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2.
J Immunol ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492741

RESUMO

Comparative analyses suggest that the MHC was derived from a prevertebrate "primordial immune complex" (PIC). PIC duplicated twice in the well-studied two rounds of genome-wide duplications (2R) early in vertebrate evolution, generating four MHC paralogous regions (predominantly on human chromosomes [chr] 1, 6, 9, 19). Examining chiefly the amphibian Xenopus laevis, but also other vertebrates, we identified their MHC paralogues and mapped MHC class I, AgR, and "framework" genes. Most class I genes mapped to MHC paralogues, but a cluster of Xenopus MHC class Ib genes (xnc), which previously was mapped outside of the MHC paralogues, was surrounded by genes syntenic to mammalian CD1 genes, a region previously proposed as an MHC paralogue on human chr 1. Thus, this gene block is instead the result of a translocation that we call the translocated part of the MHC paralogous region (MHCtrans) Analyses of Xenopus class I genes, as well as MHCtrans, suggest that class I arose at 1R on the chr 6/19 ancestor. Of great interest are nonrearranging AgR-like genes mapping to three MHC paralogues; thus, PIC clearly contained several AgR precursor loci, predating MHC class I/II. However, all rearranging AgR genes were found on paralogues derived from the chr 19 precursor, suggesting that invasion of a variable (V) exon by the RAG transposon occurred after 2R. We propose models for the evolutionary history of MHC/TCR/Ig and speculate on the dichotomy between the jawless (lamprey and hagfish) and jawed vertebrate adaptive immune systems, as we found genes related to variable lymphocyte receptors also map to MHC paralogues.

3.
Nat Commun ; 10(1): 2665, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209259

RESUMO

Estimates of Plasmodium falciparum migration may inform strategies for malaria elimination. Here we elucidate fine-scale parasite population structure and infer recent migration across Southeast Asia using identity-by-descent (IBD) approaches based on genome-wide single nucleotide polymorphisms called in 1722 samples from 54 districts. IBD estimates are consistent with isolation-by-distance. We observe greater sharing of larger IBD segments between artemisinin-resistant parasites versus sensitive parasites, which is consistent with the recent spread of drug resistance. Our IBD analyses reveal actionable patterns, including isolated parasite populations, which may be prioritized for malaria elimination, as well as asymmetrical migration identifying potential sources and sinks of migrating parasites.


Assuntos
Resistência a Medicamentos/genética , Monitoramento Epidemiológico , Genoma de Protozoário/genética , Malária Falciparum/microbiologia , Plasmodium falciparum/genética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Ásia Sudeste , Biodiversidade , Genótipo , Geografia Médica , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/isolamento & purificação , Polimorfismo de Nucleotídeo Único
4.
Genome Biol Evol ; 11(5): 1417-1430, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30942856

RESUMO

The metabolic conversion of dietary omega-3 and omega-6 18 carbon (18C) to long chain (>20 carbon) polyunsaturated fatty acids (LC-PUFAs) is vital for human life. The rate-limiting steps of this process are catalyzed by fatty acid desaturase (FADS) 1 and 2. Therefore, understanding the evolutionary history of the FADS genes is essential to our understanding of hominin evolution. The FADS genes have two haplogroups, ancestral and derived, with the derived haplogroup being associated with more efficient LC-PUFA biosynthesis than the ancestral haplogroup. In addition, there is a complex global distribution of these haplogroups that is suggestive of Neanderthal introgression. We confirm that Native American ancestry is nearly fixed for the ancestral haplogroup, and replicate a positive selection signal in Native Americans. This positive selection potentially continued after the founding of the Americas, although simulations suggest that the timing is dependent on the allele frequency of the ancestral Beringian population. We also find that the Neanderthal FADS haplotype is more closely related to the derived haplogroup and the Denisovan clusters closer to the ancestral haplogroup. Furthermore, the derived haplogroup has a time to the most recent common ancestor of 688,474 years before present. These results support an ancient polymorphism, as opposed to Neanderthal introgression, forming in the FADS region during the Pleistocene with possibly differential selection pressures on both haplogroups. The near fixation of the ancestral haplogroup in Native American ancestry calls for future studies to explore the potential health risk of associated low LC-PUFA levels in these populations.


