Grand Canyon provenance for orthoquartzite clasts in the lower Miocene of coastal southern California

This research was supported by National Science Foundation (NSF) grants EAR 10-19896 and EAR 14-51055 awarded to B. Wernicke, EAR 17-28690 awarded to J. Stock, and OPP 13-41729 awarded to J. Kirschvink. We also acknowledge NSF grant EAR 16-49254 awarded to G. Gehrels at the University of Arizona for support of the Arizona LaserChron Center.Orthoquartzite detrital source regions in the Cordilleran interior yield clast populations with distinct spectra of paleomagnetic inclinations and detrital zircon ages that can be used to trace the provenance of gravels deposited along the western margin of the Cordilleran orogen. An inventory of characteristic remnant magnetizations (CRMs) from >700 sample cores from orthoquartzite source regions defines a low-inclination population of Neoproterozoic-Paleozoic age in the Mojave Desert-Death Valley region (and in correlative strata in Sonora, Mexico) and a moderate- to high-inclination population in the 1.1 Ga Shinumo Formation in eastern Grand Canyon. Detrital zircon ages can be used to distinguish Paleoproterozoic to mid-Mesoproterozoic (1.84-1.20 Ga) clasts derived from the central Arizona highlands region from clasts derived from younger sources that contain late Mesoproterozoic zircons (1.20-1.00 Ga). Characteristic paleomagnetic magnetizations were measured in 44 densely cemented orthoquartzite clasts, sampled from lower Miocene portions of the Sespe Formation in the Santa Monica and Santa Ana mountains and from a middle Eocene section in Simi Valley. Miocene Sespe clast inclinations define a bimodal population with modes near 15 degrees and 45 degrees. Eight samples from the steeper Miocene mode for which detrital zircon spectra were obtained all have spectra with peaks at 1.2, 1.4, and 1.7 Ga. One contains Paleozoic and Mesozoic peaks and is probably Jurassic. The remaining seven define a population of clasts with the distinctive combination of moderate to high inclination and a cosmopolitan age spectrum with abundant grains younger than 1.2 Ga. The moderate to high inclinations rule out a Mojave Desert-Death Valley or Sonoran region source population, and the cosmopolitan detrital zircon spectra rule out a central Arizona highlands source population. The Shinumo Formation, presently exposed only within a few hundred meters elevation of the bottom of eastern Grand Canyon, thus remains the only plausible, known source for the moderate- to high-inclination clast population. If so, then the Upper Granite Gorge of the eastern Grand Canyon had been eroded to within a few hundred meters of its current depth by early Miocene time (ca. 20 Ma). Such an unroofing event in the eastern Grand Canyon region is independently confirmed by (U-Th)/He thermochronology. Inclusion of the eastern Grand Canyon region in the Sespe drainage system is also independently supported by detrital zircon age spectra of Sespe sandstones. Collectively, these data define a mid-Tertiary, SW-flowing "Arizona River" drainage system between the rapidly eroding eastern Grand Canyon region and coastal California.Publisher PDFPeer reviewe

Configural and featural information in facial-composite images

Eyewitnesses are often invited to construct a facial composite, an image created of the person they saw commit a crime that is used by law enforcement to locate criminal suspects. In the current paper, the effectiveness of composite images was investigated from traditional feature systems (E-FIT and PRO-fit), where participants (face constructors) selected individual features to build the face, and a more recent holistic system (EvoFIT), where they ‘evolved' a composite by repeatedly selecting from arrays of complete faces. Further participants attempted to name these composites when seen as an unaltered image, or when blurred, rotated, linearly stretched or converted to a photographic negative. All of the manipulations tested reduced correct naming of the composites overall except (i) for a low level of blur, for which naming improved for holistic composites but reduced for feature composites, and (ii) for 100% linear stretch, for which a substantial naming advantage was observed. Results also indicated that both featural (facial elements) and configural (feature spacing) information was useful for recognition in both types of composite system, but highly-detailed information was more accurate in the feature-based than the holistic method. The naming advantage of linear stretch was replicated using a forensically more-practical procedure with observers viewing an unaltered ¬composite sideways. The work is valuable to police practitioners and designers of facial-composite systems

Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA

In eukaryotes, the Cdt1-bound replicative helicase core MCM2-7 is loaded onto DNA by the ORC-Cdc6 ATPase to form a prereplicative complex (pre-RC) with an MCM2-7 double hexamer encircling DNA. Using purified components in the presence of ATP-γS, we have captured in vitro an intermediate in pre-RC assembly that contains a complex between the ORC-Cdc6 and Cdt1-MCM2-7 heteroheptamers called the OCCM. Cryo-EM studies of this 14-subunit complex reveal that the two separate heptameric complexes are engaged extensively, with the ORC-Cdc6 N-terminal AAA+ domains latching onto the C-terminal AAA+ motor domains of the MCM2-7 hexamer. The conformation of ORC-Cdc6 undergoes a concerted change into a right-handed spiral with helical symmetry that is identical to that of the DNA double helix. The resulting ORC-Cdc6 helicase loader shows a notable structural similarity to the replication factor C clamp loader, suggesting a conserved mechanism of action

