The branch point sequence is a cis-acting intronic motif required for mRNA splicing. Despite their functional importance, branch point sequences are not routinely annotated. Here we predict branch point sequences in 179,476 bovine introns and investigate their variability using a catalogue of 29.4 million variants detected in 266 cattle genomes. We localize the bovine branch point within a degenerate heptamer “nnyTrAy”. An adenine residue at position 6, that acts as branch point, and a thymine residue at position 4 of the heptamer are more strongly depleted for mutations than coding sequences suggesting extreme purifying selection. We provide evidence that mutations affecting these evolutionarily constrained residues lead to alternative splicing. We confirm evolutionary constraints on branch point sequences using a catalogue of 115 million SNPs established from 3,942 human genomes of the gnomAD database. Kadri and colleagues present the evolutionary constraints of the branch point motifs in the bovine and human genome. The functional role of these predicted branch points sequences in the bovine genome is inferred using splicing quantitative trait loci analyses.

/pdf/the-intronic-branch-point-sequence-is-under-strong-1jiglk4dxl.pdf

The intronic branch point sequence is under strong evolutionary constraint in the bovine and human genome.

Canine neuroaxonal dystrophy (NAD) is a recessive, degenerative neurological disease of young adult Rottweiler dogs (Canis lupus familiaris) characterized pathologically by axonal spheroids primarily targeting sensory axon terminals. A genome-wide association study of seven Rottweilers affected with NAD and 42 controls revealed a significantly associated region on canine chromosome 5 (CFA 5). Homozygosity within the associated region narrowed the critical interval to a 4.46 Mb haplotype (CFA5:11.28 Mb - 15.75 Mb; CanFam3.1) that associated with the phenotype. Whole-genome sequencing of two histopathologically confirmed canine NAD cases and 98 dogs unaffected with NAD revealed a homozygous missense mutation within the Vacuolar Protein Sorting 11 (VPS11) gene (g.14777774T > C; p.H835R) that was associated with the phenotype. These findings present the opportunity for an antemortem test for confirming NAD in Rottweilers where the allele frequency was estimated at 2.3%. VPS11 mutations have been associated with a degenerative leukoencephalopathy in humans, and VSP11 should additionally be included as a candidate gene for unexplained cases of human NAD.

/pdf/a-missense-mutation-in-the-vacuolar-protein-sorting-11-vps11-2g9z1t4kxw.pdf

A Missense Mutation in the Vacuolar Protein Sorting 11 (VPS11) Gene Is Associated with Neuroaxonal Dystrophy in Rottweiler Dogs

Chronic obstructive pulmonary disease (COPD) is one of the world's leading causes of death and a major chronic disease, highly prevalent in the aging population exposed to tobacco smoke and airborne pollutants, which calls for early and useful biomolecular predictors. Roles of noncoding RNAs in COPD have been proposed, however, not many studies have systematically investigated the crosstalk among various transcripts in this context. The construction of RNA functional networks such as lncRNA-mRNA, and circRNA-miRNA-mRNA interaction networks could therefore facilitate our understanding of RNA interactions in COPD. Here, we identified the expression of RNA transcripts in RNA sequencing from COPD patients, and the potential RNA networks were further constructed.All fresh peripheral blood samples of three patients with COPD and three non-COPD patients were collected and examined for mRNA, miRNA, lncRNA, and circRNA expression followed by qRT-PCR validation. We also examined mRNA expression to enrich relevant biological pathways. lncRNA-mRNA coexpression network and circRNA-miRNA-mRNA network in COPD were constructed.In this study, we have comprehensively identified and analyzed the differentially expressed mRNAs, lncRNAs, miRNAs, and circRNAs in peripheral blood of COPD patients with high-throughput RNA sequencing. 282 mRNAs, 146 lncRNAs, 85 miRNAs, and 81 circRNAs were differentially expressed. GSEA analysis showed that these differentially expressed RNAs correlate with several critical biological processes such as "ncRNA metabolic process", "ncRNA processing", "ribosome biogenesis", "rRNAs metabolic process", "tRNA metabolic process" and "tRNA processing", which might be participating in the progression of COPD. RT-qPCR with more clinical COPD samples was used for the validation of some differentially expressed RNAs, and the results were in high accordance with the RNA sequencing. Given the putative regulatory function of lncRNAs and circRNAs, we have constructed the co-expression network between lncRNA and mRNA. To demonstrate the potential interactions between circRNAs and miRNAs, we have also constructed a competing endogenous RNA (ceRNA) network of differential expression circRNA-miRNA-mRNA in COPD.In this study, we have identified and analyzed the differentially expressed mRNAs, lncRNAs, miRNAs, and circRNAs, providing a systematic view of the differentially expressed RNA in the context of COPD. We have also constructed the lncRNA-mRNA co-expression network, and for the first time constructed the circRNA-miRNA-mRNA in COPD. This study reveals the RNA involvement and potential regulatory roles in COPD, and further uncovers the interactions among those RNAs, which will assist the pathological investigations of COPD and shed light on therapeutic targets exploration for COPD. 

