Doctoral Dissertation Improvement: The Origin of Syphilis and the Evolution of the Treponema Pallidum Subspecies: A Phylogenetic Approach

自15世纪以来，围绕梅毒的起源一直存在争议。一些人推测梅毒是由哥伦布和他的手下在新大陆感染的一种病原体引起的。另一种假设是：1)梅毒一直存在于欧洲，但之前被与麻风病等其他疾病混淆；2)梅毒在文艺复兴时期到达欧洲，但起源于非洲，而不是新大陆。对梅毒螺旋体病随时间的地理跨度的回顾，如古病理学记录中所揭示的，表明梅毒螺旋体病的证据在哥伦布之前的新大陆是丰富的，在欧洲和北非遗址似乎没有。然而，14世纪90年代之前在这些地区出现的梅毒螺旋体疾病的孤立报告使这场辩论继续存在。此外，还探讨了梅毒螺旋体与梅毒螺旋体亚种之间的关系。引起梅毒的梅毒和其他引起类似但非性病的梅毒、地方性梅毒和梅毒的梅毒亚种仍然困扰着生物学家。尽管这些疾病的特征是症状截然不同，但可以用来区分病原体的形态和遗传差异仍然难以捉摸。这个项目试图用系统地理学来阐明亚种的进化轨迹。样本收集自世界各地的梅毒、雅司病和地方性梅毒。它们代表了目前实验室收集到的最大的非性传播梅毒螺旋体DNA。利用有针对性的遗传分析，将确定亚种内和亚种之间的可变点。然后将对这些差异进行系统发育分析，以检验关于梅毒起源和梅毒螺旋体亚种之间相互关系的各种假说。这个项目解决了病史上的两个长期存在的问题，同时研究了病原体进化对人类施加的选择压力的响应机制。由于来自系统发育方法的信息将与关于过去人群中梅毒螺旋体感染的丰富的古病理学数据相结合，拟议的研究提供了一个独特的机会，将病原体中的适应事件与流行病学和疾病表现以及宿主的社会和性实践的变化联系起来。这种类型的知识将适用于其他人类病原体，如艾滋病毒。传播的进化变化导致一种新的感染模式或现有模式的更高效率，在过去的流行病中发挥了重要作用，是一个主要的公共卫生问题。这项研究可能会阐明这种变化周围的条件和潜在的机制，因此可能有助于为干预提供信息。此外，比较基因分析产生的数据可能有助于理解令人费解的古病理学发现，并通过提供新的客观数据来解开围绕梅毒起源的谜团。最后，这项研究将导致培养一名博士生。

Controversy has surrounded the origin of syphilis since the 15th century. Some have speculated that syphilis arose from a pathogen acquired in the New World by Columbus and his men. Alternative hypotheses are that 1) syphilis was always present in Europe but was previously confused with other diseases such as leprosy; and 2) syphilis arrived in Europe during the Renaissance but originated in Africa and not the New World. A review of the geographical span of the treponematoses over time, as revealed in the paleopathological record, has demonstrated that evidence of treponemal disease is abundant in the Pre-Columbian New World and seemingly absent from European and North African sites. However, isolated reports of treponemal disease in these areas before the 1490s have kept the debate alive. In addition, the relationship between Treponema pallidum subsp. pallidum, the bacterium that causes syphilis, and the other T. pallidum subspecies that cause the similar but non-venereal diseases yaws, endemic syphilis, and pinta continues to puzzle biologists. Although the diseases are characterized by strikingly different symptoms, morphological and genetic differences which can be used to distinguish the pathogens have remained elusive. This project seeks to elucidate the evolutionary trajectory of the subspecies using phylogeography.Samples have been gathered from cases of syphilis, yaws, and endemic syphilis all over the world. They represent the largest collection of non-venereally transmitted T. pallidum DNA available in a lab collection today. Using targeted genetic analysis, variable sites within and between the subspecies will be identified. Phylogenetic analyses will then be performed upon these differences in order to test various hypotheses regarding the origin of syphilis and the relationship of the T. pallidum subspecies to one another.This project addresses two long-standing problems in the history of disease while simultaneously studying mechanisms of pathogen evolution in response to human-imposed selective pressures. Because information from phylogenetic methods will join copious paleopathological data on T. pallidum infection in past populations, the proposed research provides a unique opportunity to link adaptive events in a pathogen to changes in epidemiology and disease manifestations as well as host social and sexual practices. This type of knowledge will be applicable to other human pathogens, such as HIV. Evolutionary changes in transmission, resulting in either a novel mode of infection or greater efficiency in an existing mode, have played important roles in past epidemics and are a major public health concern. This study may elucidate the conditions surrounding and mechanisms underlying such changes and could thus help to inform interventions. In addition, the data produced from comparative genetic analysis may help make sense of puzzling paleopathological findings and dispel the mystery surrounding the origin of syphilis by providing novel objective data. Finally, this study will result in the training of a PhD student.