Underlying variation in height are regulatory changes to chondrocytes, cartilage cells comprising long-bone growth plates. Currently, we lack knowledge on epigenetic regulation and gene expression of chondrocytes sampled across the human skeleton, and therefore we cannot understand basic regulatory mechanisms controlling height biology. We first rectify this issue by generating extensive epigenetic and transcriptomic maps from chondrocytes sampled from different growth plates across developing human skeletons, discovering novel regulatory networks shaping human bone/joint development. Next, using these maps in tandem with height genome-wide association study (GWAS) signals, we disentangle the regulatory impacts that skeletal element-specific versus global-acting variants have on skeletal growth, revealing the prime importance of regulatory pleiotropy in controlling height variation. Finally, as height is highly heritable, and thus often the test case for complex-trait genetics, we leverage these datasets within a testable omnigenic model framework to discover novel chondrocyte developmental modules and peripheral-acting factors shaping height biology and skeletal growth.

中文翻译：

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人类骨骼发育的功能基因组学和身高遗传力的模式化


身高的潜在变化是软骨细胞的调节变化，软骨细胞由长骨生长板组成。目前，我们缺乏关于人类骨骼样本的软骨细胞的表观遗传调控和基因表达的知识，因此我们无法了解控制身高生物学的基本调控机制。我们首先通过从发育中的人类骨骼的不同生长板采样的软骨细胞生成广泛的表观遗传学和转录组图谱来纠正这个问题，发现塑造人类骨骼/关节发育的新型调节网络。接下来，将这些图谱与身高全基因组关联研究 （GWAS） 信号结合使用，我们解开骨骼元件特异性与全局作用变异对骨骼生长的调节影响，揭示了调节多效性在控制身高变化中的首要重要性。最后，由于身高具有高度遗传性，因此通常是复杂性状遗传学的测试案例，我们在可测试的全基因模型框架内利用这些数据集来发现新的软骨细胞发育模块和塑造身高生物学和骨骼生长的外周作用因子。