Higher Human Biology Unit 1 Human Cells Section

Higher Human Biology Unit 1 – Human Cells Section 4 – Mutation

Mutations – What do you remember? • What are three effects that can result from a mutation? Neutral, advantageous and disadvantageous • Where does the mutation have to occur to pass onto the offspring? During meiosis, when the sex cells are produced • Mutations result in variation within a species. Why is this a good thing? The mutation might give an advantage that will allow natural selection to select against.

a – Mutations We will be learning… • State the definition of a mutation • Describe how a mutation can result in no protein or an altered protein being synthesised

What is a Mutation • A mutation is a change in the structure or composition of the organisms genome. • They occur randomly, spontaneously and at a low frequency. • Depending on the type and location of the mutation, the resulting protein may not function properly or not be expressed at all. • If the change in the genotype is expressed in the phenotype then the individual is called a mutant

Mutagens • Mutagenic agents can artificially increase the rate of mutations. • These mutations are called induced. • Mutagenic agents include: mustard gas, gamma rays, high temperatures, nuclear bombs/power and UV light.

Experiment into UV radiation on UV sensitive yeast

b – Single Gene Mutations We will be learning… • To describe the single gene mutation which involves the alteration of a DNA nucleotide sequence as a result of substitution of nucleotides • To explain and identify nucleotide substitutions as missense, nonsense and splice-site mutations • To describe the single gene mutation which involved the alteration of a DNA nucleotide sequence as a result of insertion of nucleotides • To describe the single gene mutation which involved the alteration of a DNA nucleotide sequence as a result of deletion of nucleotides • To state that nucleotide insertions or deletions results in frame-shift mutations

Single Gene Mutations • These involve changes in one nucleotide e. g. deletion, insertion and substitution. • Since only one nucleotide is altered these changes result in minor changes to the organism. • Substitutions – Missense, Nonsense and Splice-Site mutations • Insertion and Deletion – Frame-Shift Mutations

Nucleotide Substitution • These can result three possible outcomes: 1. Missense Mutations – one amino acid being changed for another. This may result in a non-functional protein or have little effect on the protein. 2. Nonsense Mutations – result in a premature stop codon being produced which results in a shorter protein 3. Splice-site Mutations – result in some introns being retained and/or some exons not being included in the mature transcript.

Substitution – Missense – Replace a Base • Single-nucleotide substitutions include: missense (replacing one amino acid codon with another). e. g. Sickle cell disease PKU

Missense Mutation – Sickle-Cell Disease • This is a blood disorder where the red blood cells change shape into an abnormal, rigid sickle shape. • This causes problems such as blocking blood vessels. • Symptoms – delayed growth, fatigue, shorter life, infections, jaundice • Advantages – protects against malaria Mutation occurs on chromosome 11

Missense Mutation – Phenylketonuria (PKU) Mutation occurs on chromosome 12 Phenylalanine and tyrosine are amino acids we obtain from protein in our diet Usually, phenylalanine is converted, by enzyme action, to tyrosine Tyrosine is converted to melanin (skin pigment) With PKU phenylalanine is not converted to tyrosine It accumulates and some of it is converted to toxins – brain fails to develop properly New born babies are screened and, if they have the condition, are placed on a diet containing minimum phenylalanine

Substitution – Non-Sense – Replace a Base • Single-nucleotide substitutions include: non-sense (replacing one amino acid codon with a premature stop codon). Protein synthesis halted prematurely and results in the formation of a polypeptide chain that is shorter than normal and unable to function E. g. Duchenne Muscular Dystrophy

Nonsense Mutation – Duchenne Muscular Dystrophy Caused by a mutation on the X chromosome such as a nonsense mutation Affected gene fails to code for dystrophin, necessary for normal functioning of muscles – strengthens skeletal and cardiac muscle Skeletal muscles become weak Progressive loss of co-ordination DMD is a muscle wasting disease

Splice-Site Mutation Do you remember what splicing is? • Splicing is the post transcription and pre- translational of m. RNA ; removing introns and exons joined together (primary to mature m. RNA), then using certain exons (alternative splicing) • Splicing is controlled by a specific nucleotide sequence at the splice site on introns which flank (beside) exons. Mutation occurs here. • E. g. Beta (β) Thalassemia DNA Exon Intron Transcription Primary m. RNA Processing Mature m. RNA Translation Protein Exon

Splice-Site Mutation • Splice-site mutations (creating or destroying the codons for exonintron splicing). • Diseases caused by splice-site Beta (β) thalassemia Destroying codon Creating codon DNA Exon 1 Intron Altered m. RNA Exon 1 Exon 2 Intron Exon 2 Exon 3 DNA Exon 1 Intron Altered m. RNA Exon 2 Intron Exon 1 Exon 3

Splice-Site Mutation – Beta Thalassemia Caused by a mutation on chromosome 11 Sufferers have an excess of alpha globulin in their bloodstream This damages the red blood cells Many patients require blood transfusions as the are either mildly or severely anaemic.

