Publications by authors named "Gerardo Jimenez-Sanchez"

28 Publications

  • Page 1 of 1

Genomics: the Power and the Promise.

Genome 2015 Dec;58(12):vii-x

Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, MA, USA; Global Biotech Consulting Group, Mexico.

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http://dx.doi.org/10.1139/gen-2015-0143DOI Listing
December 2015

Genomics innovation: transforming healthcare, business, and the global economy.

Genome 2015 Dec 15;58(12):511-7. Epub 2015 Oct 15.

Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, MA, USA; Global Biotech Consulting Group, Mexico.

The genomics revolution has generated an unprecedented number of assets to propel innovation. Initial availability of genomics-based applications show a significant potential to contribute addressing global challenges, such as human health, food security, alternative sources of energies, and environmental sustainability. In the last years, most developed and emerging nations have established bioeconomy agendas where genomics plays a major role to meet their local needs. Genomic medicine is one of the most visible areas where genomics innovation is likely to contribute to a more individualized, predictive, and preventive medical practice. Examples in agriculture, dairy and beef, fishery, aquaculture, and forests industries include the effective selection of genetic variants associated to traits of economic value. Some, in addition to producing more and better foods, already represent an important increase in revenues to their respective industries. It is reasonable to predict that genomics applications will lead to a paradigm shift in our ability to ease significant health, economic, and social burdens. However, to successfully benefit from genomics innovations, it is imperative to address a number of hurdles related to generating robust scientific evidence, developing lower-cost sequencing technologies, effective bioinformatics, as well as sensitive ethical, economical, environmental, legal, and social aspects associated with the development and use of genomics innovations.
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http://dx.doi.org/10.1139/gen-2015-0121DOI Listing
December 2015

A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3.

Hum Mol Genet 2015 Jan 28;24(2):361-70. Epub 2014 Aug 28.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.

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.
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http://dx.doi.org/10.1093/hmg/ddu448DOI Listing
January 2015

Human genetics. The genetics of Mexico recapitulates Native American substructure and affects biomedical traits.

Science 2014 Jun 12;344(6189):1280-5. Epub 2014 Jun 12.

Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico.

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.
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http://dx.doi.org/10.1126/science.1251688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156478PMC
June 2014

Reconstructing Native American population history.

Nature 2012 Aug;488(7411):370-4

Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

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.
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http://dx.doi.org/10.1038/nature11258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615710PMC
August 2012

Sequence analysis of mutations and translocations across breast cancer subtypes.

Nature 2012 Jun 20;486(7403):405-9. Epub 2012 Jun 20.

The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

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.
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http://dx.doi.org/10.1038/nature11154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148686PMC
June 2012

Identification and pathway analysis of microRNAs with no previous involvement in breast cancer.

PLoS One 2012 16;7(3):e31904. Epub 2012 Mar 16.

Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica. Mexico City, Mexico.

microRNA expression signatures can differentiate normal and breast cancer tissues and can define specific clinico-pathological phenotypes in breast tumors. In order to further evaluate the microRNA expression profile in breast cancer, we analyzed the expression of 667 microRNAs in 29 tumors and 21 adjacent normal tissues using TaqMan Low-density arrays. 130 miRNAs showed significant differential expression (adjusted P value = 0.05, Fold Change = 2) in breast tumors compared to the normal adjacent tissue. Importantly, the role of 43 of these microRNAs has not been previously reported in breast cancer, including several evolutionary conserved microRNA*, showing similar expression rates to that of their corresponding leading strand. The expression of 14 microRNAs was replicated in an independent set of 55 tumors. Bioinformatic analysis of mRNA targets of the altered miRNAs, identified oncogenes like ERBB2, YY1, several MAP kinases, and known tumor-suppressors like FOXA1 and SMAD4. Pathway analysis identified that some biological process which are important in breast carcinogenesis are affected by the altered microRNA expression, including signaling through MAP kinases and TP53 pathways, as well as biological processes like cell death and communication, focal adhesion and ERBB2-ERBB3 signaling. Our data identified the altered expression of several microRNAs whose aberrant expression might have an important impact on cancer-related cellular pathways and whose role in breast cancer has not been previously described.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031904PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306365PMC
August 2012

Development of a panel of genome-wide ancestry informative markers to study admixture throughout the Americas.

