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What is a QTL?

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

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What is a QTL?

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  1. What is a QTL? What are QTL?

  2. 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

  3. Statistical Genetics/Genomics • Understanding variability... • what causes it? • can we account for it? • Making predictions where there is uncertainty... • Drawing conclusions from incomplete information...

  4. quantitative trait mapping (QTL) QTL expression microarray protein microarray RW Doerge; Nature Reviews Genetics.2002. 3:43-52

  5. Metabolism under phenotype • Keurentjes, J.J.B. et al. Nat. Genet.38, 842–849 (2006). | Article |

  6. Clusters of metabolite level traits are controlled by pleiotropic QTL

  7. …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

  8. 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

  9. Major Quantitative Trait Locus Doebley & Stec (1991) Genetics

  10. 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 THALIANA Maarten Koornneef,1 Carlos Alonso-Blanco,2 and Dick Vreugdenhil3 QTL mapping of many traits in the same RILs

  11. Cloned QTL in Arabidopsis

  12. Experimental Populations for QTL Study Backcross 1 Backcross 2 RW Doerge; Nature Reviews Genetics.2002. 3:43-52

  13. Estimated Genetic Map(framework for QTL mapping) Chromosome 11 mouse RW Doerge; Nature Reviews Genetics.2002. 3:43-52; Butterfield et al., 1999; Journal of Immunology

  14. 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

  15. using a simple t-test • split individuals into marker classes • calculate • sample means and variances on Y • test for differences in means

  16. …diamonds are the single markers RW Doerge. Nature Reviews Genetics.2002. 3:43-52

  17. …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

  18. Locate QTL by stepping through the interval defined by M and N M N Q Q r

  19. With arrays markers are no longer limiting • >10k SFPs

  20. Composite Interval MappingMultiple QTL Mapping (MQM) interval mapping cofactors • Y=x*b* + XB +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 Zeng 1993, 1994; Jansen 1993; Genetics

  21. QTL mapping methodology interval mapping permutation threshold composite interval mapping single marker Fisher 1935; Thoday 1961; Lander and Botstein 1989; Zeng 1994; Churchill & Doerge 1994

  22. 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

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