Publications by authors named "Xavier Soberón"

54 Publications

Altered Microbial Composition of Drug-Sensitive and Drug-Resistant TB Patients Compared with Healthy Volunteers.

Microorganisms 2021 Aug 18;9(8). Epub 2021 Aug 18.

Laboratorio de Vinculación Científica, Facultad de Medicina-UNAM en INMEGEN, Mexico City 14610, Mexico.

infection has three discernible outcomes: active tuberculosis, latent tuberculosis, or clearance of the bacterium. The outcome of the infection depends on the interaction of the bacterium, the immune system, and the microbiome of the host. The current study uses 16S rRNA sequencing to determine the diversity and composition of the respiratory microbiome of drug-resistant and drug-sensitive tuberculosis patients as well as healthy volunteers. Tuberculosis patients exhibited increased microbial diversity and differentially abundant bacteria than healthy volunteers. Compositional differences were also observed when comparing drug-sensitive or -resistant tuberculosis patients. Finally, we defined and assessed the differences in the core sputum microbiota between tuberculosis patients and healthy volunteers. Our observations collectively suggest that in sputum, infection is related to altered bacterial diversity and compositional differences of core members of the microbiome, with potential implications for the bacterial pulmonary ecosystem's stability and function.
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http://dx.doi.org/10.3390/microorganisms9081762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398572PMC
August 2021

Transporters, TBC1D4, and ARID5B Variants to Explain Glycated Hemoglobin Variability in Patients with Type 2 Diabetes.

Pharmacology 2021 Jul 15:1-9. Epub 2021 Jul 15.

Genetics Laboratory, Vitagénesis, Monterrey, Mexico.

Introduction: Genetic variants could aid in predicting antidiabetic drug response by associating them with markers of glucose control, such as glycated hemoglobin (HbA1c). However, pharmacogenetic implementation for antidiabetics is still under development, as the list of actionable markers is being populated and validated. This study explores potential associations between genetic variants and plasma levels of HbA1c in 100 patients under treatment with metformin.

Methods: HbA1c was measured in a clinical chemistry analyzer (Roche), genotyping was performed in an Illumina-GSA array and data were analyzed using PLINK. Association and prediction models were developed using R and a 10-fold cross-validation approach.

Results: We identified genetic variants on SLC47A1, SLC28A1, ABCG2, TBC1D4, and ARID5B that can explain up to 55% of the interindividual variability of HbA1c plasma levels in diabetic patients under treatment. Variants on SLC47A1, SLC28A1, and ABCG2 likely impact the pharmacokinetics (PK) of metformin, while the role of the two latter can be related to insulin resistance and regulation of adipogenesis.

Conclusions: Our results confirm previous genetic associations and point to previously unassociated gene variants for metformin PK and glucose control.
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http://dx.doi.org/10.1159/000517462DOI Listing
July 2021

Sex Dimorphic Changes in Trh Gene Methylation and Thyroid-Axis Response to Energy Demands in Maternally Separated Rats.

Endocrinology 2021 08;162(8)

Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, México.

The hypothalamus-pituitary-thyroid (HPT) axis regulates energy balance through the pleiotropic action of thyroid hormones. HPT basal activity and stimulation by cold or voluntary exercise are repressed by previous chronic stress in adults. Maternal separation (MS) modifies HPT basal activity; we thus studied the response of the axis to energy demands and analyzed possible epigenetic changes on Trh promoter. Nonhandled (NH) or MS male Wistar rats were cold exposed 1 h at adulthood; Trh expression in the hypothalamic paraventricular nucleus (PVN) and serum thyrotropin (TSH) concentration were increased only in NH rats. Two weeks of voluntary exercise decreased fat mass and increased Trh expression, and thyroid hormones concentration changed proportionally to running distance in NH male rats and MS male rats. Although NH females ran more than MS and much more than males, exercise decreased body weight and fat mass only in NH rats with no change on any parameter of the HPT axis but increased Pomc expression in arcuate-nucleus of NH and Npy in MS females. Overall, the methylation pattern of PVN Trh gene promoter was similar in NH males and females; MS modified methylation of specific CpG sites, a thyroid hormone receptor (THR)-binding site present after the initiation site was hypomethylated in MS males; in MS females, the THR binding site of the proximal promoter (site 4) and 2 sites in the first intron were hypermethylated. Our studies showed that, in a sex-dimorphic manner, MS blunted the responses of HPT axis to energy demands in adult animals and caused methylation changes on Trh promoter that could alter T3 feedback.
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http://dx.doi.org/10.1210/endocr/bqab110DOI Listing
August 2021

Association of FAAH p.Pro129Thr and COMT p.Ala72Ser with schizophrenia and comorbid substance use through next-generation sequencing: an exploratory analysis.

Braz J Psychiatry 2021 May 21. Epub 2021 May 21.

División Académica de Ciencias de la Salud, Universidad Juárez Autónoma de Tabasco, Villahermosa, Mexico.

Objective: Individuals with schizophrenia and substance use disorders have a poor prognosis and increased psychiatric symptoms. The present study aimed to explore the association of 106 genes in individuals with schizophrenia and comorbid substance use through a next-generation sequencing (NGS) analysis and different in silico algorithms.

