Evolutionary Bioinformatics of Human Mutations

描述(由申请人提供)： 将基因组进步转化为生物医学解决方案的一个长期障碍是缺乏工具和技术，使生物学家能够[a]在他们的研究工作中有效地利用大量可公开获得的基因组变异数据，并[b]有效地利用突变位置的长期(种间)进化历史来诊断新突变的功能影响。随着在个人基因组和人口调查中发现前所未有数量的新突变，这种需求变得更加迫切。因此，我们提出了一个综合性的研发项目来满足这一需求。首先，我们计划开发独特的、用户友好的和强大的软件来研究基因组规模上的长期进化(LTE)模式背景下的人类突变；LTE模式是通过一个位置的物种间比较来揭示的，它们为分析突变的性质和当代变异的频率提供了合理的基线假设。拟议的myPEG(人口进化基因组学)软件将包含来自初级基因组比对浏览器和突变数据库(例如，UCSC、1000Genome、DBSNP)的自动化数据组装和集成工具。MyPEG将使用户能够通过其跨平台的Webtop显示和分析框架进行跨分类尺度的综合分析，该框架将以传统和新颖的方式无缝地整合物种和种群序列比对和分析。MyPEG的软件设计和开发方法将是以生物学家为中心的，在这种方法中，我们模仿而不是重新发明生物学家最喜欢的工作实践。这些软件开发将从拟议的基础研究中获得信息，以开发宏观进化模式在与疾病相关的突变(例如孟德尔突变、复杂突变和体细胞突变)诊断中的直接应用，以及它们在计算机工具中使用的计算预测的成功。拟议的研究将得出与疾病相关的和其他突变(包括群体SNPs)的进化解剖以及目前用于诊断新突变的功能影响的所有主要电子工具的成功率的异同。这些发现将成为开发决策支持系统的基础，以便为突变类型和目的(疾病类型)选择最佳的计算机方法，从而使计算机推理(ROI)的可靠性最高。MyPEG将包含这一决策支持系统，以及对大量突变进行原型制作和高通量迭代分析的设施。MyPEG将在所有主要平台(Windows、Linux和MacOS)上运行，将在这些操作系统中作为分析管道的本地插件使用，并且将免费向所有用户提供(包括源代码)，包括研究、教育和培训中的用户。

DESCRIPTION (provided by applicant): An enduring impediment in translating genomic advances into biomedical solutions has been the lack of tools and techniques that enable biologists to [a] efficiently leverage the multitude of publically- available genome variation data in their research endeavors, and [b] effectively harness the long-term (inter-specific) evolutionary histories of mutant positions in diagnosing functional effects of novel mutations. This need has become more acute with the discovery of unprecedented numbers of novel mutations in personal genomes and population surveys. Therefore, we propose an integrated research and development project to address this need. First, we plan to develop unique, user-friendly, and robust software to investigate human mutations in the context of Long-Term Evolutionary (LTE) patterns on a genomic scale; LTE patterns are revealed by inter-specific comparisons at a position, and they provide sound baseline hypotheses for analyzing the nature of mutations and frequencies of contemporary variations. The proposed myPEG (Population Evolutionary Genomics) software will contain tools for automated data assembly and integration from primary genome alignment browsers and mutation databases (e.g., UCSC, 1000Genomes, dbSNP). myPEG will enable users to conduct integrative analysis across taxonomic scales via its cross-platform WebTop display and analysis framework that will seamlessly integrate species and population sequence alignments and analyses in traditional and novel ways. myPEG's approach to software design and development will be biologist- centric in which we emulate, rather than reinvent, biologists' favorite work practices. These software developments will be informed by the proposed fundamental research to develop direct applications of macro-evolutionary patterns to the diagnosis of mutations associated with disease (e.g., Mendelian, complex, and somatic-cell mutations), and the successes of their computational predictions using in silico tools. The proposed investigations will yield similarities and differences in evolutionary anatomies of disease-associated and other mutations (including population SNPs) as well as those of the success rates of all major in silico tools currently used for diagnosing functional effects of novel mutations. These discoveries will form the basis for developing a decision support system to choose the best in silico method for the type of mutation and purpose (type of disease), such that the Reliability of in silico Inference (RoI) is the highest. myPEG will contain this decision support system, along with facilities for prototyping and conducting high-throughput iterative analysis of large numbers of mutations. myPEG will run on all major platforms (Windows, Linux, and MacOS), will be useable as a plug-in into analysis pipelines natively in these operating systems, and will be available at no cost (including the source code) to all users, including those in research, education, and training.