Impaired white adipose tissue fatty acid metabolism in mice fed a high-fat diet worsened by arsenic exposure, primarily affecting retroperitoneal adipose tissue.

Fatty acid (FA) metabolism dysfunction of white adipose tissue (WAT) underlies obesity and insulin resistance in response to high calorie intake and/or endocrine-disrupting chemicals (EDCs), among other factors. Arsenic is an EDC that has been associated with metabolic syndrome and diabetes. However, the combined effect of a high-fat diet (HFD) and arsenic exposure on WAT FA metabolism has been little studied. FA metabolism was evaluated in visceral (epididymal and retroperitoneal) and subcutaneous WAT of C57BL/6 male mice fed control or HFD (12 and 40% kcal fat, respectively) for 16 weeks together with an environmentally relevant chronic arsenic exposure through drinking water (100 µg/L) during the second half of the study. In mice fed HFD, arsenic potentiated the increase of serum markers of selective insulin resistance in WAT and fatty acid re-esterification and the decrease of the lipolysis index. Retroperitoneal was the WAT most affected, where the combination of arsenic and HFD in contrast to HFD, generated higher adipose weight, larger adipocytes, increased triglyceride content, and decreased fasting stimulated lipolysis evidenced by lower phosphorylation of HSL and perilipin. At the transcriptional level, arsenic in mice fed either diet downregulated genes involved in fatty acid uptake (LPL, CD36), oxidation (PPARα, CPT1), lipolysis (ADRß3) and glycerol transport (AQP7 and AQP9). Additionally, arsenic potentiated hyperinsulinemia induced by HFD, despite a slight increase in weight gain and food efficiency. Thus, the second hit of arsenic in sensitized mice by HFD worsens fatty acid metabolism impairment in WAT, mainly retroperitoneal, along with an exacerbated insulin resistance phenotype.

Development of γδ T Cells: Soldiers on the Front Lines of Immune Battles.

While the functions of αß T cells in host resistance to pathogen infection are understood in far more detail than those of γδ lineage T cells, γδ T cells perform critical, essential functions during immune responses that cannot be compensated for by αß T cells. Accordingly, it is critical to understand how the development of γδ T cells is controlled so that their generation and function might be manipulated in future for therapeutic benefit. This introductory chapter will focus primarily on the basic processes that underlie γδ T cell development in the thymus, as well as the current understanding of how they are controlled.

Loss of Zfp335 triggers cGAS/STING-dependent apoptosis of post-ß selection thymocytes.

Production of a functional peripheral T cell compartment typically involves massive expansion of the bone marrow progenitors that seed the thymus. There are two main phases of expansion during T cell development, following T lineage commitment of double-negative (DN) 2 cells and after successful rearrangement and selection for functional TCRß chains in DN3 thymocytes, which promotes the transition of DN4 cells to the DP stage. The signals driving the expansion of DN2 thymocytes are well studied. However, factors regulating the proliferation and survival of DN4 cells remain poorly understood. Here, we uncover an unexpected link between the transcription factor Zfp335 and control of cGAS/STING-dependent cell death in post-ß-selection DN4 thymocytes. Zfp335 controls survival by sustaining expression of Ankle2, which suppresses cGAS/STING-dependent cell death. Together, this study identifies Zfp335 as a key transcription factor regulating the survival of proliferating post-ß-selection thymocytes and demonstrates a key role for the cGAS/STING pathway in driving apoptosis of developing T cells.

Loss of Ribosomal Protein Paralog Rpl22-like1 Blocks Lymphoid Development without Affecting Protein Synthesis.

Ribosomal proteins are thought to primarily facilitate biogenesis of the ribosome and its ability to synthesize protein. However, in this study, we show that Rpl22-like1 (Rpl22l1) regulates hematopoiesis without affecting ribosome biogenesis or bulk protein synthesis. Conditional loss of murine Rpl22l1 using stage or lineage-restricted Cre drivers impairs development of several hematopoietic lineages. Specifically, Tie2-Cre-mediated ablation of Rpl22l1 in hemogenic endothelium impairs the emergence of embryonic hematopoietic stem cells. Ablation of Rpl22l1 in late fetal liver progenitors impairs the development of B lineage progenitors at the pre-B stage and development of T cells at the CD44-CD25+ double-negative stage. In vivo labeling with O-propargyl-puromycin revealed that protein synthesis at the stages of arrest was not altered, indicating that the ribosome biogenesis and function were not generally compromised. The developmental arrest was associated with p53 activation, suggesting that the arrest may be p53-dependent. Indeed, development of both B and T lymphocytes was rescued by p53 deficiency. p53 induction was not accompanied by DNA damage as indicated by phospho-γH2AX induction or endoplasmic reticulum stress, as measured by phosphorylation of EIF2α, thereby excluding the known likely p53 inducers as causal. Finally, the developmental arrest of T cells was not rescued by elimination of the Rpl22l1 paralog, Rpl22, as we had previously found for the emergence of hematopoietic stem cells. This indicates that Rpl22 and Rpl22l1 play distinct and essential roles in supporting B and T cell development.

