A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes.

Heritable diseases are caused by germ-line mutations that, despite tissuewide presence, often lead to tissue-specific pathology. Here, we make a systematic analysis of the link between tissue-specific gene expression and pathological manifestations in many human diseases and cancers. Diseases were systematically mapped to tissues they affect from disease-relevant literature in PubMed to create a disease-tissue covariation matrix of high-confidence associations of >1,000 diseases to 73 tissues. By retrieving >2,000 known disease genes, and generating 1,500 disease-associated protein complexes, we analyzed the differential expression of a gene or complex involved in a particular disease in the tissues affected by the disease, compared with nonaffected tissues. When this analysis is scaled to all diseases in our dataset, there is a significant tendency for disease genes and complexes to be overexpressed in the normal tissues where defects cause pathology. In contrast, cancer genes and complexes were not overexpressed in the tissues from which the tumors emanate. We specifically identified a complex involved in XY sex reversal that is testis-specific and down-regulated in ovaries. We also identified complexes in Parkinson disease, cardiomyopathies, and muscular dystrophy syndromes that are similarly tissue specific. Our method represents a conceptual scaffold for organism-spanning analyses and reveals an extensive list of tissue-specific draft molecular pathways, both known and unexpected, that might be disrupted in disease.

Integrative analysis for finding genes and networks involved in diabetes and other complex diseases.

We have developed an integrative analysis method combining genetic interactions, identified using type 1 diabetes genome scan data, and a high-confidence human protein interaction network. Resulting networks were ranked by the significance of the enrichment of proteins from interacting regions. We identified a number of new protein network modules and novel candidate genes/proteins for type 1 diabetes. We propose this type of integrative analysis as a general method for the elucidation of genes and networks involved in diabetes and other complex diseases.

A human phenome-interactome network of protein complexes implicated in genetic disorders.

We performed a systematic, large-scale analysis of human protein complexes comprising gene products implicated in many different categories of human disease to create a phenome-interactome network. This was done by integrating quality-controlled interactions of human proteins with a validated, computationally derived phenotype similarity score, permitting identification of previously unknown complexes likely to be associated with disease. Using a phenomic ranking of protein complexes linked to human disease, we developed a Bayesian predictor that in 298 of 669 linkage intervals correctly ranks the known disease-causing protein as the top candidate, and in 870 intervals with no identified disease-causing gene, provides novel candidates implicated in disorders such as retinitis pigmentosa, epithelial ovarian cancer, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer disease, type 2 diabetes and coronary heart disease. Our publicly available draft of protein complexes associated with pathology comprises 506 complexes, which reveal functional relationships between disease-promoting genes that will inform future experimentation.

A wiring of the human nucleolus.

Recent proteomic efforts have created an extensive inventory of the human nucleolar proteome. However, approximately 30% of the identified proteins lack functional annotation. We present an approach of assigning function to uncharacterized nucleolar proteins by data integration coupled to a machine-learning method. By assembling protein complexes, we present a first draft of the human ribosome biogenesis pathway encompassing 74 proteins and hereby assign function to 49 previously uncharacterized proteins. Moreover, the functional diversity of the nucleolus is underlined by the identification of a number of protein complexes with functions beyond ribosome biogenesis. Finally, we were able to obtain experimental evidence of nucleolar localization of 11 proteins, which were predicted by our platform to be associates of nucleolar complexes. We believe other biological organelles or systems could be "wired" in a similar fashion, integrating different types of data with high-throughput proteomics, followed by a detailed biological analysis and experimental validation.

The louse-borne human pathogen Bartonella quintana is a genomic derivative of the zoonotic agent Bartonella henselae.

We present the complete genomes of two human pathogens, Bartonella quintana (1,581,384 bp) and Bartonella henselae (1,931,047 bp). The two pathogens maintain several similarities in being transmitted by insect vectors, using mammalian reservoirs, infecting similar cell types (endothelial cells and erythrocytes) and causing vasculoproliferative changes in immunocompromised hosts. A primary difference between the two pathogens is their reservoir ecology. Whereas B. quintana is a specialist, using only the human as a reservoir, B. henselae is more promiscuous and is frequently isolated from both cats and humans. Genome comparison elucidated a high degree of overall similarity with major differences being B. henselae specific genomic islands coding for filamentous hemagglutinin, and evidence of extensive genome reduction in B. quintana, reminiscent of that found in Rickettsia prowazekii. Both genomes are reduced versions of chromosome I from the highly related pathogen Brucella melitensis. Flanked by two rRNA operons is a segment with similarity to genes located on chromosome II of B. melitensis, suggesting that it was acquired by integration of megareplicon DNA in a common ancestor of the two Bartonella species. Comparisons of the vector-host ecology of these organisms suggest that the utilization of host-restricted vectors is associated with accelerated rates of genome degradation and may explain why human pathogens transmitted by specialist vectors are outnumbered by zoonotic agents, which use vectors of broad host ranges.