/pdf/comprehensive-identification-of-rna-transcripts-and-45o74q3x.pdf

Comprehensive identification of RNA transcripts and construction of RNA network in chronic obstructive pulmonary disease

The splicing of transfer RNA (tRNA) introns is a critical step of tRNA maturation, for intron‐containing tRNAs. In eukaryotes, tRNA splicing is a multi‐step process that relies on several RNA processing enzymes to facilitate intron removal and exon ligation. Splicing is initiated by the tRNA splicing endonuclease (TSEN) complex which catalyzes the excision of the intron through its two nuclease subunits. Mutations in all four subunits of the TSEN complex are linked to a family of neurodegenerative and neurodevelopmental diseases known as pontocerebellar hypoplasia (PCH). Recent studies provide molecular insights into the structure, function, and regulation of the eukaryotic TSEN complex and are beginning to illuminate how mutations in the TSEN complex lead to neurodegenerative disease. Using new advancements in the prediction of protein structure, we created a three‐dimensional model of the human TSEN complex. We review functions of the TSEN complex beyond tRNA splicing by highlighting recently identified substrates of the eukaryotic TSEN complex and discuss mechanisms for the regulation of tRNA splicing, by enzymes that modify cleaved tRNA exons and introns. Finally, we review recent biochemical and animal models that have worked to address the mechanisms that drive PCH and synthesize these studies with previous studies to try to better understand PCH pathogenesis.

Recent insights into the structure, function, and regulation of the eukaryotic transfer RNA splicing endonuclease complex

Background Shaking puppy syndrome is commonly attributed to abnormal myelination of the central nervous system. Hypothesis/objectives To report the long-term clinical course and the imaging characteristics of hypomyelinating leukodystrophy in German Shepherd dogs. Animals and methods Three related litters with 11 affected dogs. Results The 11 affected dogs experienced coarse, side-to-side tremors of the head and trunk, which interfered with normal goal-oriented movements and disappeared at rest. Signs were noticed shortly after birth. Nine dogs were euthanized, 3 dogs underwent pathological examination, and 2 littermates were raised by their breeder. Tremors improved gradually until 6 to 7 months of age. Adult dogs walked with severe residual pelvic limb ataxia. One dog developed epilepsy with tonic-clonic seizures at 15 months of age. Conventional magnetic resonance imaging (MRI) disclosed homogenous hyperintense signal of the entire subcortical white matter in 3 affected 7-week-old dogs and a hypointense signal in a presumably unaffected littermate. Subcortical white matter appeared isointense to gray matter at 15 and 27 weeks of age on repeated MRI. Abnormal white matter signal with failure to display normal gray-white matter contrast persisted into adulthood. Cerebellar arbor vitae was not visible at any time point. Clinical signs, MRI findings, and pathological examinations were indicative of a hypomyelinating leukodystrophy. All parents of the affected litters shared a common ancestor and relatedness of the puppies suggested an autosomal recessive mode of inheritance. Conclusion We describe a novel hypomyelinating leukodystrophy in German Shepherd dogs with a suspected inherited origin.

