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Variability and changes of genetic information, mutations RNDr Z.Pol


Title: Mutageneze Karcinogeneze Teratogeneze Author: Spokojen u ivatel Microsoft Office Last modified by: Zdena Created Date: 3/23/2004 10:53:10 AM – PowerPoint PPT presentation

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Title: Variability and changes of genetic information, mutations RNDr Z.Pol

Variability and changes of genetic information,
mutationsRNDr Z.Polívková Lecture No 421
course Heredity
  • Mutation permanent heritable change of
    genetic material
  • change in nucleotide sequence or arrangement
    of DNA in the genome
  • Genetic changes are frequent
  • Most of genetic changes are functionally
    insignificant, some have minor effect on
    phenotype, some are deleterious (cause genetic
    disorder or miscarriages)
  • Some genetic variants are called polymorphisms

Mutations x polymorphisms Many genes have only
one normal version wild type allele Other genes
exhibit polymorphism (many forms) in population
Normal variants (alleles) are relatively common
in population Variant allele found in more than
1 in population polymorphism this
definition is independent of functional or
pathogenetic relevance of alteration most of
common variants (polymorphisms) are without
effect on human health, but some can modify the
risk of common diseases (as tumors) Alleles with
frequencies of less than 1 are rare variants

Mutant alleles are rare variants identified
through clinically significant disorder
(disease-causing variants) More mutant alleles
at same locus (each capable of producing an
abnormal phenotype) allelic heterogeneity But
some of rare variants appear to have no
deleterious effect, i.e. there is grey zone
between definitions used for mutation and
Types of polymorphism Single nucleotide
polymorphisms (SNPs) 90 of all DNA variants are
exchanges of single nucleotide bases - in coding
or noncoding regions of human genome Frequent
SNPs are mostly without effect or have subtle
effect (alter disease susceptibility) Occurence
1/1000 base pairs Other variants deletions,
duplications, multiplications of several
nucleotides or larger genome segments Different
alleles are due to variable numbers of
repetitions at particular location Effect some
are without effect to human health, some are
pathogenetic, some can modify risk of disease
Mutations spontaneous (errors in replication)
induced (by mutagens)
Mutations somatic consequences tumors,
ageing (accumulation of
mutations) gametic
consequences in next generation
genetic disorder or carrier of
  • Mutations
  • genome mutations changes in chromosome number
  • a) euploid change multiplication of haploid
    chromosome set (triploidy, tetraploidy)
  • b) aneuploidy additional chromosome (trisomy)
    or missing chromosome (monosomy)
  • chromosome mutations structural aberrations of
    chromosomes consequences of breaks and abnormal
    rearrangement of chromosomal segments detected
    in light microscope
  • submicroscopic deletions or
    duplications of large genomic segments copy
    number variants CNVs (consequencesbenign or
    pathogenic, or risk modifiers for common
  • gene mutations qualitative or quantitative
    changes in DNA coding sequences
  • point mutation affects one single base

  • GENE mutations
  • mutation without any change of amino acid
    (degeneration of genetic code)
  • MISSENSE mutation.........replacement of one
    amino acid by different amino acid in protein
  • NONSENSE mutation.........mutation generates
    one of three stop codons ? premature
    termination of translation
  • ELONGATION mutations.....change of stop codon
    to amino acid coding triplet
  • FRAMESHIFT mutations......insertions,
    deletions of coding nucleotides in a number
    not divisible by three
  • Mutations in rRNA and tRNA genes - error in

Mechanisms of mutations Single nucleotide
SUBSTITUTION base exchange (transition
purine (A,G) for purine, pyrimidine (C,T) for
pyrimidine or transversion purine for
pyrimidine or vice versa) e.g. base alkylation,
oxidation, deamination leads to change of pairing
properties and change of nucleotide during
replication i.e. it alters triplet code ?
replacement of one amino acid by another in the
gene product (missense mutation)
consequences enzyme inactivity or changed
altered properties or structure of protein ?
stop codon (nonsense mutation) loss of protein
function ? elongation mutations - loss of
protein function
shift mutations (number of bases involved
is not divisible by three) DELETION -
alters translational reading frame? premature
stop codon Mutation in promotor region
affect gene expression - impaired
binding of transcription factors leads to reduced
transcription Mutation on the boundary of exons
and introns interfere with proces of splicing
Mutations leading to loss of enzyme function
mostly express itself as recessive Mutations
leading to gain of abnormal function or to origin
of abnormal structural protein mostly express
itself as dominant
  • Examples of mutations
  • A) SUBSTITUTION (alkylation, methylation,
    hydroxylation?error in base pairing)
  • nucleotide substitution replacement of one
    amino acid by another
  • a) Change inside coding sequences
  • in sickle cell disease
  • G A G ? G T G in ß-globin genereplacement
    of amino acid
  • glu ? val
  • HbA ? HbS

