Types of Mutations PDF

Types of Mutations A heritable change in the genetic material Essential to the continuity of life Source of variation for natural selection New mutations are more likely to be harmful than beneficial DNA repair systems reverse DNA damage Cancer is a disease caused by gene...

Types of Mutations A heritable change in the genetic material Essential to the continuity of life Source of variation for natural selection New mutations are more likely to be harmful than beneficial DNA repair systems reverse DNA damage Cancer is a disease caused by gene mutations 1 Point mutation examples Base substitution 5’ – GGCGCTAGATC – 3’ 5’ – GGCGCTGGATC – 3’ 3’ – CCGCGATCTAG – 5’ 3’ – CCGCGACCTAG – 5’ Add or delete a single base pair 5’ – GGCGCTAGATC – 3’ 5’ – GGCAGCTAGATC – 3’ 3’ – CCGCGATCTAG – 5’ 3’ – CCGTCGATCTAG – 5’ 2 Gene mutations may affect amino acid sequences Silent mutation Does not alter the amino acid sequence Loading… Due to degeneracy of genetic code Missense mutation Changes a single amino acid in a polypeptide May not alter function if substituted amino acid is similar in chemistry to original ex: Sickle-cell disease 3  Nonsense mutation Change from a normal codon to a stop codon Produces a truncated polypeptide Frameshift mutation Addition or deletion of nucleotides (excluding multiples of 3) Completely different amino acid sequence downstream from mutation 4 Gene mutations outside of coding sequences A mutation may alter the sequence within a promoter and affect the rate of transcription Loading… May enhance or inhibit transcription Mutations may occur in other regulatory elements or operator sites Mutation may alter DNA sequence of operator so that repressor protein does not bind 5 Germ-line or somatic cell mutations The time and location of a mutation determines its severity and the heritability Germ-line cells give rise to gametes Mutation can occur in sperm or egg cell, or in gamete progenitor cells Somatic cells are all other body cells Can occur early or late in development Gives a genetic mosaic with patches of mutant tissue 6  Causes of Mutations It is important to understand what causes mutations, because often they are harmful (causing cancer or other diseases) If we understand the cause of mutations, we can do a better job at preventing them Mutations may be spontaneous or induced Specific mutations are random events 7 Spontaneous or induced mutations Spontaneous mutations From abnormalities in biological processes Rates vary species to species and gene to gene Background mutation rate ~1 mutation / million genes Induced mutations Caused by environmental agents Higher rate than spontaneous mutations Mutagens – chemical or physical agents that alter DNA 8 Mutagens alter DNA Structure Disruption of base-pairing Some modify nucleotide structure Nitrous acid deaminates bases, changing C to U, so that it pairs with the wrong nucleotide Mustard gas or EMS alkylate bases, adding methyl or ethyl groups Base analogues substitute into DNA Disruption of replication Some insert between the bases and distort the helix Benzopyrene, found in cigarettes and charbroiled food 9 10  Radiation damage Ionizing radiation has high energy and penetrates deeply to create free radicals X rays and gamma rays Cause deletions or breaks in one or both DNA strands Loading… Nonionizing radiation has less energy and can only penetrate the surface UV rays can cause formation of thymine dimers, causing gaps or incorporation of incorrect bases 11 Ames test Uses Salmonella typhimurium that cannot synthesize histidine due to a point mutation Bacteria cannot grow unless histidine is added to medium Or, a second mutation occurs that fixes the original, allowing synthesis of histidine Test monitors rate at which second mutation occurs Allows us to test and quantify mutagenicity 12  DNA Repair All living organisms require the ability to repair damage to DNA in order to minimize mutation Two components: Detection of damage Repair of damage 13 Types of repair Direct repair A repair enzyme recognizes an incorrect structure in the DNA and directly converts it back. Nucleotide excision repair Portion of DNA strand containing an abnormal nucleotide is removed and replaced. Methyl-directed mismatch repair A base pair mismatch is detected, and a strand of surrounding DNA is removed and replaced. 