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Evolution, defined from a molecular biology point-of-view, is the changes in the allele frequencies over time due to processes such as mutation, drift, migration and natural selection. The search for the footprints of selection and adaptation in humans has always been a widely discussed topic in the field of evolutionary biology as well as in the related disciplines of human genetics and biological anthropology. Although these subject areas address different questions, they come together on the topic of human population genetics, where data on genetic variation is analysed to determine past demographic events and shed more light on the topic of human evolution.
Traditionally, local adaptations in a human population were identified by hypothesizing an environmental variable that would be acting on an observed phenotypic distribution as a selective pressure. This was pertinent in the case of the malaria hypothesis explaining the geographic distribution of Î²- thalassemia and HbS alleles in terms of the resistance they conferred to the malaria parasite (Haldane 1949, Allison 1954). Additional notable examples of this approach focused on phenotypes, such as ), oxygen saturation of arterial hemoglobin and altitude (Beall et al. 1997), the relationship between body mass and temperature (Katzmarzyk & Leonard 1998, Roberts 1978), and skin pigmentation and solar radiation (Jablonski & Chaplin 2000). If the phenotypes are heritable, the correlation between the distribution of phenotype and environmental variable constitutes evidence for an adaptation at the genetic level (as opposed, for example, to acclimatization). The argument for positive selection is especially strong if a correlation can also be shown between the phenotype (e.g., high oxygen saturation at high altitude) and fitness (e.g., number of offspring) (e.g., Beall et al. 2004).
Although these approaches directly test a given hypothesis concerning natural selection on a genotypic variant, it's not easy to implement them on a large scale. They require collection of phenotypic data from large samples to achieve statistical significance which is often expensive, time consuming and in some cases impractical. The recent development of technologies and resources in bioinformatics for studying genetic variation on an unprecedented scale has enabled investigators to scan the entire genome for signals of natural selection. This approach is based on the idea that natural selection introduces a local perturbation in the patterns of neutral genetic variation surrounding an advantageous allele relative to regions of the genome where variation is shaped only by genetic drift. This approach has two major advantages: First, it does not require investigators to collect phenotype information, and second, it can detect adaptive changes resulting from selection coefficients that would be very hard to detect by traditional phenotype-based approaches (Gillespie 1991). Moreover, as the same technologies are being applied to the study of common diseases, signals of natural selection can be connected to genotype-phenotype associations, where both signals arise from unbiased genome-scale analyses.
By drawing on data from the fields of anthropological, human genetic and evolutionary biology studies of human adaptations, it may soon be possible to reconstruct the course of natural selection in human evolution and also infer the role of disease in human adaptations. Three studies reporting the signature of selection are reported here. These studies are focusing on the ongoing selection as indicated by variation that is still segregating in humans, rather than mutations that have been fixed in the human population. The aim of this essay is to present a sound case in favour of currently ongoing selection in the human population.
Detecting Natural Selection
The frequency change of a beneficial allele over time is drastically different than that of a neutral allele under natural selection. Under directional selection or during the initial phase of a balanced polymorphism, beneficial alleles are characterized by a rapid rise in frequency. Additionally due to the decreasing probability of recombination between short distances of a beneficial allele, the histories of nearby neutral alleles are also strongly correlated. Due to this effect, natural selection generates a local perturbation in the pattern of variation which is tightly linked to the site under selection. In contrast, neutrally evolving genomic regions do not exhibit such linkages and their pattern of variation is only influenced by genetic drift and, therefore, by the properties of the population, including the history of population size and population structure. Therefore, detecting the signature of natural selection essentially depends on distinguishing the patterns of variation that are shaped solely by demographic history from those that are influenced by natural selection.
For a short time when a new beneficial allele is introduced into the population, it will be associated with the particular genomic background. As this allele is driven quickly to an intermediate or high frequency, the neutral alleles that define the haplotype and that are tightly linked to the selected site will also tend to increase in frequency. Owing to the rapid increase in frequency of the beneficial allele, recombination will not have had sufficient time to break associations between it and nearby neutral alleles. This would lead to the emergence of a local pattern of identical haplotypes (extended haplotype homozygosity, EHH) occurring at intermediate or high frequencies. This process is often referred to as a partial or incomplete selective sweep. If selection is directional, the beneficial allele may go to fixation and all variation near the selected site will also be fixed and only new mutations arising during the sweep will segregate in the population at low frequencies. Therefore, the expected pattern near a fixed beneficial allele will consist of a reduction in polymorphism. At a greater distance from the selected site, recombination events will tend to uncouple the beneficial allele from the neutral alleles. This may result in a pattern characterized by high frequency derived alleles and because such alleles tend to be rare under neutrality, the occurrence of multiple high frequency derived alleles within a small region would constitute a strong signal of selection.
When selection acts on an allele which is beneficial for only a subset of the population, the frequency of that allele will differ across populations to a greater extent than predicted for variants evolving neutrally in all populations. Several approaches have been devised to detect such local adaptations. Historically, the most widely used is the statistic FST and its modifications (Beaumont & Balding 2004, Consortium 2005), which simply summarizes allele frequency differences between pairs of populations (Weir 1996).Variants with unusually large FST values are interpreted as being significantly divergent at that locus and targets of local selective pressures (Lewontin & Krakauer 1973).
If the intensity of selection varies spatially in a graded fashion, advantageous allele frequencies may vary across populations following the geographic distribution of the selective pressure. Therefore, if the selective pressure is known, a test of the correlation between the advantageous allele frequency and the value of the environmental variable may provide evidence for spatially varying selection. This approach is particularly appropriate when the advantageous phenotype is known to have a clinal distribution (Jablonski & Chaplin 2000, Katzmarzyk & Leonard 1998).
Additionally by comparing pattern of variation of synonymous to non-synonymous mutations in coding regions within a population and between a population and a close out group can shed more light on the action of natural selection on genetic variation of that population. If a gene is evolving neutrally, the ratios of non-synonymous to synonymous mutations within species and among species are expected to be the same. However, if natural selection drives a beneficial allele to fixation within the same region, this action may generate an excess of non-synonymous relative to synonymous changes among species in comparison to the ratio observed within species. Alternatively, an excess of non-synonymous mutations may be observed in the variation within species relative to among species. One possible interpretation for this pattern is that diversifying selection maintains a higher number of non-synonymous variants.
Natural Selection in the Human Population
In the recent past of human evolution, we have expanded our niche to an enormous range of environments including extremes of heat, cold and ultraviolet radiation to which we have adapted by behavioural and biological responses (Trinkaus, 2005). The essential role of the physical environment in shaping the human phenotypic diversity is evident from the strong correlations between traits such as body mass, basal metabolic rate, or skin reflectance and variables such as temperature, latitude, and UV radiation (Henry & Rees 1991, Jablonski & Chaplin 2000, Leonard et al. 2005, Roberts & Kahlon 1976). Overall, studies of phenotypic variation have provided strong support for the notion that the climate has exerted strong selective pressure on humans and genetic studies of selection have largely supported these predictions.
Human populations traditionally inhabiting high-altitude environments provide a unique opportunity to study natural selection as these societies had no technology to create non-hypoxic microclimates and therefore relied solely on physiological responses. Recent literature has focused on two populations - one on the Andean and one on the Tibetan Plateau. Research with the populations that have inhabited the Andean and Tibetan Plateaus for over a millennia has identified distinctive morphological and physiological characteristics thought to offset the stress of high-altitude hypoxia, such as the relative hypoventilation (Brutsaert et al., 2005) of Andean high-altitude natives or the elevated exhaled nitric oxide of Tibetans (Beall et al., 2001). Evolutionary theory reasons that characteristics distinguishing one high-altitude native group from another may be adaptations resulting from natural selection acting on the original variation present in their respective ancestral populations. Andean and Tibetan high-altitude natives differ from each other in the mean values of many characteristics related to oxygen delivery and offer evidence that evolutionary processes have resulted in different adaptive outcomes in these two independent natural experiments (Beall et al., 2001, Brutsaert et al., 2005). Thorough tests of these hypotheses have been challenging because the genetic bases of the traits remain unknown.
The environmental stress of low oxygen is clear at higher-altitudes. Drawing decreased quantity of oxygen in every breath of air, an uninterrupted supply must be maintained at sites where oxygen using processes occur, especially in the mitochondria for energy production. The Andean Plateau has been continuously inhabited by human for âˆ¼11,000 years (âˆ¼550 generations of 20 years each) similarly the Tibetan Plateau for âˆ¼22,000 years (âˆ¼1100generations) (Aldenderfer, 2003). Both indigenous populations have had sufficient opportunity for natural selection to improve oxygen delivery or use. Adaptations to other environmental features, such as Plasmodium falciparum or a diet containing lactose, have occurred in that length of time (Wiesenfeld, 1967; Tishkoff et al., 2007). However, oxygen delivery has been conceptualized to be a more integrated process involving many physiological systems including the pulmonary and cardiovascular systems, increasing the predicted time for natural selection to become detectable by current techniques.
