Understanding the "flattening" of gene contributions to human complex trait habitability

全基因组关联研究表明，大多数人类复合体的可遗传变异 特征广泛地分布在基因组中。这很令人惊讶，因为我们预计每种性状都有 其生物学基础的特定机制和途径，然而，对于大多数特征，这些机制 从GWAS的结果来看，路径并不明显。最近，有人建议这一点 这一现象可以用自然选择对遗传力的抑制来解释。如果变种在 直接影响性状生物学的基因对导致增加的性状有很大的影响 选择时，它们将仅以低频率出现，因此对 遗传力。这种直觉最近被称为“扁平化”，因为通过保持大的有效等位基因 在低频率下，自然选择使遗传率的分布变得平坦。在这项工作中，我将采取 从基本直觉到完全充实的理论，从理论到第一个基因组-- 广泛衡量每个性状的每个基因的扁平化程度。首先，我将构建一系列模型来描述 决定扁平化的进化和基因组因素，包括多效性和人类 人口统计历史。然后，我将通过直接量化展平对 使用英国生物库数据的38个血液和尿液标志物。这些生物标志物提供了一种独特而令人兴奋的 验证我的预测的机会，因为我们知道支持合成的监管网络 这些生物标记物。最后，我将通过以下方法估计每个性状的每个基因的遗传力赤字 将基因对遗传力的贡献与中性预期进行比较。遗传力赤字将是 有史以来第一个衡量每个性状每个基因扁平化的全基因组测量方法，我将用它来描述 可利用的英国生物库特征的扁平化程度。

Genome-wide association studies (GWAS) indicate that heritable variation for most human complex traits is widely distributed across the genome. This is surprising since we expect each trait to have specific mechanisms and pathways underlying its biology and yet, for most traits, such mechanisms and pathways are not evident from GWAS results. Recently, it has been suggested that this phenomenon might be explained by the natural selection’s suppression of heritability. If variants at genes directly underlying trait biology have large effect sizes on the trait which cause increased selection, they will only appear at low frequencies and therefore only make a limited contribution to heritability. This intuition has recently been dubbed “flattening” because, by keeping large effect alleles at low frequencies, natural selection flattens the distribution of heritability. In this work, I will take the concept of “flattening” from basic intuition to fully fleshed out theory and from theory to the first genome- wide measure of flattening per gene per trait. First, I will build a series of models to describe the evolutionary and genomic factors that determine flattening, including pleiotropy and human demographic history. Then, I will validate my models by directly quantifying the effects of flattening on 38 blood and urine markers using UK Biobank data. These biomarkers provide a unique and exciting opportunity to test my predictions because we know the regulatory networks underlying the synthesis of these biomarkers. Finally, I will estimate the heritability deficit of each gene for each trait by comparing the gene’s contribution to heritability to a neutral expectation. The heritability deficit will be the first ever genome-wide measure of flattening per gene per trait and I will use it to characterize the extent of flattening on available UK Biobank traits.