Análise da estrutura populacional e do desequilíbrio de ligação de um painel de acessos de sorgo: uma abordagem usando teoria da coalescência

A estrutura populacional e o desequilíbrio de ligação são dois processos fundamentais para estudos evolutivos e de mapeamento associativo. Tradicionalmente, ambos têm sido investigados por meio de métodos clássicos comumente utilizados. Tais métodos certamente forneceram grandes avanços no entendimento dos processos evolutivos das espécies. No entanto, em geral, nenhum deles utiliza uma visão genealógica de forma a considerar eventos genéticos ocorridos no passado, dificultando a compreensão dos padrões de variação observados no presente. Uma abordagem que possibilita a investigação retrospectiva com base no atual polimorfismo observado é a teoria da coalescência. Assim, o objetivo deste trabalho foi analisar, com base na teoria da coalescência, a estrutura populacional e o desequilíbrio de ligação de um painel mundial de acessos de sorgo (Sorghum bicolor). Para tanto, análises de mutação, migração com fluxo gênico e recombinação foram realizadas para cinco regiões genômicas relacionadas à altura de plantas e maturidade (Dw1, Dw2, Dw4, Ma1 e Ma3) e sete populações previamente selecionadas. Em geral, elevado fluxo gênico médio (Μ = m/μ = 41,78 − 52,07) foi observado entre as populações considerando cada região genômica e todas elas simultaneamente. Os padrões sugeriram intenso intercâmbio de acessos e história evolutiva específica para cada região genômica, mostrando a importância da análise individual dos locos. A quantidade média de migrantes por geração (Μ) não foi simétrica entre pares recíprocos de populações, de acordo com a análise individual e simultânea das regiões. Isso sugere que a forma pela qual as populações se relacionaram e continuam interagindo evolutivamente não é igual, mostrando que os métodos clássicos utilizados para investigar estrutura populacional podem ser insatisfatórios. Baixas taxas médias de recombinação (ρL = 2Ner = 0,030 − 0,246) foram observadas utilizando o modelo de recombinação constante ao longo da região. Baixas e altas taxas médias de recombinação (ρr = 2Ner = 0,060 − 3,395) foram estimadas utilizando o modelo de recombinação variável ao longo da região. Os métodos tradicional (r2) e via coalescência (E[r2 rhomap]) utilizados para a estimação do desequilíbrio de ligação mostraram resultados próximos para algumas regiões genômicas e populações. No entanto, o r2 sugeriu padrões descontínuos de desequilíbrio em várias ocasiões, dificultando o entendimento e a caracterização de possíveis blocos de associação. O método via coalescência (E[r2 rhomap]) forneceu resultados que pareceram ter sido mais consistentes, podendo ser uma estratégia eventualmente importante para um refinamento dos padrões não-aleatórios de associação. Os resultados aqui encontrados sugerem que o mapeamento genético a partir de um único pool gênico pode ser insuficiente para detectar associações causais importantes para características quantitativas em sorgo.

Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis

Objective. The heritability of RA has been estimated to be ∼55%, of which the MHC contributes about one-third. HLA-DRB1 alleles are strongly associated with RA, but it is likely that significant non-DRB1 MHC genetic susceptibility factors are involved. Previously, we identified two three-marker haplotypes in a 106-kb region in the MHC class III region immediately centromeric to TNF, which are strongly associated with RA on HLA-DRB1*0404 haplotypes. In the present study, we aimed to refine these associations further using a combination of genotyping and gene expression studies. Methods. Thirty-nine nucleotide polymorphisms (SNPs) were genotyped in 95 DRB1*0404 carrying unrelated RA cases, 125 DRB1*0404 - carrying healthy controls and 87 parent-case trio RA families in which the affected child carried HLA-DRB1*04. Quantitative RT-PCR was used to assess the expression of the positional candidate MHC class III genes APOM, BAT2, BAT3, BAT4, BAT5, AIF1, C6orf47, CSNK2β and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and β2-microglobulin (B2M) in 31 RA cases and 21 ethnically, age- and sex-matched healthy controls. Synovial membrane specimens from RA, PsA and OA cases were stained by an indirect immunoperoxidase technique using a mouse-anti-human AIF1 monoclonal antibody. Results. Association was observed between RA and single markers or two marker haplotypes involving AIF1, BAT3 and CSNK. AIF1 was also significantly overexpressed in RA mononuclear cells (1.5- to 1.9-fold difference, P = 0.02 vs HPRT, P = 0.002 vs B2M). AIF1 protein was clearly expressed by synovial macrophages in all the inflammatory synovial samples in contrast to the non-inflammatory OA samples. Conclusions. The results of the genotyping and expression studies presented here suggest a role for AIF1 in both the aetiology and pathogenesis of RA.

