Pooled-parent exome sequencing to prioritise de novo variants in genetic disease, bioRxiv, 2019-04-07

AbstractIn the clinical setting, exome sequencing has become standard-of-care in diagnosing rare genetic disorders, however many patients remain unsolved. Trio sequencing has been demonstrated to produce a higher diagnostic yield than singleton (proband-only) sequencing. Parental sequencing is especially useful when a disease is suspected to be caused by a de novo variant in the proband, because parental data provide a strong filter for the majority of variants that are shared by the proband and their parents. However the additional cost of sequencing the parents makes the trio strategy uneconomical for many clinical situations. With two thirds of the sequencing budget being spent on parents, these are funds that could be used to sequence more probands. For this reason many clinics are reluctant to sequence parents.Here we propose a pooled-parent strategy for exome sequencing of individuals with likely de novo disease. In this strategy, DNA from all the parents of a cohort of unrelated probands is pooled together into a single exome capture and sequencing run. Variants called in the proband can then be filtered if they are also found in the parent pool, resulting in a shorter list of prioritised variants. To evaluate the pooled-parent strategy we performed a series of simulations by combining reads from individual exomes to imitate sample pooling. We assessed the recall and false positive rate and investigated the trade-off between pool size and recall rate. We compared the performance of GATK HaplotypeCaller individual and joint calling, and FreeBayes to genotype pooled samples. Finally, we applied a pooled-parent strategy to a set of real unsolved cases and showed that the parent pool is a powerful filter that is complementary to other commonly used variant filters such as population variant frequencies.

biorxiv bioinformatics 0-100-users 2019

Inferring the function performed by a recurrent neural network, bioRxiv, 2019-04-05

AbstractA central goal in systems neuroscience is to understand the functions performed by neural circuits. Previous top-down models addressed this question by comparing the behaviour of an ideal model circuit, optimised to perform a given function, with neural recordings. However, this requires guessing in advance what function is being performed, which may not be possible for many neural systems. Here, we propose an alternative approach that uses recorded neural responses to directly infer the function performed by a neural network. We assume that the goal of the network can be expressed via a reward function, which describes how desirable each state of the network is for carrying out a given objective. This allows us to frame the problem of optimising each neuron’s responses by viewing neurons as agents in a reinforcement learning (RL) paradigm; likewise the problem of inferring the reward function from the observed dynamics can be treated using inverse RL. Our framework encompasses previous influential theories of neural coding, such as efficient coding and attractor network models, as special cases, given specific choices of reward function. Finally, we can use the reward function inferred from recorded neural responses to make testable predictions about how the network dynamics will adapt depending on contextual changes, such as cell death andor varying input statistics, so as to carry out the same underlying function with different constraints.

biorxiv neuroscience 0-100-users 2019

 

Created with the audiences framework by Jedidiah Carlson

Powered by Hugo