Methods: We included 105 individuals diagnosed with schizophrenia and a family history of schizophrenia, of whom 49 (46.67%) presented comorbid substance use. Using NGS, we sequenced 106 genes previously associated with schizophrenia. Logistic regression models were used to assess differences in allele frequencies, and a generalized gene-set analysis was performed at the gene level. Functional annotations were performed using different algorithms and databases.

Results: We identified a total of 3,109 variants, of which 25 were associated with schizophrenia and comorbid substance use and were located in regulatory and coding regions. We found low-frequency variants in COMT p.Ala72Ser, independently of p.Val158Met, that were associated with substance use. The endocannabinoid functional variant FAAH p.Pro129Thr was also associated with substance use.

Conclusions: Genetic variants of genes related to dopaminergic and cannabinoid neurotransmitter systems were associated with comorbid substance use in schizophrenia. Nevertheless, more studies with larger sample sizes are needed to confirm our findings.
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http://dx.doi.org/10.1590/1516-4446-2020-1546DOI Listing
May 2021

Whole genome variation in 27 Mexican indigenous populations, demographic and biomedical insights.

PLoS One 2021 8;16(4):e0249773. Epub 2021 Apr 8.

Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos, México.

There has been limited study of Native American whole genome diversity to date, which impairs effective implementation of personalized medicine and a detailed description of its demographic history. Here we report high coverage whole genome sequencing of 76 unrelated individuals, from 27 indigenous groups across Mexico, with more than 97% average Native American ancestry. On average, each individual has 3.26 million Single Nucleotide Variants and short indels, that together comprise a catalog of 9,737,152 variants, 44,118 of which are novel. We report 497 common Single Nucleotide Variants (with allele frequency > 5%) mapped to drug responses and 316,577 in enhancer or promoter elements; interestingly we found some of these enhancer variants in PPARG, a nuclear receptor involved in highly prevalent health problems in Mexican population, such as obesity, diabetes, and insulin resistance. By detecting signals of positive selection we report 24 enriched key pathways under selection, most of them related to immune mechanisms. No missense variants in ACE2, the receptor responsible for the entry of the SARS CoV-2 virus, were found in any individual. Population genomics and phylogenetic analyses demonstrated stratification in a Northern-Central-Southern axis, with major substructure in the Central region. The Seri, a northern group with the most genetic divergence in our study, showed a distinctive genomic context with the most novel variants, and the most population specific genotypes. Genome-wide analysis showed that the average haplotype blocks are longer in Native Mexicans than in other world populations. With this dataset we describe previously undetected population level variation in Native Mexicans, helping to reduce the gap in genomic data representation of such groups.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249773PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031408PMC
April 2021

Pharmacogenomics: Current Actionable Variants.

Rev Invest Clin 2020 05 7;72(5). Epub 2020 May 7.

Instituto Nacional de Medicina Genómica,SSA, Mexico City, Mexico.

Pharmacogenomics (PGx), one of the several tools of precision medicine, has been slowly implemented in the clinic during the past decades. This process generally starts with direct and indirect genotype-phenotype associations of gene variants and drug efficacy, or adverse drug reactions, followed by replication and validation studies. Institutional efforts led by the PGx Research Network, The PGx Knowledge Base, and The Clinical Pharmacogenetics Implementation Consortium, mine all available data for further validation or research in additional populations. This data mining gives rise to a detailed classification of over 200 druggene pairs which, with enough documentation, may become part of a publishable guideline to aid clinicians in drug selection and dosing using genetics. The US Food and Drug Administration utilizes these guidelines to issue warnings and recommendations for specific drugs and their cautioning serves clinicians and pharmacists worldwide. Here, we aim to discuss the steps of this process and list existing actionable drug-gene pairs. Moreover, we describe the current status of PGx knowledge in populations from Mexico for actionable variants on the 19 genes listed by present PGx guidelines affecting 47 drugs. Our review collects current allele frequency information for these actionable variants, lists gaps of PGx information for relevant markers, and highlights the importance of continuing PGx research in Native and Mestizo populations.
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http://dx.doi.org/10.24875/RIC.20003239DOI Listing
May 2020

Pharmacogenomics: Current Actionable Variants.

Rev Invest Clin 2020 May 7;73(3). Epub 2020 May 7.

Instituto Nacional de Medicina Genómica,SSA, Mexico City, Mexico.

Pharmacogenomics (PGx), one of the several tools of precision medicine, has been slowly implemented in the clinic during the past decades. This process generally starts with direct and indirect genotype-phenotype associations of gene variants and drug efficacy, or adverse drug reactions, followed by replication and validation studies. Institutional efforts led by the PGx Research Network, The PGx Knowledge Base, and The Clinical Pharmacogenetics Implementation Consortium, mine all available data for further validation or research in additional populations. This data mining gives rise to a detailed classification of over 200 druggene pairs which, with enough documentation, may become part of a publishable guideline to aid clinicians in drug selection and dosing using genetics. The US Food and Drug Administration utilizes these guidelines to issue warnings and recommendations for specific drugs and their cautioning serves clinicians and pharmacists worldwide. Here, we aim to discuss the steps of this process and list existing actionable drug-gene pairs. Moreover, we describe the current status of PGx knowledge in populations from Mexico for actionable variants on the 19 genes listed by present PGx guidelines affecting 47 drugs. Our review collects current allele frequency information for these actionable variants, lists gaps of PGx information for relevant markers, and highlights the importance of continuing PGx research in Native and Mestizo populations.
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May 2020

Genomic diversity of prevalent multidrug-resistant strains isolated from a Children's Hospital in México City in an eight-years survey.

