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Background Current South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African. Individual variation in relative proportions of each of these ancestries may be confounded with socio-economic factors due to population stratification. Therefore, ancestry is a potential confounder variable that should be considered in epidemiologic studies and in public health plans. However, there are few studies that have assessed the ancestry of the current admixed Chilean population. This is partly due to the high cost of genome-scale technologies commonly used to estimate ancestry. In this study we have designed a small panel of SNPs to accurately assess ancestry in the largest sampling to date of the Chilean mestizo population (n = 3349) from eight cities. Our panel is also able to distinguish between the two main Amerindian components of Chileans: Aymara from the north and Mapuche from the south. Results A panel of 150 ancestry-informative markers (AIMs) of SNP type was selected to maximize ancestry informativeness and genome coverage. Of these, 147 were successfully genotyped by KASPar assays in 2843 samples, with an average missing rate of 0.012, and a 0.95 concordance with microarray data. The ancestries estimated with the panel of AIMs had relative high correlations (0.88 for European, 0.91 for Amerindian, 0.70 for Aymara, and 0.68 for Mapuche components) with those obtained with AXIOM LAT1 array. The country’s average ancestry was 0.53 ± 0.14 European, 0.04 ± 0.04 African, and 0.42 ± 0.14 Amerindian, disaggregated into 0.18 ± 0.15 Aymara and 0.25 ± 0.13 Mapuche. However, Mapuche ancestry was highest in the south (40.03%) and Aymara in the north (35.61%) as expected from the historical location of these ethnic groups. We make our results available through an online app and demonstrate how it can be used to adjust for ancestry when testing association between incidence of a disease and nongenetic risk factors. Conclusions We have conducted the most extensive sampling, across many different cities, of current Chilean population. Ancestry varied significantly by latitude and human development. The panel of AIMs is available to the community for estimating ancestry at low cost in Chileans and other populations with similar ancestry.

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+. Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.

Patagonia was the last region of the Americas reached by humans who entered the continent from Siberia ∼15,000–20,000 y ago. Despite recent genomic approaches to reconstruct the continental evolutionary history, regional characterization of ancient and modern genomes remains understudied. Exploring the genomic diversity within Patagonia is not just a valuable strategy to gain a better understanding of the history and diversification of human populations in the southernmost tip of the Americas, but it would also improve the representation of Native American diversity in global databases of human variation. Here, we present genome data from four modern populations from Central Southern Chile and Patagonia (n = 61) and four ancient maritime individuals from Patagonia (∼1,000 y old). Both the modern and ancient individuals studied in this work have a greater genetic affinity with other modern Native Americans than to any non-American population, showing within South America a clear structure between major geographical regions. Native Patagonian Kawéskar and Yámana showed the highest genetic affinity with the ancient individuals, indicating genetic continuity in the region during the past 1,000 y before present, together with an important agreement between the ethnic affiliation and historical distribution of both groups. Lastly, the ancient maritime individuals were genetically equidistant to a ∼200-y-old terrestrial hunter-gatherer from Tierra del Fuego, which supports a model with an initial separation of a common ancestral group to both maritime populations from a terrestrial population, with a later diversification of the maritime groups. © 2018 National Academy of Sciences. All Rights Reserved. aHuman Genetics Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; bCentre for GeoGenetics, University of Copenhagen, 1350 Copenhagen, Denmark; cInternational Laboratory for Human Genome Research, National Autonomous University of Mexico, Juriquilla 76230, Santiago de Querétaro, Mexico; dCenter for Computational, Evolutionary and Human Genomics, Stanford University, Stanford, CA 94305; eArc Bio, LLC, Menlo Park, CA 94025; fDepartment of Genetics, Stanford University, Stanford, CA 94305; gInstitute of Ecology and Evolution, University of Bern, 3012 Bern, Switzerland; hCentro de Estudios del Hombre Austral, Instituto de la Patagonia, Universidad de Magallanes, Punta Arenas 6213029, Chile; iNational Laboratory of Genomics for Biodiversity, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Irapuato, 36821 Guanajuato, Mexico; jInterdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edificio do Terminal de Cruzeiros do Porto de Leixões, 4450-208 Matosinhos, Portugal; kDepartment of Medicine, University of California, San Francisco, CA 94131; lDepartment of Bioengineering and Therapeutic Science, University of California, San Francisco, CA 94158; mDepartment of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; nDepartment of Zoology, University of Cambridge, Cambridge CB2 1TN, United Kingdom; and oWellcome Genome Campus, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom ACKNOWLEDGMENTS. We thank the contribution of the “Instituto de la Patagonia” and Stanford Sequencing Center. We thank Consuelo Quinto for helpful comments on earlier versions of this manuscript. This work was supported by Comisión Nacional de Investigación Científica y Tecnológica Grant USA2013-0015 and Fondo Nacional de Ciencia y Tecnología Grants 1140544 and 1170726. M.C.Á.-A.’s laboratory is supported by Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica–Universidad Nacional Autónoma de México Grant IA206817. A.-S.M. and D.C.D. were supported by Swiss National Science Foundation Grant PZ00P3_154717 and European Research Council Starting Grant 679330. A.M.-E. was supported by International Center for Genetic Engineering and Biotechnology Grant CRP/ MEX15-04_EC. Sequencing of modern DNA was partially funded by Fund of Scientific and Technological Equipment (FONDEQUIP) Grant EQM140157.

The presence of a regulatory site for monovalent cations that affects the conformation of the MgATP-binding pocket leading to enzyme activation has been demonstrated for ribokinases. This site is selective toward the ionic radius of the monovalent cation, accepting those larger than Na(+). Phosphofructokinase-2 (Pfk-2) from Escherichia coli is homologous to ribokinase, but unlike other ribokinase family members, presents an additional site for the nucleotide that negatively regulates its enzymatic activity. In this work, we show the effect of monovalent cations on the kinetic parameters of Pfk-2 together with its three-dimensional structure determined by x-ray diffraction in the presence of K(+) or Cs(+). Kinetic characterization of the enzyme shows that K(+) and Na(+) alter neither the kcat nor the KM values for fructose-6-P or MgATP. However, the presence of K(+) (but not Na(+)) enhances the allosteric inhibition induced by MgATP. Moreover, binding experiments show that K(+) (but not Na(+)) increases the affinity of MgATP in a saturable fashion. In agreement with the biochemical data, the crystal structure of Pfk-2 obtained in the presence of MgATP shows a cation-binding site at the conserved position predicted for the ribokinase family of proteins. This site is adjacent to the MgATP allosteric binding site and is only observed in the presence of Cs(+) or K(+). These results indicate that binding of the monovalent metal ions indirectly influences the allosteric site of Pfk-2 by increasing its affinity for MgATP with no alteration in the conformation of residues present at the catalytic site.

El proceso habitacional chileno ha priorizado un enfoque cuantitativo en la producción de las viviendas sociales, relegando aspectos de orden cualitativo a un segundo plano, ante la urgencia de asumir el déficit habitacional del país. De todos modos, la importancia de mejorar la calidad de vida en los barrios de menores recursos, se ha transformado en un objetivo declarado, debido tanto a la mala calidad de los productos ofrecidos por los programas estatales, como a la incapacidad de responder a las necesidades de la población. Basada en una investigación, que pretende desarrollar un enfoque integral de la calidad residencial, este artículo, presenta en primer lugar una breve descripción del enfoque habitacional implementado en el país. Luego, se explica el marco conceptual de la calidad residencial y la definición de una propuesta metodológica ad hoc, la cual a partir del análisis de los resultados de la investigación, se traduciría en propuestas de diseño y normativas mejoradas.