RPBS: a web resource for structural bioinformatics.

RPBS (Ressource Parisienne en Bioinformatique Structurale) is a resource dedicated primarily to structural bioinformatics. It is the result of a joint effort by several teams to set up an interface that offers original and powerful methods in the field. As an illustration, we focus here on three such methods uniquely available at RPBS: AUTOMAT for sequence databank scanning, YAKUSA for structure databank scanning and WLOOP for homology loop modelling. The RPBS server can be accessed at http://bioserv.rpbs.jussieu.fr/ and the specific services at http://bioserv.rpbs.jussieu.fr/SpecificServices.html.

Genome screen in the French EGEA study: detection of linked regions shared or not shared by allergic rhinitis and asthma.

In the sample of 295 French EGEA families with at least one asthmatic subject, a genome screen was conducted to identify potential linkage regions specific either to allergic rhinitis (AR) or to asthma as well as those shared by the two diseases. Two binary rhinitis phenotypes based on (1) diagnosis (ARbin1) and (2) symptoms (ARbin2) and a categorical ordered trait (ARcat) were considered. Asthma phenotype was based on answers to a standardized questionnaire plus the presence of bronchial hyper-responsiveness. Linkage analyses were conducted using the maximum likelihood binomial (MLB) method. These analyses provided potential evidence for linkage to three regions in the whole sample: 1p31 for the phenotype defined by ARbin2 plus asthma (P=0.00016), 2q32 for ARbin2 (P=0.00016) and 3p24-p14 for ARcat (P=0.001). Two other regions were detected in the subset of 185 families with at most one asthmatic sib: 9p22 and 9q22-q34 for ARbin1 (P=0.001 and 0.0007, respectively). No region showed evidence for linkage to asthma without being also linked to AR. While 1p31 may contain a genetic determinant common to asthma and AR, 2q32, 3p24-p14, 9p22 and 9q22-q34 are more likely to harbor genetic factors specific to AR.

[Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA) - First results of a multi-disciplinary study]. / Etude Epidémiologique sur les facteurs Génétiques et Environnementaux de l'Asthme, l'hyperréactivité bronchique et l'atopie (EGEA). Premiers résultats d'une étude multidisciplinaire.

The French co-operative epidemiological study EGEA realised in 1991/95 combines a case control study and a study of the families of asthmatic cases. A synthesis of the results already obtained is presented. Smoking was related to IgE, even in asthmatics and was clearly related to the clinical severity of asthma, an aspect insufficiently taken into account. The relationships of occupational exposures to asthma have been assessed using a job exposure matrix. Segregation analyses on IgE have shown, after correction for the mode of ascertainment, the existence of a dominant major gene and familial residual correlation. A systematic genome screen realised in families with 2 asthmatic siblings showed linkage of various regions in the genome implicated to asthma or related phenotypes (1p, 11p, 11q, 12q, 13q, 17q, 19q), coherent with genome screens realised in other studies. Regarding candidate genes, no association was evidenced between asthma and the AF508 mutation of the cystic fibrosis gene. The analysis is still in progress by studies on the heterogeneity of asthma with refined genetic studies and by searching to integrate results regarding environmental and genetic factors and studying their interactions.

Genome screen for asthma and related phenotypes in the French EGEA study.

A genome-wide search was conducted in 107 nuclear families with at least two siblings with asthma, as part of the French EGEA study. A two-stage analysis strategy was applied to the 107 families divided into two independent subsets of 46 and 61 families, where all regions detected in the first set of families were tested for replication in the second set. In addition, all regions reported by published genome scans in different populations were examined in the total sample. A total of 254 markers were typed in the first set of families and 70% of them in the second set. Linkage was investigated by model-free methods for asthma and four asthma-related phenotypes: bronchial responsiveness (BR), skin test response, total immunoglobulin E (IgE) levels, and eosinophil count. The two-stage analysis led to the detection of three regions: 11p13 for IgE, 12q24 for eosinophils, and 17q12-21 for asthma and skin tests. Among the regions reported by published genome screens, seven were found in the 107 French EGEA families: three being already detected by the two-stage analysis, 11p13 (p = 0.005), 12q24 (p = 0.0008), and 17q12-21 (p = 0.001), and four additional ones, 1p31 (p = 0.005) for asthma, 11q13 (p = 0.006) for IgE, 13q31 (p = 0.001) for eosinophils, and 19q13 (p = 0.02) for BR.

Segregation analysis of IgE levels in 335 French families (EGEA) using different strategies to correct for the ascertainment through a correlated trait (asthma).