A Novel Germline Heterozygous BCL11B Variant Causing Severe Atopic Disease and Immune Dysregulation.

B-cell lymphoma/leukemia 11B (BCL11B) is a C2H2 zinc finger transcription factor that is critically important for regulating the development and function of a variety of systems including the central nervous system, the skin, and the immune system. Germline heterozygous variants are associated with a spectrum of clinical disorders, including severe combined immunodeficiency as well as neurological, craniofacial, and dermal defects. Of these individuals, ~50% present with severe allergic disease. Here, we report the detailed clinical and laboratory workup of one of the most severe BCL11B-dependent atopic cases to date. Leveraging a zebrafish model, we were able to confirm a strong T-cell defect in the patient. Based on these data, we classify germline BCL11B-dependent atopic disease as a novel primary atopic disorder.

The E protein-TCF1 axis controls γδ T cell development and effector fate.

TCF1 plays a critical role in T lineage commitment and the development of αß lineage T cells, but its role in γδ T cell development remains poorly understood. Here, we reveal a regulatory axis where T cell receptor (TCR) signaling controls TCF1 expression through an E-protein-bound regulatory element in the Tcf7 locus, and this axis regulates both γδ T lineage commitment and effector fate. Indeed, the level of TCF1 expression plays an important role in setting the threshold for γδ T lineage commitment and modulates the ability of TCR signaling to influence effector fate adoption by γδ T lineage progenitors. This finding provides mechanistic insight into how TCR-mediated repression of E proteins promotes the development of γδ T cells and their adoption of the interleukin (IL)-17-producing effector fate. IL-17-producing γδ T cells have been implicated in cancer progression and in the pathogenesis of psoriasis and multiple sclerosis.

Recent advances in understanding the development and function of γδ T cells.

γδ T cells are a subset of T cells with attributes of both the innate and adaptive arms of the immune system. These cells have long been an enigmatic and poorly understood component of the immune system and many have viewed them as having limited importance in host defense. This perspective persisted for some time both because of critical gaps in knowledge regarding how the development of γδ T cells is regulated and because of the lack of effective and sophisticated approaches through which the function of γδ T cells can be manipulated. Here, we discuss the recent advances in both of these areas, which have brought the importance of γδ T cells in both productive and pathologic immune function more sharply into focus.

Host-Microbiome Interaction and Cancer: Potential Application in Precision Medicine.

It has been experimentally shown that host-microbial interaction plays a major role in shaping the wellness or disease of the human body. Microorganisms coexisting in human tissues provide a variety of benefits that contribute to proper functional activity in the host through the modulation of fundamental processes such as signal transduction, immunity and metabolism. The unbalance of this microbial profile, or dysbiosis, has been correlated with the genesis and evolution of complex diseases such as cancer. Although this latter disease has been thoroughly studied using different high-throughput (HT) technologies, its heterogeneous nature makes its understanding and proper treatment in patients a remaining challenge in clinical settings. Notably, given the outstanding role of host-microbiome interactions, the ecological interactions with microorganisms have become a new significant aspect in the systems that can contribute to the diagnosis and potential treatment of solid cancers. As a part of expanding precision medicine in the area of cancer research, efforts aimed at effective treatments for various kinds of cancer based on the knowledge of genetics, biology of the disease and host-microbiome interactions might improve the prediction of disease risk and implement potential microbiota-directed therapeutics. In this review, we present the state of the art of sequencing and metabolome technologies, computational methods and schemes in systems biology that have addressed recent breakthroughs of uncovering relationships or associations between microorganisms and cancer. Together, microbiome studies extend the horizon of new personalized treatments against cancer from the perspective of precision medicine through a synergistic strategy integrating clinical knowledge, HT data, bioinformatics, and systems biology.

