The contributions of admixture and genetic drift to diversity among post-contact populations in the Americas.

OBJECTIVE: We present a model that partitions Nei's minimum genetic distance between admixed populations into components of admixture and genetic drift. We applied this model to 17 admixed populations in the Americas to examine how admixture and drift have contributed to the patterns of genetic diversity. MATERIALS AND METHODS: We analyzed 618 short tandem repeat loci in 949 individuals from 49 population samples. Thirty-two samples serve as proxies for continental ancestors. Seventeen samples represent admixed populations: (4) African-American and (13) Latin American. We partition genetic distance, and then calculate fixation indices and principal coordinates to interpret our results. A computer simulation confirms that our method correctly estimates drift and admixture components of genetic distance when the assumptions of the model are met. RESULTS: The partition of genetic distance shows that both admixture and genetic drift contribute to patterns of genetic diversity. The admixture component of genetic distance provides evidence for two distinct axes of continental ancestry. However, the genetic distances show that ancestry contributes to only one axis of genetic differentiation. The genetic distances among the 13 Latin American populations in this analysis show contributions from both differences in ancestry and differences in genetic drift. By contrast, the genetic distances among the four African American populations in this analysis owe mostly to genetic drift because these groups have similar fractions of European and African ancestry. CONCLUSION: The genetic structure of admixed populations in the Americas reflects more than admixture. We show that the history of serial founder effects constrains the impact of admixture on allele frequencies to a single dimension. Genetic drift in the admixed populations imposed a new level of genetic structure onto that created by admixture.

The apportionment of human diversity revisited.

OBJECTIVES: Studies of the apportionment of human genetic diversity have found that local populations harbor nearly as much diversity as the species as a whole. These studies have been a valuable cornerstone in rejecting race as a biological framework in anthropology. The current study presents new analyses that use updated statistical methods based on bifurcating trees to assess the structure of human genetic diversity and its implications for the existence of canonical biological races. MATERIALS AND METHODS: We examine patterns of both goodness-of-fit and lack-of-fit of two bifurcating trees to patterns of diversity determined from autosomal short tandem repeat genotypes in 1,037 people representing 52 populations with worldwide distribution. RESULTS: From goodness-of-fit, we infer a root for the tree within Africa, and we recapitulate a pattern of decreasing genetic diversity with increasing geographic distance from Africa. From lack-of-fit, we present tentative evidence for admixture events with archaic hominins. We do not find evidence that long-range migration or local gene flow have contributed appreciably to the lack of fit at a global scale. CONCLUSION: This is the first study to find a root for a tree of human populations without comparison to a nonhuman out-group, and it is one of the first studies to identify a signature of admixture with archaic hominins without reference to ancient DNA. Our findings complement previous studies of the apportionment of human diversity and provide a more solid evolutionary foundation for the rejection of biological race. Am J Phys Anthropol 160:561-569, 2016. © 2015 Wiley Periodicals, Inc.

ENCODE data in the UCSC Genome Browser: year 5 update.

The Encyclopedia of DNA Elements (ENCODE), http://encodeproject.org, has completed its fifth year of scientific collaboration to create a comprehensive catalog of functional elements in the human genome, and its third year of investigations in the mouse genome. Since the last report in this journal, the ENCODE human data repertoire has grown by 898 new experiments (totaling 2886), accompanied by a major integrative analysis. In the mouse genome, results from 404 new experiments became available this year, increasing the total to 583, collected during the course of the project. The University of California, Santa Cruz, makes this data available on the public Genome Browser http://genome.ucsc.edu for visual browsing and data mining. Download of raw and processed data files are all supported. The ENCODE portal provides specialized tools and information about the ENCODE data sets.

ENCODE whole-genome data in the UCSC Genome Browser: update 2012.

The Encyclopedia of DNA Elements (ENCODE) Consortium is entering its 5th year of production-level effort generating high-quality whole-genome functional annotations of the human genome. The past year has brought the ENCODE compendium of functional elements to critical mass, with a diverse set of 27 biochemical assays now covering 200 distinct human cell types. Within the mouse genome, which has been under study by ENCODE groups for the past 2 years, 37 cell types have been assayed. Over 2000 individual experiments have been completed and submitted to the Data Coordination Center for public use. UCSC makes this data available on the quality-reviewed public Genome Browser (http://genome.ucsc.edu) and on an early-access Preview Browser (http://genome-preview.ucsc.edu). Visual browsing, data mining and download of raw and processed data files are all supported. An ENCODE portal (http://encodeproject.org) provides specialized tools and information about the ENCODE data sets.

