Comparison tests for dendrograms: A comparative evaluation

Classifications are generally pictured in the form of hierarchical trees, also called dendrograms. A dendrogram is the graphical representation of an ultrametric (=cophenetic) matrix; so dendrograms can be compared to one another by comparing their cophenetic matrices. Three methods used in testing the correlation between matrices corresponding to dendrograms are evaluated. The three permutational procedures make use of different aspects of the information to compare dendrograms: the Mantel procedure permutes label positions only; the binary tree methods randomize the topology as well; the double-permutation procedure is based on all the information included in a dendrogram, that is: topology, label positions, and cluster heights. Theoretical and empirical investigations of these methods are carried out to evaluate their relative performance. Simulations show that the Mantel test is too conservative when applied to the comparison of dendrograms; the methods of binary tree comparisons do slightly better; only the doublepermutation test provides unbiased type I error. Les arbres utilisés pour illustrés les groupements sont généralement représentés sous la forme de classifications hiérarchiques ou dendrogrammes. Un dendrogramme représente graphiquement l’information contenue dans la matrice ultramétrique (=cophénétique) correspondant à la classification. Dès ultramétriques correspondantes. Nous comparons trois méthodes permettant d’évaluer la signification statistique du coefficient de correlation mesuré entre deux matrices ultramétriques. Ces trois tests par permutations tiennent compte d’aspects différents pour comparer des dendrogrammes: le test de Mantel permute les feuilles de l’arbre, les méthodes pour arbres binaires permutent les feuilles et la topologie, alors que la procédure à double permutation permute les feuilles, la topologie et les niveaux de fusion des dendrogrammes comparés. L’efficacité relative des trois méthodes est évaluée empiriquement et théoriquement. Nos résultats suggèrent l’utilisation préférentielle du test à double permutation pour la comparaison de dendrogrammes: le test de Mantel s’avère trop conservateur, tandis que les méthodes pour arbres binaires ne sont pas toujours adéquates.

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This work was supported by NSERC grant no. A7738 to Pierre Legendre and by a NSERC scholarship to F.-J. Lapointe.     

Arrangement of nucleosomes in condensed chromatin fibres

Summary Condensed chromatin shows globules of 300 Å formed by 8 to 10 nucleosomes. Each globule might be an uncoiled turn of a supercoil. This supercoil forms major coils along the fibre.This work was supported by grants from Brazilian CNPq, FAPESP and FEDIB.We thank Dr A. Brunner Jr for the permission to use the electron microscope.     

The detection of earnings manipulation: the three‐phase cutting plane algorithm using mathematical programming

The primary goal of this study was to propose an algorithm using mathematical programming to detect earnings management practices. In order to evaluate the ability of this proposed algorithm, the traditional statistical models are used as a benchmark vis‐à‐vis their time series counterparts. As emerging techniques in the area of mathematical programming yield better results, application of suitable models is expected to result in highly performed forecasts. The motivation behind this paper is to develop an algorithm which will succeed in detecting companies that appeal to financial manipulation. The methodology is based on cutting plane formulation using mathematical programming. A sample of 126 Turkish manufacturing firms described over 10 financial ratios and indexes are used for detecting factors associated with false financial statements. The results indicate that the proposed three‐phase cutting plane algorithm outperforms the traditional statistical techniques which are widely used for false financial statement detections. Furthermore, the results indicate that the investigation of financial information can be helpful towards the identification of false financial statements and highlight the importance of financial ratios/indexes such as Days' Sales in Receivables Index (DSRI), Gross Margin Index (GMI), Working Capital Accruals to Total Assets (TATA) and Days to Inventory Index (DINV). Copyright © 2009 John Wiley & Sons, Ltd.     

Network modeling links breast cancer susceptibility and centrosome dysfunction

Many cancer-associated genes remain to be identified to clarify the underlying molecular mechanisms of cancer susceptibility and progression. Better understanding is also required of how mutations in cancer genes affect their products in the context of complex cellular networks. Here we have used a network modeling strategy to identify genes potentially associated with higher risk of breast cancer. Starting with four known genes encoding tumor suppressors of breast cancer, we combined gene expression profiling with functional genomic and proteomic (or 'omic') data from various species to generate a network containing 118 genes linked by 866 potential functional associations. This network shows higher connectivity than expected by chance, suggesting that its components function in biologically related pathways. One of the components of the network is HMMR, encoding a centrosome subunit, for which we demonstrate previously unknown functional associations with the breast cancer-associated gene BRCA1. Two case-control studies of incident breast cancer indicate that the HMMR locus is associated with higher risk of breast cancer in humans. Our network modeling strategy should be useful for the discovery of additional cancer-associated genes.     

Human Genome Variation 2006: emerging views on structural variation and large-scale SNP analysis

The eighth annual Human Genome Variation Meeting was held in September 2006 in the Hong Kong Special Administrative Region, China. The meeting highlighted recent advances in characterization of genetic variation, including genome-wide association studies and structural variation.     

Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis

Variants associated with meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10(-9) at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.     

Identification of ten loci associated with height highlights new biological pathways in human growth

Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet-undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in >10,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)). Together, these 12 loci account for approximately 2% of the population variation in height. Individuals with < or =8 height-increasing alleles and > or =16 height-increasing alleles differ in height by approximately 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait.     

Crystal structure and biochemical characterization of the transmembrane PAP2 type phosphatidylglycerol phosphate phosphatase from <Emphasis Type="Italic">Bacillus subtilis</Emphasis>

Type 2 phosphatidic acid phosphatases (PAP2s) can be either soluble or integral membrane enzymes. In bacteria, integral membrane PAP2s play major roles in the metabolisms of glycerophospholipids, undecaprenyl-phosphate (C₅₅-P) lipid carrier and lipopolysaccharides. By in vivo functional experiments and biochemical characterization we show that the membrane PAP2 coded by the Bacillus subtilis yodM gene is the principal phosphatidylglycerol phosphate (PGP) phosphatase of B. subtilis. We also confirm that this enzyme, renamed bsPgpB, has a weaker activity on C₅₅-PP. Moreover, we solved the crystal structure of bsPgpB at 2.25 Å resolution, with tungstate (a phosphate analog) in the active site. The structure reveals two lipid chains in the active site vicinity, allowing for PGP substrate modeling and molecular dynamic simulation. Site-directed mutagenesis confirmed the residues important for substrate specificity, providing a basis for predicting the lipids preferentially dephosphorylated by membrane PAP2s.