CAREER: Algorithms for single molecule sequence analysis

冷泉港实验室被授予PI Michael Schatz职业资助金，以开发处理来自最新高通量测序技术的DNA测序数据的新计算方法。在过去的三十年里，DNA测序的成本和吞吐量已经提高了几个数量级，尽管许多问题仍然没有得到解决，特别是因为目前可以获得的短序列长度。太平洋生物科学公司、Moleculo公司、牛津纳米孔公司和其他公司正在开发的“第三代”测序技术将使DNA和RNA的长分子测序成为可能，从而给基因组学带来革命性的变化。使用这些技术的序列长度可以达到数万个核苷酸，但很少或没有分析包能够处理这些类型的遗传序列数据。该项目将通过开发几种新的分析算法来克服这些限制，这些算法专门用于长读数单分子测序及其相关的复杂误差模型。这些结果将有助于回答对所有社会都具有深远意义的生物学问题，例如：水稻驯化的遗传影响是什么？是什么基因和调控元件产生了扁虫令人难以置信的再生特性？或者，从组装甘蔗和菠萝的参考基因组到培育更强大的植物和生物燃料，我们能理解什么？这项研究的具体目标包括努力将整个植物和动物染色体组装成完整的单倍型阶段性序列；识别与疾病或适应性有关的融合基因和复杂的替代剪接模式；以及寻找与作物产量提高或人类疾病(如癌症或自闭症)相关的结构变异。即使一些未来的技术能够直接读取整个转录本或整个基因组，这项研究仍将是必要的，以检查基因组群体之间的更高级别的关系，或在测量基因表达和剪接的动态方面。该项目将紧密结合研究和教育，通过开发新的课程材料、实践研究机会和一对一的指导经验，促进高中到博士后水平的机会。这项工作将特别针对计算机科学和生物学的交叉，促进跨学科教育，并确保下一代科学家为复杂的定量和数字生物学做好准备。为了吸引尽可能广泛的受众，沙茨博士还将开发新颖的在线教学材料，通过一年一度的生物信息学竞赛提供。第一轮比赛覆盖了全球近1000名学生和各级教育，吸引了远远超出我们身体极限的学生。这项研究的产品将以开源软件的形式提供，并安装在图形化的iPLANT发现环境中，使世界各地的大型植物研究人员能够轻松地访问它们。

The Cold Spring Harbor Laboratory is awarded a CAREER grant for the PI Michael Schatz to develop new computational methods for processing DNA sequencing data from the latest high-throughput sequencing technologies. DNA sequencing costs and throughput have improved by orders of magnitudes over the last three decades, although many questions remain unsolved, especially because of the short sequence lengths currently available. Emerging "third generation" sequencing technology from Pacific Biosciences, Moleculo, Oxford Nanopore, and other companies are poised to revolutionize genomics by enabling the sequencing of long, individual molecules of DNA and RNA. The sequence lengths with these technologies can reach up to tens of thousands of nucleotides, however few or no analysis packages are capable of dealing with these types of genetic sequence data. This project will overcome these limitations by developing several novel analysis algorithms specifically for long read single molecule sequencing and their associated complex error models. The outcomes will help answer biological questions of profound significance to all of society, such as: What were the genetic implications of the domestication of rice? What genes and regulatory elements give rise to the incredible regenerative properties of the flatworm? or, What can be understood from assembling reference genomes of sugarcane and pineapple towards breeding more robust plant crops and biofuels?Specific objectives of the research include working towards assembling entire plant and animal chromosomes into complete, haplotype-phased sequences; identifying fusion genes and complex alternative splicing patterns responsible for diseases or adaptability; and searching for structural variations associated with improved crop yield or human diseases such as cancer or autism. Even if some future technology is capable of directly reading entire transcripts or entire genomes, this research will remain necessary to examine the higher level relationships across populations of genomes or in measuring the dynamics of gene expression and splicing.This project will tightly integrate research and education, promoting opportunities at high school through postdoctoral levels with the development of new course materials, hands-on research opportunities, and one-on-one mentoring experiences. This effort will specifically target the intersection of computer science and biology, promoting interdisciplinary education, and ensuring the next generation of scientists are ready for the complexities of quantitative and digital biology. To engage the widest possible audience, Dr Schatz will also develop novel online teaching materials made available through a yearly bioinformatics contest. The first round of the contest reached nearly 1000 students around the world and at all levels of education, engaging students far beyond our physical limits. The products of the research will be made available as open-source software, and installed into the graphical iPlant Discovery Environment making them easily accessible to the large community of plant researcher around the world.