Frameshift Mutations – (insertion and deletion) If a base is inserted or deleted this leads to a frameshift mutation Every codon and amino acid coded for is altered from the point where the insertion or deletion has happened Insertion and deletion lead to large portion of the gene’s DNA to be misread. The protein that is produced differs from the normal protein by many amino acids and is usually dysfunctional.

Deletion • Nucleotide deletion of a nucleotide sequence is the removal of bases, causing a frame shift • Examples of diseases – Cystic Fibrosis

Deletion – Frame-Shift Mutation Cystic Fibrosis Three base-pair deletion on chromosome 7 A non-functioning protein is produced Normally it is a membrane protein, that assists the transport of chlorine ions into and out of cells, that is coded for In the absence of this protein a high concentration of chloride gathers outside cells This causes mucus to become thicker and stickier Lungs, pancreas and alimentary canal becomes congested and blocked

Insertion • Nucleotide insertions or an expansion of a nucleotide sequence repeat (essentially insertion of a large number of copies of the nucleotide sequence). • Examples of repeat expansion disease; • Results in extra copies of amino acid/ or fails to 1. Tay-Sachs syndrome express (silenced)

Insertion – Frame-Shift Mutation Tay - Sachs Disease • Recessive chromosome 15 disease that affects the nervous system. • Body lacks hexosaminidase A (protein which breaks down chemicals in ganglioside, fatty substance • Slow development at 6 month GM 2, thus builds up and prevents nerve functioning) • Loss of movement/ vision/hearing • Most die by 5 yrs old

c – Chromosome Structure Mutations We will be learning… • To define chromosome structure mutations – duplication, deletion, inversion and translocation. • To state that substantial changes in chromosome mutations often make them lethal

Now try these: Substitution, insertion and deletion 1. What are the types of gene mutations? 2. Which types do you think will have the greatest affect on the organism – explain/justify why. Insertion/deletion – because they cause a frameshift 3. Which type of mutations are these; Insertion Deletion Substitution

Chromosome Structure Mutations • Chromosome mutations are changes in the order or number of whole genes within a chromosome. This type of mutation involves the breakage of one or more chromosomes- the broken end is ‘sticky’ and can join to another broken end • There are four different types of chromosome mutation 1. Duplication – this is where a section of a chromosome is added from its homologous partner 2. Deletion - this is where a section of a chromosome is removed 3. Inversion – this is where a section of chromosome is reversed 4. Translocation – this is where a section of a chromosome is added to a chromosome, not its homologous partner

Duplication Chromosome Mutation A section of a chromosome replicates itself so that a set of genes is repeated. Normal section ABCDEFGHIJKL A B C D E F GH I J K L Mutant section Duplicated genes There a number of causes for duplication but a common cause is known as ‘Replication Slippage’ Replication slippage happens during the DNA replication process when the polymerase accidentally detaches from the strand replication stalls. When polymerase reattaches to the DNA strand, it starts the copying process at the wrong position and accidentally copies the same section more than once. .

Duplication A A B B C C D E F D Duplicated Genes from F BREAK E Homologous G F chromosome H Original chromosome G H New chromosome

Deletion Chromosome Mutation • A chromosome may break in two places and the section in between lost during the repair with the result that the organism loses a number of genes Normal section A B C DE F G H I J K L Break Mutant section Deleted section ABCD Deletion normally has a drastic effect as the ‘shorter’ chromosome lacks certain genes

Deletion A A B B New chromosome C C G D E F G H Original chromosome BREAK H D E Deleted genes F

Deletion Chromosome Mutation Cri-du-Chat Syndrome • Deletion of part of the short arm of chromosome 5 "Cri du chat" is French for "cry of the cat". The infants cry sounds like a cat. Most cases of cri du chat syndrome are not inherited. The chromosomal deletion usually occurs as a random event during the formation of reproductive cells (eggs or sperm) or in early foetal development. People with cri du chat typically have no history of the condition in their family.

Inversion Chromosome Mutation • Inversions involve the breakage of a segment on a chromosome which is then reversed and reattached. This mutation changes the arrangement of genes.

