5. genetic variation

Question 1

general ways to classify mutations (6)

Answer 1

1. region (genomic, subchromosomal, gene)
2. trigger (spontaneous, induced)
3. phenotypic effect
4. age of onset
5. type (deletion, insertion, frameshift, substitution)
6. effect on gene function (loss or gain of function)
7. tissue affected (somatic vs germinal)

Question 2

mutation def

Answer 2

any change in the DNA sequence of an organism –> can be good, bad or neutral and are the source of the altered versions of genes that allow evolution.

Question 3

somatic vs germinal mutations

Answer 3

somatic: occur by chance only in a subset of certain tissues and result in mosaicism (depending on stage of development at which this mutation occurs) - cant be passed to further generations.
EG cancers

germline: affects gametes hence are inheritable

Question 4

classification of mutation based on region

Answer 4

1. genomic mutation: variations of number of chromosomes in cells (usually aneploidy). occur via chromosomal segregation
2. subchromosomal mutation: alter structure of individual chromosomes (eg translocations). occur due to chromosomal rearrangement
3. gene mutations: alter individual genes at the level of the DNA sequence (eg point mutations). occur due to base pair mismatch

Question 5

mutation rate def

Answer 5

either the number of mutations per locus per cell division

OR

the number of mutations per locus per generation (which is the one most commonly used). This allows to find the incidence (number of new cases in pop) and the prevalence (number of affected individuals in a pop at a given time)

Question 6

what does mutation rate depend on

Answer 6

1. gene size (larger genes have a higher region over which mutations can occur)
2. fraction of mutant alleles that contribute to phenotypes in the population (eg lethal alleles arent considered bcos they are fatal and hence there are no individuals having them in the population)
3. gender and age of onset
4. presence of mutation hotspot on the gene in question

Question 7

mutations based on their trigger

Answer 7

1. spontaneous: arise through 3 types of chemical changes:
   -depurination
   -deamination
   -tautomeric shift
2. induced:
   -chemical mutagens
   -physical mutagens

Question 8

depurination process

Answer 8

MOST COMMON CAUSE OF SPONTANEOUS MUTATION
-removal of a purine base (A/G) from the DNA due to the fact that the bond between deoxyribose and purine is unstable
-creates apurinic site
-the repair of this site by DNA mechanisms can fail and hence produce mutation

Question 9

deamination process

Answer 9

ONE OF THE CAUSES OF SPONTANEOUS MUTATION
-removal of amino group from a cytosine base thus changing it into uracil
-DNA repair mechanisms pick up the change, and attempt to correct it
-if the system fails, there will be an eventual change from CG to AT in the sequence (mutation)

Question 10

tautomeric shift process

Answer 10

ONE OF THE CAUSES OF SPONTANEOUS MUTATION
-a temporary change in base structure from their common form to their unstable form
-TG common form is keto but they can change to enol
-AC common form is amino but they can change to imino
-these changes promote AC/GT mismatched pairing if the switch in forms happens right before DNA replication

Question 11

types of chemical mutagens (3)

Answer 11

1. base modifiers: modify nucleotide structure and can change bases (eg C to U)
2. intercalating agents: flat planar structures that intercalate between double helix, distorting it. This resynthesises DNA with additions or deletions of nucleotides. Common cause of cancer (ex = ethidium bromide)
3. base analogues: incorporated into DNA strand and mimicks other bases (eg 5-bromouracil as an analogue for thymine). This causes mismatch pairing between bases.

Question 12

types of physical mutagens (2)

Answer 12

1. ionising radiation: radiation of high frequency and energy + high penetrating (Xrays), create free radicals and can cause deletions or chromosomal nicks/ breaks
2. non ionising radiation: radiation of lower frequency and energy + low penetration (UV), causes thymine dimer formation that can cause mutations when DNA is replicated

Question 13

mutations based on phenotypic effect

Answer 13

1, lethal effect: can cause cell death or individual at young age

2, conditional: mutations do not affect the individual until they are triggered by an environmental facotr (eg favism)

3, neutral: no effect on individual

4, pleiotropic: several tissues involved and large amounts of symptoms caused by the SAME mutation

Question 14

transversion vs transition mutations

Answer 14

TRANSITION: interchange between two purines or two pyrimidines. More ommon bcos they are more conservative (bcos the bases are the same shape, so they have a lower prob of affecting the coded protein and so individual’s fitness increases)

TRANSVERSION: exchange between a purine and pyrimidine, changing the shape between one and two ring structures

Question 14

age of onset of mutation

Answer 14

1. congenital = at birth
2. early onset = at young age
3. late onset = older age

Question 15

types of substitution mutations (4)

Answer 15

1. SILENT: base change has no affect on the amino acid it codes for bcos the genetic code is degenerate
2. MISSENSE: aa substitution, effect on the protein function changes depending on each situation (eg in sickle cell when glutamic acid becomes valine)
3. NONSENSE: aa switch creates a premature stop codon. If this codon is found within the last 55bases of the protein, the protein is synthesised but is shorter, hence has drastically diff functions. If it is earlier than 55bases the mRNA is degraded via nonsense mediated decay and there is 0 protein expression
4. SENSE: codon that was previously a stop codon become a non stop codon. Hence the protein is longer which affects function.

Question 16

splicing mutations def

Answer 16

in order for introns to be removed in splicing they need to start with GT and end with AG sequences –> if these regions are mutated and they are not recognised, the introns remain in the mRNA and are translated –> causes the function of the translated polypeptide to change

Question 17

frameshift mutation def

Answer 17

addition/deletion of nucleotides NOT in multiples of 3 - this changes the groupings of the codons and changes the reading frame of the ribosome.

shifts all codons, so ALL (or most) of amino acids are changes in the final polypeptide
HENCE very severe phenotype bcos proteins are usually completely non-functional

Question 18

mutations based on the effect on gene function

Answer 18

1. loss of function: causes reduction or complete loss in protein activity. Mostly recessive, meaning that half the amount of wild type can be enough to form 50% of the protein.
   If dominant, 50% of production isnt sufficient for normal function.
   If dominant -ve: inactive protein also SPOILS activity of wild type protein by forming mixed multimer (eg role in osteogenesis imprefecta via rocollagen gene mutation)
2. gain of function: enhancement of protein functions/ increase in a protein production/ creation of a novel property that is by chance advantageous