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1PATH3305 Medical Genetics > Lecture 2: Human Genetic variation in Health and Disease > Flashcards

Lecture 2: Human Genetic variation in Health and Disease Flashcards

1
Q

What is the human genome and what does it contain?

13

A

1 * ~37 trillion cells in the body
– Many different types of cells & functions

2 * All cells with a nucleus contain DNA
(mature red blood cells; cornified cells in skin, hair, nails; no nucleus)
3 – 99.9% genes in nucleus

4 – mitochondrial DNA (mtDNA) = 37 genes

5 – Which genes are turned on or off, and when, determine cell type.

6.* 3,000,000,000 base pairs of DNA (X 2).

7 – A standard typist would take 34 years of non-stop typing to type this out!

8 – 1.8m long  1 cell nucleus (tightly wound)

9 * ~20,000 protein-coding genes

10 * ~98% of DNA is “junk DNA”

11 * Any 2 people are ~99.6 – 99.9% identical

12 – 0.4% variation = ~ 12 million base pairs

13 * Finding a molecular diagnosis is essentially searching for one or more typographical errors in 34 years of typing…

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2
Q

What is Human Genetic Variation?

A

Variation in structure or sequence of the human genome

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3
Q

Human Genetic Variation - whom/where is it among?

= 2

A

1 – Inter-individual (intra-individual)

2 – Inter-population

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4
Q

Multiple mechanisms contributing To Human Genetic Variation? =6

A
  1. Meiotic recombination

2 – DNA replication and repair

3 – Population effects

4—- * Random genetic drift
5 —- * Selection (adaptive advantage)
6 —-* Migration

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5
Q

Understanding Geographical Genetic Diversity
= 3

A

1 * Out of Africa theory
– H.sapiens evolved into modern humans solely in Africa, 100-200,000 years ago
– One African subpopulation of hominins (among several) was ancestral to all human
beings today
– Some members of that subpopulation left Africa by 60,000 yrs ago

2* Supported by study of present-day mitochondrial DNA, and Y
chromosome sequence variation.

3 * Genetic diversity decreases with migratory distance from Africa
– Due to bottlenecks during human migration (temporarily reduce population size)

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6
Q

Generally speaking ..genetic diversity in world…

A
  • General similarities between neighbouring populations.
  • Large differences between different parts of the world.
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7
Q

What are the two types of Variation?

A
  • Structural (>1000bp)
  • Sequence level (<1000bp)
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8
Q

Types of Variation

Understanding
* Structural (>1000bp) = 3

A

1 – Copy number (deletions & duplications)

2 – Positional (insertions, translocations)

3 – Orientational (inversion)

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9
Q

Types of Variation

Understanding Sequence level (<1000bp) = 3

A

1 – Single base substitutions

2 – Small insertions/deletions/duplications

3 – Repetitive sequence

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10
Q

What is Cytogenetics?

A

Structure, properties and behaviour of chromosomes

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11
Q

What is Molecular Genetics = 4

A

1 * Studies structure and function of genes at a
molecular level

2 * Uses molecular biology & genetics

3 * Inter-relationship between DNA, RNA and
synthesis of polypeptides

4 * Tests are typically DNA- or RNA-based

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12
Q

Spectrum of Variation in the Human Genome… SMALL VARIANTS = 3

VARIATION…REARRANGEMENT TYPE… SIZE RANGE

A

SMALL VARIANTS AT SEQUENCES

  • MAY BE DIEASE CAUSING
  1. SINGLE BASE-PAIR CHANGES
    - Single nucleotide polymorphisms, point mutations
    - 1bp
  2. SMALL INSERTIONS/DELETIONS
    - Binary insertion/deletion events of short sequences (majority < 10bp in size)
    - 1-50bp
  3. SHORT TANDEM REPEATS
    - Microsatellites and other simple repeats
    - 1-500 bp
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13
Q