  • b) Mutation outside coding sequences
  • in hemophilia B
  • change A ? G in promotor of gene for
    antihemophylic factor IX prevention of
    transcription factor binding
  • ? decrease in the amount of product
  • ? NONSENSE MUTATION - generates stop codon ?
    abnormal product
  • in neurofibromatosis - NF1 gene
  • C G A ? T G A
  • arg ? stop
  • NF1 tumor supressor gene
  • premature termination of translation

RNA SPLICING mutation on boundary between exon
and intron in Tay-Sachs disease mutation in
hexosamidase A gene - intron between 12. and 3.
exon is not removed Defect of hexosamidase A
  • (deletion of 1 or more base-pairs, deletion of a
    part of gene, deletion of whole gene, or deletion
    of several genes microdeletion syndromes)
  • a) small number of base-pairs (not divisible
    by three)
  • frameshift mutation
  • in ABO blood groups
  • deletion G T G ? single base-pair
    deletion at the ABO locus alters reading frame
    (allele A ? allele O)
  • in Tay Sachs disease
  • 4 base-pairs insertion ? frameshift leading to
    the origin of premature stop codon deficiency
    of enzyme hexosaminidase A
  • b) 3 or a multiple of 3 bases
  • in cystic fibrosis
  • the most frequent mutation 3 base-pair
    deletion ? 1 amino acid is missing (delta F 508
    fenylalanin is missing)

  • c) Total gene deletion
  • in X- linked ichtyosis
  • deletion of steroid sulphatase gene
  • d) Large deletion within gene
  • in Duchenne muscular dystrophy
  • large deletion within dystrophin gene (in 60
    of cases)
  • Origin of large deletion and insertions
  • Unequal crossing over or exchange between
    misaligned sister chromatids or homologous
    chromosomes (aberrant recombination)
  • deletion of ?-globin gene in ?-thalasemia
  • deletions of pigment genes in X-linked defect
    in green and red color perception
  • deletion of retinoblastoma gene (Rb1)
  • Error in replication

  • Mutagens
  • Physical radiation
  • UV (ultraviolet radiation) ? T-T, C-C, T-C
    dimers (covalent bonds) ? error in replication
    and transcription
  • ionizing (rtg, gamma)
  • direct effect ? DNA breaks
  • indirect effect ionization of molecules
    ? DNA breaks
  • Chemical alkylating agents adducts base
  • - base analogs error in base
  • - acridine dyes insertions
    frame shift mutations
  • - nitric acid base
    deamination error in base pairing
  • direct mutagens
  • indirect mutagens reactive product
    arises after metabolic activation (cytochrom
    dependent oxygenases)
  • Biological viruses - viral nucleic acid
    integrates into the genome of host cell

Dynamic mutations gradual origin
amplification of triplet repeats - in fragile X
syndrome, Huntington disease Origin through
premutation in previous generation This type of
mutation is not caused by the environmental
mutagens !
  • Genetics of cancers
  • Forms sarcomas mesenchymal tissue
  • carcinomas epithelial tissue
  • hematopoetic and lymphoid malignancies
    (leukemias, lymphomas)
  • Uncontrolled growth invasivity, metastases
  • Tumor cells in tissue culture
  • loss of contact inhibition
  • changes in surface antigens
  • chromosomal changes
  • unlimited number of cell generations

Genetic nature of cancers 5 familiar (AD with
reduced penetrance) multifactorial All
cancers mutations of specific genes in somatic
cells (growth controlling genes) 1.
protooncogenes 2. tumor suppressor genes 3.
mutator genes genes involved in reparation?
increased frequency of mutations
  • CARCINOGENESIS multistep process genetic
    environmental factors
  • Multiple mutations (growth controlling genes)
  • Multiple causes and mechanisms
  • Environmental factors
  • chemical carcinogens
  • UV, ionizing radiation
  • tumor viruses RNA, DNA viruses
  • Mutations role in iniciation of carcinogenesis

Clonal nature of tumors origin from single
Genetic change in one cell and division of cell
Protooncogenes control of cell proliferation,
differentiation Protooncogenes products
role in cell communications in transport of
signal from cell surfice to the genes which
regulate cell cycle Protooncogenes signal
molecules, their receptors, tyrosin kinases,
transcription factors, cell cycle
regulation proteins
Change of protooncogenes to oncogenes ? abnormal
cell division Mechanisms 1.gene mutation 2.
translocation 3. retroviral insertion 4.
amplification double minutes, homogenously
staining regions amplified copies of
protooncogenes 5. error in gene methylation
(gene expression) epigenetic changes
  • Consequences of change of protooncogene to
  • synthesis of abnormal product
  • increased synthesis of normal product
  • Dominant character of mutation of protooncogene
    (change in one allele)

