Genetic Basis of Thoracic Aortic Aneurysms and Dissections : Focus on Smooth Muscle Cell Contractile Dysfunction

Here we review the evidence for positive selection in the human genome and its role in human evolution and population differentiation. In recent years, there has been a dramatic increase in the use of genomewide scans to identify adaptively evolving loci in the human genome. Attention is now turning to understanding the biological relevance and adaptive significance of the regions identified as being subject to recent positive selection. Examples of adaptively evolving loci are discussed, specifically LCT and FOXP2. Comprehensive studies of these loci also provide information about the functional relevance of the selected alleles. We discuss current studies examining the role of positive selection in shaping copy number variation and noncoding genomic regions and highlight challenges presented by the study of positive selection in the human genome. 143 Click here for quick links to Annual Reviews content online, including: • Other articles in this volume • Top cited articles • Top downloaded articles • Our comprehensive search Further ANNUAL REVIEWS A nn u. R ev . G en om . H um an G en et . 2 00 8. 9: 14 316 0. D ow nl oa de d fr om a rj ou rn al s. an nu al re vi ew s. or g by U N IV E R SI T Y O F ID A H O L IB R A R Y o n 10 /0 9/ 09 . F or p er so na l u se o nl y. ANRV353-GG09-08 ARI 25 July 2008 13:38 Haplotype: linked alleles that are inherited as a unit INTRODUCTION A fundamental question in evolutionary biology is what distinguishes humans from our closest living relatives, chimpanzees? One way to uncover biologically relevant differences in our genetic makeup is to examine regions of the genome that have been subject to positive selection. In this review, we define positive selection as the process that increases the frequency of mutations that confer a fitness advantage to individuals carrying those mutations. The identification of adaptively evolving genes and regulatory regions may help to elucidate specific regions of the genome that have evolved during the past six million years to allow humans to develop language, use tools, and ultimately populate nearly every continent. Historically, the study of positive selection in human evolution was motivated by a priori assumptions about selective pressure. For example, the Duffy Fy∗O blood group mutation was shown to be under positive selection (28, 29), a discovery motivated by the finding that African individuals with the Fy∗O blood group were resistant to malaria infection by Plasmodium vivax (52). Recently, the availability of largescale polymorphism and divergence data has made it possible to scan the human genome for evidence of positive selection without making assumptions about the potential selective advantage at particular loci. Genome-wide scans for adaptations have identified hundreds of putatively selected genes in the human genome (1, 7, 9, 11, 37, 38, 40, 43, 54, 67, 79, 86, 89, 90; also see 5, 55, 68). These scans apply a range of statistical methods to divergence and variation data to investigate features of the genome such as haplotype lengths and allele frequency spectrum differences. As genotyping and largescale DNA sequencing efforts produce additional data, these scans will become more common and will ultimately provide a catalog of regions that have adaptively evolved in the human lineage and in specific populations. However, this information will not indicate which loci represent true examples of positive selection, the biological relevance of the region under positive selection, or the time of onset of the selective pressures. METHODS TO IDENTIFY POSITIVE SELECTION Positive selection may be identified in two fundamental ways: Divergence data are used to identify positive selection between species, whereas polymorphism data are used to identify positive selection within a species. Each method detects selection on a different timescale. Divergence data are used to identify older selective events, whereas polymorphism data are used to identify recent selective events. The use of both divergence and polymorphism data may provide additional support for positive selection acting in a region; however, a signature of selection with one test is sufficient evidence for selection (54).