Spectrum of Variation in the Human Genome…LARGE VARIANTS … MAY BE DISEASE CAUSING OR NOT

A

…LARGE VARIANTS
… MAY BE DISEASE CAUSING OR NOT

  1. Large-scale structural variation
    - deletions, duplications, large tandem repeats, inversions
    - 50kb to 5 Mb
  2. CHROMOSOMAL VARIATION
    - Euchromatic variants, large cytogenetically visible deletions, duplications, translocations, inversions, and aneuploidy
    – aprox 5Mb to entire chromosomes
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14
Q

Spectrum of Variation in the Human Genome…REPETITIVE ELEMENTS OF VARIOUS SIZES. === 8 features + examples

A
  1. Repetitive elements of various sizes.
    2 * Tandem (vary in length) or interspersed (vary in copy number)
    3 * Small (<5Mb) or cytogenetically visible (>5Mb)
    4 * Non disease-causing but may predispose to
    rearrangements or expansions/contractions.
  2. FINE-SCALE STRUCTURAL VARIATION
    - Deletions, duplications, tandem repeats, inversions
    - 50bp to 5 kb
  3. RETROELEMENT INSERTIONS
    - SINEs, LINEs, LTRs, ERVs
    - 300 bp to 10 kb
  4. INTERMEDIATE-SCALE STRUCTURAL VARIATION
    - deletions, duplications, tandem repeats, inversions
    - 5-kb to 50kb
  5. Large-scale structural variation
    - deletions, duplications, large tandem repeats, inversions
    - 50kb to 5 Mb
  6. CHROMOSOMAL VARIATION
    - Euchromatic variants, large cytogenetically visible deletions, duplications, translocations, inversions, and aneuploidy
    – aprox 5Mb to entire chromosomes
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15
Q

Causes of Genetic variation? = 4

A

1 * DNA repair mechanisms contending with damage due to mutagens
– Ionising radiation
– UV
– Chemicals

2 * DNA replication errors
– Proof-reading errors
– Fork stalling

3 * Homologous DNA recombination during meiosis
– Allelic and non-allelic

4 * Retrotransposition
– Elements able to amplify themselves throughout the genome.
– Copy themselves to RNA and then back into DNA that integrates back
into the genome.

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16
Q

Causes pf Genetic variation?

Understanding DNA repair mechanisms contending with damage due to mutagens… 3

A

1 – Ionising radiation

2– UV

3 – Chemicals

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17
Q

Causes pf Genetic variation?

Understanding DNA replication errors = 2

A

– Proof-reading errors

– Fork stalling

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18
Q

Causes pf Genetic variation?

Understanding Homologous DNA recombination during meiosis

A

Allelic and non-allelic

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19
Q

Causes pf Genetic variation?

Understanding RETROTRANSPOSITION ..2

A
  • Elements able to amplify themselves throughout the genome.

– Copy themselves to RNA and then back into DNA that integrates back
into the genome.

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20
Q

Defining Variation: Reference Genome

  • The human reference genome is: 5
A
  1. Maintained by the Genome Reference Consortium
  2. – A product of multiple international contributions
  3. – Updated by new full releases and minor patches/fixes
  4. – Represents “normal”
  5. However we know that there are differences between “normal” populations
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21
Q

Defining Variation: Reference Genome
* The human reference genome is:

CREATED? WHEN NOT USEFUL? 3

A
  1. Created by sampling lots of individuals of varying genetic make-up.
  2. – Not necessarily appropriate when comparing large range of ethnicities (e.g.
    Australia)?

—- 3* Probably less of an issue in Mendelian inheritance, however could be an issue when considering complex inheritance and epistasis (suppression of the effect of a gene by another).

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22
Q

Variation and Phenotype IN GENETIC VARIATION = 3

A

1 * Any individual will have 10s of thousands of structural and sequence variants when compared to
the reference genome.

