1 / 8

How do you go from QTL to gene?

x. How do you go from QTL to gene?. Fine mapping Progeny testing Collaborative cross Heterogeneous stocks Other outbred populations. From www.complextrait.org/Powerpoint/ ctc2004/karl_broman.ppt. How do you go from QTL to gene?. Fine mapping Limited resolution?

benson
Download Presentation

How do you go from QTL to gene?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. x How do you go from QTL to gene? Fine mapping • Progeny testing • Collaborative cross • Heterogeneous stocks • Other outbred populations From www.complextrait.org/Powerpoint/ ctc2004/karl_broman.ppt

  2. How do you go from QTL to gene? Fine mapping • Limited resolution? • Incomplete annotation of genes in region • Regulatory sequence within region (separate from genes)

  3. How do you prove a gene is responsible for the effect of a QTL? “The nature and identification of quantitative trait loci: a community’s view” by Members of the Complex Trait Consortium. Nature Reviews Genetics (2003) 4: 911-916. Standards will vary between taxa?

  4. How do you prove a gene is responsible for the effect of a QTL? Most conclusive: allele replacement by knock-in Or knock-outs, rescued by alternate alleles?

  5. How do you prove a gene is responsible for the effect of a QTL? Circumstantial evidence • Polymorphisms in coding or regulatory regions • Gene function • Expression differences • Homology • Knock-out studies • Mutational analysis • In vitro functional studies • Transgenesis with bacterial artificial chromosomes (BAC) • Quantitative complementation test

  6. heterozygous for gene X knock out heterozygous for QTL segment Complementation test

  7. If gene X is the gene responsible for the effect of the QTL, the genotypes at the QTG will be > will be greater than If gene X is not the gene responsible for the effect of the QTL, the genotypes at the QTG will be = will be equal to The phenotypic difference between these two genotypes the phenotypic difference between these two genotypes The phenotypic difference between these two genotypes the phenotypic difference between these two genotypes. white / KO white / white dark / white dark / KO white / white white / white dark / white dark / white Complementation test Assumptions!

  8. Example of gene identification (?): Klein et al. 2004; Science 303: 229-232 • Mapped QTL affecting BMD in mice to a 31 MB region. • Analysed gene expression by microarray. • Only one gene within region was differentially expressed. • Confirmed with RT PCR. • Gene was in a pathway known to inhibit bone formation. • Expression of bone formation markers was altered in cell cultures from the two genotypes. • Overexpression of the gene in cell culture affected markers of bone formation. • Phenotype of knock-out mouse was consistent with difference in expression between QTL genotypes (high expression -> low BMD). • Pharmacological inhibitors of the gene’s product affected BMD in a manner consistent with the QTL genotypes/ knock-outs (improved BMD in rodent models of osteoporosis).

More Related