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1.
Sci Adv ; 6(7): eaax5097, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32095519

RESUMO

While introgression from Neanderthals and Denisovans has been documented in modern humans outside Africa, the contribution of archaic hominins to the genetic variation of present-day Africans remains poorly understood. We provide complementary lines of evidence for archaic introgression into four West African populations. Our analyses of site frequency spectra indicate that these populations derive 2 to 19% of their genetic ancestry from an archaic population that diverged before the split of Neanderthals and modern humans. Using a method that can identify segments of archaic ancestry without the need for reference archaic genomes, we built genome-wide maps of archaic ancestry in the Yoruba and the Mende populations. Analyses of these maps reveal segments of archaic ancestry at high frequency in these populations that represent potential targets of adaptive introgression. Our results reveal the substantial contribution of archaic ancestry in shaping the gene pool of present-day West African populations.

2.
J Comput Biol ; 27(3): 418-428, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32053016

RESUMO

Methods to impute missing data are routinely used to increase power in genome-wide association studies. There are two broad classes of imputation methods. The first class imputes genotypes at the untyped variants, given those at the typed variants, and then performs a statistical test of association at the imputed variants. The second class, summary statistic imputation (SSI), directly imputes association statistics at the untyped variants, given the association statistics observed at the typed variants. The second class is appealing as it tends to be computationally efficient while only requiring the summary statistics from a study, while the former class requires access to individual-level data that can be difficult to obtain. The statistical properties of these two classes of imputation methods have not been fully understood. In this study, we show that the two classes of imputation methods yield association statistics with similar distributions for sufficiently large sample sizes. Using this relationship, we can understand the effect of the imputation method on power. We show that a commonly used approach to SSI that we term SSI with variance reweighting generally leads to a loss in power. On the contrary, our proposed method for SSI that does not perform variance reweighting fully accounts for imputation uncertainty, while achieving better power.

3.
Br J Anaesth ; 123(6): 877-886, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31627890

RESUMO

BACKGROUND: Rapid, preoperative identification of patients with the highest risk for medical complications is necessary to ensure that limited infrastructure and human resources are directed towards those most likely to benefit. Existing risk scores either lack specificity at the patient level or utilise the American Society of Anesthesiologists (ASA) physical status classification, which requires a clinician to review the chart. METHODS: We report on the use of machine learning algorithms, specifically random forests, to create a fully automated score that predicts postoperative in-hospital mortality based solely on structured data available at the time of surgery. Electronic health record data from 53 097 surgical patients (2.01% mortality rate) who underwent general anaesthesia between April 1, 2013 and December 10, 2018 in a large US academic medical centre were used to extract 58 preoperative features. RESULTS: Using a random forest classifier we found that automatically obtained preoperative features (area under the curve [AUC] of 0.932, 95% confidence interval [CI] 0.910-0.951) outperforms Preoperative Score to Predict Postoperative Mortality (POSPOM) scores (AUC of 0.660, 95% CI 0.598-0.722), Charlson comorbidity scores (AUC of 0.742, 95% CI 0.658-0.812), and ASA physical status (AUC of 0.866, 95% CI 0.829-0.897). Including the ASA physical status with the preoperative features achieves an AUC of 0.936 (95% CI 0.917-0.955). CONCLUSIONS: This automated score outperforms the ASA physical status score, the Charlson comorbidity score, and the POSPOM score for predicting in-hospital mortality. Additionally, we integrate this score with a previously published postoperative score to demonstrate the extent to which patient risk changes during the perioperative period.


Assuntos
Registros Eletrônicos de Saúde/estatística & dados numéricos , Nível de Saúde , Mortalidade Hospitalar , Aprendizado de Máquina , Complicações Pós-Operatórias/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , California , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Medição de Risco , Fatores de Risco , Adulto Jovem
4.
Nat Commun ; 10(1): 3417, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366909

RESUMO

High costs and technical limitations of cell sorting and single-cell techniques currently restrict the collection of large-scale, cell-type-specific DNA methylation data. This, in turn, impedes our ability to tackle key biological questions that pertain to variation within a population, such as identification of disease-associated genes at a cell-type-specific resolution. Here, we show mathematically and empirically that cell-type-specific methylation levels of an individual can be learned from its tissue-level bulk data, conceptually emulating the case where the individual has been profiled with a single-cell resolution and then signals were aggregated in each cell population separately. Provided with this unprecedented way to perform powerful large-scale epigenetic studies with cell-type-specific resolution, we revisit previous studies with tissue-level bulk methylation and reveal novel associations with leukocyte composition in blood and with rheumatoid arthritis. For the latter, we further show consistency with validation data collected from sorted leukocyte sub-types.


