Sensitized Screen in the Diversity Outcross Mouse Population

多样性异型杂交小鼠群体的敏化筛选

• 批准号: 8392559
• 负责人: Steven Carmen Munger
• 金额: $ 5.22万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2015-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392559
• 关键词: Accounting; Adult; Affect; Architecture; Automobile Driving; Buffers; Cells; Chromosome Mapping; Classification; Complex; Congenital Abnormality; Constitution; Data; Data Set; Development; Disease; Disease susceptibility; Embryo; Equilibrium; Etiology; Failure; Female; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Goals; Gonadal structure; Haplotypes; Homeostasis; Human; Hybrids; Individual; Infant; Life; Maps; Measurement; Measures; Methods; Modeling; Mus; Mutation; Network-based; Organ; Outcome; Output; Ovarian; Ovary; Phenotypic Sex; Plant Roots; Population; Population Heterogeneity; Predisposition; Pregnancy; Process; Property; Quantitative Trait Loci; RNA; Recombinant Inbred Strain; Research; Research Design; Resolution; Scheme; Severities; Severity of illness; Sex Chromosomes; Statistical Models; Structure; Surveys; System; Testing; Testis; Time; Tissues; Transcript; Treatment Effectiveness; Up-Regulation; Validation; Variant; analytical method; base; critical period; genetic strain; genetic variant; genome-wide; male; mathematical model; mutant; network models; novel; outcome forecast; predictive modeling; sex; sex determination

DESCRIPTION (provided by applicant): An individual's genetic makeup influences their susceptibility to disease or disorder, and can also affect disease severity, prognosis, and even treatment options. Most genetic variants exert subtle effects in isolation, and are thus maintained in the population. However, certain combinations of variants are incompatible; yet it remains poorly understood how an accumulation of small genetic perturbations can compromise normal homeostasis and sensitize a tissue to disorder. The current project will characterize how natural genetic variation segregating in a sensitized population interacts to disrupt the buffering capacity of a transcription network during organ development. The proposed research will take a systems genetics approach to model the transcription network in the embryonic mouse gonad during sex determination. The gonad arises at mid-gestation competent to differentiate as a testis or ovary irrespective of sex chromosome constitution. This unique plasticity is conferred by a balanced transcriptome with features associated with both differentiated sexual fates. Failure to establish or maintain one sexual fate (e.g. testis) causes sex reversal to the alternative fate (e.g. ovary). Genetic background is known to affect susceptibility to sex reversal by unbalancing the underlying transcription network. The proposed sensitized screen will introduce a background-dependent sex-reversing mutation to sensitize a genetic mapping population to sex reversal. This highly diverse population of genetically unique individuals, the Diversity Outbred (DO) stock, is derived from the same eight founder strains as the emerging Collaborative Cross (CC) recombinant inbred strains, and captures genome-wide high levels of genetic variation and provides high mapping resolution. Aim 1 will characterize the expression of a subset of known sex determination genes in gonads from the DO panel, eight CC founder strains, and the sex-reversing Dax1/Nr0b1 mutant strain. This survey will provide a baseline measurement of expression variability in the DO population and enable the modeling of an undirected transcription network based on coexpression relationships. Aim 2 will derive a large population of DO embryos that are sensitized to sex reversal by the Dax1/Nr0b1 mutation. Regions of the genome that affect gene expression in the gonad (expression quantitative trait loci, or eQTL) will be identified from a combination of RNA-Seq expression and dense genotyping data. The resulting eQTL data will be used to develop a detailed predictive network model of sex determination. PUBLIC HEALTH RELEVANCE: Congenital abnormalities (i.e. birth defects) present in 2-3 percent of infants as a result of insults to the normal process of organ development. As we refine our understanding of congenital as well as adult disorders, it is becoming apparent that most have a significant genetic component and are rooted at least in part in embryonic life. The proposed research will characterize how natural variation segregating in a genetically diverse, sensitized population interacts to disrupt the buffering capacity of a transcription network during organ development.

描述（由申请人提供）：一个人的遗传组成影响他们对疾病或病症的易感性，也可以影响疾病的严重程度，预后，甚至治疗方案。大多数遗传变异在孤立的情况下产生微妙的影响，因此在群体中得以维持。然而，某些变异的组合是不相容的;然而，人们对小的遗传扰动的积累如何损害正常的体内平衡并使组织对疾病敏感仍然知之甚少。目前的项目将描述自然遗传变异在致敏人群中的分离是如何相互作用破坏缓冲的 器官发育过程中转录网络的能力。 这项研究将采用系统遗传学方法来模拟小鼠胚胎性腺在性别决定过程中的转录网络。生殖腺在妊娠中期出现，有能力分化为睾丸或卵巢，与性染色体的构成无关。这种独特的可塑性是由一个平衡的转录组赋予的，其特征与两种分化的性命运有关。不能建立或维持一种性命运（例如睾丸）会导致另一种性命运（例如卵巢）的性逆转。已知遗传背景会影响性反转的易感性 通过打破底层转录网络的平衡所提出的敏化筛选将引入背景依赖性性别逆转突变，以使遗传作图人群对性别逆转敏感。这种高度多样化的遗传独特个体群体，即多样性远交（DO）原种，源自与新兴的协作杂交（CC）重组近交品系相同的八个创始品系，并捕获全基因组高水平的遗传变异并提供高作图分辨率。 目的1将表征来自DO组、8个CC创始菌株和性别逆转Dax 1/Nr 0 b1突变菌株的性腺中已知性别决定基因子集的表达。该调查将提供DO群体中表达变异性的基线测量，并使基于共表达关系的无向转录网络的建模成为可能。 目的2将获得大量的DO胚胎，这些胚胎对Dax 1/Nr 0 b1突变的性逆转敏感。将从RNA-Seq表达和密集基因分型数据的组合中鉴定影响性腺中基因表达的基因组区域（表达数量性状基因座，或eQTL）。所得到的eQTL数据将用于开发详细的性别决定预测网络模型。 公共卫生相关性：由于器官发育的正常过程受到损害，2%至3%的婴儿存在先天性畸形（即出生缺陷）。随着我们对先天性疾病和成人疾病的理解不断加深，越来越明显的是，大多数疾病都有重要的遗传成分，至少部分根源于胚胎生命。拟议的研究将描述在遗传多样性，致敏人群中分离的自然变异如何相互作用，以破坏转录网络的缓冲能力， 器官发育。