Mechanisms of genetic variation

DNA, the hereditary material of life

Mutations
Mutation - any change in the DNA sequence, or in chromosome number, form or structure. Everyone acquires some changes to their DNA during their lifetime
Original sequence

Mutant sequence

Types of mutations
For protein – coding regions in the DNA, DNA alterations may cause: 1. Substitution mutations 2. Frameshift mutations For non – protein coding sequences, DNA alterations may produce changes in patterns of gene expression.

Substitution mutations • mutation that exchanges one base for another .

The genetic code .

Nonsense: codon results in a "stop" codon .3 types of substitution mutation Original DNA codon: 3’-ACG-5’ mRNA codon: 5’-UGU-3’ 1. Silent: codon change produces the same amino acid 3. Missense: codon change produces a different amino acid 2.

mutation in which extra base pairs are inserted into a new place in the DNA.Types of mutations Insertion . Deletion .mutations in which a section of DNA is lost or deleted .

 frameshifts • Frameshift mutations generate incorrect or truncated proteins .Effect of insertion and deletion mutations: frameshifts • Insertions and deletions can alter a gene so that its message is no longer correctly divided.

Effect of frameshift mutations on protein sequence A B .

Sources of mutations • Replication errors • Chemical agents • Physical agents – UV • Biological agents – viruses .

The DNA double helix acts as a template for its own duplication .

Chemical mutagens • Base analogs – can be incorporated into DNA and form transient tautomers – Can lead to transition mutations • Base modifiers – Chemically modify DNA bases • DNA intercalators – slip in between adjacent base pairs in dsDNA – lead to the insertion or deletion of one or more base pairs – Results in frameshift mutations .

Mechanism of mutation induced by 5-bromouracil. a base analog .

is activated by cytochrome p450 to form a highly reactive mutagenic compound . produced by molds that grow on peanuts.Mutagen metabolism • Aflatoxin.

. inducing a transition from A-T to G-C.Base modification • Treatment of DNA with nitrous acid results in the conversion of adenine into hypoxanthine. • Hypoxanthine pairs with cytosine.

Base – modifying agents .

. leading to the incorporation of an additional base on the opposite strand.Intercalating agents Acridine dyes induce frameshift mutations by intercalating into the DNA.

UV light produces pyrimidine dimers • Ultraviolet light induces cross-links between adjacent pyrimidines • Pyrimidine dimer cannot fit into a double helix • Replication. gene expression blocked until the lesion is removed .

Viruses: biological mutagens Upon entry into host cell. Lysogeny • Genetic material is integrated into the host chromosome 2. viral genome has two possible fates: 1. Lysis • Genetic material not incorporated into host chromosome • Directs host cell to make virus proteins • Results in cell lysis .

Integration of viral genome into host genome • May result in gene alteration .

the infections are harmless and go away without treatment • HPV a risk factor for cervical cancer because of its ability to interfere with normal gene expression • HPV vaccine targets certain sexually transmitted strains of HPV – Gardasil – Cervarix .Human papilloma viruses (HPV) • Extremely common sexually transmitted infections • In >90% of cases.

How certain papillomaviruses are thought to give rise to cervical cancer .

3. 2.DNA repair mechanisms • • All cells possess mechanisms to repair damaged DNA 4 types of repair pathways: 1. 4. direct repair base-excision repair nucleotide-excision repair mismatch repair .

genome instability accessory 3′-exonuclease and DNA helicase accessory DNA helicase for replication DNA interstrand cross-link repair DNA ligase I Bloom syndrome Fanconi anemia groups A–G 46 BR patient .Table 5-2. MLH1. cellular ATM protein. a protein (AT) γ-ray sensitivity. genome kinase activated by doubleinstability strand breaks BRCA-2 breast and ovarian cancer repair by homologous recombination Werner syndrome premature aging. neurological abnormalities cellular UV sensitivity ENZYME OR PROCESS AFFECTED mismatch repair nucleotide excision-repair translesion synthesis by DNA polymerase δ Ataxia–telangiectasia leukemia. genome instability congenital abnormalities. genome instability cancer at several sites. cancer at several sites. 3. genome instability hypersensitivity to DNAdamaging agents. cellular UV sensitivity. Inherited Syndromes with Defects in DNA Repair NAME MSH2. stunted growth. lymphoma. leukemia. PMS2 Xeroderma pigmentosum (XP) groups A–G XP variant PHENOTYPE colon cancer skin cancer. 6.

heart disease and cancer..g. neturalize free radicals .Antioxidants • Aging and chronic diseases. e. believed to result from damage caused by free radicals • Free radicals’ activity combated by antioxidants – molecules or atoms with an extra electron – extra electrons stabilize.