Assuntos
Separação Celular/métodos , Biologia Computacional/métodos , Metilação de DNA/genética , Epigênese Genética/genética , Análise de Célula Única/métodos , Artrite Reumatoide/sangue , Ilhas de CpG/genética , Humanos , Contagem de Leucócitos , Leucócitos/classificação , Leucócitos/citologia
5.
Nat Genet ; 51(8): 1244-1251, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31358995

RESUMO

SNP-heritability is a fundamental quantity in the study of complex traits. Recent studies have shown that existing methods to estimate genome-wide SNP-heritability can yield biases when their assumptions are violated. While various approaches have been proposed to account for frequency- and linkage disequilibrium (LD)-dependent genetic architectures, it remains unclear which estimates reported in the literature are reliable. Here we show that genome-wide SNP-heritability can be accurately estimated from biobank-scale data irrespective of genetic architecture, without specifying a heritability model or partitioning SNPs by allele frequency and/or LD. We show analytically and through extensive simulations starting from real genotypes (UK Biobank, N = 337 K) that, unlike existing methods, our closed-form estimator is robust across a wide range of architectures. We provide estimates of SNP-heritability for 22 complex traits in the UK Biobank and show that, consistent with our results in simulations, existing biobank-scale methods yield estimates up to 30% different from our theoretically-justified approach.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Genoma Humano , Desequilíbrio de Ligação , Modelos Teóricos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Estudo de Associação Genômica Ampla , Humanos , Fenótipo
6.
PLoS Genet ; 15(5): e1008175, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31136573

RESUMO

Statistical analyses of genomic data from diverse human populations have demonstrated that archaic hominins, such as Neanderthals and Denisovans, interbred or admixed with the ancestors of present-day humans. Central to these analyses are methods for inferring archaic ancestry along the genomes of present-day individuals (archaic local ancestry). Methods for archaic local ancestry inference rely on the availability of reference genomes from the ancestral archaic populations for accurate inference. However, several instances of archaic admixture lack reference archaic genomes, making it difficult to characterize these events. We present a statistical method that combines diverse population genetic summary statistics to infer archaic local ancestry without access to an archaic reference genome. We validate the accuracy and robustness of our method in simulations. When applied to genomes of European individuals, our method recovers segments that are substantially enriched for Neanderthal ancestry, even though our method did not have access to any Neanderthal reference genomes.


Assuntos
Genética Populacional/métodos , Genômica/métodos , Hominidae/genética , Animais , Genoma Humano/genética , Humanos , Modelos Estatísticos , Homem de Neandertal/genética
7.
Mol Biol Evol ; 35(11): 2736-2750, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30169787

RESUMO

As are most non-European populations, the Han Chinese are relatively understudied in population and medical genetics studies. From low-coverage whole-genome sequencing of 11,670 Han Chinese women we present a catalog of 25,057,223 variants, including 548,401 novel variants that are seen at least 10 times in our data set. Individuals from this data set came from 24 out of 33 administrative divisions across China (including 19 provinces, 4 municipalities, and 1 autonomous region), thus allowing us to study population structure, genetic ancestry, and local adaptation in Han Chinese. We identified previously unrecognized population structure along the East-West axis of China, demonstrated a general pattern of isolation-by-distance among Han Chinese, and reported unique regional signals of admixture, such as European influences among the Northwestern provinces of China. Furthermore, we identified a number of highly differentiated, putatively adaptive, loci (e.g., MTHFR, ADH7, and FADS, among others) that may be driven by immune response, climate, and diet in the Han Chinese. Finally, we have made available allele frequency estimates stratified by administrative divisions across China in the Geography of Genetic Variant browser for the broader community. By leveraging the largest currently available genetic data set for Han Chinese, we have gained insights into the history and population structure of the world's largest ethnic group.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Evolução Biológica , Variação Genética , Adaptação Biológica , Animais , Estudos de Casos e Controles , China , Transtorno Depressivo Maior/genética , Feminino , Frequência do Gene , Humanos , Homem de Neandertal/genética , Filogeografia , Seleção Genética
8.
Bioinformatics ; 34(13): i195-i201, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29949958

