(4) Genes and proteins in health and disease (A) Structure and functions of proteins (B) Gene and Chromosome Mutations

Genes and proteins in health and disease (b) State what genetic disorders are caused by State what is meant by a mutation Explain 2 effects mutations have on protein expression Name the 2 major groups of mutations Identify single gene mutations State and describe 5 examples of single gene mutations Identify chromosome mutations State and describe 3 examples of chromosome mutations

Pic is for Mrs McLelland Mutations What effect do mutations in the DNA have? What is a mutation? What is a GENE mutation? Can you name some mutations? What is a chromosome mutation? What is a mutagenic agent? How often do mutations occur? Can you name examples of mutagenic agents? Pic is for Mrs McLelland

What do mutations result in? What is a mutation? A random change to an organism’s genetic material (DNA, genes, chromosomes) What do mutations result in? Proteins are not expressed (proteins are not made) The protein that is expressed is not functioning correctly This is how genetic disorders are caused.

Chromosome Structure Mutations Deletion Duplication Translocation Key Area 4b - Mutations Single Gene Mutations (involves the alteration of a DNA nucleotide sequence) as a result of: Substitution Missense Nonsense Splice-site Insertion Frame-shift Expansion of a nucleotide sequence repeat. Deletion Chromosome Structure Mutations Deletion Duplication Translocation

Substitutions There are 3 types of single-nucleotide substitutions including: missense, nonsense and splice-site mutations.

Missense mutations

Nonsense mutations

Splice-site mutations Remember: - before mRNA leaves the nucleus it is spliced Splicing is controlled by specific nucleotide sequences at splice sites on the introns If a mutation occurs at one of these splice sites, the codon may be affected and the intron will remain attached to the mRNA

Single-nucleotide substitutions Missense: replacing one amino acid codon with another this results in the protein having one different amino acid Nonsense: replacing an amino acid codon with a premature stop codon — no amino acid is made and the process stops This results in the process stopping and a shorter protein is formed Splice-site mutations: creating or destroying the codons for exon-intron splicing This results in the mRNA being translated into an altered protein that does not work

Some mutations are more serious than others… Substitution mutations (missense, nonsense) are called POINT mutations The mutation only occurs at ONE point They only affect ONE amino acid Insertion and Deletion mutations are called FRAMESHIFT mutations ALL amino acids AFTER the initial mutation are affected since the reading frame of 3 bases has shifted The mutation impacts the rest of the codons and therefore the rest of the amino acid sequence

Nucleotide sequence repeat expansion Clue is in the name! Repeat The proteins produced will be defective because it contains a string of extra copies of an amino acid Sometimes, such expansion of a nucleotide sequence repeat can cause a gene to be silenced and not express any protein at all

TASK: missense missense nonsense Splice-site mutation Copy the table below Work through each case study and complete your table Condition Type of mutation Effect on health Sickle cell disease Phenylketonuria (PKU) ß (beta) thalassemia Duchenne muscular dystrophy (DMD) Tay-Sachs syndrome Cystic fibrosis Huntingdon’s disease Fragile X syndrome missense missense Splice-site mutation nonsense Frameshift insertion Frameshift deletion Nucleotide sequence repeat expansion Nucleotide sequence repeat expansion

Chromosome structure mutations Chromosome mutations are normally large changes which are usually detectable under the microscope during cell division. They usually occur during crossing over when the number or sequence of genes may be altered. When a chromosome is broken it has a sticky end which can join onto other chromosomes. Therefore, the structure of a chromosome can be altered. These mutations can take the form of a deletion, duplication or a translocation. If there are substantial changes in chromosome mutations, then these often make them lethal.

Deletion 1 1 2 2 3 3 7 4 New chromosome 8 5 6 7 8 BREAK 4 5 6 Original chromosome 4 5 6 Deleted genes

Cri-du-chat

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. Cri-du-chat The clinical symptoms of cri du chat syndrome usually include a high-pitched cat-like cry, mental disturbance, delayed development, distinctive facial features, small head size, widely-spaced eyes, low birth weight and weak muscle tone in infancy.

Duplication 1 2 1 3 2 4 3 4 5 5 6 6 Duplicated 7 7 Genes from 8 New chromosome 1 2 3 4 5 6 7 8 Duplicated Genes from Homologous chromosome 1 2 3 4 5 6 7 8 BREAK Original chromosome

Translocation 1 1 2 2 3 3 4 4 5 5 21 Chromosome A 22 23 24 1 2 3 4 5 21 22 Translocated genes 1 2 3 4 5 21 22 23 24 Chromosome A Chromosome B BREAK

Chronic myeloid leukaemia

Chronic myelogenous leukemia Chronic myelogenous leukemia (CML) is a slow-growing bone marrow cancer resulting in too many white blood cells. CML is a relatively common form of leukaemia, but overall it is a relatively uncommon type of cancer.

Down’s syndrome Here we can see, there is an extra copy of chromosome 21. BUT…

Familial Down’s syndrome In 5% of cases, the additional chromosome 21 can appear because the majority of chromosome 21 is translocated to chromosome 14.

Chromosome mutations Type of Mutation Description Significance Deletion Loss of a segment of a chromosomes Genes lost Duplication repeat of a segment of a chromosome Duplicated gene could mutate Translocation the rearrangement of chromosomal material involving two or more chromosomes Problems of homologous pairing during mitosis or meiosis. Cri-du-chat ____________________ is an example of a deletion mutation because part of chromosome 5 has been deleted. __________________________ is an example of a translocation mutation because part of chromosome 22 attaches to chromosome 9. Chronic myelogenous leukemia

Genes and proteins in health and disease (b) State what genetic disorders are caused by State what is meant by a mutation Explain 2 effects mutations have on protein expression Name the 2 major groups of mutations Identify single gene mutations State and describe 5 examples of single gene mutations Identify chromosome mutations State and describe 3 examples of chromosome mutations