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。在一个生物体内——植物、动物或人类——细胞可以显示出巨大的功能多样性，履行着支撑有机体整体功能的不同角色。细胞功能的多样性反映了不同的“分子细胞身份”，这些身份来自于每个细胞基因组的变化、它们是如何被调节的以及它们表达的基因。因此，将细胞视角纳入功能基因组学实验是揭示生物体中基因组序列和调控的变化如何影响其整体功能和表型的关键。细胞基因组学计划（CELLGEN）以EI在数据科学、生物信息学和单细胞分析方面的专业知识为基础，研究基因组和转录组异质性对健康动植物的影响。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，在这个时代，对单个细胞的基因组、表观基因组和转录组的分析可以很容易地进行分析。在一些模型系统中，这些方法强调了基因组功能（以及基因组序列）在同一生物体的健康寿命期间不同细胞之间的变化程度。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中基因组和转录组异质性的起源和后果。这些分析产生高价值、高密度的数据集，我们的课程采用数据科学为主导的方法。我们的工作计划以WP1“细胞基因组学数据科学”为主导，该项目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。WP2“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（串联重复和多倍体化）及其对细胞中基因和异构体表达的直接和长期影响-使用模型细胞系或来自植物（毛状体）和小鼠（巨核细胞）的原代多倍体细胞。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遗传变异对基因调控的影响。这可以直接联系到基因在组织和整个生物体水平上的表达方式。WP3“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，我们将探讨细胞谱系承诺（造血）和对环境挑战（鱼类，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不同生物系统的研究人员能够协同工作，探索整个生命之树的共同主题。它将使EI在非模式生物、植物和动物的单细胞开发方面处于世界领先地位，超越细胞类型分类，并提供基于先进数据科学方法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将对生命规律产生新的见解

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