PMC:1271393 / 43579-47502 JSONTXT

{"project":"2_test","denotations":[{"id":"16252244-11701634-2049645","span":{"begin":212,"end":216},"obj":"11701634"},{"id":"16252244-12466284-2049646","span":{"begin":230,"end":234},"obj":"12466284"},{"id":"16252244-12610536-2049647","span":{"begin":263,"end":267},"obj":"12610536"},{"id":"16252244-15361935-2049648","span":{"begin":1264,"end":1268},"obj":"15361935"},{"id":"16252244-11901132-2049649","span":{"begin":1466,"end":1470},"obj":"11901132"},{"id":"16252244-15385553-2049650","span":{"begin":3135,"end":3139},"obj":"15385553"},{"id":"16252244-15509576-2049651","span":{"begin":3157,"end":3161},"obj":"15509576"},{"id":"16252244-15509576-2049652","span":{"begin":3511,"end":3515},"obj":"15509576"},{"id":"16252244-15385553-2049653","span":{"begin":3628,"end":3632},"obj":"15385553"},{"id":"16252244-15032573-2049655","span":{"begin":3917,"end":3921},"obj":"15032573"}],"text":"CD209: The Signature of a Functional Constraint\nFor CD209, not only nucleotide diversity but also F ST intercontinental values (0.15) were in conformity with previous worldwide estimations (Harpending and Rogers 2000; Akey et al. 2002; Cavalli-Sforza and Feldman 2003). For frequency-spectrum–based tests, only Fay and Wu's H test detected an excess of highly frequently derived alleles for the African and East Asian samples, a picture that may be interpreted as the result of a selective sweep. However, the significantly negative value observed in Africa is, again, exclusively due to the presence of cluster A, since 22 of the 35 fixed SNPs distinguishing it from cluster B corresponded to the derived allelic status in the latter cluster. Because cluster B accounts for 85% of the African variability, a clear excess of frequently derived alleles was observed. The extent to which the presence of this cluster is due to either natural selection or population structure will be discussed in detail below. For East Asia, the significance of the H test is also questionable when accounting for the confounding effects of demography. Indeed, when we plotted our H value against the empirical distribution of 132 H values from non-African populations (Akey et al. 2004), the East Asian P value became nonsignificant (P=.36). This observation reinforces the idea that the H test is particularly sensitive to past bottlenecks and/or population subdivision (Przeworski 2002). Thus, regarding the global levels of sequence diversity, the CD209 locus seems to evolve under evolutionary neutrality. Nevertheless, when we focused our analyses at the protein level, signs of natural selection were uncovered. Indeed, the McDonald-Kreitman test rejected neutrality for this gene because of a clear excess of polymorphic synonymous sites (i.e., a lack of nonsynonymous variants). In addition, when the number of synonymous sites (146) versus nonsynonymous sites (499) was compared with the observed number of synonymous (5) versus nonsynonymous (0) mutations, we detected a significant lack of nonsynonymous mutations (two-tailed Fisher exact test, P=6.3×10−4). These observations point to a strong selective constraint acting on CD209 that prevents the accumulation of amino acid replacements over time.\nFurther support for a functional constraint in CD209 comes from the patterns of diversity observed in the neck region. In contrast to CD209L, virtually no variation was observed at CD209 (fig. 5A), with the 7-repeat allele accounting for 99% of the total variability. Moreover, the low levels of heterozygosity observed resulted in a consistent rejection of mutation-drift equilibrium in almost all geographical regions (table 5). The probability of finding such a low heterozygosity value, given the overall number of alleles observed, was estimated to be \u003c0.2%, independent of the mutational model considered (table 5). Thus, the fact that no alleles other than the 7-repeat allele have increased in frequency, together with recent studies addressing the functional consequences of repeat-number variation in this region (Bernhard et al. 2004; Feinberg et al. 2005), strongly suggests a clear reduced fitness of any allele other than the 7-repeat allele. Interestingly, it has been recently shown that a protein with two fewer repeats (a 5-repeat allele) results in a partial dissociation of the final tetramer, whereas a protein with \u003c5 repeats exhibits a dramatic reduction in overall stability (Feinberg et al. 2005), with all these differences having a direct impact on the quality of ligand-binding functions (Bernhard et al. 2004). Taken together, the patterns of diversity observed at CD209 clearly point to a strong functional constraint acting on this gene and further support the proposed crucial role of this lectin in pathogen recognition and in the early steps of immune response (Geijtenbeek et al. 2000b, 2004)."}