PLoS Genet 2012 8;8(3):e1002554. Epub 2012 Mar 8.

University of California San Francisco, San Francisco, California, United States of America.

Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four admixed populations by comparing ancestry estimates based on the AIMs panel to estimates based on genome-wide association study (GWAS) data. The panel provided balanced discriminatory power among the three ancestral populations and accurate estimates of individual ancestry proportions (R² > 0.9 for ancestral components with significant between-subject variance). Finally, we genotyped samples from 18 populations from Latin America using the AIMs panel and estimated variability in ancestry within and between these populations. This panel and its reference genotype information will be useful resources to explore population history of admixture in Latin America and to correct for the potential effects of population stratification in admixed samples in the region.
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http://dx.doi.org/10.1371/journal.pgen.1002554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297575PMC
September 2012

Hypercontrols in genotype-phenotype analysis reveal ancestral haplotypes associated with essential hypertension.

Hypertension 2012 Apr 27;59(4):847-53. Epub 2012 Feb 27.

National Institute of Genomic Medicine (INMEGEN), Mexico City, Mexico.

The angiotensinogen gene locus has been associated with essential hypertension in most populations analyzed to date. Increased plasma angiotensinogen levels have been proposed as an underlying cause of essential hypertension in whites; however, differences in the genetic regulation of plasma angiotensinogen levels have also been reported for other populations. The aim of this study was to analyze the relationship between angiotensinogen gene polymorphisms and haplotypes with plasma angiotensinogen levels and the risk of essential hypertension in the Mexican population. We genotyped 9 angiotensinogen gene polymorphisms in 706 individuals. Four polymorphisms, A-6, C4072, C6309, and G12775, were associated with increased risk, and the strongest association was found for the C6309 allele (χ(2)=23.9; P=0.0000009), which resulted in an odds ratio of 3.0 (95% CI: 1.8-4.9; P=0.000006) in the recessive model. Two polymorphisms, A-20C (P=0.003) and C3389T (P=0.0001), were associated with increased plasma angiotensinogen levels but did not show association with essential hypertension. The haplotypes H1 (χ(2)=8.1; P=0.004) and H5 (χ(2)=5.1; P=0.02) were associated with essential hypertension. Using phylogenetic analysis, we found that haplotypes 1 and 5 are the human ancestral haplotypes. Our results suggest that the positive association between angiotensinogen gene polymorphisms and haplotypes with essential hypertension is not simply explained by an increase in plasma angiotensinogen concentration. Complex interactions between risk alleles suggest that these haplotypes act as "superalleles."
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.176453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306465PMC
April 2012

Expression profile of maize (Zea mays L.) embryonic axes during germination: translational regulation of ribosomal protein mRNAs.

Plant Cell Physiol 2011 Oct 31;52(10):1719-33. Epub 2011 Aug 31.

Biochemistry Department, Faculty of Chemistry, Universidad Nacional Autónoma de Mexico (UNAM), Ciudad Universitaria, 04510 Mexico, D.F. México.

Seed germination is a critical developmental period for plant propagation. Information regarding gene expression within this important period is relevant for understanding the main biochemical processes required for successful germination, particularly in maize, one of the most important cereals in the world. The present research focuses on the global microarray analysis of differential gene expression between quiescent and germinated maize embryo stages. This analysis revealed that a large number of mRNAs stored in the quiescent embryonic axes (QEAs) were differentially regulated during germination in the 24 h germinated embryonic axes (GEAs). These genes belong to 14 different functional categories and most of them correspond to metabolic processes, followed by transport, transcription and translation. Interestingly, the expression of mRNAs encoding ribosomal proteins [(r)-proteins], required for new ribosome formation during this fast-growing period, remains mostly unchanged throughout the germination process, suggesting that these genes are not regulated at the transcriptional level during this developmental period. To investigate this issue further, comparative microarray analyses on polysomal mRNAs from growth-stimulated and non-stimulated GEAs were performed. The results revealed that (r)-protein mRNAs accumulate to high levels in polysomes of the growth-stimulated tissues, indicating a translational control mechanism to account for the rapid (r)-protein synthesis observed within this period. Bioinformatic analysis of (r)-protein mRNAs showed that 5' TOP (tract of pyrimidines)-like sequences are present only in the 5'-untranslated region set of up-regulated (r)-protein mRNAs. This overall approach to the germination process allows an in-depth view of molecular changes, enabling a broader understanding of the regulatory mechanisms that occur during this process.
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http://dx.doi.org/10.1093/pcp/pcr114DOI Listing
October 2011

Variants and haplotypes in angiotensinogen gene are associated with plasmatic angiotensinogen level in Mexican population.