Person identification from aerial footage by a remote-controlled drone

Remote-controlled aerial drones (or unmanned aerial vehicles; UAVs) are employed for surveillance by the military and police, which suggests that drone-captured footage might provide sufficient information for person identification. This study demonstrates that person identification from drone- captured images is poor when targets are unfamiliar (Experiment 1), when targets are familiar and the number of possible identities is restricted by context (Experiment 2), and when moving footage is employed (Experiment 3). Person information such as sex, race and age is also difficult to access from drone-captured footage (Experiment 4). These findings suggest that such footage provides a particularly poor medium for person identification. This is likely to reflect the sub-optimal quality of such footage, which is subject to factors such as the height and velocity at which drones fly, viewing distance, unfavourable vantage points, and ambient conditions

Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum

The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (~1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.Bill & Melinda Gates FoundationEllison Medical FoundationExxon Mobil FoundationFogarty International CenterNational Institute of Allergy and Infectious Diseases (U.S.)Burroughs Wellcome FundDavid & Lucile Packard FoundationNational Science Foundation (U.S.). Graduate Research Fellowship Progra

A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors

Host proteins are essential for HIV entry and replication and can be important nonviral therapeutic targets. Large-scale RNA interference (RNAi)-based screens have identified nearly a thousand candidate host factors, but there is little agreement among studies and few factors have been validated. Here we demonstrate that a genome-wide CRISPR-based screen identifies host factors in a physiologically relevant cell system. We identify five factors, including the HIV co-receptors CD4 and CCR5, that are required for HIV infection yet are dispensable for cellular proliferation and viability. Tyrosylprotein sulfotransferase 2 (TPST2) and solute carrier family 35 member B2 (SLC35B2) function in a common pathway to sulfate CCR5 on extracellular tyrosine residues, facilitating CCR5 recognition by the HIV envelope. Activated leukocyte cell adhesion molecule (ALCAM) mediates cell aggregation, which is required for cell-to-cell HIV transmission. We validated these pathways in primary human CD4 + T cells through Cas9-mediated knockout and antibody blockade. Our findings indicate that HIV infection and replication rely on a limited set of host-dispensable genes and suggest that these pathways can be studied for therapeutic intervention

Somatic mutations affect key pathways in lung adenocarcinoma

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well- classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers - including NF1, APC, RB1 and ATM - and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.National Human Genome Research InstituteWe thank A. Lash, M.F. Zakowski, M.G. Kris and V. Rusch for intellectual contributions, and many members of the Baylor Human Genome Sequencing Center, the Broad Institute of Harvard and MIT, and the Genome Center at Washington University for support. This work was funded by grants from the National Human Genome Research Institute to E.S.L., R.A.G. and R.K.W.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62885/1/nature07423.pd

Horizontal gene transfer in Histophilus somni and its role in the evolution of pathogenic strain 2336, as determined by comparative genomic analyses

<p>Abstract</p> <p>Background</p> <p>Pneumonia and myocarditis are the most commonly reported diseases due to <it>Histophilus somni</it>, an opportunistic pathogen of the reproductive and respiratory tracts of cattle. Thus far only a few genes involved in metabolic and virulence functions have been identified and characterized in <it>H. somni </it>using traditional methods. Analyses of the genome sequences of several <it>Pasteurellaceae </it>species have provided insights into their biology and evolution. In view of the economic and ecological importance of <it>H. somni</it>, the genome sequence of pneumonia strain 2336 has been determined and compared to that of commensal strain 129Pt and other members of the <it>Pasteurellaceae</it>.</p> <p>Results</p> <p>The chromosome of strain 2336 (2,263,857 bp) contained 1,980 protein coding genes, whereas the chromosome of strain 129Pt (2,007,700 bp) contained only 1,792 protein coding genes. Although the chromosomes of the two strains differ in size, their average GC content, gene density (total number of genes predicted on the chromosome), and percentage of sequence (number of genes) that encodes proteins were similar. The chromosomes of these strains also contained a number of discrete prophage regions and genomic islands. One of the genomic islands in strain 2336 contained genes putatively involved in copper, zinc, and tetracycline resistance. Using the genome sequence data and comparative analyses with other members of the <it>Pasteurellaceae</it>, several <it>H. somni </it>genes that may encode proteins involved in virulence (<it>e.g</it>., filamentous haemaggutinins, adhesins, and polysaccharide biosynthesis/modification enzymes) were identified. The two strains contained a total of 17 ORFs that encode putative glycosyltransferases and some of these ORFs had characteristic simple sequence repeats within them. Most of the genes/loci common to both the strains were located in different regions of the two chromosomes and occurred in opposite orientations, indicating genome rearrangement since their divergence from a common ancestor.</p> <p>Conclusions</p> <p>Since the genome of strain 129Pt was ~256,000 bp smaller than that of strain 2336, these genomes provide yet another paradigm for studying evolutionary gene loss and/or gain in regard to virulence repertoire and pathogenic ability. Analyses of the complete genome sequences revealed that bacteriophage- and transposon-mediated horizontal gene transfer had occurred at several loci in the chromosomes of strains 2336 and 129Pt. It appears that these mobile genetic elements have played a major role in creating genomic diversity and phenotypic variability among the two <it>H. somni </it>strains.</p

Characterizing the cancer genome in lung adenocarcinoma

Somatic alterations in cellular DNA underlie almost all human cancers(1). The prospect of targeted therapies(2) and the development of high-resolution, genome-wide approaches(3-8) are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours ( n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in similar to 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 ( NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62944/1/nature06358.pd

Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

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. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicin