Department of Integrative Biology, University of California Berkeley, Berkeley, USA.
Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, USA.
Nat Commun. 2022 Oct 3;13(1):5803. doi: 10.1038/s41467-022-33509-0.
Age is the primary risk factor for many common human diseases. Here, we quantify the relative contributions of genetics and aging to gene expression patterns across 27 tissues from 948 humans. We show that the predictive power of expression quantitative trait loci is impacted by age in many tissues. Jointly modelling the contributions of age and genetics to transcript level variation we find expression heritability (h) is consistent among tissues while the contribution of aging varies by >20-fold with [Formula: see text] in 5 tissues. We find that while the force of purifying selection is stronger on genes expressed early versus late in life (Medawar's hypothesis), several highly proliferative tissues exhibit the opposite pattern. These non-Medawarian tissues exhibit high rates of cancer and age-of-expression-associated somatic mutations. In contrast, genes under genetic control are under relaxed constraint. Together, we demonstrate the distinct roles of aging and genetics on expression phenotypes.
年龄是许多常见人类疾病的主要风险因素。在这里，我们量化了遗传学和衰老对 948 名人类 27 种组织中基因表达模式的相对贡献。我们表明，在许多组织中，表达数量性状基因座的预测能力受到年龄的影响。通过联合建模年龄和遗传学对转录水平变化的贡献，我们发现组织间的表达遗传力 (h) 是一致的，而衰老的贡献在 5 种组织中变化超过 20 倍，[公式：见文本]。我们发现，尽管生命早期和晚期表达的基因受到净化选择的压力更强（梅达沃假说），但一些高度增殖的组织表现出相反的模式。这些非梅达沃组织表现出高的癌症发病率和与表达年龄相关的体细胞突变率。相比之下，受遗传控制的基因受到的约束较小。总的来说，我们证明了衰老和遗传学对表达表型的不同作用。
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