Signs of Selective Pressure on Genetic Variants Affecting Human Height Roberto Amato1,2,3*, Gennaro Miele1,2,3, Antonella Monticelli4, Sergio Cocozza1,5 1 Gruppo Interdipartimentale di Bioinformatica e Biologia Computazionale, Universita` di Napoli ‘‘Federico II’’ - Universita` di Salerno, Naples, Italy, 2 Dipartimento di Scienze Fisiche, Universita` degli Studi di Napoli ‘‘Federico II’’, Naples, Italy, 3 Istituto Nazionale di Fisica Nucleare – Sezione di Napoli, Naples, Italy, 4 Istituto di Endocrinologia ed Oncologia Sperimentale, CNR Napoli, Naples, Italy, 5 Dipartimento di Biologia e Patologia Cellulare e Molecolare ‘‘L. Califano’’, Universita` degli Studi di Napoli ‘‘Federico II’’, Naples, Italy Abstract Many decades of scientific investigation have proved the role of selective pressure in Homo Sapiens at least at the level of individual genes or loci. Nevertheless, there are examples of polygenic traits that are bound to be under selection, but studies devoted to apply population genetics methods to unveil such occurrence are still lacking. Stature provides a relevant example of well-studied polygenic trait for which is now available a genome-wide association study which has identified the genes involved in this trait, and which is known to be under selection. We studied the behavior of FST in a simulated toy model to detect population differentiation on a generic polygenic phenotype under selection. The simulations showed that the set of alleles involved in the trait has a higher mean FST value than those undergoing genetic drift only. In view of this we looked for an increase in the mean FST value of the 180 variants associated to human height. For this set of alleles we found FST to be significantly higher than the genomic background (p = 0.0356). On the basis of a statistical analysis we excluded that the increase was just due to the presence of outliers. We also proved as marginal the role played by local adaptation phenomena, even on different phenotypes in linkage disequilibrium with genetic variants involved in height. The increase of FST for the set of alleles involved in a polygenic trait seems to provide an example of symmetry breaking phenomenon concerning the population differentiation. The splitting in the allele frequencies would be driven by the initial conditions in the population dynamics which are stochastically modified by events like drift, bottlenecks, etc, and other stochastic events like the born of new mutations. Citation: Amato R, Miele G, Monticelli A, Cocozza S (2011) Signs of Selective Pressure on Genetic Variants Affecting Human Height. PLoS ONE 6(11): e27588. doi:10.1371/journal.pone.0027588 Editor: Thomas Mailund, Aarhus University, Denmark Received May 18, 2011; Accepted October 20, 2011; Published November 9, 2011 Copyright: 2011 Amato et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: R.A. is a recipient of a fellowship by Doctorate of Computational Biology and Bioinformatics, University ‘‘Federico II’’, Naples. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: roamato@na.infn.it Introduction One of the greatest challenges in modern biology is to understand how selection has driven human evolution. Decades of work provided evidence of selective pressure in Homo Sapiens at the level of individual genes or loci [1–3]. Among the others, methods based on population differentiation were widely used to unveil their signature [4]. However, in most cases, variation in phenotype among individuals is the result of a polygenic effect, involving multiple genetic variations at multiple unlinked loci [5]. Up to now, only few studies investigated the presence of selective pressure on polygenic traits in humans. A possible explanation for this lack of evidence is that polygenic adaptation might be largely undetected by conventional methods able to look for selection [6–7]. Furthermore, the identification of signatures of polygenic evolution could require genome-scale data sources, with a well-defined set of genetic variants involved in the polygenic effect. Stature is one of most studied polygenic traits, because measuring height is easy and replicable and its inheritance well recognized. Recently, genome-wide association studies contrib- uted in the identification of genes involved in this trait. Lango Allen and colleagues, in particular, demonstrated that hundreds of genetic variants, in at least 180 loci, influence adult height [8]. Although this result explains approximately only 10% of the phenotypic variation in height, this study provides up to now the most detailed description of a polygenic effect in humans at molecular level. From an evolutionary point of view, a complex interaction of different forces acts on stature and the complete dynamics is still not completely clear. In particular, several studies suggested a stabilizing selection on human height because of an increased number of health problems in very short and very tall individuals [9,10]. At the same time, other studies invoked a directional sexual selection on male human height in that taller men often have more reproductive chances [11]. Anyway, a worldwide distributed sexual selection seems to represent an overall reasonable scenario, even though local adaptation phenomena that could favor particular heights and body shapes in particular environmental conditions cannot be excluded. In this work we explored, in a simple simulated model, the behavior of FST, a widely used method for detecting selec- tion based on populations differentiation, on a generic polygenic trait. We then investigated whether a similar behavior was observable in a real case, namely in the set of loci related to height. PLoS ONE | www.plosone.org 1 November 2011 | Volume 6 | Issue 11 | e27588