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Computational Molecular BiologyBiochem 218 BioMedical Informatics 231

http://biochem218.stanford.edu/

Simple Nucleotide Polymorphisms (SNPs)

Doug Brutlag

Professor Emeritus

Biochemistry & Medicine (by courtesy)
http://biochem218.stanford.edu/http://creativecommons.org/licenses/by/3.0/http://biochem218.stanford.edu/

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Frequency of SNPs in the Human Genome

mutations

Simple
http://creativecommons.org/licenses/by/3.0/

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SNPs & InDels in HuRef Autosomes
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17803354http://creativecommons.org/licenses/by/3.0/http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17803354

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2007 Scientific Breakthrough of the Year

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Single (Simple) NucleotidePolymorphisms (SNPs)

SNPs are used for identification and forensics SNPs are used for mapping and genome-wide association

studies of complex diseases SNPs are used for estimating predisposition to disease SNPs are used for immigration & citizenship in the UK

SNPs are used to predict specific genetic traits SNPs are used for classifying patients in clinical trials

GCTGTATGACTAGAAGATCGAT

GCTGTATGACGAGAAGATCGAT
http://creativecommons.org/licenses/by/3.0/http://www.cellmark.co.uk/

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Orchid Cellmark Ltd.http://www.cellmark.co.uk/
http://www.cellmark.co.uk/http://www.cellmark.co.uk/http://creativecommons.org/licenses/by/3.0/http://www.cellmark.co.uk/

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A SNP Primer at NCBIhttp://www.ncbi.nlm.nih.gov/About/primer/snps.html
http://www.ncbi.nlm.nih.gov/About/primer/snps.htmlhttp://creativecommons.org/licenses/by/3.0/http://www.ncbi.nlm.nih.gov/About/primer/snps.html

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Department of Energy (DOE) SNP Pagehttp://www.ornl.gov/sci/techresources/Human_Genome/faq/snps.shtml
http://www.ornl.gov/sci/techresources/Human_Genome/faq/snps.shtmlhttp://creativecommons.org/licenses/by/3.0/http://www.ornl.gov/sci/techresources/Human_Genome/faq/snps.shtml

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Simple Nucleotide Polymorphisms (SNPs)

Most SNPs are genetically neutralo Forensicso Paternity testso Immigration in the United Kingdomo Follow ethnic migrationso Clinical trials

However SNPs can reflect distinguishing characteristicso Predisposition to diseaseo Insurability and employment => GINA, December 7, 2009o Often the basis for discrimination or other stigma

Some variations cause disease. Unlike SNPs, these variations

are usually very rare. SNPs can serve as genetic markers for other traitso Clinical trials associate SNPs with drug efficacyo Clinical trials associate SNPs adverse drug reactionso Consumer genomics associate SNPs with many other traits

23andMe, Navigenics, DNADirect
https://www.23andme.com/http://www.navigenics.com/http://www.dnadirect.com/http://creativecommons.org/licenses/by/3.0/http://www.dnadirect.com/http://www.navigenics.com/https://www.23andme.com/http://www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=GeneTests

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Carrier Frequency of Cystic Fibrosis Alleleshttp://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cf
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cfhttp://www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=GeneTestshttp://creativecommons.org/licenses/by/3.0/http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cfhttp://www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=GeneTests

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Carrier Frequency of Gauchers Alleleshttp://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gaucher
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gaucherhttp://www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=GeneTestshttp://creativecommons.org/licenses/by/3.0/http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gaucher

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Eric Greens View of SNPs(Director of NHGRI)

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Eric Greens View of SNPs(Director of NHGRI)

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Types of SNPshttp://www.ncbi.nlm.nih.gov/sites/entrez?db=snp

Noncoding SNPso 5 UTRo 3 UTR

o Introns

o Intergenic Regions

o Pseudogenes

o Regulatory Splicing

Transcriptional regulation (promoter & TF binding sites)

Translational regulation (initiation or termination)

Regulatory miRNA target sites

Coding SNPso Synonymous SNPs (third position variation)

o Replacement SNPs (change Amino acid)

Functional SNPs (acceptable amino acid replacement)

Non-functional SNPs (traits & diseases)
http://www.ncbi.nlm.nih.gov/sites/entrez?db=snphttp://creativecommons.org/licenses/by/3.0/http://www.ncbi.nlm.nih.gov/sites/entrez?db=snp

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Human Promoter SNPs

Gibson & Muse, A Primer of Genome Science
http://creativecommons.org/licenses/by/3.0/http://creativecommons.org/licenses/by/3.0/

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Human Beta Hemoglobin Genehttp://www.ncbi.nlm.nih.gov/gene/3043?ordinalpos=3&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum

H B t H l bi G SNP
http://www.ncbi.nlm.nih.gov/gene/3043?ordinalpos=3&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/3043?ordinalpos=3&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://creativecommons.org/licenses/by/3.0/http://www.ncbi.nlm.nih.gov/gene/3043?ordinalpos=3&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/3043?ordinalpos=3&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=snp&DbFrom=gene&Cmd=Link&LinkName=gene_snp&LinkReadableName=SNP&IdsFromResult=3043&ordinalpos=NaN&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVFullReport.GeneRightColMenuLinksP%27http://www.ncbi.nlm.nih.gov/sites/entrez?Db=snp&DbFrom=gene&Cmd=Link&LinkName=gene_snp&LinkReadableName=SNP&IdsFromResult=3043&ordinalpos=NaN&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVFullReport.GeneRightColMenuLinksP%27

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Human Beta Hemoglobin Gene SNPs
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=snp&DbFrom=gene&Cmd=Link&LinkName=gene_snp&LinkReadableName=SNP&IdsFromResult=3043&ordinalpos=NaN&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVFullReport.GeneRightColMenuLinksP%27http://creativecommons.org/licenses/by/3.0/http://www.ncbi.nlm.nih.gov/sites/entrez?Db=snp&DbFrom=gene&Cmd=Link&LinkName=gene_snp&LinkReadableName=SNP&IdsFromResult=3043&ordinalpos=NaN&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVFullReport.GeneRightColMenuLinksP%27http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=3043&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVFullReport.GeneRightColMenuLinksP&ordinalpos=NaN%27

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Beta-hemoglobin GeneView in dbSNP
http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=3043&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVFullReport.GeneRightColMenuLinksP&ordinalpos=NaN%27http://creativecommons.org/licenses/by/3.0/http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=3043&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVFullReport.GeneRightColMenuLinksP&ordinalpos=NaN%27

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One -Hemoglobin SNP

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GeneView of One
http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=36092904http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=36092904http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=36092904http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=36092904http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=36092904http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=36092904http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=36092904http://creativecommons.org/licenses/by/3.0/http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=36092904http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=36092904http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=36092904

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Diversity of One -Hemoglobin SNP

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SNP Variation Viewer

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OMIM SNP Variations

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dbSNP at NCBIhttp://www.ncbi.nlm.nih.gov/SNP/
http://www.ncbi.nlm.nih.gov/SNP/http://creativecommons.org/licenses/by/3.0/http://www.ncbi.nlm.nih.gov/SNP/

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Origin of Haplotypes


Li k Di ilib i d

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Linkage Disequilibrium andRecombination Rate


L k D l b (LD) A h

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Linkage Disequilibrium (LD) Across theHuman LPL Gene


b h d d

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Recombination hotspots are widespreadand account for LD structure

7q21 Gibson & Muse, A Primer of Genome Science

R bi i h id d

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Recombination hotspots are widespreadand account for LD structure

7q21 Gibson & Muse, A Primer of Genome Science

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Observation of Haplotypes


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SNPs in Populations


S d Di t B d

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Sequence and Distance-BasedPhylogenies (evolutionary trees)

Sequence-Based Methods (Parsimony)

o Assigns mutations to brancheso Minimize number of changeso Topology maximizes similarity of

neighboring leaves

Distance-based methodso Branch lengths = D(i,j)/2 for

sequences i, jo Distances must be metrico Distances can reflect time or

number of changeso Distances must be relatively

constant per unit branch length

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Francis Collins, 2008

I t ti l H M P j t
http://creativecommons.org/licenses/by/3.0/http://creativecommons.org/licenses/by/3.0/http://hapmap.ncbi.nlm.nih.gov/

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International HapMap Projecthttp://www.hapmap.org/

I t ti l H M P j t
http://www.hapmap.org/http://hapmap.ncbi.nlm.nih.gov/http://creativecommons.org/licenses/by/3.0/http://www.hapmap.org/http://hapmap.ncbi.nlm.nih.gov/

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I t ti l H M P j t

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I t ti l H M P j t

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I t ti l H M P j t

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Thousand Genomes Organization
http://www.hapmap.org/http://hapmap.ncbi.nlm.nih.gov/http://creativecommons.org/licenses/by/3.0/http://www.hapmap.org/

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Thousand Genomes Organizationhttp://www.1000genomes.org/

Thousand Genomes Organization
http://www.1000genomes.org/http://creativecommons.org/licenses/by/3.0/http://www.1000genomes.org/

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Thousand Genomes Organizationhttp://www.1000genomes.org/

10 000 G s P j ct E l ti Bi l g
http://www.1000genomes.org/http://creativecommons.org/licenses/by/3.0/http://www.1000genomes.org/

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10,000 Genomes Project Evolutionary Biologyhttp://www.genome.gov/
http://www.genome.gov/http://www.genome.gov/

16snps

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