Doctoral Dissertation Improvement: Genetic Marker Bias Effects on Inferences of Human Evolutionary History

人类作为一个物种，在其基因组中的DNA变异模式中携带着其历史的许多证据。人类学家利用人类种群的遗传变异模式来推断过去的人类迁徙和种群间的分化。遗传数据也被用来区分自然选择、人类行为和随机事件，因为它们在分子水平上对人类进化有影响。然而，那些明显表明进化力量的模式可能是在研究中包含特定类型的遗传变异的偏见的产物。在发现可测试的基因变异或设计数据库或基因芯片期间，可能会引入偏差。在这个项目中，研究人员将检查当前人类遗传变异公共数据库（即HapMap）设计中的偏差以及收集遗传数据的最新工具（基因芯片或微阵列）对分子人类学研究结果的影响程度。他们询问，医学界广泛用于基因定位的预制基因芯片和基因数据库是否适合推断种群历史和人类进化，在哪种类型的种群中，预期会出现显著的偏见影响，以及这种偏见的性质和后果。例如，本研究将主要使用东南亚人口，这些人口在人类基因组的原始研究和当前基因定位技术的发展中代表性不足。唾液样本将从居住在泰国北部的至少四个少数民族（阿卡族、傈僳族、拉祜族、苗族或克伦族）的个人身上收集，作为DNA的来源，这些少数民族通常被称为山地部落。人们对这些种群感兴趣是因为他们在亚洲有复杂的迁徙历史，而且个体不太可能与异族通婚。来自其他亚洲和非亚洲多数人群的DNA已经可以用于这项研究。每个种群内部和种群之间的遗传变异将被测量，这些信息将被汇编成人工模拟种群，用来测试假设，这将有助于研究人员更好地理解实际观察结果。然后将对结果进行分析，以作为每组遗传变异的已知进化事件的证据。对结果的比较将显示哪些类型的偏差对这种推断有重大影响，并允许对所研究的群体进行更全面的遗传表征。这项研究的更广泛的影响包括描述了科学家对人类扩散和人口历史的看法的准确性在多大程度上可能受到广泛可用的基因分型工具和最初为基因定位设计的数据库的偏见的影响。该项目还将促进国际（泰国和美国）、跨学科（人类学、精神病学和遗传学）和机构（纽约大学文理研究生院和耶鲁大学医学院）的合作。本研究收集的样本和数据将用于美国和泰国研究人员的研究生培训，并打算在未来继续这种国际合作。

Human beings carry evidence of much of their history as a species in patterns of DNA variation in their genomes. Anthropologists have used patterns of genetic variation in human populations to infer past human migrations and divergences between populations. Genetic data also have been used to distinguish between natural selection, human behavior, and random events, as influences on human evolution at the molecular level. However, patterns that are apparently indicative of evolutionary forces may instead be artifacts of biases towards the inclusion of particular types of genetic variants in a study. Biases can be introduced during the discovery of testable genetic variants or during the design of databases or gene chips. In this project, the researchers will examine the extent to which biases in the design of current public databases of human genetic variation (i.e. HapMap) and the latest tools for gathering genetic data (gene chips or microarrays) affect results of molecular anthropology studies. They ask whether or not pre-made gene chips and genetic databases widely used by the medical community for gene mapping are appropriate for inferring population history and human evolution, within what types of populations significant effects of bias would be expected, and the nature and consequences of such bias.As an example, this research will use predominantly Southeast Asian populations which were underrepresented in the original studies of the human genome and development of current gene mapping technologies. Saliva samples will be collected from individuals as a source of DNA from a minimum of four ethnic minorities (Akha, Lisu, Lahu, Hmong, or Karen), commonly referred to as Hill Tribes, residing in Northern Thailand. These populations are of interest because they are known to have complex migratory histories throughout Asia, and individuals are unlikely to marry outside of their ethnicity. DNA from other Asian and non-Asian majority populations is already available for use in this study. Genetic variation within and between each population will be measured, and this information will be compiled to create artificial simulated populations with which to test hypotheses, which will help the researchers to understand actual observations better. Results will then be analyzed for evidence of known kinds of evolutionary events for each group of genetic variants. Comparison of the results will show what types of biases have significant affects on such inferences, and allow for a more comprehensive genetic characterization of the populations under study.The broader impacts of this study include describing the extent to which the accuracy of scientists' views of human dispersal and population history may be affected by biases in widely-available genotyping tools and databases originally designed for gene mapping. This project will also facilitate international (Thailand and United States), interdisciplinary (Anthropology, Psychiatry, and Genetics), and institutional (New York University Graduate School of Arts and Sciences and Yale University School of Medicine) collaborations. Both samples and data collected for this study will be used for graduate student training of American and Thai researchers, with the intent to continue this international collaboration in the future.