GENETIC VARIATION IN MURINE LONG BONE GROWTH AND DEVELOPMENT

小鼠长骨生长和发育的遗传变异

• 批准号: 7147809
• 负责人: JAMES M CHEVERUD
• 金额: $ 33.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147809
• 关键词: aging; bone; emotions; gene expression; genes; genetics; growth /development; limbs

DESCRIPTION (provided by applicant): There are a wide range of human clinical disorders in limb growth. Some are due to single genes while others are complex, due to many genes and their interactions with each other and the environment. Longitudinal studies of the cellular and molecular bases for variation in limb growth are hampered by the need for destructive or terminal sampling to obtain phenotypic measures, even in model organisms. We propose to measure genetic variation in long bone growth, associated histomorphological features, and gene expression in mice in order to identify the genetic and physiological processes underlying limb growth variations. These studies will be carried out with animals from the LGXSM Recombinant Inbred (Rl) strains. Previous mapping studies in the F2 intercross of these strains uncovered 17 genomic locations affecting adult long bone length. However, these earlier studies do not identify which developmental periods or physiological processes are responsible for variations in limb length. We will map limb growth QTLs in the Rl strains because this allows the collection of detailed phenotypes requiring terminal preparations at a series of consecutive ages on animals of identical genotype. Thus, we will be able to obtain "longitudinal" data for limb growth traits for specific genotypes. Mapping limb growth QTLs in the Rl strains will identify genomic regions affecting long bone growth and its associated physiological and molecular processes to 15 cM regions of the genome. We will fine-map these QTLs in the Advanced Intercross (Al) line formed by repeatedly intercrossing LG/J and SM/J strains to the F32 generation. At this point they will have accumulated 16x the recombination generated in the original F2 intercross allowing for 16x the genomic mapping resolution (sub-cM scale). Positional candidate genes will be identified within the sub-cM QTL support regions and evaluated for sequence and expression differences between the parental lines. The outcome of these experiments will be a better understanding of the genetic, molecular, and cellular processes responsible for variation in limb growth with consequences for our understanding of pathologies of growth.

描述（由申请人提供）：人类肢体生长方面存在多种临床疾病。有些是由单一基因引起的，而另一些则是复杂的，由于许多基因及其彼此之间以及环境之间的相互作用。对肢体生长变异的细胞和分子基础的纵向研究受到破坏性或最终采样以获得表型测量的需要的阻碍，即使在模型生物体中也是如此。我们建议测量小鼠长骨生长的遗传变异、相关的组织形态学特征和基因表达，以识别肢体生长变异背后的遗传和生理过程。这些研究将使用 LGXSM 重组近交系 (R1) 品系的动物进行。先前对这些菌株的 F2 杂交进行的绘图研究发现了影响成年长骨长度的 17 个基因组位置。然而，这些早期的研究并没有确定哪些发育时期或生理过程导致了肢体长度的变化。我们将绘制R1品系中肢体生长QTL的图谱，因为这允许收集需要在相同基因型动物的一系列连续年龄处进行最终准备的详细表型。因此，我们将能够获得特定基因型肢体生长性状的“纵向”数据。绘制R1品系中肢体生长QTL的图谱将鉴定影响长骨生长及其相关生理和分子过程的基因组区域至基因组的15cM区域。我们将通过 LG/J 和 SM/J 品系反复杂交形成的高级互交 (Al) 系中的这些 QTL 精细定位到 F32 代。此时，它们将积累 16 倍于原始 F2 杂交中生成的重组，从而实现 16 倍的基因组作图分辨率（亚厘米尺度）。将在亚cM QTL支持区域内鉴定位置候选基因，并评估亲本系之间的序列和表达差异。这些实验的结果将是更好地理解导致肢体生长变化的遗传、分子和细胞过程，从而影响我们对生长病理学的理解。