14 Nucleotide Excision Repair (NER) Most common DNA repair system Region encompassing several nucleotides in the damaged strand is removed from the DNA Intact undamaged strand is used as a template for resynthesis of a normal complementary strand Found in all eukaryotes and prokaryotes 15 NER and human genetic disease NER was discovered in humans from genetic diseases that affect DNA repair Xeroderma pigmentosum (XP) Cockayne’s syndrome (CS) PIBIDS Photosensitivity is a common characteristic in all three syndromes because of an inability to repair UV-induced lesions 16  Cancer Disease of multicellular organisms Characterized by uncontrolled cell division ~1.5 million Americans are diagnosed with cancer each year Over 0.5 million will die from the disease In about 10% of cancers, a higher predisposition to develop the disease is an inherited trait Most cancers, about 90%, do not involve heritable genetic changes 17 Carcinogens About 80% of all human cancers are related to exposure to carcinogens – agents that increase the likelihood of developing cancer Most carcinogens, such as UV light and certain chemicals in cigarette smoke, are mutagens that promote genetic changes in somatic cells DNA alterations can lead to effects on gene expression that ultimately affect cell division, and thus lead to cancer 18  Cancers originate from a single cell Cell and its offspring mutate so cells grow abnormally Tumor – an overgrowth of cells with no useful purpose Tumor may begin as benign or pre-cancerous Do not invade or spread May become malignant 19  Malignant stage Lost normal growth regulation Invasive – can invade healthy tissue Metastatic – can migrate to other parts of the body Left untreated, malignant cells will cause the death of the organism 20 Oncogenes Cell division regulated by hormones called growth factors Bind to cell surface and initiate cascade, activating specific genes, leading to cell division Mutations in genes for cell growth signaling proteins can change them into oncogenes – producing abnormally high level of activity An oncogene may promote cancer by keeping the cell division signaling pathway in a permanent “on” position In some cancers the amount of gene product is too high In others the gene produces a functionally hyperactive protein 21 Proto-oncogene Normal gene that, if mutated, can become an oncogene Common genetic changes Missense mutation Gene amplification Chromosomal translocation 22  Missense mutation Chemical mutagens have been shown to cause missense mutations leading to cancer 23  Gene amplification Increase in copy number results in too much protein Many human cancers are associated with amplification of particular proto-oncogenes 24  Chromosomal translocation Two chromosomes break and switch ends Very specific translocations associated with certain types of tumors Can create chimeric genes 25 26  Tumor-suppressor genes Normal role to prevent cancerous growth Typical functions: Maintain genome integrity by monitoring and/or repairing DNA damage Checkpoint proteins check the integrity of the genome and prevent a cell from progressing past a certain point in the cell cycle Inhibitors of cell division Necessary to properly halt cell division otherwise division becomes abnormally accelerated 27 Checkpoint proteins Proteins called cyclins and cyclin-dependent protein kinases (cdks) are responsible for advancing a cell through the four phases of the cell cycle Formation of activated cyclin/cdk complexes can be stopped by checkpoint proteins p53 – about 50% of all human cancers are associated with defects in this gene 28 p53 G1 checkpoint protein DNA damage induces expression to prevent cell from progressing from G1 to S phase If DNA is repaired, cell may proceed Loading… 29  If the DNA damage is too severe, the p53 protein will also activate other genes that promote programmed cell death or apoptosis Caspases function as proteases that digest selected cellular proteins causing the cell to break down It is beneficial for a multicellular organism to kill an occasional cell with cancer causing potential 30 Loss of tumor-suppressor gene function Three common ways: Mutation within a tumor-suppressor gene to inactivate its function Chromosome loss may contribute if the missing chromosome carries one or more tumor-suppressor genes Abnormal methylation of CpG islands near promoter regions of the tumor-suppressor gene 31 Cancer is a series of changes Cancer usually requires multiple genetic changes to the same cell Begin with a benign genetic alteration that, over time and with additional mutations, leads to malignancy Malignancy can continue to accumulate genetic changes that make it even more difficult to treat 32 Lung cancer Diagnosed in approximately 170,000 people each year in the U.S. Worldwide, more than 1.2 million cases are diagnosed Nearly 90% of these cases are caused by smoking and are thus preventable Unlike other cancers for which early diagnosis is possible, lung cancer is usually detected late, after it has advanced and is difficult, if not impossible, to cure Five-year survival rate for lung cancer is only ~15% 33  Most lung cancers are carcinomas – epithelial cell cancers Mutations accumulate in basal cells and their numbers increase – hyperplasia As more mutations accumulate, the basal cells develop more abnormal morphologies – dysplasia In early stages, the abnormal basal cells are precancerous If the source of chronic irritation (like cigarette smoke) is eliminated, the abnormal cells are likely to disappear But if smoking continues, these abnormal cells may accumulate additional genetic changes and lose the ability to stop dividing These cells are cancerous – patient has basal cell carcinoma Metastasis of these cells to other parts of the body will typically kill the patient within a year of being diagnosed 34