Feeding kinematics and morphology of the alligator gar (Atractosteus spatula, Lacépède, 1803), bioRxiv, 2019-02-28
Modern (lepisosteid) gars are a small clade of seven species and two genera that occupy an important position on the actinopterygian phylogenetic tree as members of the Holostei (Amia+ gars), sister-group of the teleost radiation. Often referred to as living fossils, these taxa preserve many plesiomorphic characteristics used to interpret and reconstruct early osteichthyan feeding conditions. Less attention, however, has been paid to the functional implications of gar-specific morphology, thought to be related to an exclusively ram-based, lateral-snapping mode of prey capture. Previous studies of feeding kinematics in gars have focused solely on members of the narrow-snouted Lepisosteus genus, and here we expand that dataset to include a member of the broad-snouted sister-genus and largest species of gar, the alligator gar (Atractosteus spatula, Lacépède, 1803). High-speed videography reveals that the feeding system of alligator gars is capable of rapid expansion from anterior-to-posterior, precisely timed in a way that appears to counteract the effects of a bow-wave during ram-feeding and generate a unidirectional flow of water through the feeding system. Reconstructed cranial anatomy based on contrast-enhanced micro-CT data show that a lateral-sliding palatoquadrate, flexible intrasuspensorial joint, pivoting interhyal, and retractable pectoral girdle are all responsible for increasing the range of motion and expansive capabilities of the gar cranial linkage system. Muscular reconstructions and manipulation experiments show that, while the sternohyoideus is the primary input to the feeding system (similar to other basal actinopterygians), additional input from the hyoid constrictors and hypaxials play an important role in decoupling and modulating between the dual roles of the sternohyoideus hyoid retraction (jaw opening) and hyoid rotation (pharyngeal expansion) respectively. The data presented here demonstrate an intricate feeding mechanism, capable of precise control with plesiomorphic muscles, that represents one of the many ways the ancestral osteichthyan feeding mechanism has been modified for prey capture.
biorxiv evolutionary-biology 200-500-users 2019Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinsons disease, bioRxiv, 2019-02-28
Human genetic variants causing loss of function (LoF) of protein-coding genes provide natural in vivo models of gene inactivation, which are powerful indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes. Gain of kinase function variants in LRRK2 are known to significantly increase the risk of Parkinsons disease suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. Whilst preclinical studies in model organisms have raised some on-target toxicity concerns, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here we systematically analyse LoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD) and over 4 million participants in the 23andMe genotyped dataset, to assess their impact at a molecular and phenotypic level. After thorough variant curation, we identify 1,358 individuals with high-confidence predicted LoF variants in LRRK2, several with experimental validation. We show that heterozygous LoF of LRRK2 reduces LRRK2 protein level by ~50% but is not associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that downregulate LRRK2 levels or kinase activity by up to 50% are unlikely to have major on-target safety liabilities. Our results demonstrate the value of large scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.
biorxiv genomics 100-200-users 2019Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinson’s disease, bioRxiv, 2019-02-28
AbstractHuman genetic variants causing loss-of-function (LoF) of protein-coding genes provide natural in vivo models of gene inactivation, which are powerful indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. Whilst preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here we systematically analyse LoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9 and over 4 million participants in the 23andMe genotyped dataset, to assess their impact at a molecular and phenotypic level. After thorough variant curation, we identify 1,358 individuals with high-confidence predicted LoF variants in LRRK2, several with experimental validation. We show that heterozygous LoF of LRRK2 reduces LRRK2 protein level by ~50% but is not associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that downregulate LRRK2 levels or kinase activity by up to 50% are unlikely to have major on-target safety liabilities. Our results demonstrate the value of large scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.
biorxiv genomics 100-200-users 2019Interplay between the human gut microbiome and host metabolism, bioRxiv, 2019-02-28
The human gut is inhabited by a complex and metabolically active microbial ecosystem regulating host health. While many studies have focused on the effect of individual microbial taxa, the metabolic potential of the entire gut microbial ecosystem has been largely under-explored. We characterised the gut microbiome of 1,004 twins via whole shotgun metagenomic sequencing (average 39M reads per sample). We observed greater similarity, across unrelated individuals, for functional metabolic pathways (82%) than for taxonomic composition (43%). We conducted a microbiota-wide association study linking both taxonomic information and microbial metabolic pathways with 673 blood and 713 faecal metabolites (Metabolon, Inc.). Metabolic pathways associated with 34% of blood and 95% of faecal metabolites, with over 18,000 significant associations, while species-level results identified less than 3,000 associations, suggesting that coordinated action of multiple taxa is required to affect the metabolome. Finally, we estimated that the microbiome mediated a crosstalk between 71% of faecal and 15% of blood metabolites, highlighting six key species (unclassified Subdoligranulum spp., Faecalibacterium prausnitzii, Roseburia inulinivorans, Methanobrevibacter smithii, Eubacterium rectale, and Akkermansia muciniphila). Because of the large inter-person variability in microbiome composition, our results underline the importance of studying gut microbial metabolic pathways rather than focusing purely on taxonomy to find therapeutic and diagnostic targets.
biorxiv microbiology 0-100-users 2019A positively selected, common, missense variant in FBN1 confers a 2.2 centimeter reduction of height in the Peruvian population, bioRxiv, 2019-02-26
Peruvians are among the shortest people in the world. To understand the genetic basis of short stature in Peru, we examined an ethnically diverse group of Peruvians and identified a novel, population-specific, missense variant in FBN1 (E1297G) that is significantly associated with lower height in the Peruvian population. Each copy of the minor allele (frequency = 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). This is the largest effect size known for a common height-associated variant. This variant shows strong evidence of positive selection within the Peruvian population and is significantly more frequent in Native American populations from coastal regions of Peru compared to populations from the Andes or the Amazon, suggesting that short stature in Peruvians is the result of adaptation to the coastal environment.
biorxiv genomics 100-200-users 2019