chromosomes in Arctic charr have undergone rearrangements. Three metacentrics have one arm translocated and fused with another chromosome arm in brook charr to a make a new metacentrics while two metacentrics are represented by 4 acrocentric pairs in brook charr. In two cases (i.e., BC-4 and BC-16), an apparent polymorphism was observed with the identification of both a putative metacentric structure (similar to metacentric AC-4 = BC-4 and a joining of acrocentric AC-16 + one arm of AC-28 = BC-16), as well as two separate acrocentric linkage groups evident in the mapping parents. Forty-six of the expected 50 karyotypic arms could be inter-generically assigned. SEX in brook charr (BC-4) was localized to the same homologous linkage group region as in Arctic charr (AC-4). The homeologous affinities detected in the two charr species facilitated the identification of 20 (expected number = 25) shared syntenic regions with rainbow trout, although it is likely that some of these regions were partial or overlapping arm regions. Conclusions Inter-generic comparisons among 2 species of charr (genus Salvelinus) and a trout (genus Oncorhynchus) have identified that linkage group arm arrangements are largely retained among these species. Previous studies have revealed that up to 7 regions of high duplicate marker retention occur between Salmo species (i.e., Atlantic salmon and brown trout) and rainbow trout, with 5 of these regions exhibiting higher levels of pseudolinkage. Pseudolinkage was detected in the charr species (i.e., BC-1/21, AC-12/27, AC-6/23, = RT-2p/29q, RT-12p/16p, and RT-27p/31p, respectively) consistent with three of the five 'salmonid-specific' pseudolinkage regions. Chromosome arms with the highest number of duplicated markers in rainbow trout are the linkage group arms with the highest retention of duplicated markers in both charr species.