Software for exploring all forms of genetic variation in any species

现代DNA测序技术已经彻底改变了研究DNA序列的实验设计。 基因组的生物学和性状的遗传基础。可以说，最强大的应用这些 技术已经创造了精致详细的目录，描述了遗传学的景观， 多个物种的变异。然而，基因变异的发现仅仅是一个开始。探索和 需要对所产生的目录进行分析，以促进对基因型之间关系的新认识。 和表型。这一建议的动机是两个基本的限制，抑制发现从遗传 变异数据集首先，现有的用于挖掘变异以了解疾病和其他特征的软件不 可扩展到涉及数千个样本的大型数据集。其次，大多数现有工具都专注于人类 因此，这抑制了现代DNA测序在模型遗传研究中的应用。 生物、牲畜遗传学和新测序的物种。 我们建议通过建立我们的GEMINI框架来解决这些挑战。自2012年以来，我们 GEMINI是一个强大的软件框架，用于探索基因组变异。双子座的优点是 它将遗传变异与一组不同的基因组注释整合到数据库中， 优先化。它允许研究人员基于样本通过简单查询进行复杂分析 基因型、表型、遗传模式和基因组注释。双子座已经迅速成为一个非常 罕见人类疾病研究的流行工具，导致多个实验室的发现，包括我们自己的。 尽管它的力量和受欢迎程度，双子座有三个重要的限制。它不是为 涉及数百个样本的遗传变异的研究。此外，其重点是 单核苷酸（SNP）和插入-缺失（INDEL）分析;它对结构和拷贝数是盲目的 变化量最后，GEMINI只能分析人类基因组的遗传变异数据集，而不能分析其他物种。 或基因组构建得到支持。因此，这项建议旨在为研究任何物种的遗传学家提供 强大、灵活、易用的软件系统，快速且可扩展，足以支持遗传 研究多年来。我们将这样做，但实现以下具体目标： (1)开发一个可扩展的，高性能的基因型和单体型查询引擎， 大规模基因组研究。 (2)设计基因分型、整合和优先考虑结构变异的新方法。 (3)在任何物种和基因组构建中实现可扩展、灵活的基因组分析。 总之，通过完成这些目标，拟议的研究将为遗传学家研究任何 一个强大的，灵活的，简单易用的软件系统，是快速和可扩展的，足以支持 基因研究多年来。

Modern DNA sequencing technologies have revolutionized the design of experiments investigating the biology of the genome and the genetic basis of traits. Arguably the most powerful application of these technologies has been the creation of exquisitely detailed catalogs describing the landscape of genetic variation in multiple species. However, discovery of genetic variation is merely the beginning. Exploration and analysis of the resulting catalogs is required to catalyze new insights into the relationship between genotype and phenotype. This proposal is motivated by two fundamental limitations inhibiting discovery from genetic variation datasets. First, existing software for mining variation to understand disease and other traits does not scale to large datasets involving thousands of samples. Second, most existing tools are focused on human studies; consequently, this inhibits the application of modern DNA sequencing to genetic studies of model organisms, livestock genetics, and newly sequenced species. We propose to solve these challenges by building upon our GEMINI framework. Since 2012, we have maintained GEMINI as a powerful software framework for exploring genome variation. GEMINI's strength is that it integrates genetic variation with a diverse set of genome annotations into a database to facilitate variant prioritization. It allows researchers to conduct complex analyses with simple queries based on sample genotypes, phenotypes, inheritance patterns, and genome annotations. GEMINI has quickly become a very popular tool for rare human disease research leading to discoveries by multiple labs, including our own. Despite its power and popularity, GEMINI has three important limitations. It was not designed for studies involving genetic variation from more than a few hundred samples. Furthermore, its focus is the analysis of single-nucleotide (SNP) and insertion-deletion (INDEL); it is blind to structural and copy number variation. Finally, GEMINI can only analyze genetic variation datasets for the human genome; no other species or genome builds are supported. Therefore, this proposal seeks to provide geneticists studying any species with a powerful, flexible and simple to use software system that is fast and scalable enough to support genetic research for many years to come. We will do this but achieving the following Specific Aims: (1) Develop a scalable, high performance genotype and haplotype query engine to empower large scale genome studies. (2) Devise new methods for genotyping, integrating and prioritizing structural variation. (3) Enable scalable, flexible genome analysis in any species and genome build. In summary, by completing these aims, the proposed research will provide geneticists studying any species with a powerful, flexible and simple to use software system that is fast and scalable enough to support genetic research for many years to come.