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.     

30个祖先信息位点的筛选及应用

摘要：目的 筛选一组祖先信息SNPs位点（AIMs,Ancestry Informative Markers）,构建复合检测体系,用于东亚、欧洲和非洲人群遗传成分描述及个体种族来源推断。方法 以HapMap数据库9个人群的658份样本的分型数据为基础,从30个表型相关基因总共282个SNPs位点中筛选出30个AIMs位点,基于微测序-通用芯片技术构建复合检测体系,并建立人群等位基因频率数据库。使用这组位点分析HapMap数据库中658份人群样本,初步验证位点的区分效能;然后,使用研究构建的体系检验收集的5个人群194份无关个体的DNA样本。最后,通过Structure软件分析获取人群的成分构成以及个体的遗传成分,对个体样本进行种族来源推断。 结果 筛选的30个AIMs位点符合哈迪温伯格平衡（p>0.01）,位点之间没有连锁（r2<0.1）, 658份HapMap数据库样本和194份实验样本的祖先成分分析结果与已知结果完全一致。 结论 本文筛选并建立的30个AIMs位点复合检测体系,能够有效实现东亚、欧洲、非洲人群及混合人群的成分构成和个体遗传成分的分析,有效控制遗传连锁分析中由于人群分层现象带来的误差,也可以用于法医DNA检验中个体祖先来源推断。     

Primate origins: implications of a cretaceous ancestry

It has long been accepted that the adaptive radiation of modern placental mammals, like that of modern birds, did not begin until after the Cretaceous/Tertiary (K/T) boundary 65 million years (Ma) ago, following the extinction of the dinosaurs. The first undoubted fossil relatives of modern primates appear in the record 55 Ma ago. However, in agreement with evidence from molecular phylogenies calibrated with dates from denser parts of the fossil record, a statistical analysis of the primate record allowing for major gaps now indicates a Cretaceous origin of euprimates 80-90 Ma ago. If this interpretation is correct, primates overlapped with dinosaurs by some 20 Ma prior to the K/T boundary, and the initial radiation of primates was probably truncated as part of the major extinction event that occurred at the end of the Cretaceous. Following a review of evidence for an early origin of primates, implications of this are discussed with respect to the likely ancestral condition for primates, including a southern continental area of origin and moderately large body size. The known early Tertiary primates are re-interpreted as northern continental offshoots of a 'second wave' of primate evolution.     

Real‐time assessment of hybridization between wolves and dogs: combining noninvasive samples with ancestry informative markers

Wolves and dogs provide a paradigmatic example of the ecological and conservation implications of hybridization events between wild and domesticated forms. However, our understanding of such implications has been traditionally hampered by both high genetic similarity and the difficulties in obtaining tissue samples (TS), which limit our ability to assess ongoing hybridization events. To assess the occurrence and extension of hybridization in a pack of wolf–dog hybrids in northwestern Iberia, we compared the power of 52 nuclear markers implemented on TS with a subset of 13 ancestry informative markers (AIMs) typed in noninvasive samples (NIS). We demonstrate that the 13 AIMs are as accurate as the 52 markers that were chosen without regard to the power to differentiate between wolves and dogs, also having the advantage of being rapidly screened on NIS. The efficiency of AIMs significantly outperformed ten random sets of similar size and an additional commercial set of 18 markers. Bayesian clustering analysis implemented on AIMs and NIS identified nine hybrids, two wolves and two dogs. Four hybrids were unambiguously assigned to F1xWolf backcrosses. Our approach (AIMs + NIS) overcomes previous difficulties related to sample availability and informative power of markers, allowing a quick identification of wolf–dog hybrids in the first phases of hybridization episodes. This provides managers with a reliable tool to evaluate hybridization and estimate the success of their actions. This approach may be easily adapted for other pairs of wild/domesticated species, thus improving our understanding of the introgression of domestication genes into natural populations.     

