Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Signature reversion of three disease‐associated gene signatures prioritizes cancer drug repurposing candidates

Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease‐associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease‐associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low‐survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient‐derived xenograft (PDX). Our results demonstrate that by applying multiple disease‐associated gene signature methods, we prioritized several drug repurposing candidates for low‐survival cancers

Altered juvenile fish communities associated with invasive <i>Halophila stipulacea</i> seagrass habitats in the U.S. Virgin Islands

<div><p>Caribbean seagrass habitats provide food and protection for reef-associated juvenile fish. The invasive seagrass <i>Halophila stipulacea</i> is rapidly altering these seascapes. Since its arrival in the Caribbean in 2002, <i>H</i>. <i>stipulacea</i> has colonized and displaced native seagrasses, but the function of this invasive seagrass as a juvenile fish habitat remains unknown. To compare diversity, community structure, and abundance of juvenile fish between <i>H</i>. <i>stipulacea</i> and native seagrass beds, fish traps were deployed in four nearshore bays around St. Thomas, U.S. Virgin Islands. Traps were deployed in Frenchman, Lindbergh, and Sprat Bays for 24 h intervals in patches of bare sand, patches of <i>H</i>. <i>stipulacea</i> and patches of the native Caribbean seagrasses <i>Thalassia testudinum</i> and S<i>yringodium filiforme</i>. Traps were then deployed in Brewers Bay for 12 h intervals in stands of <i>H</i>. <i>stipulacea</i> and <i>S</i>. <i>filiforme</i>. Relative and total abundances of juvenile fish, identified at least to family, were compared across treatment habitats for each trap deployment period. The catch from <i>H</i>. <i>stipulacea</i>, compared to native seagrasses, comprised a greater abundance of nocturnal carnivores <i>Lutjanus synagris</i> (family Lutjanidae) and <i>Haemulon flavolineatum</i> (family Haemulidae). Additionally, the herbivore species <i>Sparisoma aurofrenatum</i> (family Labridae) and <i>Acanthurus bahianus</i> (family Acanthuridae) and the diurnal carnivore species <i>Pseudopeneus maculatus</i> (family Mullidae) were relatively scarce in <i>H</i>. <i>stipulacea</i>. The catch from sand was much smaller, compared to vegetated habitats, and comprised only <i>L</i>. <i>synagris</i>, <i>H</i>. <i>flavolineatum</i>, and <i>H</i>. <i>aurolineatum</i>. These results provide evidence of reduced family diversity and altered juvenile fish assemblages in <i>H</i>. <i>stipulacea</i>, driven by an abundance of some nocturnal carnivores and scarcity of herbivores and diurnal carnivores. The findings from the present work underpin the need for further investigation and mitigation of this invasion, particularly where <i>H</i>. <i>stipulacea</i> is driving seascape-alterations of key juvenile fish habitats.</p></div

Mean juvenile fish abundance in 12 h trap deployments.

<p>(A) Mean abundance of the total catch (<b>±</b> SEM), separated by treatment habitat and soak type. The contribution of each family to the mean abundance is indicated by stacked colored bars. For each guild, a legend with colors corresponding to each family and plots of the mean abundance (<b>± SEM)</b> across seagrass habitats are given for (B) nocturnal carnivores, (C) diurnal carnivores, and (D) herbivores.</p

NMDS of juvenile fish family relative abundance during 12 h deployments.

<p>Points represent individual traps, and 95% confidence ellipses indicate sampling distributions for each seagrass. Data were pooled across soak types.</p

Mean juvenile fish abundance (± SEM) in each trap during 24 h trap deployments.

<p>Separated by treatment habitat (<i>H</i>. <i>stipulacea</i>, <i>S</i>. <i>filiforme</i>, <i>T</i>. <i>testudinum</i>, and sand) and site (F = Frenchman Bay, L = Lindbergh Bay, and S = Sprat Bay). The contribution of each family to the mean abundance is indicated by stacked colored bars. Letters from a Tukey HSD test indicate significant differences across sites and habitats.</p

Negative binomial generalized linear model results for each guild during 12 h deployments.

<p>Negative binomial generalized linear model results for each guild during 12 h deployments.</p

Lengths at maturity for species identified in 24 and 12 h deployments.

<p>Lengths at maturity for species identified in 24 and 12 h deployments.</p

NMDS of each family’s relative abundance across benthic habitats during 24 h deployments.

<p>Points represent individual traps, and 95% confidence ellipses indicate sampling distributions for each habitat. Data were pooled across site.</p