ALBERT

Description: Mexico is preparing to develop a genomic medicine program focused on national health problems. Modern Mexicans result from an admixture of more than 65 native Indian groups with Spaniards, leading to a unique genetic makeup and a characteristic set of disease susceptibilities. Since 1999, more than 100 experts from different fields have joined efforts with government, academia, and industry to identify priorities and goals for genomic medicine in Mexico. The plan includes establishment of an Institute of Genomic Medicine with strong intramural and extramural programs. This project is expected to ease the social and financial burden of health problems in Mexico.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jimenez-Sanchez, Gerardo -- New York, N.Y. -- Science. 2003 Apr 11;300(5617):295-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Consortium for the Institute of Genomic Medicine of Mexico, Camino al Ajusco 130-101, Col. Jardines en la Montana, Mexico DF 14210, Mexico. gjimenez@inmegen.org.mx〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12690190" target="_blank"〉PubMed〈/a〉

Description: Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148686/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148686/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Banerji, Shantanu -- Cibulskis, Kristian -- Rangel-Escareno, Claudia -- Brown, Kristin K -- Carter, Scott L -- Frederick, Abbie M -- Lawrence, Michael S -- Sivachenko, Andrey Y -- Sougnez, Carrie -- Zou, Lihua -- Cortes, Maria L -- Fernandez-Lopez, Juan C -- Peng, Shouyong -- Ardlie, Kristin G -- Auclair, Daniel -- Bautista-Pina, Veronica -- Duke, Fujiko -- Francis, Joshua -- Jung, Joonil -- Maffuz-Aziz, Antonio -- Onofrio, Robert C -- Parkin, Melissa -- Pho, Nam H -- Quintanar-Jurado, Valeria -- Ramos, Alex H -- Rebollar-Vega, Rosa -- Rodriguez-Cuevas, Sergio -- Romero-Cordoba, Sandra L -- Schumacher, Steven E -- Stransky, Nicolas -- Thompson, Kristin M -- Uribe-Figueroa, Laura -- Baselga, Jose -- Beroukhim, Rameen -- Polyak, Kornelia -- Sgroi, Dennis C -- Richardson, Andrea L -- Jimenez-Sanchez, Gerardo -- Lander, Eric S -- Gabriel, Stacey B -- Garraway, Levi A -- Golub, Todd R -- Melendez-Zajgla, Jorge -- Toker, Alex -- Getz, Gad -- Hidalgo-Miranda, Alfredo -- Meyerson, Matthew -- CA089393/CA/NCI NIH HHS/ -- CA122099/CA/NCI NIH HHS/ -- R01 CA122099/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jun 20;486(7403):405-9. doi: 10.1038/nature11154.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722202" target="_blank"〉PubMed〈/a〉

Description: The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615710/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615710/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reich, David -- Patterson, Nick -- Campbell, Desmond -- Tandon, Arti -- Mazieres, Stephane -- Ray, Nicolas -- Parra, Maria V -- Rojas, Winston -- Duque, Constanza -- Mesa, Natalia -- Garcia, Luis F -- Triana, Omar -- Blair, Silvia -- Maestre, Amanda -- Dib, Juan C -- Bravi, Claudio M -- Bailliet, Graciela -- Corach, Daniel -- Hunemeier, Tabita -- Bortolini, Maria Catira -- Salzano, Francisco M -- Petzl-Erler, Maria Luiza -- Acuna-Alonzo, Victor -- Aguilar-Salinas, Carlos -- Canizales-Quinteros, Samuel -- Tusie-Luna, Teresa -- Riba, Laura -- Rodriguez-Cruz, Maricela -- Lopez-Alarcon, Mardia -- Coral-Vazquez, Ramon -- Canto-Cetina, Thelma -- Silva-Zolezzi, Irma -- Fernandez-Lopez, Juan Carlos -- Contreras, Alejandra V -- Jimenez-Sanchez, Gerardo -- Gomez-Vazquez, Maria Jose -- Molina, Julio -- Carracedo, Angel -- Salas, Antonio -- Gallo, Carla -- Poletti, Giovanni -- Witonsky, David B -- Alkorta-Aranburu, Gorka -- Sukernik, Rem I -- Osipova, Ludmila -- Fedorova, Sardana A -- Vasquez, Rene -- Villena, Mercedes -- Moreau, Claudia -- Barrantes, Ramiro -- Pauls, David -- Excoffier, Laurent -- Bedoya, Gabriel -- Rothhammer, Francisco -- Dugoujon, Jean-Michel -- Larrouy, Georges -- Klitz, William -- Labuda, Damian -- Kidd, Judith -- Kidd, Kenneth -- Di Rienzo, Anna -- Freimer, Nelson B -- Price, Alkes L -- Ruiz-Linares, Andres -- BB/1021213/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- GM057672/GM/NIGMS NIH HHS/ -- GM079558/GM/NIGMS NIH HHS/ -- GM079558-S1/GM/NIGMS NIH HHS/ -- HG006399/HG/NHGRI NIH HHS/ -- MH075007/MH/NIMH NIH HHS/ -- NS037484/NS/NINDS NIH HHS/ -- NS043538/NS/NINDS NIH HHS/ -- R01 GM079558/GM/NIGMS NIH HHS/ -- R01 GM100233/GM/NIGMS NIH HHS/ -- R01 HG006399/HG/NHGRI NIH HHS/ -- R21 DK073818/DK/NIDDK NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Aug 16;488(7411):370-4. doi: 10.1038/nature11258.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. reich@genetics.med.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22801491" target="_blank"〉PubMed〈/a〉