Informativeness of genetic markers for inference of ancestry

Inference of individual ancestry is useful in various applications, such as admixture mapping and structured-association mapping. Using information-theoretic principles, we introduce a general measure, the informativeness for assignment (I(n)), applicable to any number of potential source populations, for determining the amount of information that multiallelic markers provide about individual ancestry. In a worldwide human microsatellite data set, we identify markers of highest informativeness for inference of regional ancestry and for inference of population ancestry within regions; these markers, which are listed in online-only tables in our article, can be useful both in testing for and in controlling the influence of ancestry on case-control genetic association studies. Markers that are informative in one collection of source populations are generally informative in others. Informativeness of random dinucleotides, the most informative class of microsatellites, is five to eight times that of random single-nucleotide polymorphisms (SNPs), but 2%-12% of SNPs have higher informativeness than the median for dinucleotides. Our results can aid in decisions about the type, quantity, and specific choice of markers for use in studies of ancestry.     

Afro-derived Amazonian populations: inferring continental ancestry and population substructure

A panel of Ancestry Informative Markers (AIMs) was used to identify population substructure and estimate individual and overall interethnic admixture in 294 individuals from seven African-derived communities of the Brazilian Amazon. A panel of 48 biallelic markers, representing the insertion (IN) or the deletion (DEL) of small DNA fragments, was employed for this purpose. Overall interethnic admixture estimates showed high miscegenation with other ethnic groups in all populations (between 46% and 64%). The proportion of ancestral genes varied significantly among individuals of the sample: the contribution of African genes varied between 12% and 75%; of European genes between 10% and 73%; and of Amerindians genes between 8% and 66%. The obtained data reveal a high contribution of Amerindian genes in these communities, unlike in other African-derived communities of the Northeast and the South of Brazil. In addition, the majority of the Amerindian contribution may result from the preferential inclusion of indigenous women in the African descent groups. High heterogeneity of the proportion of interethnic admixture among analyzed individuals was found when the proportion of ancestral genes of each individual of the sample was estimated. This heterogeneity is reflected in the fact that four populations can be considered as substructured and that the global African descent sample is possibly formed by two subpopulations.     

Characterisation of a bovine/murine hybrid cell panel informative for all bovine autosomes

A bovine/murine hybrid cell panel consisting of 57 cell lines was typed with 124 markers by PCR, Southern hybridisation and isozyme analysis in order to establish its utility as a resource for genome mapping. All bovine chromosomes, including the sex chromosomes were represented in the panel. Computerised analysis of syntenies indicated that there are no cell lines containing only a single bovine chromosome. The panel was used to map 10 new bovine microsatellite markers, and the MYL6 and CPE genes. This panel is informative for all bovine chromosomes other than the sex-specific region of the X chromosome and can be used in synteny mapping studies. At present, due to the relatively small number of markers typed, the resolution of the panel does not go beyond the chromosomal level.     

A highly informative SNP linkage panel for human genetic studies

We have developed a highly informative set of single-nucleotide polymorphism (SNP) assays designed for linkage mapping of the human genome. These assays were developed on a robust multiplexed assay system to provide a combination of very high accuracy and data completeness with high throughput for linkage studies. The linkage panel is comprised of approximately 4,700 SNPs with 0.39 average minor allele frequency and 624-kb average spacing. Based on almost 2 million genotypes, data quality was shown to be extremely high, with a 99.94% call rate, >99.99% reproducibility and 99.995% genotypes consistent with mendelian inheritance. We constructed a genetic map with an average 1.5-cM resolution using series of 28 CEPH pedigrees. The relative information content of this panel was higher than those of commonly used STR marker panels. The potent combination of this SNP linkage panel with the multiplexed assay system provides a previously unattainable level of performance for linkage studies.     

