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A basic review of genetics
Dr. Danny Chan
Associate Professor
Assistant Dean (Faculty of Medicine)
Department of Biochemistry
The University of Hong Kong
Cells and genes
50,000,000,000,000 cells
Cells and genes
Mitochondria
Nucleus
(few more genes)
(99.9% of the genes)
~20, 0000 genes
Genes are on DNA
NH2
5’
O
O
P
O
N
N
CH2
Cytosine
O
O
OO
CH3
Thymine
NH
O
O
P
O
N
CH2
O
O
OO
N
N
Guanine
O
O
Deoxyribose
Nucleic
Acids
P
O
CH2
O
N
N
NH2
ONH2
N
N
Adenine
O
O
P
O
CH2
N
O
N
O-
3’
DNA sequence  genetic code  genes
Genes determine why we are the way we are!
Genes are passed on from one
generation to the next
Genetic traits
You have inherited genes from
your father that make proteins
instructing your hair cells or
eye cells to produce hairs and
eyes that are the same colours
and shape as your father.
Genetic traits can also be a behavior, feelings, or
responses to a given environment
DNA are super-coiled into chromosomes
chromosome
Human Genome
22 pairs of autosomes and 1 pair of sex chromosomes
Autosomes
Sex chromosomes
Other primate chromosome numbers
24 pairs of chromosomes
21 pairs of chromosomes
Other species
30 pairs of chromosomes
4 pairs of chromosomes
39 pairs of chromosomes
The genome projects
How similar are we to other species?
~93%
~98.5%
How about with other humans?
What makes
us different
from one
another?
~99.5%
Variations in DNA sequence or
Polymorphisms
• Variable number tandem repeats (VNTRs)
• Microsatellites
• Single nucleotide polymorphisms (SNPs)
• Small insertions and deletions (Indels)
• Copy number variations (CNVs)
Variations in DNA sequence or
Polymorphisms
• Variable number tandem repeats (VNTRs)
• Microsatellites
• Single nucleotide polymorphisms (SNPs)
• Small insertions and deletions (Indels)
• Copy number variations (CNVs)
Microsatellites
Repeat units of nucleotides 1-6bp in length
The most widely used are the (CA)n microsatellites
6 (CA) allele
CACACACACACA
8 (CA) allele
CACACACACACACACA
Single nucleotide polymorphisms (SNPs)
are substitutions, insertions or deletions of a single base
T-allele
TCGAGAGGCTAGGCTAGGA
Substitution
C-allele TCGAGAGGCCAGGCTAGGA
Insertion
(+) allele TCGAGAGGCTTAGGCTAGGA
deletion
(-) allele TCGAGAGGCAGGCTAGGA
SNPs arise during DNA replication
3 x 109 bases
107 SNPs
Opportunities for errors
Single base errors/changes create
SNPs
Genetic differences and similarities
between people
You
Rest of the world
Genetic signature
Some SNPs affect the way we look
Some affect our susceptibility to diseases
Others affect our response to drugs/pain
or .. no differences!
.. in health, personalities or
responses to the environment
SNPs affecting gene function
Newly
synthesized
protein
Gene
mRNA
t-RNA
Altered
Protein
Protein
Protein function and phenotype
Altered
protein
function
Altered
Phenotype
Altered
Protein
Protein
A pair of homologous chromosomes
Mum
Hair color
Height
Longevity
Body fat
Intelligence
Eye color
Dad
Hair color
Height
Longevity
Body fat
Intelligence
Eye color
Sperm
Somatic cell
2 sets
1 set
oocyte
1 set
Meiosis (making sperm or oocytes)
Meiosis I
Meiosis II
Diploid cell
DNA
replication
Homologous
chromosome
pairing
Four
haploid cells
Genetic recombination in meiosis
Doubling
Cross-over and exchange DNA
Genes get shuffled during recombination
Phenotypes
Observable or measurable traits
Genes + environment
Begins in the womb and continues throughout life
Phenotypes
Differences in some phenotype are determined
mostly by genes
Height
How genes influence personality, behavior and
perception is less well understood
Learning more about our phenotypes
… from our genome
We can now interrogate SNPs
across our genome all at once
Understand how some SNPs are affecting our phenotype
Genotype-phenotype relationship
phenotypes
Correlating genetic variations and diseases
• Family linkage analysis
• Case-control association study
Need a large pedigree!
phenotypes
Correlating genetic variations and diseases
• Case-control association study
Need a large cohort!
