Md2 Block3 Genetics L-10 Prt B

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Mutation: inherited or acquired

1. Hereditary (germline) mutation:

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Permanent change in ______ cells
that LATER becomes incorporated in
the DNA of all cells of ________

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reproductive (egg or sperm)
offspring

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Mutation: inherited or acquired

2. Acquired (somatic) mutations:

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Permanent changes that arise within individual cells (somatic) and accumulat e=

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throughout a person's lifetime.

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Types of point mutations

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1. Silent mutation
2. Missense mutation
3. Nonsense mutation

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***

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Frameshift mutations

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Loss or gain of 1 or 2 nucleotides resulting in_________ of affected codon and ones that follow. Different or non-functional protein

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misreading

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Mutations on noncoding regions

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Mutations on noncoding regions

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Regulatory mutations

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Some genes switch on/off other genes

Mutations in these genes can have huge effects

Genes for=

Mutation rate for the entire genome can

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DNA repair enzymes

increase or decrease

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This effect the accuracy of intron removal from hnRNA during post transcriptional processing.

If a splice site is lostSpliceosome may =

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Delete nucleotides from adjacent exon
Leave nucleotides of intron in processed mRNA
Use the next normal sequence upstream or downstream splice site, deleting an exon from the processed mRNA.

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Inaccurate Splicing after Mutation in a Splice Site
Clinical example

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Beta- Thalassemia

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Trinucleotide Repeat Expansions

Expansion of trinucleotide repeat in the mutant allele can be in coding region

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Huntington’s Chorea
Spinobulbar muscular atrophy

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Trinucleotide Repeat Expansions

In untranslated region of gene.

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Fragile X syndrome
Myotonic dystrophy

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In these diseases the number of repeats increase with successive generations and correlates with increasing severity, decreasing age of onset. This phenomenon is called ___________

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ANTICIPATION.

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In normal Huntington allele, these are 0-26 tandem repeats of___ ____ in coding region.

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CAG
(glutamine)

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Affected members may have 35-120. Normal protein has less than 26 adjacent glutamine residues where as proteins encoded by diseases associated alleles have 36 or more adjacent glutamines.

This long glutamine tract makes abnormal protein extremely unstable.

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Mutation Nomenclature

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1. The position of a mutation is designated as being either in genomic DNA or in a cDNA sequence by the prefix g. or c., respectively.

2. The A of the translational start ATG is designated +1. The next base upstream is -1; there is no 0.

3. A nucleotide change is noted first by the original base, the nucleotide number of that base, a greater than symbol (>), and the new nucleotide at that position. For example, a mutation responsible for a particular missense mutation causing Tay-Sachs disease can be designated as c.G1444>A in the cDNA.

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4. If the full genomic sequence is not known, the nucleotides in an intron (referred to by the expression "intervening sequence," or IVS) are counted as +1, +2, etc., in which +1 is the invariant G of the GT in the 5' splice donor site, or as -1, -2, etc., counting back from the highly invariant G of the AG 3' splice acceptor site.

A mutation substituting an A for the highly conserved T in a splice donor site of intron 33 of a gene is designated g.IVS33+2T>A, whereas a mutation substituting a T for an A in the highly conserved A of a splice acceptor site in the same intron would be designated g.IVS33 -2A>T.

5. Small deletions are indicated by the term "del“ written after the nucleotide numbers deleted (1524-1527del).

6. Small insertions are designated similarly by the term "ins" after the two nucleotides between which the insertion occurred, followed by the actual nucleotides inserted. For example, c.1277 - 1278insTATC denotes a four-base insertion between nucleotides 127

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Mutations exert their phenotypic effect
in one of two ways

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Loss-of-function
Gain-of-function mutations