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1.
Am J Hum Genet ; 101(2): 218-226, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28757202

RESUMO

An essential component of precision medicine is the ability to predict an individual's risk of disease based on genetic and non-genetic factors. For complex traits and diseases, assessing the risk due to genetic factors is challenging because it requires knowledge of both the identity of variants that influence the trait and their corresponding allelic effects. Although the set of risk variants and their allelic effects may vary between populations, a large proportion of these variants were identified based on studies in populations of European descent. Heterogeneity in genetic architecture underlying complex traits and diseases, while broadly acknowledged, remains poorly characterized. Ignoring such heterogeneity likely reduces predictive accuracy for minority individuals. In this study, we propose an approach, called XP-BLUP, which ameliorates this ethnic disparity by combining trans-ethnic and ethnic-specific information. We build a polygenic model for complex traits that distinguishes candidate trait-relevant variants from the rest of the genome. The set of candidate variants are selected based on studies in any human population, yet the allelic effects are evaluated in a population-specific fashion. Simulation studies and real data analyses demonstrate that XP-BLUP adaptively utilizes trans-ethnic information and can substantially improve predictive accuracy in minority populations. At the same time, our study highlights the importance of the continued expansion of minority cohorts.


Assuntos
Negro ou Afro-Americano/genética , Biologia Computacional/métodos , Etnicidade/genética , Predisposição Genética para Doença/genética , Herança Multifatorial/genética , Medicina de Precisão/métodos , Idoso , Simulação por Computador , Feminino , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas , Medição de Risco , População Branca/genética
2.
Am J Hum Genet ; 96(5): 740-52, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25892113

RESUMO

Elucidating the genetic basis of complex traits and diseases in non-European populations is particularly challenging because US minority populations have been under-represented in genetic association studies. We developed an empirical Bayes approach named XPEB (cross-population empirical Bayes), designed to improve the power for mapping complex-trait-associated loci in a minority population by exploiting information from genome-wide association studies (GWASs) from another ethnic population. Taking as input summary statistics from two GWASs-a target GWAS from an ethnic minority population of primary interest and an auxiliary base GWAS (such as a larger GWAS in Europeans)-our XPEB approach reprioritizes SNPs in the target population to compute local false-discovery rates. We demonstrated, through simulations, that whenever the base GWAS harbors relevant information, XPEB gains efficiency. Moreover, XPEB has the ability to discard irrelevant auxiliary information, providing a safeguard against inflated false-discovery rates due to genetic heterogeneity between populations. Applied to a blood-lipids study in African Americans, XPEB more than quadrupled the discoveries from the conventional approach, which used a target GWAS alone, bringing the number of significant loci from 14 to 65. Thus, XPEB offers a flexible framework for mapping complex traits in minority populations.


Assuntos
Teorema de Bayes , Estudo de Associação Genômica Ampla/métodos , Grupos Minoritários , Polimorfismo de Nucleotídeo Único/genética , Negro ou Afro-Americano , Etnicidade , Humanos , Lipídeos/genética , Fenótipo , População Branca
3.
Am J Hum Genet ; 92(6): 904-16, 2013 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-23726366

RESUMO

Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Women's Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.


Assuntos
Lipídeos/sangue , Negro ou Afro-Americano/genética , Idoso , Cromossomos Humanos , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Humanos , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
4.
PLoS Genet ; 9(3): e1003372, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23555287

RESUMO

Variation in human skin and eye color is substantial and especially apparent in admixed populations, yet the underlying genetic architecture is poorly understood because most genome-wide studies are based on individuals of European ancestry. We study pigmentary variation in 699 individuals from Cape Verde, where extensive West African/European admixture has given rise to a broad range in trait values and genomic ancestry proportions. We develop and apply a new approach for measuring eye color, and identify two major loci (HERC2[OCA2] P = 2.3 × 10(-62), SLC24A5 P = 9.6 × 10(-9)) that account for both blue versus brown eye color and varying intensities of brown eye color. We identify four major loci (SLC24A5 P = 5.4 × 10(-27), TYR P = 1.1 × 10(-9), APBA2[OCA2] P = 1.5 × 10(-8), SLC45A2 P = 6 × 10(-9)) for skin color that together account for 35% of the total variance, but the genetic component with the largest effect (~44%) is average genomic ancestry. Our results suggest that adjacent cis-acting regulatory loci for OCA2 explain the relationship between skin and eye color, and point to an underlying genetic architecture in which several genes of moderate effect act together with many genes of small effect to explain ~70% of the estimated heritability.


