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Personalised Medicine > Genomic Variation > Flashcards

Genomic Variation Flashcards

1
Q

What is a genetic variant?

A

A genetic variant is a difference between two (or more) people in some part of their DNA sequence

It may be a single base, a whole chromosome, or somewhere in between

It is usually heritable but not always

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2
Q

define locus

A

A position in the genome

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3
Q

define autosome

A

The non-sex chromosomes (1-22)

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4
Q

define allele

A

One form of a genetic variant

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5
Q

define genotype

A

The two alleles present at a locus

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6
Q

define haplotype

A

Allele order on one chromosome

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7
Q

what are the 3 possible genotypes in the pop?

A

AA – Common homozygote
Aa – Heterozygote
aa – Rare homozygote

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8
Q

what is the minor allele freq?

A

(MAF) is the frequency of the less common allele and can be a number between 0 and 0.5 or a percentage.

Two populations of the same species need not have the identical frequencies for the same allele

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9
Q

name primary seq variations

A

+SNPS
InDels
CNVs

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10
Q

name epigenetic variation

A

dna methylations

histone modification

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11
Q

name chromosomal variation

A

inversions
translocationg
aneuploidy
mosaicism

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12
Q

what is an SNP

A

single nucleotide polymorphism - change in a single base

generated by mismatch repair during mitosis

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13
Q

why does seq variation occur?

A

errors in DNA replication and repair

In proofreading, the DNA pol reads the newly-added base before adding the next one so a correction can be made.

The polymerase checks whether the newly-added base has paired correctly with the base in the template strand. If it is the correct base, the next nucleotide is added.

If an incorrect base has been added, the enzyme makes a cut at the phosphodiester bond and releases the incorrect nucleotide. This is performed by the exonuclease action of DNA pol III.

Once the incorrect nucleotide has been removed, a new one will be added again.

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14
Q

Explain SNP formation in steps

A

During DNA replication the two strands will separate and will be used as templates to synthesise complementary strands.

If that goes well then we should end up with two identical copies.

However, when synthesising this strand, instead of incorporating an A, a G has been incorporated.

The mismatch repair mechanism will identify this mistake and correct it so that the bases are a standard Watson-Crick base pair

If this change occurs in the gametes and isn’t deleterious then it will get passed on to the next generation
As time goes on it can spread through the population.

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15
Q

Name the types of SNPs

A 
Non-Synonymous
Synonymous
Promoter
Terminator
Splicing
Insertion/deletion
Neutral
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16
Q

What are non-synonymous SNPs

A

These change a three-base codon sequence and the amino acid in the gene product.

1)Missense
Change from one amino acid to another
can be Conservative, e.g. Leucine to Isoleucine
or
Non-conservative, e.g. Glycine to Histidine

2)Nonsense
These change an amino acid codon into a stop codon, causing premature truncation of the protein.

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17
Q

what are non-synonymous SNPs

A

These change the codon but due to codon degeneracy they have no effect on the amino acid composition

e.g. ….TTG… changed to …CTG…

Both are Leucine codons and the protein would be unaffected

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18
Q

what are promoter SNPs

A

Changes in the gene promoter may alter the level of gene expression.

e.g. ….TATAAA… to ….TAGAAA….

Would remove the basal TATA box and could drastically reduce or abolish transcription of the gene

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19
Q

what are terminator SNPs

A

These could affect the correct termination and polyadenylation of the messenger RNA

e.g. …AATAAA… to …AATAGA…

In alpha-globin this change disrupts the polyadenylation signal making the mRNA unstable

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20
Q

what are splicing SNPs

A

These lead to the creation or deletion of splice donor, acceptor or branch sites, affecting the final mRNA and hence protein.

e.g. …CAGGTAAGT… to …CAGATAAGT…
Removes the underlined splice donor site leading to utilisation of a different or cryptic splice site.

21
Q

what are InDels?

A

SNPs that are the result of a deletion/insertion of a single base.

Alters the subsequent reading frame, may affect the position of a binding site, or may even be neutral

22
Q

what are neutral SNPs

A

These are changes in the DNA that are in areas where they are predicted to have no discernible effect

However, “neutral” SNPs do not always remain as such

23
Q

what is the rs number?

