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Genomics > Genome Variation > Flashcards

Genome Variation Flashcards

1
Q

What is a locus?

A

unique position in genome

single base to entire genomic region

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2
Q

What is an allele?

A

particular form of a specific locus

Single base to entire genomic region

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3
Q

What is the genotype?

A

The genetic makeup of an individual
An individual has 2 alleles for any autosomal locus
(heterozygous/homozygous)

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4
Q

What does it mean to be biallelic?

A

2 possible alleles

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5
Q

What does triallelic mean?

A

3 possible alleles

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6
Q

If there are >3 possible alleles what term do we use to describe the genotype?

A

multiallelic

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7
Q

How is the presence of an allele expressed in a population?

A

For a popn, presence of an allele is expressed as a freqy or %
Two popns of same species need not have same freqy at same locus

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8
Q

Describe the gross structure of the human genome

A

Gross structure – 23 pairs chromosomes

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9
Q

Describe the molecular structure of the human genome

A

Molecular structure – DNA sequence
3 billion bases (3000Mb)
~20,000 genes

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10
Q

How much of the human genome makes up the exome?

A

~2% genome codes for protein = exome

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11
Q

What type of genome variations cause disease?

A

Major macro-level differences generally associated with disease (aneuploidy, translocations, etc)

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12
Q

What do micro/molecular level genome variations cause?

A

Micro / molecular-level pathogenic difference sometimes associated with disease (point mutation and SCA, 3bp deletion in CFTR)

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13
Q

Give examples of micro / molecular-level variations

A

Coding variants that affect traits (height, hair colour, intelligence, etc)

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14
Q

On average how much of our DNA differs from one another?

A

~99.7% same DNA between any 2 people (i.e. ~9 million bases different)

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15
Q

What is defined as polymorphic?

A

Any position in the genome that varies between individuals is considered polymorphic = a variant

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16
Q

What is the reference allele?

A

Refers to the base that is found in the reference genome

Since reference is just somebody’s genome, it is not always the major allele

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17
Q

What is the major allele?

A

the most common allele for a given SNP

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18
Q

What is the minor allele?

A

the less common allele for a SNP

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19
Q

What is the minor allele frequency (MAF)?

A

frequency at which the second most common allele occurs in a given population

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20
Q

What was the human genome mapping project?

A

1993 - 2001

4 anonymous individuals averaged out

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21
Q

What is an SNP?

A

A SNP is a change in a single base

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22
Q

How common are SNPs?

A

High frequency: 1 every 300 nucleotides in reference genome
One individual: 1 every 1000 bases
~17 million SNVs identified in human genomes

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23
Q

Where are SNPs found?

A

Majority not in exome

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24
Q

how are SNPs formed?

A

Generated by mismatch repair during DNA replication (mitosis)
Although there are mismatch repair mechanisms which should correct these mistakes, some don’t get corrected and we end up with a SNP

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25
Q

How does DNA replication normally occur?

A

During DNA replication the two strands separate and used as templates to synthesise complementary strands
=> should end up with two identical copies

26
Q

How does a mismatch form during replication?

A

When synthesising the new strand, an incorrect base is incorporated instead

Mismatch repair mechanism will identify the mistake and correct it so the bases are a standard Watson-Crick base pair or it might not…

27
Q

What is the consequence of a persistent mismatch?

A

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

28
Q

Where in a gene may a SNV be found?

A 
No amino acid change (synonymous)
Amino acid change (non-synonymous/missense)
Stop codon (nonsense)
Splice sit
UTR (gene expression)
29
Q

Where else in DNA are SNVs found?

A

Promoter - Protein expression

Non-coding Region

30
Q

When do SNVs not appear?

A

Without a deleterious effect /population annihilation => SNV doesn’t disappear

31
Q

What is a missense point mutation?

A

A point mutation where a single nucleotide change results in a codon that codes for a different amino acid
> type of nonsynonymous substitution

32
Q

Give an example of a disease associated with missense mutation

A

Sicke cell anaemia
codon GAG -> GTG
Glutamic acid -> Valine

33
Q

How common is the SCA point mutation across the globe?

A

Point mutation very rare in white European population
Relatively common in black African population

Estimated frequency of SCA variant allele:
European = 0.02%, i.e. 2 in every 10,000 chromosomes
African = 4.5%, i.e. ~1 in every 20 chromosomes

34
Q

Why is the SCA point mutation more prevalent in Black African populations?

A

Beneficial in places where malaria is rife (heterozygote advantage)

35
Q

How do we define a polymorphism?

A

If minor allele freqy >1% (i.e. at least 1 in every 100 chromosomes has non-reference allele) = polymorphism
Rare polymorphism: MAF 1-5%
Common polymorphism: MAF >5%

36
Q

Outline the features of a variant

A

Safer to use term variant

  • All variants start off rare
  • Evoly forces affect whether or not a variant remains rare
  • Rare variant may be damaging and/or recent
37
Q

How does mutation affect evolution?

A

New allele arises, we now have a Variant

38
Q

What is gene flow?

A

Migration leading to introduction of that variant into another population

39
Q

What is genetic drift?

A

Random change in variant allele frequency between generations

40
Q

What is natural selection?

A

Non-random change in variant allele frequency between generations because presence of one allele/genotype is pathogenic (negative selection) or beneficial (positive selection)

41
Q

How do we identify if a natural genetic variant is neutral?