PPARα Downregulates Hepatic Glutaminase Expression in Mice Fed Diets with Different Protein:Carbohydrate Ratios.

BACKGROUND: Glutamine is catabolized in the liver by glutaminase 2 (GLS2). Evidence suggests that peroxisome proliferator-activated receptor α (PPARα) represses the expression of several amino acid-catabolizing enzymes, but for Gls2 this is unknown. OBJECTIVE: The aim of the study was to assess whether PPARα regulates Gls2 expression. METHODS: For 8 d, 7-9-wk-old male C57BL/6 wild-type (WT) and Ppara-null mice weighing 23.4 ± 0.5 g were fed diets with different dietary protein:carbohydrate (DP:DCH) ratios (6%:77%, 20%:63%, or 50%:33%). Liver samples were obtained after 16 h of feed deprivation or 3 h of refeeding, and microarrays were performed. Hepatic glutaminase expression was measured by quantitative polymerase chain reaction and Western blotting. Cotransfection analyses in hepatocellular carcinoma cell line (HepG2) cells with PPARα and hepatocyte nuclear factor 4α (HNF4α) expression vectors were performed. RESULTS: The microarray results showed that Gls2 was the only upregulated gene in WT mice, but not in the Ppara-null mice. In the feed-deprived WT mice, the Gls2 mRNA and protein abundances in the 50%:33% group were 2.5- and 1.1-fold greater (P < 0.05), respectively, than those in the 20%:63% group, which were 2.3- and 0.4-fold greater than those in the 6%:77% group (P < 0.01). Gls2 mRNA expression in the 6%:77% group of feed-deprived Ppara-null mice was 33-fold greater than that in the same group of WT mice (P < 0.0001). GLS2 protein abundance in HepG2 cells was 78% greater than that in the controls (P < 0.0001) after HNF4α overexpression, and it was 99% greater after transfection with a short hairpin targeting PPARα. CONCLUSIONS: In Ppara-null mice, Gls2 mRNA expression was greater than in WT mice, regardless of the DP:DCH ratio. In HepG2 cells overexpressing HNF4α, Gls2 expression increased, an effect repressed by overexpression of PPARα. This suggests that Gls2 depends on the PPARα/HNF4α counterregulatory transcriptional control.

Genetic Diversity and Differentiation in Urban and Indigenous Populations of Mexico: Patterns of Mitochondrial DNA and Y-Chromosome Lineages.

Aside from the admixture between indigenous people and people from overseas, populations in Mexico changed drastically after the Spanish conquest of the sixteenth century, forming an intricate history that has been underutilized in understanding the genetic population structure of Mexicans. To infer historical processes of isolation, dispersal, and assimilation, we examined the phylogeography of mitochondrial (mt) DNA and Y-chromosome lineages in 3,026 individuals from 10 urban and nine indigenous populations by identifying single nucleotide polymorphisms. A geographic array with a predominance of Amerindian lineages was observed for mtDNA, with northern indigenous populations being divergent from the central and southern indigenous populations; urban populations showed low differentiation with isolation by distance. Y-chromosome variation distinguished urban and indigenous populations through the Amerindian haplogroup Q frequency. The MtDNA and the Y-chromosome together primarily distinguished urban and indigenous populations, with different geographic arrays for both. Gene flow across geographical distance and between the urban and indigenous realms appears to have altered the pre-Hispanic phylogeography in central and southern Mexico, mainly by displacement of women, while maintaining the indigenous isolation in the north, southeast, and Zapotec regions. Most Amerindian mtDNA diversity currently occurs in urban populations and appears to be reduced among indigenous people.

PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis.

The liver is the main organ involved in the metabolism of amino acids (AA), which are oxidized by amino acid catabolizing enzymes (AACE). Peroxisome proliferator-activated receptor-α (PPARα) stimulates fatty acid ß-oxidation, and there is evidence that it can modulate hepatic AA oxidation during the transition of energy fuels. To understand the role and mechanism of PPARα's regulation of AA catabolism, the metabolic and molecular adaptations of Ppara-null mice were studied. The role of PPARα on AA metabolism was examined by in vitro and in vivo studies. In wild-type and Ppara-null mice, fed increasing concentrations of the dietary protein/carbohydrate ratio, we measured metabolic parameters, and livers were analyzed by microarray analysis, histology and Western blot. Functional enrichment analysis, EMSA and gene reporter assays were performed. Ppara-null mice presented increased expression of AACE in liver affecting AA, lipid and carbohydrate metabolism. Ppara-null mice had increased glucagon/insulin ratio (7.2-fold), higher serum urea (73.1 %), lower body protein content (19.7 %) and decreased several serum AA in response to a high-protein/low-carbohydrate diet. A functional network of differentially expressed genes, suggested that changes in the expression of AACE were regulated by an interrelationship between PPARα and HNF4α. Our data indicated that the expression of AACE is down-regulated through PPARα by attenuating HNF4α transcriptional activity as observed in the serine dehydratase gene promoter. PPARα via HNF4α maintains body protein metabolic homeostasis by down-regulating genes involved in amino acid catabolism for preserving body nitrogen.

