Nair Shalini, Nash Denae, Sudimack Daniel, Jaidee Anchalee, Barends Marion, Uhlemann Anne-Catrin, Krishna Sanjeev, Nosten François, Anderson Tim J C
Southwest Foundation for Biomedical Research, San Antonio, Texas, USA.
Mol Biol Evol. 2007 Feb;24(2):562-73. doi: 10.1093/molbev/msl185. Epub 2006 Nov 23.
When selection is strong and beneficial alleles have a single origin, local reductions in genetic diversity are expected. However, when beneficial alleles have multiple origins or were segregating in the population prior to a change in selection regime, the impact on genetic diversity may be less clear. We describe an example of such a "soft" selective sweep in the malaria parasite Plasmodium falciparum that involves adaptive genome rearrangements. Amplification in copy number of genome regions containing the pfmdr1 gene on chromosome 5 confer resistance to mefloquine and spread rapidly in the 1990s. Using flanking microsatellite data and real-time polymerase chain reaction determination of copy number, we show that 5-15 independent amplification events have occurred in parasites on the Thailand/Burma border. The amplified genome regions (amplicons) range in size from 14.7 to 49 kb and contain 2-11 genes, with 2-4 copies arranged in tandem. To examine the impact of drug selection on flanking variation, we genotyped 48 microsatellites on chromosome 5 in 326 parasites from a single Thai location. Diversity was reduced in a 170- to 250-kb (10-15 cM) region of chromosomes containing multiple copies of pfmdr1, consistent with hitchhiking resulting from the rapid recent spread of selected chromosomes. However, diversity immediately flanking pfmdr1 is reduced by only 42% on chromosomes bearing multiple amplicons relative to chromosomes carrying a single copy. We highlight 2 features of these results: 1) All amplicon break points occur in monomeric A/T tracts (9-45 bp). Given the abundance of these tracts in P. falciparum, we expect that duplications will occur frequently at multiple genomic locations and have been underestimated as drivers of phenotypic evolution in this pathogen. 2) The signature left by the spread of amplified genome segments is broad, but results in only limited reduction in diversity. If such "soft" sweeps are common in nature, statistical methods based on diversity reduction may be inefficient at detecting evidence for selection in genome-wide marker screens. This may be particularly likely when mutation rate is high, as appears to be the case for gene duplications, and in pathogen populations where effective population sizes are typically very large.
当选择作用强烈且有益等位基因有单一起源时，预计遗传多样性会在局部降低。然而，当有益等位基因有多个起源或在选择模式改变之前就在种群中分离时，对遗传多样性的影响可能就不那么清晰了。我们描述了疟原虫恶性疟原虫中这样一种“软”选择性清除的例子，它涉及适应性基因组重排。5号染色体上包含pfmdr1基因的基因组区域的拷贝数扩增赋予了对甲氟喹的抗性，并在20世纪90年代迅速传播。利用侧翼微卫星数据和实时聚合酶链反应对拷贝数的测定，我们表明在泰国/缅甸边境的寄生虫中发生了5 - 15次独立的扩增事件。扩增的基因组区域（扩增子）大小在14.7至49 kb之间，包含2 - 11个基因，有2 - 4个拷贝串联排列。为了研究药物选择对侧翼变异的影响，我们对来自泰国一个地点的326个寄生虫的5号染色体上的48个微卫星进行了基因分型。在含有多个pfmdr1拷贝的染色体的170至250 kb（10 - 15 cM）区域内，多样性降低了，这与近期被选择的染色体快速传播导致的搭便车效应一致。然而，相对于携带单个拷贝的染色体，在带有多个扩增子的染色体上，紧邻pfmdr1的多样性仅降低了42%。我们强调这些结果的两个特征：1）所有扩增子断点都出现在单体A/T序列（9 - 45 bp）中。鉴于这些序列在恶性疟原虫中大量存在，我们预计重复会在多个基因组位置频繁发生，并且作为该病原体表型进化的驱动因素被低估了。2）扩增的基因组片段传播留下的特征是广泛的，但仅导致多样性有限降低。如果这种“软”清除在自然界中很常见，那么基于多样性降低的统计方法在全基因组标记筛选中检测选择证据时可能效率低下。当突变率很高时，情况可能尤其如此，基因重复似乎就是这种情况，并且在有效种群大小通常非常大的病原体种群中也是如此。
