1 / 68

MUTATION AND POLYMORFISM

Explore the significance of DNA mutation and genetic polymorphism in evolution. Learn about different types of mutations, their causes, and repair mechanisms. Discover the role of mutations in diseases such as cancer.

aedie
Download Presentation

MUTATION AND POLYMORFISM

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. MUTATION AND POLYMORFISM Febr.19. 2016

  2. Genetic variability • is increasedby – mutation – sexualreproduction meiosis (generation of gametes) - homologousrecombination (crossing over) - independentassortment of homologous chromosomes fertilisation - significance

  3. DNA Mutation(causinganychange) DNA variants, alleles (anycodingornon-codingsequence) Genetic (DNA) polymorphism

  4. Significance of mutation (forall species) Withoutmutation, evolutionwouldnot be possible. This is becausemutationsprovidethe "rawmaterial" uponwhichthemechanisms of naturalselectioncanact.

  5. Regardingthevariants…. • normalorwildvariant (allele) is themost frequentin a • population • polymorphism (orpolymorphic) is thevariant (allele) ifits • frequency is › 1 % inthepopulation • (havingno effectonphenotype) • formerly: • mutation (ormutant) is thevariant(allele) • (formerly: ifitsfrequency is ‹ 1 % • inthepopulation / diseasecausing, it has a • negativeconnotation) • Human Genom Variation Society offered: • „sequencevariant„ or vagy „allelicvariant” • Mutation: somaticmutationsorgermlinemutations (recent) • Polymorphism: in a populationwhenthefrequency is known

  6. Long way from mutation to polymorphism Appearance of new variant by mutation Survival of rare allele Increase in allele frequency after population expand New allele is fixed in population as novel polymorphism

  7. Classification of mutationtypes • bythecause • bythesite • bythefunction • bythefitness • bythesize

  8. Bythecausemutationsmay be • Spontaneous • Induced

  9. Spontaneouschemicalreactionsinbases • Tautomerization • Depurination • Deamination • Errorsin DNA relatedprocesses • Replication • Recombination • Repair Spontaneousmutation

  10. E.g. Tautomers of adenine FrequentRare Aminogroup Iminogroup T - A (Purine-Purine) results

  11. Depurination (hydrolysis)

  12. Deamination Mutation hot spot RepairedNotrepaired DNA methylation (regulation of DNA functions, see epigenetics)

  13. Inducedmutation Someenvironmentalagent = mutagen • physical - radiation • Heat • UV • Ionizing • chemicals • Naturaltoxins • Syntheticsubstances • Laboratorysubstances • Pollutants • Chemoterapeutics

  14. Naturalsubstances Psoralen Aflatoxin Aspergillus sp.

  15. Laboratorychemicals: acridineorange, ethidiumbromide, propidiumjodide Fluorescent dyes BrdU - thymine analogue A senescent endothelial cell stained with the fluorescent dye acridine orange to visualise the lysosomes. Acrylamide Polyacrylamide

  16. Pollutants E.g. benzpyreneMetabolizedtoepoxidesinliver polyaromatichydrocarbons (PAH) DNA adduct Mutation

  17. Biologicalwarfareagent Mustard gase Iranianvictim (end of 20th century) I. World warvictim (beginning of 20th century)

  18. Correction of DNA errors DNA polymerasewithproofreadingability Repairmechanismsare limited tothenuclearbutnotmitochondrialDNA

  19. DNA repairmechanisms Directrepair thechange is reversed no templateis needed mainlyinprokaryotes • Excisionrepair template is needed ineukaryotes

  20. Repair of single strand damage(complementerstrand is usedastemplate)

  21. Xeroderma pigmentosumis causedbythedefective nucleotideexcisionrepairenzymes

  22. Repair of double strand breaks (DSB) may result loss of nucleotides = deleterious Sisterchromatid (after S phase) orlikeinmeiosis, homologous chromosome is usedas template = safety

  23. Multicellularcellcycle M-phase cytokinesis mitosis M G1 G2 Go G2 Restriction point - Growth factors - anchorange Checkpoints: Restrictionpoint G2 M (spindle) S Interphase

  24. Function and activity of checkpointmachinery G1 G2 M DNA damage free kinetochors notcomplete DNA replication sensor protein kinases transducer effector s t o p of c e l l c y c l e repair

  25. Ataxiatelangiectasia (ATM=sensor) Itsmutationcausesrare, neurodegenerative, inheriteddisease (AR), thataffectsmanyparts of the body and causesseveredisability, characterizedbyradiosensitivity and differenttumors.

