Estimation of admixture proportions and principal component analysis (PCA) are fundamental tools in populations genetics. However, applying these methods to low- or mid-depth sequencing data without ...taking genotype uncertainty into account can introduce biases.
Here we present fastNGSadmix, a tool to fast and reliably estimate admixture proportions and perform PCA from next generation sequencing data of a single individual. The analyses are based on genotype likelihoods of the input sample and a set of predefined reference populations. The method has high accuracy, even at low sequencing depth and corrects for the biases introduced by small reference populations.
The admixture estimation method is implemented in C ++ and the PCA method is implemented in R. The code is freely available at http://www.popgen.dk/software/index.php/FastNGSadmix.
emil.jorsboe@bio.ku.dk.
Supplementary data are available at Bioinformatics online.
Present-day hunter-gatherers (HGs) live in multilevel social groups essential to sustain a population structure characterized by limited levels of within-band relatedness and inbreeding. When these ...wider social networks evolved among HGs is unknown. To investigate whether the contemporary HG strategy was already present in the Upper Paleolithic, we used complete genome sequences from Sunghir, a site dated to ~34,000 years before the present, containing multiple anatomically modern human individuals. We show that individuals at Sunghir derive from a population of small effective size, with limited kinship and levels of inbreeding similar to HG populations. Our findings suggest that Upper Paleolithic social organization was similar to that of living HGs, with limited relatedness within residential groups embedded in a larger mating network.
The origin of contemporary Europeans remains contentious. We obtained a genome sequence from Kostenki 14 in European Russia dating from 38,700 to 36,200 years ago, one of the oldest fossils of ...anatomically modern humans from Europe. We find that Kostenki 14 shares a close ancestry with the 24,000-year-old Mal'ta boy from central Siberia, European Mesolithic hunter-gatherers, some contemporary western Siberians, and many Europeans, but not eastern Asians. Additionally, the Kostenki 14 genome shows evidence of shared ancestry with a population basal to all Eurasians that also relates to later European Neolithic farmers. We find that Kostenki 14 contains more Neandertal DNA that is contained in longer tracts than present Europeans. Our findings reveal the timing of divergence of western Eurasians and East Asians to be more than 36,200 years ago and that European genomic structure today dates back to the Upper Paleolithic and derives from a metapopulation that at times stretched from Europe to central Asia.
The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during ...the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l(-1), P = 2.5 × 10(-35)) and serum insulin (β = 165 pmol l(-1), P = 1.5 × 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = -0.18 mmol l(-1), P = 1.1 × 10(-6)) and fasting serum insulin (β = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l(-1), P = 5.3 × 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We have identified a variant in ADCY3 (encoding adenylate cyclase 3) associated with markedly increased risk of obesity and type 2 diabetes in the Greenlandic population. The variant disrupts a ...splice acceptor site, and carriers have decreased ADCY3 RNA expression. Additionally, we observe an enrichment of rare ADCY3 loss-of-function variants among individuals with type 2 diabetes in trans-ancestry cohorts. These findings provide new information on disease etiology relevant for future treatment strategies.
