Clocks and Dominoes: Timing Mechanisms of Embryogenesis.

How developmental timings are regulated is a fundamental open question. Two widely considered mechanisms are the clock, in which an internal timer determines when each stage occurs, and the domino, in which the completion of each stage triggers the next. It is often unclear how to establish either mechanism. Here, we construct a quantitative framework that uses the correlation structure of developmental timings to test the clock and domino mechanisms. We apply this framework to human pre-implantation development by using ~1 million images of 2946 embryos acquired during IVF treatment, establishing mathematical models of developmental rate. We find that a domino mechanism governs the cleavage timings, while a pronuclei fade-triggered clock mechanism governs the morula and blastocyst timings. These results are consistent with the cell cycle oscillator governing the cleavage timings and the accumulation of embryonic gene products or the degradation of maternally deposited factors governing the morula and blastocyst timings. We next investigate the physiological regulators of developmental timing by analyzing how the timings are statistically associated with the clinical pregnancy outcome. While embryos that result in a clinical pregnancy tend to exhibit shorter cleavage timings, this association is primarily driven by patient-specific properties. In contrast, embryo-specific properties independently influence the pregnancy outcome and the cleavage timings, so that factors directly determining implantation potential, such as aneuploidy, can only weakly impact the cleavage timings. Taken together, this work provides a robust framework for decoding developmental timing mechanisms, with significant implications for fundamental biology and clinical practice.