Inferring genetic ancestry: opportunities, challenges, and implications.

Increasing public interest in direct-to-consumer (DTC) genetic ancestry testing has been accompanied by growing concern about issues ranging from the personal and societal implications of the testing to the scientific validity of ancestry inference. The very concept of "ancestry" is subject to misunderstanding in both the general and scientific communities. What do we mean by ancestry? How exactly is ancestry measured? How far back can such ancestry be defined and by which genetic tools? How do we validate inferences about ancestry in genetic research? What are the data that demonstrate our ability to do this correctly? What can we say and what can we not say from our research findings and the test results that we generate? This white paper from the American Society of Human Genetics (ASHG) Ancestry and Ancestry Testing Task Force builds upon the 2008 ASHG Ancestry Testing Summary Statement in providing a more in-depth analysis of key scientific and non-scientific aspects of genetic ancestry inference in academia and industry. It culminates with recommendations for advancing the current debate and facilitating the development of scientifically based, ethically sound, and socially attentive guidelines concerning the use of these continually evolving technologies.

Novel alleles gained during the Beringian isolation period.

During the Last Glacial Maximum, a small band of Siberians entered the Beringian corridor, where they persisted, isolated from gene flow, for several thousand years before expansion into the Americas. The ecological features of the Beringian environment, coupled with an extended period of isolation at small population size, would have provided evolutionary opportunity for novel genetic variation to arise as both rare standing variants and new mutations were driven to high frequency through both neutral and directed processes. Here we perform a full genome investigation of Native American populations in the Thousand Genomes Project Phase 3 to identify unique high frequency alleles that can be dated to an origin in Beringia. Our analyses demonstrate that descendant populations of Native Americans harbor 20,424 such variants, which is on a scale comparable only to Africa and the Out of Africa bottleneck. This is consistent with simulations of a serial founder effects model. Tests for selection reveal that some of these Beringian variants were likely driven to high frequency by adaptive processes, and bioinformatic analyses suggest possible phenotypic pathways that were under selection during the Beringian Isolation period. Specifically, pathways related to cardiac processes and melanocyte function appear to be enriched for selected Beringian variants.

Cryptic population structure and transmission dynamics uncovered for Schistosoma mansoni populations by genetic analyses.

Patterns of diversity in pathogen genomes provide a window into the spatiotemporal spread of disease. In this study, we tested the hypothesis that Schistosoma mansoni parasites form genetic clusters that coincide with the communities of their human hosts. We also looked for genetic clustering of parasites at the sub-community level. Our data consists of 14 microsatellite DNA markers, typed from pooled DNA samples from [Formula: see text] infected individuals living in three Brazilian communities. We found a one-to-one correspondence between genetic clusters found by K-means cluster analysis and communities when [Formula: see text]. These clusters are also easily identified in a neighbor-joining tree and principal coordinates plots. K-means analysis with [Formula: see text] also reveals genetic clusters of parasites at the sub-community level. These sub-clusters also appear on the neighbor-joining tree and principal coordinates plots. A surprising finding is a genetic relationship between subgroups in widely separated human communities. This connection suggests the existence of common transmission sites that have wide influence. In summary, the genetic structure of S. mansoni in Brazil juxtaposes local isolation that is occasionally broken by long-range migration. Permanent eradication of schistosomes will require both local efforts and the identification of regional infection reservoirs.

Ancestral heterogeneity in a biethnic stroke population.

To test for and characterize heterogeneity in ancestral contributions to individuals among a population of Mexican American (MA) and non-Hispanic white (NHW) stroke/transient ischemic attack (TIA) cases, data from a community-based stroke surveillance study in south Texas were used. Strokes/TIA cases were identified (2004-2006) with a random sample asked to provide blood. Race-ethnicity was self-reported. Thirty-three ancestry informative markers were genotyped and individual genetic admixture estimated using maximum likelihood methods. Three hypotheses were tested for each MA using likelihood ratio tests: (1) H(0) : µi = 0 (100% Native American), (2) H(0) : µi = 1.00 (100% European), (3) H(0) : µi = 0.59 (average European). Among 154 self-identified MAs, estimated European ancestry varied from 0.26 to 0.98, with an average of 0.59 (SE = 0.014). We rejected hypothesis 1 for every MA and rejected hypothesis 2 for all but two MAs. We rejected hypothesis 3 for 40 MAs (20 < 59%, 20 > 59%). Among 84 self-identified NHWs, the estimated fraction of European ancestry ranged from 0.83 to 1.0, with an average of 0.97 (SE = 0.014). Self-identified MAs, and to a lesser extent NHWs, from an established bi-ethnic community were heterogeneous with respect to genetic admixture. Researchers should not use simple race-ethnic categories as proxies for homogeneous genetic populations when conducting gene mapping and disease association studies in multi-ethnic populations.