Assuntos
Evolução Molecular , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Insaturados/metabolismo , Hominidae/genética , Animais , Ácidos Graxos Dessaturases/metabolismo , Hominidae/metabolismo , Humanos , Índios Norte-Americanos/genética , Seleção Genética , Sibéria
5.
Cancer ; 125(12): 2076-2088, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30865299

RESUMO

BACKGROUND: Although cell lines are an essential resource for studying cancer biology, many are of unknown ancestral origin, and their use may not be optimal for evaluating the biology of all patient populations. METHODS: An admixture analysis was performed using genome-wide chip data from the Catalogue of Somatic Mutations in Cancer (COSMIC) Cell Lines Project to calculate genetic ancestry estimates for 1018 cancer cell lines. After stratifying the analyses by tissue and histology types, linear models were used to evaluate the influence of ancestry on gene expression and somatic mutation frequency. RESULTS: For the 701 cell lines with unreported ancestry, 215 were of East Asian origin, 30 were of African or African American origin, and 453 were of European origin. Notable imbalances were observed in ancestral representation across tissue type, with the majority of analyzed tissue types having few cell lines of African American ancestral origin, and with Hispanic and South Asian ancestry being almost entirely absent across all cell lines. In evaluating gene expression across these cell lines, expression levels of the genes neurobeachin line 1 (NBEAL1), solute carrier family 6 member 19 (SLC6A19), HEAT repeat containing 6 (HEATR6), and epithelial cell transforming 2 like (ECT2L) were associated with ancestry. Significant differences were also observed in the proportions of somatic mutation types across cell lines with varying ancestral proportions. CONCLUSIONS: By estimating genetic ancestry for 1018 cancer cell lines, the authors have produced a resource that cancer researchers can use to ensure that their cell lines are ancestrally representative of the populations they intend to affect. Furthermore, the novel ancestry-specific signal identified underscores the importance of ancestral awareness when studying cancer.

6.
Nat Commun ; 10(1): 880, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787307

RESUMO

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.


Assuntos
Afro-Americanos/genética , Asma/genética , Predisposição Genética para Doença/genética , Asma/epidemiologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
7.
Cell ; 176(1-2): 405-406, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30633908
8.
Cell ; 175(5): 1173-1174, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445034

RESUMO

Ancient DNA is a powerful tool to understand the evolutionary dynamics of both current and ancestral populations. Posth et al. use ancient DNA to elucidate important questions surrounding the peopling of Central and South America, giving us greater insights into the ancestry of genetically understudied populations.

9.
Trends Cancer ; 4(9): 643-654, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30149882

RESUMO

Liquid biopsy, or the capacity to noninvasively isolate and analyze plasma tumor DNA (ptDNA) using blood samples, represents an important tool for modern oncology that enables increasingly safe, personalized, and robust cancer diagnosis and treatment. Here, we review advances in the development and implementation of liquid biopsy approaches, and we focus on the capacity of liquid biopsy to noninvasively detect oncological disease and enhance early detection strategies. In addition to noting the distinctions between mutation-targeted and mutation-agnostic approaches, we discuss the potential for genomic analysis and longitudinal testing to identify somatic lesions early and to guide intervention at more manageable disease stages.

10.
Proc Natl Acad Sci U S A ; 115(28): E6526-E6535, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29946025

RESUMO

Native Americans from the Amazon, Andes, and coastal geographic regions of South America have a rich cultural heritage but are genetically understudied, therefore leading to gaps in our knowledge of their genomic architecture and demographic history. In this study, we sequence 150 genomes to high coverage combined with an additional 130 genotype array samples from Native American and mestizo populations in Peru. The majority of our samples possess greater than 90% Native American ancestry, which makes this the most extensive Native American sequencing project to date. Demographic modeling reveals that the peopling of Peru began ∼12,000 y ago, consistent with the hypothesis of the rapid peopling of the Americas and Peruvian archeological data. We find that the Native American populations possess distinct ancestral divisions, whereas the mestizo groups were admixtures of multiple Native American communities that occurred before and during the Inca Empire and Spanish rule. In addition, the mestizo communities also show Spanish introgression largely following Peruvian Independence, nearly 300 y after Spain conquered Peru. Further, we estimate migration events between Peruvian populations from all three geographic regions with the majority of between-region migration moving from the high Andes to the low-altitude Amazon and coast. As such, we present a detailed model of the evolutionary dynamics which impacted the genomes of modern-day Peruvians and a Native American ancestry dataset that will serve as a beneficial resource to addressing the underrepresentation of Native American ancestry in sequencing studies.


