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GEN > The Contribution of Genetic Changes to Human Disease > Flashcards

The Contribution of Genetic Changes to Human Disease Flashcards

1
Q

How do genomes compare between indiv?

A
  • genomes unique to each person but overall v.sim + small % varies
  • some of variation is common, some rare, some unique to our families and each of us
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2
Q

What does the genomes of each indiv consist of?

A

each have 1 mat + 1 pat genome - shuffled versions of our parents genomes

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3
Q

What makes our genome unique?

A

Combo of variation patterns (alleles)

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4
Q

What is DNA variant/variation?

A

Specific sites (locus(i)) within genome at which 2/more versions (alleles) may be present

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5
Q

What is polymorphism?

A

Common DNA variant

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6
Q

What is a mutation?

A

Pathogenic DNA variant/process through which new DNA variant may arise (de novo)

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7
Q

How does a DNA variant arise?

A

Through process of mutation which is constantly occuring

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8
Q

What causes variation in genome?

A

Mutation events occurring over 1000s of yrs

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9
Q

What is the role of selection?

A

Determines what variant remains in pop i.e. if trait has less -ve/more +ve phenotypic consequences - more likely to inc freq in pop

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10
Q

What mixture will be contained in our genome?

A

Old mutation events not -vely selected that are likely to be common in pop + more recent mutation events that gen variants unique to ourselves + specific parts of our bodies (somatic)

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11
Q

List ways DNA Sequences can vary?

A
  1. Single nucleotide sub
  2. Deletion
  3. Insertion
  4. Translocation
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12
Q

What is single nucleotide sub?

A

Straight sub of 1 base for another

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13
Q

How can single nucleotide sub be subdivided?

A
  1. Transition

2. Transversion

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14
Q

What is a transition?

A

Sub which conserves base chem

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15
Q

What is a transversion?

A

Sub which changes base chem e.g. go from purine to py + vice versa

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16
Q

Why are transitions roughly 2x common as transversions?

A

Although there’s 2x as many poss transversions as transitions, transitions more common as easier to go from same base chem than a diff one

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17
Q

What is a deletion?

A

Loss of single base/continuous block of seq

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18
Q

What is an insertion?

A

Insertion of single base/continuous block of seq between 2 prev adj bases

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19
Q

What is tandem dup?

A

Special case of an insertion where inserted material identical to adj sequence
- can be 3bp/repeat/microsatellite repeat expansion

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20
Q

What is an inversion?

A
  • Block of seq is inverted - bc of nature of DNA pairing, inverted seq replaced with its rev compliment
  • as DNA double stranded, seq gets inverted also + placed back into DNA strand
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21
Q

What is a translocation?

A

DNA exchanged between chr

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22
Q

How many bp can be involved in del, ins, tandem dup + inv?

A

Single base to sev milli bases in size

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23
Q

As rearrangements are often imperfect, what can happen as a result?

A

seq at ends of blocks may also be disrupted

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24
Q

Why might inv/translocations be benign?

A

if breakpoints don’t disrupt genes e.g. in non-coding region of genome - not much of an effect

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25
Q

Where do DNA variants occur?

A

Throughout our genomes

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26
Q

What types of consequences can DNA variants have?

A

Some have functional (post phenotypic) consequence

Others are benign - changing seq has no effect on biology/phenotype

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27
Q

What is functional consequence of a variant defined by?

A

effect it has on functional regions of genome i.e. changing seq will have detrimental consequences which leads to functional then phenotypic consequences

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28
Q

What do almost all disease causing variants directly affect?

A

Functional parts of known genes

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29
Q

What do most known functional parts of genes depend critically on and what is the result of this?

A

Nucleotide seq and is therefore sensitive to variation

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30
Q

What are the diff parts of a gene?

A
  • upstream ass site
  • promoter
  • 5’ UTR
  • initiation codon
  • coding region
  • splice donor site
  • splice acceptor site
  • splice branch site
  • intron (cryptic splice)
  • stop codon
  • 3’ UTR
  • polyadenylation site
31
Q

How do the effects of coding region single nucleotide sub vary?

A

Can be silent, missense/nonsense sub

32
Q

What is a silent sub and its effect?

A
  • single bp sub but result is it still codes for same aa

- not affect protein directly but may affect splicing

33
Q

What is a missense sub and its effect?

A
  • single bp sub causes single aa change

- may be neutral/harmful effect resulting in gain or direct/indirect loss of function

34
Q

What is a nonsense sub and its effect?

A
  • single bp sub causes stop codon
  • cause premature termination of reading frame resulting in truncated protein/NMD (nonsense mediated decay = mech in cell detects early stop codon and degrades protein being made)
35
Q

What are the effects of small rearrangements e.g. del, ins, dup, inv?

A

effects confined to single exon of gene

36
Q

Which effect of a variant is the most important?

A

Effect on reading frame

37
Q

What is the result if bp ins/del is multiple of 3?

A

Don’t get frame shift

38
Q

What do variants in all known splice recognition elements cause?

A
  • Disruption of splicing process
  • some exonic variants (ESEs) important for correct splicing to occur
  • results depend on rel strength of elements, severity of change and proximity of alt options
39
Q

What are the commonest consequences of variants in splice recognition elements?

A
  • exon skipping = no splicing for certain exon
  • use of cryptic splice sites (in exon/intron) - if seq damaged, nearby alt version used
  • intron retention (small introns only) - if intron not spliced out, it’s retained
  • combos of above
40
Q

What do sizes of rearrangements form?

A

Continuum from 1bp to whole chr

41
Q

What is the result of large rearrangements of 1/more exons of a gene if exon is multiple of 3?

A

Can get full length of transcript as won’t disrupt reading frame but if not, can disrupt

42
Q

If an exon is 30bp and is dup, how man aa does it encode and what is the effect?

A
  • encodes 10 aa

- dup adds just 10 aa - less disruptive than if its not 30bp

43
Q

What is the effect of large rearrangements such as inversion on an exon?

A
  • disrupts seq for splicing as they’ll be in wrong orientation and therefore exon is removed
44
Q

What is the critical determinant of effect of large rearrangements?

A
  • whether/not removal/insertion of exon (s) affects reading frame
45
Q

What accounts for the vast majority of reported functional variants?

A
  • small rearrangements (del, ins, dup, inv)

- large rearrangements of 1/more exons of a gene, del, dup and inv

46
Q

What can also be pot sites of functional variation and why are they rarely described?

A
  • variants in promoters
  • variants in UTRs
  • variants in polyadenylation signals
47
Q

Why might variants in promoters be rare?

A
  • promoters may be rel insensitive to variantion
48
Q

What is effect of variants in promoters?

A
  • can result in tissue/stage specific phenotype (if it promotes expression of gene in particular tissue/stage in dev) which can lead to phenotype
49
Q

Why might variants be found in UTRs and which ones?

A
  • some UTRs more highly conserved than coding regions

- v. few confirmed pathogenic variants e.g. myotonic dystrophy, fukuyama muscular dystrophy

50
Q

Why might functions of variants in UTRs be poorly understood?

A
  • transcript stability

- subcellular location

51
Q

What effects does variants in polyadenylation signals cause?

A
  • few characterised variants result in dec transcript levels
  • ev from yeast that NMD pathway involved
52
Q

Which terms classify mutations based on their behaviour in various genetic situations?

A
  • loss of function: amorph + hypomorph

- gain of function: hypermorph, antimorph, neomorphic

53
Q

What is an amorph?

A

variant that causes complete loss of gene function e.g. truncated gene

54
Q

What is a hypomorph?

A

variant that causes partial loss of gene function e.g. by sub where protein works but not as well

55
Q

What is a hypermorph?

A

variant that causes inc in normal gene function e.g. variant disrupts enz but its now more active as a result

56
Q

What is an antimorph?

