Communication Biophysics

Contains reports on six research projects.National Institutes of Health (Grant 5 PO1 NS13126)National Institutes of Health (Grant 5 RO1 NS18682)National Institutes of Health (Grant 5 RO1 NS20322)National Institutes of Health (Grant 5 R01 NS20269)National Institutes of Health (Grant 5 T32NS 07047)Symbion, Inc.National Science Foundation (Grant BNS 83-19874)National Science Foundation (Grant BNS 83-19887)National Institutes of Health (Grant 6 RO1 NS 12846)National Institutes of Health (Grant 1 RO1 NS 21322

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Generic, deformable models for 3-d vehicle surveillance

Vehicle surveillance is the task of measuring moving road vehicles to automatically obtain information about vehicle shape, appearance, identity, path of motion, and, ultimately, driver behavior. While various vehicle sensors exist, none are as versatile as the surveillance camera. Computer vision algorithms can interpret digital images to make a wide variety of vehicle measurements using a single sensor. An ideal algorithm would reconstruct a detailed three-dimensional (3-d) representation of the dynamic traffic scene complete with 3-d vehicle surfaces, trajectories of motion, and identities. Unfortunately, much of the 3-d information is lost during the projection of the world into a 2-d image. As a result, the reconstruction problem is ill-posed. Several researchers have addressed this problem by incorporating prior knowledge about the world to rule out implausible reconstructions. Specifically, in the case of vehicle surveillance, a prior model of 3-d vehicle shape is often used. A constrained alignment of the model to images allows for 3-d shape recovery, tracking, and recognition. Previous 3-d vehicle models are either generic but overly simple or rigid and overly complex. Rigid models represent exactly one vehicle design, so a large collection is needed. A single generic model can deform to a wide variety of shapes, but those shapes have been far too primitive. This thesis presents a new generic 3-d vehicle model that deforms to match a wide variety of passenger vehicles. It is adjustable in complexity between the two extremes. The model is aligned to images by predicting and matching image intensity edges. Novel algorithms are presented for fitting models to images, tracking in video, and learning shape deformation from a collection of detailed rigid models. Experiments compare the proposed model to simple generic models in accuracy and reliability of 3-d shape recovery from images and tracking in video. Standard techniques for recognition are also used to compare the models. The proposed model out performs the existing simple models at each task. Yet, there is still much room for improvement, especially since training data is limited

Learning background and shadow appearance with 3-D vehicle models

This paper presents a novel algorithm for simultaneous background appearance modeling and coarse-scale vehicle recognition in traffic surveillance applications. 3-d mesh models representing a small set of vehicle classes are used to the hypothesize image segmentations into background, shadow, and vehicle regions. The algorithm optimizes vehicle class and motion parameters to best agree with a Hidden Markov Model for the image appearance. The best hypothesis, combined with image data, is used to adapt the parameters of the appearance model. Experiments on real video show that an appearance model trained in this way performs almost as well as one trained using manually segmented images.

Learning Background and Shadow Appearance with 3-D Vehicle Models ∗

This paper presents a novel algorithm for simultaneous background appearance modeling and coarse-scale vehicle recognition in traffic surveillance applications. 3-d mesh models representing a small set of vehicle classes are used to the hypothesize image segmentations into background, shadow, and vehicle regions. The algorithm optimizes vehicle class and motion parameters to best agree with a Hidden Markov Model for the image appearance. The best hypothesis, combined with image data, is used to adapt the parameters of the appearance model. Experiments on real video show that an appearance model trained in this way performs almost as well as one trained using manually segmented images.

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

The contribution of de novo coding mutations to autism spectrum disorder

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females