Use of next-generation sequencing and candidate gene analysis to identify underlying defects in patients with inherited platelet function disorders

Background: Inherited platelet function disorders (PFDs) are heterogeneous, and identification of the underlying genetic defects is difficult when based solely on phenotypic and clinical features of the patient. Objective: To analyze 329 genes regulating platelet function, number, and size in order to identify candidate gene defects in patients with PFDs. Patients/methods: Targeted analysis of candidate PFD genes was undertaken after next-generation sequencing of exomic DNA from 18 unrelated index cases with PFDs who were recruited into the UK Genotyping and Phenotyping of Platelets (GAPP) study and diagnosed with platelet abnormalities affecting either Gi signaling (n = 12) or secretion (n = 6). The potential pathogenicity of candidate gene defects was assessed using computational predictive algorithms. Results: Analysis of the 329 candidate PFD genes identified 63 candidate defects, affecting 40 genes, among index cases with Gi signaling abnormalities, while 53 defects, within 49 genes, were identified among patients with secretion abnormalities. Homozygous gene defects were more commonly associated with secretion abnormalities. Functional annotation analysis identified distinct gene clusters in the two patient subgroups. Thirteen genes with significant annotation enrichment for 'intracellular signaling' harbored 16 of the candidate gene defects identified in nine index cases with Gi signaling abnormalities. Four gene clusters, representing 14 genes, with significantly associated gene ontology annotations were identified among the cases with secretion abnormalities, the most significant association being with 'establishment of protein localization.' Conclusion: Our findings demonstrate the genetic complexity of PFDs and highlight plausible candidate genes for targeted analysis in patients with platelet secretion and Gi signaling abnormalities

The hand of Homo naledi

A nearly complete right hand of an adult hominin was recovered from the Rising Star cave system, South Africa. Based on associated hominin material, the bones of this hand are attributed to Homo naledi. This hand reveals a long, robust thumb and derived wrist morphology that is shared with Neandertals and modern humans, and considered adaptive for intensified manual manipulation. However, the finger bones are longer and more curved than in most australopiths, indicating frequent use of the hand during life for strong grasping during locomotor climbing and suspension. These markedly curved digits in combination with an otherwise human-like wrist and palm indicate a significant degree of climbing, despite the derived nature of many aspects of the hand and other regions of the postcranial skeleton in H. naledi

Quaternary time scales for the Pontocaspian domain: interbasinal connectivity and faunal evolution

The Pontocaspian (Black Sea - Caspian Sea) region has a very dynamic history of basin development and biotic evolution. The region is the remnant of a once vast Paratethys Sea. It contains some of the best Eurasian geological records of tectonic, climatic and paleoenvironmental change. The Pliocene-Quaternary co-evolution of the Black Sea-Caspian Sea is dominated by major changes in water (lake and sea) levels resulting in a pulsating system of connected and isolated basins. Understanding the history of the region, including the drivers of lake level and faunal evolution, is hampered by indistinct stratigraphic nomenclature and contradicting time constraints for regional sedimentary successions. In this paper we review and update the late Pliocene to Quaternary stratigraphic framework of the Pontocaspian domain, focusing on the Black Sea Basin, Caspian Basin, Marmara Sea and the terrestrial environments surrounding these large, mostly endorheic lake-sea systems

Effect of gender difference on platelet reactivity

Background Previous studies have suggested that women do not accrue equal therapeutic benefit from antiplatelet medication as compared with men. The physiological mechanism and clinical implications behind this gender disparity have yet to be established. Methods On-treatment platelet reactivity was determined in 717 men and 234 women on dual antiplatelet therapy, undergoing elective coronary stent implantation. Platelet function testing was performed using arachidonic acid and adenosine diphosphate-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 and Aspirin assays. Also the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischaemic stroke was evaluated. Results Women had higher baseline platelet counts than men. Women exhibited a higher magnitude of on-aspirin platelet reactivity using LTA, but not using the VerifyNow Aspirin assay. The magnitude of on-clopidogrel platelet reactivity was significantly higher in women as compared with men with both tests used. The cut-off value to identify patients at risk as well as the incidence of clinical endpoints was similar between women and men (16/234[6.8%] vs. 62/717[8.6%], p=0.38). Conclusion Although the magnitude of platelet reactivity was higher in women, the absolute difference between genders was small and both the cut-off value to identify patients at risk and the incidence of the composite endpoint were similar between genders. Thus, it is unlikely that the difference in platelet reactivity accounts for a worse prognosis in women