Assuntos
Índios Sul-Americanos/genética , Modelos Genéticos , Dinâmica Populacional , História Antiga , Humanos , Índios Sul-Americanos/história , Peru
11.
Sci Rep ; 7: 46398, 2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28429804

RESUMO

A primary goal of The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to develop an 'African Diaspora Power Chip' (ADPC), a genotyping array consisting of tagging SNPs, useful in comprehensively identifying African specific genetic variation. This array is designed based on the novel variation identified in 642 CAAPA samples of African ancestry with high coverage whole genome sequence data (~30× depth). This novel variation extends the pattern of variation catalogued in the 1000 Genomes and Exome Sequencing Projects to a spectrum of populations representing the wide range of West African genomic diversity. These individuals from CAAPA also comprise a large swath of the African Diaspora population and incorporate historical genetic diversity covering nearly the entire Atlantic coast of the Americas. Here we show the results of designing and producing such a microchip array. This novel array covers African specific variation far better than other commercially available arrays, and will enable better GWAS analyses for researchers with individuals of African descent in their study populations. A recent study cataloging variation in continental African populations suggests this type of African-specific genotyping array is both necessary and valuable for facilitating large-scale GWAS in populations of African ancestry.

12.
Genome Biol ; 18(1): 42, 2017 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-28241850

RESUMO

In a recent study, Petrovski and Goldstein reported that (non-Finnish) Europeans have significantly fewer nonsynonymous singletons in Online Mendelian Inheritance in Man (OMIM) disease genes compared with Africans, Latinos, South Asians, East Asians, and other unassigned non-Europeans. We use simulations of Exome Aggregation Consortium (ExAC) data to show that sample size and ratio interact to influence the number of these singletons identified in a cohort. These interactions are different across ancestries and can lead to the same number of identified singletons in both Europeans and non-Europeans without an equal number of samples. We conclude that there is a need to account for the ancestry-specific influence of demography on genomic architecture and rare variant analysis in order to address inequalities in medical genomic analysis.The authors of the original article were invited to submit a response, but declined to do so. Please see related Open Letter: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1016-y.


Assuntos
Demografia , Genômica/métodos , Genômica/normas , Tamanho da Amostra , Grupos Étnicos , Humanos , Reprodutibilidade dos Testes
13.
Bioinformatics ; 33(8): 1147-1153, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28035032

RESUMO

Motivation: Variant calling from next-generation sequencing (NGS) data is susceptible to false positive calls due to sequencing, mapping and other errors. To better distinguish true from false positive calls, we present a method that uses genotype array data from the sequenced samples, rather than public data such as HapMap or dbSNP, to train an accurate classifier using Random Forests. We demonstrate our method on a set of variant calls obtained from 642 African-ancestry genomes from the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA), sequenced to high depth (30X). Results: We have applied our classifier to compare call sets generated with different calling methods, including both single-sample and multi-sample callers. At a False Positive Rate of 5%, our method determines true positive rates of 97.5%, 95% and 99% on variant calls obtained using Illuminas single-sample caller CASAVA, Real Time Genomics multisample variant caller, and the GATK UnifiedGenotyper, respectively. Since NGS sequencing data may be accompanied by genotype data for the same samples, either collected concurrent to sequencing or from a previous study, our method can be trained on each dataset to provide a more accurate computational validation of site calls compared to generic methods. Moreover, our method allows for adjustment based on allele frequency (e.g. a different set of criteria to determine quality for rare versus common variants) and thereby provides insight into sequencing characteristics that indicate call quality for variants of different frequencies. Availability and Implementation: Code is available on Github at: https://github.com/suyashss/variant_validation. Contacts: suyashs@stanford.edu or mtaub@jhsph.edu. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma/métodos , Confiabilidade dos Dados , Genoma Humano , Genômica/métodos , Genômica/normas , Genótipo , Técnicas de Genotipagem/métodos , Técnicas de Genotipagem/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Sequenciamento Completo do Genoma/normas
14.
Nat Commun ; 7: 12521, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27725664

