A new approach to in silico SNP detection and some new SNPs in the Bacillus anthracis genome

<p>Abstract</p> <p>Background</p> <p><it>Bacillus anthracis </it>is one of the most monomorphic pathogens known. Identification of polymorphisms in its genome is essential for taxonomic classification, for determination of recent evolutionary changes, and for evaluation of pathogenic potency.</p> <p>Findings</p> <p>In this work three strains of the <it>Bacillus anthracis </it>genome are compared and previously unpublished single nucleotide polymorphisms (SNPs) are revealed. Moreover, it is shown that, despite the highly monomorphic nature of <it>Bacillus anthracis</it>, the SNPs are (1) abundant in the genome and (2) distributed relatively uniformly across the sequence.</p> <p>Conclusions</p> <p>The findings support the proposition that SNPs, together with indels and variable number tandem repeats (VNTRs), can be used effectively not only for the differentiation of perfect strain data, but also for the comparison of moderately incomplete, noisy and, in some cases, unknown <it>Bacillus anthracis </it>strains. In the case when the data is of still lower quality, a new DNA sequence fingerprinting approach based on recently introduced markers, based on combinatorial-analytic concepts and called cyclic difference sets, can be used.</p

Infochemical-tritrophic Interactions of Soybean Aphids-host Plants-natural Enemies and Their Practical Applications in Pest Management

The soybean aphid, Aphis glycines Matsumura, is a newly invasive insect species that seriously threatens U.S. soybean production. This aphid pest has kept haunting many soybean growers by developing large colonies on soybeans in North America since 2000. Since its first appearance inWisconsin, it has spread to over half of US states and southern provinces in Canada. The heavy infestation of this pest whittles soybean growers’ profits and causes hundreds of million dollar losses. The present chapter will mainly describe efforts in studying aphid chemical ecology and sensory physiology for understanding how male aphids find their mates and host plants. It will also cover research efforts to understand host plant associated volatiles being used as cues for overwintering host plant location. In addition, findings on how soybean plant defensive system works against aphid infestation, as well as how those induced plant volatiles are used by aphid’s natural enemies for prey location will be presented. Finally, the use the basic understandings for developing useful tools for soybean aphid practical control will be discussed

Potentiation of photodynamic therapy of cancer by complement: the effect of γ-inulin

Host response elicited by photodynamic therapy (PDT) of cancerous lesions is a critical contributor to the clinical outcome, and complement system has emerged as its important element. Amplification of complement action was shown to improve tumour PDT response. In search of a clinically relevant complement activator for use as a PDT adjuvant, this study focused on γ-inulin and examined its effects on PDT response of mouse tumours. Intralesional γ-inulin (0.1 mg mouse−1) delivered immediately after PDT rivaled zymosan (potent classical complement activator) in delaying the recurrence of B16BL6 melanomas. This effect of γ-inulin was further enhanced by IFN-γ pretreatment. Tumour C3 protein levels, already elevated after individual PDT or γ-inulin treatments, increased much higher after their combination. With fibrosarcomas MCA205 and FsaR, adjuvant γ-inulin proved highly effective in reducing recurrence rates following PDT using four different photosensitisers (BPD, ce6, Photofrin, and mTHPC). At 3 days after PDT plus γ-inulin treatment, over 50% of cells found at the tumour site were CTLs engaged in killing specific targets via perforin–granzyme pathway. This study demonstrates that γ-inulin is highly effective PDT adjuvant and suggests that by amplifying the activation of complement system, this agent potentiates the development of CTL-mediated immunity against PDT-treated tumours

Analyses and Comparison of Imputation-Based Association Methods

Genotype imputation methods have become increasingly popular for recovering untyped genotype data. An important application with imputed genotypes is to test genetic association for diseases. Imputation-based association test can provide additional insight beyond what is provided by testing on typed tagging SNPs only. A variety of effective imputation-based association tests have been proposed. However, their performances are affected by a variety of genetic factors, which have not been well studied. In this study, using both simulated and real data sets, we investigated the effects of LD, MAF of untyped causal SNP and imputation accuracy rate on the performances of seven popular imputation-based association methods, including MACH2qtl/dat, SNPTEST, ProbABEL, Beagle, Plink, BIMBAM and SNPMStat. We also aimed to provide a comprehensive comparison among methods. Results show that: 1). imputation-based association tests can boost signals and improve power under medium and high LD levels, with the power improvement increasing with strengthening LD level; 2) the power increases with higher MAF of untyped causal SNPs under medium to high LD level; 3). under low LD level, a high imputation accuracy rate cannot guarantee an improvement of power; 4). among methods, MACH2qtl/dat, ProbABEL and SNPTEST perform similarly and they consistently outperform other methods. Our results are helpful in guiding the choice of imputation-based association test in practical application

