BBSRC Institute Strategic Programme: Cellular Genomics (CELLGEN) - Partner Grant

细胞是生物学的基本单位，细胞异质性是多细胞生命的标志。在一个有机体-植物，动物或人类-细胞可以显示出巨大的功能多样性，履行不同的角色，支持有机体的整体功能。细胞功能的多样性反映了不同的“分子细胞身份”，来自每个细胞基因组的变化，它们是如何调节的，以及它们表达的基因。因此，将细胞视角引入功能基因组学实验是揭示生物体内基因组序列和调控的变化如何有助于其整体功能和表型的关键。细胞基因组学项目（CELLGEN）建立在EI在数据科学、生物信息学和单细胞分析方面的专业知识基础上，旨在研究健康植物和动物的基因组和转录组异质性的影响。分子和计算科学的最新发展开创了单细胞基因组学的时代，可以轻松分析单个细胞的基因组、表观基因组和转录组。在几个模型系统中，这些方法强调了基因组功能-以及基因组序列-在健康寿命期间在同一生物体的细胞之间可以变化的程度。在这里，我们寻求利用和发展这些方法来探索模型和非模型生物体内基因组和转录组异质性的起源和后果。这些分析生成高价值，高密度的数据集，我们的计划采取数据科学主导的方法。我们的工作计划以WP 1“细胞基因组学的数据科学”为主导，该计划开发了管理和协调数据集的方法，以实现可重复性，可重用性，比较，最重要的是跨研究的整合。WP 2“体细胞突变对性状的影响”研究了生物体内基因组变异的多样性和后果。我们将开发方法来测量新出现的基因组异质性（串联重复序列和多倍体）及其对细胞中基因和亚型表达的即时和长期影响-使用模型细胞系或来自植物（毛状体）和小鼠（巨核细胞）的初级多倍体细胞。我们将测试关于细胞基因组变异与生物体更广泛表型之间关系的新假设，例如测量单个细胞之间的遗传变异对基因调控的影响。这可以直接关系到基因如何在组织和整个生物体水平上表达。WP 3“细胞异质性和表达调控”描述了细胞转录组异质性及其对细胞和生物体对环境反应的影响。在这里，我们将探索细胞谱系定型（造血）和对环境挑战（鱼，植物）和饮食干预的反应的植物和动物模型中的基因表达调控。这项工作计划将使研究人员能够在不同的生物系统协同工作，探索整个生命之树的共同主题。它将使EI成为非模型生物、植物和动物单细胞开发的世界领导者，超越细胞类型分类，并提供以先进数据科学方法为基础的可扩展细胞功能基因组学的新方法。通过探索健康生命周期中基因组和转录组变异的后果，以及细胞多样性如何支撑生物体对环境的适应，CELLGEN将产生对生命规则的新见解

Cells are a fundamental unit of biology and cellular heterogeneity is a hallmark of multicellular life. Within an organism -plant, animal or human - cells can display enormous functional diversity, fulfilling distinct roles that underpin the overall function of the organism. The diversity of cell function reflects distinct "molecular cell identities", emerging from variation in the genomes of each cell, how they are regulated, and the genes they express. Incorporating a cellular perspective into functional genomics experiments is therefore key to unravel how variation in sequence and regulation of the genome within an organism can contribute to its overall function and phenotype. The Cellular Genomics programme (CELLGEN) builds on EI expertise in data science, bioinformatics and single-cell analysis to investigate the impact of genomic and transcriptomic heterogeneity in healthy plants and animals.Recent developments in molecular and computational science have ushered in an era of single-cell genomics, in which the analysis of the genomes, epigenomes and transcriptomes of individual cells can readily be analysed. In several model systems, these approaches have highlighted the extent to which genome function - but also genome sequence - can vary between cells of the same organism during the healthy lifespan. Here, we seek to leverage and develop these approaches to explore the origins and consequences of genomic and transcriptomic heterogeneity within model and non-model organisms.These analyses generate high-value, highly-dense datasets, and our programme takes a data-science led approach. Our programme of work leads with WP1 "Data Science for Cellular Genomics" which develops approaches to curate and harmonise datasets, to enable reproducibility, reusability, comparison, and most importantly integration across studies.WP2 "Consequences of somatic mutations on traits" investigates the diversity and consequences of intraorganismal genomic variation. We will develop approaches to measure emerging genomic heterogeneity (tandem repeats and polyploidisation) and their immediate and long term effects on gene and isoform expression in cells - using model cell lines or primary polyploid cells from plants (trichomes) and mouse (megakaryocytes). We will test novel hypotheses about the relationship between cellular genomic variation and the wider phenotype of the organism, for example measuring the impact of genetic variation between individual cells on gene regulation. This can then be directly related to how genes are expressed at the tissue and whole organism levels.WP3 "Cellular heterogeneity and expression regulation" characterises cellular transcriptomic heterogeneity and its impact on cell and organism responses to the environment. Here we will explore the regulation of gene expression in plant and animal models of cell lineage commitment (haematopoiesis) and responses to environmental challenges (fish, plant) and dietary intervention.This programme of work will enable researchers working on diverse biological systems to work synergistically to explore common themes across the tree of life. It will position EI as a world leader in single-cell developments for non-model organisms, plants and animals, going beyond cell-type classification and delivering novel approaches for scalable cellular functional genomics underpinned by advanced data science approaches. By exploring consequences of genomic and transcriptomic variation during a healthy lifespan and into how cellular diversity underpins organismal adaptation to environment, CELLGEN will generate new insights into the rules of life