SUMMARY Type 2 Diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ~20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly-linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function, and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter, and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D.

Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFRdependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFRindependent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival. epidermal growth factor receptor | non-small cell lung cancer | ORF

The base sequences of the nucleic acids corresponding to ten proteins (aconitase, alcohol dehydrogenase, enolase, fumarase, isocitrate dehydrogenase, lactate dehydrogenase, phosphofructokinase, phosphoglycerate mutase, pyruvate kinase and succinate dehydrogenase) belonging to a total of 154 species, ranging from prokaryotes to vertebrates, were compared with the base sequences of oligoribotides whose growth rates were calculated by a chemical kinetics model. It was shown that oligoribotides grown according to the kinetics model have a fraction of repetitive bases larger than expected from random processes. The base sequences of nucleic acids of prokaryotes and eukaryotes retain, in decreasing proportions, this feature of their abiotic past. Chemically synthesized pentameric stretches with repetitive bases are slightly more abundant than those present in prokaryotes. Genetic drift and natural selection, operating as fundamental laws even for the most primitive living systems, reduced the original, chemically controlled, repetitive base frequency in prokaryotes, which was further reduced for eukaryotes.