Recent and ongoing selection in the human genome

Abstract

The recent availability of genome-scale genotyping data has led to the identification of regions of the human genome that seem to have been targeted by selection. These findings have increased our understanding of the evolutionary forces that affect the human genome, have augmented our knowledge of gene function and promise to increase our understanding of the genetic basis of disease. However, inferences of selection are challenged by several confounding factors, especially the complex demographic history of human populations, and concordance between studies is variable. Although such studies will always be associated with some uncertainty, steps can be taken to minimize the effects of confounding factors and improve our interpretation of their findings.The past few years have seen an explosion of studies using molecular data to detect Darwinian natural selection [1][2][3][4][5][6] . With the recent availability of large-scale genotyping data, genome-wide scans for genes or genomic regions that have been targeted by selection have become feasible. These studies have greatly advanced our understanding of human evolution and molecular evolution in general, but they have also sparked considerable controversy.The interest in detecting selection is twofold. First, it stems from a natural curiosity about our evolutionary past and the basic mechanisms that govern molecular evolution. Much of the work in this field through the past four decades has focused on quantifying the relative importance of Darwinian selection and random genetic drift in determining levels of variability within species, as well as divergence between species (for example, REFS 7,8 ). However, as evidence accumulates for a strong role of selection, efforts are increasingly concentrating on identifying and characterizing particular instances of selection and adaptation at the molecular level. In humans, in particular, there has been a strong interest in identifying genes that have undergone recent selection relating to key human traits such as cognitive abilities 4,9,10 .Correspondence to R.N., rasmus@binf.ku.dk. DATABASES Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptA second motivation for studying selection stems from the realization that inferences about selection can provide important functional information. For example, genes that are targeted by selection acting on segregating mutations are more likely to be associated with disease (for example, REF. 3 ). Even small fitness effects can, on an evolutionary timescale, leave a distinct pattern. Therefore, it might be possible to identify putative genetic disease factors by identifying regions of the human genome that currently are under selection 3,11 . In general, positions in the genome that are under selection must be of functional importance, otherwise selection could not be operating.The aim of this Review is to discuss some of the major findings regarding selection in humans, and explain...

The evolutionary history of the CD209 (DC-SIGN) family in humans and non-human primates

“…6 As a category, immunity-and defense-related genes have experienced by far the most positive selection in humans and other organisms. 7 The aim of the present study was to extend the analysis of the distribution of the three recognized CD209 family genes in primates to thoroughly assess the evolutionary history of this gene family, to identify possible domains and amino acids under selective pressure, to date the gene-duplication events resulting in this family and to understand the evolutionary process giving rise to the neck repeat region. To trace the evolutionary history of these genes, gene-coding sequences are determined for a representative number of primates (hominoids, Old World and New World monkeys), followed by the analysis of amino-acid substitutional patterns in the framework of the accepted primate phylogeny.…”

Genomic landscape of positive natural selection in Northern European populations

“…Thus, additional caution is necessary when disease association is observed in selected genes, which poses a further challenge for discovering functions of genes under natural selection by genome-wide analysis. 46 Both empirical analyses and simulation studies showed that sample size and SNP density affect the performance of the iHS and LRH statistics. Although very dense data sets clearly yield the best power, the available genome-wide data sets with large sample sizes also seem adequate for successful selection scans, which is consistent with earlier results.…”

“…1,2,20,46 However, the increased population differentiation because of positive selection makes these loci particularly vulnerable to false-positive associations. [47][48][49] As an example, in our data set, the haplotype in the PDE11A gene showing very high population differentiation has been reported to associate with depression in Mexican Americans 50 -possibly due to confounding population structure.…”

“…Statistical methods to scan for signs of positive natural selection are plagued by several limitations, and no method is suitable for covering the full spectrum of natural selection. 46 Specifically, the iHS and LRH statistics are efficient only when the selected haplotype has not yet reached fixation. This may be at least a partial explanation to the non-overlapping patterns of iHS or LRH with F ST , which may detect more ancient selection than the other tests.…”

Detecting loci under selection in a hierarchically structured population

“…This observation has recently led to the development of several methods comparing levels of genetic diversity and differentiation within and between populations (Beaumont and Nichols, 1996;Schlotterer, 2002;Beaumont and Balding, 2004;Tang et al, 2007;Foll and Gaggiotti, 2008;Riebler et al, 2008), which have been applied to various genome scan studies to detect specific loci under selection (see for example, Kayser et al, 2003;Storz et al, 2004;Storz, 2005;Tang et al, 2007;Thornton and Jensen, 2007;Egan et al, 2008;Mäkinen et al, 2008). Although tests of selection based on various aspects of genetic diversity within population seem very sensitive to past demographic events, such as population bottlenecks or demographic expansions (Teshima et al, 2006;Nielsen et al, 2007), the sensitivity of tests based on inter-population differences (summarized by the F ST statistic) has been little investigated (but see for example, Beaumont and Nichols, 1996;Schlotterer, 2002).…”