The main objective of this study was to search for a major gene controlling total serum immunoglobulin E (IgE) levels, an intermediate phenotype for asthma and allergy. We studied 335 French nuclear families of the EGEA study (Epidemiological study of the Genetics and Environment of Asthma), ascertained through asthmatic probands (123 are parents in the family, 212 children). Segregation analyses were performed by regressive models, which can take into account a major gene effect, various sources of familial covariation (genetic and/or environmental) as well as measured risk factors (i.e. , age, sex, smoking habits). Different strategies were considered to account for the mode of ascertainment of the families through a correlated trait (asthma): the ascertainment mode was either ignored (strategy A) or taken into account by adjusting IgE levels for the position in the family, i.e., probands, blood relatives, spouses (strategy B) or excluding the asthmatic children-probands and computing the likelihood of each family conditionally on parents' IgE levels (strategy C). Whereas a major gene effect could not be detected with strategy A, strategies B and C showed evidence for the transmission of a dominant major gene for high IgE levels, which was more significant with strategy B. This gene does not interact with any of the covariates and is responsible for approximately 15% of IgE variation (the allele frequency is 0.65).

Surname distribution in France: a distance analysis by a distorted geographical map.

The distribution of surnames in 90 distinct regions in France during two successive periods, 1889-1915 and 1916-1940, is analysed from the civil birth registers of the 36,500 administrative units in France. A new approach, called 'Mobile Site Method' (MSM), is developed to allow representation of a surname distance matrix by a distorted geographical map. A surname distance matrix between the various regions in France is first calculated, then a distorted geographical map called the 'surname similarity map' is built up from the surname distances between regions. To interpret this map we draw (a) successive map contours obtained during the step-by-step distortion process, revealing zones of high surname dissimilarity, and (b) maps in grey levels representing the displacement magnitude, and allowing the segmentation of the geographical and surname maps into 'homogeneous surname zones'. By integrating geography and surname information in the same analysis, and by comparing results obtained for the two successive periods, the MSM approach produces convenient maps showing: (a) 'regionalism' of some peripheral populations such as Pays Basque, Alsace, Corsica and Brittany; (b) the presence of preferential axes of communications (Rhodanian corridor, Garonne valley); (c) barriers such as the Central Massif, Vosges; (d) the weak modifications of the distorted maps associated with the two periods studied suggest an extension (but limited) of the tendency of surname uniformity in France. These results are interpreted, in the nineteenth- and twentieth century context, as the consequences of a slow process of local migrations occurring over a long period of time.

The French Wilms' tumour study: no clear evidence for cancer prone families.

Wilms' tumour of the kidney is known to occur in Beckwith-Wiedemann syndrome. It has also been described in four cancer prone families displaying Li-Fraumeni syndrome but it is not usually considered to be part of this syndrome. In order to detect particular familial cancer aggregations associated with this tumour, we studied the cancer incidence and mortality among relatives of the 501 Wilms' tumour patients in the French Wilms' Tumour Study. We found no familial association with breast cancer or soft tissue sarcomas which are the most common cancers in the Li-Fraumeni syndrome. However, we found two significant familial associations of Wilms' tumour with bone cancers on the one hand and with brain tumours on the other hand. These associations could reflect a small proportion of families segregating for some susceptibility gene. This should then be confirmed at the molecular level.

Testing genomic imprinting in Wilm's tumor.

Data from 511 cases of Wilms' tumor in France (including 12 familial cases) and 8 pedigrees from the literature were analyzed to test three modifications of Knudson's classical bimutational theory, based on genomic imprinting in Wilms' tumor carcinogenesis. Analysis of data of age at diagnosis and segregation analysis were performed to determine the number of independent events for Wilms' tumor development and to search for a differential role of paternal and maternal alleles. Unexpectedly, we show that only one rare event is required for tumor development in isolated unilateral cases which are considered to be mainly nonhereditary. In familial cases, we observe no effect of the sex of the transmitting parent on either hge at diagnosis or segregation ratio. We show that this could be explained by models of genomic imprinting which assume two nonindependent events, or only one rare genetic event. In bilateral cases we show a bimodality for age at diagnosis which could be due to a mixture of hereditary and nonhereditary cases. This result completely questions the classical assumption according to which all bilateral cases would be hereditary. These findings support the hypothesis that this childhood cancer arises from a variety of etiological pathways and might be useful to find strategies for further molecular investigations.

Genetics and epidemiology of Wilms' tumor: the French Wilms' tumor study.