Inversion Chromosome Mutation Haemophilia A • This involves a rearrangement of genetic material called an inversion. • This cases mutated coagulation Factor 8. Clotting factors work to clot our blood to stop the flow. • Symptoms vary in severity e. g. deep internal bleeding, easy bruising and joint damage.

Translocation Chromosome Mutation In this case a piece of one chromosome breaks off and joins onto another non-homologous chromosome e. g. a chromosome that is not its matching partner normal chromosome 1 A B C DE F G chromosome 2 UVWX normal mutant two pieces of chromosome join here Problems occur during pairing of homologous chromosomes. Gametes formed are often not viable. Translocation is a second less common reason for Down Syndrome compared to trisomy ( 3 chromosomes on 21)

Translocation A A B B Chromosome 1 C C D D E E S Translocated genes S T T Chromosome 2 BREAK U U V V

Translocation Chromosome Mutation Familial Down’s Syndrome • in 5% of cases one parent has the majority of chromosome 21 translocated to chromosome 14 In people with Down's syndrome, all or some of the cells in their bodies contain 47 chromosomes, as there is an extra copy of chromosome 21. The additional genetic material causes physical and developmental characteristics associated with Down's syndrome.

Translocation Chromosome Mutation Chronic Myeloid Leukaemia • Reciprocal translocation of a gene from chromosome 22 fused with a gene on chromosome 9. This is a form of cancer where the protein produced promotes uncontrolled cell growth. The image above shows a blood sample from a patient with CML with many more white cells than normal

Conclusion • How frequent are mutations? (1) Random, spontaneous at low frequency • What is a mutant? (1) a change in the structure or composition of the organisms genome. gas, gamma rays, high temperatures, • Name 4 mutagenic agents. (4) mustard nuclear bombs/power and UV light. • Name and describe 2 chromosome mutations. (4) Duplication, deletion, translocation & inversion • Explain the difference between a chromosome mutation and a gene mutation Gene mutation is a change in the nucleotide sequence, in a particular gene, whereas chromosomal mutation is a change in several genes, in the chromosome. • Using a sample chromosome with genes labelled A-H show each type of chromosome mutation changes the original chromosome

Now I can…. . a • State the definition of a mutation • Describe how a mutation can result in no protein or an altered protein being synthesised b • To describe the single gene mutation which involves the alteration of a DNA nucleotide sequence as a result of substitution of nucleotides • To explain and identify nucleotide substitutions as missense, nonsense and splice-site mutations • To describe the single gene mutation which involved the alteration of a DNA nucleotide sequence as a result of insertion of nucleotides • To describe the single gene mutation which involved the alteration of a DNA nucleotide sequence as a result of deletion of nucleotides • To state that nucleotide insertions or deletions results in frame-shift mutations c To define chromosome structure mutations – duplication, deletion, inversion and translocation. • To state that substantial changes in chromosome mutations often make them lethal

Word Meaning Mutation change in structure/composition of genome Frequency arise spontaneously, at random and rarely Mutagenic Agents Mutagenic agents artificially increase the rate of mutation – resultant mutations are said to be induced e. g. mustard gas, X rays and UV light Genetic Disorder a condition/disease that is directly related to an individual’s genotype Single Gene Mutation alteration of a nucleotide sequence e. g. substitution, insertion or deletion Substitution single-gene mutation in which one nucleotide is replaced by another Chromosome mutation This type of mutation brings about a change in the number or sequence of genes in a chromosome Insertion single-gene mutation in which an additional nucleotide is placed into a sequence Deletion single-gene mutation involving removal of a nucleotide from a sequence Missense substitution mutation; a single nucleotide change results in a codon for different amino acid Nonsense substance mutation in which a codon is changed to a stop codon, shortening the resulting protein Splice site mutation at a point where coding and non-coding regions meet in a section of DNA

Word Meaning Frame shift gene mutation in which all amino acids coded for after the mutation are affected Duplication chromosome mutation in which a sequence of genes is repeated on a chromosome Translocation chromosome mutation in which part of a chromosome becomes attached to another Intron non-coding sequence of DNA Exon sequence of DNA that codes for protein Sickle Cell Disease disease caused by a substitution mutation in the gene encoding haemoglobin Haemophilia inherited disease in which blood clotting fails or is very slow

Cf. E HH 2016 A Q 2 D

Cf. E HH 2015 A Q 4 D

Revised Higher 2014 A Q 6 A

Cf. E HH 2017 B Q 2

Suggested activities • UV sensitive yeast • Mind map • Poster of gene and chromosome mutations