Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases

Degradation of lucerne stem cell walls by five rumen bacterial species

The rumen bacterial strains Butyrivibrio fibrisolvens H17c, Fibrobacter succinogenes S85, Lachnospira multiparus 40, Ruminococcus albus 7 and R. flavefaciens FD-1 were compared individually and as a five-species mixture with a rumen inoculum for their ability to degrade lucerne (Medicago sativa L.) stem cell wall polysaccharides. Two maturity stages of lucerne (bud and full flower) were utilized as substrates and incubation periods of 24 and 96 h were employed. Lucerne stem substrates and fermentation residues were analysed for cell wall content and composition. Degradation of total cell wall polysaccharides and all polysaccharide fractions was greater for immature than for mature lucerne stems. The 96-h incubation resulted in significantly more degradation of all cell wall polysaccharides than did the 24-h incubation. The R. albus culture was able to degrade all cell wall polysaccharide fractions as well or better than any other culture, including the rumen inoculum. Co-culture of R. albus with the four other ruminal species did not improve degradation of any wall polysaccharides compared with R. albus alone. Microscopic examination indicated that R. albus and the five-species mixture appeared to degrade Lucerne tissues in thin sections to almost the same extent as did rumen fluid