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Presentation MEDIA: Genetics & Evolution Series Mutations Set No. 2 Set 2: Mutations Presentation MEDIA © 1993-2001 Biozone International Ltd ISBN 0-909031-41-X Index to OHT Titles OHT Title OHT Title 1 Mutations 29 Duplication on Human Chromosome 9 2 Causes of Mutations 30 Aneuploidy 3 Effects of Mutagens 31 Down Syndrome 4 Rates of Mutation 32 Causes of Down Syndrome 5 Human Mutation Rates 33 Down Syndrome Phenotype 6 Location of Mutations 34 Patau Syndrome 7 The Effects of Mutations 35 Patau Syndrome Phenotype 8 Types of Mutations 36 Edward Syndrome 9 Single Gene Mutations 37 Edward Syndrome Phenotype 10 Point Mutations: Missense Substitution 38 Maternal Age Effect in Aneuploidy 11 Point Mutations: Nonsense Substitution 39 Causes of Maternal Age Effect 12 Point Mutations: Reading Frame Shift by Insertion 40 The Fate of Conceptions 13 Point Mutations: Partial Reading Frame Shift 41 Aneuploidy in Human Sex Chromosomes 14 Tautomerism 42 Human Sex Aneuploidy Phenotypes 15 Sickle Cell Disease 43 Faulty Sperm Production 16 Sickle Cell Mutation 44 Faulty Egg Production 17 Cystic Fibrosis 45 Klinefelter Syndrome 18 Cystic Fibrosis Mutation 46 Turner Syndrome 19 ß-Thalassaemia 47 Polyploidy 20 Huntington Disease 48 Polyploidy in Humans 21 Block Mutations 49 Autopolyploidy 22 Block Mutations: Deletion 50 Allopolyploidy 23 Deletion on Human Chromosome 1 51 The Evolution of Wheat 24 Block Mutations: Translocation 52 Mutations: Overview 25 Translocation on Human Chromosomes 9 & 22 53 Evolutionary Significance of Mutations 26 Block mutations: Inversion 27 Inversion on Human Chromosome 2 28 Block Mutations: Duplication NEW ZEALAND: Biozone International Ltd P.O. Box 13-034 Hamilton Telephone: +64 (7) 856-8104 FAX: +64 (7) 856-9243 E-mail: [email protected] AUSTRALIA: Biozone Learning Media Australia P.O. Box 7523 GCMC 4217 QLD Telephone: +61 (7) 5575-4615 FAX: +61 (7) 5572-0161 E-mail: [email protected] UNITED KINGDOM: Biozone Learning Media (UK) P.O. Box 16710, Glasgow G12 9WS Telephone: +44 (141) 337-3355 FAX: +44 (141) 337-2266 E-mail: [email protected] Mutations Mutations are alterations in the DNA of chromosomes. Many mutations may be neutral or 'silent' (i.e. they have no observable effect on the organism). Harmful mutations become evident because they may alter the survival capacity of the organism. Cell Mutations can alter the cell’s chemistry Chromosome Mutation Nucleus This may cause an observable change in the organism’s: • physiology • anatomy • behaviour Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 1 Causes of Mutations Mutations may occur randomly and spontaneously. They may also be induced by environmental factors. Spontaneous Mutations – Arise from errors in replication – Different genes mutate at different rates Induced Mutations Mutations can be induced by mutagens (environmental factors that cause a change in DNA): Examples: – – – – – radiation (e.g. UV rays) viruses microorganisms Environmental poisons and irritants Alcohol and diet The Effect of Mutagens on DNA UV Light Thymine dimer After exposure to UV light, a potent mutagen, adjacent thymine bases in DNA become cross-linked to form a 'thymine dimer'. DNA of tumour suppressor gene This disrupts the normal base pairing and throws the controlling gene's instructions into chaos. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 2 Effects of Mutagens Type of Mutagen Effects Nuclear and ultraviolet radiation, X-rays and gamma rays. Ionising radiation is associated with the development of cancers. Ionising Radiation Those Most at Risk • Those working with radioisotopes. • Living near nuclear plants, waste dumps, or testing sites. • Fair skinned people in tropical regions and sub tropical areas. • Excess use of tanning beds. Some viruses integrate into the human chromosome, upsetting genes and triggering cancers. • Hepatitis B: Intravenous drug users. Many chemicals are mutagenic. Synthetic and natural examples include: organic solvents (e.g. benzene), asbestos, tobacco tar, vinyl chlorides, and nitrites. • Chemical industry workers, including the glue, paint, rubber, resin, and leather industries. Viruses and Microorganisms • HIV: Intravenous drug users, those with unsafe sexual activity (i.e. unprotected sex with new partners). • Smokers. • Coal and other mining workers. Environmental Poisons • Exposure to petroleum volatiles and vehicle exhaust emissions. Diets high in fat, slow the passage of food through the gut giving time for mutagenic irritants to form. High alcohol intake increases the risk of some cancers. Alcohol and Diet • Those with a diet high in total fats. • There may be familial (inherited) susceptibility. • Risks may be compounded by other lifestyle choices e.g. smoking. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 3 Rates of Mutation Genes mutate at known rates, but the rate varies depending on the gene involved - some genes have high spontaneous mutation rates. Calculation of the average number of mutant genes in a human: 1. There are thought to be about 100,000 genes making up the human genome. 2. Since there are two copies of each gene (on homologous chromosomes), each cell has a total of 200,000 genes. 3. In higher organisms, a mutation for a specific gene will occur in one gamete in 300,000. 4. Then each of us on average: carries about 1 new mutant gene! 2 x 105 ÷ 3 x 10-5 = 0.67 Rates of mutation for different genes within a single species are probably similar, but the viability of mutations varies greatly. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 4 Human Mutation Rates Examples of human genes with known mutation rates are listed below: mutations per million gametes per generation Retinoblastoma Dominant 15-23 Produces a tumour in the eye Tay-Sachs disease Recessive 11 Sex-linked 25-32 Sex-linked 43-100 Recessive 28 Produces blindness, paralysis, mental deficiency, death, with onset at about 6 years of age Haemophilia Produces uncontrollable bleeding due to an inability of the blood to clot Muscular Dystrophy Produces progressive wasting of muscles and eventual death Albinism Production of melanin affected, resulting in lack of pigment in skin, eyes, and hair All genes causing death before early adulthood: 40,000 Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 5 aa Location of Mutations The location of a mutation determines whether or not it will be inherited. Most mutations occur in somatic (body) cells and are not inherited (not involved in reproduction). Gametic mutations occur in the cells of gonads (sperm and eggs) and may be inherited. Gametic Mutations Sperm Somatic Mutations Mutation Sperm Egg Egg Fertilisation Cleavage. Prior to implantation Mutation Foetus Baby Cells of tissues affected by the mutation Gametic Mutations are inherited and occur in the testes of males and the ovaries of females Somatic Mutations occur in body cells – they are not inherited but may affect the person during their lifetime Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 6 The Effects of Mutations Harmful Mutations: There are many examples of harmful mutations that result from alterations to the DNA base sequence. Examples include: – Sickle-cell disease – Cystic fibrosis – Thalassemias These mutations are harmful because they alter the DNA sequence, thereby upsetting the structure and function of the protein they code for. Neutral Mutations: Because these often produce little or no change in the phenotype, neutral mutations are hard to detect. They may have little or no effect on the survival of an organism or its ability to reproduce. May be the result of a ‘same-sense’ mutation where a change in the third base sequence still codes for the same amino acid. Beneficial Mutations: Beneficial mutations are best observed in species with short generation times. Examples include: – Bacterial resistance to antibiotics. – Insecticide (e.g. DDT) resistance in insect pests. – Rapid mutation rates in the protein coats of viruses. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 7 Types of Mutations Single Gene Mutations Genetic change affecting the base sequence of a single gene. Mutation: Substitute T instead of C Original DNA May result in the formation of a new allele. Mutant DNA Chromosome Rearrangements (Block mutations) Chromosome segment is lost Change in the structure of a chromosome involving large pieces being rearranged. Whole groups of genes are affected. C D E F A B G H Break Break M N O P Q R S T Genes Changes in Chromosome Number Aneuploidy: Loss or gain of whole chromosomes. Polyploidy: Loss or gain of complete sets of chromosomes. 