RESUMO

To characterize the extent and impact of ancestry-related biases in precision genomic medicine, we use 642 whole-genome sequences from the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) project to evaluate typical filters and databases. We find significant correlations between estimated African ancestry proportions and the number of variants per individual in all variant classification sets but one. The source of these correlations is highlighted in more detail by looking at the interaction between filtering criteria and the ClinVar and Human Gene Mutation databases. ClinVar's correlation, representing African ancestry-related bias, has changed over time amidst monthly updates, with the most extreme switch happening between March and April of 2014 (r=0.733 to r=-0.683). We identify 68 SNPs as the major drivers of this change in correlation. As long as ancestry-related bias when using these clinical databases is minimally recognized, the genetics community will face challenges with implementation, interpretation and cost-effectiveness when treating minority populations.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Genômica , Disparidades em Assistência à Saúde , Medicina de Precisão , Viés , Variação Genética , Humanos , Anotação de Sequência Molecular , Fatores de Tempo
15.
Nat Commun ; 7: 12522, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27725671

RESUMO

The African Diaspora in the Western Hemisphere represents one of the largest forced migrations in history and had a profound impact on genetic diversity in modern populations. To date, the fine-scale population structure of descendants of the African Diaspora remains largely uncharacterized. Here we present genetic variation from deeply sequenced genomes of 642 individuals from North and South American, Caribbean and West African populations, substantially increasing the lexicon of human genomic variation and suggesting much variation remains to be discovered in African-admixed populations in the Americas. We summarize genetic variation in these populations, quantifying the postcolonial sex-biased European gene flow across multiple regions. Moreover, we refine estimates on the burden of deleterious variants carried across populations and how this varies with African ancestry. Our data are an important resource for empowering disease mapping studies in African-admixed individuals and will facilitate gene discovery for diseases disproportionately affecting individuals of African ancestry.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Fluxo Gênico , Genoma Humano , Migração Humana , Sequência de Bases , DNA Intergênico/genética , Feminino , Heterogeneidade Genética , Geografia , Humanos , Masculino , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Sexismo
16.
Nat Commun ; 7: 12218, 2016 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-27447865

RESUMO

Mucormycosis is a life-threatening infection caused by Mucorales fungi. Here we sequence 30 fungal genomes, and perform transcriptomics with three representative Rhizopus and Mucor strains and with human airway epithelial cells during fungal invasion, to reveal key host and fungal determinants contributing to pathogenesis. Analysis of the host transcriptional response to Mucorales reveals platelet-derived growth factor receptor B (PDGFRB) signaling as part of a core response to divergent pathogenic fungi; inhibition of PDGFRB reduces Mucorales-induced damage to host cells. The unique presence of CotH invasins in all invasive Mucorales, and the correlation between CotH gene copy number and clinical prevalence, are consistent with an important role for these proteins in mucormycosis pathogenesis. Our work provides insight into the evolution of this medically and economically important group of fungi, and identifies several molecular pathways that might be exploited as potential therapeutic targets.


Assuntos
Genoma Fúngico , Mucorales/genética , Mucormicose/microbiologia , Transcriptoma/genética , Células A549 , Amidoidrolases/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas Fúngicas/química , Genes Fúngicos , Humanos , Masculino , Camundongos Endogâmicos ICR , Anotação de Sequência Molecular , Mucorales/enzimologia , Mucorales/isolamento & purificação , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Rhizopus/genética , Análise de Sequência de RNA , Especificidade da Espécie
17.
Source Code Biol Med ; 10(1): 2, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25678934

