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Mendelian inheritance

Introduction History of science. Mendelian inheritance. 2019. Gregor Johann Mendel (1822–1884) Brno (Moravia) – 1856-1863 28.000 pea seedlings Febr 8th 1865. – lecture - Natural History Society of Brno

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Mendelian inheritance

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  1. Introduction History of science Mendelianinheritance 2019.

  2. Gregor Johann Mendel (1822–1884) • Brno (Moravia) – 1856-1863 28.000 peaseedlings • Febr 8th 1865. – lecture - Natural History Society of Brno • 1866. Mendel, G., VersucheüberPflanzen-Hybriden. (Verh. Naturforsch. Ver. Brünn 4: 3–47) • 1900. Rediscovery of Mendelsworks (Hugo de Vries, Carl Corrensand Erich von Tschermak)

  3. When Mendel described his „factors” … Chromosomes DNA Genes Were NOT described !!!

  4. HYPOTHESIS of MENDEL Mendel assumedpresence of chromosomes 37 years beforewtheyweredescibedbySutton. Mendel usedstatistical analysis of datato descibeeffects of „factors”. Suttonusedmicroscope todescribethat chromosomesworksimilarly tomendelian „factors”. Mendelianfactors Chromosomes Occureinpairs Occureinpairs Segregateduringmeiosis Segregateingameteproduction Pairs sort independently Pairs sort independently

  5. Features Phenotype Protein DNA /Gene Genotype

  6. Allels Locus

  7. Identicalallel - thetwoallels of the sameallelareidentical (thesame) Non identicalallel – thephenotypedetermined bythealleles is similar Isoallel - wecandistinguishthese allelsonlyinspecial environmentalconditions Multipleallelism - there are more than two phenotypesavailable depending on the dominant or recessive alleles that are available in the trait

  8. Homozygote Heterozygote X Y Hemyzygote

  9. Mendelianinheritance - Principles Segregation During gamete formation, the alleles for each gene segregate from each other so that each gamete carries only one allele for each gene. Independent assortment Genes for different traits can segregate independently during the formation of gametes. Dominance Some alleles are dominant while others are recessive; an organism with at least one dominant allele will display the effect of the dominant allele.

  10. Mendelianinheritance • Phenotypedoesnotfollowalwaysthecharacteristic • giveninthegenotype. • Dominantallelsareabletosuppresseffects of recessive • allels – seeheterozygotes of F1 generation. • Frequency of phenotypicexpressionofrecessiveallels is 25% (3:1 ratio) incrossbreeding of heterozygotes. • Crossbreeding of homozygoterecessivesresults • recessivesin 100%.

  11. Analysis of inheritanceof more thanonetreat

  12. Mendels Principle-3 - Independent assortment- It is validwithcertain Restrictions.

  13. Incompletdominance (Intermedier inheritance) Heterozygotes have an intermedier phenotype

  14. Autosomalmonogenicinheritance Dr. habil. KohidaiLaszlo Department of Genetics, Cell- and Immunobiology Semmelweis University Budapest /2019/

  15. Autosomal - Dominant ! • Minimum one of the parents is affected • Phenotype of homozygotes is more severe than heterozygotes • Male and female are affected equally • Male and female transmit evenly • Affected x Non affected results 50%<affetced (sick)phenotype • Vertical pedigree • Frequency of the mutations shows correlation to the age of father • AD mutations influence receptor, structural or carrier proteins • Variable expressivity and penetrance

  16. Dominant autosomal • ~ 2200 known dominant trait • frequency 0.1-3/1000/birth • most frequently affected organs: skeleton central nerve system

  17. ! 4p16.3 Achondroplasia Frequency 1:25000 • FGFR3 genemutation • (fibroblast-growth • factor receptor 3) • Longitudinalgrowth of tubularbones is affected • Limbsareaffected • Forehead is dominant, middle part of theface is less developed

  18. Achondroplasia

  19. Rhinoceros unicornis sheeps Teleoceras fossiger

  20. FGFR3 gene locus:4p16.3 • DNA: 16.5 Kb; 19 exon; exon 1 is notknownin human • RNA: 4.0 Kb mRNS;alternativesplicing • Exons 7 and 8: twomRNAisoformsIIIbandIIIc • Expressedin: brain, cartilage, liver, kidney, innerear

