Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance–negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.
Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions.
It is commonly thought that deep phylogenetic conservation of plant microRNAs (miRNAs) and their targets 1,2 indicates conserved regulatory functions. We show that the blind (bl) mutant of Petunia hybrida 3 and the fistulata (fis) mutant of Antirrhinum majus 4,5 , which have similar homeotic phenotypes, are recessive alleles of two homologous miRNA-encoding genes. The BL and FIS genes control the spatial restriction of homeotic class C genes 6,7 to the inner floral whorls, but their ubiquitous early floral expression patterns are in contradiction with a potential role in patterning C gene expression. We provide genetic evidence for the unexpected function of the MIRFIS and MIRBL genes in the center of the flower and propose a dynamic mechanism underlying their regulatory role. Notably, Arabidopsis thaliana, a more distantly related species, also contains this miRNA module but does not seem to use it to confine early C gene expression to the center of the flower.The spatial partitioning of floral homeotic gene expression is crucial for wild-type flower development. Several transcription factors participate in this control, which aims at transcriptional silencing of the so-called 'C genes' outside their genuine expression domain in the inner two whorls of the flower, where they govern reproductive organ (stamen and carpel) development 6,7 . The functions of orthologous repressor genes, constituting the A function of the floral ABCs 6 , are, in part, comparable between different species 8 , as are some of the cis-acting regulatory regions within the large second intron of their structurally and functionally related target C genes AGAMOUS (AG) in Arabidopsis thaliana 7 , pMADS3 in P. hybrida 9 and PLENA and FARINELLI (PLE and FAR) in A. majus 10 . There are also exceptions to these overall similarities among species. For instance, orthologs of the A. thaliana APETALA2 (AP2) gene have no role in C gene regulation in P. hybrida 11 or A. majus 12 , raising the question of whether other genes fulfill this role. Candidates are the BL gene in P. hybrida and FIS in A. majus, which, when mutated, show markedly similar homeotically converted stamenoid petals in their second floral whorls 4,5 (Fig. 1).By a combination of transposon tagging and map-based cloning strategies, we cloned the BL and FIS genes and found that they encode homologous bona fide miRNAs (miRBL and miRFIS), related in their core sequences to members of the large miR169 family 13,14 (Fig. 2). The bl-1 and fis-1 alleles lie within large genomic deletions and thus represent null alleles; bl-2 and fis-2 are transposon induced and genetically unstable alleles (Fig. 2a). miRNA-encoding genes are relatively small targets for mutation, and therefore, recessive mutants are infrequent; bl and fis thus offer a rare opportunity to study and compare the function of potential orthologs in two plant species. miRNAs control gene expression by recognizing short complementary sequences in their transcripts (miRNA-recognition elements, or MREs), which are then post-transcrip...
*Finding causal relationships between genotypic and phenotypic variation is a key focus of evolutionary biology, human genetics and plant breeding. To identify genome-wide patterns underlying trait diversity, we assembled a high-quality reference genome of Cardamine hirsuta, a close relative of the model plant Arabidopsis thaliana. We combined comparative genome and transcriptome analyses with the experimental tools available in C. hirsuta to investigate gene function and phenotypic diversification. Our findings highlight the prevalent role of transcription factors and tandem gene duplications in morphological evolution. We identified a specific role for the transcriptional regulators PLETHORA5/7 in shaping leaf diversity and link tandem gene duplication with differential gene expression in the explosive seed pod of C. hirsuta. Our work highlights the value of comparative approaches in genetically tractable species to understand the genetic basis for evolutionary change.Parallel genetic studies in C. hirsuta and the related model A. thaliana have provided a powerful platform to identify the molecular causes of trait diversity between these species at a geneby-gene level [1][2][3][4] . In particular, leaf shape differences have provided an attractive model to investigate the genetic basis for morphological evolution [1][2][3][4][5]
SUMMARYA major goal in biology is to identify the genetic basis for phenotypic diversity. This goal underpins research in areas as diverse as evolutionary biology, plant breeding and human genetics. A limitation for this research is no longer the availability of sequence information but the development of functional genetic tools to understand the link between changes in sequence and phenotype. Here we describe Cardamine hirsuta, a close relative of the reference plant Arabidopsis thaliana, as an experimental system in which genetic and transgenic approaches can be deployed effectively for comparative studies. We present high-resolution genetic and cytogenetic maps for C. hirsuta and show that the genome structure of C. hirsuta closely resembles the eight chromosomes of the ancestral crucifer karyotype and provides a good reference point for comparative genome studies across the Brassicaceae. We compared morphological and physiological traits between C. hirsuta and A. thaliana and analysed natural variation in stamen number in which lateral stamen loss is a species characteristic of C. hirsuta. We constructed a set of recombinant inbred lines and detected eight quantitative trait loci that can explain stamen number variation in this population. We found clear phylogeographic structure to the genetic variation in C. hirsuta, thus providing a context within which to address questions about evolutionary changes that link genotype with phenotype and the environment.
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