ABI Innovation: Beyond dN/dS: Population Genetics, Genome Structure, and Protein Structure

全基因组序列，包括所有编码蛋白质的基因的序列，现在存在于许多不同的物种中。在这些序列中存在着物种分化的分子基础。目前，系统地比较不同物种的同源基因并预测哪些基因的功能发生了变化是不可能的。将开发新的机制模型来描述潜在的种群遗传、进化和生化过程以及对物种之间氨基酸变化的限制，并将其应用于基因组比较，包括人类和黑猩猩之间的差异。此外，该项目将为本科生和研究生提供教育机会，以及博士后培训。此外，还将制作关于比较基因组学的流行视频、互动教育网站和基于海报的博物馆展览，向科普观众解释比较基因组分析的概念。该项目涉及与美国自然历史博物馆和新西兰奥塔戈大学的研究人员的合作。目前比较基因组学中广泛使用的方法只是寻找改变编码氨基酸的核苷酸变化的统计过剩，根据同义核苷酸变化的预期(非同义核苷酸替换率与同义核苷酸替换率的比率)进行归一化，但没有关注氨基酸生物化学或结构生物学。他们也没有考虑基因组结构(连锁)或群体遗传学考虑的氨基酸变化的固定概率。这项研究将开发出一种方法，在一个群体遗传模型中以不同的方式明确地考虑染色体上的位点链接，并考虑氨基酸变化的生化和结构背景。新的模型最初将用于比较人类和黑猩猩的基因组蛋白质编码集，随后将在系统发育的背景下实施，以实现对来自多个物种的基因家族的比较。这种建模方法的潜在下游应用包括预测蛋白质或功能发生变化的途径，这种方法能够更好地从机制上理解谱系特定的进化。这可以指向使物种独一无二的蛋白质和途径，并验证模式生物何时可能成为特定分子系统的良好模型。与该项目相关的信息将在http://www.wyomingbioinformatics.org/LiberlesGroup.上获得

Full genome sequences, including the sequence for all protein-encoding genes, now exist for many different species. Within these sequences lie the molecular underpinnings of species differentiation. Presently it is not possible to systematically compare homologous genes from different species and predict which have changed function. New mechanistic models that describe the underlying population genetic, evolutionary, and biochemical processes and constraints on amino acid change between species will be developed and applied to genome comparisons, including to the divergence between humans and chimpanzees. Additionally, the project will provide educational opportunities for undergraduate and graduate students as well as postdoctoral training. Further, a popular video, interactive educational website, and poster-based museum exhibit on comparative genomics will be produced to explain the concepts of comparative genomic analysis to a popular science audience. The project involves collaboration with the American Museum of Natural History and researchers at University of Otago in New Zealand.Current widely used approaches in comparative genomics simply look for a statistical excess of nucleotide changes that change the encoded amino acid, normalized by the expectation from synonymous nucleotide changes (the ratio of nonsynonymous to synonymous nucleotide substitution rates), but do not look at amino acid biochemistry or structural biology. They also do not consider genome structure (linkage) or population genetic considerations of the probability of fixation of an amino acid change. This research will develop approaches that explicitly consider the linkage of sites on chromosomes in a population genetic model and in different ways, also consider the biochemical and structural context of amino acid changes. The new models will be used initially in comparisons of the human and chimpanzee genome protein coding set and will subsequently be implemented in a phylogenetic context to enable comparison of gene families from multiple species. Potential downstream applications of this modeling approach that enables better mechanistic understanding of lineage-specific evolution include prediction of proteins or pathways where functions have changed. This can point to proteins and pathways that make a species unique as well as validating when model organisms are likely to be good models for particular molecular systems. Information related to this project will be available at http://www.wyomingbioinformatics.org/LiberlesGroup.