RESUMO

MOTIVATION: Correctly modeling population structure is important for understanding recent evolution and for association studies in humans. While pre-existing knowledge of population history can be used to specify expected levels of subdivision, objective metrics to detect population structure are important and may even be preferable for identifying groups in some situations. One such metric for genomic scale data is implemented in the cross-validation procedure of the program ADMIXTURE, but it has not been evaluated on recently diverged and potentially cryptic levels of population structure. Here, I develop a new method, AdmixKJump, and test both metrics under this scenario. FINDINGS: I show that AdmixKJump is more sensitive to recent population divisions compared to the cross-validation metric using both realistic simulations, as well as 1000 Genomes Project European genomic data. With two populations of 50 individuals each, AdmixKJump is able to detect two populations with 100% accuracy that split at least 10KYA, whereas cross-validation obtains this 100% level at 14KYA. I also show that AdmixKJump is more accurate with fewer samples per population. Furthermore, in contrast to the cross-validation approach, AdmixKJump is able to detect the population split between the Finnish and Tuscan populations of the 1000 Genomes Project. CONCLUSION: AdmixKJump has more power to detect the number of populations in a cohort of samples with smaller sample sizes and shorter divergence times. AVAILABILITY: A java implementation can be found at https://sites.google.com/site/igsevolgenomicslab/home/downloads.

18.
Mol Biol Evol ; 32(3): 653-60, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25415970

RESUMO

Understanding the genetic structure of human populations has important implications for the design and interpretation of disease mapping studies and reconstructing human evolutionary history. To date, inferences of human population structure have primarily been made with common variants. However, recent large-scale resequencing studies have shown an abundance of rare variation in humans, which may be particularly useful for making inferences of fine-scale population structure. To this end, we used an information theory framework and extensive coalescent simulations to rigorously quantify the informativeness of rare and common variation to detect signatures of fine-scale population structure. We show that rare variation affords unique insights into patterns of recent population structure. Furthermore, to empirically assess our theoretical findings, we analyzed high-coverage exome sequences in 6,515 European and African American individuals. As predicted, rare variants are more informative than common polymorphisms in revealing a distinct cluster of European-American individuals, and subsequent analyses demonstrate that these individuals are likely of Ashkenazi Jewish ancestry. Our results provide new insights into the population structure using rare variation, which will be an important factor to account for in rare variant association studies.


Assuntos
Exoma/genética , Genética Populacional/métodos , Grupos Étnicos/genética , Humanos , Teoria da Informação , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal
19.
Curr Opin Genet Dev ; 23(6): 678-83, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24287334

RESUMO

More than 150 years after Mendel discovered the laws of heredity, the genetic architecture of phenotypic variation remains elusive. Here, we discuss recent progress in deciphering how genotypes map onto phenotypes, sources of genetic complexity, and how model organisms are illuminating general principles about the relationship between genetic and phenotypic variation. Moreover, we highlight insights gleaned from large-scale sequencing studies in humans, and how this knowledge informs outstanding questions about the genetic architecture of quantitative traits and complex diseases. Finally, we articulate how the confluence of technologies enabling whole-genome sequencing, comprehensive phenotyping, and high-throughput functional assays of polymorphisms will facilitate a more principled and mechanistic understanding of the genetic architecture of phenotypic variation.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Locos de Características Quantitativas/genética , Interação Gene-Ambiente , Genótipo , Humanos , Modelos Genéticos , Fenótipo
20.
Evol Bioinform Online ; 9: 301-16, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23926418

RESUMO

Variation in substitution rates across a phylogeny can be indicative of shifts in the evolutionary dynamics of a protein or non-protein coding regions. One way to understand these signals is to seek the phenotypic correlates of rate variation. Here, we extended a previously published likelihood method designed to detect evolutionary associations between genotypic evolutionary rate and phenotype over a phylogeny. In simulation with two discrete categories of phenotype, the method has a low false-positive rate and detects greater than 80% of true-positives with a tree length of three or greater and a three-fold or greater change in substitution rate given the phenotype. In addition, we successfully extend the test from two to four phenotype categories and evaluated its performance. We then applied the method to two major hypotheses for rate variation in the mitochondrial genome of primates-longevity and generation time as well as body mass which is correlated with many aspects of life history-using three categories of phenotype through discretization of continuous values. Similar to previous results for mammals, we find that the majority of mitochondrial protein-coding genes show associations consistent with the longevity and body mass predictions and that the predominant signal of association comes from the third codon position. We also found a significant association between maximum lifespan and the evolutionary rate of the control region of the mtDNA. In contrast, 24 protein-coding genes from the nuclear genome do not show a consistent pattern of association, which is inconsistent with the generation time hypothesis. These results show the extended method can robustly identify genotype-phenotype associations up to at least four phenotypic categories, and demonstrate the successful application of the method to study factors affecting neutral evolutionary rate in protein-coding and non-coding loci.

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