A

By asking the following questions:
Where are they?
In a gene?
Not in a gene?

What sort of gene?
Key developmental gene, e.g. HOXD1
Pigmentation, e.g. MC1R

Not straightforward
Depends on the type of variant (lots of variants in every gene –some pathogenic, some not; depends on the environment)

42
Q

Summarise SNVs

A

Millions in genome
A position in genome at which the base can vary
Can be anywhere in the genome (genic or non-genic)
May do nothing, may affect a trait, may be associated with disorder
Generally bi-allelic
Due to mutation and mismatch repair
These are base substitutions
When pathogenic, may call point mutations

43
Q

What is a microsatellite?

A

a set of short repeated DNA sequences at a particular locus on a chromosome, which vary in number in different individuals and so can be used for genetic fingerprinting

44
Q

what is a STR?

A

a short tandem repeat is a micrsatellite
Can be variation in number of repeats between people
Reference often smallest allele but a range is often quoted

45
Q

What is polymerase slippage?

A

when the polymerase slips from the template strand during replication (error in DNA replication causing microsatellite expansion)

46
Q

what is the consequence of polymerase slippage?

A

Polymerase slippage causes the new strand to unpair (release) from the template strand, and is the main reason for codon expansion

47
Q

Using the huntingtin gene to describe how polymerase slippage causes expansion

A
  1. Slip occurs at codon repeat region of Huntigntin gene
  2. New strand has many identical codon copies to choose
    from when trying to reattach
  3. New strand may reattach to template at wrong copy,
    (usually 1 away from the copy that was adjacent to the
    polymerase before it slipped)
  4. Forms a bubble of unpaired bases, representing
    expansion of new strand
  5. Once DNA replication is complete, an unknown
    mechanism allows template strand to realign with new
    strand and bring bases from the bubble back into line
    with the template strand => forms complementary base
    pairs

The brand new double helix of DNA contains more CAGs in the repeat region of the Huntington gene than existed before.
Polymerase slippage has caused expansion

48
Q

Where in the genome are microsatellites found?

A

Part of the 98% of the genome not coding for protein

  • Intronic or UTR: may affect gene expression
  • Intergenic

Exonic

  • Extra amino acids in protein
  • pathogenic example?
49
Q

Outline the features of expansion disorders

A

Expansion disorders, e.g. Huntington’s = trinucleotide repeat expansion disorder, basically a “bad” microsatellite

1000s in genome
Repeat units
Varying numbers of repeats
Alters actual size of that region of the genome
Multiallelic
Can be anywhere in genome
May do nothing….
50
Q

What is a CNV?

A

A copy number variation (CNV) is when the number of copies of a particular gene varies from one individual to the next

51
Q

What is the reference number of a CNV?

A

Reference copy number = 1

52
Q

What is the simplest type of Copy number variation?

A

The simplest type of copy number variation is the presence or absence of a gene.
An individual’s genome could therefore contain two, one, or zero copies

53
Q

What causes multiple copies of a variation?

A

Duplication of a genomic segment

could result in diploid copy numbers of two, three, or four.

54
Q

What is the result of allelic recombination during meiosis?

A

Allelic recombination is good! – shuffling of alleles

But non-allelic recombination results in duplication/deletion and copy number change

55
Q

Outline the features of CNVs

A 
Intergenic
But – quite large (>1kb) so often affect one or more genes (parts of genes)
~12% genome = CNV
>2000 identified
1kb-5000kb
56
Q

Give examples of pathogenic CNVs

A

Microdeletion disorders, e.g. diGeorge syndrome

57
Q

Outline types of common genetic variants

A

Single Nucleotide Polymorphisms (SNPs)
~17 million identified; ~3 million/genome

Microsatellites ~3% of the genome

Copy Number Variants (CNVs) >2000 identified; ~100 per genome

Remember – everyone “has” every variant, what may differ between individuals is the genotype

58
Q

How do we determine if biallelic variants are common?

A

If biallelic: high frequency of the minor allele
Population frequency
i.e. proportion of chromosomes that carry each allele in the population

59
Q

How do we assess multiallelic variants being common?

A

Compare with translocations or aneuploidies – we don’t see thousands or millions of those because they’re generally damaging

60
Q

How commonly do variants associate with disease?

A

Most common variants not causing Mendelian, monogenic disorders.
Majority are probably neutral (particularly intergenic variants).

BUT!
May well impact upon complex, non-Mendelian disorders and undoubtedly contribute to general individual variation (personality, sporting ability, looks etc)

61
Q

List a few traits / non-mendelian disorders variants contribute to

A 
Height
Allergies
Haemochromatosis
Type 1 and Type 2 diabetes
Alzheimer’s
Anxiety
Dyslexia
Memory
Sexual desire
Aging
Nicotine dependance
Faithfulness
Age-related hearing loss
Gout
Sciatica
Sense of smell
HIV susceptibility
Anti-social behaviour
62
Q

What are the effects of variants?

A

Can be beneficial
Can be pathogenic
Most are neutral
Are these of any use?
Yes, can be used as markers to help find disease-causing genes and mutations
Autozygosity mapping & linkage studies (Microsatellites, SNPs)
Association analysis (SNPs, CNVs)

Genomics (20 decks)

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