| Summary: | Abstract Recent work has provided strong empirical support for the classic polygenic model for trait variation. Population‐based findings suggest that most regions of genome harbor variation affecting most traits. Here, we use the approach of experimental genetics to show that, indeed, most genomic regions carry variants with detectable effects on growth and reproduction in Caenorhabditis elegans populations sensitized by nickel stress. Nine of 15 adjacent intervals on the X chromosome, each encompassing ∼0.001 of the genome, have significant effects when tested individually in near‐isogenic lines (NILs). These intervals have effects that are similar in magnitude to those of genome‐wide significant loci that we mapped in a panel of recombinant inbred advanced intercross lines (RIAILs). If NIL‐like effects were randomly distributed across the genome, the RIAILs would exhibit phenotypic variance that far exceeds the observed variance. However, the NIL intervals are arranged in a pattern that significantly reduces phenotypic variance relative to a random arrangement; adjacent intervals antagonize one another, cancelling each other's effects. Contrary to the expectation of small additive effects, our findings point to large‐effect variants whose effects are masked by epistasis or linkage disequilibrium between alleles of opposing effect.
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