Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells

To elucidate the genomics of cellular responses to cancer treatment, we analyzed the expression of over 9,600 human genes in acute lymphoblastic leukemia cells before and after in vivo treatment with methotrexate and mercaptopurine given alone or in combination. Based on changes in gene expression, we identified 124 genes that accurately discriminated among the four treatments. Discriminating genes included those involved in apoptosis, mismatch repair, cell cycle control and stress response. Only 14% of genes that changed when these medications were given as single agents also changed when they were given together. These data indicate that lymphoid leukemia cells of different molecular subtypes share common pathways of genomic response to the same treatment, that changes in gene expression are treatment-specific and that gene expression can illuminate differences in cellular response to drug combinations versus single agents.     

Have environmental mutagens caused oncomutations in people?

Age-specific cancer rates show large historical increases that indict environmental risk factors. But these environmental factors did not necessarily act by increasing oncomutation rates. Mathematical analyses suggest selective effects on pre-existing oncomutants. The widely held hypothesis that environmental chemicals induce a substantial fraction of human point mutations has not been supported by observation. Direct measurement of the kinds and numbers of point mutations in human tissues have, in fact, found no clear relationship with exposure to environmental agents, save for sunlight in the skin. Alternative hypotheses that point mutations arise primarily as errors during turnover of undamaged DNA and that environmental conditions select rather than induce oncomutants seem to better explain the facts of environmental carcinogenesis in humans.     

Positional cloning of a novel gene influencing asthma from chromosome 2q14

Asthma is a common disease in children and young adults. Four separate reports have linked asthma and related phenotypes to an ill-defined interval between 2q14 and 2q32 (refs. 1-4), and two mouse genome screens have linked bronchial hyper-responsiveness to the region homologous to 2q14 (refs. 5,6). We found and replicated association between asthma and the D2S308 microsatellite, 800 kb distal to the IL1 cluster on 2q14. We sequenced the surrounding region and constructed a comprehensive, high-density, single-nucleotide polymorphism (SNP) linkage disequilibrium (LD) map. SNP association was limited to the initial exons of a solitary gene of 3.6 kb (DPP10), which extends over 1 Mb of genomic DNA. DPP10 encodes a homolog of dipeptidyl peptidases (DPPs) that cleave terminal dipeptides from cytokines and chemokines, and it presents a potential new target for asthma therapy.     

Compartments revealed in food-web structure

Compartments in food webs are subgroups of taxa in which many strong interactions occur within the subgroups and few weak interactions occur between the subgroups. Theoretically, compartments increase the stability in networks, such as food webs. Compartments have been difficult to detect in empirical food webs because of incompatible approaches or insufficient methodological rigour. Here we show that a method for detecting compartments from the social networking science identified significant compartments in three of five complex, empirical food webs. Detection of compartments was influenced by food web resolution, such as interactions with weights. Because the method identifies compartmental boundaries in which interactions are concentrated, it is compatible with the definition of compartments. The method is rigorous because it maximizes an explicit function, identifies the number of non-overlapping compartments, assigns membership to compartments, and tests the statistical significance of the results. A graphical presentation reveals systemic relationships and taxa-specific positions as structured by compartments. From this graphic, we explore two scenarios of disturbance to develop a hypothesis for testing how compartmentalized interactions increase stability in food webs.     

The vector alignments of asteroid spins by thermal torques

Collisions have been thought to be the dominant process altering asteroid rotations, but recent observations of the Koronis family of asteroids suggest that this may be incorrect. This group of asteroids was formed in a catastrophic collision several billion years ago; in the intervening period their rotational axes should have become nearly random because of subsequent collisions, with spin rates that follow a maxwellian distribution. What is seen, however, is that the observed family members with prograde spins have nearly identical periods (7.5-9.5 h) and obliquities between 42 and 50 degrees, while those with retrograde spins have obliquities between 154 and 169 degrees with periods either <5 h or >13 h. Here we show that these non-random orientations and spin rates can be explained by 'thermal torques' (arising from differential solar heating), which modify the spin states over time. In some cases, the asteroids become trapped in spin-orbit resonances. Our results suggest that thermal torques may be more important than collisions in changing the spin states (and possibly shapes) of asteroids with diameters <40 km.     

TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis

Recently, TDP-43 was identified as a key component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS), an adult-onset neurological disorder that leads to the degeneration of motor neurons. Here we report eight missense mutations in nine individuals--six from individuals with sporadic ALS (SALS) and three from those with familial ALS (FALS)--and a concurring increase of a smaller TDP-43 product. These findings further corroborate that TDP-43 is involved in ALS pathogenesis.     

BRCA1--sowing the seeds crooked in the furrow

Breast tumors with deficiency in DNA double-strand break repair might be expected to show aneuploidy. A new study shows that microdeletions in PTEN, resulting in complete loss of PTEN protein, are signature lesions in these cancers, particularly those arising in BRCA1-mutation carriers.     

Newly identified loci that influence lipid concentrations and risk of coronary artery disease

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.     

Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12

We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, approximately 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 x 10(-9) for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP.