Ard Louis

Abstract:

Engineers routinely design systems to be modular and symmetric in order to increase robustness to perturbations and to facilitate alterations at a later date. Biological structures also frequently exhibit modularity and symmetry, but the origin of such trends is much less well understood. It can be tempting to assume – by analogy to engineering design – that symmetry and modularity arise from natural selection. But evolution, unlike engineers, cannot plan ahead, and so these traits must also afford some immediate selective advantage which is hard to reconcile with the breadth of systems where symmetry is observed. Here we introduce an alternative non-adaptive hypothesis based on an algorithmic picture of evolution. It suggests that symmetric structures preferentially arise not just due to natural selection, but also because they require less specific information to encode, and are therefore much more likely to appear as phenotypic variation through random mutations. Arguments from algorithmic information theory can formalise this intuition, leading to the prediction that many genotype-phenotype maps are exponentially biased towards phenotypes with low descriptional complexity. A preference for symmetry is a special case of this bias towards compressible descriptions. We test these predictions with extensive biological data, showing that that protein complexes, RNA secondary structures, and a model gene-regulatory network all exhibit the expected exponential bias towards simpler (and more symmetric) phenotypes. Lower descriptional complexity also correlates with higher mutational robustness, which may aid the evolution of complex modular assemblies of multiple components.

Abstract:

Counterfactual questions such as "what would happen if you re-run the tape of life?" turn on the nature of the landscape of biological possibilities. Since the number of potential sequences that store genetic information grows exponentially with length, genetic possibility spaces can be so unimaginably vast that commentators frequently reach of hyper-astronomical metaphors that compare their size to that of the universe. Re-run the tape of life and the likelihood of encountering the same sequences in such hyper-astronomically large spaces is infinitesimally small, suggesting that evolutionary outcomes are highly contingent. On the other hand, the wide-spread occurrence of evolutionary convergence implies that similar phenotypes can be found again with relative ease. How can this be? Part of the solution to this conundrum must lie in the manner that genotypes map to phenotypes. By studying simple genotype-phenotype maps, where the counterfactual space of all possible phenotypes can be enumerated, it is shown that strong bias in the arrival of variation may explain why certain phenotypes are (repeatedly) observed in nature, while others never appear. This biased variation provides a non-selective cause for certain types of convergence. It illustrates how the role of randomness and contingency may differ significantly between genetic and phenotype spaces.

Abstract:

<jats:p>DNA–RNA hybrid strand displacement underpins the function of many natural and engineered systems. Understanding and controlling factors affecting DNA–RNA strand displacement reactions is necessary to enable control of processes such as CRISPR-Cas9 gene editing. By combining multiscale modeling with strand displacement experiments, we show that the distribution of bases within the displacement domain has a very strong effect on reaction kinetics, a feature unique to DNA–RNA hybrid strand displacement. Merely by redistributing bases within a displacement domain of fixed base composition, we are able to design sequences whose reaction rates span more than four orders of magnitude. We extensively characterize this effect in reactions involving the invasion of dsDNA by an RNA strand, as well as the invasion of a hybrid duplex by a DNA strand. In all-DNA strand displacement reactions, we find a predictable but relatively weak sequence dependence, confirming that DNA–RNA strand displacement permits far more thermodynamic and kinetic control than its all-DNA counterpart. We show that oxNA, a recently introduced coarse-grained model of DNA–RNA hybrids, can reproduce trends in experimentally observed reaction rates. We also develop a simple kinetic model for predicting strand displacement rates. On the basis of these results, we argue that base distribution effects may play an important role in natural R-loop formation and in the function of the guide RNAs that direct CRISPR-Cas systems.</jats:p>

Abstract:

The remarkable performance of overparameterized deep neural networks (DNNs) must arise from an interplay between network architecture, training algorithms, and structure in the data. To disentangle these three components for supervised learning, we apply a Bayesian picture based on the functions expressed by a DNN. The prior over functions is determined by the network architecture, which we vary by exploiting a transition between ordered and chaotic regimes. For Boolean function classification, we approximate the likelihood using the error spectrum of functions on data. Combining this with the prior yields an accurate prediction for the posterior, measured for DNNs trained with stochastic gradient descent. This analysis shows that structured data, together with a specific Occam’s razor-like inductive bias towards (Kolmogorov) simple functions that exactly counteracts the exponential growth of the number of functions with complexity, is a key to the success of DNNs.