Computational inference of scenarios for alpha-proteobacterial genome evolution.

The alpha-proteobacteria, from which mitochondria are thought to have originated, display a 10-fold genome size variation and provide an excellent model system for studies of genome size evolution in bacteria. Here, we use computational approaches to infer ancestral gene sets and to quantify the flux of genes along the branches of the alpha-proteobacterial species tree. Our study reveals massive gene expansions at branches diversifying plant-associated bacteria and extreme losses at branches separating intracellular bacteria of animals and humans. Alterations in gene numbers have mostly affected functional categories associated with regulation, transport, and small-molecule metabolism, many of which are encoded by paralogous gene families located on auxiliary chromosomes. The results suggest that the alpha-proteobacterial ancestor contained 3,000-5,000 genes and was a free-living, aerobic, and motile bacterium with pili and surface proteins for host cell and environmental interactions. Approximately one third of the ancestral gene set has no homologs among the eukaryotes. More than 40% of the genes without eukaryotic counterparts encode proteins that are conserved among the alpha-proteobacteria but for which no function has yet been identified. These genes that never made it into the eukaryotes but are widely distributed in bacteria may represent bacterial drug targets and should be prime candidates for future functional characterization.

Mitochondrial gene history and mRNA localization: is there a correlation?

Phylogenetic studies of the yeast mitochondrial proteome have shown a complex evolutionary scenario, in which proteins of bacterial origin form complexes with proteins of eukaryotic origin. Exciting new results from whole-genome microarray studies of subcellular mRNA localizations have shown that mRNAs that are of putative bacterial origin are mainly translated on polysomes that are associated with the mitochondrion, whereas those of eukaryotic origin are generally translated on free cytosolic polysomes. Understanding these newly discovered relationships promises insights into old questions about organelle origins and mRNA localization in the eukaryotic cell.

Lung function reference values in Chinese children and adolescents in Hong Kong. I. Spirometric values and comparison with other populations.

As part of a comprehensive evaluation of lung function in Hong Kong-born Chinese children and adolescents, this study was conducted to determine updated prediction equations for spirometry, to evaluate the secular changes of lung function during the past decade, and to compare these results with other data sets. The results are based on 852 (392 male, 460 female) healthy students, age 7 to 19 yr, recruited from seven schools in Hong Kong. All were born and lived in Hong Kong, nonsmokers, free from past or present symptoms or diseases affecting the respiratory tract. A body plethysmograph was used to record lung function measurements. Natural logarithmic values of lung volumes and body height were used in the final regression model. Prediction equations for FVC, FEV(1), and maximal expiratory flow at 50% of the FVC (MEF(50)) for both sexes are presented, with standing height as the dependent variable. Compared with Hong Kong data from 1985, the results show a significant increase in height-corrected FVC and FEV(1) in both boys and girls, over the whole height range. Compared with recent data of whites, FVC in boys were 8 to 10% lower in the study population, and the difference increased to 12% above the 165 cm height ranges, while FVC in Chinese girls had similar or only slightly lower predicted values. FEV(1) values showed a similar pattern with lesser difference between the two ethnic groups. Compared with recent data from Chinese children in Singapore, a similar pattern with overall lesser difference of the two populations was present in boys, whereas there was no significant difference between girls in the two places. Our findings support the conclusion that exogenous factors may contribute significantly to the differences in lung function values among ethnic groups and that it is important to examine normative values of various populations for secular trends.

Lung function reference values in Chinese children and adolescents in Hong Kong. II. Prediction equations for plethysmographic lung volumes.

As part of a comprehensive evaluation of lung function in Hong Kong Chinese children and adolescents, over a thousand healthy subjects aged 7-19 yr from seven schools were recruited for lung function testing that included spirometry and, in many cases, lung subdivision measurements. Lung function tests were performed using SensorMedics Automated Body Plethysmograph according to published standards. Of these, 551 subjects (219 males), aged 8-19 yr, had satisfactory lung subdivision indices recorded. Analysis for the values of lung subdivisions including total lung capacity (TLC), residual volume (RV), and functional residual capacity (FRC) demonstrated that standing height and sitting height were the best predictors of lung volumes. After allowing for standing height or sitting height in the regression models for lung volumes, age at examination was the second best parameter, although its inclusion into the equations contributed to less than 1% of explained variance for boys and 3% for girls. These are the first reported data in international literature on reference values for lung subdivisions in Chinese children and adolescents.

Kinematics of the chest cage and spine during breathing in healthy individuals and in patients with adolescent idiopathic scoliosis.