Generosity Pays in the Presence of Direct Reciprocity: A Comprehensive Study of 2×2 Repeated Games

By applying a technique previously developed to study ecosystem assembly [Capitán et al., Phys. Rev. Lett. 103, 168101 (2009)] we study the evolutionary stable strategies of iterated 22 games. We focus on memory-one strategies, whose probability to play a given action depends on the actions of both players in the previous time step. We find the asymptotically stable populations resulting from all possible invasions of any known stable population. The results of this invasion process are interpreted as transitions between different populations that occur with a certain probability. Thus the whole process can be described as a Markov chain whose states are the different stable populations. With this approach we are able to study the whole space of symmetric 22 games, characterizing the most probable results of evolution for the different classes of games. Our analysis includes quasi-stationary mixed equilibria that are relevant as very long-lived metastable states and is compared to the predictions of a fixation probability analysis. We confirm earlier results on the success of the Pavlov strategy in a wide range of parameters for the iterated Prisoner's Dilemma, but find that as the temptation to defect grows there are many other possible successful strategies. Other regions of the diagram reflect the equilibria structure of the underlying one-shot game, albeit often some non-expected strategies arise as well. We thus provide a thorough analysis of iterated 22 games from which we are able to extract some general conclusions. Our most relevant finding is that a great deal of the payoff parameter range can still be understood by focusing on win-stay, lose-shift strategies, and that very ambitious ones, aspiring to obtaining always a high payoff, are never evolutionary stable

Early Pleistocene enamel proteome from Dmanisi resolves Stephanorhinus phylogeny

The sequencing of ancient DNA has enabled the reconstruction of speciation, migration and admixture events for extinct taxa. However, the irreversible post-mortem degradation2 of ancient DNA has so far limited its recovery—outside permafrost areas—to specimens that are not older than approximately 0.5 million years (Myr). By contrast, tandem mass spectrometry has enabled the sequencing of approximately 1.5-Myr-old collagen type I, and suggested the presence of protein residues in fossils of the Cretaceous period—although with limited phylogenetic use. In the absence of molecular evidence, the speciation of several extinct species of the Early and Middle Pleistocene epoch remains contentious. Here we address the phylogenetic relationships of the Eurasian Rhinocerotidae of the Pleistocene epoch, using the proteome of dental enamel from a Stephanorhinus tooth that is approximately 1.77-Myr old, recovered from the archaeological site of Dmanisi (South Caucasus, Georgia). Molecular phylogenetic analyses place this Stephanorhinus as a sister group to the clade formed by the woolly rhinoceros (Coelodonta antiquitatis) and Merck’s rhinoceros (Stephanorhinus kirchbergensis). We show that Coelodonta evolved from an early Stephanorhinus lineage, and that this latter genus includes at least two distinct evolutionary lines. The genus Stephanorhinus is therefore currently paraphyletic, and its systematic revision is needed. We demonstrate that sequencing the proteome of Early Pleistocene dental enamel overcomes the limitations of phylogenetic inference based on ancient collagen or DNA. Our approach also provides additional information about the sex and taxonomic assignment of other specimens from Dmanisi. Our findings reveal that proteomic investigation of ancient dental enamel—which is the hardest tissue in vertebrates, and is highly abundant in the fossil record—can push the reconstruction of molecular evolution further back into the Early Pleistocene epoch, beyond the currently known limits of ancient DNA preservation