Assuntos
Albinismo Oculocutâneo/genética , População Negra/genética , Cor de Olho/genética , Pigmentação da Pele/genética , População Branca/genética , Cabo Verde , Genótipo , Cor de Cabelo/genética , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único
6.
Breast Cancer Res ; 16(2): R36, 2014 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-24708766

RESUMO

INTRODUCTION: Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies. Phosphatidylinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are frequently activated in TNBC patient tumors at the genome, gene expression and protein levels, and mTOR inhibitors have been shown to inhibit growth in TNBC cell lines. We describe a panel of patient-derived xenografts representing multiple TNBC subtypes and use them to test preclinical drug efficacy of two mTOR inhibitors, sirolimus (rapamycin) and temsirolimus (CCI-779). METHODS: We generated a panel of seven patient-derived orthotopic xenografts from six primary TNBC tumors and one metastasis. Patient tumors and corresponding xenografts were compared by histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) sequencing; TNBC subtypes were determined. Using a previously published logistic regression approach, we generated a rapamycin response signature from Connectivity Map gene expression data and used it to predict rapamycin sensitivity in 1,401 human breast cancers of different intrinsic subtypes, prompting in vivo testing of mTOR inhibitors and doxorubicin in our TNBC xenografts. RESULTS: Patient-derived xenografts recapitulated histology, biomarker expression and global genomic features of patient tumors. Two primary tumors had PIK3CA coding mutations, and five of six primary tumors showed flanking intron single nucleotide polymorphisms (SNPs) with conservation of sequence variations between primary tumors and xenografts, even on subsequent xenograft passages. Gene expression profiling showed that our models represent at least four of six TNBC subtypes. The rapamycin response signature predicted sensitivity for 94% of basal-like breast cancers in a large dataset. Drug testing of mTOR inhibitors in our xenografts showed 77 to 99% growth inhibition, significantly more than doxorubicin; protein phosphorylation studies indicated constitutive activation of the mTOR pathway that decreased with treatment. However, no tumor was completely eradicated. CONCLUSIONS: A panel of patient-derived xenograft models covering a spectrum of TNBC subtypes was generated that histologically and genomically matched original patient tumors. Consistent with in silico predictions, mTOR inhibitor testing in our TNBC xenografts showed significant tumor growth inhibition in all, suggesting that mTOR inhibitors can be effective in TNBC, but will require use with additional therapies, warranting investigation of optimal drug combinations.


Assuntos
Antineoplásicos/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Western Blotting , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Doxorrubicina/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Células MCF-7 , Camundongos , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Fosfatidilinositol 3-Quinases/genética , Fosforilação/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Transcriptoma/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
7.
PLoS Genet ; 7(12): e1002410, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22194699

RESUMO

For most of the world, human genome structure at a population level is shaped by interplay between ancient geographic isolation and more recent demographic shifts, factors that are captured by the concepts of biogeographic ancestry and admixture, respectively. The ancestry of non-admixed individuals can often be traced to a specific population in a precise region, but current approaches for studying admixed individuals generally yield coarse information in which genome ancestry proportions are identified according to continent of origin. Here we introduce a new analytic strategy for this problem that allows fine-grained characterization of admixed individuals with respect to both geographic and genomic coordinates. Ancestry segments from different continents, identified with a probabilistic model, are used to construct and study "virtual genomes" of admixed individuals. We apply this approach to a cohort of 492 parent-offspring trios from Mexico City. The relative contributions from the three continental-level ancestral populations-Africa, Europe, and America-vary substantially between individuals, and the distribution of haplotype block length suggests an admixing time of 10-15 generations. The European and Indigenous American virtual genomes of each Mexican individual can be traced to precise regions within each continent, and they reveal a gradient of Amerindian ancestry between indigenous people of southwestern Mexico and Mayans of the Yucatan Peninsula. This contrasts sharply with the African roots of African Americans, which have been characterized by a uniform mixing of multiple West African populations. We also use the virtual European and Indigenous American genomes to search for the signatures of selection in the ancestral populations, and we identify previously known targets of selection in other populations, as well as new candidate loci. The ability to infer precise ancestral components of admixed genomes will facilitate studies of disease-related phenotypes and will allow new insight into the adaptive and demographic history of indigenous people.