A

unique identifier given to each SNP

24
Q

Example of a causal SNP

A

Melanocortin 1 receptor (MC1R)

25
Q

Explain MC1R

A

αMSH binds leads to eumelanin synthesis

MSH does not bind therefore phaeomelanin synthesis

SNPs affect binding and therefore red hair, freckling, pale skin are common

26
Q

example of causal InDel

A

Delta F508 in CF

27
Q

exlain delta f508

A

CTT deleted in gene this deletes amino acid 508 in protein, which is phenylalanine
Ctfr protein fails to fold correctly, becomes protease-sensitive and is degraded before it can enter the golgi

28
Q

what are microsatellites?

A

Number of repeats varies between individuals (short tandem repeats) (simple sequnce repeats)

Total length of microsatellite sequence varies between individuals

29
Q

what is the polymerase slippage model?

A

during replication, polymerase slippage and subsequent reattachment may cause a bubble to form in the new strand.

Slippage is thought to occur in sections of DNA with repeated patterns of bases (such as CAG). Then DNA repair mechanisms realign the template stranf with the new strand and the bubble is straighened out, resulting double helix this expanded.

Polymerase slippage cannot occur in DNA wihout repeating partterns of bases

30
Q

example of causal microsatellite

A

Triplet repeat disorders

Increasing length of a 3-base repeat sequence correlates with increasing chance of disease#

Huntington’s Disease
Poly-Glutamine repeat (CAG)
6-35 repeats typically unaffected
36->120 affected

31
Q

what is a minisatellite?

A

variable number tandem repeats

32
Q

what are mini satellites widely used for?

A

Widely used for forensic DNA fingerprinting and for paternity testing because they have large numbers of alleles

33
Q

what is a copy number variant?

A

Typically defined as sequences greater than 1kb that have different copy numbers in different people

34
Q

the simplest type of copy number variation is…

A

is the presence or absence of a sequence

35
Q

what is non-allelic homologous recombination?

A

a form of homologous recombination that occurs between two lengths of DNA that have high sequence similarity, but are not alleles

36
Q

what are the types of chromosomal abnormalities and define

A

Numerical – aneuploidy, loss or gain

Structural – translocations, deletions, insertions, inversions, rings

Mosaicism – different cell lineages

37
Q

Chromosome abnormalities are present in:

A

60% of early spontaneous miscarriages
4-5% of still births
7.5% of all conceptions, 0.6% of live births

38
Q

Explain mosaicism

A

Mosaicism is where there is more than one cell lineage in a tissue, i.e. some cells might have an extra chromosome 21 and others have the normal number (see later). This is due to mitotic non-disjunction. How early it happens determines how many tissues and which tissues the genetic abnormality might affect. A late non-disjunction event may have no visible effect whereas an early one might have severe effects.

39
Q

What is aneuploidy?

A

Numerical abnormalities involving the loss or gain of one or more chromosomes

40
Q

define monosomy

A

loss of a single chromosome is almost always lethal

41
Q

define trisomy

A

gain of one chromosome can be tolerated

42
Q

define tetrasomy

A

gain of two chromosomes can be tolerated

43
Q

example of a trisomy

A

trisomy 21: down syndrome

44
Q

biggest risk factor of down syndrome?

A

increased maternal age

45
Q

what is non-disjunction?

A

failure of homologous chromosomes or sister chromatids to separate properly during cell division.

46
Q

causes of trisomy 21?

A

90% maternal origin of extra chromosome

Non-disjunction in meiosis I (75%) or II (25%)

47
Q

what is a translocation?

A

the transfer of genetic material from one chromosome to another when a chromosome break occurs during meiosis or mitosis.

can be either, normal, balance or unbalanced

48
Q

translocations and down syndrome?

A

4% of all down cases

robertsonian - breakage of acrocentric chromosomes (13,14,15,21,22) and fusion of their long arms

49
Q

mosaicism and downs?

A

1% of all down cases
children less severley affected
caused by mitotic non-disjunction

Personalised Medicine (17 decks)

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