Description: Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156478/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156478/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moreno-Estrada, Andres -- Gignoux, Christopher R -- Fernandez-Lopez, Juan Carlos -- Zakharia, Fouad -- Sikora, Martin -- Contreras, Alejandra V -- Acuna-Alonzo, Victor -- Sandoval, Karla -- Eng, Celeste -- Romero-Hidalgo, Sandra -- Ortiz-Tello, Patricia -- Robles, Victoria -- Kenny, Eimear E -- Nuno-Arana, Ismael -- Barquera-Lozano, Rodrigo -- Macin-Perez, Gaston -- Granados-Arriola, Julio -- Huntsman, Scott -- Galanter, Joshua M -- Via, Marc -- Ford, Jean G -- Chapela, Rocio -- Rodriguez-Cintron, William -- Rodriguez-Santana, Jose R -- Romieu, Isabelle -- Sienra-Monge, Juan Jose -- del Rio Navarro, Blanca -- London, Stephanie J -- Ruiz-Linares, Andres -- Garcia-Herrera, Rodrigo -- Estrada, Karol -- Hidalgo-Miranda, Alfredo -- Jimenez-Sanchez, Gerardo -- Carnevale, Alessandra -- Soberon, Xavier -- Canizales-Quinteros, Samuel -- Rangel-Villalobos, Hector -- Silva-Zolezzi, Irma -- Burchard, Esteban Gonzalez -- Bustamante, Carlos D -- BB/I021213/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- ES015794/ES/NIEHS NIH HHS/ -- GM007546/GM/NIGMS NIH HHS/ -- GM061390/GM/NIGMS NIH HHS/ -- HL004464/HL/NHLBI NIH HHS/ -- HL078885/HL/NHLBI NIH HHS/ -- HL088133/HL/NHLBI NIH HHS/ -- HL111636/HL/NHLBI NIH HHS/ -- K23 HL004464/HL/NHLBI NIH HHS/ -- K23 HL111636/HL/NHLBI NIH HHS/ -- M01 RR000083/RR/NCRR NIH HHS/ -- P60 MD006902/MD/NIMHD NIH HHS/ -- P60MD006902/MD/NIMHD NIH HHS/ -- R01 ES015794/ES/NIEHS NIH HHS/ -- R01 GM083606/GM/NIGMS NIH HHS/ -- R01 GM090087/GM/NIGMS NIH HHS/ -- R01 HG003229/HG/NHGRI NIH HHS/ -- R01 HL078885/HL/NHLBI NIH HHS/ -- R01 HL088133/HL/NHLBI NIH HHS/ -- R01GM090087/GM/NIGMS NIH HHS/ -- R01HG003229/HG/NHGRI NIH HHS/ -- R13 MD008154/MD/NIMHD NIH HHS/ -- RR000083/RR/NCRR NIH HHS/ -- T32 GM007175/GM/NIGMS NIH HHS/ -- T32 GM007546/GM/NIGMS NIH HHS/ -- T32 HG000044/HG/NHGRI NIH HHS/ -- T32GM007175/GM/NIGMS NIH HHS/ -- T32HG000044/HG/NHGRI NIH HHS/ -- U01 GM061390/GM/NIGMS NIH HHS/ -- ZIA ES049019-14/Intramural NIH HHS/ -- ZIA ES049019-15/Intramural NIH HHS/ -- ZIA ES49019/ES/NIEHS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 13;344(6189):1280-5. doi: 10.1126/science.1251688. Epub 2014 Jun 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. cdbustam@stanford.edu morenoe@stanford.edu esteban.burchard@ucsf.edu. ; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA. cdbustam@stanford.edu morenoe@stanford.edu esteban.burchard@ucsf.edu. ; Instituto Nacional de Medicina Genomica (INMEGEN), Mexico City, Mexico. ; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. ; Escuela Nacional de Antropologia e Historia (ENAH), Mexico City, Mexico. Department of Genetics, Evolution and Environment, University College London, London, UK. ; Department of Medicine, University of California, San Francisco, CA, USA. ; Instituto de Investigacion en Genetica Molecular, Universidad de Guadalajara, Ocotlan, Mexico. ; Escuela Nacional de Antropologia e Historia (ENAH), Mexico City, Mexico. ; Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico. ; Department of Medicine, University of California, San Francisco, CA, USA. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA. ; The Brooklyn Hospital Center, Brooklyn, NY, USA. ; Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico. ; Veterans Caribbean Health Care System, San Juan, Puerto Rico. ; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Instituto Nacional de Medicina Genomica (INMEGEN), Mexico City, Mexico. ; International Agency for Research on Cancer, Lyon, France. ; Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico. ; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA. ; Department of Genetics, Evolution and Environment, University College London, London, UK. ; Instituto Nacional de Medicina Genomica (INMEGEN), Mexico City, Mexico. Facultad de Quimica, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico. ; Department of Medicine, University of California, San Francisco, CA, USA. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA. cdbustam@stanford.edu morenoe@stanford.edu esteban.burchard@ucsf.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24926019" target="_blank"〉PubMed〈/a〉

Description: ABCD3 is one of three ATP-binding cassette (ABC) transporters present in the peroxisomal membrane catalyzing ATP-dependent transport of substrates for metabolic pathways localized in peroxisomes. So far, the precise function of ABCD3 is not known. Here, we report the identification of the first patient with a defect of ABCD3. The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma. Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes. Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced. Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1). Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation. To corroborate our findings in the patient, we studied a previously generated Abcd3 knockout mouse model. Abcd3–/– mice accumulated the branched chain fatty acid phytanic acid after phytol loading. In addition, analysis of bile acids revealed a reduction of C24 bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3–/– mice. Thus, both in the patient and in Abcd3–/– mice, there was evidence of a bile acid biosynthesis defect. In conclusion, our studies show that ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids into the peroxisome and that this is a crucial step in bile acid biosynthesis.