Personalized copy number and segmental duplication maps using next-generation sequencing

Despite their importance in gene innovation and phenotypic variation, duplicated regions have remained largely intractable owing to difficulties in accurately resolving their structure, copy number and sequence content. We present an algorithm (mrFAST) to comprehensively map next-generation sequence reads, which allows for the prediction of absolute copy-number variation of duplicated segments and genes. We examine three human genomes and experimentally validate genome-wide copy number differences. We estimate that, on average, 73-87 genes vary in copy number between any two individuals and find that these genic differences overwhelmingly correspond to segmental duplications (odds ratio = 135; P < 2.2 x 10(-16)). Our method can distinguish between different copies of highly identical genes, providing a more accurate assessment of gene content and insight into functional constraint without the limitations of array-based technology

Fine-Tuning and the Stability of Recurrent Neural Networks

A central criticism of standard theoretical approaches to constructing stable, recurrent model networks is that the synaptic connection weights need to be finely-tuned. This criticism is severe because proposed rules for learning these weights have been shown to have various limitations to their biological plausibility. Hence it is unlikely that such rules are used to continuously fine-tune the network in vivo. We describe a learning rule that is able to tune synaptic weights in a biologically plausible manner. We demonstrate and test this rule in the context of the oculomotor integrator, showing that only known neural signals are needed to tune the weights. We demonstrate that the rule appropriately accounts for a wide variety of experimental results, and is robust under several kinds of perturbation. Furthermore, we show that the rule is able to achieve stability as good as or better than that provided by the linearly optimal weights often used in recurrent models of the integrator. Finally, we discuss how this rule can be generalized to tune a wide variety of recurrent attractor networks, such as those found in head direction and path integration systems, suggesting that it may be used to tune a wide variety of stable neural systems

Personalized copy number and segmental duplication maps using next-generation sequencing

7 páginas, 6 figuras, 2 tablas.-- et al.Despite their importance in gene innovation and phenotypic variation, duplicated regions have remained largely intractable owing to difficulties in accurately resolving their structure, copy number and sequence content. We present an algorithm (mrFAST) to comprehensively map next-generation sequence reads, which allows for the prediction of absolute copy-number variation of duplicated segments and genes. We examine three human genomes and experimentally validate genome-wide copy number differences. We estimate that, on average, 73–87 genes vary in copy number between any two individuals and find that these genic differences overwhelmingly correspond to segmental duplications (odds ratio = 135; P < 2.2 10-16). Our method can distinguish between different copies of highly identical genes, providing a more accurate assessment of gene content and insight into functional constraint without the limitations of array-based technology.J.M.K. is supported by a US National Science Foundation Graduate Research Fellowship. T.M.-B. is supported by a Marie Curie fellowship (FP7). This work was supported, in part, by U.S. National Institutes of Health grant HG004120 to E.E.E. E.E.E. is an investigator of the Howard Hughes Medical Institute.Peer reviewe

Model for a robust neural integrator

Integrator circuits in the brain show persistent firing that reflects the sum of previous excitatory and inhibitory inputs from external sources. Integrator circuits have been implicated in parametric working memory, decision making and motor control. Previous work has shown that stable integrator function can be achieved by an excitatory recurrent neural circuit, provided synaptic strengths are tuned with extreme precision (better than 1% accuracy). Here we show that integrator circuits can function without fine tuning if the neuronal units have bistable properties. Two specific mechanisms of bistability are analyzed, one based on local recurrent excitation, and the other on the voltage-dependence of the NMDA (N-methyl-D-aspartate) channel. Neither circuit requires fine tuning to perform robust integration, and the latter actually exploits the variability of neuronal conductances

Alexander’s Law in Patients with Acute Vestibular Tone Asymmetry—Evidence for Multiple Horizontal Neural Integrators

Alexander’s law (AL) states that the slow-phase velocity of spontaneous nystagmus of peripheral vestibular origin is dependent on horizontal gaze position, with greater velocity when gaze is directed in the fast-phase direction. AL is thought to be a compensatory reaction resulting from adaptive changes in the horizontal ocular motor neural integrator. Until now, only horizontal eye movements have been investigated with respect to AL. Because spontaneous nystagmus usually includes vertical and torsional components, we asked whether horizontal gaze changes would have an effect on the 3D drift of spontaneous nystagmus and, thus, on the vertical/torsional neural integrator. We hypothesized that AL reduces all nystagmus components proportionally. Moreover, we questioned the classical theory of a single bilaterally organized horizontal integrator and searched for nonlinearities of AL implying a network of multiple integrators. Using dual scleral search coils, we measured AL in 17 patients with spontaneous nystagmus. Patients followed a pulsed laser dot at eye level jumping in 5° steps along the horizontal meridian between 25° right and left in otherwise complete darkness. AL was observed in 15 of 17 patients. Whereas individual patients typically showed a change of 3D-drift direction at different horizontal eye positions, the average change in direction was not different from zero. The strength of AL (= rate of change of total velocity with gaze position) correlated with nystagmus slow-phase velocity (Spearman’s rho = 0.5; p < 0.05) and, on average, did not change the 3D nystagmus drift direction. In general, eye velocity did not vary linearly with eye position. Rather, there was a stronger dependence of velocity on horizontal position when subjects looked in the slow-phase direction compared to the fast-phase direction. We conclude that the theory of a simple leak of a single horizontal neural integrator is not sufficient to explain all aspects of AL