PeerJ 2019 20;7:e8068. Epub 2019 Nov 20.

Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México.

is a human commensal and pathogen worldwide distributed. In this work, we surveyed for multi-resistant strains in eight years at a children's health-care unit in México City. Multidrug-resistant were present in all years of the study, including resistance to methicillin, beta-lactams, fluoroquinolones, and macrolides. To understand the genetic basis of antibiotic resistance and its association with virulence and gene exchange, we sequenced the genomes of 17 isolates. Whole-genome nucleotide identities between all the pairs of S. epidermidis strains were about 97% to 99%. We inferred a clonal structure and eight Multilocus Sequence Types (MLSTs) in the sequenced collection. The profile of virulence includes genes involved in biofilm formation and phenol-soluble modulins (PSMs). Half of the analyzed lacked the ica operon for biofilm formation. Likely, they are commensal strains but multi-antibiotic resistant. Uneven distribution of insertion sequences, phages, and CRISPR-Cas immunity phage systems suggest frequent horizontal gene transfer. Rates of recombination between strains were more prevalent than the mutation rate and affected the whole genome. Therefore, the multidrug resistance, independently of the pathogenic traits, might explain the persistence of specific highly adapted clonal lineages in nosocomial settings.
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http://dx.doi.org/10.7717/peerj.8068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874853PMC
November 2019

Variation in Actionable Pharmacogenetic Markers in Natives and Mestizos From Mexico.

Front Pharmacol 2019 10;10:1169. Epub 2019 Oct 10.

Pharmacogenomics Laboratory, INMEGEN, CDMX, Mexico City, Mexico.

The identification and characterization of pharmacogenetic variants in Latin American populations is still an ongoing endeavor. Here, we investigated SNVs on genes listed by the Pharmacogenomics Knowledge Base in 1284 Mestizos and 94 Natives from Mexico. Five institutional cohorts with NGS data were retrieved from different research projects at INMEGEN, sequencing files were filtered for 55 pharmacogenes present in all cohorts to identify novel and known variation. Bioinformatic tools VEP, PROVEAN, and FATHMM were used to assess, , the functional impact of this variation. Next, we focused on 17 genes with actionable variants that have been clinically implemented. Allele frequencies were compared with major continental groups and differences discussed in the scope of a pharmacogenomic impact. We observed a wide genetic variability for known and novel SNVs, the largest variation was on and the lowest on and . Although with allele frequencies around 1%, novel variation was observed in 16 of 17 PGKB genes. In Natives we identified 59 variants and 58 in Mestizos. Several genes did not show novel variation, on , , and in Natives; and , , and in Mestizos. Similarities in allele frequency, comparing major continental groups for VIP pharmacogenes, hint towards a comparable PGx for drugs metabolized by , , , , , and ; in contrast to variants on and for which significant MAF differences were identified. Our observations offer some discernment into the extent of pharmacogenetic variation registered up-to-date in Mexicans and contribute to quantitatively dissect actionable pharmacogenetic variants in Natives and Mestizos.
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http://dx.doi.org/10.3389/fphar.2019.01169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796793PMC
October 2019

EXPLORATORY ANALYSIS OF RARE AND NOVEL VARIANTS IN MEXICAN PATIENTS DIAGNOSED WITH SCHIZOPHRENIA AND DEMENTIA.

Rev Invest Clin 2019 ;71(4):246-254

Genomics Laboratory of Psychiatric and Neurodegenerative Diseases, Instituto Nacional de Medicina Genómica, Mexico City.

Background: Schizophrenia (SCZ) and dementia, often related, are two of the most common neuropsychiatric diseases; epidemiological studies have shown that SCZ patients present a 2-fold increased risk for dementia compared to non-schizophrenic individuals. We explored the presence of rare and novel damaging gene variants in patients diagnosed with late-onset dementia of Alzheimer's type (DAT) or SCZ.

Methods: We included 7 DAT and 12 SCZ patients and performed high-depth targeted sequencing of 184 genes.

Results: We found novel and rare damaging variants in 18 genes in these Mexican patients. Carriers of these variants showed extreme phenotypes, including, treatment-resistant SCZ or cognitive decline. Furthermore, we found a variation on ABCC1 as a possible link between psychosis and cognitive impairment.

Discussion: As an exploratory analysis, we report some interesting variations that should be corroborated in larger sample size studies.
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http://dx.doi.org/10.24875/RIC.19002923DOI Listing
January 2020

Whole genomic sequencing as a tool for diagnosis of drug and multidrug-resistance tuberculosis in an endemic region in Mexico.

PLoS One 2019 5;14(6):e0213046. Epub 2019 Jun 5.

Instituto de Salud Pública, Universidad Veracruzana, Veracruz, México.

Background: Whole genome sequencing (WGS) has been proposed as a tool for diagnosing drug resistance in tuberculosis. However, reports of its effectiveness in endemic countries with important numbers of drug resistance are scarce. The goal of this study was to evaluate the effectiveness of this procedure in isolates from a tuberculosis endemic region in Mexico.