RESUMO

Motivation: A large proportion of risk regions identified by genome-wide association studies (GWAS) are shared across multiple diseases and traits. Understanding whether this clustering is due to sharing of causal variants or chance colocalization can provide insights into shared etiology of complex traits and diseases. Results: In this work, we propose a flexible, unifying framework to quantify the overlap between a pair of traits called UNITY (Unifying Non-Infinitesimal Trait analYsis). We formulate a Bayesian generative model that relates the overlap between pairs of traits to GWAS summary statistic data under a non-infinitesimal genetic architecture underlying each trait. We propose a Metropolis-Hastings sampler to compute the posterior density of the genetic overlap parameters in this model. We validate our method through comprehensive simulations and analyze summary statistics from height and body mass index GWAS to show that it produces estimates consistent with the known genetic makeup of both traits. Availability and implementation: The UNITY software is made freely available to the research community at: https://github.com/bogdanlab/UNITY. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Software , Teorema de Bayes , Humanos , Desequilíbrio de Ligação , Modelos Genéticos
9.
Bioinformatics ; 34(13): i187-i194, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29950019

RESUMO

Motivation: Heritability, the proportion of variation in a trait that can be explained by genetic variation, is an important parameter in efforts to understand the genetic architecture of complex phenotypes as well as in the design and interpretation of genome-wide association studies. Attempts to understand the heritability of complex phenotypes attributable to genome-wide single nucleotide polymorphism (SNP) variation data has motivated the analysis of large datasets as well as the development of sophisticated tools to estimate heritability in these datasets. Linear mixed models (LMMs) have emerged as a key tool for heritability estimation where the parameters of the LMMs, i.e. the variance components, are related to the heritability attributable to the SNPs analyzed. Likelihood-based inference in LMMs, however, poses serious computational burdens. Results: We propose a scalable randomized algorithm for estimating variance components in LMMs. Our method is based on a method-of-moment estimator that has a runtime complexity O(NMB) for N individuals and M SNPs (where B is a parameter that controls the number of random matrix-vector multiplications). Further, by leveraging the structure of the genotype matrix, we can reduce the time complexity to O(NMBmax( log⁡3N, log⁡3M)). We demonstrate the scalability and accuracy of our method on simulated as well as on empirical data. On standard hardware, our method computes heritability on a dataset of 500 000 individuals and 100 000 SNPs in 38 min. Availability and implementation: The RHE-reg software is made freely available to the research community at: https://github.com/sriramlab/RHE-reg.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Software , Feminino , Humanos , Funções Verossimilhança , Modelos Lineares , Masculino
10.
Science ; 360(6389): 656-660, 2018 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-29674434

RESUMO

To investigate the consequences of hybridization between species, we studied three replicate hybrid populations that formed naturally between two swordtail fish species, estimating their fine-scale genetic map and inferring ancestry along the genomes of 690 individuals. In all three populations, ancestry from the "minor" parental species is more common in regions of high recombination and where there is linkage to fewer putative targets of selection. The same patterns are apparent in a reanalysis of human and archaic admixture. These results support models in which ancestry from the minor parental species is more likely to persist when rapidly uncoupled from alleles that are deleterious in hybrids. Our analyses further indicate that selection on swordtail hybrids stems predominantly from deleterious combinations of epistatically interacting alleles.