21 Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 8 Single Gene Mutations Point mutations change the sequence of bases in DNA for a single gene and may produce a new allele of a gene. Single gene mutations involving a single nucleotide are usually called point mutations. The new DNA sequence will result in a new sequence of amino acids making up a protein. Because of the degeneracy in the genetic code not all changes in a DNA sequence will result in a new sequence of amino acids. Even with a change in amino acid sequence, protein function may not be affected. Original Unaltered Code Original DNA Transcription mRNA Translation Amino Acids Phe Tyr Glu Glu Val Leu Amino acid sequence forms a normal polypeptide chain Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 9 Single Gene Mutations: Missense Substitution A single base is substituted by another. This usually results in coding for a new amino acid in the polypeptide chain. If the third base in a triplet had been substituted, the resulting amino acid may not be altered (due to degeneracy in the code). Mutation: Substitute T instead of C Original DNA Mutant DNA mRNA Amino Acids Phe Tyr Lys Glu Val Leu Polypeptide chain with wrong amino acid Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 10 Single Gene Mutations: Nonsense Substitution A single base is substituted by another. This results in a new triplet that does not code for an amino acid. The resulting triplet may be an instruction to terminate the synthesis of the polypeptide chain. Mutation: Substitute A instead of C Original DNA Mutant DNA mRNA Amino Acids Phe Tyr Mutated DNA creates a STOP codon which prematurely ends synthesis of the polypeptide chain Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 11 Single Gene Mutations: Reading Frame Shift by Insertion A single base is inserted, upsetting the reading sequence for all those after it. This results in new amino acids in the polypeptide chain from the point of insertion onwards. The resulting protein will be grossly different from the one originally coded for (therefore non-functional). Mutation: Insertion of C Original DNA Mutant DNA mRNA Amino Acids Phe Tyr Gly Arg Gly Ser Large scale frame shift resulting in a completely new sequence of amino acids – the resulting protein is unlikely to have any biological activity This type of reading frame shift can also be caused by a base deletion. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 12 Single Gene Mutations: Partial Reading Frame Shift A single base is inserted and another is deleted at a different location, resulting in a localised frame shift. This results in a new amino acid sequence between these points in the polypeptide chain. Depending on how many amino acids are affected, the resulting protein may have some useful function (biological activity). Mutation: Insertion of C Mutation: Deletion of C Original DNA Mutant DNA mRNA Amino Acids Phe Val Arg Lys Val Leu Altered chain which may or may not produce a protein with biological activity Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 13 Tautomerism Some point mutations may result from bases with an unusual number of hydrogen-bonding sites. Results in mismatching of base pairs. Irregular base configurations are called tautomers and are indicated by abnormal base combinations below: Usual base combinations Normal partner Normal base C Guanine A T Thymine A Abnormal base C G Cytosine Abnormal base combinations A Abnormal Cytosine Adenine G T Adenine Abnormal Thymine T A Adenine Thymine Abnormal partner Abnormal Adenine Guanine C Cytosine Hydrogen bonds G C Guanine Cytosine T G Abnormal Guanine Thymine Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 14 Sickle Cell Disease Synonym: Sickle cell anaemia Incidence: Most common in people of African ancestry. West Africans: 1% (10-45% are carriers) West Indians: 0.5% Gene Type: Autosomal recessive mutation which results in the substitution of a single nucleotide in the HBB gene that codes for the beta chain of haemoglobin. Gene Location: Chromosome 11 HBB p q Symptoms: Include the following: • Pain, ranging from mild to severe, in the chest, joints, back, or abdomen • Swollen hands and feet • Jaundice • Repeated infections, particularly pneumonia or meningitis • Kidney failure • Gallstones (at an early age) • Strokes (at an early age) • Anaemia. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 15 Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Sickle Cell Mutation The mutation responsible for causing sickle cell disease is a point substitution mutation. Set 2: Mutations Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . Haemoglobin molecules are made up of 2 α-chains and 2 β-chains linked together Normal Red Blood Cells containing normal haemoglobin (soluble) Beta (β) chain Alpha (α) chain Haemoglobin clustered together to form fibres that deform the red blood cells into a sickle shape β-Chain Haemoglobin Chromosome 11 Sickle Cells containing mutant haemoglobin (less soluble) HBB gene p OHT 16 First base q DNA Codes for the 1st amino acid Normal base: T Substituted base: A The sickle cell mutation involves the substitution of one base for another in the HBB gene, causing a single amino acid to be altered. Cystic Fibrosis Synonyms: Mucoviscidosis, CF Incidence: Varies with populations: Asians: 1 in 10,000; Caucasians: 1 in 20-28 are carriers Gene Type: Autosomal recessive. Over 500 different recessive mutations (deletions, missense, nonsense, terminator codon) of the CFTR gene have been identified. Gene Location: Chromosome 7 CFTR p q Symptoms: • infertility occurs in males and females. Disruption of the following glands: • the pancreas • intestinal glands • biliary tree (biliary cirrhosis) • bronchial glands (chronic lung infections) • sweat glands (high salt content of which becomes depleted in a hot environment) Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 17 Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Cystic Fibrosis Mutation The mutation responsible for causing most cases of cystic fibrosis is a single gene deletion mutation. Chromosome 7 Set 2: Mutations Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . Base 1630 p DNA The 508th triplet is lost (not present) in the mutant form This triplet codes for the 500th amino acid q CFTR gene CFTR Protein Cl- Cl- Water ClClOutside the cell Outside the cell OHT 18 Cell Membrane Cell cytoplasm Cell cytoplasm Cl- Cl- Cl- ClCl- Cl- Cl- Normal CFTR Protein Mutant CFTR Protein correctly controls chloride ion balance in the cell allows chloride ions to remain in the cell and leads to water entering the cell ß-Thalassaemia Synonyms: Cooley anaemia, Mediterranean anaemia Incidence: Most common type of thalassaemia affecting 1% of some populations. More common in Asia, Middle East and Mediterranean. Gene Type: Autosomal recessive mutation of the HBB gene coding for the haemoglobin beta chain. It may arise through a gene deletion or a nucleotide deletion or insertion. Gene Location: Chromosome 11 HBB p q Symptoms: • The result of haemoglobin with few or no beta chains, causes a severe anaemia during the first few years of life. • People with this condition are tired and pale because not enough oxygen reaches the cells. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 19 Huntington Disease Synonym: Huntington’s chorea, HD (abbreviated) Incidence: An uncommon genetic disease present in 1 in 20,000 people. Gene: An autosomal dominant mutation of the HD gene (IT15) caused by an increase in the length (36-125) of a CAG repeat region (normal range is 11-30 repeats). Gene Location: Chromosome 4 IT15 p q Symptoms: • Mutant gene forms defective protein: Huntingtin. • Progressive, selective nerve cell death associated with chorea (jerky, involuntary movements) • Psychiatric disorders • Dementia (memory loss, disorientation, impaired ability to reason, and personality changes). Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 20 Block Mutations Causes of Block Mutations Some can result from errors in the crossing over process during meiosis. Mutagens (e.g. X-rays) may cause some forms of block mutation. Types Fate of Chromosome Fragments Inversion Pieces of chromosome are flipped upside down so the genes appear in the reverse order. Translocation Pieces of chromosome are moved from one chromosome into another. Duplication Pieces of chromosome are repeated so there are duplicate segments. Deletion Pieces of chromosome are lost. Block mutations cause genetic imbalances that usually disrupt the development of an organism. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 21 Block Mutations: Deletion Break occurs at two points on the chromosome and the middle piece falls out. The two ends then rejoin to form a chromosome deficient in some genes. Alternatively, the end of a chromosome may break off and be lost. Break Break Genes A B C D E F G H G H M N O P Q R S T M N O P Q R S T A B Step 1 Chromosome rejoins A B G H C D E F M N O P Q R S T Segment is lost Step 2 Step 3 Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 22 Deletion on Human Chromosome 1 Human chromosome 1 shows two forms of deletion. These may involve deletion of either a chromosome tip (left) or a middle segment with the tip rejoined (right). This loss of genetic material may be harmful. Tip Deletion Before After Mid-Segment Deletion Before After Tip rejoins 1 1 Lost 1 Lost 1 Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 23 Block Mutations: Translocation Translocation involves the movement of a group of genes between different chromosomes. A piece of one chromosome breaks off and joins onto another chromosome. Consequence: A chromosome deficient in genes. Segment Removed Break Genes A B C D E F G H M N O P Q R S T 1 2 3 4 5 6 7 8 9 0 Step 1 A B C D E F G H M N O P Q R S T 1 2 3 4 5 6 7 8 9 0 Step 2 G H M N O P Q R S T A B C D E F 1 2 3 4 Segments join 5 6 7 8 9 0 Step 3 The large chromosome (green) and the small chromosome (dark blue) are not homologous Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 24 Translocation on Human Chromosomes 9 & 22 Translocation can occur between human chromosomes 9 and 22. The tips of the two chromosomes are exchanged. Before Translocation After Translocation 22 22 The tips of the chromosomes swap 9 9 This is the translocation observed in chronic myeloid leukaemia. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 25 Block Mutations: Inversion The middle piece of the chromosome falls out and rotates through 180° and then rejoins. There is no loss of genetic material. Break Break Genes A B C D E F G H G H M N O P Q R S T M N O P Q R S T A B A B F E D C G H C D E F Step 1 Segment Rotates 180° Step 2 Segment rejoins M N O P Q R S T Step 3 Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 26 Inversion on Human Chromosome 2 A segment of chromosome 2 is inverted (caused by looping of the chromosome). Normal Inversion Flip 2 2 Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 27 Block Mutations: Duplication A segment is lost from one chromosome and is added to its homologue. The chromosome on the left (below) was the 'donor' of the duplicated piece of chromosome. The chromosome with the duplication will become incorporated into a gamete, which may later contribute to an embryo. A B C D E F A B C D E F F A B C D E A B C D E F M N O P Q M N O P Q M N O P Q M N O P Q Segment removed Break Genes A B C D E F A B C D E F M N O P Q M N O P Q Step 1 Joins onto Homologous chromosome Step 2 Step 3 Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 28 Duplication on Human Chromosome 9 A segment of chromosome 9 is duplicated. A segment is taken from its homologue and inserted to produce double copies of some genes. Some genes may be disrupted by this process. Normal Duplication Duplicate segment A segment is tansferred from one chromosome into its homologue Identical segment 9 9 Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 29 Aneuploidy The normal condition for a body cell is for chromosomes to be present as homologous pairs (a condition known as disomy). Aneuploidy is a condition where one or more chromosomes are missing from or added to the normal body cell chromosome number. Examples: Nullisomy 0 homologues Monosomy 1 homologue Trisomy 3 homologues Tetrasomy 4 homologues May involve autosomes – examples are: Down Syndrome: Edward Syndrome: Patau Syndrome: Chromosome 21 Chromosome 18 Chromosome 13 May involve sex chromosomes – examples are: Klinefelter Syndrome: XXY Turner Syndrome: XO Why are they called syndromes? When a disease causes multiple effects it is called a syndrome (virtually all chromosome abnormalities are in this category). Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 30 Down Syndrome Chromosome affected: Trisomy 21 Incidence rate of 1 in 800 births in women giving birth at 30 to 31 years of age (this is the most common form of aneuploidy in humans). ArtToday.com The young boy below shows the typical appearance of Down Syndrome: Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 31 Causes of Down Syndrome There are three causes of Down syndrome, each producing a different severity of the syndrome: 92% of all cases result from non-disjunction of chromosome 21 during meiosis (see the karyotype shown below). 