  21. The protein • 806aa; 115 kDa • Function: tyrosinkinase receptor • Structure: extracellular part 3 Ig-likeloops (I, II, III) stronglyhydrophobe TM domain (22 aa) -TM intracellulardomainwithttyrosinekinaseactivity -TK

  22. Mutationsa of the FGFR3 gene 3 diseases are associated to the mutations of FGFR3

  23. Arachnodactylia – Marfan syndrome Antoine Bernard-Jean Marfan (1896) Gabrielle

  24. Arachnodactylia – Marfan syndrome Tutankhamen pharaoh Ehnaton pharaoh

  25. Mary of Scotland Abraham Lincoln

  26. Marfan syndrome – Symptomes • affected bones and joints • height • chest • long fingers • hyperflexibility

  27. Eye and vision • myopia (short sight) • axis of the eye is longer • position of the lens is abnormál Heart and circulation • valve prolapse • aorta aneurysm • hypotension Marfan syndrome - Symptomes Frequency of mutations is increasing by age

  28. 15q21.1 There are several mutations of fibrillin gene (see green bands) Fibrillin protein • ~ 60 domain • binds 47 Ca2+ • similar to epidermal growth factor (EGF) ! Marfan syndrome Fibrillin gene (FBN1)

  29. Osteogenesis imperfecta I. blue sclera Penetrance 100% extremely fragile bones Deafness or loss of hearing (penetrance is less than 100%) Level of pleiotropy is high

  30. Osteogenesis imperfecta RNA: 2 RNA: 5.8 kb and 4.8 kb difference in 3’ UTR Protein :140 kDa 17q21.31-q22 ! COL1A1 gene • COL1A1 - 18 kb • 52 exon ( 6 – 49: alpha helical domain) • short exons: 45 bp, 54 bp or repeats of these two

  31. ! Structure of collagen fibre Healthy Osteogenesis imp. Type I. Central helical domain: - 338 x repeat of Gly-X-Ytriplet - X and Y amino acids are frequently prolins (Pro)

  32. Osteogenesis Imperfecta: Mutation map of collagen

  33. Osteogenesis imperfecta

  34. Familiar hypercholesterinaemy • Main clinical symptoms: • early onset of cardial and • circulatory system diseases • (myocardial innfarction, • vascular diseases of brain and • peripherial blood vessels) • xanthoma • diseases of the eye

  35. Familiar hypercholesterinaemy (FH) LDL lifespan in the body healthy: 2.5 days FH: 4.5 days LDL-level in sera is increased Reasons: - Mutation of LDL-receptor - ApoB defect LDL

  36. !

  37. ! 19p13.1-13.3

  38. Familiar hypercholesterinaemy Mutations of LDL-receptor Heterozygtes: 1:500-1000 Homozygotes: 1:1.000.000 Most frequent mutation: 9. exon 408 kodon CTG → CTA Val →Met

  39. O-linked szénh.dom. Citopl. domain EGFP domain Ligand kötő domain Membrán ! Familiar hypercholesterinaemy Outcomes of LDL-receptor mutation Joseph Goldstein, Michael Brown (Nobel Prize 1985)

  40. Trinucleotide-repeat diseases !

  41. ! CAG trinucleotiderepeats Number of CAG repeats: Normal - >26 Transient 27-35 Low penetrance 36-39 High penetrance above 40 Huntington chorea • Starts in age 35-44 • Complex disease of locomotor, cognitive and psychiatric symptomes

  42. Huntington chorea

  43. 4 ! Huntington chorea - (CAGn) • Gain-of-function mutation • The function of the Huntingtin gene in human is not known

  44. Huntington chorea

  45. Huntington chorea – CNS partsaffected

  46. ! Huntington choreaEffects of huntingtinongenelevel Inhibitedexpression of Dopamine D2 receptor gene

  47. Huntington choreaEffectsoncytoskeletonlevel BDNF - brain-derived neurotrophic factor Transport of vesiclescontainingneurotransmitters viamicrotubularsystem: Huntingtin – huntingtin-related-protein (HAP) – dynactin - dynein

  48. ! Correlation between the ‘CAG’ repeat-number and the age of onset

  49. George Huntington (1850-1916) • Grandfather and father were farmer doctors – their anamnestic files supported Huntington to describe the disease • The disease was described in 1872 • Medical and Surgical Reporter of Philadelphia chorea = maniacdance

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