SUMMARY Embryonal rhabdomyosarcoma (eRMS) shows the most myodifferentiation amongst sarcomas, yet the precise cell of origin remains undefined. Using Ptch1, p53 and/or Rb1 conditional mouse models and controlling prenatal or postnatal myogenic cell of origin, we demonstrate that eRMS and undifferentiated pleomorphic sarcoma (UPS) lie in a continuum, with satellite cells predisposed to giving rise to UPS. Conversely, p53 loss in maturing myoblasts gives rise to eRMS, which have the highest myodifferentiation potential. Irrespective of origin, Rb1 loss modifies tumor phenotype to mimic UPS. In human sarcomas that lack pathognomic chromosomal translocations, p53 loss of function is prevalent whereas Shh or Rb1 alterations likely act primarily as modifiers. Thus, sarcoma phenotype is strongly influenced by cell of origin and mutational profile.

The Tasmanian devil ( Sarcophilus harrisii ) is threatened with extinction because of a contagious cancer known as Devil Facial Tumor Disease. The inability to mount an immune response and to reject these tumors might be caused by a lack of genetic diversity within a dwindling population. Here we report a whole-genome analysis of two animals originating from extreme northwest and southeast Tasmania, the maximal geographic spread, together with the genome from a tumor taken from one of them. A 3.3-Gb de novo assembly of the sequence data from two complementary next-generation sequencing platforms was used to identify 1 million polymorphic genomic positions, roughly one-quarter of the number observed between two genetically distant human genomes. Analysis of 14 complete mitochondrial genomes from current and museum specimens, as well as mitochondrial and nuclear SNP markers in 175 animals, suggests that the observed low genetic diversity in today's population preceded the Devil Facial Tumor Disease disease outbreak by at least 100 y. Using a genetically characterized breeding stock based on the genome sequence will enable preservation of the extant genetic diversity in future Tasmanian devil populations.

Background The aim of this study was to elucidate whether genetic screening test results of pediatric steroid-resistant nephrotic syndrome (SRNS) patients vary with ethnicity. Methods Using high-throughput DNA sequencing, 28 nephrotic syndrome-related genes were analyzed in 110 children affected with SRNS and 10 children with isolated proteinuria enrolled by 5 centers in China (67 males, 53 females). Their age at disease onset was 1 day to 208 months (median, 48.8 months). Patients were excluded if their age of onset of disease was beyond 18 years or if they were diagnosed as Alport’s syndrome. Results A genetic etiology was identified in 28.3% of our cohort and the likelihood of establishing a genetic diagnosis decreased as the age of onset of nephrotic syndrome increased. The most common mutated genes were ADCK4 (6.67%), NPHS1 (5.83%), WT1 (5.83%), and NPHS2 (3.33%), and the difference in the frequencies of ADCK4 and NPHS2 mutations between this study and a study on monogenic causes of SRNS in the largest international cohort of 1,783 different families was significant. A case with congenital nephrotic syndrome was attributed to a homozygous missense mutation in ADCK4, and a de novo missense mutation in TRPC6 was detected in a case with infantile nephrotic syndrome. Conclusions Our results showed that, in the first and the largest multicenter cohort of Chinese pediatric SRNS reported to date, ADCK4 is the most common causative gene, whereas there is a low prevalence of NPHS2 mutations. Our data indicated that the genetic testing results for pediatric SRNS patients vary with different ethnicities, and this information will help to improve management of the disease in clinical practice.

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A stepwise mutation that occurred in both pathogens and their respective hosts has played a seminal role in the co-evolutionary arms race evolution in diverse pathosystems. The process driven by rice blast AvrPik and Pik alleles was investigated through population genetic and evolutionary approaches. The genetic diversity of the non-signal domain of AvrPik was higher than that in its signal peptide domain. Positive selection for particular AvrPik alleles in the northeastern region of China was stronger than in the south. The perfect relationship between the functional lineages and AvrPik allele-specific pathotypes was established by ruling out the nonfunctional lineages derived from additional copies. Only four alleles conditioning stepwise pathotypes were detected in natural populations, which were likely created by only one evolutionary pathway with three recognizable mutation steps. Two non-stepwise pathotypes were determined by two blocks in a network constructed by all 16 possible alleles, indicating that a natural evolution process can be artificially changed by a combination of specific single-nucleotide polymorphisms. Assuming that AvrPik evolution has been largely driven by host selection, the co-evolutionary stepwise relationships between AvrPik and Pik was established. The experimental validation of stepwise mutation is required for the development of sustainable management strategies against plant disease.