Am J Med Sci 2011 Sep;342(3):205-11

Division of Cardiovascular Genomics, National Institute of Genomic Medicine (INMEGEN), Mexico City, Mexico.

Introduction: The plasmatic angiotensinogen (AGT) level has been associated with essential hypertension. Linkage analysis has found a relationship between the AGT gene locus and hypertension in the Mexican-American population, but studies have failed to identify genetic variants associated with hypertension or plasma AGT levels. This study analyzes the relationship between polymorphisms in the AGT gene and plasmatic AGT levels in Mexican population.

Methods: Nine polymorphisms in AGT gene were genotyped, and plasma AGT level was determined by enzyme-linked immunosorbent assay.

Results: Differences in AGT plasma levels were associated with 2 polymorphisms: T-20G, TT = 25.3 ± 8.3 versus TG + GG = 21.6 ± 8.8 μg/mL; P = 0.008 and C3389T (T174M), CC = 25.8 ± 9.9 versus TC + TT = 20.5 ± 5.4 μg/mL; P = 0.0002. Haplotype 2 was associated with low plasma AGT (-5.1 μg/mL [95% confidence interval: -8.6 to -1.6], P = 0.004) and Haplotype 8 was associated with high plasma AGT (6.5 μg/mL [95% confidence interval: 2.5 to 10.6], P = 0.001). This association remained after adjustment for covariates. A Likelihood Ratio Test for haplotype-phenotype association adjusted for covariates resulted in χ = 38.9, P = 0.0005. The total effect of the haplotypes on plasma AGT level variance was 19.5%. No association was identified between haplotypes and quantitative traits of blood pressure.

Conclusions: Two polymorphisms (T-20G and C3389T) and 2 haplotypes (H2 and H8) showed an association with plasma AGT levels in Mexican population.
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http://dx.doi.org/10.1097/MAJ.0b013e3182121020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203016PMC
September 2011

Association of the genetic marker for abacavir hypersensitivity HLA-B*5701 with HCP5 rs2395029 in Mexican Mestizos.

Pharmacogenomics 2011 Jun 21;12(6):809-14. Epub 2011 Apr 21.

National Institute of Genomic Medicine, Periferico Sur No. 4124, Torre Zafiro II, 6to. Piso, Col. Jardines del Pedregal, Mexico D.F. 01900, Mexico.

Unlabelled: Prospective screening for HLA-B*5701 decreases or abolishes abacavir hypersensitivity reaction. In Caucasians, the HLA complex protein 5 gene (HCP5) rs2395029(G) allele is in complete linkage disequilibrium (LD) with HLA-B*5701 (r(2) = 1).

Aim: To assess the frequency of HLA-B*5701 and its LD with HCP5 rs2395029(G) allele, to extend our knowledge of genetic variants that are of critical relevance for the development of pharmacogenetics in Mexico.

Materials & Methods: We genotyped 300 Mexican Mestizos from the Mexican Genome Diversity Project. HLA-B*5701 genotyping was performed using a DNA sequencing method. HCP5 rs2395029 was genotyped using a custom TaqMan(®) SNP genotyping assay and confirmed by direct sequencing. Genotypes for 14 SNPs in the HCP5 region were retrieved from the Mexican Genome Diversity Project database for LD analysis.

Results: HLA-B*5701 carrier frequency was 2% and the allelic frequency was 0.010. Haplotype analysis revealed that HLA-B*5701 and the HCP5 rs2395029(G) allele are in complete LD (r(2) = 1) in this Mexican Mestizos sample.