High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19

OBJECTIVE To refine a previously reported linkage peak for endometriosis on chromosome 10q26, and conduct follow-up analyses and a fine-mapping association study across the region to identify new candidate genes for endometriosis. DESIGN Case-control study. SETTING Academic research. PATIENT(S) Cases=3,223 women with surgically confirmed endometriosis; controls=1,190 women without endometriosis and 7,060 population samples. INTERVENTION(S) Analysis of 11,984 single nucleotide polymorphisms on chromosome 10. MAIN OUTCOME MEASURE(S) Allele frequency differences between cases and controls. RESULT(S) Linkage analyses on families grouped by endometriosis symptoms (primarily subfertility) provided increased evidence for linkage (logarithm of odds score=3.62) near a previously reported linkage peak. Three independent association signals were found at 96.59 Mb (rs11592737), 105.63 Mb (rs1253130), and 124.25 Mb (rs2250804). Analyses including only samples from linkage families supported the association at all three regions. However, only rs11592737 in the cytochrome P450 subfamily C (CYP2C19) gene was replicated in an independent sample of 2,079 cases and 7,060 population controls. CONCLUSION(S) The role of the CYP2C19 gene in conferring risk for endometriosis warrants further investigation.

Mapping of domains on HIV envelope protein mediating association with calnexin and protein-disulfide isomerase.

The cell catalysts calnexin (CNX) and protein-disulfide isomerase (PDI) cooperate in establishing the disulfide bonding of the HIV envelope (Env) glycoprotein. Following HIV binding to lymphocytes, cell-surface PDI also reduces Env to induce the fusogenic conformation. We sought to define the contact points between Env and these catalysts to illustrate their potential as therapeutic targets. In lysates of Env-expressing cells, 15% of the gp160 precursor, but not gp120, coprecipitated with CNX, whereas only 0.25% of gp160 and gp120 coprecipitated with PDI. Under in vitro conditions, which mimic the Env/PDI interaction during virus/cell contact, PDI readily associated with Env. The domains of Env interacting in cellulo with CNX or in vitro with PDI were then determined using anti-Env antibodies whose binding site was occluded by CNX or PDI. Antibodies against domains V1/V2, C2, and the C terminus of V3 did not bind CNX-associated Env, whereas those against C1, V1/V2, and the CD4-binding domain did not react with PDI-associated Env. In addition, a mixture of the latter antibodies interfered with PDI-mediated Env reduction. Thus, Env interacts with intracellular CNX and extracellular PDI via discrete, largely nonoverlapping, regions. The sites of interaction explain the mode of action of compounds that target these two catalysts and may enable the design of further new competitive agents.