Assuntos
Quimera/genética , Epistasia Genética , Evolução Molecular , Recombinação Genética , Seleção Genética , Alelos , Animais , Peixes , Hibridização Genética
11.
Am J Hum Genet ; 100(5): 789-802, 2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28475861

RESUMO

Recent successes in genome-wide association studies (GWASs) make it possible to address important questions about the genetic architecture of complex traits, such as allele frequency and effect size. One lesser-known aspect of complex traits is the extent of allelic heterogeneity (AH) arising from multiple causal variants at a locus. We developed a computational method to infer the probability of AH and applied it to three GWASs and four expression quantitative trait loci (eQTL) datasets. We identified a total of 4,152 loci with strong evidence of AH. The proportion of all loci with identified AH is 4%-23% in eQTLs, 35% in GWASs of high-density lipoprotein (HDL), and 23% in GWASs of schizophrenia. For eQTLs, we observed a strong correlation between sample size and the proportion of loci with AH (R2 = 0.85, p = 2.2 × 10-16), indicating that statistical power prevents identification of AH in other loci. Understanding the extent of AH may guide the development of new methods for fine mapping and association mapping of complex traits.


Assuntos
Alelos , Frequência do Gene , Locos de Características Quantitativas , Bases de Dados Genéticas , Estudos de Associação Genética , Humanos , Desequilíbrio de Ligação , Modelos Moleculares , Fenótipo
12.
Am J Hum Genet ; 99(6): 1245-1260, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27866706

RESUMO

The vast majority of genome-wide association study (GWAS) risk loci fall in non-coding regions of the genome. One possible hypothesis is that these GWAS risk loci alter the individual's disease risk through their effect on gene expression in different tissues. In order to understand the mechanisms driving a GWAS risk locus, it is helpful to determine which gene is affected in specific tissue types. For example, the relevant gene and tissue could play a role in the disease mechanism if the same variant responsible for a GWAS locus also affects gene expression. Identifying whether or not the same variant is causal in both GWASs and expression quantitative trail locus (eQTL) studies is challenging because of the uncertainty induced by linkage disequilibrium and the fact that some loci harbor multiple causal variants. However, current methods that address this problem assume that each locus contains a single causal variant. In this paper, we present eCAVIAR, a probabilistic method that has several key advantages over existing methods. First, our method can account for more than one causal variant in any given locus. Second, it can leverage summary statistics without accessing the individual genotype data. We use both simulated and real datasets to demonstrate the utility of our method. Using publicly available eQTL data on 45 different tissues, we demonstrate that eCAVIAR can prioritize likely relevant tissues and target genes for a set of glucose- and insulin-related trait loci.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Modelos Estatísticos , Locos de Características Quantitativas/genética , Conjuntos de Dados como Assunto , Regulação da Expressão Gênica/genética , Genótipo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Desequilíbrio de Ligação , Especificidade de Órgãos , Probabilidade , Tamanho da Amostra
13.
Nature ; 538(7624): 201-206, 2016 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-27654912

RESUMO

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.


Assuntos
Grupos de Populações Continentais/genética , Variação Genética/genética , Genoma Humano/genética , Genômica , Taxa de Mutação , Filogenia , Grupo com Ancestrais do Continente Africano/genética , Animais , Austrália , Conjuntos de Dados como Assunto , Genética Populacional , História Antiga , Migração Humana/história , Humanos , Homem de Neandertal/genética , Nova Guiné , Grupo com Ancestrais Oceânicos/genética , Análise de Sequência de DNA , Especificidade da Espécie , Fatores de Tempo
14.
Proc Natl Acad Sci U S A ; 113(20): 5652-7, 2016 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-27140627

RESUMO

The study of human evolution has been revolutionized by inferences from ancient DNA analyses. Key to these studies is the reliable estimation of the age of ancient specimens. High-resolution age estimates can often be obtained using radiocarbon dating, and, while precise and powerful, this method has some biases, making it of interest to directly use genetic data to infer a date for samples that have been sequenced. Here, we report a genetic method that uses the recombination clock. The idea is that an ancient genome has evolved less than the genomes of present-day individuals and thus has experienced fewer recombination events since the common ancestor. To implement this idea, we take advantage of the insight that all non-Africans have a common heritage of Neanderthal gene flow into their ancestors. Thus, we can estimate the date since Neanderthal admixture for present-day and ancient samples simultaneously and use the difference as a direct estimate of the ancient specimen's age. We apply our method to date five Upper Paleolithic Eurasian genomes with radiocarbon dates between 12,000 and 45,000 y ago and show an excellent correlation of the genetic and (14)C dates. By considering the slope of the correlation between the genetic dates, which are in units of generations, and the (14)C dates, which are in units of years, we infer that the mean generation interval in humans over this period has been 26-30 y. Extensions of this methodology that use older shared events may be applicable for dating beyond the radiocarbon frontier.