  26. Role of BRCA (transducer) proteinsin DNA repair BRCA mutationsarefoundinbreast and ovariantumors.

  27. p53

  28. Site of mutations - intheorganism Somatic- insomaticcells localized-inheritedwithincells of an organism (mosaicism: tumors, antibodydiversity, etc.) higherindividingcells Generative– inprimordialgerm line inheritedfromone generationtothenextone

  29. And nondisjunction of sex chromosomes

  30. Site of mutations - in a genemay be 1 2 UTR UTR 3 4 1/ Promotermutations decreasedtranscription 2/ Exonmutations  aminoacidchangeortruncated protein (stop) seelater 3/ Intronmutations  errorsinsplicing 4/ Polyadenylation site mutations  decreasedmRNAstability 5 5 UTR  disturbedribosomebinding Mutations of otherregulatorysequences (enhancers, silencers) alsomay influencetranscription. B.R. Korf: Human Genetics and Genomics,2006

  31. Splicingmutations B.R. Korf: Human Genetics and Genomics,2006

  32. Splicingmutations B.R. Korf: Human Genetics and Genomics,2006

  33. Differentmutations of a genemay lead todifferentmalfunctions of the protein (=CFTR) Most frequent

  34. Function and mutations Back mutation or reversionis a point mutation that restores the original sequence and hence the original phenotype. Lethal mutationsare mutations that lead to the death of the organisms which carry the mutations. Gain-of-function mutations- change the gene product such that it gains a new and abnormal function. These mutations usually have dominant phenotypes. Loss-of-function mutations - gene product having less or no function. Phenotypes associated with such mutations are most often recessive. Exception is when the reduced dosageof a normal gene product is not enough for a normalphenotye (this is calledhaploinsufficiency). Dominant negative mutations- the altered geneproductactsantagonistically to the wild-type allele. These mutations are characterised by a dominant phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g. mutations in genes p53,ATM).

  35. Fitness and mutations • Most areneutral – duringevolutionlatermay be harmful • orbeneficial • Somearebeneficial– • - harmfulonemutates back towild • - gettingbeneficialfunction • – diversity of antibody • - CCR532 – HIV resistency • - sicklecellanemia – malaria • resistency • Someareharmful – causingdiseases (allmonogenic • inheriteddiseases)

  36. Size of mutations Large Genomemutation= change of chromosomenumber Medium Chromosomemutations= change of chromosomestructure Small genemutations= ranging from a change of singlenucleotideto a whole gene (notvisible) Affectingthelenght of DNA Deletion (singlebaseorshorter-longersequences) Insertion (singlebaseorshorter-longersequences- repetitive more insertionthandeletion No effectonthelength of DNA nucleotidesubstitution Cytogenetics

  37. Repetitive insertions • Tandem repeats • Satellite DNA • pericentromeric heterochromatin • Minisatellite (VNTR) • 10-60bp • Telomere • Microsatellite (STR=short tandem repeats) • 2- somebp • good markers of kinship • Repeat number expansion diseases • Interspersed repeats • SINEs (Short Interspersed Elements), • LINEs (Long …) e. g. L1

  38. Microsatellite(STR = short tandem repeats) 1-4 bp Trinucleotide (triplet) repeatsareveryfrequent onlyfew of themcausedisease

  39. Trinucleotiderepeatsmay be eitherincoding(C) ornoncoding (NC) region NC C NC C (huntingtin) (Huntingtin) C coding NC noncoding

  40. PolyglutaminePolyalanine disordersdisorders • CAG repeats • Neurodegenerativedisorders • Differentproteins • Gain of functionmutations • Variablelength • Expansion • Replicationalslippage

  41. Replicationslippage

  42. Huntingtin MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQQQPPPP PPPPPPPQLPQPPPQAQPLLPQPQPPPPPPPPPPGPAVAEEPLHRPK KELSATKKDRVNHCLTICENIVAQSVRNSPEFQKLLGIAHELFLLCSDD... • 350 kD protein • ubiquitously expressed • function unknown • correlation between repeatsize and age of onset and theseverity of disease (Huntington chorea) Huntington healthy

  43. PolyglutaminePolyalanine disordersdisorders • CAG repeats • Neurodegenerativedisorders • Differentproteins • Gain of functionmutations • Variablelength • Expansion • Replicationalslippage • GCX repeats • Developmentalabnormalities • Transcriptionfactors • Loss of functionmutations • Constantlength • Stable • Unevencrossing over

  44. Unevencrossing over

  45. Uneven sisterchromatidexchange

  46. Polyalaninedisorder DisorderGene • Holoprosencephaly ZIC2

  47. Deletionorinsertion of a singlenucleotide (InDel) It is a frameshiftmutationifnumber of nucleotide is not a multiple of three, and in-frameifnumber of nucleotide is a multiple of three

  48. DNA mRNA protein Mutant protein

  49. MediumInDelmutations Deletion Pl. Hypodontia(Deletion of Pax 9) Insertion (retro)transposons Eg. L1 hemophilia A L1 is a LINE: Long Interspersed Elements

More Related