Last, 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.
Table 6 AMOVA for the Neck Region of CD209L
AMOVA Value (95% CI) Inferred forCD209Lb
Samplea No. of Regions No. of Populations Within Populations Among Populations within Regions Among Regions
World 7 52 90.4 (93.8–94.3) 2.1 (2.3–2.5) 7.57 (3.3–3.9)
Africa 1 6 93.9 (96.7–97.1) 6.1 (2.9–3.3)
Eurasia 3 21 97.0 (98.2–98.4) .2 (1.1–1.3) 2.8 (.4–.6)
 Europe 1 8 99.5 (99.1–99.4) .5 (0.6–0.9)
 Middle-East 1 4 100 (98.6–98.8) 0 (1.2–1.4)
 Central/South Asia 1 9 99.5 (98.5–98.8) .5 (1.2–1.5)
East Asia 1 18 99.3 (98.6–98.9) .7 (1.1–1.4)
Oceania 1 2 96.0 (92.8–94.3) 4.0 (5.7–7.2)
America 1 5 86.7 (87.7–89) 13.3 (11.0–12.3)
Note.—
No comparisons were performed for the CD209 neck region, because virtually no variation was observed at that locus.
a Populations are grouped as described by Rosenberg et al. (2002).
b AMOVA values are from our CD209L study; 95% CIs are defined from 377 autosomal microsatellites in the same population panel (Rosenberg et al. 2002).