Based on a conceptual framework published by Harrison (1966), the most common strategy to identify the possibility of genetic adaptation begins by considering if the current phenotype can be explained by acclimatization. If a non-indigenous individual grows up in the high-altitude environment and lacks the high-altitude phenotype, then the inference is that the high-altitude gene pool has changed from the ancestral state and the feature has a genetic basis unique to the high-altitude population.
A response within the common human homeostatic capacity is the elevated haemoglobin concentration of Andean high-altitude natives and European residents at altitudes of about 1500m and higher that is reversible upon return to sea level (Okin et al., 1966; Faura et al., 1969; Hochachka et al., 1996b; Ward et al., 2000; Beall, 2001b). Since the elevated haemoglobin is a reversible trait and exhibited in non-indigenous population, it may be interpreted as being an ancestral trait discounting any role of natural selection in its emergence in this specific population.
Mathematical models to analyze the benefits of the elevated haemoglobin concentration of Andean highlanders concluded that the optimal haemoglobin concentration at high-altitude is the normal sea-level range rather than the normal, elevated Andean high-altitude range (Villafuerte et al., 2004). This implies better function for those with relatively low haemoglobin concentrations at high altitude. Some studies reported that reducing haemoglobin concentration improves exercise capacity (Winslow et al., 1985; Villafuerte et al., 2004). However, another reported a comparison of samples of Andean men at 3700m with normal and low (for Andean high-landers) haemoglobin concentrations revealing that the men with low haemoglobin concentrations also had low exercise capacity (Tufts et al., 1985). Clearly, there is a need for more research relating haemoglobin concentration with function.
Another model reasons that the population of the Andean region has both high and low-altitude ancestry (indigenous Andean and immigrant Spanish) and that an individual's ancestry is quantifiable as a proportion of Native American ancestry ranging from 0 to 100%. It reasons that if a response to hypoxia has a genetic basis then individuals with a higher proportion of Native American ancestry will respond more adaptively to high altitude. For example, compared with lowlanders at high altitude, Andean highlanders have relatively low hypoxic ventilatory response (HVR, the increase in ventilation when the arterial partial pressure of oxygen or percent oxygen saturation of haemoglobin is lowered) and low ventilation during exercise. One study quantified the association of Native American ancestry with these traits by evaluating a sample of low-altitude Peruvian natives of mixed Native American and Spanish ancestry at sea level and after 10-12 h at 4338m (Brutsaert et al., 2005). The average estimated "Native American Ancestry Proportion" (NAAP) was 85%. Higher NAAP correlated with lower HVR after ten minutes of experimental hypoxia at high altitude and with ventilation during exercise (R2âˆ¼25%). These results can be interpreted to imply that natural selection produced a distinctive 'Andean' gene pool at unknown loci regulating these traits.
Traditional population comparison studies, such as these have presented evidence for the possibility of natural selection acting on the indigenous population leading to unique genetic variation for some oxygen transport traits including oxygen saturation of haemoglobin, haemoglobin concentration, resting ventilation, HVR, exhaled nitric oxide concentration, and birth weight, but cannot identify the genetic loci or alleles involved or give clues about their nature.
Perception of smell and taste
The capacity of individuals to sense their environment is without a doubt necessary for ensuring survival and reproduction. Olfaction may be important to detect and identify food and mates, whereas taste is likely crucial to identify suitable foods. Evidence that genes responsible for olfaction and taste evolved under positive selection is beginning to emerge.
Gilad et al. (2003) found evidence of positive selection on the human lineage on the basis of the ratio of non-synonymous to synonymous substitutions, low levels of polymorphism, and an excess of rare variants. Additional evidence for adaptation in olfactory receptor genes was detected in genome-wide scans. One study identified a signal for a complete selective sweep in a region within a cluster of olfactory receptor genes (Williamson et al. 2007); other studies found evidence for selection based on the frequency spectrum in several olfactory receptor genes (Carlson et al. 2005) and an enrichment of signals based on haplotype structure in genes involved in olfaction (Voight et al. 2006).