A Schistosoma mansoni tri- and tetramer microsatellite catalog for genetic population diversity and differentiation.

All Schistosoma mansoni tri- and tetranucleotide repeat microsatellites published as of December 2018 were identified. All 52 were evaluated for autosomal location, strength of amplification, scorability and behavior as single-copy loci by polyacrylamide and capillary gel electrophoresis. Of these, 27 were unique, autosomal, polymorphic, easily scored and single copy as assessed on pooled adult worm DNA from two different continental origins and adult worm clones. These microsatellites were distributed across all seven autosomal chromosomes. On laboratory strains their heterozygosity ranged from 0.22 to 0.77. Individual markers had 5-13 alleles, allelic richness of 2-10 and an effective allele number of 1.3-8.14. Those infected by Schistosoma mansoni carry many genetically distinct, sexually reproducing parasites, therefore, for an individual infection the complete allele frequency profile of their progeny consists of a pool of DNA from multiple diploid eggs. Using a set of 25 microsatellites, we calculated allele frequency profiles of eggs in fecal samples from people in two Brazilian communities separated by 6 km: Jenipapo (n = 80) and Volta do Rio (n = 38). There were no a priori characteristics that could predict the performance of markers in natural infections based on their performance with laboratory strains. Increasing marker number did not change accuracy for differentiation and diversity but did improve precision. Our data suggest that using a random set of 10-20 microsatellites appears to result in values that exhibit low standard deviations for diversity and differentiation indices. All identified microsatellites as well as PCR conditions, allele size, primer sequences and references for all tri- and tetramer microsatellites markers presented in this work are available at: https://sites.google.com/case.edu/cwru-and-fiocruz-wdrc/home.

Native South American genetic structure and prehistory inferred from hierarchical modeling of mtDNA.

Genetic diversity in Native South Americans forms a complex pattern at both the continental and local levels. In comparing the West to the East, there is more variation within groups and smaller genetic distances between groups. From this pattern, researchers have proposed that there is more variation in the West and that a larger, more genetically diverse, founding population entered the West than the East. Here, we question this characterization of South American genetic variation and its interpretation. Our concern arises because others have inferred regional variation from the mean variation within local populations without taking into account the variation among local populations within the same region. This failure produces a biased view of the actual variation in the East. In this study, we analyze the mitochondrial DNA sequence between positions 16040 and 16322 of the Cambridge reference sequence. Our sample represents a total of 886 people from 27 indigenous populations from South (22), Central (3), and North America (2). The basic unit of our analyses is nucleotide identity by descent, which is easily modeled and proportional to nucleotide diversity. We use a forward modeling strategy to fit a series of nested models to identity by descent within and between all pairs of local populations. This method provides estimates of identity by descent at different levels of population hierarchy without assuming homogeneity within populations, regions, or continents. Our main discovery is that Eastern South America harbors more genetic variation than has been recognized. We find no evidence that there is increased identity by descent in the East relative to the total for South America. By contrast, we discovered that populations in the Western region, as a group, harbor more identity by descent than has been previously recognized, despite the fact that average identity by descent within groups is lower. In this light, there is no need to postulate separate founding populations for the East and the West because the variability in the East could serve as a source for the Western gene pools.

Intergenerational transmission of neuropsychological executive functioning.

Relationships between parent and child executive functioning were examined, controlling for the critical potential confound of IQ, in a family study involving 434 children (130 girls and 304 boys) and 376 parents from 204 community recruited families at high risk for the development of substance use disorder. Structural equation modeling found evidence of separate executive functioning and intelligence (IQ) latent variables. Mother's and father's executive functioning were associated with child's executive functioning (beta = 0.34 for father-child and 0.51 for mother-child), independently of parental IQ, which as expected was associated with child's IQ (beta = 0.52 for father-child and 0.54 for mother-child). Familial correlations also showed a significant relationship of executive functioning between parents and offspring. These findings clarify that key elements of the executive functioning construct are reliably differentiable from IQ, and are transmitted in families. This work supports the utility of the construct of executive function in further study of the mechanisms and etiology of externalizing psychopathologies.

The global pattern of gene identity variation reveals a history of long-range migrations, bottlenecks, and local mate exchange: implications for biological race.

