PLoS One

[This corrects the article DOI: 10.1371/journal.pone.0221789.]

Inference of population splits and mixtures from genome-wide allele frequency data

Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In this model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication, and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and "ancient" Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.comComment: 28 pages, 6 figures in main text. Attached supplement is 22 pages, 15 figures. This is an updated version of the preprint available at http://precedings.nature.com/documents/6956/version/

Insights gained from the reverse engineering of gene networks in keloid fibroblasts

<p>Abstract</p> <p>Background</p> <p>Keloids are protrusive claw-like scars that have a propensity to recur even after surgery, and its molecular etiology remains elusive. The goal of reverse engineering is to infer gene networks from observational data, thus providing insight into the inner workings of a cell. However, most attempts at modeling biological networks have been done using simulated data. This study aims to highlight some of the issues involved in working with experimental data, and at the same time gain some insights into the transcriptional regulatory mechanism present in keloid fibroblasts.</p> <p>Methods</p> <p>Microarray data from our previous study was combined with microarray data obtained from the literature as well as new microarray data generated by our group. For the physical approach, we used the fREDUCE algorithm for correlating expression values to binding motifs. For the influence approach, we compared the Bayesian algorithm BANJO with the information theoretic method ARACNE in terms of performance in recovering known influence networks obtained from the KEGG database. In addition, we also compared the performance of different normalization methods as well as different types of gene networks.</p> <p>Results</p> <p>Using the physical approach, we found consensus sequences that were active in the keloid condition, as well as some sequences that were responsive to steroids, a commonly used treatment for keloids. From the influence approach, we found that BANJO was better at recovering the gene networks compared to ARACNE and that transcriptional networks were better suited for network recovery compared to cytokine-receptor interaction networks and intracellular signaling networks. We also found that the NFKB transcriptional network that was inferred from normal fibroblast data was more accurate compared to that inferred from keloid data, suggesting a more robust network in the keloid condition.</p> <p>Conclusions</p> <p>Consensus sequences that were found from this study are possible transcription factor binding sites and could be explored for developing future keloid treatments or for improving the efficacy of current steroid treatments. We also found that the combination of the Bayesian algorithm, RMA normalization and transcriptional networks gave the best reconstruction results and this could serve as a guide for future influence approaches dealing with experimental data.</p

Tracing the origins of rescued chimpanzees reveals widespread chimpanzee hunting in Cameroon

<p>Abstract</p> <p>Background</p> <p>While wild chimpanzees are experiencing drastic population declines, their numbers at African rescue and rehabilitation projects are growing rapidly. Chimpanzees follow complex routes to these refuges; and their geographic origins are often unclear. Identifying areas where hunting occurs can help law enforcement authorities focus scarce resources for wildlife protection planning. Efficiently focusing these resources is particularly important in Cameroon because this country is a key transportation waypoint for international wildlife crime syndicates. Furthermore, Cameroon is home to two chimpanzee subspecies, which makes ascertaining the origins of these chimpanzees important for reintroduction planning and for scientific investigations involving these chimpanzees.</p> <p>Results</p> <p>We estimated geographic origins of 46 chimpanzees from the Limbe Wildlife Centre (LWC) in Cameroon. Using Bayesian approximation methods, we determined their origins using mtDNA sequences and microsatellite (STRP) genotypes compared to a spatial map of georeferenced chimpanzee samples from 10 locations spanning Cameroon and Nigeria. The LWC chimpanzees come from multiple regions of Cameroon or forested areas straddling the Cameroon-Nigeria border. The LWC chimpanzees were partitioned further as originating from one of three biogeographically important zones occurring in Cameroon, but we were unable to refine these origin estimates to more specific areas within these three zones.</p> <p>Conclusions</p> <p>Our findings suggest that chimpanzee hunting is widespread across Cameroon. Live animal smuggling appears to occur locally within Cameroon, despite the existence of local wildlife cartels that operate internationally. This pattern varies from the illegal wildlife trade patterns observed in other commercially valuable species, such as elephants, where specific populations are targeted for exploitation. A broader sample of rescued chimpanzees compared against a more comprehensive grid of georeferenced samples may reveal 'hotspots' of chimpanzee hunting and live animal transport routes in Cameroon. These results illustrate also that clarifying the origins of refuge chimpanzees is an important tool for designing reintroduction programs. Finally, chimpanzees at refuges are frequently used in scientific investigations, such as studies investigating the history of zoonotic diseases. Our results provide important new information for interpreting these studies within a precise geographical framework.</p

