Transcript Slide 1

SNPs
• DNA differs between humans by 0.1%, (1 in
1300 bases)
• This means that you can map DNA variation to
around 10,000,000 sites in the genome
• Almost all variation is ancient and 90% of SNP
variation are constant across all populations
• These Single Nucleotide Polymorphisms
(SNPs) can be correlated to human disease
• 1998 – 4,000 SNPs, 1994 – 7,800,000 nearly all
mapped
Alzheimer's Disease
• Apolipoprotein E (ApoE) carries cholesterol and
fat. It comes in three variants with two SNPs
APoE2 (T-T), APoE3 (T-C), ApoE4 (C-C).
• In 1993, ApoE4 was correlated with 1/3 of the
cases of Alzheimer’s disease
• If you have the E4 variant, you have a 60-70%
lifetime risk of Alzheimer’s Disease
• Current research is focused on drug
development that takes advantage of this
knowledge
Haplotype Maps
• Although there are around 10,000,000 SNPs,
they group into a small number of groups of
SNPs that are correlated with each other.
• So, there are around around 300,000 unique
arrangements of the SNPS
• This is not that big of a number!
• CS people can imagine an exhaustive search
Imagine …
SNP
1 2 3 4 5… 10,000,000
Alzheimers
0 1 0 1 0 0
0
Leukemia
1 0 0 0 0 0
1
Breast Cancer
0 0 1 1 0 0
1
…
1 0 0 0 0 0
0
Differences between individuals
• Pima Indians
• Anti-depressants
• Coronary Artery Disease
Basic Concepts
Parent 2
Parent 1
A
a
B
b
A B
a b
A B
a b
X
OR
a b
A B
A B
a b
High LD -> No Recombination
(r2 = 1) SNP1 “tags” SNP2
A
a
B
b
A b
A B
a B
A B
A b
a B
A B
A b
etc…
Low LD -> Recombination
Many possibilities
HapMap Glossary
• LD (linkage disequilibrium): For a pair of SNP alleles,
it’s a measure of deviation from random association
(i.e., no recombination). Measured by D’, r2, LOD
• Phased haplotypes: Estimated distribution of SNP
alleles. Alleles transmitted from Mom are in same
chromosome haplotype, while Dad’s form the paternal
haplotype.
• Tag SNPs: Minimum SNP set to identify a
haplotype. r2= 1 indicates two SNPs are redundant,
so each one perfectly “tags” the other.
• Questions?
[email protected]
HapMap Project
Phase 1
Phase 2
Phase 3
Samples & POP
panels
269 samples
(4 panels)
270 samples
(4 panels)
1,115 samples
(11 panels)
Genotyping
centers
HapMap
International
Consortium
Perlegen
Broad & Sanger
Unique QC+
SNPs
1.1 M
3.8 M
(phase I+II)
1.6 M (Affy 6.0 &
Illumina 1M)
Reference
Nature (2005)
437:p1299
Nature (2007)
449:p851
Draft Rel. 1
(May 2008)
Release Notes
• Phase 1+2: Latest Release #24, October 2008 (NCBI
build 36):
3.9 M unique QC+ SNPs -- > 1 SNP/700 bp
http://ftp.hapmap.org/00README.releasenotes_rel24
– Added back chrX SNPs dropped in previous releases
– Corrected allele flips from rel#23a
• Phase 3: Draft release #1 (NCBI build 36)
http://ftp.hapmap.org/genotypes/2008-07_phaseIII/00README.txt
– HapMap3 sites @ Broad Institute, Sanger Center and Baylor College
Phase 3 Samples
label
A SW*
C E U*
C HB
C HD
GIH
JP T
L WK
M E X*
M K K*
T SI
Y RI*
population sample
# samples
A fric an anc es try in Southwes t U SA
90
U tah res idents with N orthern and Wes tern
180
E uropean anc es try from the C E P H c ollec tion
H an C hines e in Beijing, C hina
90
C hines e in M etropolitan D enver, C olorado
100
G ujarati I ndians in H ous ton, T exas
100
J apanes e in T okyo, J apan
91
L uhya in Webuye, Kenya
100
M exic an anc es try in L os A ngeles , C alifornia
90
M aas ai in Kinyawa, Kenya
180
T os c ans in I taly
100
Y oruba in I badan, N igeria
180
1 ,3 0 1
* Population is made of family trios
QC+ Draf t 1
71
162
82
70
83
82
83
71
171
77
163
1,115
1: Surf to the HapMap Browser
1a. Go to
www.hapmap.org
1b. Select
“HapMap phase 3”
2: Search for TCF7L2
2. Type search term
– “TCF7L2”
Search for a gene
name, a chromosome
band, or a phrase like
“insulin receptor”
3: Examine Region
Chromosome-wide
summary data is
shown in overview
Default tracks show
HapMap genotyped SNPs,
refGenes with exon/intron
splicing patterns, etc.
Region view puts
your ROI in
genomic context
3: This exonic region has
many typed SNPs. Click
on ruler to re-center
image.
3: Examine Region (cont)
Use the
Scroll/Zoom
buttons and menu
to change position
& magnification
3: Mouse over a SNP to see
allele frequency table
As you zoom in
Click
to gothe
to SNP
further,
details
pageto
display
changes
include more detail
4: Generate Text Reports
4: Select the desired
“Download” option and press
“Go” or “Configure”
Available phase 3 downloads:
- Individual genotypes
- Population allele &
genotype frequencies
4: Generate Reports (cont)
The Genotype download
format can be saved to
disk or loaded directly
into Haploview v4.1
5: Find GWA hits
5a: Scroll down to turn on
GWA studies tracks in
overview & region panels
5b: Find GWA hits in
nearby region. Click on a
GWA hit to re-center
5: Find GWA hits (cont)
5c: Mouse over & click on
GWA hit for more info
6: Examine GWA hits in entire
genome
6: From www.hapmap.org,
select “Karyogram”
6: Custom GWA hits in karyogram
6: Follow these instructions to
upload your own GWA data
Detailed help on
the format is under
the “Help” link
Epigenomics
• Even with identical DNA, offspring can retain
features for up to 4 generations
• Work with Huntsman on Methelation
Progress in Disease Treatment
• Personalized medicine is becoming more
prevalent for several kinds of cancer treatment
• 10-Feb-2009 – Breast Bioclassifier developed at
the Huntsman Cancer Institute
– 1/8 women will be diagnosed with breast cancer
– Microarray analysis can separate large group who
need no treatment
– Savings in cost and lifestyle
– With $100 human genomes, doctors can determine
which drugs will be effective for your genotype