Assuntos
Evolução Biológica , Técnicas Genéticas , Genoma Humano , Homem de Neandertal/genética , Datação Radiométrica/métodos , Animais , Humanos , Polimorfismo de Nucleotídeo Único
15.
Curr Biol ; 26(9): 1241-7, 2016 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-27032491

RESUMO

Some present-day humans derive up to ∼5% [1] of their ancestry from archaic Denisovans, an even larger proportion than the ∼2% from Neanderthals [2]. We developed methods that can disambiguate the locations of segments of Denisovan and Neanderthal ancestry in present-day humans and applied them to 257 high-coverage genomes from 120 diverse populations, among which were 20 individual Oceanians with high Denisovan ancestry [3]. In Oceanians, the average size of Denisovan fragments is larger than Neanderthal fragments, implying a more recent average date of Denisovan admixture in the history of these populations (p = 0.00004). We document more Denisovan ancestry in South Asia than is expected based on existing models of history, reflecting a previously undocumented mixture related to archaic humans (p = 0.0013). Denisovan ancestry, just like Neanderthal ancestry, has been deleterious on a modern human genetic background, as reflected by its depletion near genes. Finally, the reduction of both archaic ancestries is especially pronounced on chromosome X and near genes more highly expressed in testes than other tissues (p = 1.2 × 10(-7) to 3.2 × 10(-7) for Denisovan and 2.2 × 10(-3) to 2.9 × 10(-3) for Neanderthal ancestry even after controlling for differences in level of selective constraint across gene classes). This suggests that reduced male fertility may be a general feature of mixtures of human populations diverged by >500,000 years.


Assuntos
Grupos de Populações Continentais/genética , Homem de Neandertal/genética , Animais , Demografia , Genoma Humano , Humanos , Modelos Genéticos , Fatores de Tempo
16.
Am J Hum Genet ; 97(6): 775-89, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26581902

RESUMO

The rate at which human genomes mutate is a central biological parameter that has many implications for our ability to understand demographic and evolutionary phenomena. We present a method for inferring mutation and gene-conversion rates by using the number of sequence differences observed in identical-by-descent (IBD) segments together with a reconstructed model of recent population-size history. This approach is robust to, and can quantify, the presence of substantial genotyping error, as validated in coalescent simulations. We applied the method to 498 trio-phased sequenced Dutch individuals and inferred a point mutation rate of 1.66 × 10(-8) per base per generation and a rate of 1.26 × 10(-9) for <20 bp indels. By quantifying how estimates varied as a function of allele frequency, we inferred the probability that a site is involved in non-crossover gene conversion as 5.99 × 10(-6). We found that recombination does not have observable mutagenic effects after gene conversion is accounted for and that local gene-conversion rates reflect recombination rates. We detected a strong enrichment of recent deleterious variation among mismatching variants found within IBD regions and observed summary statistics of local sharing of IBD segments to closely match previously proposed metrics of background selection; however, we found no significant effects of selection on our mutation-rate estimates. We detected no evidence of strong variation of mutation rates in a number of genomic annotations obtained from several recent studies. Our analysis suggests that a mutation-rate estimate higher than that reported by recent pedigree-based studies should be adopted in the context of DNA-based demographic reconstruction.


Assuntos
Genoma Humano , Mutação em Linhagem Germinativa , Modelos Genéticos , Taxa de Mutação , Alelos , Frequência do Gene , Haplótipos , Humanos , Mutação INDEL , Modelos Lineares , Recombinação Genética
17.
PLoS Genet ; 11(11): e1005550, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26562831

RESUMO

The human mutation rate is an essential parameter for studying the evolution of our species, interpreting present-day genetic variation, and understanding the incidence of genetic disease. Nevertheless, our current estimates of the rate are uncertain. Most notably, recent approaches based on counting de novo mutations in family pedigrees have yielded significantly smaller values than classical methods based on sequence divergence. Here, we propose a new method that uses the fine-scale human recombination map to calibrate the rate of accumulation of mutations. By comparing local heterozygosity levels in diploid genomes to the genetic distance scale over which these levels change, we are able to estimate a long-term mutation rate averaged over hundreds or thousands of generations. We infer a rate of 1.61 ± 0.13 × 10-8 mutations per base per generation, which falls in between phylogenetic and pedigree-based estimates, and we suggest possible mechanisms to reconcile our estimate with previous studies. Our results support intermediate-age divergences among human populations and between humans and other great apes.