Exploration of the utility of ancestry informative markers for genetic association studies of African Americans with type 2 diabetes and end stage renal disease

Admixture and population stratification are major concerns in genetic association studies. We wished to evaluate the impact of admixture using empirically derived data from genetic association studies of African Americans (AA) with type 2 diabetes (T2DM) and end-stage renal disease (ESRD). Seventy ancestry informative markers (AIMs) were genotyped in 577 AA with T2DM–ESRD, 596 AA controls, 44 Yoruba Nigerian (YRI) and 39 European American (EA) controls. Genotypic data and association results for eight T2DM candidate gene studies in our AA population were included. Ancestral estimates were calculated using FRAPPE, ADMIXMAP and STRUCTURE for all AA samples, using varying numbers of AIMs (25, 50, and 70). Ancestry estimates varied significantly across all three programs with the highest estimates obtained using STRUCTURE, followed by ADMIXMAP; while FRAPPE estimates were the lowest. FRAPPE estimates were similar using varying numbers of AIMs, while STRUCTURE estimates using 25 AIMs differed from estimates using 50 and 70 AIMs. Female T2DM-ESRD cases showed higher mean African proportions as compared to female controls, male cases, and male controls. Age showed a weak but significant correlation with individual ancestral estimates in AA cases (r ² = 0.101; P = 0.019) and in the combined set (r ² = 0.131; P = 3.57 × 10⁻⁵). The absolute difference between frequencies in parental populations, absolute δ, was correlated with admixture impact for dominant, additive, and recessive genotypic models of association. This study presents exploratory analyses of the impact of admixture on studies of AA with T2DM-ESRD and supports the use of ancestral proportions as a means of reducing confounding effects due to admixture. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. An erratum to this article can be found at     

Examination of ancestry and ethnic affiliation using highly informative diallelic DNA markers: application to diverse and admixed populations and implications for clinical epidemiology and forensic medicine

We and others have identified several hundred ancestry informative markers (AIMs) with large allele frequency differences between different major ancestral groups. For this study, a panel of 199 widely distributed AIMs was used to examine a diverse set of 796 DNA samples including self-identified European Americans, West Africans, East Asians, Amerindians, African Americans, Mexicans, Mexican Americans, Puerto Ricans and South Asians. Analysis using a Bayesian clustering algorithm (STRUCTURE) showed grouping of individuals with similar ethnic identity without any identifier other than the AIMs genotyping and showed admixture proportions that clearly distinguished different individuals of mixed ancestry. Additional analyses showed that, for the majority of samples, the predicted ethnic identity corresponded with the self-identified ethnicity at high probability (P > 0.99). Overall, the study demonstrates that AIMs can provide a useful adjunct to forensic medicine, pharmacogenomics and disease studies in which major ancestry or ethnic affiliation might be linked to specific outcomes.Electronic Supplementary Material Supplementary material is available for this article at     

Markers informative for ancestry demonstrate consistent megabase-length linkage disequilibrium in the African American population

Admixture mapping is a potentially powerful tool for mapping complex genetic diseases. For application of this method, admixed individuals must have genomes composed of large segments derived intact from each founding population. Such segments are thought to be present in African Americans (AA) and should be demonstrable by examination of linkage disequilibrium (LD). Previous studies using a variety of polymorphic markers have variably reported long-range LD or rapid decay of LD. To further define the extent and characteristics of LD caused by admixture in the AA population, the current study utilized a set of 52 diallelic markers that were selected for large standard variances between putative representatives of the founder populations. LD was examined in over 250 marker-pairs, including linked markers from four different chromosomal regions and an equal number of matched unlinked comparisons. In the representative founder populations, strong LD was not observed for markers separated by more than 10 kb. In contrast, results indicated significant LD ( P<0.001, D'>0.3) in AA over large genomic segments exceeding 10 centiMorgans (cM) and 15 megabases (Mb). Only marginally significant LD was present between unlinked markers in this population, suggesting that choosing appropriate levels of significance for admixture mapping can minimize false positive results. The ability to detect LD for extended chromosomal segments in AA decayed not only as a function of the distance between markers, but also as a function of the standard variance of the markers. This examination of several genomic segments provides strong evidence that appropriate selection of informative markers is a crucial prerequisite for the application of admixture mapping to the AA population.     

Bayesian nonparametric inference for panel count data with an informative observation process

In this paper, the panel count data analysis for recurrent events is considered. Such analysis is useful for studying tumor or infection recurrences in both clinical trial and observational studies. A bivariate Gaussian Cox process model is proposed to jointly model the observation process and the recurrent event process. Bayesian nonparametric inference is proposed for simultaneously estimating regression parameters, bivariate frailty effects, and baseline intensity functions. Inference is done through Markov chain Monte Carlo, with fully developed computational techniques. Predictive inference is also discussed under the Bayesian setting. The proposed method is shown to be efficient via simulation studies. A clinical trial dataset on skin cancer patients is analyzed to illustrate the proposed approach.     

