Models of Complex Genetic Systems

描述（由申请人提供）：新的DNA测序方法已经产生了大量来自人类和许多其他物种的DNA序列，包括现已灭绝的物种。拟议的研究将有助于分析和解释DNA序列数据，以了解基本的遗传过程，如自然选择和重组，并了解人类的历史和遗传疾病的遗传基础。拟议的研究包括四个方面：(i)分析来自尼安德特人骨骼的DNA序列数据，以了解尼安德特人与现代人之间的关系，并了解现代人自与尼安德特人分离以来的近代史；（ii）预测最近范围扩张的人群的基因频率模式，特别强调过去在欧洲、亚洲和美洲的现代人类种群的范围扩张；（三）分析从极端环境样品中获得的细菌物种的DNA序列，以便量化不同菌株之间的基因重组和分化程度；（四）建立复杂遗传疾病（如精神分裂症、许多癌症以及1型和2型糖尿病）的遗传基础模型；为了量化产生高风险的基因之间的相互作用，并设计新的方法来识别与高风险相关的基因。虽然这四个领域的目标有些不同，但每个领域都将使用类似的数学和统计方法。人口遗传力量的模型，包括自然选择、重组、遗传漂变和迁移，将根据现有数据进行开发和测试。这些模型的计算机模拟将用于产生假设的数据集，以检验提出的统计方法。

DESCRIPTION (provided by applicant): New methods of DNA sequencing have produced a great abundance of DNA sequences from humans and many other species, including species now extinct. The proposed research will be intended to help analyze and interpret DNA sequence data both for understanding basic genetic processes such as natural selection and recombination and for understanding the history of humans and the genetic basis of inherited diseases. The proposed research is in four areas: (i) the analysis of DNA sequence data from Neanderthal bones for the purpose of understanding the relationship between Neanderthals and modern humans and for understanding the recent history of modern humans since their separation from Neanderthals, (ii) the prediction of patterns in gene frequencies in populations that have undergone a recent range expansion, with particular emphasis on past range expansions of modern humans populations in Europe, Asia, and the Americas, (iii) the analysis of DNA sequences of bacterial species obtained in samples from extreme environments, for the purpose of quantifying the extent of genetic recombination and differentiation between different strains, (iv) modeling the genetic basis of complex inherited diseases such as schizophrenia, many cancers, and type 1 and 2 diabetes, for the purpose of quantifying the interactions among genes that create higher risk and for devising new methods for identifying genes associated with higher risk. Although the goals of the four areas are somewhat different, similar mathematical and statistical methods will be used in each. Models of population genetic forces, including natural selection, recombination, genetic drift, and migration will be developed and tested against available data. Computer simulations of those models will be used to generate hypothetical data sets for testing proposed statistical methods. PUBLIC HEALTH RELEVANCE: Diseases, such as cancer, heart disease, and diabetes, that are partly inherited yet are not caused by defects in single genes, are the leading cause of mortality in the US and other developed countries. The proposed research will develop mathematical and statistical tools that will help with understanding the genetic basis of such diseases, both by improving the understanding of the history of modern humans and by finding new ways to identify genes causing a higher risk of such diseases.