Conclusion: It is feasible to have a pharmacogenetic program based on HCP5 rs2395029 genotyping as a screening tool with confirmation of HLA-B*5701 carriage by sequenciation, to prevent abacavir hypersensitivity reaction in Mexican patients before initiating abacavir therapy.
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http://dx.doi.org/10.2217/pgs.11.31DOI Listing
June 2011

Resequencing, haplotype construction and identification of novel variants of CYP2D6 in Mexican Mestizos.

Pharmacogenomics 2011 May 11;12(5):745-56. Epub 2011 Mar 11.

National Institute of Genomic Medicine (MEXICO), Periférico Sur 4124 Torre Zafiro II Piso 6, Col. Ex-Rancho de Anzaldo, Mexico DF 01900, Mexico.

Aim: The CYP2D6 enzyme participates in the metabolism of commonly prescribed drugs: antidepressants, antipsychotics and antihypertensives. The CYP2D6 gene shows a high degree of interindividual and interethnic variability that influences its expression and function. Mexican Mestizos are a recently admixed population resulting from the combination of Amerindian, European and, to a lesser extent, African populations. This study aimed to comprehensively characterize the CYP2D6 gene in Mexican Mestizos.

Materials & Methods: We performed linkage disequilibrium and network analyses in resequencing data of 96 individuals from two regions within Mexico with a different history of admixture and particular population dynamics, the Northwestern state of Sonora and the Central-Pacific state of Guerrero.

Results & Conclusion: We identified 64 polymorphisms, including 14 novel variants: 13 SNPs and a CYP2D7 exon 2 conversion, that was assigned CYP2D6*82 by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee. Three novel SNPs were predicted to have functional effects. For CYP2D6*82 we hypothesize an Amerindian origin that is supported by its identification in three Mexican Amerindian groups (Mayas, Tepehuanos and Mixtecos). Frequencies of CYP2D6*1, *2, *4, *5, *10, *29, *53, *82 and its duplications were 50.0, 25.5, 14.1, 2.0, 2.6, 1.0, 0.5, 2.1 and 3.6%, respectively. We found significant frequency differences in CYP2D6*1 and *2 between Mexican Mestizos and in CYP2D6*1, *2, *4, *5, *10 and *29 between Mexicans and at least one other population. We observed strong linkage disequilibrium and phylogenetic relationships between haplotypes. To our knowledge, this study is the first comprehensive resequencing analysis of CYP2D6 in Mexicans or any other Latin American population, providing information about genetic diversity relevant in the development of pharmacogenomics in this region.
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http://dx.doi.org/10.2217/pgs.11.8DOI Listing
May 2011

White adipose tissue genome wide-expression profiling and adipocyte metabolic functions after soy protein consumption in rats.

J Nutr Biochem 2011 Feb 14;22(2):118-29. Epub 2010 May 14.

Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, DF 14000, México.

Obesity is associated with an increase in adipose tissue mass due to an imbalance between high dietary energy intake and low physical activity; however, the type of dietary protein may contribute to its development. The aim of the present work was to study the effect of soy protein versus casein on white adipose tissue genome profiling, and the metabolic functions of adipocytes in rats with diet-induced obesity. The results showed that rats fed a Soy Protein High-Fat (Soy HF) diet gained less weight and had lower serum leptin concentration than rats fed a Casein High-Fat (Cas HF) diet, despite similar energy intake. Histological studies indicated that rats fed the Soy HF diet had significantly smaller adipocytes than those fed the Cas HF diet, and this was associated with a lower triglyceride/DNA content. Fatty acid synthesis in isolated adipocytes was reduced by the amount of fat consumed but not by the type of protein ingested. Expression of genes of fatty acid oxidation increased in adipose tissue of rats fed Soy diets; microarray analysis revealed that Soy protein consumption modified the expression of 90 genes involved in metabolic functions and inflammatory response in adipose tissue. Network analysis showed that the expression of leptin was regulated by the type of dietary protein and it was identified as a central regulator of the expression of lipid metabolism genes in adipose tissue. Thus, soy maintains the size and metabolic functions of adipose tissue through biochemical adaptations, adipokine secretion, and global changes in gene expression.
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http://dx.doi.org/10.1016/j.jnutbio.2009.12.006DOI Listing
February 2011

[Genomic basis for breast cancer: advances in personalized medicine].

Salud Publica Mex 2009 ;51 Suppl 2:s197-207

Instituto Nacional de Medicina Genómica, México.