Exploring the distribution of genetic markers of pharmacogenomics relevance in Brazilian and Mexican populations.

Studies of pharmacogenomics-related traits are increasingly being performed to identify loci that affect either drug response or susceptibility to adverse drug reactions. However, the effect of the polymorphisms can differ in magnitude or be absent depending on the population being assessed. We used the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array to characterize the distribution of polymorphisms of pharmacogenetics and pharmacogenomics (PGx) relevance in two samples from the most populous Latin American countries, Brazil and Mexico. The sample from Brazil included 268 individuals from the southeastern state of Rio de Janeiro, and was stratified into census categories. The sample from Mexico comprised 45 Native American Zapotecas and 224 self-identified Mestizo individuals from 5 states located in geographically distant regions in Mexico. We evaluated the admixture proportions in the Brazilian and Mexican samples using a panel of Ancestry Informative Markers extracted from the DMET array, which was validated with genome-wide data. A substantial variation in ancestral proportions across census categories in Brazil, and geographic regions in Mexico was identified. We evaluated the extent of genetic differentiation (measured as FST values) of the genetic markers of the DMET Plus array between the relevant parental populations. Although the average levels of genetic differentiation are low, there is a long tail of markers showing large frequency differences, including markers located in genes belonging to the Cytochrome P450, Solute Carrier (SLC) and UDP-glucuronyltransferase (UGT) families as well as other genes of PGx relevance such as ABCC8, ADH1A, CHST3, PON1, PPARD, PPARG, and VKORC1. We show how differences in admixture history may have an important impact in the distribution of allele and genotype frequencies at the population level.

Geographical and ethnic distribution of single nucleotide polymorphisms within genes of the folate/homocysteine pathway metabolism.

High levels of plasma homocysteine are associated with an increased risk of many health conditions influenced by both environmental and genetic factors. The objective of this study was to provide the geographical distribution of folate pathway genetic polymorphisms in Mexico and the comparison with the reported frequencies in different continental populations. This study included the analysis of the genotypic frequencies of eight polymorphisms in genes of the folate/homocysteine metabolic pathway in 1,350 Mestizo and Amerindian subjects from different regions in Mexico and 836 individuals from European, African and Asian populations of the 1,000 Genomes Project. In Mexican Mestizo and Amerindian populations, the MTHFR C677T risk genotype (TT) was highly prevalent (frequency: 25 and 57 %, respectively). In Mestizos, the frequency showed clear regional variation related to ancestry; the Guerrero subpopulation with the highest Amerindian contribution had the highest TT frequency (33 %). The MTHFD1 G1958A AA risk genotype was also enriched in Mexican Mestizos and Amerindians (frequency: 34 and 58 %, respectively), whereas in African and Asian ancestry populations the frequency for AA was low (~4 %). All together risk genotypes showed regional differences, and Sonora had significantly different genetic frequencies compared with the other regions (P value <0.05). Our study illustrates differential geographical distribution of the risk variants in the folate/homocysteine metabolic pathway relative to ethnic background. This work supports that certain areas of the world have increased needs for folic acid and vitamin B supplementation, and this information needs to be considered in public health guidelines and eventually policies.

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

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.

CFH haplotypes and ARMS2, C2, C3, and CFB alleles show association with susceptibility to age-related macular degeneration in Mexicans.