Kennewick Man, referred to as the Ancient One by Native Americans, is a male human skeleton discovered in Washington state (USA) in 1996 and initially radiocarbon dated to 8,340-9,200 calibrated ...years before present (BP). His population affinities have been the subject of scientific debate and legal controversy. Based on an initial study of cranial morphology it was asserted that Kennewick Man was neither Native American nor closely related to the claimant Plateau tribes of the Pacific Northwest, who claimed ancestral relationship and requested repatriation under the Native American Graves Protection and Repatriation Act (NAGPRA). The morphological analysis was important to judicial decisions that Kennewick Man was not Native American and that therefore NAGPRA did not apply. Instead of repatriation, additional studies of the remains were permitted. Subsequent craniometric analysis affirmed Kennewick Man to be more closely related to circumpacific groups such as the Ainu and Polynesians than he is to modern Native Americans. In order to resolve Kennewick Man's ancestry and affiliations, we have sequenced his genome to ∼1× coverage and compared it to worldwide genomic data including for the Ainu and Polynesians. We find that Kennewick Man is closer to modern Native Americans than to any other population worldwide. Among the Native American groups for whom genome-wide data are available for comparison, several seem to be descended from a population closely related to that of Kennewick Man, including the Confederated Tribes of the Colville Reservation (Colville), one of the five tribes claiming Kennewick Man. We revisit the cranial analyses and find that, as opposed to genome-wide comparisons, it is not possible on that basis to affiliate Kennewick Man to specific contemporary groups. We therefore conclude based on genetic comparisons that Kennewick Man shows continuity with Native North Americans over at least the last eight millennia.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Association studies using genetic data from SNP-chip-based imputation or low-depth sequencing data provide a cost-efficient design for large-scale association studies. We explore methods for ...performing association studies applicable to such genetic data and investigate how using different priors when estimating genotype probabilities affects the association results. Our proposed method, ANGSD-asso's latent model, models the unobserved genotype as a latent variable in a generalized linear model framework. The software is implemented in C/C++ and can be run multi-threaded. ANGSD-asso is based on genotype probabilities, which can be estimated using either the sample allele frequency or the individual allele frequencies as a prior. We explore through simulations how genotype probability-based methods compare with using genetic dosages. Our simulations show that in a structured population using the individual allele frequency prior has better power than the sample allele frequency. In scenarios with sequencing depth and phenotype correlation ANGSD-asso's latent model has higher statistical power and less bias than using dosages. Adding additional covariates to the linear model of ANGSD-asso's latent model has higher statistical power and less bias than other methods that accommodate genotype uncertainty, while also being much faster. This is shown with imputed data from UK Biobank and simulations.
During the last decade genome‐wide association studies have proven to be a powerful approach to identifying disease‐causing variants. However, for admixed populations, most current methods for ...association testing are based on the assumption that the effect of a genetic variant is the same regardless of its ancestry. This is a reasonable assumption for a causal variant but may not hold for the genetic variants that are tested in genome‐wide association studies, which are usually not causal. The effects of noncausal genetic variants depend on how strongly their presence correlate with the presence of the causal variant, which may vary between ancestral populations because of different linkage disequilibrium patterns and allele frequencies. Motivated by this, we here introduce a new statistical method for association testing in recently admixed populations, where the effect size is allowed to depend on the ancestry of a given allele. Our method does not rely on accurate inference of local ancestry, yet using simulations we show that in some scenarios it gives a substantial increase in statistical power to detect associations. In addition, the method allows for testing for difference in effect size between ancestral populations, which can be used to help determine if a given genetic variant is causal. We demonstrate the usefulness of the method on data from the Greenlandic population.
Significance Thirty years after the first DNA fragment from the extinct quagga zebra was sequenced, we set another milestone in equine genomics by sequencing its entire genome, along with the genomes ...of the surviving equine species. This extensive dataset allows us to decipher the genetic makeup underlying lineage-specific adaptations and reveal the complex history of equine speciation. We find that Equus first diverged in the New World, spread across the Old World 2.1–3.4 Mya, and finally experienced major demographic expansions and collapses coinciding with past climate changes. Strikingly, we find multiple instances of hybridization throughout the equine tree, despite extremely divergent chromosomal structures. This contrasts with theories promoting chromosomal incompatibilities as drivers for the origin of equine species.
Horses, asses, and zebras belong to a single genus, Equus , which emerged 4.0–4.5 Mya. Although the equine fossil record represents a textbook example of evolution, the succession of events that gave rise to the diversity of species existing today remains unclear. Here we present six genomes from each living species of asses and zebras. This completes the set of genomes available for all extant species in the genus, which was hitherto represented only by the horse and the domestic donkey. In addition, we used a museum specimen to characterize the genome of the quagga zebra, which was driven to extinction in the early 1900s. We scan the genomes for lineage-specific adaptations and identify 48 genes that have evolved under positive selection and are involved in olfaction, immune response, development, locomotion, and behavior. Our extensive genome dataset reveals a highly dynamic demographic history with synchronous expansions and collapses on different continents during the last 400 ky after major climatic events. We show that the earliest speciation occurred with gene flow in Northern America, and that the ancestor of present-day asses and zebras dispersed into the Old World 2.1–3.4 Mya. Strikingly, we also find evidence for gene flow involving three contemporary equine species despite chromosomal numbers varying from 16 pairs to 31 pairs. These findings challenge the claim that the accumulation of chromosomal rearrangements drive complete reproductive isolation, and promote equids as a fundamental model for understanding the interplay between chromosomal structure, gene flow, and, ultimately, speciation.