Genomic analysis of breast cancer has allowed the development of new tools for the prediction of recurrence and the response to treatment of this disease. Gene expression profiles allow better tumor classification, identifying tumor subgroups with particular clinical outcomes. New potential molecular targets involved in breast carcinogenesis have also been identified through the analysis of DNA copy number aberrations and microRNA expression patterns. Whole genome association studies have identified genetic variants associated with a higher risk to develop this tumor, providing more information for public health decisions. Progress in DNA sequencing methods will also allow for the analysis of all the genetic alterations present in a tumor. In this review, we describe the current state of genomic research in breast cancer as well as how these findings are being translated into clinical practice, contributing to development of personalized medicine.
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http://dx.doi.org/10.1590/s0036-36342009000800010DOI Listing
May 2010

Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico.

Proc Natl Acad Sci U S A 2009 May 11;106(21):8611-6. Epub 2009 May 11.

National Institute of Genomic Medicine (INMEGEN), Periferico Sur No. 4124, Torre Zafiro II, 6to. Piso, Col. Jardines del Pedregal, Mexico D.F. 01900, Mexico.

Mexico is developing the basis for genomic medicine to improve healthcare of its population. The extensive study of genetic diversity and linkage disequilibrium structure of different populations has made it possible to develop tagging and imputation strategies to comprehensively analyze common genetic variation in association studies of complex diseases. We assessed the benefit of a Mexican haplotype map to improve identification of genes related to common diseases in the Mexican population. We evaluated genetic diversity, linkage disequilibrium patterns, and extent of haplotype sharing using genomewide data from Mexican Mestizos from regions with different histories of admixture and particular population dynamics. Ancestry was evaluated by including 1 Mexican Amerindian group and data from the HapMap. Our results provide evidence of genetic differences between Mexican subpopulations that should be considered in the design and analysis of association studies of complex diseases. In addition, these results support the notion that a haplotype map of the Mexican Mestizo population can reduce the number of tag SNPs required to characterize common genetic variation in this population. This is one of the first genomewide genotyping efforts of a recently admixed population in Latin America.
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http://dx.doi.org/10.1073/pnas.0903045106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680428PMC
May 2009

The next steps for genomic medicine: challenges and opportunities for the developing world.

Nat Rev Genet 2008 10;9 Suppl 1:S23-7

McLaughlin-Rotman Centre for Global Health, Program on Life Sciences, Ethics and Policy, University Health Network and University of Toronto, MaRS Centre, South Tower, Suite 406, 101 College Street, Toronto, Ontario M5G 1L7, Canada.

This is a historical moment on the path to genomic medicine - the point at which theory is about to be translated into practice. We have previously described human genome variation studies taking place in Mexico, India, Thailand, and South Africa. Such investments into science and technology will enable these countries to embark on the path to the medical and health applications of genomics, and to benefit economically. Here we provide a perspective on the challenges and opportunities facing these and other countries in the developing world as they begin to harness genomics for the benefit of their populations.
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http://dx.doi.org/10.1038/nrg2444DOI Listing
October 2008

Genomic medicine in Mexico: initial steps and the road ahead.

Genome Res 2008 Aug;18(8):1191-8

National Institute of Genomic Medicine, Mexico DF, Mexico.

Mexico faces important demographic and epidemiological transitions with significant implications to patterns of disease, disability, and death. On the one hand, there are problems of underdevelopment and, on the other, the emerging challenges of the chronic and degenerative diseases of the industrialized world. For these diseases, prevention becomes a key strategy for alleviating a major burden to the economy and health of the Mexican population. Genomic medicine has become a priority to the Mexican government as a means of finding new strategies to tackle common diseases. In 2000, strategic planning for genomic medicine began, from a feasibility study and a multi-institutional consortium effort, to the creation of a National Institute of Genomic Medicine by the Mexican congress in 2004. Current research programs in genomic medicine in Mexico include the construction of a haplotype map of the Mexican population, several genome-wide association studies for common diseases, such as diabetes, obesity, cardiovascular disease, and cancer, as well as translational medicine projects that include biomarkers discovery for several kinds of cancer, pharmacogenomics, and nutrigenomics. Although this strategy has been successful, there are challenges that still need to be addressed, including increased investment in science and technology to stimulate a more vigorous and competitive research environment, development of more effective basic and clinical research synergies, recruitment and training of more human resources in genomic medicine, developing mechanisms to stimulate translational research, and developing a more modern regulatory framework to ensure that genomic medicine will successfully contribute to improve healthcare in the Mexican population.
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http://dx.doi.org/10.1101/gr.065359.107DOI Listing
August 2008

GPDTI: a Genetic Programming Decision Tree induction method to find epistatic effects in common complex diseases.

