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Genetics for undergraduates

Dec 19, 2014

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genetics ppt for undergraduates

  • 1. GENETICS

2. INTRODUCTION Humans have only about 30,000 genes Genetics is study of single or few genes and theirphenotypic effects. Genomics is the study of all the genes in thegenome and their phenotypic effects 3. Any 2 individuals share greater than 99.5% oftheir DNA sequences. Remarkable diversity of humans is encoded inless than 0.5% of our DNA 4. DISEASES time-honored classification of human diseases (1) those that are genetically determined, (2) those that are almost entirelyenvironmentally determined, (3) those to which both nature and nurturecontribute. 5. MUTATIONSPERMANENT change inDNA GENE MUTATION: (may, and often,result in a single base error) CHROMOSOME MUTATION:(visible chromosome change) GENOME MUTATION: (wholechromosome) 6. Those that affect germ cells are transmitted tothe progeny and may give rise to inheriteddiseases.Mutations in somatic cells are not transmitted tothe progeny but are important in the causation ofcancers and some congenital malformations. 7. Point mutations result from the substitution of asingle nucleotide base by a different base,resulting in the replacement of one amino acid byanother in the protein product. EX: sickle cell anemia. "nonsense" mutations interrupt translation, andthe resultant truncated proteins are rapidlydegraded. 8. POINT MUTATION 9. Frameshift mutations occur when the insertion ordeletion of one or two base pairs alters thereading frame of the DNA strand Trinucleotide repeat mutations mutations are characterized by amplification of asequence of 3 nucleotides. 10. MENDELIAN INHERITANCEPATTERNSAUTOSOMALDOMINANTAUTOSOMAL RECESSIVESEX-LINKED (recessive), involving X chromosome 11. AUTOSOMAL DOMINANT Disease is in HETEROZYGOTES NEITHER parent may have the disease (NEW mut.)REDUCEDPENETRANCE(environment?, other genes?)VARIABLEEXPRESSIVITY(environment?, other genes?) DELAYED ONSETMay have aUsually result in a REDUCEDPRODUCTION or INACTIVE protein 12. AUTOSOMAL DOMINANT HUNTINGTON DISEASEPOLYCYSTICNEUROFIBROMATOSIKIDNEY S MYOTONIC DYSTROPHY TUBEROUSHEREDITARYSCLEROSISSPHEROCYTOSISVONWILLEBRANDMARFAN SYNDROMEDISEASEEHLERS-DANLOS SYNDROMES(some)OSTEOGENESIS IMPERFECTAACHONDROPLASIAACUTE INTERMITTENTPORPHYRIAFAMILIALHYPERCHOLESTEROLEMIA 13. AUTOSOMAL DOMINANTPEDIGREE1) BOTH SEXES INVOLVED2) GENERATIONS NOT SKIPPED 14. AUTOSOMAL RECESSIVE Disease is in HOMOZYGOTES UNIFORM expression than ADMoreOften COMPLETE PENETRANCEOnset usually EARLY in life NEW mutations rarely detected clinicallyProteins show LOSS of FUNCTION Include ALL inborn errors of metabolism MUCH more common that autosomal dominant 15. AUTOSOMALRECESSIVE CFHgb S PKUTHALASSEMIAS GALACTOSEMIACONG. ADRENAL HYPERPLASIA HOMOCYSTINURIAEHLERS-DANLOS (some) LYSOSOMALSTORAGEALKAPTONURIA -1 ANTITRYPSIN NEUROGENIC MUSC. ATROPHIES WILSON DISEASEFRIEDREICH ATAXIA HEMOCHROMATOSIS SPINAL MUSCULAR ATROPHY GLYCOGEN STORAGEDISEASES 16. AUTOSOMAL RECESSIVE PEDIGREE 1) BOTH SEXES INVOLVED 2) GENERATIONS SKIPPED 17. SEX (X) LINKED MALES ONLY HIS SONS are OK, right? ALL his DAUGHTERS are CARRIERS The Y chromosome is NOThomologous to the X, i.e., the conceptof dominant/recessive has no meaninghere HETEROZYGOUS FEMALES have nophenotypic expression (carriers).usually, this means autosomalrecessive, right? 18. SEX (X) LINKEDDUCHENNE MUSCULAR DYSTROPHYHEMOPHILIA , A and BG6PD DEFICIENCYAGAMMAGLOBULINEMIAWISKOTT-ALDRICH SYNDROMEDIABETES INSIPIDUSLESCH-NYHAN SYNDROMEFRAGILE-X SYNDROME 19. SEX LINKED PEDIGREE1) MALES ONLY, sons of affected males are OK2) GENERATION SKIPPING DOESNT MATTER 20. SINGLE GENE DISORDERS ENZYME DEFECT (Most of them, e.g., PKU) Accumulation of substrate Lack of product Failure to inactivate a protein which causes damage RECEPTOR/TRANSPORT PROTEIN DEFECT(Familial Hypercholesterolemia) STRUCTURAL PROTEIN DEFECT (Marfan,Ehl-Dan) Structure Function Quantity ENZYMEDEFECT WHICH INCREASES DRUG SUSCEPTIBILITY: G6PDPrimaquine 21. MARFAN SYNDROMEautosomal dominant disorder of connective tissues,the basic biochemical abnormality affects fibrillin 1. This glycoprotein, secreted by fibroblasts, is the majorcomponent of microfibrils found in the extracellularmatrix.Microfibrils serve as scaffolding for the deposition ofelastin and are considered integral components ofelastic fibers. Fibrillin 1 is encoded by the FBN1 gene, which mapsto chromosome 15q21.Mutations in the FBN1 gene are found in all patientswith Marfan syndrome. 22. ABRAHAM LINCOLN 23. SKELETAL ABNORMALITIESPatients have a slender, elongated habitus withabnormally long legs, arms, and fingers(arachnodactyly); a high-arched palate; hyperextensibility of joints. A variety of spinal deformities, such as severekyphoscoliosis, may appear.The chest is deformed, exhibiting either pectusexcavatum (i.e., deeply depressed sternum) or apigeon-breast deformity. 