Taxonomy and biogeography of Bunopus spatalurus (Reptilia; Gekkonidae) from the Arabian Peninsula

In the last decade, taxonomic studies have drastically increased the number of species known to inhabit the Arabian deserts. While ongoing phylogenetic studies continue to identify new species and high levels of intraspecific genetic diversity, few studies have yet explored the biogeographic patterns in this arid region using an integrative approach. In the present work, we apply different phylogenetic methods to infer relationships within the Palearctic naked‐toed geckos. We specifically address for the first time the taxonomy and biogeography of Bunopus spatalurus Anderson, 1901, from Arabia using multilocus concatenated and species tree phylogenies, haplotype networks and morphology. We also use species distribution modelling and phylogeographic interpolation to explore the phylogeographic structure of Bunopus spatalurus hajarensis in the Hajar Mountains and the roles of climatic stability and possible biogeographic barriers on lineage occurrence and contact zones in this arid mountain endemism hot spot. According to the inferred topology recovered using concatenated and species tree methods, the genus ‘Bunopus’ is polyphyletic. Bunopus tuberculatus and B. blanfordii form a highly supported clade closely related to Crossobamon orientalis, while the two subspecies of ‘Bunopus’ spatalurus branch together as an independent highly supported clade that diverged during the Miocene according to our estimations. Within B. s. hajarensis, three geographically structured clades can be recognized that according to our estimations diverged during the Late Miocene to Pliocene. The paleodistribution models indicate climatic stability during the Late Pleistocene and the lineage occurrence, and predicted contact zones obtained from phylogeographic interpolation therefore probably result from the older splits of the groups when these lineages originated in allopatry. As demonstrated by the results of the multilocus molecular phylogenetic analyses and the topological test carried out in this study, the genus ‘Bunopus’ is not monophyletic. To resolve this, we resurrect the genus Trachydactylus Haas and Battersby, 1959; for the species formerly referred to as Bunopus spatalurus. Considering the morphological differences, the high level of genetic differentiation in the 12S mitochondrial gene and the results of the phylogenetic and the cmos haplotype network analysis, we elevate Trachydactylus spatalurus hajarensis to the species level Trachydactylus hajarensis (Arnold, 1980).     

Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response

Selective small-molecule inhibitors represent powerful tools for the dissection of complex biological processes. ES(I) (eeyarestatin I) is a novel modulator of ER (endoplasmic reticulum) function. In the present study, we show that in addition to acutely inhibiting ERAD (ER-associated degradation), ES(I) causes production of mislocalized polypeptides that are ubiquitinated and degraded. Unexpectedly, our results suggest that these non-translocated polypeptides promote activation of the UPR (unfolded protein response), and indeed we can recapitulate UPR activation with an alternative and quite distinct inhibitor of ER translocation. These results suggest that the accumulation of non-translocated proteins in the cytosol may represent a novel mechanism that contributes to UPR activation.     

Integrating Linguistics,Social Structure,and Geography to Model Genetic Diversity within India

India represents an intricate tapestry of population substructure shaped by geography, language, culture, and social stratification. Although geography closely correlates with genetic structure in other parts of the world, the strict endogamy imposed by the Indian caste system and the large number of spoken languages add further levels of complexity to understand Indian population structure. To date, no study has attempted to model and evaluate how these factors have interacted to shape the patterns of genetic diversity within India. We merged all publicly available data from the Indian subcontinent into a data set of 891 individuals from 90 well-defined groups. Bringing together geography, genetics, and demographic factors, we developed Correlation Optimization of Genetics and Geodemographics to build a model that explains the observed population genetic substructure. We show that shared language along with social structure have been the most powerful forces in creating paths of gene flow in the subcontinent. Furthermore, we discover the ethnic groups that best capture the diverse genetic substructure using a ridge leverage score statistic. Integrating data from India with a data set of additional 1,323 individuals from 50 Eurasian populations, we find that Indo-European and Dravidian speakers of India show shared genetic drift with Europeans, whereas the Tibeto-Burman speaking tribal groups have maximum shared genetic drift with East Asians.     

Elevation of Proteasomal Substrate Levels Sensitizes Cells to Apoptosis Induced by Inhibition of Proteasomal Deubiquitinases

Inhibitors of the catalytic activity of the 20S proteasome are cytotoxic to tumor cells and are currently in clinical use for treatment of multiple myeloma, whilst the deubiquitinase activity associated with the 19S regulatory subunit of the proteasome is also a valid target for anti-cancer drugs. The mechanisms underlying the therapeutic efficacy of these drugs and their selective toxicity towards cancer cells are not known. Here, we show that increasing the cellular levels of proteasome substrates using an inhibitor of Sec61-mediated protein translocation significantly increases the extent of apoptosis that is induced by inhibition of proteasomal deubiquitinase activity in both cancer derived and non-transformed cell lines. Our results suggest that increased generation of misfolded proteasome substrates may contribute to the mechanism(s) underlying the increased sensitivity of tumor cells to inhibitors of the ubiquitin-proteasome system.     

