Hajheidari Mohsen, Sunyaev Shamil, de Meaux Juliette
Institute for Plant Sciences, Cluster of Excellence on Plant Sciences (CEPLAS), University of Cologne, Cologne 50674, Germany.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Plant Cell Physiol. 2025 May 17;66(4):444-460. doi: 10.1093/pcp/pcae140.
Variation in complex traits is controlled by multiple genes. The prevailing assumption is that such polygenic complex traits are underpinned by variation in elementary molecular traits, such as gene expression, which themselves have a simple genetic basis. Here, we review recent advances that reveal the captivating complexity of gene regulation: the cell type, time point, and magnitude of gene expression are not merely dependent on a couple of regulators; rather, they result from a probabilistic process shaped by cis- and trans-regulatory elements collaboratively integrating internal and external cues with the tightly regulated dynamics of DNA. In addition, the finding that genetic variants linked to complex diseases in humans often do not co-localize with quantitative trait loci modulating gene expression, along with the role of nonfunctional transcription factor (TF) binding sites, suggests that some of the genetic effects influencing gene expression variation may be indirect. If the number of genomic positions responsible for TF binding, TF binding site search time, DNA conformation and accessibility as well as regulation of all trans-acting factors is indeed vast, is it plausible that the complexity of elementary molecular traits approaches the complexity of higher-level organismal traits? Although it is hard to know the answer to this question, we motivate it by reviewing the complexity of the molecular machinery further.
复杂性状的变异由多个基因控制。目前普遍的假设是，这种多基因复杂性状是由基本分子性状的变异所支撑的，比如基因表达，而基因表达本身具有简单的遗传基础。在此，我们回顾近期的进展，这些进展揭示了基因调控引人入胜的复杂性：基因表达的细胞类型、时间点和幅度不仅仅取决于几个调控因子；相反，它们是由顺式和反式调控元件共同作用形成的概率过程所导致的，这些元件将内部和外部线索与严格调控的DNA动态整合在一起。此外，与人类复杂疾病相关的遗传变异通常并不与调节基因表达的数量性状位点共定位，再加上非功能性转录因子（TF）结合位点的作用，这表明一些影响基因表达变异的遗传效应可能是间接的。如果负责TF结合、TF结合位点搜索时间、DNA构象和可及性以及所有反式作用因子调控的基因组位置数量确实很多，那么基本分子性状的复杂性是否接近更高层次生物体性状的复杂性呢？尽管很难知道这个问题的答案，但我们通过进一步回顾分子机制的复杂性来提出这个问题。