Methods: WGS analysis was performed in 81 tuberculosis positive clinical isolates with a known phenotypic profile of resistance against first-line drugs (isoniazid, rifampin, ethambutol, pyrazinamide and streptomycin). Mutations related to drug resistance were identified for each isolate; drug resistant genotypes were predicted and compared with the phenotypic profile. Genotypes and transmission clusters based on genetic distances were also characterized.

Findings: Prediction by WGS analysis of resistance against isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin showed sensitivity values of 84%, 96%, 71%, 75% and 29%, while specificity values were 100%, 94%, 90%, 90% and 98%, respectively. Prediction of multidrug resistance showed a sensitivity of 89% and specificity of 97%. Moreover, WGS analysis revealed polymorphisms related to second-line drug resistance, enabling classification of eight and two clinical isolates as pre- and extreme drug-resistant cases, respectively. Lastly, four lineages were identified in the population (L1, L2, L3 and L4). The most frequent of these was L4, which included 90% (77) of the isolates. Six transmission clusters were identified; the most frequent was TC6, which included 13 isolates with a L4.1.1 and a predominantly multidrug-resistant condition.

Conclusions: The results illustrate the utility of WGS for establishing the potential for prediction of resistance against first and second line drugs in isolates of tuberculosis from the region. They also demonstrate the feasibility of this procedure for use as a tool to support the epidemiological surveillance of drug- and multidrug-resistant tuberculosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213046PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550372PMC
February 2020

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Nature 2019 06 22;570(7759):71-76. Epub 2019 May 22.

Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, South Korea.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10) and candidate genes from knockout mice (P = 5.2 × 10). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
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http://dx.doi.org/10.1038/s41586-019-1231-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699738PMC
June 2019

Microbiome-MX 2018: microbiota and microbiome opportunities in Mexico, a megadiverse country.

Res Microbiol 2019 Jun - Aug;170(4-5):235-241. Epub 2019 Mar 25.

Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos, 62210, Mexico. Electronic address:

A weekly conference series paired with lectures entitled "Microbiome-MX: exploring the Microbiota and Microbiome Research in Mexico" was organized to provide a multidisciplinary overview of the most recent research done in Mexico using high-throughput sequencing. Scientists and postgraduate students from several disciplines such as microbiology, bioinformatics, virology, immunology, nutrition, and medical genomics gathered to discuss state of the art in each of their respective subjects of expertise, as well as advances, applications and new opportunities on microbiota/microbiome research. In particular, high-throughput sequencing is a crucial tool to understand the challenges of a megadiverse developing country as Mexico, and moreover to know the scientific capital and capabilities available for collaboration. The conference series addressed three main topics important for Mexico: i) the complex role of microbiota in health and prevalent diseases such as obesity, diabetes, inflammatory bowel disease, tuberculosis, HIV, autoimmune diseases and gastric cancer; ii) the use of local, traditional and prehispanic products as pre/probiotics to modulate the microbiota and improve human health; and iii) the impact of the microbiota in shaping the biodiversity of economically important terrestrial and marine ecosystems. Herein, we summarize the contributions that Mexican microbiota/microbiome research is making to the global trends, describing the highlights of the conferences and lectures, rather than a review of the state-of-the-art of this research. This meeting report also presents the efforts of a multidisciplinary group of scientist to encourage collaborations and bringing this research field closer for younger generations.
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http://dx.doi.org/10.1016/j.resmic.2019.03.001DOI Listing
August 2019

Fate of uptaken host proteins in and cysticerci.

Biosci Rep 2018 08 6;38(4). Epub 2018 Jul 6.

Department of Immunology, Institute for Biomedical Research, Universidad Nacional Autónoma de México, Ciudad de México, México

During the study of host-parasite relationships in taeniid parasite diseases, including cysticercosis and hydatidosis, reports have described the presence of host proteins in the cyst fluid and tissue of metacestodes. However, the fate or role of host elements inside the parasite remains barely explored. After the publication of genomes of four cestode species, it became clear that these organisms possess a limited biosynthetic capability. The initial goal of the present study was to determine if uptaken host proteins could be a source of essential amino acids for cysticerci. To track the utilization of uptaken proteins, we added metabolically labeled IgG-H and GFP-H to the culture medium of cysticerci. Incorporation of labeled amino acid was evaluated by fluorography in cysticerci extracts. Our results showed that the use of uptaken proteins by cysticerci as a source of amino acids appeared negligible. Exploring alternative fates for the host proteins, proteomic analysis of the protein matrix in calcareous corpuscles was carried out. Since does not contain calcareous corpuscles, proteomic analyses were performed in corpuscles of cysticerci. Our results demonstrated that host proteins represented approximately 70% of protein content in the calcareous corpuscles. The presence of the two major uptaken host proteins, namely albumin and IgG, was also demonstrated by Western blot in the matrix of corpuscles. Our findings strongly suggested that the uptake and disposal of host proteins involve calcareous corpuscles, expanding the physiological role of these mineral concretions to a far more important level than previously proposed.
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http://dx.doi.org/10.1042/BSR20180636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435539PMC
August 2018

Identification and characterization of Taenia solium enolase as a plasminogen-binding protein.

Acta Trop 2018 Jun 18;182:69-79. Epub 2018 Feb 18.