Assuntos
Evolução Molecular , Taxa de Mutação , Mutação/genética , Recombinação Genética , Animais , Diploide , Genética Populacional , Genoma Humano , Hominidae/genética , Humanos , Linhagem , Filogenia
18.
Proc Natl Acad Sci U S A ; 112(44): 13621-6, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26483472

RESUMO

Nonrandom mating in human populations has important implications for genetics and medicine as well as for economics and sociology. In this study, we performed an integrative analysis of a large cohort of Mexican and Puerto Rican couples using detailed socioeconomic attributes and genotypes. We found that in ethnically homogeneous Latino communities, partners are significantly more similar in their genomic ancestries than expected by chance. Consistent with this, we also found that partners are more closely related--equivalent to between third and fourth cousins in Mexicans and Puerto Ricans--than matched random male-female pairs. Our analysis showed that this genomic ancestry similarity cannot be explained by the standard socioeconomic measurables alone. Strikingly, the assortment of genomic ancestry in couples was consistently stronger than even the assortment of education. We found enriched correlation of partners' genotypes at genes known to be involved in facial development. We replicated our results across multiple geographic locations. We discuss the implications of assortment and assortment-specific loci on disease dynamics and disease mapping methods in Latinos.


Assuntos
Genética Médica , Hispano-Americanos , Relações Interpessoais , Fatores Socioeconômicos , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Masculino , México/etnologia , Porto Rico/etnologia
19.
Bioinformatics ; 31(12): i190-6, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-26072482

RESUMO

MOTIVATION: A basic problem of broad public and scientific interest is to use the DNA of an individual to infer the genomic ancestries of the parents. In particular, we are often interested in the fraction of each parent's genome that comes from specific ancestries (e.g. European, African, Native American, etc). This has many applications ranging from understanding the inheritance of ancestry-related risks and traits to quantifying human assortative mating patterns. RESULTS: We model the problem of parental genomic ancestry inference as a pooled semi-Markov process. We develop a general mathematical framework for pooled semi-Markov processes and construct efficient inference algorithms for these models. Applying our inference algorithm to genotype data from 231 Mexican trios and 258 Puerto Rican trios where we have the true genomic ancestry of each parent, we demonstrate that our method accurately infers parameters of the semi-Markov processes and parents' genomic ancestries. We additionally validated the method on simulations. Our model of pooled semi-Markov process and inference algorithms may be of independent interest in other settings in genomics and machine learning.


Assuntos
Grupos de Populações Continentais/genética , Genômica/métodos , Algoritmos , Criança , Feminino , Genética Populacional/métodos , Técnicas de Genotipagem , Humanos , Masculino , Cadeias de Markov , México , Pais , Porto Rico
20.
Nat Rev Genet ; 16(6): 359-71, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25963373

RESUMO

As modern and ancient DNA sequence data from diverse human populations accumulate, evidence is increasing in support of the existence of beneficial variants acquired from archaic humans that may have accelerated adaptation and improved survival in new environments - a process known as adaptive introgression. Within the past few years, a series of studies have identified genomic regions that show strong evidence for archaic adaptive introgression. Here, we provide an overview of the statistical methods developed to identify archaic introgressed fragments in the genome sequences of modern humans and to determine whether positive selection has acted on these fragments. We review recently reported examples of adaptive introgression, grouped by selection pressure, and consider the level of supporting evidence for each. Finally, we discuss challenges and recommendations for inferring selection on introgressed regions.


Assuntos
Modelos Genéticos , Adaptação Biológica/genética , Animais , Evolução Molecular , Fluxo Gênico , Genoma Humano , Haplótipos , Humanos , Desequilíbrio de Ligação , Cadeias de Markov , Homem de Neandertal/genética , Filogenia , Seleção Genética
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