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Jan, 2003 YMGC Genotyping Core
Searching Microsatellite Markers for Mapping a
Disease Gene
林明薇 Ming-Wei Lin, PhD
陽明大學醫學系家庭醫學科台北榮民總醫院教學研究部
Jan, 2003 YMGC Genotyping Core
Genetic Markers•Protein marker
blood group, HLA tissue types…etc..
•DNA markerRFLPs (restriction fragment length
polymorphisms)Minisatellites (VNTR - variable
number tandem repeats)Microsatellites (STR - short tandem
repeats)SNPs (single nucleotide
polymorphisms)
Jan, 2003 YMGC Genotyping Core
Jan, 2003 YMGC Genotyping Core
Polymorphic Markers• Heterozygosity
H= 1- (p12 + p2
2 + p32 + …)
• Polymorphism information content (PIC)
PIC = 1- pi2 - 2pi2pj2
Jan, 2003 YMGC Genotyping Core
Jan, 2003 YMGC Genotyping Core
Microsatellite Markers
•Types:di- (CA)n,tri- (CAG)n,tetra- (GATA)n nucleotide repeats.
•Evenly distributed through genome.
Jan, 2003 YMGC Genotyping Core
Microsatellite Markers
CA CA CA
Primer 1
Primer 2
CA CA CA CA
CA CA CA CA CA
CA CA CA CA CA CA
Jan, 2003 YMGC Genotyping Core
Genotyping Results
Child 1
Child 2
Child 3
Father
Mother
Child 1
Child 2
Child 3
Father
Mother
D13S121- dinucleotide
D13S770 - trinucleotide
Jan, 2003 YMGC Genotyping Core
Applications•Linkage mapping and association study (linkage disequilibrium)
•Loss of heterozygosity•Microsatellite instability•Forensic application•Paternity identification
Jan, 2003 YMGC Genotyping Core
Collins FS. (1992) Nature genetics 1:3-6
Jan, 2003 YMGC Genotyping Core
Collins FS. (1992) Nature genetics 1:3-6
Jan, 2003 YMGC Genotyping Core
Linkage Mapping for Disease Genes
•Linkage analysis (Lod score method)•Allele-sharing methods
Jan, 2003 YMGC Genotyping Core
Linkage Analysis Family
Jan, 2003 YMGC Genotyping Core
IBD = 2 IBD = 1 IBD = 0
AC AB
BC BC
AC BC
AC AB
AB CD
AD BC
Allele-Sharing Method
Jan, 2003 YMGC Genotyping Core
Loss of Heterozygosity
Loss of one allele at a heterozygous locus in
a tumour cell, resulting in a homozygous genotype.
Jan, 2003 YMGC Genotyping Core
Jan, 2003 YMGC Genotyping Core
Microsatellite Instability
•Microsatellite instability is numerous or aberrant allele at a microsatellite locus.
•Many tumours show
microsatellite instability.
Jan, 2003 YMGC Genotyping Core
Jan, 2003 YMGC Genotyping Core
Microsatellite Marker Databases
• GDB: http://www.gdb.org• Marshfield:
http://research.marshfieldclinic.org/genetics/
• CHLC (Cooperative Human Linkage Center): http:/www.chlc.org
• Genethon: http://www.genethon.fr/genethon_en.html
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
GDB
Jan, 2003 YMGC Genotyping Core
Marshfield
Jan, 2003 YMGC Genotyping Core
Marshfield
Jan, 2003 YMGC Genotyping Core
Marshfield
Jan, 2003 YMGC Genotyping Core
Marshfield
Jan, 2003 YMGC Genotyping Core
Marshfield
Jan, 2003 YMGC Genotyping Core
Marshfield
Jan, 2003 YMGC Genotyping Core
Marshfield
Jan, 2003 YMGC Genotyping Core
Marshfield
Jan, 2003 YMGC Genotyping Core
Marshfield
Jan, 2003 YMGC Genotyping Core
CHLC
Jan, 2003 YMGC Genotyping Core
CHLC
Jan, 2003 YMGC Genotyping Core
CHLC
Jan, 2003 YMGC Genotyping Core
CHLC
Jan, 2003 YMGC Genotyping Core
CHLC
Jan, 2003 YMGC Genotyping Core
CHLC
Jan, 2003 YMGC Genotyping Core
Genethon
Jan, 2003 YMGC Genotyping Core
Microsatellite Marker Databases
• NCBI: http://www.ncbi.nlm.nih.gov/
• CEPH (Centre d’Etude du Polymorphisme Humain): http://www.cephb.fr
• Utah: http://www.genetics.utah.edu/home.html
Jan, 2003 YMGC Genotyping Core
NCBI
Jan, 2003 YMGC Genotyping Core
NCBI
Jan, 2003 YMGC Genotyping Core
CEPH
Jan, 2003 YMGC Genotyping Core
CEPH
Jan, 2003 YMGC Genotyping Core
CEPH
Jan, 2003 YMGC Genotyping Core
Standardized Genotype Data
• CEPH 1331-01
• CEPH 1331-02
• CEPH 1347-02
Jan, 2003 YMGC Genotyping Core
ABI PRISM Linkage Mapping Set
• http://home.appliedbiosystems.com/
Jan, 2003 YMGC Genotyping Core
ABI PRISM Linkage Mapping Set
Jan, 2003 YMGC Genotyping Core
ABI PRISM Linkage Mapping Set
Jan, 2003 YMGC Genotyping Core
ABI PRISM Linkage Mapping Set
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