Low Physical Activity Accentuates the Effect of the FTO rs9939609 Polymorphism on Body Fat Accumulation
Camilla H. Andreasen 1 ,
Kirstine L. Stender-Petersen 1 ,
Mette S. Mogensen 1 ,
Signe S. ...Torekov 1 ,
Lise Wegner 1 ,
Gitte Andersen 1 ,
Arne L. Nielsen 1 ,
Anders Albrechtsen 2 ,
Knut Borch-Johnsen 1 3 4 ,
Signe S. Rasmussen 1 ,
Jesper O. Clausen 1 ,
Annelli Sandbæk 5 ,
Torsten Lauritzen 5 ,
Lars Hansen 6 ,
Torben Jørgensen 3 ,
Oluf Pedersen 1 4 and
Torben Hansen 1
1 Steno Diabetes Center, Gentofte, Denmark
2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
3 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
4 Faculty of Health Science, University of Aarhus, Aarhus, Denmark
5 Department of General Practice, University of Aarhus, Aarhus, Denmark
6 Science and Medicine, Novo Nordisk, Bagsværd, Denmark
Address correspondence and reprint requests to Camilla H. Andreasen, Steno Diabetes Center, Niels Steensens Vej 1, NLC2.13,
DK-2820 Gentofte, Denmark. E-mail: cila{at}novonordisk.com
Abstract
OBJECTIVE— Three independent studies have shown that variation in the fat mass and obesity-associated ( FTO ) gene associates with BMI and obesity. In the present study, the effect of FTO variation on metabolic traits including obesity, type 2 diabetes, and related quantitative phenotypes was examined.
RESEARCH DESIGN AND METHODS— The FTO rs9939609 polymorphism was genotyped in a total of 17,508 Danes from five different study groups.
RESULTS— In studies of 3,856 type 2 diabetic case subjects and 4,861 normal glucose-tolerant control subjects, the minor A-allele of
rs9939609 associated with type 2 diabetes (odds ratio 1.13 95% CI 1.06–1.20, P = 9 × 10 −5 ). This association was abolished when adjusting for BMI (1.06 0.97–1.16, P = 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 1.13–1.24, P = 1 × 10 −12 ) and obesity (1.27 1.20–1.34, P = 2 × 10 −16 ). Furthermore, obesity-related quantitative traits such as body weight, waist circumference, fat mass, and fasting serum
leptin levels were significantly elevated in A-allele carriers. An interaction between the FTO rs9939609 genotype and physical activity ( P = 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 ± 0.3 kg/m 2 increase in BMI compared with homozygous T-allele carriers.
CONCLUSIONS— We validate that variation in FTO is associated with type 2 diabetes when not adjusted for BMI and with an overall increase in body fat mass. Furthermore,
low physical activity seems to accentuate the effect of FTO rs9939609 on body fat accumulation.
BIGTT, β-cell function, insulin sensitivity, and glucose tolerance testing
BIGTT-AIR, BIGTT acute insulin response
BIGTT-Si, BIGTT insulin sensitivity index
SDC, Steno Diabetes Center
SNP, single-nucleotide polymorphism
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 17 October 2007. DOI: 10.2337/db07-0910.
C.H.A. and K.L.S.-P. contributed equally to this article.
K.B.-J. has received honorarium for invited lectures by Novo Nordisk, Bristol-Myers Squibb, Novartis, Pfizer, Hermedico, and
AstraZeneca.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0910 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted October 10, 2007.
Received July 4, 2007.
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