MUTATION  What is the mutation ?  The causes of mutations  Mutations of Structural Genes  mutation of a DNA codons  frameshift mutations  splicing mutations  Chromosome Abnormalities

MUTATION Definition: Permanent change in nucleotide sequence.  It can be at Chromosomal Or DNA levels.  Chromosomal is Gross lesions & Accounts for less than 8%.  DNA is Micro-lesions & Accounts for more than 92%)

The cause of mutations The cause of mutation could be through Exposure to Exposure to mutagenic agents 1. Internal Causes a. Errors in chromosome construction or chromosome distribution b. Errors in DNA replication 2. External Causes chemicalschemicals ultraviolet light radiationradiation radioactive compounds

Where mutation can occur ?  somatic cells  germline cells  A mutation arising in a somatic cell cannot be transmitted to offspring, whereas if it occurs in a gamete it can be transmitted to future generations.  Mutations can occur either in non-coding or coding sequences  Mutation in the coding sequence is recognized as an inherited disorder or disease  Mutation could be in :

Mutations of Structural Genes These include single base pair (point mutation) : Substitutions Insertions Deletions Duplications

. SUBSTITUTION Definition: substitution is the replacement of a single nucleotide by another Two types of substitution:  pyrimidine for a pyrimidine (C T )  purine for a purine (A G )

DELETION  If it occurs in coding sequences and involves one, two or more nucleotides which are not a multiple of three, it will disrupt the reading frame Definition: deletion involves the loss of one or more nucleotides.

INSERTION Definition: An insertion involves the addition of one or more nucleotides into a gene.  If an insertion occurs in a coding sequence and involves one, two or more nucleotides which are not a multiple of three, it will disrupt the reading frame. video

mutation of a DNA codons Its damage depend on : which nucleotide pair is changed the nature of the substitution the specificity of the new codon and the relative location of the mutated codon in an mRNA In general, DNA codon mutations are classified as silent neutral missense nonsense

 change of a DNA codon, but the amino acid that is inserted into the protein is not changed  A silent mutation has no impact on the function of the protein.

 change at the DNA level that alters a codon so that another amino acid is incorporated into the protein with no apparent loss of function  if the substitution occurs in a part of the protein that is not important for its function.  if the alternative amino acid has physicochemical properties similar to the original one, as when valine substitutes for leucine This occurs when :

 A base pair substitution producing a codon that specifies another amino acid  The severity of a missense mutation depends on: the nature of the substituted amino acid the original amino acid plays an essential role in the function of the protein

occurs when a nucleotide substitution changes a codon that specifies an amino acid into one that is a stop codon causes an incomplete (truncated) protein to be produced

 These types of changes are called frameshift mutations because the reading frame of the normal array of codons is shifted  A frameshift mutation usually has a devastating effect on the function of a protein, because of : the sequence of codons can be changed protein truncation addition of an aberrant string of amino acids video

insertion deletion

Stop codon

a 5’ splice site to those of the next 3’ splice site  The splicing machinery joins nucleotides of a 5’ splice site to those of the next 3’ splice site if a 3’ splice site is mutated This aberrant form of splicing is called exon skipping

if a 5’ splice site is modified an intron will be included as part of the processed mRNA

 Mutation can also create a new splice site within an intron  will cause part of an intron sequence to be included in the processed mRNA

 whole chromosomes may be lost or gained because of defects in spindle function  change in the chromosome number (aneuploidy)  the failure of chromosomes to segregate properly during meiosis I or meiosis II can result in gametes with an extra chromosome or the loss of a whole single chromosome

Non-disjunction during meiosis results in changes in the number of chromosomes Non-disjunction during meiosis results in changes in the number of chromosomes

Trisomy (47,21+) –Down syndrome

Trisomy (47,18+) (Edwards syndrome)

Trisomy(47, 13+) (Patau syndrome)

Trisomy 9 is quite rare

(47,XXY) Klinefelter syndrome Turner syndrome (45,X)

Trisomy X (47,XXX) An extra Y chromosome (47,XYY)

Chromosome Structural Changes

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