Vacancies and career opportunities
Francois Malecaze & Patrick Calvas // Job description:
ESR (PhD Student)
Research Focus:
Myopia is the most frequent form of ametropia. There are three types of myopia: low myopia
(most frequent, characterized by a refraction defect of up to -3 dioptries (D), average myopia (between -3 and -6D)
and high myopia (less than -6D). The latter, which concerns 1,7% of the general population, is the most severe: it can cause complications
leading to severe sight impairment, which in terms of public health make high myopia the fourth cause of legal blindness.
Stretching and the onset of modifications to the biochemical composition of the sclera are the key mechanisms to the disease.
However, the physiopathology of the affection remains unknown. Studies carried out in man and in animals show without any possible doubt
that heredity and environmental factors (essentially a preponderance of close-work activity) intervene in the determinism of high myopia.
The decisive role of the hereditary feature was then confirmed by the work of an American team which had just published two localizations
on chromosomes 18p11-31 (MYP2 locus; MIM #160700) and 12q21-23 (MYP3 locus; (MIM # 603221). A subsequent cohort linkage study enabled us to identify a new region of susceptibility to high myopia in 7q36 (MYP4 locus; MIM #608367). Since then the complexity of the genetic determinism of the affection has been underlined by the description of several other loci of susceptibility. In a new cohort of French families, our team recently demonstrated the implication of chromosome 7p15.3.
Aim of the project:
To evaluate the genetics component of myopia in familial cases and in a case control study. Two major themes are to be developed:
1 - To evaluate candidate genes mutations or variants in the known myopia susceptibility loci Mainly in loci which we described on chromosomes 7q36 and 7p15.
2 - To achieve statistics, considering participation of several genes and evaluating multiple quantitative loci traits.
The large number of regions identified during the past 4 years would seem to indicate that high myopia has complex heredity and the results must therefore be evaluated using different methods. We intend to use and develop new approaches based on the creation of a high density map of the candidate regions and the study of linkage disequilibrium with the phenotype. The combined intervention of several loci in the disease determinism will be evaluated using new linkage analysis and association methods.
a) Segregation analysis :a " two locus " model evaluation.A more precise evaluation of the segregation model will be carried out using software able to estimate the intervention of 2 loci.
b) Revaluation of phenotype as a quantitative trait.Myopia can be considered as a quantitative trait through measurement of refraction and the axial length of the eye. Our aim is to apprend the weight of the different covariants in the determinism of the trait by bi and multipoint analysis of the polymorphic markers using the linkage method of the variance composant. Considering high myopia as a quantitative trait will free the study from the arbitrary threshold used to define an individual's status.
c) Localization of familial myopia genes by positional cloning. A wide genome scan at 5cM with microsatellite markers (set ABI PRISM LMSv2.5-MD10-HD-5) will be carried out in the new families. The loci with suggestive lod-scores will be reduced by densification with new satellite markers. SNPs genotyping will then make it possible to reduce the intervals to less than 1 Mb. Bipoint and multipoint liaison analyses will be performed using MLINK, LINKMAP, MERLIN and GENEHUNTER software.
d) Familial data study - association study. In multi-case families, linkage analysis will be completed by the PDT method (Pedigree Disequilibrium Test) ; this association test is suitable for large families and renders the study of pedigrees possible when several children are affected whose parents are genotyped or in families with discordant pairs. The results of the association tests will enable the intervals to be reduced.
e) Gene/loci interaction study. Until now, only the hypothesis of genetic heterogeneity has been considered, given the multiplicity of the described loci. We wish to evaluate the multi-genic hypothesis and the possible collaboration between different loci in the trait determinism. We will therefore use a linkage analysis method capable of considering the combined effect of at least 2 loci, GENEHUNTER-TWOLOCUS II.2.3. Study of isolated or sporadic cases of high myopia
f) Case-control analysis will parallel the familial studies. It will be based on linkage disequilibrium, using the patients and unrelated controls. We will use different approaches, to analyse in particular tagSNPs which will be used to target the regions of interest on the map. It will then be possible where there is a known environmental risk (close work, educational level), to evaluate the existence of linkage disequilibrium between the polymorphic markers and the phenotype, by replacing the usual familial analyses with case-control analyses. The trios will be included in the transmission distortion tests (TDT).
The laboratory is part of the "Functional genetics of epithelial diseases" department in the INSERM U563 research unit, located on the campus of Toulouse hospital (Purpan). This research unit provides a very attractive scientific environment and all the necessary facilities for the project (DNA genotyping and sequencing platform).
Candidates should have a background in molecular biology and/or in statistical genetics.
The position is currently available. Candidates should hold a Master degree and send a curriculum vitae, a brief statement of research interest to :
Pr. P. CALVAS (calvas.p@chu-toulouse.fr) and or Pr F. MALECAZE (malecaze.f@chu-toulouse.fr), CPTP, INSERM U563, Hopital purpan, 31059 Toulouse Cedex, France.
ER (Post Doc)
Research Focus:
Myopia is a highly prevalent disorder characterized by nearsightedness and retinal complications. The pathophysiology of the disease remains unknown and most recent studies involved environmental and genetic components whose major effect are the biochemical modification of the eye sclera and lengthening of the eye globe.
Aim of the project:
To evaluate the genetics component of myopia in familial cases and in a case control study. Two major themes are to be developed:
1 - To evaluate candidate genes mutations or variants in the known myopia susceptibility loci including two loci that we described on chromosome 7(MYP4 and unpublished data) and those we recently confirmed by linkage analysis in cohort studies on chromosomes 17q (MYP5) and 18q (MYP2).
2 - To achieve statistics, considering participation of several genes and evaluating multiple quantitative loci traits
The laboratory is part of the "Functional genetics of epithelial diseases" department in the INSERM U563 research unit, located on the campus of Toulouse hospital (Purpan). This research unit provides a very attractive scientific environment and all the necessary facilities for the project (DNA genotyping and sequencing platform).
Candidates should have a strong background in molecular biology and/or in statistical genetics. An experience in linkage analysis and association studies, quantitative traits genetics and in experimental or in silico gene identification would be appreciated.
The position is currently available. Candidates should hold a Ph.D. degree and send a curriculum vitae, a brief statement of research interest and the names of two references to:
Pr. P. CALVAS (calvas.p@chu-toulouse.fr) and or Pr F. MALECAZE (malecaze.f@chu-toulouse.fr), CPTP, INSERM U563, Hopital purpan, 31059 Toulouse Cedex, France.