Antioxidant defense system • Includes vitamins E and C. and the carotenoids (pigments present in colored vegetables and some colored fruits) • Higher intakes of these nutrients are associated with lower rates of cancer and cardiovascular disease .

occur in reproductive cells like eggs and sperm The only mutations that matter to evolution are those that can be passed on to offspring. .g.. i. Germline mutations . Its seeds will not carry the mutation.e.. germline mutations.Mutation effects depend on affected cell type 1. 2. e. the golden color on half of this Red Delicious apple was caused by a somatic mutation. Somatic mutations .occur in non-reproductive cells and won't be passed on to offspring.

can result in proteins being made at the wrong time or in the wrong cell type 2. can also result in too much or too little of the protein being made.Types of mutations DNA expression mutation • Protein itself is not changed • Effect is on where and how much of a protein is made 1. .

• Mutations in control genes can substantially change the way the organism is built. .Mutations in control genes • Mutation in a gene "conductor" can cause a cascade of effects in the behavior of genes under its control.

a control gene.Effects of mutations in control genes • Hox. • Scientists have studied flies carrying Hox mutations that sprout legs on their foreheads instead of antennae! . designates where the head goes and which regions of the body grow appendages.

. • If a single mutation is required to trigger cancer and this mutation had an equal chance of occurring at any time.A single mutation is not enough to cause cancer • Cancer incidence rises steeply as a function of age. the incidence would be independent of age.

A tumor develops through repeated rounds of mutation and proliferation .

chemical carcinogens 2. viruses . ionizing radiations such as x-rays 3.Cancers result from somatic mutation • damage to DNA a fundamental event in carcinogenesis • Clear correlation for three classes of agents: 1.

Cancer and gene mutations • Three classes of genes are frequently mutated in cancer: 1. DNA repair genes • Genes involved in metabolism also modulate cancer risk . Tumor suppressor genes 3. Proto-oncogenes 2.

K-ras. converted into oncogenes – Abnormal protein activity promotes abnormal cell growth.g. c-myc . proliferation • e.oncogenes • Stimulate normal cell development • When mutated.Proto ..

p53 .. cell division and differentiation • May also induce apoptosis • e.g.Tumor suppressor genes • Negative effect on regulation of the cell cycle.

Mutational events in colorectal cancer development OMIM-175100 .

not directed • Mutations can be beneficial. mutations are random — whether a particular mutation happens or not is unrelated to how useful that mutation would be. e.g. exposure to harmful chemicals may increase the mutation rate. . BUT do not "try" to supply what the organism "needs.Mutations are random. neutral. THEREFORE. or harmful for the organism.." • Factors in the environment may influence the rate of mutation but do not influence the direction of mutation. but will NOT cause more mutations that make the organism resistant to those chemicals.

including pain and anemia • The disease is caused by a mutated version of the gene that helps make hemoglobin — a protein that carries oxygen in red blood cells (RBCs).Sickle cell anemia: a case study of the effects of mutation • Sickle cell anemia: a genetic disease with severe symptoms. • Gene is homozygous recessive .

allowing it to clump together.Sickle cell anemia: a case study • There are effects at the DNA level • There are effects at the protein level The mutation in the DNA slightly changes the shape of the hemoglobin molecule. .

a carrier of the sickle cell allele may occasionally show symptoms such as pain and fatigue. This shape can sometimes interrupt blood flow. There are positive effects at the whole organism level Carriers of the sickle cell allele are resistant to malaria. • Normal red blood cells • sickle cells . There are negative effects at the whole organism level Under conditions such as high elevation and intense exercise. they become "sickle-shaped" . because the parasites that cause this disease are killed inside sickle-shaped blood cells.Sickle cell anemia: a case study • There are effects at the cellular level When RBCs carrying mutant hemoglobin are deprived of oxygen.