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Population
Pathway
?
GenesSNPs
Analysis
Phenotypes
• Haplotypes/coding SNPs• SNP discovery• Sequencing/genotyping technology
• Polymorphism function• Replication
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PolymorphismPolymorphism
Base pair substitutions
Synonymous - Do not result in a new amino acid in the protein
sequence.
GCA (Alanine) to GCG (Alanine) (Silent mutation)
Non-synonymous - Result in a new amino acid in the protein sequence.
GAG (Glutamate) to GTG (Valine) (Missense mutation)
- codon 6 substitution in the beta-globin protein chain causes sickle-cell
anemia
Nonsense mutations - Result in a termination codon.
CAG (Glutamine) to TAG (stop)
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PolymorphismPolymorphism
Insertions - Deletions
GAG TTT TCT CGG AAT GGT GGT GCT AAT
GLU PHE SER ARG ASN GLY GLY ALA ASN
GAG TTT CGG AAT GGT GGT GCT AAT
GLU PHE ARG ASN GLY GLY ALA ASN
- Fragile X Syndrome (X-linked retardation)
Tandem CCG repeats - severity of disease depends on number of repeats
- Huntington’s Disease
Tandem CAG repeats adding Glutamine to encoded Huntingtin protein.
Increasing number of proteins destabilizes the protein and interferes with synaptic
transmission and leads to apoptosis of brain cells.
GAG TTT TCT CGG AAT GGT GGT GCT AAT
GLU PHE SER ARG ASN GLY GLY ALA ASN
GAG TTT TCG GAA TGG TGG TGC TAA
GLU PHE SER GLU TRP TRP CYS STOP
(Often result in new stop codons and truncated proteins)
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O6-MGMTO6-MGMT
Ile143ValLeu84Phe
Lys178Arg
145Cys
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DNA Repair
Metabolism
Inflammation
Immunity
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Vitamin D MetabolismVitamin D Metabolism
• 25-Hydroxylase (P450C25): Hydroxylates Vitamin D3 producing 25(OH)D. • 1-a-Hydroxylase (CYP27B1): Activates 25(OH)D to 1,25(OH)2D.• 24-Hydroxylase (P450C24): Removes excess 25(OH)D from circulation and excess
1,25(OH)2D from the kidney.• VDR: Mediates effects of 1,25(OH)2D.
(1-a-Hydroxylase)
(24-Hydroxylase)
(24-Hydroxylase)
(25-Hydroxylase)
VDR
Ohmdahl et al. Ann. Rev. Nutr. 2002.
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PathwaysPathways
‘Dynamic’ graphic models of molecular and biochemical pathways.
WARNING: THIS IS A COMMERCIAL SITE!
BioCartahttp://www.biocarta.com/index.asp
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Calorie restriction
SIRTUIN
NAD+
Dependence
Glucose Homeostasis
G6Pase
PEPCK
PGC1 HNF4
LPK
GCKATP-synthase
Cyt-C
Glycolysis
Glugoneogenesis
Mitochondria
Fat Mobilization
NCOR1
SMRT RXR
PPARANT1
GDH
IDE
nDNA - Mitochondria
NMNAT1
PBEF1
NNMT
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HaplotypesHaplotypes
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7q21
Haplotype Blocks & Recombination HotspotsHaplotype Blocks & Recombination Hotspots
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Tags:
SNP 1SNP 3SNP 6
3 in total
Test for association:
SNP 1SNP 3SNP 6
A/T1
G/A2
G/C3
T/C4
G/C5
A/C6
high r2 high r2 high r2
AATT
GC
CG
GC
CG
TCCC
ACCC
GC
CG
TCCC
GGAA
GGAA
Pairwise TaggingPairwise Tagging
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Vitamin D ReceptorVitamin D Receptor
•Sequenced 94/164 kb.•245 SNPs discovered•916 GB individuals genotyped•68 SNPs > 10% MAF
Nejetsev et al. 2004. Human Molecular Genetics.
FokIApaI, TaqI, BsmI
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Vitamin D ReceptorVitamin D Receptor
•55 SNPs common in Britons, Norwegians, Gambians, Finns, Romanians
•TagSNPs (r2 ≥ 0.8):
Europeans:26 TagSNPs
Gambians:42 TagSNPs
Nejetsev et al. 2004. Human Molecular Genetics.
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HapMapHapMap
The International HapMap Project is analyzing DNA from a total of 270 people from populations with African, Asian, and European ancestry.
Nigeria - 30 trio samples (two parents and an adult child) from YorubaJapan - 45 unrelated individuals from TokyoChina - 45 unrelated individuals from Beijing U.S. – 30 trio samples with northern and western European ancestry.
Genotyping all individuals for a SNP ~ 1,000 – 2,000 base-pairs.
www.hapmap.org
http://www.broad.mit.edu/mpg/haploview/
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ResequencingResequencing
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Resequencing ResourcesResequencing Resources
Systematic identification and genotyping of single nucleotide polymorphisms (SNPs) in environmental response, inflammation, immunity genes.
Candidate genes are sequenced across a panel of individuals (~90) of known ethniticies to identify common sequence variation for functional analysis and population-based studies.
Websites provide tools for haplotype determination and TagSNP selection.
Environmental Genome Projecthttp://egp.gs.washington.edu/
Seattle SNPshttp://pga.gs.washington.edu/
Innate Immunityhttp://innateimmunity.net/
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SNP databasesSNP databases
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SNP DatabasesSNP Databases
Warehouses of SNP information.
WARNING: NOT ALL SNPs ARE VALIDATED!
NCBIhttp://www.ncbi.nlm.nih.gov/
Utah SNPshttp://www.genome.utah.edu/genesnps/
Children’s Hospital Informatics Programhttp://snpper.chip.org/
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EvolutionEvolution
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VISTA ToolsVISTA Tools
VISTA is a comprehensive suite of programs and databases for comparative analysis of genomic sequences.
VISTA Toolshttp://genome.lbl.gov/vista/index.shtml