Dept. of Immunology, Institute for Biomedical Research, Universidad Nacional Autónoma de México, Mexico City, Mexico.. Electronic address:

The larval stage of Taenia solium (cysticerci) is the causal agent of human and swine cysticercosis. When ingested by the host, T. solium eggs are activated and hatch in the intestine, releasing oncospheres that migrate to various tissues and evolve into cysticerci. Plasminogen (Plg) receptor proteins have been reported to play a role in migration processes for several pathogens. This work is aimed to identify Plg-binding proteins in T. solium cysticerci and determine whether T. solium recombinant enolase (rTsEnoA) is capable of specifically binding and activating human Plg. To identify Plg-binding proteins, a 2D-SDS-PAGE ligand blotting was performed, and recognized spots were identified by MS/MS. Seven proteins from T. solium cysticerci were found capable of binding Plg: fascicilin-1, fasciclin-2, enolase, MAPK, annexin, actin, and cytosolic malate dehydrogenase. To determine whether rTsEnoA binds human Plg, a ligand blotting was performed and the results were confirmed by ELISA both in the presence and absence of εACA, a competitive Plg inhibitor. Finally, rTsEnoA-bound Plg was activated to plasmin in the presence of tPA. To better understand the evolution of enolase isoforms in T. solium, a phylogenetic inference analysis including 75 enolase amino acid sequences was conducted. The origin of flatworm enolase isoforms, except for Eno4, is independent of their vertebrate counterparts. Therefore, herein we propose to designate tapeworm protein isoforms as A, B, C, and 4. In conclusion, recombinant enolase showed a strong plasminogen binding and activating activity in vitro. T. solium enolase could play a role in parasite invasion along with other plasminogen-binding proteins.
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http://dx.doi.org/10.1016/j.actatropica.2018.02.020DOI Listing
June 2018

A novel approach for human whole transcriptome analysis based on absolute gene expression of microarray data.

PeerJ 2017 8;5:e4133. Epub 2017 Dec 8.

Departamento de Microbiología Molecular, Universidad Nacional Autónoma de México, Instituto de Biotecnología, Cuernavaca, Morelos, México.

Background: In spite of the emergence of RNA sequencing (RNA-seq), microarrays remain in widespread use for gene expression analysis in the clinic. There are over 767,000 RNA microarrays from human samples in public repositories, which are an invaluable resource for biomedical research and personalized medicine. The absolute gene expression analysis allows the transcriptome profiling of all expressed genes under a specific biological condition without the need of a reference sample. However, the background fluorescence represents a challenge to determine the absolute gene expression in microarrays. Given that the Y chromosome is absent in female subjects, we used it as a new approach for absolute gene expression analysis in which the fluorescence of the Y chromosome genes of female subjects was used as the background fluorescence for all the probes in the microarray. This fluorescence was used to establish an absolute gene expression threshold, allowing the differentiation between expressed and non-expressed genes in microarrays.

Methods: We extracted the RNA from 16 children leukocyte samples (nine males and seven females, ages 6-10 years). An Affymetrix Gene Chip Human Gene 1.0 ST Array was carried out for each sample and the fluorescence of 124 genes of the Y chromosome was used to calculate the absolute gene expression threshold. After that, several expressed and non-expressed genes according to our absolute gene expression threshold were compared against the expression obtained using real-time quantitative polymerase chain reaction (RT-qPCR).

Results: From the 124 genes of the Y chromosome, three genes (DDX3Y, TXLNG2P and EIF1AY) that displayed significant differences between sexes were used to calculate the absolute gene expression threshold. Using this threshold, we selected 13 expressed and non-expressed genes and confirmed their expression level by RT-qPCR. Then, we selected the top 5% most expressed genes and found that several KEGG pathways were significantly enriched. Interestingly, these pathways were related to the typical functions of leukocytes cells, such as antigen processing and presentation and natural killer cell mediated cytotoxicity. We also applied this method to obtain the absolute gene expression threshold in already published microarray data of liver cells, where the top 5% expressed genes showed an enrichment of typical KEGG pathways for liver cells. Our results suggest that the three selected genes of the Y chromosome can be used to calculate an absolute gene expression threshold, allowing a transcriptome profiling of microarray data without the need of an additional reference experiment.

Discussion: Our approach based on the establishment of a threshold for absolute gene expression analysis will allow a new way to analyze thousands of microarrays from public databases. This allows the study of different human diseases without the need of having additional samples for relative expression experiments.
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http://dx.doi.org/10.7717/peerj.4133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724404PMC
December 2017

Pharmacogenetic Variation in Over 100 Genes in Patients Receiving Acenocumarol.

Front Pharmacol 2017 23;8:863. Epub 2017 Nov 23.

Instituto Nacional de Medicina Genomica, Mexico City, Mexico.

Coumarins are widely prescribed worldwide, and in Mexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on , and . A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, , and , and a low proportion of novel-to-known variants on , and . Using a Bayesian approach, we identified variants influencing acenocumarol dosing on, , and explaining 40-55% of dose variability. A collection of pharmacogenetic variation on 110 genes related to the PK/PD of coumarins is also presented. Our results offer an initial insight into the use of a targeted NGS approach in the pharmacogenomics of coumarins in Mexican Mestizos.
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http://dx.doi.org/10.3389/fphar.2017.00863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703746PMC
November 2017

Demographic history and biologically relevant genetic variation of Native Mexicans inferred from whole-genome sequencing.

Nat Commun 2017 10 18;8(1):1005. Epub 2017 Oct 18.

Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, 14610, Mexico.

