Genome sequences of Tropheus moorii and Petrochromis trewavasae, two eco-morphologically divergent cichlid fishes endemic to Lake Tanganyika.

With more than 1000 species, East African cichlid fishes represent the fastest and most species-rich vertebrate radiation known, providing an ideal model to tackle molecular mechanisms underlying recurrent adaptive diversification. We add high-quality genome reconstructions for two phylogenetic key species of a lineage that diverged about ~ 3-9 million years ago (mya), representing the earliest split of the so-called modern haplochromines that seeded additional radiations such as those in Lake Malawi and Victoria. Along with the annotated genomes we analysed discriminating genomic features of the study species, each representing an extreme trophic morphology, one being an algae browser and the other an algae grazer. The genomes of Tropheus moorii (TM) and Petrochromis trewavasae (PT) comprise 911 and 918 Mbp with 40,300 and 39,600 predicted genes, respectively. Our DNA sequence data are based on 5 and 6 individuals of TM and PT, and the transcriptomic sequences of one individual per species and sex, respectively. Concerning variation, on average we observed 1 variant per 220 bp (interspecific), and 1 variant per 2540 bp (PT vs PT)/1561 bp (TM vs TM) (intraspecific). GO enrichment analysis of gene regions affected by variants revealed several candidates which may influence phenotype modifications related to facial and jaw morphology, such as genes belonging to the Hedgehog pathway (SHH, SMO, WNT9A) and the BMP and GLI families.

Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.

OBJECTIVE: Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations are commonly associated with autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy; however, in rare instances, they also lead to autosomal dominant Charcot-Marie-Tooth (ADCMT). We aimed to investigate the frequency of disease-causing heterozygous GDAP1 mutations in ADCMT and their associated phenotype. METHODS: We performed mutation analysis in a large cohort of ADCMT patients by means of bidirectional sequencing of coding regions and exon-intron boundaries of GDAP1. Intragenic GDAP1 deletions were excluded using an allele quantification assay. We confirmed the pathogenic character of one sequence variant by in vitro experiments assaying mitochondrial morphology and function. RESULTS: In 8 Charcot-Marie-Tooth disease (CMT) families we identified 4 pathogenic heterozygous GDAP1 mutations, 3 of which are novel. Three of the mutations displayed reduced disease penetrance. Disease onset in the affected individuals was variable, ranging from early childhood to adulthood. Disease progression was slow in most patients and overall severity milder than typically seen in autosomal recessive GDAP1 mutations. Electrophysiologic changes are heterogeneous but compatible with axonal neuropathy in the majority of patients. CONCLUSIONS: With this study, we broaden the phenotypic and genetic spectrum of autosomal dominant GDAP1-associated neuropathies. We show that patients with dominant GDAP1 mutations may display clear axonal CMT, but may also have only minimal clinical and electrophysiologic abnormalities. We demonstrate that cell-based functional assays can be reliably used to test the pathogenicity of unknown variants. We discuss the implications of phenotypic variability and the reduced penetrance of autosomal dominant GDAP1 mutations for CMT diagnostic testing and counseling.

Immunohistochemical and mutational analysis of PDGF and PDGFR in desmoid tumours: is there a role for tyrosine kinase inhibitors in c-kit-negative desmoid tumours?

AIM: To determine the platelet-derived growth factor (PDGF) alpha and beta status of desmoid tumours. Desmoid tumours are rare monoclonal neoplasms that appear to have no metastatic potential. Surgical resection and radiotherapy in the event of a positive surgical margin is the first-line treatment. Recurrences are frequent. Treatment results using non-steroidal anti-inflammatory agents, anti-oestrogen compounds and other agents such as Imatinib mesylate have been published. Therapy with Imatinib has been proposed as a therapeutic option, although in most reports desmoid tumours are reported to be c-kit-. METHODS AND RESULTS: We performed immunohistochemical analysis on 124 archived samples (85 patients) of desmoid tumours using antibodies to PDGFalpha, PDGFbeta, PDGFRalpha and PDGFRbeta. All desmoid tumours showed immunoreactivity with antibodies to PDGFalpha and PDGFRalpha, whereas with antibodies to PDGFbeta and PDGFRbeta no specific reaction could be detected. Mutational analysis of PDGFRalpha (exons 11, 12, 17 and 18) and PDGFRbeta (exon 12) on frozen material from 14 patients was performed, but no mutations leading to amino acid changes in the mature protein were identified. CONCLUSION: The absence of an activating mutation in a protooncogene does not exclude the efficacy of tyrosine kinase inhibitors through other possible mechanisms, and these might be a therapeutic option for patients with desmoid tumours in whom established local and systemic approaches fail to control the disease.