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Population

Haplotypes/coding SNPs SNP discovery Sequencing/genotyping technology. Pathway. Genes. SNPs. ?. Analysis. Polymorphism function Replication. Population. Phenotypes. Polymorphism Polymorphism Base pair substitutions

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Population

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  1. Haplotypes/coding SNPs • SNP discovery • Sequencing/genotyping technology Pathway Genes SNPs ? Analysis • Polymorphism function • Replication Population Phenotypes

  2. Polymorphism Polymorphism 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)

  3. Polymorphism Polymorphism Insertions - Deletions GAG TTT TCT CGG AAT GGT GGT GCT AAT GLUPHESERARGASNGLYGLYALAASN GAG TTT CGG AAT GGT GGT GCT AAT GLUPHEARGASNGLYGLYALAASN - 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 GLUPHESERARGASNGLYGLYALAASN GAG TTT TCG GAA TGG TGG TGC TAA GLUPHESERGLUTRP TRPCYS STOP (Often result in new stop codons and truncated proteins)

  4. O6-MGMT O6-MGMT 145Cys Leu84Phe Ile143Val Lys178Arg

  5. DNA Repair Metabolism Inflammation Immunity

  6. (25-Hydroxylase) (1-a-Hydroxylase) (24-Hydroxylase) VDR (24-Hydroxylase) Ohmdahl et al. Ann. Rev. Nutr. 2002. • Vitamin D Metabolism • Vitamin 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.

  7. Pathways Pathways ‘Dynamic’ graphic models of molecular and biochemical pathways. WARNING: THIS IS A COMMERCIAL SITE! BioCarta http://www.biocarta.com/index.asp

  8. NAD+ Dependence Calorie restriction PBEF1 NMNAT1 NNMT Fat Mobilization GDH SIRTUIN ANT1 NCOR1 PPARg IDE SMRT RXR nDNA - Mitochondria PGC1a HNF4a Cyt-C LPK PEPCK ATP-synthase GCK G6Pase Glycolysis Mitochondria Glugoneogenesis Glucose Homeostasis

  9. Haplotypes Haplotypes

  10. Haplotype Blocks & Recombination Hotspots Haplotype Blocks & Recombination Hotspots 7q21

  11. G/C 3 G/A 2 T/C 4 G/C 5 A/T 1 A/C 6 G G A A G G G T T G G A C C C C C C C C C C C C A A A A T T G G G C C C high r2 high r2 high r2 Pairwise Tagging Pairwise Tagging Tags: SNP 1 SNP 3 SNP 6 3 in total Test for association: SNP 1 SNP 3 SNP 6

  12. Vitamin D Receptor • Vitamin D Receptor • Sequenced 94/164 kb. • 245 SNPs discovered • 916 GB individuals genotyped • 68 SNPs > 10% MAF • Nejetsev et al. 2004. Human Molecular Genetics. ApaI, TaqI, BsmI FokI

  13. Vitamin D Receptor • Vitamin 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.

  14. HapMap HapMap 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 Yoruba Japan - 45 unrelated individuals from Tokyo China - 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/

  15. Resequencing Resequencing

  16. Resequencing Resources Resequencing 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 Project http://egp.gs.washington.edu/ Seattle SNPs http://pga.gs.washington.edu/ Innate Immunity http://innateimmunity.net/

  17. SNP databases SNP databases

  18. SNP Databases SNP Databases Warehouses of SNP information. WARNING: NOT ALL SNPs ARE VALIDATED! NCBI http://www.ncbi.nlm.nih.gov/ Utah SNPs http://www.genome.utah.edu/genesnps/ Children’s Hospital Informatics Program http://snpper.chip.org/

  19. Evolution Evolution

  20. VISTA Tools VISTA Tools VISTA is a comprehensive suite of programs and databases for comparative analysis of genomic sequences. VISTA Tools http://genome.lbl.gov/vista/index.shtml

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