Understanding the genetic structure of Native American populations is important to clarify their diversity, demographic history, and to identify genetic factors relevant for biomedical traits. Here, we show a demographic history reconstruction from 12 Native American whole genomes belonging to six distinct ethnic groups representing the three main described genetic clusters of Mexico (Northern, Southern, and Maya). Effective population size estimates of all Native American groups remained below 2,000 individuals for up to 10,000 years ago. The proportion of missense variants predicted as damaging is higher for undescribed (~ 30%) than for previously reported variants (~ 15%). Several variants previously associated with biological traits are highly frequent in the Native American genomes. These findings suggest that the demographic and adaptive processes that occurred in these groups shaped their genetic architecture and could have implications in biological processes of the Native Americans and Mestizos of today.
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http://dx.doi.org/10.1038/s41467-017-01194-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647344PMC
October 2017

Quantitative multiplexed proteomics of Taenia solium cysts obtained from the skeletal muscle and central nervous system of pigs.

PLoS Negl Trop Dis 2017 Sep 25;11(9):e0005962. Epub 2017 Sep 25.

Dept. of Immunology, Institute for Biomedical Research, Universidad Nacional Autónoma de México, Ciudad de México, México.

In human and porcine cysticercosis caused by the tapeworm Taenia solium, the larval stage (cysts) can infest several tissues including the central nervous system (CNS) and the skeletal muscles (SM). The cyst's proteomics changes associated with the tissue localization in the host tissues have been poorly studied. Quantitative multiplexed proteomics has the power to evaluate global proteome changes in response to different conditions. Here, using a TMT-multiplexed strategy we identified and quantified over 4,200 proteins in cysts obtained from the SM and CNS of pigs, of which 891 were host proteins. To our knowledge, this is the most extensive intermixing of host and parasite proteins reported for tapeworm infections.Several antigens in cysticercosis, i.e., GP50, paramyosin and a calcium-binding protein were enriched in skeletal muscle cysts. Our results suggested the occurrence of tissue-enriched antigen that could be useful in the improvement of the immunodiagnosis for cysticercosis. Using several algorithms for epitope detection, we selected 42 highly antigenic proteins enriched for each tissue localization of the cysts. Taking into account the fold changes and the antigen/epitope contents, we selected 10 proteins and produced synthetic peptides from the best epitopes. Nine peptides were recognized by serum antibodies of cysticercotic pigs, suggesting that those peptides are antigens. Mixtures of peptides derived from SM and CNS cysts yielded better results than mixtures of peptides derived from a single tissue location, however the identification of the 'optimal' tissue-enriched antigens remains to be discovered. Through machine learning technologies, we determined that a reliable immunodiagnostic test for porcine cysticercosis required at least five different antigenic determinants.
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http://dx.doi.org/10.1371/journal.pntd.0005962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634658PMC
September 2017

Experimental and Theoretical Approaches To Investigate the Immunogenicity of Taenia solium-Derived KE7 Antigen.

Infect Immun 2017 12 17;85(12). Epub 2017 Nov 17.

Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, México

cysticercosis, a parasitic disease that affects human health in various regions of the world, is preventable by vaccination. Both the 97-amino-acid-long KETc7 peptide and its carboxyl-terminal, 18-amino-acid-long sequence (GK-1) are found in Both peptides have proven protective capacity against cysticercosis and are part of the highly conserved, cestode-native, 264-amino-acid long protein KE7. KE7 belongs to a ubiquitously distributed family of proteins associated with membrane processes and may participate in several vital cell pathways. The aim of this study was to identify the KE7 (TsKE7) full-length protein and to determine its immunogenic properties. Recombinant TsKE7 (rTsKE7) was expressed in Rosetta2 cells and used to obtain mouse polyclonal antibodies. Anti-rTsKE7 antibodies detected the expected native protein among the 350 spots developed from cyst vesicular fluid in a mass spectrometry-coupled immune proteomic analysis. These antibodies were then used to screen a phage-displayed 7-random-peptide library to map B-cell epitopes. The recognized phages displayed 9 peptides, with the consensus motif Y(F/Y)PS sequence, which includes YYYPS (named GK-1M, for being a GK-1 mimotope), exactly matching a part of GK-1. GK-1M was recognized by 58% of serum samples from cysticercotic pigs with 100% specificity but induced weak protection against murine cysticercosis. analysis revealed a universal T-cell epitope(s) in native TsKE7 potentially capable of stimulating cytotoxic T lymphocytes and helper T lymphocytes under different major histocompatibility complex class I and class II mouse haplotypes. Altogether, these results provide a rationale for the efficacy of the KETc7, rTsKE7, and GK-1 peptides as vaccines.
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http://dx.doi.org/10.1128/IAI.00395-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695116PMC
December 2017

A Loss-of-Function Splice Acceptor Variant in Is Protective for Type 2 Diabetes.

Diabetes 2017 11 24;66(11):2903-2914. Epub 2017 Aug 24.

Department of Genetics, Harvard Medical School, Boston, MA.

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of isoform 2. In individuals who do not carry the protective allele, expression of isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.
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http://dx.doi.org/10.2337/db17-0187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652606PMC
November 2017

Prediction of atorvastatin plasmatic concentrations in healthy volunteers using integrated pharmacogenetics sequencing.