The rise and transformation of Bronze Age pastoralists in the Caucasus

The Caucasus and surrounding areas, with their rich metal resources, became a crucible of the Bronze Age1 and the birthplace of the earliest steppe pastoralist societies2. Yet, despite this region having a large influence on the subsequent development of Europe and Asia, questions remain regarding its hunter-gatherer past and its formation of expansionist mobile steppe societies3,4,5. Here we present new genome-wide data for 131 individuals from 38 archaeological sites spanning 6,000 years. We find a strong genetic differentiation between populations north and south of the Caucasus mountains during the Mesolithic, with Eastern hunter-gatherer ancestry4,6 in the north, and a distinct Caucasus hunter-gatherer ancestry7 with increasing East Anatolian farmer admixture in the south. During the subsequent Eneolithic period, we observe the formation of the characteristic West Eurasian steppe ancestry and heightened interaction between the mountain and steppe regions, facilitated by technological developments of the Maykop cultural complex8. By contrast, the peak of pastoralist activities and territorial expansions during the Early and Middle Bronze Age is characterized by long-term genetic stability. The Late Bronze Age marks another period of gene flow from multiple distinct sources that coincides with a decline of steppe cultures, followed by a transformation and absorption of the steppe ancestry into highland populations

Genome-wide population affinities and signatures of adaptation in hydruntines, sussemiones and Asian wild asses

Abstract The extremely rich palaeontological record of the horse family, also known as equids, has provided many examples of macroevolutionary change over the last ~55 Mya. This family is also one of the most documented at the palaeogenomic level, with hundreds of ancient genomes sequenced. While these data have advanced understanding of the domestication history of horses and donkeys, the palaeogenomic record of other equids remains limited. In this study, we have generated genome-wide data for 25 ancient equid specimens spanning over 44 Ky and spread across Anatolia, the Caucasus, Central Asia and Mongolia. Our dataset includes the genomes from two extinct species, the European wild ass, Equus hydruntinus, and the sussemione Equus ovodovi. We document, for the first time, the presence of sussemiones in Mongolia and their survival around ~3.9 Kya, a finding that should be considered when discussing the timing of the first arrival of the domestic horse in the region. We also identify strong spatial differentiation within the historical ecological range of Asian wild asses, Equus hemionus, and incomplete reproductive isolation in several groups yet considered as different species. Finally, we find common selection signatures at ANTXR2 gene in European, Asian and African wild asses. This locus, which encodes a receptor for bacterial toxins, shows no selection signal in E.?ovodovi, but a 5.4-kb deletion within intron 7. Whether such genetic modifications played any role in the sussemione extinction remains unknown.1 Introduction 2 Materials and methods 2.1 Samples 2.2 Ancient DNA extraction, library construction and sequencing 2.3 Read processing, trimming and alignment 2.4 Mitochondrial sequencing data processing 2.5 Genomic variation calling 2.6 Principal component analysis (PCA) 2.7 Neighbour-joining phylogeny, genetic continuity and population modelling 2.8 Ancestry modelling 2.9 Gene flow and signatures of introgression 2.10 Selection signatures 3 Results 3.1 Genome sequencing and species identification 3.2 Genetic structure and diversity 3.3 Selection and adaptive introgression 4 Discussio

Neurocranium versus Face: A Morphometric Approach with Classical Anthropometric Variables for Characterizing Patterns of Cranial Integration in Extant Hominoids and Extinct Hominins

The relative importance of the two main cranial complexes, the neurocranium and the splanchnocranium, has been examined in the five species of extant hominoids and in a huge sample of extinct hominins using six standard craniometric variables that measure the length, width and height of each cranial module. Factor analysis and two-block partial least squares were used for establishing the major patterns of developmental and evolutionary integration between both cranial modules. The results obtained show that all extant hominoids (including the anatomically modern humans) share a conserved pattern of developmental integration, a result that agrees with previous studies. The pattern of evolutionary integration between both cranial modules in australopiths runs in parallel to developmental integration. In contrast, the pattern of evolutionary and developmental integration of the species of the genus Homo is the opposite, which is probably the consequence of distinctive selective regimes for both hominin groups.JAPC, JMJA and PP received fundings from Ministerio de Ciencia e Innovación, Gobierno de España (http://www.idi.mineco.gob.es), project CGL2011-30334, and Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía, España (http://www.juntadeandalucia.es/organismo​s/economiainnovacioncienciayempleo.html), project P11-HUM-7248 and Research Groups RNM-146 and HUM-607