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A Few Examples of Laboratory Work and Results - Some Results in
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The CNS, directed by Jean Weissenbach, participated in sequencing the Arabidopsis thaliana genome, completed in December 2000. The CNS coordinated the European effort in sequencing chromosome 3. The complete sequence of the 25 000 known genes of the Arabidopsis thaliana five chromosomes will help advance knowledge of plants of agronomic interest and will serve as a basis for future functional genomics projects. The CNS also sequenced human chromosome 14, in the international HGP (Human Genome Project). The almost complete version of the human genome obtained to date was presented on 12 February 2001 by the partners of the HGP International Consortium and the American firm Celera Genomics. The enormous effort of "reading" the human genome provides extremely valuable information and confirms the estimates announced in May 2000 by Jean Weissenbach, which placed the number of human genes at no more than 34 000, barely twice the number of genes of the drosophile (fruit fly). In 1998, the Genoscope began to sequence a fish (T. nigroviridis) with a very compact genome . The genome sequence is being assembled and should provide a powerful method to improve the analysis of vertebrates genomes. Finally, the Genoscope is
currently in the race to sequence the rice genome. Representing
France's contribution in the IRGSP (International Rice Genome
Sequencing Program) international consortium, it is responsible
for sequencing the rice chromosome 12. The complete sequence will
be completed in 2003. Work identifying and annotating rice genes
is being done at the same time.
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Identifying Variations in DNA Sequences The priority of the CNG, directed by Mark Lathrop, is to identify the variations present in DNA sequences responsible for genetic diseases. The CNG is currently studying auto-immune diseases, the HLA region, cardiovascular disease, infectious diseases, cancer and monogenic diseases. Monogenic diseases (such as muscular dystrophies, cystic fibrosis, etc.) are caused by one or more mutations in a single gene. Although these diseases affect a small number of people worldwide, they are of major importance to medicine: they affect several members of a single family and are often very serious, invalidating or even fatal. Identifying genetic factors through gene typing would help to understand their causes and facilitate the development of diagnostic tools and new treatments. In cardiovascular diseases, cancer and diabetes -- called multifactor or complex diseases -- the variations present in many genes interact with environmental factors (lifestyle, etc.) and cause a predisposition to these diseases. Because of their high degree of complexity, these diseases require to study large portion of the genome. This is made possible thanks to the use of high-speed gene typing techniques. Identifying these genetic factors will help us better understand the causes of multifactor diseases; it will allow the development of prevention methods, diagnostic tools and new therapies. At the CNG, researchers are also working on diabetes, dermatological diseases (psoriasis), deafness, Paget's disease, hypertrophic cardiomyopathy and liver cancer. Recently, when studying six
families with a recessive form of ichthyosis (a skin disease,
characterized by serious flaking of the skin over the entire body,
often with erythema), a team led by Judith Fischer, of the CNG,
identified mutations on two genes coding for enzymes playing a
major role in moisturizing the skin, lipoxygenases. These two
genes are located on chromosome 17 and might participate in the
same metabolic pathway. This discovery was a colaboration with
the Genoscope–CNS and Généthon. These results
may have a major impact on the development of new dermatological
and cosmetic treatments.
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Généthon : an Approach to Gene Therapies Since 1997, Généthon engaged a wide approach to gene therapy techniques by combining fundamental research and industrial development. Its goal is to make genes a medication, which will require the production of vectors capable of transporting the medication-genes to the cell. Expectations are high in this area, both for genetic diseases (for which gene therapy is the only generic method available today) and for pathologies such as cancer, HIV, degenerative diseases, etc. Clinical trials, in the most favorable cases, have confirmed the wisdom of this approach. However, the vectors used must be improved. This research is being done at Généthon under the scientific management of Olivier Danos. A team led by Anne Galy, recently
set up on the campus, studies on blood stem cells and the immune
system. The goal of this work, in the long term, is to develop
cellular vaccines and cell based therapy.