A complete family history was obtained for 501 patients with Wilms' tumor, treated in departments of pediatric oncology in whole France. The information was collected by self-questionnaire and/or by interview of parents. The proportion of bilateral cases is 4.6% and there are 12 patients (2.4%) with a positive family history of Wilms' tumor. The affected relatives are most often distant and no first degree relative was affected. Apart from the well-known associations with aniridia, hemihypertrophy, genitourinary anomalies, Beckwith-Wiedeemann, and Drash syndromes, there is also a significant excess of congenital heart defects (P = .008) which remains to be explained. Several findings support the bimutational hypothesis such as earlier diagnosis and increased parental age in bilateral cases. No particular anomalies and no increased frequency of childhood cancer were found in patients' relatives. The frequency of Wilms' tumor in relatives was estimated to be less than 0.4% in sibs, 0.06% in uncles and aunts, and 0.04% in first cousins. These figures are very different from those found in retinoblastoma and suggest that the mechanism may be more complex in Wilms' tumor. This conclusion is in agreement with molecular biology studies in tumors and linkage analysis in multiple case families which suggest that more than one locus is involved.

Two-disease-locus model: segregation analysis using information on two markers in nuclear families. Application to IDDM.

In the present paper, an extension of segregation analysis is proposed using information on the joint segregation of two unlinked markers conditional on the disease status in nuclear families, in order to consider two-locus models with one locus linked to the first marker and the other linked to the second marker. We propose tests for examining evidence for the effect of genes located at these two loci and whether this effect is multiplicative or not. This method is then applied to a sample of IDDM families typed for the HLA and Gm markers to test, in addition to a factor of the HLA region, the potential involvement of the Gm system in the susceptibility to IDDM. The analysis does not provide evidence for such an involvement.

Segregation analysis of two genetic markers in IDDM families under two-locus models.

The purpose of our study was to examine evidence for the role of a second genetic factor in the susceptibility to IDDM, in addition to that located in the HLA region. To do this, we have studied the joint segregation of HLA and another marker conditional on disease status using the IDDM families of GAW5, under a two-locus model, one locus in the HLA region, the other close to the other marker. This marker has been, successively, Gm and the DNA polymorphism of the insulin gene 5' region. The study has been carried out using a segregation analysis method developed to make use of information on the segregation of two markers and the disease in nuclear families. The GAW5 data do not provide evidence for the role of a genetic factor in the Gm or insulin region in the etiology of IDDM.

[Incidence of congenital malformations at birth in a series of maternity patients of Guadeloupe]. / Incidence des malformations congénitales à la naissance dans une maternité guadeloupéenne.

A study of 8,142 live and still-born babies was carried out from July 1979 to February 1983 in Guadeloupe (French West Indies). The total incidence of malformations detected at birth was 1.71% (minor malformations such as polydactyly being very frequent in this population were excluded). Among the malformed children, 25% had multiple malformations and 17% were still-born. Two types of malformations seem to be particularly frequent: those of the central nervous system (3.8%) and of the digestive tract (2.45%). The malformed group differs in birth-weight and size, in still-birth rate and in the incidence of obstetrical history.

Effects of misspecifying genetic parameters in lod score analysis.

The lod score method is widely used to test linkage and to estimate the recombination fraction between a disease locus and a marker locus. The parameters (gene frequency, penetrance, and degree of dominance) are assumed to be known at each locus. This condition may not be fulfilled at the disease locus. In this paper, we evaluate the errors due to the use of wrong parameters. The power of the linkage test is sensitive to the degree of dominance, and slightly to the penetrance, but not to the gene frequency. In contrast, the estimation of the recombination fraction may be strongly affected by an error on any genetic parameter.

Studies on an isolated West Indies population: IV. Genetic study of hearing loss.

Hearing troubles were found to be very frequent among inhabitants of French origin in a small Caribbean island. Segregation analysis of hearing loss was performed in 165 complete nuclear families and revealed that familial aggregation could be entirely explained by a single recessive gene with high frequency (0.40). Homozygous individuals for this gene would probably be more susceptible to ototoxic agents than other individuals. High frequency of this gene may be due to a founder effect.

Studies on an isolated West Indies population: IV. Genetic study of hearing loss

Hearing troubles were found to be very frequent among inhabitants of French origin in a small Caribbean island. Segregation analysis of hearing loss was performed in 165 complete nuclear families and revealed that familial aggregation could be entirely explained by a single recessive gene with high frequency (0.40). Homozygous individuals for this gene would probably be more suscepticle to ototoxic agents than other individuals. High frequency of this gene may be due to a founder effect (AU)

[Congenital adrenal hyperplasia (21-OH) in France. Population genetics]. / L'hyperplasie congénitale des surrénales (21-OH) en France. Génétique des populations.

Incidence of congenital adrenal hyperplasia due to 21 hydroxylase deficiency was studied in France. Five hundred and twenty six patients born during the period 1963-1979 were found. Assuming complete ascertainment in females, the incidence of the disease is 0.43 X 10(-4) or 1: 23,044. The frequency of the carriers is 0.013 (1/76). The birth places of patients show an unequal geographic distribution. The mean inbreeding coefficient is 270 X 10(-5), a figure higher than the mean coefficient of France. The frequency of marriages between first cousins is slightly raised, 0.3%.