PURPOSE: To evaluate the contribution of genetic variants of complement factor H (CFH), complement component 2 and 3 (C2 and C3), complement factor B (CFB), and age-related maculopathy susceptibility 2 (ARMS2) to age-related macular degeneration (AMD) risk in the Mexican Mestizo population. METHODS: Analysis included 282 unrelated Mexican patients with advanced AMD, 205 healthy controls, and 280 population controls. Stereoscopic fundus images were graded on the Clinical Age-Related Maculopathy System (CARMS). We designed a resequencing strategy using primers with M13 adaptor for the 23 exons of the CFH gene in a subgroup of 96 individuals clinically evaluated: 48 AMD cases and 48 age- and sex-matched healthy controls. Single nucleotide polymorphisms (SNPs) in C3 (Arg80Gly and Pro292Leu), C2 (rs547154), CFB (Leu9His), and ARMS2 (Ala69Ser) were genotyped in all patients, healthy and population controls using TaqMan assay. RESULTS: All evaluated individuals were Mexican Mestizos, and their genetic ancestry was validated using 224 ancestry informative markers and calculating F(st) values. The CFH resequencing revealed 19 SNPs and a common variant in the intron 2 splice acceptor site; three CFH haplotypes inferred from individual genotypes, showed significant differences between cases and controls. The risk alleles in C3 (rs1047286, odds ratio [OR]=2.48, 95% confidence interval [CI]=1.64-3.75, p=1.59E-05; rs2230199, OR=2.15, 95% CI=1.48-3.13, p=6.28E-05) and in ARMS2 (rs10490924, OR=3.09, 95% CI=2.48-3.86, p=5.42E-23) were strongly associated with risk of AMD. The protective effect of alleles in C2 (rs547154) and CFB (rs4151667) showed a trend but was not significantly associated after correction for multiple testing. CONCLUSIONS: Our results show that ARMS2 and C3 are major contributors to advanced AMD in Mexican patients, while the contributions of CFH, C2, and CFB are minor to those of other populations, reveling significant ethnic differences in minor allele frequencies. We provide evidence that two specific common haplotypes in the CFH gene predispose individuals to AMD, while another may confer reduced risk of disease in this admixed population.

PPAR-α as a key nutritional and environmental sensor for metabolic adaptation.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the superfamily of nuclear hormone receptors and regulate the expression of several genes involved in metabolic processes that are potentially linked to the development of some diseases such as hyperlipidemia, diabetes, and obesity. One type of PPAR, PPAR-α, is a transcription factor that regulates the metabolism of lipids, carbohydrates, and amino acids and is activated by ligands such as polyunsaturated fatty acids and drugs used to treat dyslipidemias. There is evidence that genetic variants within the PPARα gene have been associated with a risk of the development of dyslipidemia and cardiovascular disease by influencing fasting and postprandial lipid concentrations; the gene variants have also been associated with an acceleration of the progression of type 2 diabetes. The interactions between genetic PPARα variants and the response to dietary factors will help to identify individuals or populations who can benefit from specific dietary recommendations. Interestingly, certain nutritional conditions, such as the prolonged consumption of a protein-restricted diet, can produce long-lasting effects on PPARα gene expression through modifications in the methylation of a specific locus surrounding the PPARα gene. Thus, this review underlines our current knowledge about the important role of PPAR-α as a mediator of the metabolic response to nutritional and environmental factors.

Hepatic amino acid-degrading enzyme expression is downregulated by natural and synthetic ligands of PPARα in rats.

Body nitrogen retention is dependent on the amount of dietary protein consumed, as well as the fat and carbohydrate content in the diet, due to the modulation of amino acid oxidation. PPARα is a transcription factor involved in the upregulation of the expression of enzymes of fatty acid oxidation. However, the role of putative PPARα response elements (PPREs) in the promoter of several amino acid-degrading enzymes (AADEs) is not known. The aim of this work was to study the effect of the synthetic ligand Wy 14643 and the natural ligands palmitate, oleate, and linoleate in rats fed graded concentrations of dietary protein (6, 20, or 50 g/100 g of total diet) on the expression of the AADEs histidase, serine dehydratase, and tyrosine aminotransferase. Thus, we fed male Wistar rats diets containing 6, 20, or 50% casein for 10 d. The results showed that addition of Wy 14643 to the diet significantly reduced the expression of the AADEs. Furthermore, the incubation of hepatocytes with natural ligands of PPARα or feeding rats with diets containing soybean oil, safflower oil, lard, or coconut oil as sources of dietary fat significantly repressed the expression of the AADEs. Gene reporter assays and mobility shift assays demonstrated that the PPRE located at -482 bp of the histidase gene actively bound PPARα in rat hepatocytes. These data indicate that PPARα ligands may reduce amino acid catabolism in rats.

Reconstructing Native American population history.

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.

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

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.

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

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.