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What is a QTL? What are QTL?. Current methods for QTL Single Marker Methods ( Student, 17?? ) ...
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Transcript of What is a QTL? What are QTL?. Current methods for QTL Single Marker Methods ( Student, 17?? ) ...
What is a QTL?What are QTL?
Current methods for QTL Single Marker Methods (Student, 17??)
t-tests
Interval Mapping Method (Lander and Botstein, Genetics 1989)
Mapping: estimate genetic maps Locating QTL: based on genetic map
Composite Interval Mapping (Jansen 1993; Zeng 1993, 1994; Genetics)
Locating QTL: based on genetic map
Understanding variability... what causes it? can we account for it?
Making predictions where there is uncertainty...
Drawing conclusions from incomplete information...
Statistical Genetics/Genomics
microarray
QTL
protein
microarray
quantitative
expression
trait mapping (QTL)
RW Doerge; Nature Reviews Genetics.2002. 3:43-52
Metabolism under phenotype
• Keurentjes, J.J.B. et al. Nat. Genet. 38, 842–849 (2006). | Article |
• Clusters of metabolite level traits are controlled by pleiotropic QTL
…the big picture
There are “genes” or “regions’’ of DNA associated with traits, diseases, resistances of interest.
yield in corn oil content in soybean sugars of tomato multiple sclerosis in human
Statistical Genetics aims to understand these genomic regions
Quantitative Trait Loci (QTL): genomic regions associated with a quantitative trait of interest.
Complex traits: are controlled by many QTL, often behaving differently in changing environments and under different conditions.
…example
Major Quantitative Trait Locus
Doebley & Stec (1991) Genetics
QTL mapping of many traits in the same RILs
Annual Review of Plant BiologyVol. 55: 141-172 (Volume publication date June 2004)
(doi:10.1146/annurev.arplant.55.031903.141605)
First published online as a Review in Advance on December 12, 2003 NATURALLY OCCURRING GENETIC VARIATION IN
ARABIDOPSIS THALIANAMaarten Koornneef,1 Carlos Alonso-Blanco,2 and Dick
Vreugdenhil3
Cloned QTL in ArabidopsisLocus Trait Molecular function
Functional polymorphism
Functional alteration References
CAL Inflorescence morphology MADS TF SNP Altered protein (66)
FRI Flowering Unknown INDELs (1-345 bp) Truncated protein
(43, 58, 79)
FLC Flowering MADS TF INDELs (1.2 to 4.2 kb)
Expression level
(43, 109)
EDI Flowering CRY2 photoreceptor SNP AA substitution (37)
PHYA Hypocotyl length PHYA photoreceptor SNP AA substitution (99)
PHYD Flowering/hypocotyl length
PHYD photoreceptor INDEL (14 bp) Truncated protein
(12)
AOP2 Glucosinolate biosynthesis
2-oxoglutarate-dioxygenase
INDEL (5 bp) Expression level
(71)
AOP3 Glucosinolate biosynthesis
2-oxoglutarate-dioxygenase
Unknown Expression level
(71)
ESP Glucosinolate hydrolysis Epithiospecifier protein
INDELs, SNP Expression level
(87)
MAM1 Glucosinolate biosynthesis
Methylthioalkylmalate synthase
INDELs, (several kb)
Deleted gene (80)
MAM2 Glucosinolates/insect resistance
Methylthioalkylmalate synthase
INDELs, (several kb)
Deleted gene (80)
RTM1 Virus resistance Jacalin-like protein SNP Truncated protein
(30)
RPS2 Resistance to pseudomonas
LRR protein INDEL (10 bp), SNP Truncated protein
(111)
RPM1 Resistance to pseudomonas
LRR protein INDEL (2.8 kb) Deleted gene (150)
Experimental Populations for QTL Study
Backcross 1 Backcross 2
RW Doerge; Nature Reviews Genetics.2002. 3:43-52
Estimated Genetic Map(framework for QTL mapping)
Chromosome 11 mouseRW Doerge; Nature Reviews Genetics.2002. 3:43-52; Butterfield et al., 1999; Journal of Immunology
Single Marker Analysis
Using a recombinant inbred (RI) or backcross population there are two possible alleles at each marker and, two genotypic classes per marker
RI: M1/M1 and M2/M2 Backcross: M1/M1 and M1/M2
Each individual: genotypic and phenotypic data
consider: marker M and trait Y every marker has 2 states:
homozygous 1: M1/M1 heterozygous 2: M1/M2
using a simple t-test
split individuals into marker classes calculate
sample means and variances on Y
test for differences in means
…diamonds are the single markers
RW Doerge. Nature Reviews Genetics.2002. 3:43-52
…take advantage of marker order Interval Mapping
Marker M: alleles M1 and M2
Marker N: alleles N1 and N2
Distance between M and R defined by recombination r the values of r is estimated and known M-------r--------N
Use the additional information from knowing ‘r’ to locate QTL
Lander and Bostein. 1989. Genetics
M NQ Q
r
Locate QTL by stepping through the interval defined by M and N
1r 2r1r 2r
• With arrays markers are no longer limiting
• >10k SFPs
Composite Interval MappingMultiple QTL Mapping (MQM)
• Y=x*b* + X B +E
• Y is a quantitative trait (gene expression) vector, i=1,…,n• b* effects of the putative QTL being tested • x* is an indicator variable specifying the probability of an
individual being in the different genotypic classes for the supposed QTL, depending on the flanking markers which define the interval.
• B is the vector of effects of selected markers fitted in the model
• X is the design matrix for the selected markers
• E is the error vector
cofactors
Zeng 1993, 1994; Jansen 1993; Genetics
interval mapping
QTL mapping methodology
Churchill & Doerge 1994
interval mapping
composite interval mapping
permutation threshold
single marker
Fisher 1935; Thoday 1961; Lander and Botstein 1989; Zeng 1994;
Overall Summary QTL methodology
Detect and locate QTL
Locating QTL depends on genetic map Many statistical and genetic issues
Permutation thresholds are specific to experiment
eQTL utilize expression data as quantitative traits to map expression variation molecular dissection of complex traits