Next Steps for Functional Genomics Proceedings of a Workshop (2020) / Chapter Skim
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6 Predicting Current and Future Sources of Variation in Quantitative Traits
6 Predicting Current and Future Sources of Variation in Quantitative Traits
Pages 75-86
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From page 75... ...
Wittkopp started by explaining the two pieces of her title. "Predicting current sources of variation in quantitative traits" refers to the ability to predict where the genetic basis of a particular variation or trait will lie within the genome -- within a certain type of gene, for instance, or inside non-coding sequences.
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From page 76... ...
In this case, existing datasets are heavily biased toward candidate genes and coding sequences, among other things, and so it is important to be cautious when synthesizing those data. DISCOVERING THE GENETIC BASIS OF A CHANGE: AN EXAMPLE Having finished her introductory remarks, Wittkopp turned to the first part of her talk in which she described an example from her own lab of looking for the genetic basis of a change in an organism.
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From page 77... ...
The distribution of pigmentation phenotypes in this back-crossed population is not continuous, Wittkopp said, but instead the phenotypes fell into about five distinct classes, suggesting that only two, three, or possibly four genes are contributing to the pigmentation patterns (Wittkopp et al., 2003)
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From page 78... ...
. At that point she also wanted to locate the nucleotide changes that cause the difference in gene expression, which presumably cause the pigmentation differences.
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From page 79... ...
"So this was obviously a little heartbreaking and depressing," she said. This points to another technical barrier, Wittkopp said -- that even if a researcher can insert transgenes into a species of interest, it matters where they land, and the exact landing site can affect the results (John et al., 2016)
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From page 80... ...
. In all three cases, she said, the number of regions that increased gene expression were approximately balanced out by those that decreased gene expression.
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From page 81... ...
This may be because creating changes in gene expression makes it possible to alter a gene's function in one part of the organism but not others, while a change in the gene's coding sequence changes that gene everywhere. Wittkopp began by discussing some of the single-gene strategies she has used to study the evolution of gene regulation, particularly her studies of enhancers.
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From page 82... ...
Some of this variation is expected to contribute to trait differences, she said, but it is likely that much of it does not. This means that a major challenge for understanding the role of regulatory variation in evolution is determining how much of the variation in gene expression is neutral and how much is not.
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From page 83... ...
"We're starting to get ways to actually survey the mutational space" and generate the empirical data necessary to gain an insight into the role of selection in gene regulation. Wittkopp explained the basic idea in this way: "If we have the mutational distribution and mutational effects for a quantitative trait and we can compare those to the effects of variants we see in natural populations, which have been subject to the same mutational processes but also selection, then we can separate the roles of neutral and non-neutral processes." If polymorphisms turn out to be a random subset of the mutational distribution, there is no need to invoke selection -- the variation that is seen may be explained by the mutation process alone.
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From page 84... ...
In her study of the effects of mutations on gene expression in yeast, Wittkopp found that mutations tended to increase expression noise, while the polymorphisms they found in the natural population did not, which indicated that selection had acted to maintain a particular degree of noise (Metzger et al., 2015)
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From page 85... ...
. "So, I don't think we should assume that all the plasticity we see is adaptive," she said, "but I think it's an open question about how much of it is or isn't." CONCLUSIONS AND NEXT STEPS Summing up her results, Wittkopp said that her work has shown that the relationship between genotype and phenotype for gene expression is not just about the average expression level, but also involves the plasticity in that expression level, the noisiness of that expression level, and various other pieces, all of which shape the variation that exists within a species.
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