Pharmacogenomics 2017 Jan 15;18(2):121-131. Epub 2016 Dec 15.

Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Delegación Tlalpan, México, D.F. C.P. 14610, Mexico.

Aim: To use variants found by next-generation sequencing to predict atorvastatin plasmatic concentration profiles (AUC) in healthy volunteers.

Subjects & Methods: A total of 60 healthy Mexican volunteers were enrolled in this study. We used variants with a predicted functional effect across 20 genes involved in atorvastatin metabolism to construct a regression model using a support vector approach with a radial basis function kernel to predict AUC refining it afterwards in order to explain a greater extent of the variance.

Results: The final support vector regression model using 60 variants (including six novel variants) explained 94.52% of the variance in atorvastatin AUC.

Conclusion: An integrated analysis of several genes known to intervene in the different steps of metabolism is required to predict atorvastatin's AUC.
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http://dx.doi.org/10.2217/pgs-2016-0072DOI Listing
January 2017

Protein profiles of Taenia solium cysts obtained from skeletal muscles and the central nervous system of pigs: Search for tissue-specific proteins.

Exp Parasitol 2017 Jan 29;172:23-29. Epub 2016 Nov 29.

Dept. of Immunology, Institute for Biomedical Research, Universidad Nacional Autónoma de México, México D.F, 04510, Mexico. Electronic address:

Taeniasis/cysticercosis caused by the tapeworm Taenia solium is a parasite disease transmitted among humans and pigs, the main intermediate host. The larvae/cysts can lodge in several tissues of the pig, i.e. skeletal muscles and different locations of the central nervous system. The molecular mechanisms associated to tissue preferences of the cysts remain poorly understood. The major public health concern about this zoonosis is due to the human infections by the larval form in the central nervous system, causing a highly pleomorphic and debilitating disease known as neurocysticercosis. This study was aimed to explore the 2DE protein maps of T. solium cysts obtained from skeletal muscles and central nervous system of naturally infected pigs. The gel images were analyzed through a combination of PDQuest™ and multivariate analysis. Results showed that differences in the protein patterns of cysts obtained from both tissues were remarkably discrete. Only 7 protein spots were found specifically associated to the skeletal muscle localization of the cysts; none was found significantly associated to the central nervous system. The use of distinct protein fractions of cysts allowed preliminary identification of several tissue-specific antigenic bands. The implications of these findings are discussed, as well as several strategies directed to achieve the complete characterization of this parasite's proteome, in order to extend our understanding of the molecular mechanisms underlying tissue localization of the cysts and to open avenues for the development of immunological tissue-specific diagnosis of the disease.
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http://dx.doi.org/10.1016/j.exppara.2016.11.006DOI Listing
January 2017

Exploring Variation in Known Pharmacogenetic Variants and its Association with Drug Response in Different Mexican Populations.

Pharm Res 2016 11 7;33(11):2644-52. Epub 2016 Jul 7.

Laboratorio de Farmacogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Ciudad de Mexico, Mexico.

Purpose: Information on genetic variants that affect the pharmacokinetics and pharmacodynamics (PK/PD) of drugs in different populations from Mexico is still an ongoing endeavor. Here, we investigate allele frequencies on pharmacogenetic targets in Mexican Mestizos and Natives from three different States and its association with drug efficacy in individuals receiving either anticoagulants or antipsychotic drugs.

Methods: Natives from three different states and Mestizo patients receiving acenocoumarol or antipsychotics were genotyped using the DMET microarray (Affymetrix).

Results: We provide a collection of genetic variants that indicate that there are 3-times more variation than similarities between populations from Mexico and major continental groups. These differences were observed in several relevant targets including ABCB1, SLCO1A1, NAT2, UGTs, TYMS, VKORC1, and NR1I3. Moreover, Mexican Mestizos also showed allele frequency differences when compared to Natives for variants on DPYD, ADH1A, CYP3A4, SLC28A3, and SLC28A1. Significant allele differences also arose among the three Native groups here studied, mostly for transporters of the ABC-binding cassette and the solute carrier gene family. Finally, we explored genotype-drug response associations and pinpointed variants on FMOs (coumarins), and GSTM1 (haloperidol).

Conclusions: These findings confirm previous results and further delve into the pharmacogenetics of Mexican populations including different Native groups.
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http://dx.doi.org/10.1007/s11095-016-1990-5DOI Listing
November 2016

Role of porcine serum haptoglobin in the host-parasite relationship of Taenia solium cysticercosis.

Mol Biochem Parasitol 2016 06 24;207(2):61-7. Epub 2016 May 24.

Dept. of Immunology, Institute for Biomedical Research, Universidad Nacional Autónoma de México, México D.F. 04510, Mexico. Electronic address:

Human and porcine cysticercosis is a parasitic disease caused by the larval stage (cysts) of the tapeworm Taenia solium. Cysts may live in several host tissues such as skeletal muscle or brain. We have previously described the presence of host haptoglobin (Hp) and hemoglobin (Hb) in different protein extracts of the T. solium cysts. Here, we report the binding of host Hp and Hb to a number of cyst proteins, evaluated through measuring electrophoretic and light absorbance changes. In the sera obtained from 18 cysticercotic pigs, Hp-Hb complexes were abundant, whereas free Hp was undetectable. In contrast, in the sera from non 18 cysticercotic pigs, Hp-Hb and free Hp were found. In the soluble protein fraction of cysts tissue, free Hp was detected showing a considerable Hb-binding ability, whereas in the vesicular fluid, Hp is mainly bound to Hb. Interestingly, assays carried out with the insoluble fraction of T. solium cysts tissue, showed binding of Hp and Hp-Hb in a saturable way, suggesting the existence of specific interactions. Our results suggested that the parasite can take advantage of the uptaken host Hp and Hb, either free or in complexes, as a source of iron or as a way to modulate the inflammatory response surrounding the T. solium cysts.
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http://dx.doi.org/10.1016/j.molbiopara.2016.05.010DOI Listing
June 2016

Combining metagenomics, metatranscriptomics and viromics to explore novel microbial interactions: towards a systems-level understanding of human microbiome.

