introductory genetics paulj/intro_genetics.ppt
Post on 28-Mar-2015
218 Views
Preview:
TRANSCRIPT
Introductory Genetics
http://www.stats.gla.ac.uk/~paulj/intro_genetics.ppt
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
Overview of this talk
• Why genetics is important• How genes work• Mendel’s laws of inheritance for simple genetic traits• “Post-genomic” genetics
Why genetics is important
G×E interaction
Health
Genetics
Environment
ISI Web of Science topic search for "genetic AND disease"
0
1000
2000
3000
4000
5000
6000
7000
800019
91
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
Nu
mb
er
of
jou
rna
l re
co
rds
How genes work
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
Genes are located in the cell nucleus on chromosomes
Karyotype
Down syndrome karyotype (trisomy 21)
DNA(deoxyribonucleic acid)
mR
NA
Protein
Transcription movie
Translation
Translation
Translation
Translation movie
Gene expression movie
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
Mendel’s laws
Genetic knowledge used for 1000s of years: agriculture
Patterns of disease inheritance known for 1000s of years, e.g. haemophilia
Mendel deduced the underlying principles of genetics from these patterns
1. Segregation
2. Dominance
3. Independent assortment
Mendel’s experiments
Mendel’s data
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
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
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
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)
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
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%
Mendel’s law of independent assortment
S Y
s y
Gametophytes(gamete-producing cells)
S Y
s yGametes
A b
a BRecombinants
Segregation
Mendel’s law of independent assortment
S Y
s y
Gametophytes(gamete-producing cells)
S Y
s yGametes
S y
s YRecombinants
Recombination
Segregation
Statistical aside: Mendel’s data too good to be true?
• 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
Human eye colour
?
What is the probability of a child being born with blue eyes?
Human eye colour
?
Human eye colour
?
B?
B?B?B? bb
bb B?
Human eye colour
?
Bb
BbBbB? bb
bb B?
Human eye colour
?
Bb
BbBb
B?
Human eye colour
?
BbP(BB)=1/3
BbBb
P(Bb)=2/3
Human eye colour
?
BbP(BB)=1/3
BbBb
P(Bb)=2/3
P(b)=2/3x1/2=1/3 P(b)=1/2
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
• Haemophilia A• Males with a mutant gene are
affected• Females with one mutant gene
are unaffected carriers
Non-Mendelian inheritance: Haemophilia
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
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
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
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
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
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
Non-Mendelian inheritance: polygenic traits
For example, height
Non-Mendelian inheritance: mtDNA
Phenotypes associated with mtDNA mutations
• Longevity• Optic neuritis• Occipital stroke in migraine• Asthenozoospermia • Migraine without aura• Cyclic vomiting syndrome• Bipolar disorder• Athletic performance
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
“Post-genomic” genetics
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)
HapMap project
Frequency
Case 0.200
Control 0.165
Odds ratio: 1.26
1. Eye-catching headline of the form “Gene for…”
2. Highly qualified factual paragraph
HTR1D
HTR1D
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
top related