PCA-correlated SNPs for structure identification in worldwide human populations

Existing methods to ascertain small sets of markers for the identification of human population structure require prior knowledge of individual ancestry. Based on Principal Components Analysis (PCA), and recent results in theoretical computer science, we present a novel algorithm that, applied on genomewide data, selects small subsets of SNPs (PCA-correlated SNPs) to reproduce the structure found by PCA on the complete dataset, without use of ancestry information. Evaluating our method on a previously described dataset (10,805 SNPs, 11 populations), we demonstrate that a very small set of PCA-correlated SNPs can be effectively employed to assign individuals to particular continents or populations, using a simple clustering algorithm. We validate our methods on the HapMap populations and achieve perfect intercontinental differentiation with 14 PCA-correlated SNPs. The Chinese and Japanese populations can be easily differentiated using less than 100 PCA-correlated SNPs ascertained after evaluating 1.7 million SNPs from HapMap. We show that, in general, structure informative SNPs are not portable across geographic regions. However, we manage to identify a general set of 50 PCA-correlated SNPs that effectively assigns individuals to one of nine different populations. Compared to analysis with the measure of informativeness, our methods, although unsupervised, achieved similar results. We proceed to demonstrate that our algorithm can be effectively used for the analysis of admixed populations without having to trace the origin of individuals. Analyzing a Puerto Rican dataset (192 individuals, 7,257 SNPs), we show that PCA-correlated SNPs can be used to successfully predict structure and ancestry proportions. We subsequently validate these SNPs for structure identification in an independent Puerto Rican dataset. The algorithm that we introduce runs in seconds and can be easily applied on large genome-wide datasets, facilitating the identification of population substructure, stratification assessment in multi-stage whole-genome association studies, and the study of demographic history in human populations.     

Reduced genetic variation and strong genetic population structure in the freshwater killifish Valencia letourneuxi (Valenciidae) based on nuclear and mitochondrial markers

The genetic variation of the critically endangered Corfu killifish (Valencia letourneuxi), an endemic freshwater fish species of the western Balkans, was assessed for nine populations sampled in eight water systems in western continental Greece, the Peloponnese and the Ionian Island of Corfu, using mitochondrial and microsatellite markers. The analyses were based on data from three mtDNA regions (D‐loop, COI and 16S rRNA sequences) and 14 microsatellite loci. Samples from the congeneric species Valencia hispanica and the phylogenetically closely related species Aphanius fasciatus were also used in the study as outgroups. Both the mitochondrial and the microsatellite analyses revealed three distinct population groupings associated with the geographical distribution of the populations: one southern group occupying rivers draining to the Patraikos Gulf, the second one including the populations flowing into the Amvrakikos Gulf and the third, more northern group, including the other populations from rivers in Corfu Island and Epirus flowing into the Ionian Sea. Within these groupings there is limited genetic differentiation between populations; in addition, there is reduced intrapopulation genetic variation, evidenced by low heterozygosity values, number of alleles and haplotype diversity. In terms of taxonomic implications and appropriate management actions for conservation, our data suggest that the major population groups should be regarded at least as three distinct conservation units (CUs), with translocation and restocking actions to take place only within the geographical range of the CU concerned. © 2013 The Linnean Society of London, Biological Journal of the Linnean Society, 2014, 111 , 334–349.     

Birth Weight and Polycystic Ovary Syndrome in Adult Life: Is There a Causal Link?

Objectives

Several studies have demonstrated associations of birth weight with metabolic and reproductive abnormalities in adults. The aim of this study was to investigate the birth weight in women with PCOS and its correlation with clinical and biochemical characteristics of the syndrome.

Materials and Methods

We studied 288 women with PCOS according to the NIH criteria and 166 women with normal cycle and without clinical hyperandrogenism. Birth weight and anthropometric characteristics were recorded, and levels of serum androgens, SHBG, insulin and fasting glucose were measured.

Results

Birth weight data were available for 243/288 women with PCOS and age- and BMI-matched 101/166 controls. No differences were found (p> 0.05) in birth weight among women with PCOS and normal controls. Birth weight of PCOS women was negatively correlated with DHEAS levels (p = 0.031, r = -0.143) and positively correlated with waist circumference (p <0.001, r = 0.297) and body mass index (BMI) (p = 0.040, r = 0.132). Birth weight of controls was negatively correlated with SHBG levels (p = 0.021, r = -0.234). Women from both groups were further divided in 6 categories according to birth weight (A. <2.500 gr, B. 2.501-3.000 gr, C. 3.001-3.500 gr, D. 3.501-4.000 gr, E. 4.001-4.500 gr, F. > 4.500 gr). No statistically significant differences were observed in the distribution percentages between PCOS women and controls. (A. 7% vs 7.9%, B. 26.8% vs 20.8%, C. 39.1% vs 48.5%, D. 21.4% vs 20.8%, E. 4.9% vs 2%, F. 0.8% vs 0%), (in all comparisons, p> 0.05).

