PMC:1271393 / 47504-56372 JSONTXT

{"project":"2_test","denotations":[{"id":"16252244-11062480-2049656","span":{"begin":856,"end":860},"obj":"11062480"},{"id":"16252244-11420360-2049657","span":{"begin":876,"end":880},"obj":"11420360"},{"id":"16252244-12897772-2049658","span":{"begin":906,"end":910},"obj":"12897772"},{"id":"16252244-10570998-2049659","span":{"begin":935,"end":939},"obj":"10570998"},{"id":"16252244-11130070-2049660","span":{"begin":955,"end":959},"obj":"11130070"},{"id":"16252244-12509511-2049661","span":{"begin":976,"end":980},"obj":"12509511"},{"id":"16252244-11179020-2049662","span":{"begin":1014,"end":1018},"obj":"11179020"},{"id":"16252244-11452081-2049663","span":{"begin":1070,"end":1074},"obj":"11452081"},{"id":"16252244-15361935-2049664","span":{"begin":1088,"end":1092},"obj":"15361935"},{"id":"16252244-3114877-2049665","span":{"begin":1296,"end":1300},"obj":"3114877"},{"id":"16252244-9106523-2049666","span":{"begin":1889,"end":1893},"obj":"9106523"},{"id":"16252244-12149450-2049667","span":{"begin":1910,"end":1914},"obj":"12149450"},{"id":"16252244-4379525-2049668","span":{"begin":2068,"end":2072},"obj":"4379525"},{"id":"16252244-11701634-2049669","span":{"begin":2096,"end":2100},"obj":"11701634"},{"id":"16252244-12466284-2049670","span":{"begin":2114,"end":2118},"obj":"12466284"},{"id":"16252244-12560807-2049671","span":{"begin":2140,"end":2144},"obj":"12560807"},{"id":"16252244-12610536-2049672","span":{"begin":2173,"end":2177},"obj":"12610536"},{"id":"16252244-14997422-2049673","span":{"begin":2505,"end":2509},"obj":"14997422"},{"id":"16252244-15361935-2049674","span":{"begin":3623,"end":3627},"obj":"15361935"},{"id":"16252244-11384997-2049675","span":{"begin":4373,"end":4377},"obj":"11384997"},{"id":"16252244-15385553-2049676","span":{"begin":4395,"end":4399},"obj":"15385553"},{"id":"16252244-15509576-2049677","span":{"begin":4417,"end":4421},"obj":"15509576"},{"id":"16252244-12493913-2049678","span":{"begin":5550,"end":5554},"obj":"12493913"},{"id":"16252244-12493913-2049679","span":{"begin":6683,"end":6687},"obj":"12493913"}],"text":"CD209L: Relaxation of the Functional Constraint or Balancing Selection?\nIn clear contrast to its homologue, CD209L presented extremely elevated nucleotide-diversity levels. High levels of diversity can result either from a relaxation of the functional constraint, which allows the stochastic accumulation of new mutations, or from the action of balancing selection, which maintains over time two or more functionally different alleles (and all linked variation) at intermediate frequencies. Several lines of evidence lend support to the selective hypothesis. First, if CD209L nucleotide diversity has been driven by the action of balancing selection, population-genetics relationships would have been accordingly altered. In this context, diversity studies in neutral, or assumedly neutral, regions of the genome—such as the Y chromosome (Underhill et al. 2000; Hammer et al. 2001; Jobling and Tyler-Smith 2003), mtDNA (Wallace et al. 1999; Ingman et al. 2000; Mishmar et al. 2003), Alu insertions (Watkins et al. 2001), as well as some autosomal genes (Stephens et al. 2001; Akey et al. 2004)—showed that African populations are genetically more diverse than are non-Africans, an observation generally interpreted as a support of the “Out of Africa” model for the origin of modern humans (Lewin 1987). For CD209L, even if we observed 1.5 times more segregating sites in African than in non-African populations, as indicated by the higher θw value found in Africa, similar values of nucleotide diversity were detected in the three groups, with Europeans presenting even higher π values than do Africans. This unusual scenario, which is at odds with neutral expectations, has already been described for other regions of the genome, such as the β-globin gene and the 5′cis-regulatory region of CCR5, for which the action of balancing selection has been convincingly proposed (Harding et al. 1997; Bamshad et al. 2002). Second, balancing selection tends to increase within-population diversity while decreasing F ST, compared with neutrally evolving loci (Cavalli-Sforza 1966; Harpending and Rogers 2000; Akey et al. 2002; Bamshad and Wooding 2003; Cavalli-Sforza and Feldman 2003). Indeed, our data are compatible with these predictions, since the 5%F ST value observed for CD209L is threefold lower than that estimated for CD209 (15%) and is similar to that found, for example, for the bitter-taste receptor gene (5.6%), for which there is compelling evidence of balancing-selection action (Wooding et al. 2004). Third, results of our Tajima's D analysis were significantly positive for European and East Asian populations, because of the skew of CD209L frequency spectrum toward an excess of intermediate-frequency alleles (table 2), a pattern that further supports the action of balancing selection. However, since the null model used to assess significance makes unrealistic assumptions about past population demography (i.e., constant population sizes), the rejection of the standard neutral model cannot be interpreted as unambiguous evidence of selection. Indeed, the observation that only non-African populations showed a significant departure from neutrality raises the question of whether these patterns could have resulted instead from the bottleneck that occurred during the Out of Africa exodus. A way to circumvent this conundrum is to analytically integrate the fact that demography affects all the genome equally, whereas selection directs its effects toward specific loci. Thus, to correct for the confounding effects of demography, we plotted our results against the empirical distributions of Akey et al. (2004) for Tajima's D statistics. Our values remained significant for CD209L, which therefore reinforces the idea that the pattern observed is unlikely to be the sole result of demography.