Chromosomal mapping of repetitive DNAs in the beetle Dichotomius geminatus provides the first evidence for an association of 5S rRNA and histone H3 genes in insects, and repetitive DNA similarity between the B chromosome and A complement

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk

Association of myocardial T1-mapping CMR with hemodynamics and RV performance in pulmonary hypertension

Early detection of right ventricular (RV) involvement in chronic pulmonary hypertension (PH) is essential due to prognostic implications. T1 mapping by cardiac magnetic resonance (CMR) has emerged as a noninvasive technique for extracellular volume fraction (ECV) quantification. We assessed the association of myocardial native T1 time and equilibrium contrast ECV (Eq-ECV) at the RV insertion points with pulmonary hemodynamics and RV performance in an experimental model of chronic PH. Right heart catheterization followed by immediate CMR was performed on 38 pigs with chronic PH (generated by surgical pulmonary vein banding) and 6 sham-operated controls. Native T1 and Eq-ECV values at the RV insertion points were both significantly higher in banded animals than in controls and showed significant correlation with pulmonary hemodynamics, RV arterial coupling, and RV performance. Eq-ECV values also increased before overt RV systolic dysfunction, offering potential for the early detection of myocardial involvement in chronic PH.

Graduate Attribute Mapping With the Extended CDIO Framework

The CDIO (Conceive-Design-Implement-Operate) Initiative has been globally recognised as an enabler for engineering education reform. With the CDIO process, the CDIO Standards and the CDIO Syllabus, many scholarly contributions have been made around cultural change, curriculum reform and learning environments. In the Australasian region, reform is gaining significant momentum within the engineering education community, the profession, and higher education institutions. This paper presents the CDIO Syllabus cast into the Australian context by mapping it to the Engineers Australia Graduate Attributes, the Washington Accord Graduate Attributes and the Queensland University of Technology Graduate Capabilities. Furthermore, in recognition that many secondary schools and technical training institutions offer introductory engineering technology subjects, this paper presents an extended self-rating framework suited for recognising developing levels of proficiency at a preparatory level. A demonstrator mapping tool has been created to demonstrate the application of this extended graduate attribute mapping framework as a precursor to an integrated curriculum information model.

Regional performance : mapping "The North"

Paul Makeham’s work in AusStage Phase 3 has centred on regional mapping of live performance activity. A pilot mapping project was developed to identify regional clusters of performance as well as key regional organisations. In designing this pilot project, reference was made to two other ARC-funded projects. The first of these was Talking Theatre, an audience development research initiative for Queensland and the Northern Territory supported by an ARC Projects-Linkage grant. Talking Theatre was funded between 2004 and 2006 as a Linkage between the ARC, NARPACA (the Northern Australian Regional Performing Arts Centres Association), Arts Queensland, Arts Northern Territory, and QUT. The second project was the Creative Digital Industries National Mapping Project, operating through QUT’s Centre for Excellence in the Creative Industries (CCi). The NMP is designed to develop and publish a range of accurate and timely measures of the Creative Digital Industries in Australia.

Mapping equity and diversity : from counting to culture change

This paper investigates the links between various approaches to managing equity and diversity and their effectiveness in changing the measures of inclusivity of women in organisations as a means of auditing and mapping managing diversity outcomes in Australia. The authors argue that managing diversity is more than changing systems and counting numbers it is also about managing the substantive culture change required in order to achieve inclusivity particularly intercultural inclusivity. Research in one sector of the education industry that investigated the competency skills required for culture change is offered as a model or guide for understanding and reflecting upon intercultural competency and its sequential development.

Hippocampal models for simultaneous localisation and mapping on an autonomous robot

To navigate successfully in a novel environment a robot needs to be able to Simultaneously Localize And Map (SLAM) its surroundings. The most successful solutions to this problem so far have involved probabilistic algorithms, but there has been much promising work involving systems based on the workings of part of the rodent brain known as the hippocampus. In this paper we present a biologically plausible system called RatSLAM that uses competitive attractor networks to carry out SLAM in a probabilistic manner. The system can effectively perform parameter self-calibration and SLAM in one dimension. Tests in two dimensional environments revealed the inability of the RatSLAM system to maintain multiple pose hypotheses in the face of ambiguous visual input. These results support recent rat experimentation that suggest current competitive attractor models are not a complete solution to the hippocampal modelling problem.