Assuntos
Indígena Americano ou Nativo do Alasca/genética , População Negra/genética , Genoma Humano , Haplótipos/genética , População/genética , População Branca/genética , Negro ou Afro-Americano/genética , Estudos de Coortes , Demografia , Etnicidade/genética , Evolução Molecular , Hispânico ou Latino/genética , Humanos , México , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Seleção Genética
8.
J Urol ; 188(6): 2158-64, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23088973

RESUMO

PURPOSE: AR-V7, a ligand independent splice variant of androgen receptor, may support the growth of castration resistant prostate cancer and have prognostic value. Another variant, AR-V1, interferes with AR-V7 activity. We investigated whether AR-V7 or V1 expression would predict biochemical recurrence in men at indeterminate (about 50%) risk for progression following radical prostatectomy. MATERIALS AND METHODS: AR-V7 and V1 transcripts in a mixed grade cohort of 53 men in whom cancer contained 30% to 70% Gleason grade 4/5 and in a grade 3 only cohort of 52 were measured using a branched chain DNA assay. Spearman rank correlations of the transcripts, and histomorphological and clinical variables were determined. AR-V7 and V1 levels were assessed as determinants of recurrence in the mixed grade cohort by logistic regression and survival analysis. The impact of TMPRSS2-ERG gene fusion on prognosis was also evaluated. RESULTS: Neither AR-V7 nor V1 levels in grade 3 or 4/5 cancer in the mixed grade cohort were associated with recurrence or time to recurrence. However, AR-V7 and V1 inversely correlated with serum prostate specific antigen and positively correlated with age. The AR-V1 level in grade 3 cancer in the grade 3 only cohort was higher than in grade 3 or grade 4/5 components of mixed grade cancer. TMPRSS2-ERG fusion was not associated with AR-V7, AR-V1 or recurrence but it was associated with the percent of grade 4/5 cancer. CONCLUSIONS: The AR-V1 or V7 transcript level does not predict recurrence in patients with high grade prostate cancer at indeterminate risk for progression. Grade 3 cancer in mixed grade tumors may differ from 100% grade 3 cancer, at least in AR-V1 expression.


Assuntos
Biomarcadores Tumorais/metabolismo , Antígeno Prostático Específico/sangue , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Idoso , Progressão da Doença , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Próstata/patologia , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/cirurgia , Recidiva , Risco
9.
ACS Infect Dis ; 8(1): 66-77, 2022 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-34937332

RESUMO

Combination therapies are common in many therapeutic contexts, including infectious diseases and cancer. A common approach for evaluating combinations in vitro is to assess effects on cell growth as synergistic, antagonistic, or neutral using "checkerboard" experiments to systematically sample combinations of agents in multiple doses. To further understand the effects of antibiotic combinations, we employed high-content imaging to study the morphological changes caused by combination treatments in checkerboard experiments. Using an automated, unsupervised image analysis approach to group morphologies, and an "expert-in-the-loop" to annotate them, we attributed the heterogeneous morphological changes ofEscherichia coli cells to varying doses of both single-agent and combination treatments. We identified patterns of morphological change, including morphological potentiation, competition, and the emergence of unexpected morphologies. We found these frequently did not correlate with synergistic or antagonistic effects on viability, suggesting morphological approaches may provide a distinctive signature of the biological interaction between compounds over a range of conditions. Among the unexpected morphologies we observed, there were transitional changes associated with intermediate doses of compounds and uncharacterized phenotypes associated with well-studied antibiotics. Our approach exemplifies how unsupervised image analysis and expert knowledge can be combined to reckon with complex phenotypic changes arising from combination screening, dose titrations, or polypharmacology. In this way, quantification of morphological diversity across treatment conditions could aid in analysis and prioritization of complementary pairings of antibiotic agents by more closely capturing the true signature of the integrated cellular response.


