|Lai, Chao Qiang|
Submitted to: Nature Methods
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/2/2007
Publication Date: 10/1/2007
Citation: Lai, C., Leips, J., Zou, W., Roberts, J.F., Wollenberg, K.R., Parnell, L.D., Zeng, Z., Ordovas, J.M., Mckay, T.F. 2007. Speed-Mapping Quantitative Trait Loci Using Microarrays. Nature Methods. 4(10):839-841. Interpretive Summary: Determining the genetic architecture of complex traits is important for human health, agriculture, and understanding how certain populations have adapted to their local environment. At the same time, this is challenging because high-resolution mapping of traits, known as QTLs or quantitative trait loci, requires evaluation of thousands of progeny and the genetic relationship of the trait of interest to numerous closely spaced polymorphic (ability to exist in different forms) molecular markers. In this report we described a new method for rapid, high-resolution QTL mapping using gene chips, designed to measure gene expression, for selective evaluation of pooled DNA samples from large populations. This evaluation called genotyping yields data on small genetic differences between two tested populations. We have applied this method to swiftly map QTLs for lifespan in the fruity Drosophila melanogaster. Modification of previous gene chip-based genotyping methods allowed identification of 2326 robust genetic differences between two inbred Drosophila strains with known QTLs affecting longevity. Sequencing a sample of the identified points of genetic difference confirmed their occurence and that each contains at least one single nucleotide polymorphism. This method made possible by a number of technological and statistical enhancements, allows simultaneous detection of thousands of genetic markers which exhibit different values between DNA samples pooled from two different sources. To map genetic elements pertinent to lifespan, we generated 21,207 second generation males and females, and for each sex analyzed DNA pools of young and long-lived flies. We identified six lifespan QTLs reported prevously and 12 additional new QTLs. This method of employing gene chips to rapidly map genetic differences is widely applicable to numerous organisms with available gene chips including humans.
Technical Abstract: Determining the genetic architecture of complex traits is important for human health, agriculture, and understanding adaptive evolution, but is challenging because high resolution quantitative trait locus (QTL) mapping requires evaluation of thousands of recombinant individuals for the trait and closely spaced polymorphic molecular markers. Here, we report a new method for rapid, high resolution QTL mapping using expression microarrays for selective genotyping of pooled DNA samples from a large mapping population, and its application to mapping QTLs for Drosophila lifespan. We modified previous microarray genotyping methods and identified 2326 single feature polymorphisms (SFPs) between two inbred Drosphila strains with known QTLs affecting longevity. We generated 21,207 F2 males and females, and for each sex hybridized DNA pools of young and long-lived flies to each of the three microarrays. We identified six QTLs reported previously, and 12 addtional QTLs. This approach was applicable to organisms with available whole genome expression or gentoyping arrays.