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Introductory Genetics
http://www.stats.gla.ac.uk/~paulj/intro_genetics.ppt
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Overview of talks
• This talk: broad overview of genetics• Future talks: genetic data analysis
– Important general genetic concepts• heritability, penetrance, linkage/linkage disequilibrium, Hardy-
Weinberg equilibrium– Types of genetic analysis
• association analysis– family-based vs population-based– candidate gene vs genome scan– genotype v haplotype– problems: population stratification, missing data, data errors,
inferring haplotypes • twin studies
– “Omics”: genomics, proteomics, metabolomics, genetical genomics, integrative genomics
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Overview of this talk
• Why genetics is important• How genes work• Mendel’s laws of inheritance for simple genetic traits• “Post-genomic” genetics
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Why genetics is important
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G×E interaction
Health
Genetics
Environment
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ISI Web of Science topic search for "genetic AND disease"
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How genes work
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What is a gene?
• A gene is a stretch of DNA whose sequence determines the structure and function of a specific functional molecule (usually a protein)
DNA
Protein
…GAATTCTAATCTCCCTCTCAACCCTACAGTCACCCATTTGGTATATTAAAGATGTGTTGTCTACTGTCTAGTATCC…
Computer program
Specific function
…function sf(){document.f.q.focus()}…
Working copymRNA
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Genes are located in the cell nucleus on chromosomes
Karyotype
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Down syndrome karyotype (trisomy 21)
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DNA(deoxyribonucleic acid)
mR
NA
Protein
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Transcription movie
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Translation
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Translation
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Translation movie
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Gene expression movie
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Summary
• A gene is a length of DNA that contains instructions for making a specific protein
• Genes are arranged along 23 pairs of chromosomes in the cell nucleus
• Genes work by specifying the amino acid sequence of a protein
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Mendel’s laws
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Genetic knowledge used for 1000s of years: agriculture
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Patterns of disease inheritance known for 1000s of years, e.g. haemophilia
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Mendel deduced the underlying principles of genetics from these patterns
1. Segregation
2. Dominance
3. Independent assortment
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Mendel’s experiments
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Mendel’s data
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Mendel’s law of segregation
• A normal (somatic) cell has two variants (alleles) for a Mendelian trait.
• A gamete (sperm, egg, pollen, ovule) contains one allele, randomly chosen from the two somatic alleles.
• E.g. if you have one allele for brown eyes (B) and one for blue eyes (b), somatic cells have Bb and each gamete will carry one of B or b chosen randomly.
B b
B BB Bb
b Bb bbEggs
Sperm
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Mendel’s law of dominance
• If your two alleles are different (heterozygous, e.g. Bb), the trait associated with only one of these will be visible (dominant) while the other will be hidden (recessive). E.g. B is dominant, b is recessive.
B b
B BB Bb
b Bb bbEggs
Sperm
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Mendel’s law of dominance
• If your two alleles are different (heterozygous, e.g. Bb), the trait associated with only one of these will be visible (dominant) while the other will be hidden (recessive). E.g. B is dominant, b is recessive.
B b
B BB Bb
b Bb bbEggs
Sperm
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Terminology…
• Haploid: containing one copy of each chromosome (n=23)
B b
B BB Bb
b Bb bbEggs
Sperm
• Diploid: containing two copies of each chromosome
(2n=46)
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Terminology…
• Genotype: the states of the two alleles at one or more locus associated with a trait
• Phenotype: the state of the observable trait
Genotype Phenotype
BB (homozygous) Brown eyes
Bb (heterozygous) Brown eyes
bb (homozygous) Blue eyes
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Mendel’s law of independent assortment
• Knowledge of which allele has been inherited at one locus gives no information on the allele has been inherited at the other locus
S/s Y/y
SY Sy sY sy
25% 25% 25% 25%
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Mendel’s law of independent assortment
S Y
s y
Gametophytes(gamete-producing cells)
S Y
s yGametes
A b
a BRecombinants
Segregation
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Mendel’s law of independent assortment
S Y
s y
Gametophytes(gamete-producing cells)
S Y
s yGametes
S y
s YRecombinants
Recombination
Segregation
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Statistical aside: Mendel’s data too good to be true?