Several recent studies have argued that human genetic variation conforms to a model of isolation by distance, whereas others see a predominant role for long-range migrations and bottlenecks. It is unclear whether either of these views fully describes the global pattern of human genetic variation. In this article, we use a coalescent-based simulation approach to compare the pattern of neutral genetic variation predicted by these views to the observed pattern estimated from neutral autosomal microsatellites assayed in 1,032 individuals from 53 globally-distributed populations. We find that neither view predicts every aspect of the observed pattern of variation on its own, but that a combination of the two does. Specifically, we demonstrate that the observed pattern of global gene identity variation is consistent with a history of serial population fissions, bottlenecks and long-range migrations associated with the peopling of major geographic regions, and gene flow between local populations. This history has produced a nested pattern of genetic structure that is inconsistent with the existence of independently evolving biological races. We consider the implications of our findings for methods that apportion variation into within- and between-group components and for medical genetics.

Human DNA sequences: more variation and less race.

Interest in genetic diversity within and between human populations as a way to answer questions about race has intensified in light of recent advances in genome technology. The purpose of this article is to apply a method of generalized hierarchical modeling to two DNA data sets. The first data set consists of a small sample of individuals (n = 32 total, from eight populations) who have been fully resequenced for 63 loci that encode a total of 38,534 base pairs. The second data set consists of a large sample of individuals (n = 928 total, from 46 populations) who have been genotyped at 580 loci that encode short tandem repeats. The results are clear and somewhat surprising. We see that populations differ in the amount of diversity that they harbor. The pattern of DNA diversity is one of nested subsets, such that the diversity in non-Sub-Saharan African populations is essentially a subset of the diversity found in Sub-Saharan African populations. The actual pattern of DNA diversity creates some unsettling problems for using race as meaningful genetic categories. For example, the pattern of DNA diversity implies that some populations belong to more than one race (e.g., Europeans), whereas other populations do not belong to any race at all (e.g., Sub-Saharan Africans). As Frank Livingstone noted long ago, the Linnean classification system cannot accommodate this pattern because within the system a population cannot belong to more than one named group within a taxonomic level.

Stroke among siblings in a biethnic community.

BACKGROUND: Mexican Americans (MAs) have an increased risk of stroke compared with non-Hispanic whites (NHWs), especially at younger ages. Little is known regarding patterns of familial aggregation of stroke and whether familial risk assessment might prove a potentially useful tool in assessing stroke risk in this population. This study's objective was to estimate the sibling recurrence risk ratio (lambda(s)) for stroke and to compare this ratio between MAs and NHWs. METHODS: Stroke and transient ischemic attack (TIA) cases (n = 181) between the ages of 45 and 64 years were identified by a population-based stroke study in a biethnic Texas community. lambda(s) was calculated overall and by ethnicity. RESULTS: Siblings of ischemic stroke/TIA cases had a doubling in stroke risk compared to what would be expected based on national stroke prevalence estimates (lambda(s) = 1.92; 95% CI: 1.39-2.61). lambda(s) was 2.0 (95% CI: 1.39-2.81) among MA stroke/TIA cases and 1.66 (95% CI: 0.82-3.10) among NHW stroke/TIA cases. CONCLUSION: The sibling recurrence risk for stroke was elevated in MA stroke/TIA cases suggesting that further ischemic stroke genetic studies across ethnicities may be warranted. In addition, a positive family history could prove a useful factor in the clinical setting for identifying MAs at increased stroke risk.

Pre- and post-Columbian gene and cultural continuity: the case of the Gaucho from southern Brazil.

OBJECTIVE: To investigate the evolutionary and demographic history of the Gaucho, a distinct population of southern Brazil, relating it to their culture, to assess possible parallel continuity. METHODS: Six binary polymorphisms, an Alu insertion polymorphism (YAP) and 12 short tandem repeat loci in the non-recombining region of the Y-chromosome, as well as the sequence of the first hypervariable segment (HVS-I) of the mitochondrial DNA (mtDNA) control region were studied in 150 unrelated males born in the Pampa region of Rio Grande do Sul. RESULTS: Comparison of the results with the other Brazilian and Uruguayan populations, as well as with their putative ancestors, indicated a stronger male Spanish influence than that observed elsewhere in Brazil, a former Portuguese colony. Extensive mtDNA analyses of their Amerindian component gave clear indications of the presence there of material from extinct (Charrua), as well as extant (Guarani) tribes. CONCLUSIONS: The genetic analyses contributed in a significant way to reveal that the known cultural continuity between pre- and post-Columbian Pampa populations was also accompanied by an extraordinary genetic continuity.