2 – Any may contribute to that individual’s phenotype

3 – Phenotype = “set of observable characteristics of an individual resulting from the interaction of it’s genotype with the environment”.

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23
Q

Spectrum of consequences of genetic variation and Phenotype…4

A

1 – No change in phenotype

2 – Alternative phenotypes of no medical consequence

3 – Disease susceptibility

4 – Pathogenic

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24
Q

Continuous Vs Discontinuous Variation …IN POPULATION =6 GRAPH?

A

*1 Continuous variation has no limit on the value that
can occur within a population.

2 – Line graph is used to represent.
3 * Height
4 * Weight
5 * Heart rate
6 * Finger length

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25
Q

Continuous Vs Discontinuous Variation IN ORGANISIMS.. GRAPH? =7

A

1 * Discontinuous variation has distinct groups for
organisms to belong to

2 – A bar graph is used to represent
3 * Tongue rolling
4 * Finger prints
5 * Eye colour
6 * Blood groups
7* Detached ear-lobes

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26
Q

Databases of Variation… TYPES…3

A

1 * Range of web-based databases containing normal or disease-associated variants.

  1. – “Normal” variation
    * Database of Genomic Variants - Copy number variants (CNVs)
    * ExAC, Exome Variant Server, 1000 Genomes, dbSNP (sequence variants).
  2. – Disease-associated variation
    * Disease/gene specific databases
    * Database of Human Gene Mutation Data (HGMD, sequence variants)
    * DECIPHER (CNVs)
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27
Q

Databases of Variation… Generally speaking… 4

A

1 – Different levels of curation, evidence base

2 – Generally free to access, some require a fee

3 – In-house collection of variants.

….4 * International pressure to contribute local data to
international databases

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28
Q

What is a Reference genome?

normal vs Abnormal …5

A

1 * Caution needs to be taken when calling genetic variation “normal”
vs “abnormal” using a single reference

2 – Variation occurs between populations.

3 – Common variant = “normal”
* BRCA2, c.865A>C (p.Asn289His)
* ExAC frequency all people = 0.052 (e.g. not rare)

4 – Rare variant = “abnormal”
* DMD, c.10412T>A (p.Leu3471*)
– * = X or stop

5 * Does not exist in any benign variant databases
– most likely disease-causing
– also gene fits with phenotype, and type of mutation fits with previous
knowledge for this gene.

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29
Q

Genetic vs Complex vs Environmental Diseases

A

1 * Genetic diseases
– Down syndrome
– Cystic fibrosis
– Sickle cell disease

2 * Complex diseases
– Diabetes (type 2)
– Alzheimer disease
– Cardiovascular disease
– Obesity

3 * Environmental diseases
– Measles
– Hepatitis
– Influenza

30
Q

Genetic diseases = 3

A
  1. Down syndrome
  2. Cystic fibrosis
  3. Sickle cell disease
31
Q

Complex diseases …4

A
  1. Diabetes (type 2)
  2. Alzheimer disease
  3. Cardiovascular disease
  4. Obesity
32
Q

Environmental diseases…3

A
  1. Measles
  2. Hepatitis
  3. Influenza
33
Q

Mendelian Inheritance
(monogenic disease)…. 8

A

1 * Gregor Mendel (1822 - 1884) - Austrian Augustinian monk

2 – “father” of genetics.

3 * Autosomal dominant

4 * Autosomal recessive

5 * X-linked dominant

6 * X-linked recessive

7 * Mitochondrial

8 * De novo

34
Q

Understanding Online Mendelian Inheritance in Man (OMIM https://omim.org) = 5

A
  1. > 15,500 genes
  2. – >4,900 phenotypes described, molecular basis known
  3. – >1,600 phenotype/locus, molecular basis unknown

…. 4* Too many genes and diseases to try to learn!

    • A large number of genetic diseases have the molecular basis known, but there is still a significant proportion that are yet to be solved.
35
Q

What is Epigenetics?

