The study investigates the unequal contribution of the first two blastomeres to the human embryo, revealing that the majority of the future body originates from one of the two-cell stage blastomeres. The research uses live imaging and non-invasive cell labeling to track the lineage of each 2-cell blastomere from the 2-cell stage to the blastocyst stage. Key findings include: 1. **Lineage Tracing and Labeling**: The study employs live imaging and non-invasive cell labeling to trace the lineage of each 2-cell blastomere. 2. **Clonal Imbalance**: The majority of epiblast cells (future body) originate from only one 2-cell stage blastomere, with the first dividing blastomere contributing more asymmetrically at the 8-cell stage. 3. **Asymmetric Divisions**: The first dividing 2-cell blastomere generates more asymmetric divisions at the 8-cell stage, leading to a small number of founding epiblast cells before implantation. 4. **Bottleneck Effect**: The limited number of cell internalizations at the 8-to-16-cell transition creates a bottleneck that leads to clonal imbalances in the ICM. 5. **Computational Model**: A computational model is developed to predict clonal imbalances in human blastocysts, validating the observed data. 6. **Asynchronous Cell Division**: Asynchronous cell division of the 2-cell blastomeres influences the ultimate lineage composition, with the faster-dividing blastomere contributing more ICM founder cells. The study concludes that early bottlenecks and cell division dynamics in the early embryo establish asymmetry in the clonal composition of the future human body, with the majority of epiblast cells originating from one blastomere at the 2-cell stage.The study investigates the unequal contribution of the first two blastomeres to the human embryo, revealing that the majority of the future body originates from one of the two-cell stage blastomeres. The research uses live imaging and non-invasive cell labeling to track the lineage of each 2-cell blastomere from the 2-cell stage to the blastocyst stage. Key findings include: 1. **Lineage Tracing and Labeling**: The study employs live imaging and non-invasive cell labeling to trace the lineage of each 2-cell blastomere. 2. **Clonal Imbalance**: The majority of epiblast cells (future body) originate from only one 2-cell stage blastomere, with the first dividing blastomere contributing more asymmetrically at the 8-cell stage. 3. **Asymmetric Divisions**: The first dividing 2-cell blastomere generates more asymmetric divisions at the 8-cell stage, leading to a small number of founding epiblast cells before implantation. 4. **Bottleneck Effect**: The limited number of cell internalizations at the 8-to-16-cell transition creates a bottleneck that leads to clonal imbalances in the ICM. 5. **Computational Model**: A computational model is developed to predict clonal imbalances in human blastocysts, validating the observed data. 6. **Asynchronous Cell Division**: Asynchronous cell division of the 2-cell blastomeres influences the ultimate lineage composition, with the faster-dividing blastomere contributing more ICM founder cells. The study concludes that early bottlenecks and cell division dynamics in the early embryo establish asymmetry in the clonal composition of the future human body, with the majority of epiblast cells originating from one blastomere at the 2-cell stage.