A coalescent simulation of marker selection strategy for candidate gene association studies.

Recent efforts have focused on the challenges of finding alleles that contribute to health-related phenotypes in genome-wide association studies. However, in candidate gene studies, where the genomic region of interest is small and recombination is limited, factors that affect the ability to detect disease-susceptibility alleles remain poorly understood. In particular, it is unclear how varying the number of markers on a haplotype, the type of marker (e.g., single nucleotide polymorphism (SNP), short tandem repeat (STR)), including the causative site (cs) as a genetic marker, or population demographics influences the power to detect a candidate gene. We evaluated the power of association tests using coalescent-modeled computer simulations. Results show that an effective number of markers on a haplotype is dependent on whether the cs is included as a marker. When the analyses include the cs, highest power is achieved with a single-marker association test. However, when the cs is excluded from analyses, the addition of more nonfunctional SNPs on the haplotype increases power to a certain point under most scenarios. We find a rapidly expanding population always has lower power compared to a population of constant size; although utilizing markers with a frequency of at least 5% improves the chance of detecting an association. Comparing the mutational properties of a nonfunctional SNP versus an STR, multi-allelic STRs provide more or comparable power than a bi-allelic SNP unless SNP frequencies are constrained to 10% or more. Similarly, including an STR with SNPs on a haplotype improves power unless SNP frequencies are 5% or more.

Haplotype-based localization of an alcohol dependence gene to the 5q34 {gamma}-aminobutyric acid type A gene cluster.

CONTEXT: Pharmacobehavioral and pharmacogenetic evidence links gamma-aminobutyric acid type A (GABA(A)) receptors and chromosomal regions containing GABA(A) receptor genes to ethanol-related responses. The GABA(A) gene cluster on chromosome 5q34 is of particular interest in the genetics of alcohol dependence because of the gamma2 subunit requirement for ethanol's modulatory action on GABA(A) receptors, previous linkage findings in mice and humans implicating both GABRA6 and GABRG2, and reported associations of GABRA6, GABRB2, and GABRG2 alleles with alcohol dependence. OBJECTIVE: To determine whether variation at the 5q34 GABA(A) gene cluster is implicated in differential susceptibility to alcohol dependence. METHODS: Two large psychiatrically interviewed samples, a Southwestern Native American population sample (N = 433) and a Finnish sample (N = 511) with alcohol-dependent subjects and unaffected individuals, were genotyped for 6 single nucleotide polymorphisms at the 5q34 GABA(A) gene cluster. In addition to sib-pair linkage and case-control association analyses, linkage disequilibrium mapping with haplotypes was used. RESULTS: Sib-pair linkage of GABRG2 to alcohol dependence was observed in Finns (P = .008). Association of the GABRB2 1412T allele with alcohol dependence was detected in both populations (Finns, P = .01; Southwestern Native Americans, P = .008), and the GABRA6 1519T allele was associated in both Finns (P = .01) and Southwestern Native Americans (P = .03). Linkage disequilibrium mapping with 3-locus haplotypes yielded evidence for an alcohol-dependence locus at the GABA(A) gene cluster region in both populations. The most highly significant signals were at 3-locus haplotypes that included 1 or more GABRA6 polymorphisms, with the peak signal at a GABRA6 3-locus haplotype (Finns, empirical P = .004; Southwestern Native Americans, empirical P = .02). CONCLUSIONS: We detected sib-pair linkage of 5q34 GABA(A) receptor genes to alcohol dependence in Finns and found association both in Finns and in Southwestern Native Americans. In both populations, the haplotype localization implicates the region containing the Pro385Ser GABRA6 polymorphism and 2 other polymorphisms at GABRA6.

Informativeness of the CODIS STR loci for admixture analysis.

Population admixture (or ancestry) is used as an approach to gene discovery in complex diseases, particularly when the disease prevalence varies widely across geographic populations. Admixture analysis could be useful for forensics because an indication of a perpetrator's ancestry would narrow the pool of suspects for a particular crime. The purpose of this study was to use Fisher's information to identify informative sets of markers for admixture analysis. Using published founding population allele frequencies we test three marker sets for efficacy for estimating admixture: the FBI CODIS Core STR loci, the HGDP-CEPH Human Genome Diversity Cell Line Panel and the set of 39 ancestry informative SNPS from the Shriver lab at Pennsylvania State University. We conclude that the FBI CODIS Core STR set is valid for admixture analysis, but not the most precise. We recommend using a combination of the most informative markers from the HGDP-CEPH and Shriver loci sets.