A genomewide single-nucleotide-polymorphism panel with high ancestry information for African American admixture mapping

Admixture mapping requires a genomewide panel of relatively evenly spaced markers that can distinguish the ancestral origins of chromosomal segments in admixed individuals. Through use of the results of the International HapMap Project and specific selection criteria, the current study has examined the ability of selected single-nucleotide polymorphisms (SNPs) to extract continental ancestry information in African American subjects and to explore parameters for admixture mapping. Genotyping of two linguistically diverse West African populations (Bini and Kanuri Nigerians, who are Niger-Congo [Bantu] and Nilo-Saharan speakers, respectively), European Americans, and African Americans validated a genomewide set of >4,000 SNP ancestry-informative markers with mean and median F(ST) values >0.59 and mean and median Fisher's information content >2.5. This set of SNPs extracted a larger amount of ancestry information in African Americans than previously reported SNP panels and provides nearly uniform coverage of the genome. Moreover, in the current study, simulations show that this more informative panel improves power for admixture mapping in African Americans when ethnicity risk ratios are modest. This is particularly important in the application of admixture mapping in complex genetic diseases for which only modest ethnicity risk ratios of relevant susceptibility genes are expected.     

Synteny-mapping horse microsatellite markers using a heterohybridoma panel

A panel of horse-mouse heterohybridoma cells was tested for genetic markers using biochemical and polymerase chain reaction-(PCR-) based tests. Biochemical markers included phospho-glucomutase ( PGM ), glucose phosphate isomerase ( GPI ) and 6-phosphogluconate dehydrogenase ( PGD ). Markers detected using PCR-based tests included microsatellite markers HTG2–15, HMS 1–3, 5–8, VHL20, ECA2 and genes for equine major histocompatibility gene ELA-DRA , tumour necrosis factor alpha (TNFA) and transferrin. The results were analysed for correlation and concordance. Based on the results, five synteny groups were identified, specifically between ELA-DRA, TNFA, HMS5 and HTG5 ; between HTG3 and HTG13 ; between HTG4, HTG8 and HMS3 ; between HTG6 and HMS1 ; and between HTG7, HTG9 and HMS6. Evidence was also found for synteny between HTG12, HMS7 and ECA2 , however, confirmation requires further testing. Cytogenetic evaluation of the cell lines making up the panel indicated that large metacentric chromosomes were preferentially lost or tended to break at the centromere. Consequently, the results from this analysis can be used to identify synteny, but not to exclude synteny.     

A PCA-based method for ancestral informative markers selection in structured populations

Identification of population structure can help trace population histories and identify disease genes. Structured association (SA) is a commonly used approach for population structure identification and association mapping. A major issue with SA is that its performance greatly depends on the informativeness and the numbers of ancestral informative markers (AIMs). Present major AIM selection methods mostly require prior individual ancestry information, which is usually not available or uncertain in practice. To address this potential weakness, we herein develop a novel approach for AIM selection based on principle component analysis (PCA), which does not require prior ancestry information of study subjects. Our simulation and real genetic data analysis results suggest that, with equivalent AIMs, PCA-based selected AIMs can significantly increase the accuracy of inferred individual ancestries compared with traditionally randomly selected AIMs. Our method can easily be applied to whole genome data to select a set of highly informative AIMs in population structure, which can then be used to identify potential population structure and correct possible statistical biases caused by population stratification.     

