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Imad Fadl-Elmula Department of Pathology Faculty of Medicine Al Neelain University Definition Study of the genes Medical genetics Clinical genetics 40.000 History Charles Darwin • On the evolution of species Evolution Theory Darwin Fadl-Elmula Hybridization Experiments • Basic Laws of Heredity and Law of Independent Assortment. • Findings rediscovered in1900. Gregor Mendel (1822-1884) • Augustinian monk in Fadl-Elmula Czechoslovakia. • Attended University of Vienna The somatic mutation theory of cancer Theodor Boveri (1862-1915) Acquired genetic changes are the main causes of malignant transformation of target cells. Fadl-Elmula Rise of Modern Genetics Discovery of Chromosomes • Walter Flemming in 1882. Salamander larva Thomas Hunt Morgan 1910 • Fruit fly experiments in 1910. Trait are sex linked and reside on chromosome. • Realization that chromosomes are blueprints of life. Chromosomes (?) , XX Painter (1921) (?) , XY Watson and Crick Discovered double helix structure of DNA in 1953 46,XY 46,XX (Tjio & Levan, 1956) Fadl-Elmula Fadl-Elmula Mutations Altered gene Altered Protein Altered function Fadl-Elmula . High incidence 2-5% of all liveborn. 30% of pediatric addmision. Incurable and often severe .........prevention ....Genetic counsleing Clinical services 1. Accurate diagnosis 2. The risk of devoloping and transmision prognosis 3. Treatment (genetherapy) The scope of genetics The human genome has been sequenced! Approximately 35,000 genes, most of which encode a 9 protein, in a haploid genome of 3 X 10 base pairs Only about 1.5 % of the DNA actually encodes functional genes All living organisms are remarkably similar at the genetic level Same genetic code. About 50 % of genes comparable between us and plants. All nucleated somatic cells have a complete set of genes. Only a small fraction of genes are active in a single cell Enables cloning. Prevalence of genetic disease Type of genetic disease Prevalence per 1000 Single gene Autosomal dominant Autosomal recessive X linked recessive 2-10 2 1-2 Chromosomal changes Disease with genetic base 6-7 7-10 Congenital malformations Total 20 38-51 Genetic disease 1. Single gene (Mendelelian-4000) 2. Somatic Mutation (cancer) 3. Chromosomal (conostitusion) 4. Multifactorial (Diabetis, IHD) Specialized laboratory 1. Cytogenetics 2. Molecular cytogenetics 3. Biochemical genetic 4. Molecular genetic Clinical applications Diagnostic Diagnostic. Preventative Preventative. ☻Carrier detection ☻Population screening Preclinical diagnosis Genetic monitoring Therapeutic. Therapeutic Consultations and management Clinical geneticist. Developmental pediatrician. Cardiologist. Ophthalmologist. Neurosurgeon. Orthopedic specialist. Psychiatrist. Physical and occupational therapist. Speech-language pathologist. Audiologist. Is it all what we see ? Fadl-Elmula Fadl-Elmula Fadl-Elmula LOOK FROM ANOTHER ANGLE! Fadl-Elmula E E E E E Earth Sudan Country North Kordofan Cell Chromosome Region Chromosome segment Cities Region genes S. Nucleotide Clinical applications Diagnostic Diagnostic. Preventative Preventative. ☻Carrier detection. ☻Population screening. Preclinical diagnosis. diagnosis Genetic monitoring. monitoring Therapeutic. Therapeutic The genetic profiles of a disease can be assessed at different level of resolution Array Fadl-Elmula CML (Bcr/Abl) (Rowley, 1973) Fadl-Elmula FISH of BCR-ABL Green: BCR Red: ABL BCR-ABL Gel Pt 1 Pt 2 K562 Pt 1 ABL BCR-ABL 10-4 BCR-ABL Pt 2 K562 ABL Prevention Fadl-Elmula Genetic counseling Fadl-Elmula Follow up Evaluation of bone marrow transplants (BMT) A girl transplanted with BM cells from her brother interphase FISH RELAPSE Y chromosome X chromosome PROGNOSIS AML and ALL 11q23-aberrations Probes: wcp10 wcp11 11 10 der(11)inv(11)(q13q23)del(11)(q13) del(10)(p11) 11 der(14)t(11;14)(q13;q32)t(10;11)(?;q23) 14 11q13 11q23 742f9 (MLL) 11 14 VERY POOR in general wcp11 Mitochondrial DNA polymorphisms track human migrations (Wallace Sci. Amer. 277:40) "Every scientist, physician, or paramedical who practices in the 21st century must have an in-depth knowledge of the principles of clinical genetics and their application to a wide variety of clinical conditions. Each Health School is demanded to incorporate genetics teaching into its curriculum" Fadl-Elmula