Lecture 4: Mutations and Disease

Question 1

Define mutation

Answer 1

a chnage or variation in the base sequence of DNA, can have a downstream influence on RNA and protein

Question 2

What are the two origins of new mutations?

Answer 2

1. endogenous mutations
2. mutagens

Question 3

What is the difference between an endogenous mutation and mutagens?

Answer 3

endogenous - spontaneous errors in DNA replication and repair, increased mutation load with aging in mitochondiral DNA

mutagens - the environment, somatic mutations, damage a particular nucleotide or become incorporated into the nucleic acid, increases frequency of mutant load

Question 4

Name three types of mutations (class)

Answer 4

1. chromosome disorders
2. single gene (monogenic) disorders
3. complex/ultifactorial disorders

Question 5

What are chromosome disorders and how does this relate to phenotype?

Answer 5

• excess or deficiency of the genes contained in the whole chromosome or chromosome segments
• phenotype depends on how many genes are added or lost
• small - no severe phenotype chages
• large - can lead to miscarriage

rare 7/1000 liveborn infants
~50% spontaneous 1 trimerster miscarriages

Question 6

Give an exaple of a chromosome disorder

Answer 6

• Trisomy 13- Patau syndrome
• 3 copies of chromosome 13
• increasing risk with maternal age
• 95% cases lead to miscarriage
• abnormally shaped heads, heart defects, seizures, intellectual disparity

Question 7

explain what single gene disorders are and some examples

Answer 7

• caused by individual mutant genes
• may be recessive or dominant
• may be contained in the mitochondrial or nuclear genomes

Question 8

how are single gene disorders visualised

Answer 8

pedigree patterns (inheritance through a family)

Question 9

what are examples of gene mutations

Answer 9

substitutions
deletions
insertions

Question 10

what are the two types of substitution mutations and explain the difference between them

Answer 10

transition - substitution of purines w/ purines (AG) or pyrimidines w/ pyrimidines (CT) - 2/3 of mutations

transversion - purine replaced by pyrimidine vice verca - 1/3 of mutations

Question 11

what transition is most common and what triggers it

Answer 11

CT transition, triggered by UV damage in cancer

Question 12

What are the different classes of substitutions

Answer 12

1. synonymous (silent): no change in amino acid, usually in third base position
2. nonsense (non-synonymous): replacement of amino acid with termination codon, drammatic reduction in gene function, premature protein truncation
3. missense mutations (non-synonymous): replacement of amino acid with different amino acid. two types.

Question 13

what are the two types of missense mutations?

Answer 13

a. conservative: replacement amino acid is similar = minimal effect on function
b. non-conservative: replacement amino acid is dissimilar = more serious effect on function

Question 14

what is the molecular pathology of mutation to disease. what relationship does this show?

Answer 14

mutation - altered protein - abnormal functon - disease

shows close relationship between genotype and phenotype

Question 15

how can the phenotype/genotype relationship be used in clinical diagnosis?

Answer 15

• look at genotype and succesfully predsct the phenotype of offspring
• can screen the genes that are the culprit of disease in other families and get those genes screened in patient

Question 16

where do pathogenic mutations occur?

Answer 16

1. protein coding regions (exons) - includes non synonymous mutations
2. mutations disrupting RNA stability or RNA splicing - mutation in intron, 10% of m.
3. Mutations affecting gene regulation or dosage - promoter/enhancer region mutation, ~1% of m

Question 17

what effect does a framshift mutation have on phenotype and on the genotype

Answer 17

insertion or deletion results in different sequence of amino acid, usually ends in premature truncation of protein

associated with severe phenotypes

Question 18

explain the difference between point mutations and frameshift mutations in terms of protein

Answer 18

point mutation - still get some product made that isnt affected
frameshift - product from instertion/deletion thereon down makes no sense, protein affected a lot more

Question 19

the affect of the premature protein truncation will depend?

Answer 19

• the stability of the polypeptide product
• the extent of the truncation
• the functional importance of the missing amino acids

depends on what part of the protein is truncated

eg. if a key domain that is v important to protein function is affceted - bigger problem than if it is retained and other area is mutated

Question 20

explain why a frameshift in a multiple of three is less severe?

Answer 20

they dont change the reading frame
insertion of new or removal of one aa - not as severe as complete shift in reading frame

Question 21

Give an example of a 3base frameshift mutation

Answer 21

F508 mutation is cystic fibrosis 1:30 caucasians
one copy - carrier with mild symptoms
two copies - cystic fibrosis

high heterozgote incidence = evoliutionary survival advantage from cholera and typhoid fever

Question 22

explain autosomal recessive inheritance pedigree patterns

Answer 22

• male and female equally affected
• appeards mainly in brother/sister proband
• Don’t tend to see it in the parents, both need to be carriers so you get two copies in proband
• Each mother and father is heterozygote, wont exhibit phenotype themselves - asymptomatic carriers of mutant alleles
• Each offspirn has a 1 in 4 chance in being affected
• 1 in 2 cahnce of being a carrier and pass on to offspring
• occurs more frequently when parents are relatives (consanguineous)

Question 23

what is an example of an autosomal recessive disorder?

Answer 23

cystic fibrosis
1:30 caucasians
carriers are not clinically recognisable becuase remaining non-mutated copy of the gene creates enough good protein to compensate

Question 24

explain autosomal dominant inheritance pedigree patterns

Answer 24

• Phenotype present in each generation
• each affected person has an unaffeced parent
• Heterozgous mutant and wildtype, you will exhibit the disease
• Every child has 50% risk of getting disorder themselves
• Male femlae equal affected
• Phenotypically normal family members do not transmit the phenotype to their children

Question 25

what is an example of an autosomal dominant disease?

Answer 25

huntingtons, myotonic distrophy
- half of mendelian diseases are autosomal dominant

Question 26

explain x-linked recessive inheritance pedigree patterns

Answer 26

• Much more prevalent in males than females
• Heterozygous females are mildly affected due to random x inactivation
• All affected males will pass gene onto their daughter who will be carriers
• Look out for father to son transmission – cant be x linked
• Dots represent carrier
• Transmission to males through carrier femlaes

Question 27

give an example of an x-linked recessive inheritance disease

Answer 27

androgen insensitivity syndrome, muscular dystrophy

Question 28

what is meant by random x-inactivation

Answer 28

• disease is milder in heterozygous women becuase of the random inactivation of one of the chromosomes (i.e inactivation of mutant copy or wildtype copy)

Question 29

explain x-linked dominant inhetiance pedigree patterns

Answer 29

• affected males have no affected sons and no normal daughters, always pass onto female offspring
• daughter of affected male is affected themselves
• both male and female carriers have 50 % risk of inheriting phenotype
• affected females twice as common as affected males, but have milder diseas due to x inactivation
• similar to AD inheritance

Question 30

what is an example of an x-linked dominant disease

Answer 30

retinitis pigmentosa

Question 31

Explain the y-linked dominant inheritance pedigree pattern

Answer 31

• affects only laes
• affected males always have an affected father unless there is a sporadic ne dovo mutation