24. ocular change is bilateral dislocation, orsubluxation, of the lens owing to weakness of itssuspensory ligaments.It should be noted that the ciliary zonules thatsupport the lens are devoid of elastin and aremade up exclusively of fibrillin 25. SUBLUXATION OF LENS 26. cardiovascular system. Fragmentation of the elastic fibers in the tunicamedia of the aorta predisposes to aneurysmaldilation and aortic dissection The cardiac valves, especially the mitral and, lesscommonly, the tricuspid valve, may beexcessively distensible and regurgitant (floppyvalve syndrome), giving rise to congestive cardiacfailure Death from aortic rupture may occur at any ageand is the most common cause of death. Lesscommonly, cardiac failure is the terminal event. 27. EHLERS-DANLOS SYNDROMES(EDSs) are characterized by defects in collagensynthesis or structure. 30 distinct types of collagen, and all of them havecharacteristic tissue distributions and are theproducts of different genes. the clinical heterogeneity of EDS can beexplained by mutations in different collagengenes. 28. tissues rich in collagen, such as skin, ligaments,and joints, are frequently involved in mostvariants of EDS. Because the abnormal collagen fibers lackadequate tensile strength, skin is hyperextensibleand joints are hypermobile. These features permit grotesque contortions,such as bending the thumb backward to touchthe forearm and bending the knee upward tocreate almost a right angle. 29. The skin is extraordinarily stretchable, extremelyfragile, and vulnerable to trauma. Minor injuries produce gaping defects, andsurgical repair or any surgical intervention isaccomplished only with great difficulty because ofthe lack of normal tensile strength. 30. The basic defect in connective tissue may lead toserious internal complications, including rupture of the colon and large arteries (vascularEDS); ocular fragility, with rupture of the cornea andretinal detachment (kyphoscoliosis EDS); diaphragmatic hernias (classic EDS), 31. MOLECULAR BASE Deficiency of the enzyme lysyl hydroxylase. Decreased hydroxylation of lysyl residues intypes I and III collagen interferes with thenormal cross-links among collagen molecules. 32. Diseases Caused by Mutations in Receptor Familial Hypercholesterolemia 33. FAMILIALHYPERCHOLESTEROLEMIA is among the most common mendelian disorders; thefrequency of heterozygotes is one in 500 in thegeneral population.It is caused by a mutation in the gene that specifiesthe receptor for LDL, the form in which 70% of totalplasma cholesterol is transported. Dietary triglycerides and cholesterol are incorporatedinto chylomicrons in the intestinal mucosa, whichdrain via the gut lymphatics into the blood. These chylomicrons are hydrolyzed by an endotheliallipoprotein lipase in the capillaries of muscle and fat.The chylomicron remnants, rich in cholesterol, arethen delivered to the liver 34. Some of the cholesterol enters the metabolic pooland some is excreted as free cholesterol or bileacids into the biliary tract. The endogenous synthesis of cholesterol and LDLbegins in the liver The first step in the synthesis of LDL is thesecretion of triglyceride-rich very-low-densitylipoprotein (VLDL) by the liver into the blood. In the capillaries of adipose tissue and muscle,the VLDL particle undergoes lipolysis and isconverted to intermediate-density lipoprotein(IDL). 35. In familial hypercholesterolemia, mutations inthe LDL receptor gene impair the intracellulartransport and catabolism of LDL, resulting inaccumulation of LDL cholesterol in the plasma. In addition, the absence of LDL receptors on livercells also impairs the transport of IDL into theliver, and hence a greater proportion of plasmaIDL is converted into LDL. 36. Thus, patients with familialhypercholesterolemia develop excessive levels ofserum cholesterol as a result of the combinedeffects of reduced catabolism and excessivebiosynthesis In the presence of such hypercholesterolemia,there is a marked increase of cholesterol trafficinto the monocyte macrophages and vascularwalls via the scavenger receptor. This accounts for the appearance of skinxanthomas and premature atherosclerosis 37. Diseases Caused by Mutations in EnzymeProteins Phenylketonuria 38. affects 1 in 12,000 live-born Caucasian infants. Homozygotes with this autosomal recessivedisorder classically have a severe lack ofphenylalanine hydroxylase, leading tohyperphenylalaninemia and PKU. Affected infants are normal at birth but within afew weeks develop a rising plasma phenylalaninelevel, which in some way impairs braindevelopment. Usually by 6 months of life severe mentalretardation becomes all too evident; fewer than 4% of untreated phenylketonuricchildren have IQs greater than 50 or 60.. 39. About one-third of these children are never ableto walk, and two-thirds cannot talk. Seizures, other neurologic abnormalities,decreased pigmentation of hair and skin, andeczema often accompany the mental retardationin untreated children. Hyperphenylalaninemia and the resultantmental retardation can be avoided by restrictionof phenylalan