Inter-individual variation in the ability to taste phenylthiocarbamide (PTC) has been known for more than 70 years, but the genetic basis for this trait was only recently elucidated (Drayna et al. 2003). Identification of the region that influences the PTC phenotype allowed testing for evidence of positive selection at the genetic level (Wooding et al. 2004). Two high-frequency haplotypes, defined by three non-synonymous variants, were observed, consistent with the action of balancing selection at this locus. An additional 21 bitter taste receptor genes have been analyzed for evidence of selection. The average ratio of non-synonymous to synonymous substitutions was high compared with that observed in 151 other genes. In addition, polymorphism levels tended to be high in the bitter taste receptor genes (Kim et al. 2005).
Heat and Cold Stress
The sodium-retention hypothesis summarises the role of heat stress as a selective pressure in humans (Denton 1982). It states that, in hot, humid environments, selection for high sodium retention is strong because salts are lost quickly through sweat but are important for maintaining temperature homeostasis (Gleibermann 1973). One prediction of this hypothesis is that genetic variation underlying adaptations to heat stress is correlated with climatic variables such as temperature and humidity or an indirect factor such as latitude. Consistent with these predictions, the frequency of genetic variation in sodium retention and risk to hypertension was significantly correlated with latitude. Researchers observed this pattern in a number of genes including those coding for angiotensinogen (AGT), which plays a vital role in the renin-angiotensin pathway, cytochrome P450 3A5 (CYP3A5), which activates cortisol in the kidney, and the G-protein beta-3 subunit, which is involved in signal transduction in a number of tissues (Thompson et al. 2004,Young et al. 2005).
In addition to heat tolerance, selective pressures related to climate probably acted to increase cold tolerance by shaping genetic variation in energy metabolism. Consistent with a role for positive selection on cold tolerance, Mishmar et al. (2003) and Ruiz-Pesini et al. (2004) showed that the number and frequencies of non-synonymous mutations in mitochondrial genes increase with distance from Africa. Furthermore, a recent investigation into a large number of candidate susceptibility genes for common metabolic disorders found that variation in these genes was significantly correlated with climate variables in worldwide population samples (Hancock et al. 2008). Several of the strongest signals included variants previously associated with thermogenesis pathway genes.
The results of genome-wide selection scans have generally been consistent with those from hypothesis-driven studies. Carlson et al. (2005) scanned the human genome for signals of selection using the frequency spectrum and found evidence for selection at CYP3A5. Voight et al. (2006) used the genotype data from the HapMap project to test for evidence of an incomplete selective sweep by detecting regions of extended haplotype homozygosity (EHH) across the genome (Voight et al. 2006). This study found significant signals at the CYP3A5 and the leptin receptor (LEPR) genes, both showing strong correlations between allele frequency and climate variables. Tang et al. (2007) used a different measure of EHH that preferentially targeted signals in high frequency alleles. This study found signals for the CYP3A5 region and for a group of genes with similar function (i.e., oxidoreductase activity).
As seen from the first example, high-altitude natives have distinctive biological characteristics that appear to offset the stress of hypoxia, such as the elevated haemoglobin concentration of Andean high-altitude natives or the elevated resting ventilation of Tibetans. Evolutionary theory reasons that they reflect genetic adaptations resulting from natural selection favouring more effective adaptive responses. Because natural selection operates on heritable variation, a major research focus has been determining the genetic basis of these traits. This has been difficult for several reasons including the difficulty of deciding which components of the integrated oxygen-dependent system to study. The traditional research design compared physiological traits measured in samples of natives and migrants between altitudes. If acclimatization or developmental adaptation could not account for the distinctive high-altitude physiology, a genetic basis unique to the high-altitude populations was inferred. That is, the conclusion was based on exclusion of alternatives rather than demonstration of an association between a gene or genes and the biological characteristic.
With the advent of DNA sequencing and genotyping technologies and the development of methods to detect evidence of selection from sequence variation data, testing for evidence of genetic adaptations in single genes became feasible. More recently, the availability of dense, genome-wide genotype data for multiple populations and the development of methods for detecting selection using single nucleotide polymorphism data have elicited many genome-wide scans for evidence of positive selection in human populations. In addition, the 1000 Genomes Project was recently launched, which aims to re-sequence completely the genomes of 1000 individuals from diverse worldwide populations. The continued collection of data from large-scale projects will be useful for conducting more complete genome scans to detect evidence for natural selection. At the same time, more focused studies to test specific hypotheses or to follow up on results from genome-wide scans will continue to have an important place in reconstructing the overall history of selective pressures among human populations.