A
  • dom alleles that act in opposition to normal gene activity e.g. protein that forms disomer
  • mutations in 1 copy of gene - when dimers form, some have mutated copy which disrupts normal copy
57
Q

What is a neomorphic variant?

A
  • variant that causes dom gain of gene function that’s diff from normal function
58
Q

What happens as a result of loss of function variation?

A
  • protein product fails to perform its normal function
59
Q

What causes loss of function variation?

A
  • little/no protein produced (e.g. whole genome del, nonsense variant resulting in NMD
  • mutation makes protein unstable/inappropriately targeted and is degraded (e.g. in frame del causing misfolding)
  • residue/domain essential for function is missing/critically altered (missense variant in enz active site)
60
Q

Why is loss of function variation usually rec?

A
  • presence of 2nd, normal allele can usually rescue phenotype resulting in normal heterozygotes
61
Q

In what ways can loss of function alleles exhibit dom form of inheritance?

A
  • haploinsufficiency
  • dom -ve effect
  • somatic second hits
62
Q

What is haploinsufficiency?

A

org so sensitive to levels of protein that 50% of dec in quantity causes noticeable phenotype

63
Q

What is dom -ve effect?

A
  • formation of homomultimeric complexes means that not only does protein lose its function but it disrupts function of its normal counterpart
64
Q

What are somatic second hits?

A
  • org largely normal but somatic 2nd mutations give rare clones of null cells which are defective
  • rec at cellular level but dom inherited in families
  • indiv inherits loss of function copy of gene and somatic 2nd mutation hits 2nd copy of gene
    e. g. predis of BRCA to breast cancer + 2nd hit causes disease to manifest
65
Q

What happens in gain of function variation?

A
  • rather than lose its principal function, protein may become less specific in its normal function/even acquire novel function
66
Q

In what ways can gain of function alleles exhibit dom form of inheritance?

A
  • loss of regulation

- novel function

67
Q

What is loss of regulation?

A
  • activity of protein (enz etc) loses its spacial/temporal specificity
  • may be due to loss of regulatory region/mislocation in cell
  • variant in inhib domain - constitutive activity (dom) or variant in active domain - loss of function (rec)
68
Q

What is novel function?

A
  • protein has novel effect which is not characteristic of normal product
  • common novel function is formation if insol aggregates
  • e.g. HD + triplet repeat expansion due to mutation of huntingtin which forms aggregates which is basically new function of protein but has detrimental effect
69
Q

What was identified as cause of infantile onset epilepsy in Amish?

A
  • identified on chr 2, homozygosity in affected indiv
  • in SIAT9 gene, affected indiv homo have C to T sub for stop codon
  • SIAT9 encodes GM3 synthase - critical in syn of a + b series gangliosides
  • mutation identified predicted to lead to loss of function of GM3 syn - don’t get gangliosides which leads to seizures
70
Q

How did carriers compare to affected in Amish case?

A
  • carriers have 1 copy of arg + stop codon
  • measurement of levels of gangliosides of affected indiv homo for disease causing variant confirmed complete lack of a + b series gangliosides
  • measurement in carrier parents hetero for disease causing variant demonstrated normal levels of a + b
  • demonstrated that 1 normal copy of gene is OK but no normal copies resulted in loss of a + b series and epileptic phenotype
71
Q

What did profiles between carriers and affected show?

A
  • parents have wild type and mutated copy (50% normal activity of gene and protein but prfiles are same as control therefore 50% of enz sufficient for pathway to work
  • affected had no GM3 peaka and therefore no gangliosides
  • higher peaks also as lactosyl cermaide goes down other pathways due to no GM3 syn
  • lac cer also builds up which may be whats actually causing seizues
72
Q

What do certain bio biases mean?

A
  • Certain types of mutation events more freq
73
Q

What do consequences of variation depend on?

A
  • pos of variation wrt functional seq
74
Q

What is functional consequence of disease causing variants?

A
  • leads to phenotypic effect

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