Comput Struct Biotechnol J 2015 9;13:390-401. Epub 2015 Jun 9.

Unidad de Genómica de Poblaciones Aplicada la Salud, Facultad de Química, UNAM, Instituto Nacional de Medicina Genómica (INMEGEN), México, D.F. 14610, Mexico ; Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de Mexico, Avenida Universidad 2001, Cuernavaca C.P. 62210, Mexico.

The advances in experimental methods and the development of high performance bioinformatic tools have substantially improved our understanding of microbial communities associated with human niches. Many studies have documented that changes in microbial abundance and composition of the human microbiome is associated with human health and diseased state. The majority of research on human microbiome is typically focused in the analysis of one level of biological information, i.e., metagenomics or metatranscriptomics. In this review, we describe some of the different experimental and bioinformatic strategies applied to analyze the 16S rRNA gene profiling and shotgun sequencing data of the human microbiome. We also discuss how some of the recent insights in the combination of metagenomics, metatranscriptomics and viromics can provide more detailed description on the interactions between microorganisms and viruses in oral and gut microbiomes. Recent studies on viromics have begun to gain importance due to the potential involvement of viruses in microbial dysbiosis. In addition, metatranscriptomic combined with metagenomic analysis have shown that a substantial fraction of microbial transcripts can be differentially regulated relative to their microbial genomic abundances. Thus, understanding the molecular interactions in the microbiome using the combination of metagenomics, metatranscriptomics and viromics is one of the main challenges towards a system level understanding of human microbiome.
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http://dx.doi.org/10.1016/j.csbj.2015.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484546PMC
July 2015

Genome analysis of Excretory/Secretory proteins in Taenia solium reveals their Abundance of Antigenic Regions (AAR).

Sci Rep 2015 May 19;5:9683. Epub 2015 May 19.

Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM-Instituto Nacional de Medicina Genómica (INMEGEN), Periférico Sur No. 4809, Col. Arenal Tepepan, Delegación Tlalpan México, D.F. C.P. 14610, México.

Excretory/Secretory (ES) proteins play an important role in the host-parasite interactions. Experimental identification of ES proteins is time-consuming and expensive. Alternative bioinformatics approaches are cost-effective and can be used to prioritize the experimental analysis of therapeutic targets for parasitic diseases. Here we predicted and functionally annotated the ES proteins in T. solium genome using an integration of bioinformatics tools. Additionally, we developed a novel measurement to evaluate the potential antigenicity of T. solium secretome using sequence length and number of antigenic regions of ES proteins. This measurement was formalized as the Abundance of Antigenic Regions (AAR) value. AAR value for secretome showed a similar value to that obtained for a set of experimentally determined antigenic proteins and was different to the calculated value for the non-ES proteins of T. solium genome. Furthermore, we calculated the AAR values for known helminth secretomes and they were similar to that obtained for T. solium. The results reveal the utility of AAR value as a novel genomic measurement to evaluate the potential antigenicity of secretomes. This comprehensive analysis of T. solium secretome provides functional information for future experimental studies, including the identification of novel ES proteins of therapeutic, diagnosis and immunological interest.
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http://dx.doi.org/10.1038/srep09683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437048PMC
May 2015

Genotype frequencies of VKORC1 and CYP2C9 in native and Mestizo populations from Mexico, potential impact for coumarin dosing.

Gene 2015 Mar 2;558(2):235-40. Epub 2015 Jan 2.

Laboratorio de Farmacogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Periferico Sur 4809, Col. Arenal Tepepan, 14610 Mexico City, Mexico. Electronic address:

The collection of pharmacogenetic variants in Mexican populations remains incomplete, thus, we aimed to characterize the genotype frequency of 11 SNP on CYP2C9 and VKORC1 in more than one-thousand individuals, and to explore their potential impact on coumarin dosing. In natives, genotype frequencies indicate that over 92% would reflect an extensive metabolism. For Mestizo populations, the proportion of CYP2C9 extensive (79%), intermediate (20.0%) and poor metabolizers (1.0%) was significantly different from that of natives, and varied among the different states of Mexico. Genotype frequencies of 7 SNP on VKORC1, were more homogenously distributed among natives and Mestizos. VKORC1 haplotype analysis revealed that most natives can be grouped into haplotypes H1 or H7-H8, while Mestizos showed a wider frequency distribution for other haplotypes. Our observations confirm previous reports on the genotype distribution of major CYP2C9 alleles, and contribute to the collection of genotype frequencies on relevant VKORC1 variants.
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http://dx.doi.org/10.1016/j.gene.2014.12.068DOI Listing
March 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
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