Quantitative traits important to organismal function and fitness, such as brain size, are presumably controlled by many small-effect loci. Deciphering the genetic architecture of such traits with traditional quantitative trait locus (QTL) mapping methods is challenging. Here, we investigated the genetic architecture of brain size (and the size of five different brain regions) in nine-spined sticklebacks (Pungitius pungitius) with the aid of novel multi-locus QTL mapping approaches based on a de-biased LASSO method. Single-locus analyses of an F2-interpopulation cross with 15 198 fully informative single locus polymorphisms (SNPs) uncovered 79 QTL associated with variation in stickleback brain size traits. Many of these loci were in strong linkage disequilibrium (LD) with each other, and consequently, a multi-locus mapping of individual SNPs, accounting for LD structure in the data, recovered very few significant QTL. However, a multi-locus mapping of SNPs grouped by linkage group (LG) identified 14 LGs (1-6 depending on the trait) that influence variation in brain size traits. For instance, 17.6% of the variation in relative brain size was explainable by cumulative effects of SNPs distributed over six LGs, whereas 42% of the variation was accounted for by all 21 LGs. Hence, the results suggest that variation in stickleback brain traits is influenced by many loci, each with relatively small phenotypic effects. Apart from suggesting multifactorial genetic architecture of brain traits, the results highlight the difficulties in identifying the identities of the individual loci contributing to variation in quantitative traits. Nevertheless, the results demonstrate that the novel multi-QTL mapping approaches developed here can have distinctive advantages over the traditional QTL mapping methods in analyses of dense marker panels.
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