The Variance of Identity-by-Descent Sharing in the Wright–Fisher Model

Widespread sharing of long, identical-by-descent (IBD) genetic segments is a hallmark of populations that have experienced recent genetic drift. Detection of these IBD segments has recently become feasible, enabling a wide range of applications from phasing and imputation to demographic inference. Here, we study the distribution of IBD sharing in the Wright–Fisher model. Specifically, using coalescent theory, we calculate the variance of the total sharing between random pairs of individuals. We then investigate the cohort-averaged sharing: the average total sharing between one individual and the rest of the cohort. We find that for large cohorts, the cohort-averaged sharing is distributed approximately normally. Surprisingly, the variance of this distribution does not vanish even for large cohorts, implying the existence of “hypersharing” individuals. The presence of such individuals has consequences for the design of sequencing studies, since, if they are selected for whole-genome sequencing, a larger fraction of the cohort can be subsequently imputed. We calculate the expected gain in power of imputation by IBD and subsequently in power to detect an association, when individuals are either randomly selected or specifically chosen to be the hypersharing individuals. Using our framework, we also compute the variance of an estimator of the population size that is based on the mean IBD sharing and the variance in the sharing between inbred siblings. Finally, we study IBD sharing in an admixture pulse model and show that in the Ashkenazi Jewish population the admixture fraction is correlated with the cohort-averaged sharing.IN isolated populations, even purported unrelated individuals often share genetic material that is identical-by-descent (IBD). Traditionally, the term IBD sharing referred to coancestry at a single site (or autozygosity, in the case of a diploid individual) and was widely investigated as a measure of the degree of inbreeding in a population (Hartl and Clark 2006). Recent years have brought dramatic increases in the quantity and density of available genetic data and, together with new computational tools, these data have enabled the detection of IBD sharing of entire genomic segments (see, e.g., Purcell et al. 2007; Kong et al. 2008; Albrechtsen et al. 2009; Gusev et al. 2009; Browning and Browning 2011; Carr et al. 2011; Brown et al. 2012). The availability of IBD detection tools that are efficient enough to detect shared segments in large cohorts has resulted in numerous applications, from demographic inference (Davison et al. 2009; Palamara et al. 2012) and characterization of populations (Gusev et al. 2012a) to selection detection (Albrechtsen et al. 2010), relatedness detection and pedigree reconstruction (Huff et al. 2011; Kirkpatrick et al. 2011; Stevens et al. 2011; Henn et al. 2012), prioritization of individuals for sequencing (Gusev et al. 2012b), inference of HLA type (Setty et al. 2011), detection of haplotypes associated with a disease or a trait (Akula et al. 2011; Gusev et al. 2011; Browning and Thompson 2012), imputation (Uricchio et al. 2012), and phasing (Palin et al. 2011).Recently, some of us used coalescent theory to calculate several theoretical quantities of IBD sharing under a number of demographic histories. Then, shared segments were detected in real populations, and their demographic histories were inferred (Palamara et al. 2012). Here, we expand upon Palamara et al. (2012) to investigate additional aspects of the stochastic variation in IBD sharing. Specifically, we provide a precise calculation for the variance of the total sharing in the Wright–Fisher model, either between a random pair of individuals or between one individual and all others in the cohort.Understanding the variation in IBD sharing is an important theoretical characterization of the Wright–Fisher model, and additionally, it has several practical applications. For example, it can be used to calculate the variance of an estimator of the population size that is based on the sharing between random pairs. In a different domain, the variance in IBD sharing is needed to accurately assess strategies for sequencing study design, specifically, in prioritization of individuals to be sequenced. This is because imputation strategies use IBD sharing between sequenced individuals and genotyped, not-sequenced individuals to increase the number of effective sequences analyzed in the association study (Palin et al. 2011; Gusev et al. 2012b; Uricchio et al. 2012).In the remainder of this article, we first review the derivation of the mean fraction of the genome shared between two individuals (Palamara et al. 2012). We then calculate the variance of this quantity, using coalescent theory with recombination. We provide a number of approximations, one of which results in a surprisingly simple expression, which is then generalized to a variable population size and to the sharing of segments in a length range. We also numerically investigate the pairwise sharing distribution and provide an approximate fit. We then turn to the average total sharing between each individual and the entire cohort. We show that this quantity, which we term the cohort-averaged sharing, is approximately normally distributed, but is much wider than naively expected, implying the existence of hypersharing individuals. We consider several applications: the number of individuals needed to be sequenced to achieve a certain imputation power and the implications to disease mapping, inference of the population size based on the total sharing, and the variance of the sharing between siblings. We finally calculate the mean and the variance of the sharing in an admixture pulse model and show numerically that admixture results in a broader than expected cohort-averaged sharing. Therefore, large variance of the cohort-averaged sharing can indicate admixture. In the Ashkenazi Jewish population, we show that the cohort-averaged sharing is strongly anticorrelated with the fraction of European ancestry.     

Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues

Cinnamic acids and quinolines are known as useful scaffolds in the discovery of antitumor agents. Therefore, N-cinnamoylated analogues of chloroquine, recently reported as potent dual-action antimalarials, were evaluated against three different cancer cell lines: MKN-28, Caco-2, and MCF-7. All compounds display anti-proliferative activity in the micromolar range against the three cell lines tested, and most of them were more active than their parent drug, chloroquine, against all cell lines tested. Hence, N-cinnamoyl-chloroquine analogues are a good start towards development of affordable antitumor leads.     

Synthesis and antimicrobial activity of novel amphiphilic aromatic amino alcohols

We report in this work the preparation and in vitro antimicrobial evaluation of novel amphiphilic aromatic amino alcohols synthesized by reductive amination of 4-alkyloxybenzaldehyde with 2-amino-2-hydroxymethyl-propane-1,3-diol. The antibacterial activity was determined against four standard strains (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa) and 21 clinical isolates of methicillin-resistant Staphylococcus aureus. The antifungal activity was evaluated against four yeast (Candida albicans, Candida tropicalis, Candida glabrata and Candida parapsilosis). The results obtained showed a strong positive correlation between the lipophilicity and the antibiotic activity of the tested compounds. The best activities were obtained against the Gram-positive bacteria (MIC = 2–16 μg ml^?1) for the five compounds bearing longer alkyl chains (4c–g; 8–14 carbons), which were also the most active against Candida (MIC = 2–64 μg ml^?1). Compound 4e exhibited the highest levels of inhibitory activity (MIC = 2–16 μg ml^?1) against clinical isolates of MRSA. A concentration of twice the MIC resulted in bactericidal activity of 4d against 19 of the 21 clinical isolates.     

Cytherella maremensis sp. n., a new ostracod from the Sea of Marmara (Turkey) (Crustacea: Ostracoda)

Cytherella maremensis sp. n., belonging to the family Cytherellidae, is described as new from a hydrothermal vent, located in the west of Marmara Island on the North Anatolian Fault crossing the Sea of Marmara. It was collected from a sediment core 55 m below sea level. Cytherella maremensis sp. n. is clearly separated from closely related species by its shape, length-height ratio and ornamentation.     

Activity of native hydrolytic enzymes and their association with the cell wall of three ectomycorrhizal fungi

The ecological and biogeochemical relevance of hydrolytic enzymes associated with the fungal cell wall has been poorly studied in ectomycorrhizal (ECM) fungi. We used a modified sequential extraction procedure to investigate the activity of various hydrolytic enzymes (β-glucosidase, acid-phosphatase, leucine-aminopeptidase, chitinase, xylanase and glucuronidase) and their association with the cell wall of three ECM fungi (Rhizopogon roseolus, Paxillus involutus and Piloderma croceum). Fungi were grown on C-rich solid medium under three different P concentrations (3.7, 0.37 and 0.037 mM). The sequential extraction procedure classifies enzymes as: (a) cytosolic, (b) loosely bound, (c) hydrophobically bound, (d) ionically bound and (e) covalently bound. Results showed that for the same fungus absolute enzymatic activity was affected by P concentration, whilst enzymatic compartmentalization among the cytosol and the cell wall fractions was not. The association of enzymes with the cell wall was fungus- and enzyme-specific. Our data indicate also that enzymes best known for being either extracellular or cytosolic or both, do act in muro as well. The ecological implications of cell wall-bound enzymes and the potential applications and limitations of sequential extractions are further discussed.     

