Several inferential methods using genomic data have been proposed to quantify and date population size changes in the history of species. At the same time an increasing number of studies have shown that population structure can generate spurious signals of population size change. Recently, Mazet et al. (2016) introduced, for a sample size of two, a time-dependent parameter, which they called the IICR (inverse instantaneous coalescence rate). The IICR is equivalent to a population size in panmictic models, but not necessarily in structured models. It is characterised by a temporal trajectory that suggests population size changes, as a function of the sampling scheme, even when the total population size was constant. Here, we extend the work of Mazet et al. (2016) by (i) showing how the IICR can be computed for any demographic model of interest, under the coalescent, (ii) applying this approach to models of population structure (1D and 2D stepping stone, split models, two- and three-island asymmetric gene flow, continent-island models), (iii) stressing the importance of the sampling strategy in generating different histories, (iv) arguing that IICR plots can be seen as summaries of genomic information that can thus be used for model choice or model exclusion (v) applying this approach to the question of admixture between humans and Neanderthals. Altogether these results are potentially important given that the widely used PSMC (pairwise sequentially Markovian coalescent) method of Li and Durbin (2011) estimates the IICR of the sample, not necessarily the history of the populations.

Little has been reported on the factors, genetic or other, that underlie the variability in individual response, particularly for autism. In this study we simultaneously explored the effects of multiple candidate genes on clinical improvement and occurrence of adverse drug reactions, in 45 autistic patients who received monotherapy with risperidone up to 1 year. Candidate genes involved in the pharmacokinetics (CYP2D6 and ABCB1) and pharmacodynamics (HTR2A, HTR2C, DRD2, DRD3, HTR6) of the drug, and the brain-derived neurotrophic factor (BDNF) gene, were analysed. Using the generalized estimating equation method these genes were tested for association with drug efficacy, assessed with the Autism Treatment Evaluation Checklist, and with safety and tolerability measures, such as prolactin levels, body mass index (BMI), waist circumference and neurological adverse effects, including extrapyramidal movements. Our results confirm that risperidone therapy was very effective in reducing some autism symptoms and caused few serious adverse effects. After adjusting for confounding factors, the HTR2A c.-1438G4A, DRD3 Ser9Gly, HTR2C c.995G4A and ABCB1 1236C4T polymorphisms were predictors for clinical improvement with risperidone therapy. The HTR2A c.-1438G4A, HTR2C c.68G4C (p.C33S), HTR6 c.7154-2542C4T and BDNF c.196G4A (p.V66M) polymorphisms influenced prolactin elevation. HTR2C c.68G4C and CYP2D6 polymorphisms were associated with risperidone-induced increase in BMI or waist circumference. We thus identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Although association results require replication, given the small sample size, the study makes a preliminary contribution to the personalized therapy of risperidone in autism.

Differences in metabolism of drugs can lead to severe toxicity or therapeutic failure. In addition to cytochrome P450 2D6, which plays a critical role in drug metabolism, ABCB1 encoded P-glycoprotein (PGP) is also an important determinant in drug bioavailability. The genes encoding these molecules are highly variable among populations and, given their clinical importance in drug therapy, determining CYP2D6 and ABCB1 allele frequencies in specific populations is very important for useful application in clinical settings. In this study the frequency of the pharmacologically relevant CYP2D6*3, *4, *5, *6 allelic variants and gene duplication, and ABCB1 C1236T and C3435T gene polymorphisms and their haplotypes was determined in a population sample of 100 Portuguese healthy subjects. CYP2D6 allele frequencies were 1.4% (*3), 13.3% (*4), 2.8% (*5), 1.8% (*6) and 6.1% (gene duplication), with 5% of the individuals classified as PM and 8.4% as UM. The frequencies obtained for the non-functional alleles and for the CYP2D6 gene duplication are in agreement with other South European populations, and reinforce the previously suggested south/north gradient of CYP2D6 duplications. Allelic frequencies for the ABCB1 polymorphisms were 52% (3435C) and 54% (1236C) and the most common haplotype (1236C-3435C) occurred with a frequency of 45.5%. Although allele and haplotype frequency data for ABCB1 in Southern Europe is limited, some discrepancies were found with other European populations, with possible therapeutic implications for PGP substrate drugs.

These results suggest that UC has a dual mitochondrial and nuclear genetic control that warrants further replication in independent data sets and reinforces its etiopathogenic complexity.

Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22–2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08–2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29–2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis.

To reconstruct aspects of human demographic history, linguistics and genetics complement each other, reciprocally suggesting testable hypotheses on population relationships and interactions. Relying on a linguistic comparative method based on syntactic data, here we focus on the non-straightforward relation of genes and languages among Finno-Ugric (FU) speakers, in comparison to their Indo-European (IE) and Altaic (AL) neighbors. Syntactic analysis, in agreement with the indications of more traditional linguistic levels, supports at least three distinct clusters, corresponding to these three Eurasian families; yet, the outliers of the FU group show linguistic convergence with their geographical neighbors. By analyzing genome-wide data in both ancient and contemporary populations, we uncovered remarkably matching patterns, with north-western FU speakers linguistically and genetically closer in parallel degrees to their IE-speaking neighbors, and eastern FU speakers to AL speakers. Therefore, our analysis indicates that plausible cross-family linguistic interference effects were accompanied, and possibly caused, by recognizable demographic processes. In particular, based on the comparison of modern and ancient genomes, our study identified the Pontic-Caspian steppes as the possible origin of the demographic processes that led to the expansion of FU languages into Europe.

To reconstruct aspects of human demographic history, linguistics and genetics complement each other, reciprocally suggesting testable hypotheses on population relationships and interactions. Relying on a linguistic comparative method exclusively based on syntactic data, here we focus on the complex relation of genes and languages among Finno-Ugric (FU) speakers, in comparison to their Indo-European (IE) and Altaic (AL) neighbors. Syntactic analysis supports three distinct clusters corresponding to these three Eurasian families; yet, the outliers of the FU group show linguistic convergence with their geographical neighbors. By analyzing genome-wide data in both ancient and contemporary populations, we uncovered remarkably matching patterns, with north-western FU speakers linguistically and genetically closer in parallel degrees to their IE-speaking neighbors, and eastern FU speakers to AL-speakers. Therefore, our study indicates plausible secondary convergence in the syntax of languages of different families, providing evidence that such interference effects were accompanied, and possibly caused, by recognizable processes at the population level. In particular, based on the comparison of modern and ancient genomes, our analysis identified the Pontic-Caspian steppes as the possible origin of the demographic processes that led to the expansion of the FU into Europe.

Strokes are a major cause of motor, perceptual and cognitive dysfunction. Thus, perceptual stimulation in individuals with stroke is a fundamental procedure in the rehabilitation process, since it contributes to improved performance in activities of daily living. Perceptive rehabilitation could be performed with conventional procedures or by applying technology. However, the methods used to evaluate and treat perceptual changes using visual stimuli are generic and not personalized. Therefore, an innovative platform called RehabVisual was developed and already used with little children. It has the objective of stimulating the visuomotor competence. The platform is now applied to 3 subjects with stroke. The purpose of this article is to describe the platform and present the results of the application in stroke patients.