A
  • Heritable changes to gene expression that do not involve changes to the underlying DNA sequence.

– Change in phenotype without change in genotype.

36
Q
  • Epigenetic mechanisms = 3
A

– DNA methylation

– histone modification

– non-coding RNA

37
Q

Epigenetic changes are influenced by; 3

A

– age

– environment/lifestyle

– disease state

38
Q

Epigenetic changes associated with; 3

A

– Cancer

– Chromosomal instabilities

– Mental retardation

39
Q

Epigenetic tests

A

Epigenetic tests in most diagnostic labs are limited to detection of DNA methylation

40
Q

Central Dogma of Molecular Biology

A

The central dogma of molecular biology is a theory stating that genetic information flows only in one direction, from DNA, to RNA, to protein, or RNA directly to protein.

41
Q

Locus vs Allele

A
  • Locus:
    – location of a gene/marker on the chromosome
  • Allele:
    – one variant form of a marker at a particular locus
42
Q

Draw locus vs allele

A

slide 39

43
Q

Polymorphism vs Mutation = 8

A
  • Polymorphism
    1 – Variations in DNA sequence (e.g. deletions, insertions etc)
    2 * >1% in a population.
    3 – Ancient & common
    4 – Weak or no effect
  • Mutation
    5 – Variants in DNA sequences (substitutions, deletions etc)
    6 * <1% in a population.
    7 – Recent & rare
    8 – Can produce a loss or gain of function
44
Q

What is Monogenic Disease = 8

A

1 * Monogenic: change/s in one gene sufficient for disease.

2 – One gene —> one disorder

  1. – One gene —> multiple disorders
  2. – Multiple genes —> individually cause same single disorder
  3. – Comparatively rare
    • ~3000 males with Fragile X (AUS)
    • ~3000 people with cystic fibrosis (AUS)
    • ~3.5M people with cardiovascular disease (AUS)
45
Q

Polygenic & Complex Disease = 3

A
  • Polygenic:
    1 – multiple genes contribute to phenotype, each exerting
    a small effect.
    2 – e.g. eye colour.
  • Complex/multifactorial
    3 – gene(s) & environment.
46
Q

Germline Vs Somatic = 5

A

1 * Germ line is the cell line from which gametes are derived.

2 * Cells of the germline are called germ cells.

3 * Germ cells are deliberately set aside to later form gametes.
….4 – Originate in the primitive streak and migrate to the developing gonads
where they undergo cell division & differentiation  sperm, ova.

5 * Somatic cells arise from the germline, but are not part of it

47
Q

What happens in Germline Mutation …each stages….4

A
  1. GAMETES… germ-line mutation in SPERM ONLY
  2. EMBRYO: ….
  3. ORGANISM…. Entire organism carries the mutation
  4. GAMETES OF THE ORGANISM: Half of the gametes carry the mutation
48
Q

What happens in SOMATIC Mutation …each stages….4

A
  1. GAMETE - …zygote
  2. EMBRYO: SOMATIC MUTATION OCCURS
  3. ORGANISM: Patch of affected area
  4. GAMETES: None of the gametes carry the mutation
49
Q

Germline vs Somatic Mutations = 4

A
  • Germline mutation
    1 – Any tissue from that patient can be sampled for genetic testing.
    2 – Can give genetic predisposition to certain cancers (e.g. BRCA1,
    BRCA2)
  • Somatic mutation
    3 – Mutation will only be in affected tissues, not all tissues.
    4– Cancer can occur due to the accumulation of somatic mutations in
    DNA over time.
50
Q

DNA Variant “Jargon”
* Variant

A

= any change

51
Q

DNA Variant “Jargon”
* Pathogenic

A

= capable of causing disease

52
Q

DNA Variant “Jargon”
* Mutation

A

= change that causes disease

– e.g. a pathogenic variant

53
Q

DNA Variant “Jargon”
* Polymorphisim

A

= variant is common in normal population, therefore presumed benign.