\nLast, if the patterns of variation in CD209L represent the molecular signature of balancing selection, at least in non-Africans, then a functional target of such selective regime is needed. In this context, the neck region constitutes an excellent candidate, since it plays a major mediating role in the orientation and flexibility of the carbohydrate-recognition domain. Since this domain is directly involved in pathogen recognition, neck-region length variation has important consequences for the pathogen-binding properties of these lectins (Mitchell et al. 2001; Bernhard et al. 2004; Feinberg et al. 2005). In perfect agreement with the results of our sequence-based data set, higher diversity in repeat variation was observed in the neck region among non-African populations (Native Americans excepted). Out of Africa, at least three alleles account for most population diversity, whereas, in Africa, the 6- and 7-repeat alleles alone account for 96% of the global variability (fig. 5B). Again, the higher diversity observed out of Africa could be due to a higher level of relaxation of the functional constraint of the neck region in non-African compared with African populations, which would lead to a random accumulation of proteins with varying neck-region lengths among non-Africans. Conversely, these patterns could also be explained by the action of balancing selection in non-Africans and could therefore point to the neck region as the functional target of such selective regime. To evaluate the plausibility of these two conflicting scenarios, we compared the variation in the CD209L neck region with that inferred from 377 neutral autosomal microsatellites typed elsewhere for the same population panel (Rosenberg et al. 2002). We reasoned that if CD209L diversity has been shaped only by demography (i.e., bottleneck out of Africa), the distribution of genetic variance at different hierarchical levels should be comparable to that inferred through the neutral markers. On the other hand, if selection has driven the CD209L neck-region diversity, population-genetics distances would be influenced accordingly and would therefore differ from neutral expectations. Indeed, the AMOVA values inferred for CD209L fell systematically outside the 95% CI defined for the microsatellite data set (table 6 ). We observed that populations within Europe, Asia, the Middle East, and Oceania exhibited lower-than-expected diversity among populations within the same region. A reduction of genetic distances between populations is expected under balancing selection; therefore, the results from the CD209L neck region favor, once again, the action of this selective regime in most non-African populations, in detriment of the neutral hypothesis. One may argue that the differences in the proportions of genetic variance between our data and those of Rosenberg et al. (2002) could be due to differences in the pace of mutation between microsatellite loci and our neck repeated region that could be considered a “coding minisatellite.” However, under neutrality, differences in mutation rate should have a similar and proportional effect in all population comparisons and should influence all values with a similar tendency (i.e., higher or lower values). Indeed, this is not the case: populations within Europe, the Middle East, Central/South Asia, East Asia, and Oceania turned out to be genetically closer than expected, whereas populations within Africa and the Americas exhibited the opposite pattern (table 6), which makes it highly unlikely that mutation-rate differences influenced our conclusions.\nTable 6 AMOVA for the Neck Region of CD209L\nAMOVA Value (95% CI) Inferred forCD209Lb\nSamplea No. of Regions No. of Populations Within Populations Among Populations within Regions Among Regions\nWorld 7 52 90.4 (93.8–94.3) 2.1 (2.3–2.5) 7.57 (3.3–3.9)\nAfrica 1 6 93.9 (96.7–97.1) 6.1 (2.9–3.3)\nEurasia 3 21 97.0 (98.2–98.4) .2 (1.1–1.3) 2.8 (.4–.6)\n Europe 1 8 99.5 (99.1–99.4) .5 (0.6–0.9)\n Middle-East 1 4 100 (98.6–98.8) 0 (1.2–1.4)\n Central/South Asia 1 9 99.5 (98.5–98.8) .5 (1.2–1.5)\nEast Asia 1 18 99.3 (98.6–98.9) .7 (1.1–1.4)\nOceania 1 2 96.0 (92.8–94.3) 4.0 (5.7–7.2)\nAmerica 1 5 86.7 (87.7–89) 13.3 (11.0–12.3)\nNote.—\nNo comparisons were performed for the CD209 neck region, because virtually no variation was observed at that locus.\na Populations are grouped as described by Rosenberg et al. (2002).\nb AMOVA values are from our CD209L study; 95% CIs are defined from 377 autosomal microsatellites in the same population panel (Rosenberg et al. 2002).\nTaken together, the integration of the results from levels of nucleotide and amino acid diversity, neutrality tests, population-genetics distances, and neck-region length variation in CD209 and CD209L clearly points to a situation in which CD209 has been under a strong selective constraint that prevents accumulation of any of amino acid changes over time, whereas CD209L variability has most likely been driven by the action of balancing selection, at least in non-African populations."}