• Rare genetic diseases
• Common diseases
Rare genetic diseases
Single gene
Monogenic disorder
(Osteogenesis imperfecta)
Rare
(1:30,000 – 1:70,000)
Early-onset
(prenatal)
An autosomal
dominant
disease for which the
gene resides on
this chromosome
1 (CA) allele CA
2 (CA) allele CACA
……
3 (CA) allele CACACA
6 (CA) allele CACACACACACA
7 (CA) allele CACACACACACACA
8 (CA) allele CACACACACACACACA
Marker studied
56
47
23
Marker studied
23
15
44
Marker studied
15
35
67
Marker studied
24
25
27
Marker studied
13
12
45
Marker studied
24
25
27
Genotype other family members
(23) (16)
(14) (26) (34) (13) (58) (12) (13) (78)
(24) (46) (33) (14) (18) (25)
(18)
(26) (47)
(27) (46) (67) (24)
The key is to identify a genetic marker that is always
inherited by family members with the disease but not
by those who do not have the disease
Define the region of maximal linkage
Fine mapping
Gene resides here
Disease gene
Causative mutation!
Logarithm of odds (LOD) score
• The logarithm (in base 10) of the odds of linkage
– the ratio of the likelihood that loci are linked to the
likelihood that they are not linked
• A LOD of 3.0 = odds of 1000/1 in favour of linkage
– Equivalent to a 5% chance of error
Degree of linkage
Family linkage studies
• Advantages:
– Localization of areas associated with increase
disease risk across the genome
– Can study multiple markers simultaneously
• Disadvantages
– Multi-generational cases difficult to recruit with
high mortality conditions
– Difficult to study late-onset diseases/traits
– Difficult to study complex traits
Complex traits
(common)
Environment
Diabetes
Osteoporosis
Osteoarthritis
Alzheimer
Cancer
Interactions between
environment and genes
1
2
Genetics
4
Interaction between genes
3
Many genes may be involved
(Risk factors)
Association study for complex traits
• Linkage deals with a specific genetic relationship
between loci on a chromosome
• Association describes a statistical relationship
between genes or genetic variants and the
disease/trait of interest
Case-Control Association Studies
Large Cohort required
Good phenotype definition
Case
Control
An example for one SNP in a gene
Gene A
Allele 1
(T)
Allele 2
(A)
Case
Control
Control case association study
Uneven distribution of the SNP variants indicates an association
Case
Allele 2 is a possible risk allele
Control
Association studies
• Identifies disease susceptibility gene variants by
comparing genetic variants between people with
and without the disease of interest.
• Any particular association between a genetic
variant and a disease does not mean that the
variant is important in causation.
Linkage disequilibrium (LD)
“a huge assistance in high
throughput mapping of polygenic
diseases and a minor pest”
LD relates to recombination events
The nonrandom association
between alleles in a
population due to their
tendency to be co-inherited
because of reduced
recombination between them
Hot spots
Cold spots
Mutation
Group of extant
chromosomes
Ancestral
chromosome
Ancestral segment
New segment introduced by recombination
SNPs
Mutation
Group of extant
chromosomes
Ancestral
chromosome
Ancestral segment
New segment introduced by recombination
Mutation
Group of extant
chromosomes
Ancestral
chromosome
Ancestral segment
New segment introduced by recombination
Haplotype block
polymorphic segment of DNA marking an ancestral variant
Ancestral
chromosome
LD Map
Polymorphisms within regions
of reduced recombination will
mark the same association
The International HapMap Project
To identify all common
DNA polymorphisms
Define the LD pattern for
different populations
Started October 2002
Using high density of SNPs for disease hunting
Microsatellites
SNPs
Enhancing mapping
Accuracy and speed
~ 107 to choose from
Genome wide association scan (GWAS)
Now able to assess ~2.5M SNPs in a genome all at once
Various platforms are available for mostly common
SNPs (>5 % in the general population)
Published Genome-Wide Associations through 12/2010,
1212 published GWA at p<5x10-8 for 210 traits
Missing heritability
Rare SNPs with strong effect not yet identified?
NHGRI GWA Catalog
www.genome.gov/GWAStudies
Next generation sequencing
1000 genomes project
http://www.1000genomes.org
Goal of the 1000 genomes project
?
Knowledge gap
Rare genetic
variants
Common genetic
variants
discover >95 % of
SNPs, CNVs, indels
~1% across the genome,
0.1-0.5% in gene regions
Cystic fibrosis
Huntington disease
Osteogenesis imperfecta
Achondroplasia
?
Diabetes
Osteoporosis
Osteoarthritis
Alzheimer
Cancer
Other variations for consideration
• Small insertions and deletions (indels)
• Copy number variations (CNVs)
• miRNA
• Epigenetic controls
Mega load of genetic data will be available ..
Are we ready with the phenotype information?
Genotype
Phenotype
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Genotype
Phenotype
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Genotype
Phenotype
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Genotype
Phenotype
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