STUDY DESIGN: The lung function test by a Plethysmograph enabled calculations to be made of the total lung capacity and vital capacity. A Motion Analysis System (Elite, BTS Inc., Milano, Italy) was used to observe and record chest cage and spinal movements and as to correlate lung function with the chest cage and spine kinematics. OBJECTIVES: To determine the three-dimensional kinematics and the shape and size changes of the chest cage and thoracic spine motion during deep breathing in healthy and scoliotic individuals. SUMMARY OF BACKGROUND DATA: Lateral flexion plus rotation of the involved vertebrae around a vertical axis causing a decrease in lung function is the main disfigurement of scoliosis. Reports show that even after spinal fusion, reduced vital capacity associated with an increased residual volume are detected. Factors such as angle of scoliosis, length of the spinal column involved, and duration of the deformity influence pulmonary function but do not significantly affect its reduction. Mechanical inefficiency during breathing has not been studied. METHODS: Three-dimensional kinematics of the chest cage and spine during breathing were studied in 41 scoliotic patients and in 20 healthy individuals. Three-dimensional chest cage motions relative to the spine and thoracic spine motions relative to T12 were calculated. To examine stiffness of the spine, lateral bending angles were calculated. The lung function test, which including spirometry and lung subdivision, also was performed for the scoliotic patients. RESULTS: Significant differences (P < 0.05) were found in the movements of the upper level of the chest cage in anteroposterior and vertical directions, ranging from 16.7 to 28.6 mm in healthy individuals and from 12.1 to 24.2 mm in scoliotic patients. The thoracic spine displayed two-dimensional movements posteriorly and vertically during breathing, whereas less movement was seen in scoliotic patients. In addition, overall the scoliotic spine showed signs of stiffness in lateral bending. CONCLUSIONS: The range of movement of the chest cage and spine is more limited in the scoliotic cases. This overall stiffness of the chest cage and the spine may contribute to the mechanical inefficiency and impairment of pulmonary function found in scoliotic patients.

Psychological and respiratory physiological effects of a physical exercise programme on boys with severe asthma.

Ten boys 9-12 years of age with severe perennial asthma participated in a physical exercise programme lasting 8 months. Pulmonary function and psychological tests were performed before training, immediately after, and one year after the end of the exercise programme. Static lung volumes, flow-volume variables and histamine tolerance were used as indicators of pulmonary function. Ego structure, body image, social development and concentration capacity were used as indicators of personality development. Before the study, the group had high FRC (p less than 0.05) and RV (p less than 0.001), low FEV1, MEF50 and MEF25 (all p less than 0.001) and low histamine tolerance. They showed marked disturbances in their personality development with low scores in psychological variables. During the training period, MEF50 and MEF25 increased slightly (p less than 0.01). Marked improvement was observed in all psychological variables (p less than 0.001). The positive effects remained during the following year. The marked and lasting improvement in personality development was regarded as an essential factor behind the more modest positive clinical and pulmonary function changes. The results emphasize the importance of including exercise programmes in the treatment of children with asthma.

Corticotropin, cortisol and beta-endorphin responses to the human corticotropin-releasing hormone during melancholia and after unilateral electroconvulsive therapy.

Previous research in neuroendocrinology has evidenced that hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) depends on hypersecretion of corticotropin-releasing hormone (CRH). The aim of this study was to investigate the activity of HPA before and after recovery in depressed patients treated with electroconvulsive therapy (ECT). An h-CRH-stimulation test was performed on 2 occasions with examination of the HPA axis before ECT treatment during episodes of major depressive disorders with melancholia, and during the recovery phase after treatment. The results showed that patients during depression had significantly higher plasma levels of cortisol at 15 and 30 min after h-CRH-administration than after recovery. Depressed patients had significantly higher plasma levels of beta-endorphin 30 min after h-CRH-stimulation. The results are in agreement with previous studies, which have shown hypercortisolemia during depression. A possible hypersecretion of CRH may explain the effect on cortisol and beta-endorphin. No significant differences were found between cumulative responses of corticotropin, cortisol and beta-endorphin, calculated as the areas under the concentration curves.

Children of alcoholic mothers. Growth and motor performance compared to matched controls.

Twenty-one children born 1970-76, selected from 103 children of 30 alcoholic women, were paired to controls matched for sex, age, birth weight and gestational age. The sample (10 girls, 11 boys) was representative of the whole group with regard to weight, length and head circumference at birth. At follow-up (mean age 70 months) the study group was significantly leaner, shorter and had smaller mean head circumference than the control group. The controls had significant catch-up growth from birth to follow-up of weight, height and head circumference to the mean for Swedish children. The study group had no catch-up growth. Compared to controls the study group had significantly lower fine and gross motor age test scores and inferior coordination. One child had cerebral palsy (spastic hemiplegia) and in 6 other children slight tremor and ataxia were observed. Malformations and/or other signs of the fetal alcohol syndrome (FAS) were found in 10 cases. Study group children with FAS had significantly slower growth of head circumference than others without FAS. Children placed in foster home care (n = 11) were found to have significantly (p less than 0.05) lower birth weight, birth length and head circumference than children raised at home (n = 10). There were no significant differences at follow up between study group children raised in foster homes or in homes of their biological mother.