Bioinformatics 2007 Jul;23(13):i167-74

Computer Science Department, Instituto Tecnológico y de Estudios Superiores de Monterrey Campus Estado de Mexico, Mexico.

Motivation: The identification of risk-associated genetic variants in common diseases remains a challenge to the biomedical research community. It has been suggested that common statistical approaches that exclusively measure main effects are often unable to detect interactions between some of these variants. Detecting and interpreting interactions is a challenging open problem from the statistical and computational perspectives. Methods in computing science may improve our understanding on the mechanisms of genetic disease by detecting interactions even in the presence of very low heritabilities.

Results: We have implemented a method using Genetic Programming that is able to induce a Decision Tree to detect interactions in genetic variants. This method has a cross-validation strategy for estimating classification and prediction errors and tests for consistencies in the results. To have better estimates, a new consistency measure that takes into account interactions and can be used in a genetic programming environment is proposed. This method detected five different interaction models with heritabilities as low as 0.008 and with prediction errors similar to the generated errors.

Availability: Information on the generated data sets and executable code is available upon request.
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http://dx.doi.org/10.1093/bioinformatics/btm205DOI Listing
July 2007

Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus.

Eur J Hum Genet 2007 Mar 17;15(3):336-41. Epub 2007 Jan 17.

Instituto Nacional de Medicina Genómica, Mexico City, Mexico.

A regulatory single nucleotide polymorphism (SNP) PD1.3G/A located on programmed cell death 1 (PDCD1) gene, was shown to be involved in susceptibility to systemic lupus erythematosus (SLE) in Swedish, European American, and Mexican cases. However, association to childhood-onset SLE has not been analyzed. The aim of this study was to investigate the association of PDCD1 polymorphisms and haplotypes with susceptibility to childhood-onset SLE in Mexican population. Three PDCD1 SNPs, PD1.3G/A, PD1.5C/T, PD1.6G/A, were analyzed in 250 childhood-onset SLE Mexican patients and 355 healthy controls in a case-control association study. Polymorphisms were genotyped by TaqMan technology. Stratification analysis was performed on the SLE cohort to investigate the SNP association with renal disorder. In addition, haplotypes were constructed with these three SNPs. The PD1.3A allele was significantly associated to childhood-onset SLE (P=0.0019, odds ratio (OR) 2.73, 95% confidence interval (95% CI) 1.35-5.56). The other PDCD1 SNPs did not show association. A total of 155 patients (62%) had nephritis, and no association was observed with PDCD1 SNPs. The ACG haplotype (PD1.3A, PD1.5C, PD1.6G) included almost all PD1.3A alleles, and it was more frequent in SLE patients (5.5%) than in controls (2.1%) (P=0.003; OR 2.73, 95% CI 1.37-5.46). The haplotype structure in Mexican controls was significantly different from those reported in Spanish and Swedish. Our results support association of the PD1.3A SNP to susceptibility of childhood-onset SLE in Mexican population and does not show association to lupus nephritis in this age group.
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http://dx.doi.org/10.1038/sj.ejhg.5201767DOI Listing
March 2007

Mouse liver PMP70 and ALDP: homomeric interactions prevail in vivo.

Biochim Biophys Acta 2004 Aug;1689(3):235-43

Instituto de Biologia Molecular e Celular, Rua do Campo Alegre, Porto, Portugal.

