Ultra-rare constrained missense variants in the epilepsies: Shared and specific enrichment patterns in neuronal gene-sets

Background: Burden analysis in epilepsy has shown an excess of deleterious ultra-rare variants (URVs) in few gene-sets, such as known epilepsy genes, constrained genes, ion channel or GABAA receptor genes. We set out to investigate the burden of URVs in a comprehensive range of gene-sets presumed to be implicated in epileptogenesis. Methods: We investigated several constraint and conservation-based strategies to study whole exome sequencing data from European individuals with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), and non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls. The burden of 12 URVs types in 92 gene-sets was compared between epilepsy cases (DDE, GGE, NAFE) and controls using logistic regression analysis. Results: Burden analysis of brain-expressed genes revealed an excess of different URVs types in all three epilepsy categories which was largest for constrained missense variants. The URVs burden was prominent in neuron-specific, synaptic and developmental genes as well as genes encoding ion channels and receptors, and it was generally higher for DEE and GGE compared to NAFE. The patterns of URVs burden in gene-sets expressed in inhibitory vs. excitatory neurons or receptors suggested a high burden in both in DEE but a differential involvement of inhibitory genes in GGE, while excitatory genes were predominantly affected in NAFE. Top ranking susceptibility genes from a recent genome-wide association study (GWAS) of generalized and focal epilepsies displayed a higher URVs burden in constrained coding regions in GGE and NAFE, respectively. Conclusions: Using exome-based gene-set burden analysis, we demonstrate that missense URVs affecting mainly constrained sites are enriched in neuronal genes in both common and rare severe epilepsy syndromes. Our results indicate a differential impact of these URVs in genes expressed in inhibitory vs. excitatory neurons and receptors in generalized vs. focal epilepsies. The excess of URVs in top-ranking GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies.

Age and Sex Differences in the Genetics of Cardiomyopathy

Aims: Cardiomyopathy is a clinically and genetically heterogeneous disorder with age and sex-related differences in severity and outcomes. The aim of our study was to identify age and sex-related differences in the genetic architecture of cardiomyopathy. Methods and Results: We analyzed whole genome sequence data from 471 pediatric and 926 adult cardiomyopathy patients from our Heart Centre Biobank and from the Genomics England cohort. Overall yield of rare deleterious coding variants was higher in pediatric compared to adult onset cardiomyopathy, but not different by sex. MYH7, TNNT2, MYL3, and VCL variants were more frequent in pediatric patients; TTN and OBSCN variants were more frequent in adult patients, with MYH7 (Odds ratio 3.6; CI 2.1-6.3) and OBSCN (Odds ratio 5.5, CI 2.0-21.4) remaining significant after adjusting for multiple testing. Variants in early-onset cardiomyopathy clustered in highly constrained coding regions compared to those in adult patients (p=3.9x10-3). There were also differences between pediatric and adult patients in variant location within MYH7 and TTN genes. When analyzed by sex, variants in female compared to male patients were in more highly constrained coding regions (p=0.002). Conclusion: Our findings highlight under-appreciated genetic differences in early versus late onset cardiomyopathy. Variants in childhood cardiomyopathy and in female patients were in highly constrained coding regions of the genome suggesting greater deleterious effects and strong purifying selection in the general population. Knowledge of the affected gene, variant location within the gene, and variant constraint scores may be useful in predicting early versus late onset cardiomyopathy.

A functional enrichment test for molecular convergent evolution finds a clear protein-coding signal in echolocating bats and whales

Distantly related species entering similar biological niches often adapt by evolving similar morphological and physiological characters. How much genomic molecular convergence (particularly of highly constrained coding sequence) contributes to convergent phenotypic evolution, such as echolocation in bats and whales, is a long-standing fundamental question. Like others, we find that convergent amino acid substitutions are not more abundant in echolocating mammals compared to their outgroups. However, we also ask a more informative question about the genomic distribution of convergent substitutions by devising a test to determine which, if any, of more than 4,000 tissue-affecting gene sets is most statistically enriched with convergent substitutions. We find that the gene set most overrepresented (q-value = 2.2e-3) with convergent substitutions in echolocators, affecting 18 genes, regulates development of the cochlear ganglion, a structure with empirically supported relevance to echolocation. Conversely, when comparing to nonecholocating outgroups, no significant gene set enrichment exists. For aquatic and high-altitude mammals, our analysis highlights 15 and 16 genes from the gene sets most affected by molecular convergence which regulate skin and lung physiology, respectively. Importantly, our test requires that the most convergence-enriched set cannot also be enriched for divergent substitutions, such as in the pattern produced by inactivated vision genes in subterranean mammals. Showing a clear role for adaptive protein-coding molecular convergence, we discover nearly 2,600 convergent positions, highlight 77 of them in 3 organs, and provide code to investigate other clades across the tree of life.

A Constrained Coding-Aware Routing Scheme in Wireless Ad-Hoc Networks

In wireless multi-hop networks, instead of using the traditional store-and-forward method, the relay nodes can exploit the network coding idea to encode and transmit the packets in the distributed coding-aware routing (DCAR) mechanisms, which can decrease the transmission number and achieve higher throughput. However, depending on the primary coding conditions of DCAR, the DCAR-type schemes may not only detect more coding opportunities, but also lead to an imbalanced distribution of the network load. Especially, they are not energy efficient in more complex scenarios, such as wireless ad-hoc networks. In this paper, to solve these shortcomings, we propose a constrained coding-aware routing (CCAR) mechanism with the following benefits: (1) by the constrained coding conditions, the proposed mechanism can detect good coding opportunities and assure a higher decoding probability; (2) we propose a tailored “routing + coding” discovery process, which is more lightweight and suitable for the CCAR scheme; and (3) by evaluating the length of the output queue, we can estimate the states of coding nodes to improve the efficient coding benefit. To those ends, we implement the CCAR scheme in different topologies with the ns-2 simulation tool. The simulation results show that a higher effective coding benefit ratio can be achieved by the constrained coding conditions and new coding benefit function. Moreover, the CCAR scheme has significant advantages regarding throughput, average end-to-end delay, and energy consumption.