Outline to SNP bioinformatics lecture

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Outline to SNP bioinformatics lecture

• Brief introduction
• SNPs in cell biology
• SNP discovery
• SNP assessment
• SNP databases
• SNPs in genome browsers

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Single Nucleotide Polymorphisms

• Must be present in at least 1 of the population
• Most (90) of the sequence variation between two
  genomes
• Two humans differ 0.1
• 1/300 bp in the human genome
• Lower in coding regions
• 10 million in the human genome

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Categories of SNPs

• Missense/Non-synonymous
• Changes an amino acid
• About half of the SNPs in coding sequence
• Can alter function and or structure of the
  protein
• Cause of most monogenetic diseases
• Hemochromatosis (HFE)
• Cystic fibrosis (CFTR)
• Hemophilia (F8)
• Nonsense
• Introduces a stop codon
• Same consequences as non-synonymous

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Categories of SNPs

• Synonymous
• Does not alter the coding sequence
• May alter splicing
• Non-coding
• Can be located in promoter or regulatory regions
• Can impact the expression of the gene
• All SNPs can be used as markers

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Use to cell biologist

• Association studies
• Use SNPs as markers to find regions associated
  with phenotype
• Causative SNPs
• Altered protein
• Altered expression
• Regions of altered conservation between
  strains/species/individuals
• Evolutionary analyses
• Etc

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SNP discovery

• Discovery of SNPs usually from sequencing
• Discovery is based on separating sequencing
  errors from real differences and assessing the
  frequency in the sequenced population
• Separation of parologous sequences
• Validation, genotyping

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SNP discovery resources

• Polybayes
• SNP discovery in redundant sequences
• Polyphred
• SNP discovery based on phred/phrap/consed
• NovoSNP
• Graphical identification of SNPs

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Example PolyPhred

• Detects heterozygotes from chromatograms
• Runs together with phred/phrap/consed
• Command line

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SNP assessment

• Assess SNPs for functional effects
• Non-synonymous SNPs
• Conservation across species
• Amino acid properties
• Protein structure
• Transmembrane regions, signal peptides etc.

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SNP assessment resources

• SIFT
• PolyPhen
• Pmut
• SNPs3D
• PANTHER PSEC
• TopoSNP
• MAPP
• Etc

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Example SIFT

• Sorting Intolerant From Tolerant
• Builds an alignment of similar sequences
• Calculates a score based on the aa in the
  alignment
• Takes the environment into account
• Takes the properties of the aa into account
• Does not use structure

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SNP databases

• Maps of SNPs in human, mouse, etc
• Haplotype maps
• Functional SNPs
• Disease databases

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SNP databases

• dbSNP
• F-SNP
• HGVBase
• PolyDoms
• OMIN
• Etc

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Example dbSNP

• 50 million submissions
• 18 million clusters
• 7 million in genes
• 44 organisms
• 91 million SNPs submitted

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dbSNP

• Search for SNPs, location, etc
• Information submitted on method, flanking
  sequence, alleles, population, sample size,
  validation etc
• Information computed on SNPs at same location
  including functional analysis, population
  diversity etc

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SNPs in genome browsers

• Ensembl
• UCSC

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Example UCSC
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HapMap

• Aim a haplotype map of the human genome
  describing common patterns of sequence variation
• A haplotype map is based on alleles of SNPs close
  together are inherited together
• HapMap will identify which SNPs are informative
  in mapping, reducing the number of SNPs to
  genotype by a magnitude
• Populations from Asia, Europe and Africa
• 2nd generation map with over 3.1 million SNPs

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• Ng PC, Henikoff S.
• Predicting the effects of amino acid
  substitutions on protein function.
• Annu Rev Genomics Hum Genet. 2006761-80.
  Review.
• Bhatti P, Church DM, Rutter JL, Struewing JP,
  Sigurdson AJ.
• Candidate single nucleotide polymorphism
  selection using publicly available tools a guide
  for epidemiologists.
• Am J Epidemiol. 2006 Oct 15164(8)794-804. Epub
  2006 Aug 21.
• Clifford RJ, Edmonson MN, Nguyen C, Scherpbier T,
  Hu Y, Buetow KH.
• Bioinformatics tools for single nucleotide
  polymorphism discovery and analysis.
• Ann N Y Acad Sci. 2004 May1020101-9. Review.
• The International HapMap Consortium.
• A second generation human haplotype map of over
  3.1 million SNPs.
• Nature 449, 851-861. 2007.