An evidence-based consensus for the classification of arbuscular mycorrhizal fungi (Glomeromycota)

The publication of a large number of taxon names at all levels within the arbuscular mycorrhizal fungi (Glomeromycota) has resulted in conflicting systematic schemes and generated considerable confusion among biologists working with these important plant symbionts. A group of biologists with more than a century of collective experience in the systematics of Glomeromycota examined all available molecular–phylogenetic evidence within the framework of phylogenetic hypotheses, incorporating morphological characters when they were congruent. This study is the outcome, wherein the classification of Glomeromycota is revised by rejecting some new names on the grounds that they are founded in error and by synonymizing others that, while validly published, are not evidence-based. The proposed “consensus” will provide a framework for additional original research aimed at clarifying the evolutionary history of this important group of symbiotic fungi.     

Novel nanoimaging approach: Antibodious polymeric nanolabel for intracellular alpha‐fetoprotein targeted monitoring

This study describes preparation and use of novel labeled and antibodious polymeric nanolabels (anti‐alpha fetoprotein cross‐linked nanolabels) as an immunogenic and semisynthetic nanolabel with potential prognostic and therapeutic roles for hepatoma cancer. Specificity, uptake, and binding efficiencies of the nanolabel have been examined in a human hepatosarcoma cell line HepG2, a human colorectal cell line DLD‐1, and a mouse myoblast cell line C2. Labeling of the cells has been performed by treating live and fixed cells with varying concentrations of the nanolabels and then, the cells have been examined under a fluorescence microscope. In addition, all cell lines have also been labeled using FITC‐conjugated nanotrastuzumab to compare the results obtained with those of the binding of the FITC‐nanoanti‐alpha fetoprotein nanolabels. Results show that FITC‐conjugated anti‐alpha fetoprotein cross‐linked nanolabels have been taken up by both live and fixed cells and have efficiently and specifically labeled HepG2 cells at a quite low concentration. Taken all together, the results indicate that the novel targeted nanoimaging tools and technique demonstrated their ability to detect the distribution of the nanolabels as probes in hepatoma cells. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29: 472–479, 2013     

Gastrointestinal absorption and metabolism of apple polyphenols ex vivo by the pig intestinal mucosa in the Ussing chamber

Polyphenols contained in food have various positive effects on human health. The absorption and metabolism of polyphenols in the intestinal tract needs to be studied to estimate these effects. The Ussing chamber technique was used to investigate the transport behavior of apple polyphenols through pig small intestinal mucosa, which served as a model for human gastrointestinal mucosa. The identities and concentrations of polyphenols and their metabolites in the half-chambers (luminal and basolateral) within an incubation period of 4 h were determined by HPLC–MS/MS and HPLC–DAD (DAD = diode-array detection). Flux values were also measured. It was found that 5-caffeoylquinic acid and caffeic acid were absorbed and translocated to the basolateral side (1.9 and 3.7%, respectively), but other compounds, including glycosides of phloretin and quercetin, were observed without translocation. A Ussing chamber utilizing pig small intestinal mucosa is a suitable model for assessing the effect of apple polyphenols on mucosal integrity and nutrition absorption across porcine mucosa.     

Comparing the Response of Birds and Butterflies to Vegetation-Based Mountain Ecotones Using Boundary Detection Approaches

Mountains provide an opportunity to examine changes in biodiversity across environmental gradients and areas of transition (ecotones). Mountain ecotones separate vegetation belts. Here, we aimed to examine whether transition areas for birds and butterflies spatially correspond with ecotones between three previously described altitudinal vegetation belts on Mt. Hermon, northern Israel. These include the Mediterranean Maquis, xero-montane open forest and Tragacanthic mountain steppe vegetation belts. We sampled the abundance of bird and butterfly species in 34 sampling locations along an elevational gradient between 500 and 2200 m. We applied wombling, a boundary-detection technique, which detects rapid changes in a continuous variable, in order to locate the transition areas for bird and butterfly communities and compare the location of these areas with the location of vegetation belts as described in earlier studies of Mt. Hermon. We found some correspondence between the areas of transition of both bird and butterfly communities and the ecotones between vegetation belts. For birds and butterflies, important transitions occurred at the lower vegetation ecotone between Mediterranean maquis and the xero-montane open forest vegetation belts, and between the xero-montane open forest and the mountain steppe Tragacanthic belts. While patterns of species turnover with elevation were similar for birds and butterflies, the change in species richness and diversity with elevation differed substantially between the two taxa. Birds and butterflies responded quite similarly to the elevational gradient and to the shift between vegetation belts in terms of species turnover rates. While the mechanisms generating these patterns may differ, the resulting areas of peak turnover in species show correspondence among three different taxa (plants, birds and butterflies).