Historical sampling reveals dramatic demographic changes in western gorilla populations

Background: Today many large mammals live in small, fragmented populations, but it is often unclear whether this subdivision is the result of long-term or recent events. Demographic modeling using genetic data can estimate changes in long-term population sizes while temporal sampling provides a way to compare genetic variation present today with that sampled in the past. In order to better understand the dynamics associated with the divergences of great ape populations, these analytical approaches were applied to western gorillas (Gorilla gorilla) and in particular to the isolated and Critically Endangered Cross River gorilla subspecies (G. g. diehli).Results: We used microsatellite genotypes from museum specimens and contemporary samples of Cross River gorillas to infer both the long-term and recent population history. We find that Cross River gorillas diverged from the ancestral western gorilla population ~17,800 years ago (95% HDI: 760, 63,245 years). However, gene flow ceased only ~420 years ago (95% HDI: 200, 16,256 years), followed by a bottleneck beginning ~320 years ago (95% HDI: 200, 2,825 years) that caused a 60-fold decrease in the effective population size of Cross River gorillas. Direct comparison of heterozygosity estimates from museum and contemporary samples suggests a loss of genetic variation over the last 100 years.Conclusions: The composite history of western gorillas could plausibly be explained by climatic oscillations inducing environmental changes in western equatorial Africa that would have allowed gorilla populations to expand over time but ultimately isolate the Cross River gorillas, which thereafter exhibited a dramatic population size reduction. The recent decrease in the Cross River population is accordingly most likely attributable to increasing anthropogenic pressure over the last several hundred years. Isolation of diverging populations with prolonged concomitant gene flow, but not secondary admixture, appears to be a typical characteristic of the population histories of African great apes, including gorillas, chimpanzees and bonobos

A Selection Index for Gene Expression Evolution and Its Application to the Divergence between Humans and Chimpanzees

The importance of gene regulation in animal evolution is a matter of long-standing interest, but measuring the impact of selection on gene expression has proven a challenge. Here, we propose a selection index of gene expression as a straightforward method for assessing the mode and strength of selection operating on gene expression levels. The index is based on the widely used McDonald-Kreitman test and requires the estimation of four quantities: the within-species and between-species expression variances as well as the sequence heterozygosity and divergence of neutrally evolving sequences. We apply the method to data from human and chimpanzee lymphoblastoid cell lines and show that gene expression is in general under strong stabilizing selection. We also demonstrate how the same framework can be used to estimate the proportion of adaptive gene expression evolution

Early infant HIV-1 diagnosis programs in resource-limited settings: opportunities for improved outcomes and more cost-effective interventions

Early infant diagnosis (EID) of HIV-1 infection confers substantial benefits to HIV-infected and HIV-uninfected infants, to their families, and to programs providing prevention of mother-to-child transmission (PMTCT) services, but has been challenging to implement in resource-limited settings. In order to correctly inform parents/caregivers of infant infection status and link HIV-infected infants to care and treatment, a 'cascade' of events must successfully occur. A frequently cited barrier to expansion of EID programs is the cost of the required laboratory assays. However, substantial implementation barriers, as well as personnel and infrastructure requirements, exist at each step in the cascade. In this update, we review challenges to uptake at each step in the EID cascade, highlighting that even with the highest reported levels of uptake, nearly half of HIV-infected infants may not complete the cascade successfully. We next synthesize the available literature about the costs and cost effectiveness of EID programs; identify areas for future research; and place these findings within the context of the benefits and challenges to EID implementation in resource-limited settings

Does Speciation between Arabidopsis halleri and Arabidopsis lyrata Coincide with Major Changes in a Molecular Target of Adaptation?

