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Identification of genes associated to multifactorial diseases and Quantitative Traits through the study of genetic isolates  (2002)

The Population Genetics Institute carries on since 1995 a multidisciplinary project for the identification of genes predisposing to multifactorial diseases and to complex traits. This project is conducted in the villages of the Ogliastra geographic isolate of central-eastern Sardinia. These villages are examined under the epidemiological, genealogical, genetic, molecular and statistical profile. The identification of genes associated to pathological phenotypes in such populations is important non only for a better comprehension of etiopathogenesis of common diseases but also for the opportunity to create better statistical models for the study of complex traits in population isolates.
The project was initially conducted in one village (Talana) identified as ideal model for these type of studies. His population indeed possess all the desired characteristics: antiquity, slow demographic growth, isolation and high degre of endogamy and consanguinity that render it particularly apt for the proposed study. The proposed approach consists in the identification of identical by descent haplotypes through a stepwise genome-wide search.
For some prevalent pathologies in Talana such as essential hypertension and nephrolithiasis we identified two main loci and one candidate gene. These results were obtained through genome wide search of a negligible number of initial samples (about twenty!) strategically placed on large and deep rooted genealogical trees which connect all the people affected by the same pathology in one village.
The gene associated to nephrolithiasis has already undergone mutational analysis and we are studying the protein variants associated to this pathology.
Research results on this model population have great potential for molecular diagnostics, for the development of new pharmacological treatments and for the pharmacogenomic field.
A patent has been deposited for this gene.

Population structure studies on mtDNA and on Y chromosome are being conducted on other villages and they have revealed a much greater antiquity than expected form historical sources and a high degree of genetic drift among them.
Epidemiological research is enriching the number of affected by pathologies under study and is providing other research leads
Financing has been obtained so far only by private contributors such as Renato Soru, the Sardinian Bank, the Sardinian Financial agency S.F.I.R.S., by a private clinic from Jerzu (NU), and the Consortium 21. Another financing agency has been the Ogliastra Genetic Park, a consortium that collects various Ogliastra villages which have invested in this project in order to give job and training opportunities to their youths.

Image - Talana
Image - Laboratorio Talana
Image - Laboratorio Perdasdefogu
Image - Firma del Protocollo di Intesa a Ca
Image - Firma del Protocollo di Intesa a Ca
Image - Firma del Protocollo di Intesa a Ca
Document - Progetto di Ricerca Isolati Genetic


Genetic and functional analysis of tumors: study of both familiar and sporadic cases for the identification of new cancer genes and the assessment of a new molecular classification of tumors and cancer-prone diseases  (2002)

Identification of the genes that are mutated in cancer is a central aim of cancer research. It forms the foundation for understanding the biological abnormalities within neoplastic cells, provides information on the function of gene products, and sheds light on more complex questions such as the relationships between genes and biochemical pathways. Current strategies for the development of new therapeutic and preventive agents in cancer are increasingly dependent upon modulation of these critical molecular targets. Moreover, cancer classification and predictive or prognostic indices will increasingly be based upon detection of abnormalities in cancer genes. Although there has been considerable progress in the identification of genes that are mutated in cancer, several lines of evidence indicate that there are many (probably the large majority) yet to be discovered. Studies of the age dependent incidence of cancer suggest that five to seven low frequency, random mutational events are required for the development of common adult cancers. However, this type of analysis can only reflect rate-limiting steps and therefore may well underestimate the full set of genetic events present. Moreover, for most cases of most classes of cancer even this number of abnormalities has not been detected. In addition, there are clearly differences between cancer types with respect to the genes that are mutated and every cancer of a particular type does not acquire mutations in exactly the same set of genes.
Constitution of a cooperative group including some of the main institutions which are involved into the biomedical and biotechnological research as well as into the scientific teaching for the Southern areas of Campania and Sardegna, has contributed to create a network of collaborations among the different areas of advanced biomedical and biotechnological research [at present, interactions between research institutions (University, National Research Council, etc.), health institutions (Hospitals, Aziende Sanitarie Locali), I.R.C.C.S. (Istituti di ricovero e cura a carattere scientifico) and Companies are very poor, with a limited role into the development of territorial activities, and based on personal contacts or on collaborations restricted to specific fields], focused on:
- Definition of existing correlation between presence of genetic mutations (at both somatic and gemline level) and cell phenotype in order to identify the mechanisms involved into the development and progression of cancer
- Molecular characterization of the products (mRNA and protein) of the mutated candidate genes
- Identification of the mutation pattern among a large group of proteins and peptides specifically expressed in cancer cells and associated to the tumorigenesis
- Generation of new tumor markers for molecular diagnosis based on data obtained by combined genomic and proteomic analyses in order to early detect cancer progression
- Correlation between genotype, proteic phenotype, histopathology, clinical outcome and response to therapy in order to define new prognostic factors, which should classify the different risk subsets of cancer patients, optimizing both management and therapy of the disease
- Identification of new tumor targets for developing new therapeutical approaches

Document - Relazione attività Genetica Tumori


Identification of genes associated to multifactorial diseases and Quantitative Traits through the study of genetic isolates  (2003)

The Population Genetics Institute carries on since 1995 a multidisciplinary project for the identification of genes predisposing to multifactorial diseases and to complex traits. This project is conducted in the villages of the Ogliastra geographic isolate of central-eastern Sardinia. These villages are examined under the epidemiological, genealogical, genetic, molecular and statistical profile. The identification of genes associated with pathological phenotypes in such populations is important non only for a better comprehension of etiopathogenesis of common diseases but also for the opportunity to create better statistical models for the study of complex traits in population isolates.
The project was initially conducted in one village (Talana) identified as ideal model for these type of studies. His population indeed possess all the desired characteristics: antiquity, slow demographic growth, isolation and high degre of endogamy and consanguinity that render it particularly apt for the proposed study. The proposed approach consists in the identification of identical by descent haplotypes through a stepwise genome-wide search.
Population studies on mitochondrial DNA and Y chromosome structure were extended from Talana to three other Ogliastra villages. The comparison of data revealed that all these geographical isolates are genetically different because of genetic drift and are all much more ancient than is revealed by historic data. Epidemiological investigations are increasing the number of individuals affected by the pathologies under investigation and are suggesting new research avenues.
For some of the pathologies under study in these villages we identified five loci associated with essential hypertension and one gene associated with renal stones. Moreover in the study of factors controlling the variation of lipid metabolism we found one QTL associated with total cholesterol and HDL cholesterol levels.
These results were reached through an initial genome-wide scan carried out on a very limited number of samples aptly selected on large and deep genealogical trees that included all the individuals affected by a single pathology in the village. The renal stones associated gene has already been examined for mutations and we are studying the protein variants associated with the pathology. We have applied for …
The results obtained in this model population have great potential for the development of molecular diagnostic kits, of new drugs and for the development of a pharmacogenomic approach.
Financial support has so far come mostly from private sources such as Renato Soru, Banco di Sardegna, a Jerzu (NU) private clinic, the private Sardinian Bank SFIRS and the Consorzio 21.
The Parco Genos Consortium through its Ogliastra member villages, has greatly supported the research and has given the opportunity to many Ogliastra youths to work and learn in collaboration with our Institute.

Image - Vista di Talana, Urzulei e Perdasde
Image - Laboratori presenti sul territorio
Image - Firma del protocollo d'intesa
Document - PROGETTO OGLIASTRA


 
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