Examples of chromosomal translocations involving
protooncogenes CML chronic myelogenous
leukemia Ph1 chromosome t(9q22q)
translocation of protooncogene c-abl from 9q to
22q near to protooncogene bcr ? fused gene
bcr/abl ?abnormal protein with stable
tyrosinkinase activity abnormal stimulation of
cell division BL Burkitt lymphoma t
(8q14q) Protooncogene c-myc transfered from 8q
to 14q near to immunoglobuline genes (IgH) ?
abnormal transcriptional activity of
protooncogene in a new position ? increased
synthesis of normal product
Fused gene bcr/abl in CML detected by locus
specific probe (FISH)
Wysis 1996/97
Fused gene bcr/abl in CML
Translocation 8q/14q in Burkitt lymphoma
  • Cytogenetic manifestation of amplification
  • double minutes free copies of oncogene
  • HSRhomogenously staining regions copies
    tandemly integrated to chromosome
  • or copies inserted to different sites of

Tumor suppressor genes Products - suppress cell
division and abnormal proliferation loss of
function of both alleles? malignant
transformation recessive character of mutation
  • Example RB retinoblastoma two-step origin of
  • Hereditary tumor bilateral
  • 1st step germline mutation (or deletion) of
    one allele of Rb1 gene heritable or de novo
    origin in one germ cell of parent (mutation in
    all cells of body individual is heterozygote)
  • 2nd step somatic mutation of the 2nd allele
    in one cell of retina loss of
    heterozygosity (LOH)
  • b) Sporadic form unilateral
  • mutation of both alleles are somatic - in one
    cell of retina
  • tumor suppressor gene Rb1 gene on chromosome No

  • Wilms tumor embryonal tumor of kidney
  • tumor suppressor gene on 11p
  • Tumor suppressor gene TP53 protein p53
  • Manager of genes involved in DNA reparation and
  • blocks cell cycle and starts reparation in G1
    or G2 (cell cycle checkpoints)
  • if DNA damage is unrepaired it starts
  • Mutation of TP53 in many tumors
  • Li Fraumeni syndrome heritable mutation of
    TP53 tumor families tumors in young people in

Mutator genes Genes responsible for DNA repair -
Mutations have recessive character Example
heritable nonpolyposis colon cancer
Role of viruses in tumorigenesis Neoplastic
  • Integration of viral promoters (enhancers) to
    the host genome near the cell protooncogenes ?
    increased expression of the cell protooncogenes
    latent tumor viruses
  • Insertion of viral oncogenes acute tumor
  • DNA viruses - oncogene viral
  • RNA viruses transmit cell

  • Retroviruses RNA tumor viruses
  • Their oncogenes homologous to cell
  • viral oncogenes without introns
  • Probable origin from cell protooncogenes
  • Integration of virus (DNA after reverse
    transcription) to host genome, replication and
    transcription with host genome
  • mRNA protooncogene transcript after introns
    splicing is picked up by virus altogether with
    viral genome and transfered to other cell (e.g.
    Rous sarcoma virus)

Viral infection Viral RNA ? DNA (by reverse
transcriptase) integration to the host
genome replication, transcription with the host
genome translation complete viral particules
oncogene product ? cell transformation
Other factors of carcinogenesis Different ability
of metabolisation of mutagenic and carcinogenic
compounds Example enzyme aryl hydrocarbone
hydroxylase (family of cytochrome P450 genes)
genetic polymorphisms in drug metabolisation
polycyclic hydrocarbons (from cigarette smoke)
are converted to epoxydes (carcinogenic
metabolites) Individuals with high-inducible
allele and smokers great risk of lung
cancer Recessive homozygotes
resistant Individuals with variant alleles
different activity of enzyme
DNA reparation gene polymorphisms differenet
ability to repair DNA damage Immunity T
lymphocytes cell immunity cytotoxic
effect defect in immunity, inborn or
acquired(AIDS)?risk of tumors Chemical
carcinogens Radiation Viruses Complex
origin of tumors
Mutagenic, carcinogenic, immunosuppressive efects
Multistep origin of colon cancer - multiple
genetic changes step also heritable change
mutation on 5q in polyposis coli, Gardner sy
DNA hypomethylation
Mutation/deletion tu su gene MCC 5q
Mutation K-ras oncogene 12p
Normal cell
Increased proliferation
Adenoma I
Mutation/deletion, chrom.loss tu su gene DCC 18q
Mutation/deletion chrom.loss tu su gene p53 on
Adenoma II
Adenoma III
  • Genotoxic effects
  • mutagenic
  • carcinogenic
  • teratogenic affects embryonal development
  • immunosuppressive
  • allergenic
  • Each mutagen possible carcinogen
  • But not all carcinogens are mutagenic
    (nongenotoxic carcinogens)

(No Transcript)
Thompson Thompson Genetics in medicine,7th ed.
Chapter 9 Genetic variation in individuals and
population Mutation and polymorphism (till page
184) Chapter 16 Cancer genetics and genomics
informations from presentation http//dl1.cuni.c