5% result from translocation of chromosome 21 (usually onto chromosome 14). 3% arise from a failure during mitosis (nondisjunction of chromosome 21) in a cell of a very early embryo – the resulting individual is a ‘mosaic’ of normal and Down syndrome cells. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 32 Down Syndrome Phenotype The expression of traits in the Down syndrome phenotype varies greatly, depending on which of the three chromosome abnormalities caused it. The most common phenotypic traits are: 1. Skin fold over the eye. 2. Reduced mental capacity (varies greatly). 3. Short stature, stubby fingers, heart defects. Small and arched palate Big wrinkled tongue Slanting eyes Dental anomalies Epicanthic eyefold Short and broad hands Back of head flat Broad flat face Short nose Absence of one rib on one or both sides Abnormal ears Congenital heart disease Many “loops” on finger tips Palm creases Intestinal blockage Special skin ridge patterns Big toes widely spaced Enlarged colon Umbilical hernia Abnormal pelvis Poor muscle tone Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 33 Patau Syndrome Chromosome affected: Trisomy 13 Incidence rate of 1 in 3,000 live births (with a maternal age effect). Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 34 Patau Syndrome Phenotype Phenotype of an Patau syndrome child: 1. Multiple defects (see below). 2. Usually death by age 1 to 3 months. Abnormal palm pattern Polydactyly (extra finger) Structural eye defects Faulty retina Small eyes Small head Scalp defects Cleft palate and hare lip Low set ears Heart defects Spinal defects (meningomyelocele) Polydactyly (extra toe) Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 35 Edward Syndrome Chromosome affected: Trisomy 18 Incidence rate of 1 in 5,000 live births (with a maternal age effect). Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 36 Edward Syndrome Phenotype Phenotype of an Edward syndrome child: 1. Ear deformities. 2. Heart defects. 3. Spasticity and other defects. 4. Usually death by age 1 year. A small head (microcephaly) Small mouth and unusually small jaw Underdeveloped or absent thumbs Low set malformed ears Redundant skin folds, especially over the back of the neck Big toe is shortened and frequently bent backward Small chest Congenital anomalies of the lung, kidneys and ureters Club feet Nails are underdeveloped Clenched fists with characteristic overlapping index finger Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 37 Maternal Age Effect in Aneuploidy Many aneuploidies show a ‘maternal age effect’, with incidence increasing with age of the mother. Example: Down syndrome is 100 times more likely in children of mothers over 45 years, than in those of mothers less than 19 years. Estimated Rate of Down Syndrome (per 1000 births) 90 1 in 46 80 Maternal Age (years) Incidence per 1000 Live Births 70 < 30 30 - 34 35 - 39 40 - 44 > 44 <1 1-2 2-5 5 - 10 10 - 20 60 50 1 in 100 40 30 1 in 2,300 1 in 880 1 in 290 20 10 0 20 25 30 35 Maternal Age 40 45 50 Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 38 Causes of Maternal Age Effect Maternal age effect probably arises because: 1. All eggs are present at birth but are suspended in their development in early prophase until puberty. 2. A woman, on average, will produce about 400 eggs in her lifetime (12 per year). 3. Therefore, by the end of her reproductive life, the egg cells that remain are old and there is a greater chance that errors in meiosis will occur. A similar, though less marked effect is exerted by the age of the father. Sperm from older men have a slight tendency to be deficient in chromosomes Old egg cells are prone to faulty meiosis Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 39 Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 The Fate of Conceptions For every million conceptions that occur, a significant number have genetic abnormalities and fail to develop into a completely normal child. Set 2: Mutations Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . Conceptions 1,000,000 Spontaneous Miscarriages Live Births 150,000 850,000 Chromosome Abnormalities 75,000 Other Causes Children Perinatal Deaths 75,000 833,000 17,000 With Chromosome Abnormalities 5,165 OHT 40 Trisomics ............. 39,000 XO ....................... 13,500 Triploids ............... 12,750 Tetraploids ............. 