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biol 202 > Nilson2_mutations > Flashcards

Nilson2_mutations Flashcards

1
Q

Can mutations in all cells be inherited?

A

No, only mutation in the germline

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2
Q

What is a positive effect of mutations?

A

They generate diversity → adaptation/evolution

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3
Q

What are 3 general classes of mutations?

A

Chromosomal mutations → gain or loss of a part of a chromosome

Insertional mutations → insertion of large regions of DNA (ex: transposable elements)

Point mutations → changes in single nucleotides, indels (1 or more nt)

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4
Q

What are different types of base substitutions?

A

Transition:
- Purine → purine
- Pyrimidine → pyrimidine

Transversion:
- Pyrimidine → purine
- Purine → pyrimidine

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5
Q

Which nitrogen bases are pyrimidines and which are purines?

A

Pyrimidines → C, T

Purines → A, G

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6
Q

What are consequences/types of point mutations in the open reading frame?

A
  1. Synounymous mutations (Silent mutations) → doesn’t change the amino acid it codes for
  2. Nonsynonymous mutations (Missense mutations) → change the sequences of amino acids
    - Conservative mutations → chemically similar AA (K → R)
    - Non-conservative mutations → chemically different AA (K → T)
  3. Nonsense mutations → change the sequence of codons to add stop codon
    - effect depends on the distance from the 3’ end of the ORF
    - Can trigger nonsense-mediated decay → degrades mRNA
  4. Frameshift mutations
    - Caused by indels
    - Change the translation reading frame for all codons downstream from mutation
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7
Q

What are the stop codons?

A

UAA
UAG
UGA

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8
Q

What are different effect point mutations can have on a gene’s function?

A
  1. WT function (no effect)
  2. Loss-of-function (partial or complete)
    - Hypomorphic → protein retains some funciton or is produced at a reduced level
    - Null → protein is non-functional/not produced
  3. Gain-of-function (gene function increased or novel)
    - hypermorphic → protein is hyperactive
    - ectopic → more protein is made or made in wrong time/palce
    - neomorphic → protein gains new function
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9
Q

Why would only half of the F1 indivudals carry a mutation and not all of them?

A

Because the mutatio could be found in only 1 of the 2 copies of homologous chromosomes

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10
Q

What is an example of a gain-of-function mutant allele?

A

WT Glycin at 12th position → Valine (G12V)
This mutation locks Ras in active form → blocks hydrolysis of GTP to GDP

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11
Q

What can non-conding region mutations have an effect on?

A
  • Transcription
  • Splicing → at snRNP binding site, a mutation could genrate a new splice donor or acceptor
  • Stability → in 3’ UTR (RISC/miRNA)
  • Translation → at the promotor or enhancer site
  • Function
  • etc.
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12
Q

What sequence is associated with a splice donor site and a splice acceptor site?

A

Splice donor = GT (5’/start of intron)
Splice acceptor = AG (end of intron)

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13
Q

What methods can be used to detect if the mutation affects the mRNA transcript or protein levels?

A

Northern blot → RNA
Western blot → Protein

Ex:
- Early stop codon → short mRNA
- Mutation leading to nonsense mediated decay → no bands in either
- Misense mutation → single AA substitution → no change in either blots
- Mutation in a regulatory region → no bands in either (no transcription)
- Mutation in promotor region → no band in western, but normal northern

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14
Q

What are possible origins of spontaenous mutations?

A
  1. Error in DNA replication:
    - Base mispairing
    - Strand slippage
  2. Spontaneous chemical changes to the DNA → errors in replication
    - Depurination
    - Deamination
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15
Q

What is DNA polymerase’s error rate?

A

10^-8 *3x10^9 base pairs → ~ 300 mutation/mitosis → >99% are fixed by DNA repair mechanisms

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16
Q

What are tautomers?

A

Isomers that differ in the position of their atoms and in the bonds between the atoms
The forms are in equilibrium

Ex: 2 bonds N-N-H become N=N — H
*They exist in equilibrium

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17
Q

How does spontaneous C-T mutation occur?

A

When G is in its enol form, it interacts with T instead of C (mismatch)
If it is not repaired, in the next replication, CG → TA

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18
Q

What does spontaneous strand slippage lead to during replication?

