Accurate proteome-wide missense variant effect prediction with AlphaMissense.

The vast majority of missense variants observed in the human genome are of unknown clinical significance. We present AlphaMissense, an adaptation of AlphaFold fine-tuned on human and primate variant population frequency databases to predict missense variant pathogenicity. By combining structural context and evolutionary conservation, our model achieves state-of-the-art results across a wide range of genetic and experimental benchmarks, all without explicitly training on such data. The average pathogenicity score of genes is also predictive for their cell essentiality, capable of identifying short essential genes that existing statistical approaches are underpowered to detect. As a resource to the community, we provide a database of predictions for all possible human single amino acid substitutions and classify 89% of missense variants as either likely benign or likely pathogenic.

Learning efficient navigation in vortical flow fields.

Efficient point-to-point navigation in the presence of a background flow field is important for robotic applications such as ocean surveying. In such applications, robots may only have knowledge of their immediate surroundings or be faced with time-varying currents, which limits the use of optimal control techniques. Here, we apply a recently introduced Reinforcement Learning algorithm to discover time-efficient navigation policies to steer a fixed-speed swimmer through unsteady two-dimensional flow fields. The algorithm entails inputting environmental cues into a deep neural network that determines the swimmer's actions, and deploying Remember and Forget Experience Replay. We find that the resulting swimmers successfully exploit the background flow to reach the target, but that this success depends on the sensed environmental cue. Surprisingly, a velocity sensing approach significantly outperformed a bio-mimetic vorticity sensing approach, and achieved a near 100% success rate in reaching the target locations while approaching the time-efficiency of optimal navigation trajectories.

Optimal Flow Sensing for Schooling Swimmers.

Fish schooling implies an awareness of the swimmers for their companions. In flow mediated environments, in addition to visual cues, pressure and shear sensors on the fish body are critical for providing quantitative information that assists the quantification of proximity to other fish. Here we examine the distribution of sensors on the surface of an artificial swimmer so that it can optimally identify a leading group of swimmers. We employ Bayesian experimental design coupled with numerical simulations of the two-dimensional Navier Stokes equations for multiple self-propelled swimmers. The follower tracks the school using information from its own surface pressure and shear stress. We demonstrate that the optimal sensor distribution of the follower is qualitatively similar to the distribution of neuromasts on fish. Our results show that it is possible to identify accurately the center of mass and the number of the leading swimmers using surface only information.

Efficient collective swimming by harnessing vortices through deep reinforcement learning.

Fish in schooling formations navigate complex flow fields replete with mechanical energy in the vortex wakes of their companions. Their schooling behavior has been associated with evolutionary advantages including energy savings, yet the underlying physical mechanisms remain unknown. We show that fish can improve their sustained propulsive efficiency by placing themselves in appropriate locations in the wake of other swimmers and intercepting judiciously their shed vortices. This swimming strategy leads to collective energy savings and is revealed through a combination of high-fidelity flow simulations with a deep reinforcement learning (RL) algorithm. The RL algorithm relies on a policy defined by deep, recurrent neural nets, with long-short-term memory cells, that are essential for capturing the unsteadiness of the two-way interactions between the fish and the vortical flow field. Surprisingly, we find that swimming in-line with a leader is not associated with energetic benefits for the follower. Instead, "smart swimmer(s)" place themselves at off-center positions, with respect to the axis of the leader(s) and deform their body to synchronize with the momentum of the oncoming vortices, thus enhancing their swimming efficiency at no cost to the leader(s). The results confirm that fish may harvest energy deposited in vortices and support the conjecture that swimming in formation is energetically advantageous. Moreover, this study demonstrates that deep RL can produce navigation algorithms for complex unsteady and vortical flow fields, with promising implications for energy savings in autonomous robotic swarms.

Synchronisation through learning for two self-propelled swimmers.

The coordinated motion by multiple swimmers is a fundamental component in fish schooling. The flow field induced by the motion of each self-propelled swimmer implies non-linear hydrodynamic interactions among the members of a group. How do swimmers compensate for such hydrodynamic interactions in coordinated patterns? We provide an answer to this riddle though simulations of two, self-propelled, fish-like bodies that employ a learning algorithm to synchronise their swimming patterns. We distinguish between learned motion patterns and the commonly used a-priori specified movements, that are imposed on the swimmers without feedback from their hydrodynamic interactions. First, we demonstrate that two rigid bodies executing pre-specified motions, with an alternating leader and follower, can result in substantial drag-reduction and intermittent thrust generation. In turn, we study two self-propelled swimmers arranged in a leader-follower configuration, with a-priori specified body-deformations. These two self-propelled swimmers do not sustain their tandem configuration. The follower experiences either an increase or decrease in swimming speed, depending on the initial conditions, while the swimming of the leader remains largely unaffected. This indicates that a-priori specified patterns are not sufficient to sustain synchronised swimming. We then examine a tandem of swimmers where the leader has a steady gait and the follower learns to synchronize its motion, to overcome the forces induced by the leader's vortex wake. The follower employs reinforcement learning to adapt its swimming-kinematics so as to minimize its lateral deviations from the leader's path. Swimming in such a sustained synchronised tandem yields up to [Formula: see text] reduction in energy expenditure for the follower, in addition to a [Formula: see text] increase in its swimming-efficiency. The present results show that two self-propelled swimmers can be synchronised by adapting their motion patterns to compensate for flow-structure interactions. Moreover, swimmers can exploit the vortical structures of their flow field so that synchronised swimming is energetically beneficial.