4,500 Sex Chromosome Aneuploids Autosomal Trisomics Other Abnormalities Others ................... 5,250 Male ............ 1,427 Trisomy 13 ........... 42 Trisomy 18 ......... 100 Trisomy 21 ...... 1,041 Total ............ 2,133 Female ........... 422 Aneuploidy in Human Sex Chromosomes The normal complement for human sex chromosomes is: Male: Female: XY XX Unusual sex chromosome configurations can arise from mistakes made during gamete formation (failure of sex chromosomes to separate properly during meiosis). Sex Chromosomes Apparent Sex Phenotype XO Female Turner syndrome XX Female Normal Female XY Female* No pubertal development XXX Female Apparently normal female, greater tendency to criminality XXXX Female Rather like Down syndrome, low fertility/intelligence XXXXX Female Rather like Down syndrome, low fertility/intelligence YO ? XY Male Normal male XX Male* Short, broad chested, sterile, hypogonadism XYY Male Jacob syndrome, apparently normal male, tall, aggressive XXY Male Klinefelter syndrome XXYY Male Resembles Klinefelter, sterile XXXY Male Extreme Klinefelter, mentally retarded XXXXY Male Down-like syndrome, very retarded Not Known (non-viable) * These apparent males and females appear to have the wrong sex chromosome complement. this is due to hormonal deficiencies or developmental errors. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 41 Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Human Sex Aneuploidy Phenotypes Four phenotypes of people with abnormal numbers of sex chromosomes (together with the normal male and female ones): Set 2: Mutations Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 42 Normal Male Jacob Syndrome Klinefelter Syndrome Turner Syndrome Super Female Normal Female XY XYY, XYYY XXY, XXXY, XXXXY XO XXX, XXXX, XXXXX XX Faulty Sperm Production Aneuploidy in human sex chromosomes may result from faulty sperm production. Results from failure of the X and Y chromosomes to separate during meiosis. Male Female XY XX Primary spermatocyte Mistake during meiosis X XY Faulty gametes Offspring XY XY X X X X X XXY XO XXY XO Klinefelter Syndrome Turner Syndrome Klinefelter Syndrome Turner Syndrome Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 43 Faulty Egg Production Aneuploidy in human sex chromosomes may result from faulty egg production. Results from failure of the two X chromosomes to separate during meiosis. Male Female XY XX X X Y X XXX Super Female Y Primary oocyte Mistake during meiosis XX Y XXY Klinefelter Syndrome XX Faulty gametes XX Offspring XO YO Turner Syndrome Not viable Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 44 Klinefelter Syndrome Chromosome complement: 44 + XXY Karyotype and phenotype: Mildly impaired IQ (intelligence) Poor beard growth Chest hair is sparse Frequently some breast development (low levels of testosterone) Osteoporosis Penis and testes underdeveloped, low levels of testosterone. Always infertile. Female type public hair pattern Limbs tend to be longer than average Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 45 Turner Syndrome Chromosome complement: 44 + XO Karyotype and phenotype: Mental development normal, difficulty with spatial memory Characteristic residual lateral web neck Low posterior hair line Elbow deformity Poor breasts development Constriction of aorta Degenerate ovaries almost always infertile Puffy fingers with deep set, hyperconvex finger nails Reduced stature - body is typically short brown spots (nevi) Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 46 Polyploidy An organism that has three or more complete sets of chromosomes (3N or greater). Types of Polyploidy: Autopolyploid: A polyploid involving the duplication of chromosomes from a single species. Allopolyploid: A polyploid involving the duplication of chromosomes in a hybrid between two species. Amphiploid: Describes the result of the last stage of allopolyploidy where a (usually) fertile hybrid is formed by doubling of chromosomes in a hybrid. Examples of Polyploid Plants Name Number Name Number Common wheat ........6N = 42 Banana ...................3N = 27 Tobacco ....................4N = 48 Boysenberry ...........7N = 49 Potato .......................4N = 48 Strawberry ..............8N = 56 Many ferns are polyploid with chromosome number up to 400N Polyploidy is common in plants because vegetative growth can produce numerous individuals with the same chromosome type/number. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 47 Polyploidy in Humans Polyploidy is rarely observed in humans, but it is thought to be one of the more common causes of spontaneous abortion. The example below shows a triploidy (3N = 69) condition found in a baby that went to term (9 months gestation) and then died at birth. The phenotype of this individual is unknown. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 48 Autopolyploidy Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Autopolyploidy is a type of polyploidy. It involves a multiple of identical sets of chromosomes from the same species. Hybrid may be fertile or sterile, depending on the number of chromosome sets. Set 2: Mutations Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . Hybrids with an even number of homologous chromosome sets (e.g. 4, 6, 8...28) will be fertile because chromosome pairing can occur at meiosis. Same Species Normal haploid gamete Same Species BB BB B BB OHT 49 BBB Sterile hybrid AA Diploid gamete AA AA Diploid gametes AA AAAA Fertile hybrid Allopolyploidy Allopolyploidy is a type of polyploidy. It involves the combination of chromosomes from two or more different species, to form a hybrid. Fertile polyploids may arise from doubling of the chromosome complement in the infertile hybrid (a process called amphiploidy). Many commercial plant varieties, being hybrids, are polyploids of this type. Species A AA Amphiploidy A AB Species B Infertile hybrid BB AB B Species C AB Haploid gametes Diploid gametes from identical infertile hybrids. (in flowering plants, this could be self pollination) AABB Fertile allotetraploid Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 50 The Evolution of Wheat The common wheat has developed as a result of several polyploid events after the formation of hybrids between different grass species: Domesticated in the Middle East Interbreed to form sterile hybrid Wild Einkorn Genome: AA 2N No. X 14 Einkorn Genome: AA 2N No. 14 Wild Grass Sterile Hybrid Genome: BB 2N No. AB 14 2N No. 14 Amphiploidy doubles chromosome number and creates fertile hybrid Goat Grass Interbreed to form sterile hybrid Emmer Wheat Genome: DD X Genome: AABB 2N No. 2N No. 14 28 Sterile Hybrid ABD Common Wheat 2N No. 21 Genome: AABBDD 2N No. Amphiploidy doubles chromosome number and creates fertile hybrid 42 Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 51 Mutations: Overview All new alleles originate by mutation. New alleles introduce genetic variation upon which natural selection can act. Most mutations occur in somatic cells and are not inherited. Only mutations in gametes can be inherited. Fitness of Mutations Fitness describes the value of a mutation to the survival and reproductive success of the organism. A mutation may turn out to be: 1. Lethal Mutation Many mutations are lethal and embryos are nonviable (causing spontaneous abortions). 2. Harmful Mutation Non-lethal mutations may be expressed as effects that lower survival or reproductive capacity. e.g. Down syndrome; sickle cell disease. 3. Silent or Neutral Mutation Most point mutations are probably harmless, with no noticeable effect on the phenotype. 4. Useful Mutation Occasionally mutations may occur which are useful, particularly in a new environment. e.g. DDT resistance in insects, antibiotic resistance in bacteria. Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 52 Evolutionary Significance of Mutations The role of chromosomal aberrations in speciation: Polyploidy can result in the formation of “instant species” by creating a barrier to chromosome pairing at meiosis (common in plants). Fusion of chromosomes (a form of translocation) may result in a reduction in chromosome number – resulting in reproductive isolation and therefore a new species. Example: Fusion of chromosomes may have taken place during the course of human evolution. The chromosome number in the great apes is 2N = 48, whereas in humans 2N = 46. Possible fusion of two chromosomes to create the No. 2 chromosome in humans. Note the similar banding patterns of chromosomes from related primate species. 12 12 12 13 11 11 2 Human Chimpanzee Gorilla Orangutan Set 2: Mutations Produced by: BIOZONE INTERNATIONAL © 1993 – 2001 Printing onto Paper Prohibited T h e s e m a s t e r s m ay o n l y b e u s e d t o g e n e r a t e O ve r h e a d Tr a n s p a r e n c i e s ( O H T s ) . OHT 53