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Human genetics

Human genetics. Human genetics. Lectures – 17x2 (Med); 17x1 ( Stom ) ; Seminars – 17x3 (Med); 17x2 ( Stom ) ; 3 concluding tests ( tests + practical part ) Final examination ( tests + practical part ) Consultations www.biologiemoleculara.usmf.md http://e.usmf.md

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Human genetics

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  1. Human genetics

  2. Human genetics • Lectures– 17x2 (Med); 17x1 (Stom); • Seminars – 17x3 (Med); 17x2 (Stom); • 3 concluding tests (tests + practical part) • Final examination (tests + practical part) • Consultations • www.biologiemoleculara.usmf.md • http://e.usmf.md • Passkey – bmgu

  3. Average mark • Written test 1 (max. 10) • Computer test 1 (max. 10) • Written test 2 (max. 10) • Computer test 2 (max. 10) • Computer test 3 (max. 10) • Attendance in lectures (max. 10) • Scientific report (max. 10, for Med only)

  4. Final grade • Average per semester – 50% • Written (practical) part – 30% • Multiple choice test – 20%

  5. Agricultural revolution –XVII-XVIII century Industrial revolution – XIX century Informational revolution – XX century Genetic revolution – XXI century

  6. Development of Human and Medical genetics • 1956 – identification of number of human chromosomes (46,XX; 46,XY); • 1961- relationship between chromosomal aberrations and human diseases; • 1966 – decoding of genetic code, description of inherited metabolic diseases; prenatal diagnosis via amniocentesis. • 1980 – cloning of first human gene.

  7. 1981 - molecular methods used for location of genes in chromosomes. • 1985 - PCR used for identification of mutations. • 1991 – cloning of genes involved in many human diseases: Dushenne muscle distrophy, cystic fibrosis, neurofibromatosis, retinitapigmentosum, Marfansdr.

  8. 1994 – McKusick published „Mendelian Inheritance in Man; A Catalog of Human Genes and Genetic Disorders”. On-line version OMIM http://www.ncbi.nlm.nih.gov/omim/ • 1996 – preimplantation diagnostic of embryos obtained by in vitrofertilisation. • 1996 - 2001 more then 1000 genes involved in human pathology were described.

  9. In 2001 „Human genome project” starts. During 2001-2003 many visions were changed: • From structure – to function of genes; • From location of genes in chromosomes – to sequencing of DNA; • From diagnostic of genetic diseases – to calculation of predisposition to genetic diseases; • From etiology – to mechanisms; • From analysis of monogenic traits – to analysis of polygenic traits; • From genome – to proteome; • From medical genetics – to genetic medicine;

  10. Cell Chromosomes Organism Nucleus DNA Amino acids Protein

  11. The “omics” cascade

  12. What is the problem? Patient What to do in order to solve this problem? CLASSIC VISION GENETIC VISION Whythis patienthasthis diseasenow? What possibilities are forpreventionor reducing of effect of disease for patient or/andhis family? Which is the prognostic and prophylaxis of complications in this patient? What is the risk for this disease for other members of the family?

  13. Prenatal diagnostic Prognosis of disease evolution Preimplantation diagnostic New methods of diagnostic How does genetics benefit medicine? Family planning Understanding of etiopathology Cell therapy New etiopathological drugs Gene therapy

  14. Compartments of genetics

  15. Human genetics – • Fundamental and applicative science • Genetics isfundamental sciencebecause it is studying: • structure, • main mechanisms, • main principles, • - which ensure keeping, transmission and expression of human traits, • - which ensure formation, development and functions of human organism.

  16. Genetics is a clinic science • Which study relationships between heredity and diseases: • mutations (monogenic, polygenic or chrs) determine • * a disease or • * a predisposition for a genetic disease. • - Genetic diseases are: • * numerous - 9000; • * frequent - 5-8% in newborns. • - Genetic diseases are present in all medical fields.

