Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

Highlights d Blood gene expression predicts gestational age in normal and complicated pregnancies d RNA changes preceding preterm prelabor rupture of the membranes are shared between cohorts d Plasma proteomic profiles from asymptomatic women predict spontaneous preterm birth

Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by unknown mechanisms. We report here the results of a large metabolomics study showing that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. We found that immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, we found a positive correlation between levels of specific inflammatory cytokines and KP dysregulation.Using metabolic flux assays, we found that IFN stimulation causes IDO1 overexpression and kynurenine overproduction in cells with T21, dependent on overexpression of IFN receptors encoded on chromosome 21. Finally, KP dysregulation is conserved in a mouse model of DS carrying triplication of the IFN receptors. Altogether, these results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS. 3 INTRODUCTION.

Prostate cancer genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of prostate cancer characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy; however, CHD1 is rarely lost without codeletion of MAP3K7. Here, we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. Although CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. Prostate cancer cell line models engineered to cosuppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of prostate cancer that poses challenges to conventional therapeutic approaches.Implications: These findings strongly implicate MAP3K7 loss as a biomarker for aggressive prostate cancer with significant risk for recurrence that poses challenges for conventional androgen receptor-targeted therapies.

Highlights d FN-RMS tumors are highly dependent on SIX1 for growth d In RMS, SIX1 enhances open chromatin at stem/oncogenic superenhancers d SIX1 KD reprograms MYOD1 to occupy muscle differentiation rather than stem loci d A gene signature derived from SIX1 loss is predictive of advanced RMS