A

Lead to indels in repeated sequences:

If the newly synthesized strand slips (extra base loops out) → insertion (in the next replication cycle, the double helix for which the new strand will be a template will have insertions)

If the template strand slips out (extra base loops out) → deletion (in the next replication cycle, the double helix for which the new strand will be a template will have deletions)

*only in repeated sequences, bc template and insertion can stilll be complementary

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19
Q

How do trinucleotide repeat disorders arise?

A

Arise from expansion of repeated sequence (nt.)

The greater the number of repeats → the greater the chances of slippage → increase number of repeats (cycle) → when reach threshold, phenotype of the disease appears

20
Q

What are polyQ diseases?

A

Disease caused by expanded CAG repeats (CAG = Glutamine) → abnormal folding → protein aggregation → neural degeneration

Normal # repeats ~ 4 - 40
Disease # repeats ~ 40 - 80 (depends, up to 300)

21
Q

What is Fragile X Syndrome caused by?

A

It is caused be trinucleotide repeat expansion in non-coding region of the FMR1 gene
FMR1 gene = CpG - CGG repeats - ATG + coding sequence
The number of CGG repeats in 5’ UTR affects phenotype, stability, methylation, transcription

CGG < 45 → stable, no methylation, normal phenotype, transcription
55 < CGG < 200 → unstable/prone to expansion, no methylation, normal phenotype, transcription
CGG > 200 → unstable/prone to expansion, affected phenotype, methylation → no transcription

22
Q

What is Huntington’s Disease caused by?

A

It is caused by trinucleotide repeat (CAG) expansion in the CODING region of the HTT gene

Number of CAG repeats:
Normal allele < 26
Mutable normal allele 27 - 35
HD allele with reduced penetrance 36-39
HD allele > 40
*greater n → greated slippage

Passed on to progeny → if an offspring gets the to alleles of the parents that have the higher number of repeats → more chances

23
Q

What is a deamination spontaneous mutation?

A

Caused by chemical change leading to the transcription from C → U (C-G → T-A)

Cytosine + H2O → Uracil + NH3
*N=C(-C)-NH2 → HN-C(-C)=O
NH2 is replaced by =O

24
Q

What is a depurination spontaneous mutation?

A

It has the effect of blocking DNA replication and transcription → can’t base pair

Pentose + Guanine → (apurinic site) pentose-OH at the site where guanine was attached (1’C) + Guanine detached

*Can lead to sequence errors during replication → 10,000 purines lost/cell in a day (usually repaired)

If not repaired → apurinic site (deletion of G) → in the next replication, on the the dsDNA has a single nt deletion

25
Q

What mutations can be caused by oxidative damage?

A
  1. Thymine → Thymine glycol (addition of OH on 2Cs) → no possible base pairing
  2. Guanine → 8-Oxoguanine → interacts with Adenine (to C) → Transversion (GC → TA)
26
Q

What is the major cause of oxidative damage induced mutations?

A

Caused by byproducts generated in the mitochondria by normal aerobic metabolism of molecular Oxygen → ROS
ex: superoxide radicals (- O2-), hydrogen peroxide (H2O2), hydroxyl raidcals (- OH)

27
Q

By which 3 different mechanisms can mutagens induce mutations?

A
  1. Replace a base in DNA (gets incorporated instead of the actual base)
  2. Alter a base so that it mispaires with another base (ex: alkylating agents)
  3. Damage a base so that it can no longer base pair with any base (ex: UV light, ionizing radiation)
28
Q

How can UV light damage bases?

A

UVB light induces covalent interactions betwe Thymines → if not repaired, blocks DNA replication

29
Q

How can ionizing radation induce base damage in DNA?

A

Causes strand breaks → mutations in homologous rejoining
+ Oxidative damage

30
Q

How can we know if something is a mutagen?

A

Ames test:
1. Start with cells that have a mutation that makes them unable to grow without histidine (in a plate)
2. Inubate with a media without histidine, but with different potential mutagens
3. If see cell growth → mutation was reverted → the compounds were mutagens (different degrees)

*If treatment of this his-mutant slamonella with a compound increases the number of revertants, then that compound is a mutagen

31
Q

How can we use the Ames test to assess for compounds that might become mutagenic only when metabolized?

A

Add liver enzymes to the mixture

32
Q

How can we use Ames test to better understand the type of mutation a mutagen induces?

A

Strain 1 = His-transition mutant
Strain 2 = His-frameshift mutat

33
Q

What is forward genetic vs reversed genetics?