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• Simplified view of eye colour inheritance: biallelic Mendelian trait
– Brown dominant: BB, Bb
– Blue recessive: bb
Human eye colour
B b
B BB Bb
b Bb bbEggs
Sperm
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Human eye colour
?
What is the probability of a child being born with blue eyes?
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Human eye colour
?
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Human eye colour
?
B?
B?B?B? bb
bb B?
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Human eye colour
?
Bb
BbBbB? bb
bb B?
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Human eye colour
?
Bb
BbBb
B?
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Human eye colour
?
BbP(BB)=1/3
BbBb
P(Bb)=2/3
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Human eye colour
?
BbP(BB)=1/3
BbBb
P(Bb)=2/3
P(b)=2/3x1/2=1/3 P(b)=1/2
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Human eye colour
?
BbP(BB)=1/3
BbBb
P(Bb)=2/3
P(b)=2/3x1/2=1/3 P(b)=1/2
P(bb)=1/3x1/2=1/6
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• Haemophilia A• Males with a mutant gene are
affected• Females with one mutant gene
are unaffected carriers
Non-Mendelian inheritance: Haemophilia
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Non-Mendelian inheritance: additive traits
Dominant vs additive inheritance
0%
50%
100%
0 1 2
Number trait alleles inherited
Tra
it v
alu
e
Dominant
Additive
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Non-Mendelian inheritance: additive traits
Brown eye colour is dominant
Dominant vs additive inheritance
0%
50%
100%
0 1 2
Number trait alleles inherited
Tra
it v
alu
e
Dominant
Additive
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Non-Mendelian inheritance: additive traits
Snapdragon red colour is additive
Dominant vs additive inheritance
0%
50%
100%
0 1 2
Number trait alleles inherited
Tra
it v
alu
e
Dominant
Additive
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Non-Mendelian inheritance: polygenic traits
Distribution of trait measures for single gene additive trait
0
0.1
0.2
0.3
0.4
0.5
0.6
0 1 2
Trait value
Fre
qu
en
cy
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Non-Mendelian inheritance: polygenic traits
Distribution of trait measures for polygenic additive trait (2 loci)
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0 1 2 3 4
Trait value
Fre
qu
en
cy
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Non-Mendelian inheritance: polygenic traits
Distribution of trait measures for polygenic additive trait (10 loci)
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0.2
0 2 4 6 8 10 12 14 16 18 20
Trait value
Fre
qu
en
cy
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Non-Mendelian inheritance: polygenic traits
For example, height
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Non-Mendelian inheritance: mtDNA
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Phenotypes associated with mtDNA mutations
• Longevity• Optic neuritis• Occipital stroke in migraine• Asthenozoospermia • Migraine without aura• Cyclic vomiting syndrome• Bipolar disorder• Athletic performance
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Summary
• Mendel deduced three simple laws of inheritance:– Segregation– Dominance– Random assortment
• The majority of traits don’t follow these rules but Mendel’s laws are nevertheless crucial to understanding almost all genetic inheritance
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“Post-genomic” genetics
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Human Genome Project
• Sequenced almost all 3 billion DNA base pairs (2003)• Current work includes:
– ENCODE Project (ENCyclopedia Of DNA Elements) to characterise functional elements in genome
• 20,000-25,000 genes (1.5% of genome)• The bits in between (98.5% of genome)
– Characterise human DNA sequence variation• Find and describe DNA sequence variation (International
HapMap Project) • Find significance of sequence variation (e.g. contribution to
complex diseases)
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HapMap project
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Frequency
Case 0.200
Control 0.165
Odds ratio: 1.26
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1. Eye-catching headline of the form “Gene for…”
2. Highly qualified factual paragraph
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HTR1D
HTR1D
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Summary
• Post-genomic genetics has enormous promise for tracking down the genes involved in common complex diseases
• Currently our ability to exploit this potential is limited by– study size– difficulty of correcting for confounding factors