Cancer-Associated Mutations in Endometriosis without Cancer.

BACKGROUND: Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis. METHODS: We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in microdissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations. RESULTS: Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P=0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions. CONCLUSIONS: We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.

Genomic Signatures of Speciation in Sympatric and Allopatric Hawaiian Picture-Winged Drosophila.

The Hawaiian archipelago provides a natural arena for understanding adaptive radiation and speciation. The Hawaiian Drosophila are one of the most diverse endemic groups in Hawaiì with up to 1,000 species. We sequenced and analyzed entire genomes of recently diverged species of Hawaiian picture-winged Drosophila, Drosophila silvestris and Drosophila heteroneura from Hawaiì Island, in comparison with Drosophila planitibia, their sister species from Maui, a neighboring island where a common ancestor of all three had likely occurred. Genome-wide single nucleotide polymorphism patterns suggest the more recent origin of D. silvestris and D. heteroneura, as well as a pervasive influence of positive selection on divergence of the three species, with the signatures of positive selection more prominent in sympatry than allopatry. Positively selected genes were significantly enriched for functional terms related to sensory detection and mating, suggesting that sexual selection played an important role in speciation of these species. In particular, sequence variation in Olfactory receptor and Gustatory receptor genes seems to play a major role in adaptive radiation in Hawaiian pictured-winged Drosophila.

Hypothalamic differences in expression of genes involved in monoamine synthesis and signaling pathways after insulin injection in chickens from lines selected for high and low body weight.

Long-term selection for juvenile body weight from a common founder population resulted in two divergent chicken lines (low-weight selected line (LWS), high-weight selected line (HWS)) that display distinct food intake and blood glucose responses to exogenous neuropeptides and insulin. The objective of this study was to elucidate putative targets affecting food intake and energy homeostasis by sequencing hypothalamic RNA from LWS and HWS chickens after insulin injection. Ninety-day-old female LWS and HWS chickens were injected with either vehicle or insulin and hypothalamus collected at 1 h postinjection. Through RNA sequencing, a total of 361 differentially expressed genes (DEGs) were identified. There was greater expression of genes, mainly tyrosine hydroxylase (TH), L-aromatic amino acid decarboxylase (DDC), and vesicular monoamine transporter (VMAT), involved in serotonin and dopamine biosynthesis and signaling in LWS than in HWS vehicle-injected chickens. In contrast, after insulin injection, these genes were more highly expressed in HWS than in LWS. We identified 90 single nucleotide polymorphisms (SNPs) existing only in the HWS and 121 SNPs specific to LWS and 5119 SNPs close to fixation (with absolute frequency difference ≥0.9). Four were located in genes encoding enzymes associated with serotonergic and dopaminergic pathways, such as DDC, TH, and solute carrier family 18, member 2 (VMAT). These data implicate differences in biogenic amines such as serotonin and dopamine in hypothalamic physiology between the chicken lines, and these differences might be associated with polymorphisms during long-term selection. Changes in serotonergic and dopaminergic signaling pathways in response to insulin injection suggest a role in whole-body energy homeostasis.