A

Forward genetics: Phenotype → Genotype
Reversed genetics: Genotype → Phenotype (start with the sequence)

34
Q

What is the first thing we can look for as evidence of possible exons in a DNA sequence?

A

Look for open reading frames → looking for long sequence without stop codon?

35
Q

Why is it complicated to identify protein coding genes?

A
  • Genes are normally have multiple exons (~10 in human)
  • Exons can be big or small
  • Introns can be big or small → exons can be close or far from each other
  • Alternative splicing and/or transcriptional start sites can generate multiple mRNA isoforms
36
Q

What is codon bias? What can it be an indicator of?

A

Codon bias can be an evidence that ORF is part of a real gene

Differetn species have different frequencies of synonymous codon usage → condon preference reflects relative tRNA abundance and can be signature of an ORF that’s part of a real gene
Ex: in human, R → AGA, AGG, CGC mostly
in drosophila R → CGC (48%)
in E. coli → CGC (39%), CGU (29%)

*Peak conservation align with exons

37
Q

What is the best evidence that ORF is part of a real protein coding gene?

A

If we find a cDNA maps to its exons or an EST

EST = expressed sequence tag → cDNA than has not benn completely sequenced (only parts of both ends

38
Q

What method can help predict that some sequences of amino acid are related to specific protein?

A

BLAST similarities

39
Q

If 3% of the DNA in the human genome represents exons of genes, why does only 1% encode protein sequences?

A

*Exons + introns ~ 28%

Not all exons of a protein coding gene are in the actual protein:
- alternative splicing
- some stay in heterochromatin state
- long 5’ UTR before start codon (AUG)
- 3’ UTR after stop codon
- some genes might be missing a promotor

40
Q

What can comparison of sequences within a genome reveal?

A

Can reveal families of related genes → PARALOGS (2-100 members)

  • Can be functionally redundant of have indepent functions
  • Can arise through gene duplication during evolution for example (human keratin-associated protein 1 family)

*Involves sequencing just ethe exome → cost-effective, faster

41
Q

What are the steps for sequencing of only the exome?

A
  1. Shear DNA into segments
  2. Bind exonic DNA to immobiliseed probed and purify
  3. Elute and amplify exonic DNA
  4. Sequence exonic DNA
42
Q

What information can be taken from comparing genomes within a species?

A
  • # different genes affect dog size
  • Some dog breeds have higher incidence of X cancer
  • Breeds with short legs have en extra copy of FGF4 gene → involved in limb development
  • At least 3 genes control length, texture and curl of a dog’s coat
  • NOT codon bias
43
Q

What is Synteny?

A

Synteny is the conserved order of genes between the 2 genomes → similarities in genome organization between species (at levels of the genes and of the chromosomal rearrangements)

*Overall genome organization including relative order of genes and non-coding regions is also highly conserved between mice and human genome

99% of mouse genes have homologs in the human genome AND 99% of human genes have homolog in the mouse genome

44
Q

What is Phylogenetic interference?

A

Study of orthologs and paralogs:

Orthologs → homologous genes at the same genetic locus in different species, inherited from common ancestor

Paralogs → homologous genes at different loci in the same species, arisen from gene duplication

45
Q

Why do platypus lay eggs?

A

*Used phylogenetic interference to understand it

Laying eggs required presence of the vitellogenin gene (“egg yolk”)
Chicken has 3 vitellogenin genes, platypus has one → suggests animal closer to platypus that don’t lay eggs lost that gene (platypus didn’t gain it)

46
Q

How can uni parental disomy occur?
(F1 has 2 father (instead of 1 father/1 mother) chromosome 5, but all the rest is normal)

A

Non-disjunction in meiosis followed by “trisomy rescue” in the embryo
*the rescued chromosome has to be from the other gamete (to keep uni parentality)

Nondisjunction in Meiosis I → HetUPD (in meiosis I, a gamete with 2 homologous 2x chromatid sisters, 1 gamete with nothing) → both homologs from one parent represented in the child
Nondisjunciton in Meiosis II → IsoUPD (sister chromatids don’t separate) → only 1 homolog from 1 parent is represented in the child (x2 for disomy)

47
Q

Are all chromosomes equally likely to be found in Uni parental disomy?

A

No
Mostly maternal chromosomes are disomic
Non-disjunction → very plastic cellular process

Not all chromosomes have the same probability → ex: maternal Chr 16 is by far the most frequent

biol 202 (7 decks)

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