Pattern classification of large-scale functional brain networks: identification of informative neuroimaging markers for epilepsy

The accurate prediction of general neuropsychiatric disorders, on an individual basis, using resting-state functional magnetic resonance imaging (fMRI) is a challenging task of great clinical significance. Despite the progress to chart the differences between the healthy controls and patients at the group level, the pattern classification of functional brain networks across individuals is still less developed. In this paper we identify two novel neuroimaging measures that prove to be strongly predictive neuroimaging markers in pattern classification between healthy controls and general epileptic patients. These measures characterize two important aspects of the functional brain network in a quantitative manner: (i) coordinated operation among spatially distributed brain regions, and (ii) the asymmetry of bilaterally homologous brain regions, in terms of their global patterns of functional connectivity. This second measure offers a unique understanding of brain asymmetry at the network level, and, to the best of our knowledge, has not been previously used in pattern classification of functional brain networks. Using modern pattern-recognition approaches like sparse regression and support vector machine, we have achieved a cross-validated classification accuracy of 83.9% (specificity: 82.5%; sensitivity: 85%) across individuals from a large dataset consisting of 180 healthy controls and epileptic patients. We identified significantly changed functional pathways and subnetworks in epileptic patients that underlie the pathophysiological mechanism of the impaired cognitive functions. Specifically, we find that the asymmetry of brain operation for epileptic patients is markedly enhanced in temporal lobe and limbic system, in comparison with healthy individuals. The present study indicates that with specifically designed informative neuroimaging markers, resting-state fMRI can serve as a most promising tool for clinical diagnosis, and also shed light onto the physiology behind complex neuropsychiatric disorders. The systematic approaches we present here are expected to have wider applications in general neuropsychiatric disorders.     

Development of cost-effective Hordeum chilense DNA markers: molecular aids for marker-assisted cereal breeding

Hordeum chilense is a potential source of useful genes for wheat breeding. The use of this wild species to increase genetic variation in wheat will be greatly facilitated by marker-assisted introgression. In recent years, the search for the most suitable DNA marker system for tagging H. chilense genomic regions in a wheat background has lead to the development of RAPD and SCAR markers for this species. RAPDs represent an easy way of quickly generating suitable introgression markers, but their use is limited in heterogeneous wheat genetic backgrounds. SCARs are more specific assays, suitable for automatation or multiplexing. Direct sequencing of RAPD products is a cost-effective approach that reduces labour and costs for SCAR development. The use of SSR and STS primers originally developed for wheat and barley are additional sources of genetic markers. Practical applications of the different marker approaches for obtaining derived introgression products are described.     

Estimating ancestry and heterozygosity of hybrids using molecular markers

ABSTRACT: BACKGROUND: Hybridization, genetic mixture of distinct populations, gives rise to myriad recombinant genotypes. Characterizing the genomic composition of hybrids is critical for studies of hybrid zone dynamics, inheritance of traits, and consequences of hybridization for evolution and conservation. Hybrid genomes are often summarized either by an estimate of the proportion of alleles coming from each ancestral population or classification into discrete categories like F1, F2, backcross, or merely ``hybrid' vs. ``pure'. In most cases, it is not realistic to classify individuals into the restricted set of classes produced in the first two generations of admixture. However, the continuous ancestry index misses an important dimension of the genotype. Joint consideration of ancestry together with interclass heterozygosity (proportion of loci with alleles from both ancestral populations) captures all of the information in the discrete classification without the unrealistic assumption that only two generations of admixture have transpired. Here I describe a maximum likelihood method for joint estimation of ancestry and interclass heterozygosity. RESULTS: I present two worked examples illustrating the value of the approach for describing variation among hybrid populations and evaluating the validity of the assumption underlying discrete classification. Naively classifying natural hybrids into the standard six line cross categories can be misleading, and false classification can be a serious problem for datasets with few molecular markers. CONCLUSIONS: My analysis underscores previous work showing that many (50 or more) ancestry informative markers are needed to avoid erroneous classification. However, valuable inferences can be obtained by focusing directly on distributions of ancestry and heterozygosity. Estimating and visualizing the joint distribution of ancestry and interclass heterozygosity is an effective way to compare the genetic structure of hybrid populations and these estimates can be used in classic quantitative genetic methods for assessing additive, dominant, and epistatic genetic effects on hybrid phenotypes and fitness. The methods are implemented in a freely available package ``HIest' for the R statistical software (http://cran.r-project.org/web/packages/HIest/index.html).