Pearce Richard, Malisa Allen, Kachur S Patrick, Barnes Karen, Sharp Brian, Roper Cally
London School of Hygiene and Tropical Medicine, Pathogen Molecular Biology Unit, Department of Infectious Tropical Diseases, London, United Kingdom.
Mol Biol Evol. 2005 Sep;22(9):1834-44. doi: 10.1093/molbev/msi177. Epub 2005 May 25.
We have measured microsatellite diversity at 26 markers around the dhfr gene in pyrimethamine-sensitive and -resistant parasites collected in southeast Africa. Through direct comparison with diversity on sensitive chromosomes we have found significant loss of diversity across a region of 70 kb around the most highly resistant allele which is evidence of a selective sweep attributable to selection through widespread use of pyrimethamine (in combination with sulfadoxine) as treatment for malaria. Retrospective analysis through four years of direct and continuous selection from use of sulfadoxine-pyrimethamine as first-line malaria treatment on a Plasmodium falciparum population in KwaZulu Natal, South Africa, has revealed how recombination significantly narrowed the margins of the selective sweep over time. A deterministic model incorporating selection coefficients measured during the same interval indicates that the transition was toward a state of recombination-selection equilibrium. We compared loss of diversity around the same resistance allele in two populations at either extreme of the range of entomological inoculation rates (EIRs), namely, under one infective bite per year in Mpumalanga, South Africa, and more than one per day in southern Tanzania. EIRs determine effective recombination rates and are expected to profoundly influence the dimensions of the selective sweep. Surprisingly, the dimensions were broadly consistent across both populations. We conclude that despite different recombination rates and contrasting drug selection histories in neighboring countries, the region-wide movement of resistant parasites has played a key role in the establishment of resistance in these populations and the dimensions of the selective sweep are dominated by the influence of high initial starting frequencies.
我们在从非洲东南部收集的对乙胺嘧啶敏感和耐药的寄生虫中，测量了二氢叶酸还原酶（dhfr）基因周围26个微卫星标记的多样性。通过与敏感染色体上的多样性直接比较，我们发现在最具抗性的等位基因周围70 kb的区域内多样性显著丧失，这证明了由于广泛使用乙胺嘧啶（与磺胺多辛联合使用）治疗疟疾而导致的选择性清除。通过对南非夸祖鲁-纳塔尔省恶性疟原虫群体连续四年使用磺胺多辛-乙胺嘧啶作为一线疟疾治疗进行直接和持续选择的回顾性分析，揭示了重组如何随着时间的推移显著缩小了选择性清除的范围。一个纳入同一时期测量的选择系数的确定性模型表明，这种转变趋向于重组-选择平衡状态。我们比较了在昆虫接种率（EIRs）范围两端的两个群体中，围绕相同抗性等位基因的多样性丧失情况，即在南非姆普马兰加每年少于一次感染性叮咬的情况下，以及在坦桑尼亚南部每天多于一次感染性叮咬的情况下。EIRs决定有效重组率，并预计会深刻影响选择性清除的范围。令人惊讶的是，两个群体的范围大致一致。我们得出结论，尽管邻国的重组率不同且药物选择历史不同，但耐药寄生虫的区域传播在这些群体中耐药性的建立中起到了关键作用，并且选择性清除的范围主要受高初始起始频率的影响。