Conclusions

Women with PCOS do not differ from controls in birth weight distribution. However, birth weight may contribute to subtypes of the syndrome that are characterized by adrenal hyperandrogenism and central obesity.     

A global view of the OCA2-HERC2 region and pigmentation

Mutations in the gene OCA2 are responsible for oculocutaneous albinism type 2, but polymorphisms in and around OCA2 have also been associated with normal pigment variation. In Europeans, three haplotypes in the region have been shown to be associated with eye pigmentation and a missense SNP (rs1800407) has been associated with green/hazel eyes (Branicki et al. in Ann Hum Genet 73:160-170, 2009). In addition, a missense mutation (rs1800414) is a candidate for light skin pigmentation in East Asia (Yuasa et al. in Biochem Genet 45:535-542, 2007; Anno et al. in Int J Biol Sci 4, 2008). We have genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region including those previously associated with eye or skin pigmentation. We report that the blue-eye associated alleles at all three haplotypes were found at high frequencies in Europe; however, one is restricted to Europe and surrounding regions, while the other two are found at moderate to high frequencies throughout the world. We also observed that the derived allele of rs1800414 is essentially limited to East Asia where it is found at high frequencies. Long-range haplotype tests provide evidence of selection for the blue-eye allele at the three haplotyped systems but not for the green/hazel eye SNP allele. We also saw evidence of selection at the derived allele of rs1800414 in East Asia. Our data suggest that the haplotype restricted to Europe is the strongest marker for blue eyes globally and add further inferential evidence that the derived allele of rs1800414 is an East Asian skin pigmentation allele.     

Evaluation of the LIM homeobox genes LHX6 and LHX8 as candidates for Tourette syndrome

The etiology and pathophysiology of Tourette Syndrome (TS) remain poorly understood. Multiple lines of evidence suggest that a complex genetic background and the cortico-striato-thalamo-cortical circuit are involved. The role of Lhx6 and Lhx8 in the development of the striatal interneurons, prompted us to investigate them as novel candidate genes for TS. We performed a comparative study of the expression of Lhx6 and Lhx8 and investigated genetic association with TS using two samples of trios (TSGeneSEE and German sample - 222 families). We show that Lhx6 and Lhx8 expression in the forebrain is evolutionarily conserved, underlining their possible importance in TS-related pathophysiological pathways. Our tagging-single nucleotide polymorphism (tSNP)-based association analysis was negative for association with LHX8. However, we found positive association with LHX6 in the TSGeneSEE sample (corrected P-value = 0.006 for three-site haplotype around SNP rs3808901) but no association in the sample of German families. Interestingly, the SNP allele that was identified to be significantly associated in the TSGeneSEE dataset, showed an opposite trend of transmission in the German dataset. Our analysis of the correlation of the LHX6 region with individual ancestry within Europe, revealed the fact that this particular SNP demonstrates a high degree of population differentiation and is correlated with the North to South axis of European genetic variation. Our results indicate that further study of the LHX6 gene in relation to the TS phenotype is warranted and suggest the intriguing hypothesis that different genetic factors may contribute to the etiology of TS in different populations, even within Europe.     

Tracing sub-structure in the European American population with PCA-informative markers

Genetic structure in the European American population reflects waves of migration and recent gene flow among different populations. This complex structure can introduce bias in genetic association studies. Using Principal Components Analysis (PCA), we analyze the structure of two independent European American datasets (1,521 individuals-307,315 autosomal SNPs). Individual variation lies across a continuum with some individuals showing high degrees of admixture with non-European populations, as demonstrated through joint analysis with HapMap data. The CEPH Europeans only represent a small fraction of the variation encountered in the larger European American datasets we studied. We interpret the first eigenvector of this data as correlated with ancestry, and we apply an algorithm that we have previously described to select PCA-informative markers (PCAIMs) that can reproduce this structure. Importantly, we develop a novel method that can remove redundancy from the selected SNP panels and show that we can effectively remove correlated markers, thus increasing genotyping savings. Only 150-200 PCAIMs suffice to accurately predict fine structure in European American datasets, as identified by PCA. Simulating association studies, we couple our method with a PCA-based stratification correction tool and demonstrate that a small number of PCAIMs can efficiently remove false correlations with almost no loss in power. The structure informative SNPs that we propose are an important resource for genetic association studies of European Americans. Furthermore, our redundancy removal algorithm can be applied on sets of ancestry informative markers selected with any method in order to select the most uncorrelated SNPs, and significantly decreases genotyping costs.