– e.g. a benign variant

54
Q

DNA Variant “Jargon”
* Benign

A

not harmful in effect

55
Q

Types of mutations : 4

A

1 * Mode of inheritance
– Dominant, recessive, autosomal, X-linked

2 * Genomic location
– Coding, promoter/regulatory, splice-site

3 * Molecular change
– Structural or sequence level
– Substitution (synonymous, non-synonymous, missense, nonsense),
deletion/insertion, expansion/contraction
– Homozygous, heterozygous, compound heterozygous, hemizygous

4 * Functional effect
– Loss or gain of function, haploinsufficiency and dominant negative

56
Q

Mutation: Mode of inheritance…4

A

Dominant,

recessive,

autosomal,

X-linked

57
Q

Genomic location… mutation type..3

A

Coding,

promoter/regulatory,

splice-site

58
Q

mutation: MOLECULAR CHANGE …3

A
  1. Structural or sequence level
  2. Substitution (synonymous, non-synonymous, missense, nonsense), deletion/insertion, expansion/contraction

3 – Homozygous, heterozygous, compound heterozygous, hemizygous

59
Q

MUTATION TYPE: Functional effect… 3

A

– Loss or gain of function,

haploinsufficiency

dominant negative

60
Q

Sequence level mutations: 5

A

1 * Missense mutations
– altered function due to changes in protein structure
(functional domains and binding sites)

2 * Nonsense and frame-shifting mutations
– nonsense mediated decay or truncated protein

3 * Splicing mutations
– exon skipping or inclusion of novel exons

4 * Other mutations that affect gene expression by
– affecting interactions of the promoter with transcription
enhancers/suppressors,
– resulting in unstable mRNA that is rapidly degraded
– affecting splicing efficiency or translation

5 * Dynamic mutations (triplet repeats)

61
Q

Missense mutations

A

– altered function due to changes in protein structure
(functional domains and binding sites)

61
Q

Nonsense and frame-shifting mutations:

A

– nonsense mediated decay or truncated protein

62
Q

Splicing mutations

A

– exon skipping or inclusion of novel exons

63
Q

Other mutations that affect gene expression by …3

A

1 – affecting interactions of the promoter with transcription enhancers/suppressors,

2 – resulting in unstable mRNA that is rapidly degraded

3 – affecting splicing efficiency or translation

64
Q

Dynamic mutations

A

Dynamic mutations (triplet repeats)

65
Q

Copy number mutations

A
  • Single gene, contiguous gene and multiple gene syndromes
66
Q

Copy number mutations…Molecular mechanisms: 5

A
  1. Gene dosage
  2. Gene interruption
  3. Gene fusion
  4. Position effects
  5. “Unmasking” of recessive alleles
67
Q

Cytogenetics & Molecular Genetics

  • Line between both cytogenetics & molecular genetics specialties is blurring:
A
  • Line between both cytogenetics & molecular genetics specialties IS BLURRING:

Molecular methods can detect cytogenetic abnormalities,

e.g. microarray for submicroscopic deletions & duplications.

68
Q

Molecular Diagnosis – significance? 6

A
  1. Accurate Diagnosis
  2. Possible Prognosis
  3. Better Informed Genetic Counseling (cascade screening)

4.Prenatal, preimplantation,
presymptomatic diagnosis

  1. Appropriate trial enrolment, treatment
  2. Drug interactions/ pharmacogenomics
69
Q

Genotype-phenotype correlation…. 5

A

1 * The link between a specific genetic mutation (genotype) and disease characteristics (phenotype)

2 * Observed genotype-phenotype correlations for loss of function mutations can sometimes be explained by considering residual protein function

3 * Other important mechanisms that might explain the presence or
absence of a genotype-phenotype correlation include:
4 – Mosaicism
5 – Modifier genes, chance effects and environment

1PATH3305 Medical Genetics (20 decks)

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