  17. Lymphocytes – 374 Brain – 3195 genes Eye – 547 genes Endothelial cells – 1031 Bons– 904 genes Salivary glands – 17 Adipose tissue – 581 genes Thyroid gland – 584 Thymus – 261 genes Parathyroid glands – 46 Esophagus – 76 genes Smooth muscle – 127 Lungs – 1887 genes Skeletal muscle – 735 Heart – 1195 genes Mammal glands – 696 Liver – 2091 genes Pancreas – 1094 Erythrocyte – 8 genes Spleen – 1094 Trombocytes– 22 genes Adrenal glands – 658 Large intestine – 874 genes Gallbladder – 788 Kidney – 712 genes Small intestine – 297 Ovary – 504 genes Testis – 370 genes Placenta – 1290 Uterus – 1859 genes Prostate – 1283 Embryo – 1989 genes Leucocytes – 2164 Synovial membrane – 813 genes Skin – 620 Genes involved in human development and functions of tissues and organs

  18. Genetics is a science which study: - heredity and - variability of human organism. Substrate of heredity and variability: Cellular Genetic apparatus Molecular DNA Morphologic Chromosomes

  19. Heredity • Heredity is the passing of traits to offspring (from its parent or ancestors). This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. 

  20. Heredity is based on

  21. Importance of heredity

  22. Variability

  23. Importance of variability:

  24. Mutations

  25. All pathologies have a genetic component

  26. Genetic diseases arenumerous. • There are knownover 10.000of disease determined or conditioned by genetic factors. • Arehighly diverse. • May appear atany age. • May affect any organpresent in all fields of medicine. • Present in5-8% of newborns. • Genetic factors may be responsible for reproductive disorders(sterility, miscarriage). • Genetic diseases responsible forinfantile mortality and morbidity. • Genetic diseases are chronic diseasesand produce physical or mental disorders.

  27. Causes of mutations

  28. Types of mutations

  29. Frequency of genetic disorders

  30. Types of mutations

  31. Expression of mutations in phenotype

  32. Migration

  33. Adaptive modifications in the limit of norm of reaction • Norm of reaction is under control of genotype • Under the pressure of environment gene expression changes to ensure optimal activity of organism • Short-time adaptations • Long-time adaptations

  34. Spontaneous abnormalities induced by environment • Abnormalities produced during development caused by destructive factors • Congenital abnormalities • Determined by teratogen factors • Mime genetic disorders PHENOCOPIES • Postnatal abnormalities

  35. Levels of organization of genetic material • Genome – complement of cell DNA (nuclear + mitochondrial) • Chromosome – a linkage group of genes • Gene – elementary unit responsible for synthesis of a protein and expression of a trait

  36. Peculiarities of the human genome Haploid nuclear genome 3,2 x 109bp ~ 30000 genes Mitochondrial genome 16,6 kb 37 genes Gene DNA 25% Extra-gene DNA 75% Coding DNA 10% Non-coding DNA 90% Single copy or low number copies sequences 60% Moderate or highly repetitive sequences 40%

  37. Sequences of the Human genome

  38. Alternation of genome elements • Structural genes • Coding sequence in tandem (e.g., Nucleolar organizer) • Spacers • Satellite DNA (e.g., centromeric DNA) • LINEs (Long Interspersed Repeated Elements) – 16% • SINEs (Short Interspersed Repeated Elements) – 11% • LTRs (LongTerminalRepeats) • VNTRs (Variable Number Tandem Repeats) • SSRs (Simple Sequence Repeats) • etc.

  39. Repetitive elements in human geneHGO (homogentisate1,2-dioxygenase)Deficiency of enzyme encoded by HGO leads to alkaptonuria

  40. Human chromosomes • morphologic substrate of H and V; • supramolecular level of organization of genetic material (DNA + histones + non-histones + RNA) • dynamic structures with different shape, level of condensation, gene activity: • single-chromatidor two-chromatid; • chromatin or chromosome; • transcriptional active or inactive.

  41. self-reproduction of chromosomes takes place during S phase of interphase (replication). • chromosomes represent linkage groups of genes: • each chrs contains a specific number of genes; • each gene has a specific place in chrs - locus; • genes of one chromosome are inherited together • a diploid set of chromosomes is called karyotype: • 23 pairs: 22 pairs of autosomes + • 1 pair of gonosomes (XX or XY). • Pair of chromosomes = homolougus chromosomes

  42. Origin of gonosomes

  43. landmarks of karyotype: • relative and absolute length of chrs, • position of centromere = primary constriction- c, • presence of secondary constrictions - h, • presence of satellites- s • chromosomes may be analyzed during: • metaphase (homogenous painting or banding) • prometaphase (banding) • interphase (hybridization with fluorescent probes)

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