Ever since Darwin proposed natural selection as the driving force for the origin of species, the role of adaptive processes in speciation has remained controversial. In particular, a largely unsolved issue is whether key divergent ecological adaptations are associated with speciation events or evolve secondarily within sister species after the split. The plant Arabidopsis halleri is one of the few species able to colonize soils highly enriched in zinc and cadmium. Recent advances in the molecular genetics of adaptation show that the physiology of this derived ecological trait involves copy number expansions of the AhHMA4 gene, for which orthologs are found in single copy in the closely related A. lyrata and the outgroup A. thaliana. To gain insight into the speciation process, we ask whether adaptive molecular changes at this candidate gene were contemporary with important stages of the speciation process. We first inferred the scenario and timescale of speciation by comparing patterns of variation across the genomic backgrounds of A. halleri and A. lyrata. Then, we estimated the timing of the first duplication of AhHMA4 in A. halleri. Our analysis suggests that the historical split between the two species closely coincides with major changes in this molecular target of adaptation in the A. halleri lineage. These results clearly indicate that these changes evolved in A. halleri well before industrial activities fostered the spread of Zn- and Cd-polluted areas, and suggest that adaptive processes related to heavy-metal homeostasis played a major role in the speciation process

Role of Nonbehavioral Factors in Adjusting Long Bone Diaphyseal Structure in Free-ranging Pan troglodytes

Limb bones deform during locomotion and can resist the deformations by adjusting their shapes. For example, a tubular-shaped diaphysis best resists variably-oriented deformations. As behavioral profiles change during adulthood, patterns of bone deformation may exhibit age trends. Habitat characteristics, e.g., annual rainfall, tree density, and elevation changes, may influence bone deformations by eliciting individual components of behavioral repertoires and suppressing others, or by influencing movements during particular components. Habituated chimpanzee communities provide a unique opportunity to examine these factors because of the availability of morphological data and behavioral observations from known-age individuals inhabiting natural habitats. We evaluated adult femora and humeri of 18 female and 10 male free-ranging chimpanzees (Pan troglodytes) from communities in Gombe (Tanzania), Mahale Mountains (Tanzania), and Taï Forest (Côte d’Ivoire) National Parks. We compare cross sections at several locations (35%, 50%, 65% diaphyseal lengths). Community comparisons highlight different diaphyseal shapes of Taï females relative to Mahale and Gombe females, particularly in humeral diaphyses. Age trends in diaphyseal shapes are consistent with reduced activity levels in general, not only reduced arboreal activity. Age-related bone loss is apparent among community females, but is less striking among males. Community trends in diaphyseal shape are qualitatively consistent with ranked annual rainfall at localities, tree density, and elevation change or ruggedness of terrain. Habitat characteristics may contribute to variation in diaphyseal shape among chimpanzee communities, much like among modern human groups, but verification awaits further rigorous experimental and comparative analyses

Strategy for the management of diabetic macular edema: the European Vitreo-Retinal Society macular edema study

Objective. To compare the efficacy of different therapies in the treatment of diabetic macular edema (DME). Design. Nonrandomized, multicenter clinical study. Participants. 86 retina specialists from 29 countries provided clinical information on 2,603 patients with macular edema including 870 patients with DME. Methods. Reported data included the type and number of treatment(s) performed, the pre-and posttreatment visual acuities, and other clinical findings.The results were analyzed by the French INSEE (National Institute of Statistics and Economic Studies). Main Outcome Measures. Mean change of visual acuity and mean number of treatments performed. Results.The change in visual acuity over time in response to each treatment was plotted in second order polynomial regression trend lines. Intravitreal triamcinolone monotherapy resulted in some improvement in vision. Treatmentwith threshold or subthreshold grid laser also resulted in minimal vision gain. Anti-VEGF therapy resulted in more significant visual improvement. Treatment with pars plana vitrectomy and internal limiting membrane (ILM) peeling alone resulted in an improvement in vision greater than that observed with anti-VEGF injection alone. In our DME study, treatment with vitrectomy and ILM peeling alone resulted in the better visual improvement compared to other therapies