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AFM and Généthon: Some Results
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Rheumatoid arthritis, which currently has no real cure, affects 1% of the population. It affects primarily women and causes joint deformations by altering cartilage, ligaments and bones. Although new treatments can slow its progression, the some 400 000 sufferers in France have had no real treatment. François Cornélis,
director of the European rheumatoid arthritis research laboratory
at Genopole®, launched a campaign to collect DNA from 10 000
people having the disease: “We have set ourselves the goal
of better understanding the disease in order to better treat it”.
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Model for an Animal Spinal Muscular Atrophy A generation of mice with
spinal muscular atrophy was created in the molecular neurogenetics
laboratory directed by Judith Melki. After showing that this muscular
disease combines a primitive attack on muscle and neurons, the
study of this model is being refined and should help to understand
the mechanisms causing spinal muscular atrophy in order to develop
therapeutic strategies for this often fatal childhood disease.
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A New Discipline, Physiogenomics Researchers from the functional genomics department at the CEA have shown how, thanks to global post-genomics techniques, it is possible to understand today the physiological meaning of modifications to cellular transcriptome and proteome. The team calls this new area of genomics research “physiogenomics”. In the April 2002 issue of the journal “Molecular Cell”, they demonstrated a survival strategy in Saccharomyces cerevisiae yeast cells for toxic exposure to cadmium. Their work shows a major
metabolic reorientation of yeast cells exposed to cadmium, a toxic
metal whose presence causes stress. In response to this stress,
the cells modify the expression of many new genes, leading to
the mobilization of cellular sulphur to produce glutathion (molecule
central to the detoxification process), thereby reducing the production
of proteins rich in sulphur, which are abundant under normal conditions.
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Epidemiological genetics, is seldom studied in North American campuses and even less in European campuses. Epidemiological genetics is dedicated to the development of mathematic models, statistics methods and computer programs to better understand the role of genetic factors in the most frequent human diseases resulting from the interaction between individual genetic heritage and environment (infectious, cardiovascular diseases, etc.). The creation on the Genopole® site, of the “Statistic and epidemiological methodology of multifactor diseases” unit, directed by Florence Demenais, is a major advantage for the campus. Its research program is to understand the genetic component and gene-environment interactions in multifactor pathologies (primarily cancers, asthma and allergies, diabetes, neurological and psychiatric diseases) and benefits from collaboration with its partners on the Evry site, on aspects such as mathematics and computing, and biology. Their goal is to identify certain genes involved in these complex pathologies, one of the major challenges of the post-genome period. In April 2002, in collaboration
with the Howard University Cancer Center in Washington, the team
published the results of an epidemiological study conducted over
five years in the United States on an African-American population,
in which the breast cancer incidence rate is lower than in the
white population. The study showed that the incidence of breast
cancer is related, in part, to the presence of a dominant gene,
and in part to an interaction between this gene and individual
hormonal factors. This study opens the way to a better evaluation
of the risk of breast cancer.
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Génopolante, a national
agronomic research program, is a scientific interest grouping
created in 1999, which aims to structure French research in agronomics,
to strengthen industrial property in this sector and to help create
biotechnologies companies. It is based on the equal association
of public (INRA, CNRS, IRD and CIRAD) and private partners (Bayer
Cropscience, Biogemma and Bioplant). The research is organized
along two axes: “Génopolante Generics”, which
develops work on model species (Arabidopsis thaliana, rice) and
the creation of technological tools (bioinformatics, DNA chips,
etc.); “Génopolante Species”, which brings
together specific programs on species of agronomic interest (wheat,
corn, colza, sunflower and pea). In the Génoplant program,
in collaboration with the private laboratory RhoBio, also located
on the Genopole® campus, the URGV (agronomic research unit)
developed a DNA chip containing 8 000 genes from the model plant
Arabidopsis thaliana. It can be used to study some of its physiological
functions such as nitrogen nutrition.
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