Ch7. Sequence Polymorphisms

IDB Lab.Seoul National UniversityBioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Third Edition

ContentsIntroductionOverview of Evolution and Origins of PolymorphismsTypes of PolymorphismsSNP Discovery MethodsPublic Databases and BrowsersGenotypingThe International Haplotype Map ProjectSummary

Introduction 1000(bp) Polymorphism vs. Varient 1% , 1% , , , , , ,

ContentsIntroductionOverview of Evolution and Origins of PolymorphismsTypes of PolymorphismsSNP Discovery MethodsPublic Databases and BrowsersGenotypingThe International Haplotype Map ProjectSummary

Mutations: An Evolutionary ProcessDNA

Coalescent Framework to Model Mutation (coalescent theory) , , , , population subdivision

Mutations in Populations

ContentsIntroductionOverview of Evolution and Origins of PolymorphismsTypes of PolymorphismsSNP Discovery MethodsPublic Databases and BrowsersGenotypingThe International Haplotype Map ProjectSummary

Types of Polymorphisms(1/3) ()( ) SNP()SSLP()-GACCAGCAGTCAGAAATCAA--GACCAGCAGTCACAAATCAA-Allele 1Allele 2SNP-TCTGAGAGAGGC--TCTGAGAGAGAGAGGC-Allele 1Allele 2SSLP

Types of Polymorphisms(2/3) (SNP: , SSLP: ) ( ) exon intron

Types of Polymorphisms(3/3) (in silico) ,

ContentsIntroductionOverview of Evolution and Origins of PolymorphismsTypes of PolymorphismsSNP Discovery MethodsPublic Databases and BrowsersGenotypingThe International Haplotype Map ProjectSummary

Pairwise Sequence Comparison(1/2) NCBI TraceArchive , , TSC(The SNP Consortium), HapMap Consortium Shotgun BAC(Bacterial Artificial Chromosome)

Pairwise Sequence Comparison(2/2)

Deep Resequencing(1/2)PCR(Polymerase Chain Reaction) (consensus sequence) Japanese Millennium Genome Project 17 SNP 1 DIP(Deletion and Insertion Polymorphism)

Deep Resequencing(2/2)

DHPLC/SSCPDNA

How reliable and useful are the results?Reliability Double-hit analysis false positive Usefulness (: ) ,

ContentsIntroductionOverview of Evolution and Origins of PolymorphismsTypes of PolymorphismsSNP Discovery MethodsPublic Databases and BrowsersGenotypingThe International Haplotype Map ProjectSummary

dbSNP(1/7)

dbSNP(2/7)

dbSNP(3/7) , , (mRNA) () ,3

dbSNP(4/7)

dbSNP(5/7)

dbSNP(6/7)(a): (b), (c): .

dbSNP(7/7) 7.7refSNP (synonymous / nonsynonymous)3 (term, , , ) (AND, OR, NOT) FTP

Other SNP Databases(1/2)ALFRED SNP, STRP, VNTR, INDEL JSNP SNP

Other SNP Databases(2/2)HGVbase(Human Genome Variation database) SNP EMBL TSC SNP

SNP Integration in Genome Browsers(1/4)Ensembl

SNP Integration in Genome Browsers(2/4)EnsMart

SNP Integration in Genome Browsers(3/4)UCSC

SNP Integration in Genome Browsers(4/4)NCBI LocusLink

ContentsIntroductionOverview of Evolution and Origins of PolymorphismsTypes of PolymorphismsSNP Discovery MethodsPublic Databases and BrowsersGenotypingThe International Haplotype Map ProjectSummary

Genotyping

ContentsIntroductionOverview of Evolution and Origins of PolymorphismsTypes of PolymorphismsSNP Discovery MethodsPublic Databases and BrowsersGenotypingThe International Haplotype Map ProjectSummary

The International Haplotype Map Project(1/4) SNP haplotypeHapMap(Haplotype Map) DNA haplotype block 3~4 tag SNP

The International Haplotype Map Project(2/4)

The International Haplotype Map Project(3/4)

The International Haplotype Map Project(4/4)

ContentsIntroductionOverview of Evolution and Origins of PolymorphismsTypes of PolymorphismsSNP Discovery MethodsPublic Databases and BrowsersGenotypingThe International Haplotype Map ProjectSummary

Summary (, ) , (haplotype)

Glossary(1/2)Leading strand / lagging strand, Antisense / sense

Glossary(2/2)Single letter, triple letter, and genetic codes

James C. Mullkin NIH National Human Genome Research Institute Genome Technology Branch Associate Investigator. NHGRI Sanger Instituted Stephen T. Sherry NIH National Library of Medicine(NLM) NCBI Staff Scientist, dbSNP DNA . 9.11 2003 Library's Board of Regents Award for Scholarship or Technical Achievement . (physical mapping): ( ) (genetic mapping): ( )(gene): DNA( RNA) . (exon), (intron) . (allele): , . (coalescent theory): . : . ., . , GCC GCA .population subdivision: (, ) , population subdivision . : SNP( ): bp SNP . SNP G,A,C,T/U SNP SSLP (VNTR, minisatellite) (STR, microsatellite) ()VNTR(minisatellite): (~25bp) STR(microsatellite): (2~4bp) in vivo: in vitro: in silico: wild type: a gene, cell or organism that displays the typical phenotype and/or genotype for the species and is therefore adopted as a standardcall: Phred: (base-calling) , (trace; ) 1~40 Phred . ( ) = 1 / 10^(Phred /10). Phred 20 . 642 Guanine( ) Guanine Thymine( ) G-G G-T .Phred score : a score based on the probability that it is real. The score is generally a number between 1 and 40, where the number represents the power to 10. Phred score 20 0.01(10-2) . (p=1/100.1s)PCR(Polymerase Chain Reaction): DNA allele SNP minor allele . k=2 k>1000 , rare allele .(ascertainment bias)double-hit analysis: shotgun , SNP SNP . , (R r ) R/r .false positive: SNP SNP (; ssSNP) (; refSNP) . . 1998~2003 () STR(), DIP(), SNP( ) . , ss#: (submitted SNP) IDHandle: rs#: (refSNP), IDAllele: Assay: (Method), (Ascertainment Samplesize; SNPASSAY SAMPLE SIZE), (SNPPOPUSE SAMPLE SIZE) Variation: Validation: (Validation Status) FASTA sequence: SNP . 5-ACATG[G/A]GTAAT-3Submitted Frequency: (Population ID, Class) , ( ). synonymous substitution , nonsynonymous substitution . , nonsynonymous substitution nonsynonymous variation , synonymous substitution synonymous variation . : alternative splicing( ), dense packing( ) Table 7.1 Figure 7.8haplotype(): haploid genotype . (statistically associated) SNP , .Leading strand: DNA 3 . Lagging strand: DNA 5 . . Antisense(template) direction: mRNA (35)Sense direction: mRNA (53, antisense ) International Union of Pure and Applied Chemistry(IUPAC)