MUTATION

Mutation: damage to genetic material or Changes in DNA that affect genetic information

Mutations causes
There are two ways in which DNA can become mutated:
Mutations can be inherited.
Parent to child

Mutations can be acquired.

Environmental damage Mistakes when DNA is copied

 A mutation to genetic material is usually not beneficial. Mutagens are things that cause mutations, they include: 1. High Temperatures 2. Toxic Chemicals (pesticides, etc) 3. Radiation (nuclear and solar)

Somatic vs Germ Mutations

New mutations occur in: somatic cells (not inherited but particularly important for tumour origin, mutations in the skin cells or hair. ) or the germline Germ mutations occur only in the sex cells. These mutations are more threatening because they can be passed to offspring (forever).

 Mutations effect protein synthesis Transcription: Mutated DNA will produce faulty mRNA leading to the production of a bad protein.

Types of mutations
Chromosomal: affecting whole or a part of a chromosome . Largescale chromosome abnormalities, with loss or gain of chromosomes, breakage and rejoining e.g. deletions, duplications, inversions, translocations Gene: changes to the bases in the DNA of one gene. Smaller-scale mutations in the structure of a coding gene sequence or the non-coding DNA. Often milder effect.

Gene Mutations: DNA base alterations

Point Mutations changes in one or a few nucleotides. only affect a small part of the gene. Changes in the third base of a codon often have no effect

Substitution Insertion Deletion Inversion Frame Shifts

NORMAL PROCESS
DNA (antisense strand)
mRNA
Normal gene GGTCTCCTCACGCCA CCAGAGGAGUGCGGU Codons Pro-Glu-Glu-Cys-Gly Amino acids

Polypeptide

Gene Mutations: DNA base alterations

Substitution- when a base is replaced with a different base. CGG CCC AAT to CGG CGC AAT Guanine for Cytosine Insertion - when a base is added CGG CCC AAT to CGG CGC CAA T Guanine is added Deletion - the loss of a base CGG CCC AAT to CGG CCA A T loss of Cytosine

Gene Mutations: DNA base alterations No change

Normal gene GGTCTCCTCACGCCA CCAGAGGAGUGCGGU Codons Pro-Glu-Glu-Cys-Gly Amino acids Substitution mutation GGTCTTCTCACGCCA CCAGAAGAGUGCGGU Pro-Glu-Glu-Cys-Gly

Gene Mutations: DNA base alterations Disaster

Normal gene GGTCTCCTCACGCCA CCAGAGGAGUGCGGU Codons Pro-Glu-Glu-Cys-Gly Amino acids Substitution mutation GGTCTCCTCACTCCA CCAGAAGAGUGAGGU Pro-Glu-Glu-STOP

Gene Mutations: DNA base alterations

Frame Shift mutations A frame shift mutation results from a base deletion or insertion. Each of these changes the triplets that follow the mutation. CGG CCC AAT to CGG CGC CAA T Frame shift mutations have greater effects than a point mutation because they involve more triplets (recall how important triplets are to protein synthesis)

Gene Mutations: DNA base alterations

The Frame shift changes the mRNA produced. mRNA from DNA as expected.. GGG CCC TTT AAA to CCC GGG AAA UUU Mutated DNA GGC GCC CTT TAA A to

CCG CGG GAA AUU U

All the triplets are changed, this in turn changes the amino acids of the protein!

Gene Mutations: DNA base alterations

Protein shape determines how a protein will function. A change in one amino acid may change the shape enough to distort the protein (as in sickle cell disease). Thus, change in one base could potentially distort a whole protein. It is more likely that a frame shift mutation will change several triplets and distort a proteins structure.

Gene Mutations: DNA base alterations Sickle Cell Anemia

Discover in 1910 in severely anemic black youth (9% among black people, every 1 in 70300 population) Occurred only during low PO2 Genetically inherited, recessive and autosomal dominant sickle crisis with 5000ft flight

Gene Mutations: DNA base alterations Sickle Cell Anemia

Electrophoretogram
+

Hb F Hb A Hb S

_ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ N SD Prone to SD

Gene Mutations: DNA base alterations Sickle Cell Anemia

Protein Analysis: Hb A Val-His-Leu-Thr-Pro-Glu-Glu-Lis Hb S Val-His-Leu-Thr-Pro-Val-Glu-Lis

Changing at the 6th amino acid chain creating polymers, linear, jelly Hb sickling cell
cell clotted, plugging small vessels

Chromosome Mutations
Changes in number and structure of entire chromosomes Original Chromosome ABC * DEF Deletion AC * DEF Duplication ABBC * DEF Inversion AED * CBF Translocation ABC * JKL GHI * DEF

Chromosome Mutations
Down Syndrome
Chromosome 21 does not separate correctly. They have 47 chromosomes in stead of 46. Children with Down Syndrome develop slower, may have heart and stomach illnesses and vary greatly in their degree of inteligence.

HUMAN GULO GENE MUTATION

Vitamin C was first isolated in 1928, and in it was proved to be the agent which prevents scurvy. In 1937 Albert Szent-Gyorgyi was awarded the Nobel price in medicine for this feat. all animals and plants synthesize their own vitamin C, except for humans and a small number of other animals, including, apes, guinea pigs, the red-vented bulbul, a fruit-eating bat and a species of trout

HUMAN GULO GENE MUTATION

mutation in a portion of the human Gulo (Lgulono-gamma-lactone oxidase) pseudogene results in lack of ability to synthesise ascorbic acid

HUMAN GULO GENE MUTATION

Lots of mutations in the amino acidcoding regions of the human sequence; over the span of 54 aas, -18 conserved amino acid, -27 non-synonymous substitutions - -7 synonymous changes; many of which led to nonconservative amino acid changes. -2 stop codons (observed as dashes) in the sequence. It is very likely that the accumulation of random mutations in the gene for the relevant enzyme has led to massive changes and destroyed the functional capacity of the enzyme.

HUMAN GULO GENE MUTATION

Nikishima et al (1988): restated the fact that the sequences in human genomes may represent the remnants of the gene for the enzyme that was once active but became nonfunctional during the course of evolution. They isolated a cDNA encoding L-gulono-gamma-lactone oxidase of the rat then used this cDNA as a probe for hybridization. The results confirmed existence of a human DNA sequence related to this enzyme. The nature cause of the mutation in this gene, as stated by Nikishima et al (1976) is because unadequate dietary intake of ascorbic acid among these animals. And since the enzyme is not highly required in the particular environment, the constraint of selection is removed

HUMAN GULO GENE MUTATION

In the Eskimos case, because their main food are raw meat and fish, which contain high source of vitamin C, their GULO enzyme is remain highly required in their ordinary life. The natural selection did not perform any changing on this enzyme biological function because during their evolutionary course of life, they highly required the capacity to synthesize ascorbic acid.