Assuntos
Antibacterianos , Farmacorresistência Bacteriana Múltipla , Antibacterianos/farmacologia , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana
10.
PLoS One ; 7(5): e33788, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22586443

RESUMO

BACKGROUND: To improve cancer therapy, it is critical to target metastasizing cells. Circulating tumor cells (CTCs) are rare cells found in the blood of patients with solid tumors and may play a key role in cancer dissemination. Uncovering CTC phenotypes offers a potential avenue to inform treatment. However, CTC transcriptional profiling is limited by leukocyte contamination; an approach to surmount this problem is single cell analysis. Here we demonstrate feasibility of performing high dimensional single CTC profiling, providing early insight into CTC heterogeneity and allowing comparisons to breast cancer cell lines widely used for drug discovery. METHODOLOGY/PRINCIPAL FINDINGS: We purified CTCs using the MagSweeper, an immunomagnetic enrichment device that isolates live tumor cells from unfractionated blood. CTCs that met stringent criteria for further analysis were obtained from 70% (14/20) of primary and 70% (21/30) of metastatic breast cancer patients; none were captured from patients with non-epithelial cancer (n = 20) or healthy subjects (n = 25). Microfluidic-based single cell transcriptional profiling of 87 cancer-associated and reference genes showed heterogeneity among individual CTCs, separating them into two major subgroups, based on 31 highly expressed genes. In contrast, single cells from seven breast cancer cell lines were tightly clustered together by sample ID and ER status. CTC profiles were distinct from those of cancer cell lines, questioning the suitability of such lines for drug discovery efforts for late stage cancer therapy. CONCLUSIONS/SIGNIFICANCE: For the first time, we directly measured high dimensional gene expression in individual CTCs without the common practice of pooling such cells. Elevated transcript levels of genes associated with metastasis NPTN, S100A4, S100A9, and with epithelial mesenchymal transition: VIM, TGFß1, ZEB2, FOXC1, CXCR4, were striking compared to cell lines. Our findings demonstrate that profiling CTCs on a cell-by-cell basis is possible and may facilitate the application of 'liquid biopsies' to better model drug discovery.


Assuntos
Neoplasias da Mama , Regulação Neoplásica da Expressão Gênica , Células Neoplásicas Circulantes , Análise de Célula Única/instrumentação , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Linfoma/sangue , Análise em Microsséries/métodos , Técnicas Analíticas Microfluídicas , Metástase Neoplásica , Células Neoplásicas Circulantes/metabolismo , Análise de Célula Única/métodos
11.
PLoS One ; 6(9): e24920, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21935487

RESUMO

Author-supplied citations are a fraction of the related literature for a paper. The "related citations" on PubMed is typically dozens or hundreds of results long, and does not offer hints why these results are related. Using noun phrases derived from the sentences of the paper, we show it is possible to more transparently navigate to PubMed updates through search terms that can associate a paper with its citations. The algorithm to generate these search terms involved automatically extracting noun phrases from the paper using natural language processing tools, and ranking them by the number of occurrences in the paper compared to the number of occurrences on the web. We define search queries having at least one instance of overlap between the author-supplied citations of the paper and the top 20 search results as citation validated (CV). When the overlapping citations were written by same authors as the paper itself, we define it as CV-S and different authors is defined as CV-D. For a systematic sample of 883 papers on PubMed Central, at least one of the search terms for 86% of the papers is CV-D versus 65% for the top 20 PubMed "related citations." We hypothesize these quantities computed for the 20 million papers on PubMed to differ within 5% of these percentages. Averaged across all 883 papers, 5 search terms are CV-D, and 10 search terms are CV-S, and 6 unique citations validate these searches. Potentially related literature uncovered by citation-validated searches (either CV-S or CV-D) are on the order of ten per paper--many more if the remaining searches that are not citation-validated are taken into account. The significance and relationship of each search result to the paper can only be vetted and explained by a researcher with knowledge of or interest in that paper.


Assuntos
Armazenamento e Recuperação da Informação/métodos , PubMed , Indexação e Redação de Resumos , Medical Subject Headings , Processamento de Linguagem Natural , Descritores
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