BMP4 induction of trophoblast from mouse embryonic stem cells in defined culture conditions on laminin

Because mouse embryonic stem cells (mESCs) do not contribute to the formation of extraembryonic placenta when they are injected into blastocysts, it is believed that mESCs do not differentiate into trophoblast whereas human embryonic stem cells (hESCs) can express trophoblast markers when exposed to bone morphogenetic protein 4 (BMP4) in vitro. To test whether mESCs have the potential to differentiate into trophoblast, we assessed the effect of BMP4 on mESCs in a defined monolayer culture condition. The expression of trophoblast-specific transcription factors such as Cdx2, Dlx3, Esx1, Gata3, Hand1, Mash2, and Plx1 was specifically upregulated in the BMP4-treated differentiated cells, and these cells expressed trophoblast markers. These results suggest that BMP4 treatment in defined culture conditions enabled mESCs to differentiate into trophoblast. This differentiation was inhibited by serum or leukemia inhibitory factor, which are generally used for mESC culture. In addition, we studied the mechanism underlying BMP4-directed mESC differentiation into trophoblast. Our results showed that BMP4 activates the Smad pathway in mESCs inducing Cdx2 expression, which plays a crucial role in trophoblast differentiation, through the binding of Smad protein to the Cdx2 genomic enhancer sequence. Our findings imply that there is a common molecular mechanism underlying hESC and mESC differentiation into trophoblast

Biological processes, properties and molecular wiring diagrams of candidate low-penetrance breast cancer susceptibility genes

Background: Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined. Methods: We applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence. Results: First, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the 'omic' properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk. Conclusion: This study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins

A Whole-Genome SNP Association Study of NCI60 Cell Line Panel Indicates a Role of Ca2+ Signaling in Selenium Resistance

Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33–34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase-scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca2+ signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis

Functional Copy-Number Alterations in Cancer

Understanding the molecular basis of cancer requires characterization of its genetic defects. DNA microarray technologies can provide detailed raw data about chromosomal aberrations in tumor samples. Computational analysis is needed (1) to deduce from raw array data actual amplification or deletion events for chromosomal fragments and (2) to distinguish causal chromosomal alterations from functionally neutral ones. We present a comprehensive computational approach, RAE, designed to robustly map chromosomal alterations in tumor samples and assess their functional importance in cancer. To demonstrate the methodology, we experimentally profile copy number changes in a clinically aggressive subtype of soft-tissue sarcoma, pleomorphic liposarcoma, and computationally derive a portrait of candidate oncogenic alterations and their target genes. Many affected genes are known to be involved in sarcomagenesis; others are novel, including mediators of adipocyte differentiation, and may include valuable therapeutic targets. Taken together, we present a statistically robust methodology applicable to high-resolution genomic data to assess the extent and function of copy-number alterations in cancer

A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci

Allergic disease is very common and carries substantial public-health burdens. We conducted a meta-analysis of genome-wide associations with self-reported cat, dust-mite and pollen allergies in 53,862 individuals. We used generalized estimating equations to model shared and allergy-specific genetic effects. We identified 16 shared susceptibility loci with association P < 5 × 10-8, including 8 loci previously associated with asthma, as well as 4p14 near TLR1, TLR6 and TLR10 (rs2101521, P = 5.3 × 10 -21); 6p21.33 near HLA-C and MICA (rs9266772, P = 3.2 × 10 -12); 5p13.1 near PTGER4 (rs7720838, P = 8.2 × 10 -11); 2q33.1 in PLCL1 (rs10497813, P = 6.1 × 10-10), 3q28 in LPP (rs9860547, P = 1.2 × 10-9); 20q13.2 in NFATC2 (rs6021270, P = 6.9 × 10-9), 4q27 in ADAD1 (rs17388568, P = 3.9 × 10-8); and 14q21.1 near FOXA1 and TTC6 (rs1998359, P = 4.8 × 10-8). We identified one locus with substantial evidence of differences in effects across allergies at 6p21.32 in the class II human leukocyte antigen (HLA) region (rs17533090, P = 1.7 × 10-12), which was strongly associated with cat allergy. Our study sheds new light on the shared etiology of immune and autoimmune disease