A hypomyelinating leukodystrophy in German Shepherd dogs

Several genetically distinct forms of cerebellar ataxia exist in Belgian shepherd dogs. We investigated a litter in which two puppies developed cerebellar ataxia. The clinical signs stabilized at around six weeks of age, but remained visible into adulthood. Combined linkage and homozygosity mapping delineated a 5.5 Mb critical interval. The comparison of whole-genome sequence data of one affected dog to 929 control genomes revealed a private homozygous ~4.8 kb deletion in the critical interval, Chr8:14,468,376_14,473,136del4761. The deletion comprises exon 35 of the RALGAPA1 gene, XM_038544497.1:c.6080-2893_6944+1003del. It is predicted to introduce a premature stop codon into the transcript, truncating ~23% of the wild-type open reading frame of the encoded Ral GTPase-activating protein catalytic subunit α 1, XP_038400425.1:(p.Val2027Glnfs*7). Genotypes at the deletion showed the expected co-segregation with the phenotype in the family. Genotyping additional ataxic Belgian shepherd dogs revealed three additional homozygous mutant dogs from a single litter, which had been euthanized at five weeks of age due to their severe clinical phenotype. Histopathology revealed cytoplasmic accumulation of granular material within cerebellar Purkinje cells. Genotyping a cohort of almost 900 Belgian shepherd dogs showed the expected genotype–phenotype association and a carrier frequency of 5% in the population. Human patients with loss-of-function variants in RALGAPA1 develop psychomotor disability and early-onset epilepsy. The available clinical and histopathological data, together with current knowledge about RALGAPA1 variants and their functional impact in other species, suggest the RALGAPA1 deletion is the likely causative defect for the observed phenotype in the affected dogs.

RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia

Atypically located arachnoid cyst in a five-year-old cat.

We report a hereditary leukodystrophy in Standard Schnauzer puppies. Clinical signs occurred shortly after birth or started at an age of under 4 weeks and included apathy, dysphoric vocalization, hypermetric ataxia, intension tremor, head tilt, circling, proprioceptive deficits, seizures and ventral strabismus consistent with a diffuse intracranial lesion. Magnetic resonance imaging revealed a diffuse white matter disease without mass effect. Macroscopically, the cerebral white matter showed a gelatinous texture in the centrum semiovale. A mild hydrocephalus internus was noted. Histopathologically, a severe multifocal reduction of myelin formation and moderate diffuse edema without inflammation was detected leading to the diagnosis of leukodystrophy. Combined linkage analysis and homozygosity mapping in two related families delineated critical intervals of approximately 29 Mb. The comparison of whole genome sequence data of one affected Standard Schnauzer to 221 control genomes revealed a single private homozygous protein changing variant in the critical intervals, TSEN54:c.371G>A or p.(Gly124Asp). TSEN54 encodes the tRNA splicing endonuclease subunit 54. In humans, several variants in TSEN54 were reported to cause different types of pontocerebellar hypoplasia. The genotypes at the c.371G>A variant were perfectly associated with the leukodystrophy phenotype in 12 affected Standard Schnauzers and almost 1000 control dogs from different breeds. These results suggest that TSEN54:c.371G>A causes the leukodystrophy. The identification of a candidate causative variant enables genetic testing so that the unintentional breeding of affected Standard Schnauzers can be avoided in the future. Our findings extend the known genotype-phenotype correlation for TSEN54 variants.

/pdf/tsen54-missense-variant-in-standard-schnauzers-with-5523dccm3z.pdf

TSEN54 missense variant in Standard Schnauzers with leukodystrophy.

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RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia

Atypically located arachnoid cyst in a five-year-old cat.

TSEN54 missense variant in Standard Schnauzers with leukodystrophy.