title: Sensitivity of quantitative traits to mutational effects and number of loci.
abstract: When models of quantitative genetic variation are built from population genetic first principles, several assumptions are often made. One of the most important assumptions is that traits are controlled by many genes of small effect. This leads to a prediction of a Gaussian trait distribution in the population, via the Central Limit Theorem. Since these biological assumptions are often unknown or untrue, we characterized how finite numbers of loci or large mutational effects can impact the sampling distribution of a quantitative trait. To do so, we developed a neutral coalescent-based framework, allowing us to gain a detailed understanding of how number of loci and the underlying mutational model impacts the distribution of a quantitative trait. Through both analytical theory and simulation we found the normality assumption was highly sensitive to the details of the mutational process, with the greatest discrepancies arising when the number of loci was small or the mutational kernel was heavy-tailed. In particular, skewed mutational effects will produce skewed trait distributions and fat-tailed mutational kernels result in multimodal sampling distributions, even for traits controlled by a large number of loci. Since selection models and robust neutral models may produce qualitatively similar sampling distributions, we advise extra caution should be taken when interpreting model-based results for poorly understood systems of quantitative traits.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, United States. Electronic address: schraib@uw.edu.
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Schraiber
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, CA 94720, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Landis
mesh_terms: D014644:Genetic Variation / Q000235:genetics*; D005828:Genetics, Population; D006801:Humans; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*
keywords: Characteristic function; Coalescent theory; Neutral theory; Quantitative genetics
references.citation: Genet Res. 1999 Dec;74(3):215-21
references.pmid: 10689799
references.citation: Bioinformatics. 2002 Feb;18(2):337-8
references.pmid: 11847089
references.citation: Genetics. 1992 Feb;130(2):315-32
references.pmid: 1311697
references.citation: Evolution. 2005 Jan;59(1):126-37
references.pmid: 15792233
references.citation: Genetics. 2005 Jun;170(2):929-39
references.pmid: 15834146
references.citation: Science. 2005 Sep 16;309(5742):1850-4
references.pmid: 16141373
references.citation: Evolution. 2006 Aug;60(8):1537-50
references.pmid: 17017055
references.citation: Proc Biol Sci. 2007 Feb 7;274(1608):347-57
references.pmid: 17164198
references.citation: Am Nat. 2007 Feb;169(2):227-44
references.pmid: 17211806
references.citation: Genetics. 2008 Nov;180(3):1379-89
references.pmid: 18791252
references.citation: Genetics. 2011 Oct;189(2):621-32
references.pmid: 21840853
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):15908-13
references.pmid: 21873251
references.citation: Nature. 2012 Feb 05;482(7385):390-4
references.pmid: 22307276
references.citation: PLoS Genet. 2012 Feb;8(2):e1002497
references.pmid: 22346762
references.citation: Syst Biol. 2013 Mar;62(2):193-204
references.pmid: 23034385
references.citation: Nature. 2013 Sep 26;501(7468):506-11
references.pmid: 24037378
references.citation: PLoS Genet. 2014 Aug 07;10(8):e1004412
references.pmid: 25102153
references.citation: Evolution. 1986 Sep;40(5):915-935
references.pmid: 28556213
references.citation: Evolution. 1976 Jun;30(2):314-334
references.pmid: 28563044
references.citation: Proc Natl Acad Sci U S A. 1965 Sep;54(3):731-6
references.pmid: 5217452
references.citation: Genetics. 1970 Sep;66(1):165-86
references.pmid: 5512470
references.citation: Genetics. 1994 Nov;138(3):901-12
references.pmid: 7851784