ALDP, ALDPR, PMP70 and PMP70R are half ATP-binding cassette (ABC) transporters of the mammalian peroxisomal membrane. By analogy with other members of this family, it is assumed that peroxisomal ABC transporters must dimerize to become functional units. However, not much is known regarding the type of dimers (i.e., homodimers and/or heterodimers) that are formed in vivo under normal expression conditions. In this work, we have characterized the quaternary structure of mouse liver PMP70 and ALDP. The PMP70 protein complex was purified to apparent homogeneity using a two-step purification protocol. The ALDP-containing protein complex was characterized by preparative immunoprecipitation experiments. In both cases, no evidence for the existence of heteromeric interactions or for the presence of accessory proteins in these ABC transporter protein complexes could be obtained. Our data indicate that the majority (if not all) of mouse liver PMP70 and ALDP are homomeric proteins.
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http://dx.doi.org/10.1016/j.bbadis.2004.04.001DOI Listing
August 2004

Developing a platform for genomic medicine in Mexico.

Science 2003 Apr;300(5617):295-6

Consortium for the Institute of Genomic Medicine of Mexico, Camino al Ajusco 130-101, Col. Jardines en la Montaña, Mexico DF 14210, Mexico.

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.
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http://dx.doi.org/10.1126/science.1084059DOI Listing
April 2003

PEX11alpha is required for peroxisome proliferation in response to 4-phenylbutyrate but is dispensable for peroxisome proliferator-activated receptor alpha-mediated peroxisome proliferation.

Mol Cell Biol 2002 Dec;22(23):8226-40

Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

The PEX11 peroxisomal membrane proteins promote peroxisome division in multiple eukaryotes. As part of our effort to understand the molecular and physiological functions of PEX11 proteins, we disrupted the mouse PEX11alpha gene. Overexpression of PEX11alpha is sufficient to promote peroxisome division, and a class of chemicals known as peroxisome proliferating agents (PPAs) induce the expression of PEX11alpha and promote peroxisome division. These observations led to the hypothesis that PPAs induce peroxisome abundance by enhancing PEX11alpha expression. The phenotypes of PEX11alpha(-/-) mice indicate that this hypothesis remains valid for a novel class of PPAs that act independently of peroxisome proliferator-activated receptor alpha (PPARalpha) but is not valid for the classical PPAs that act as activators of PPARalpha. Furthermore, we find that PEX11alpha(-/-) mice have normal peroxisome abundance and that cells lacking both PEX11alpha and PEX11beta, a second mammalian PEX11 gene, have no greater defect in peroxisome abundance than do cells lacking only PEX11beta. Finally, we report the identification of a third mammalian PEX11 gene, PEX11gamma, and show that it too encodes a peroxisomal protein.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC134051PMC
http://dx.doi.org/10.1128/mcb.22.23.8226-8240.2002DOI Listing
December 2002

[Opportunities for the pharmaceutical industry at the Mexican Genomic Medicine Institute].

Gac Med Mex 2002 May-Jun;138(3):291-4

Instituto de Medicina Genómica, Camino Picacho al Ajusco 130 Departamento 101, Col. Jardines en la Montaña, Delegación Tlalpan 14210.

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September 2002

PEX11 beta deficiency is lethal and impairs neuronal migration but does not abrogate peroxisome function.

Mol Cell Biol 2002 Jun;22(12):4358-65

Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Zellweger syndrome is a lethal neurological disorder characterized by severe defects in peroxisomal protein import. The resulting defects in peroxisome metabolism and the accumulation of peroxisomal substrates are thought to cause the other Zellweger syndrome phenotypes, including neuronal migration defects, hypotonia, a developmental delay, and neonatal lethality. These phenotypes are also manifested in mouse models of Zellweger syndrome generated by disruption of the PEX5 or PEX2 gene. Here we show that mice lacking peroxisomal membrane protein PEX11 beta display several pathologic features shared by these mouse models of Zellweger syndrome, including neuronal migration defects, enhanced neuronal apoptosis, a developmental delay, hypotonia, and neonatal lethality. However, PEX11 beta deficiency differs significantly from Zellweger syndrome and Zellweger syndrome mice in that it is not characterized by a detectable defect in peroxisomal protein import and displays only mild defects in peroxisomal fatty acid beta-oxidation and peroxisomal ether lipid biosynthesis. These results demonstrate that the neurological pathologic features of Zellweger syndrome can occur without peroxisomal enzyme mislocalization and challenge current models of Zellweger syndrome pathogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC133847PMC
http://dx.doi.org/10.1128/mcb.22.12.4358-4365.2002DOI Listing
June 2002