Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk

Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit interindividual differences in effect, termed 'variable penetrance'. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.Peer reviewe

Performance and nutrient utilisation of dairy cows offered silages produced from three successive harvests of either a red clover–perennial ryegrass sward or a perennial ryegrass sward

The need to reduce reliance on imported protein feeds within the UK and Ireland has stimulated interest in locally grown forage legume crops, including red clover (Trifolium pratense L.). This 13-wk study examined the performance of 28 dairy cows offered silages produced from three successive harvests (H) of either a pure grass sward (GS) receiving 315 kg N/ha per annum or a red clover–perennial ryegrass sward (RCGS) receiving 22 kg N/ha per annum. The crops of H1, H2 and H3 were wilted for 48, 72 and 72 h, respectively. Silages from H1, H2 and H3 were offered for 5, 5 and 3 wk, respectively, with cows supplemented with 8.0 kg concentrate/d throughout the experiment. Digestibility of DM and the effectively degradable protein content were lower, while protein degradability was higher, for RCGS than for GS. Silage DM intakes (DMIs) were higher for RCGS than for GS at H1 and H2, with no differences at H3. Milk yield was higher with RCGS than with GS at H3, with no differences at H1 and H2. Milk fat and milk protein contents were lower with RCGS than with GS at H3 but did not differ at H1 and H2. Faecal N/N intake was higher in the RCGS group than in the GS group at H1, with no differences at H2 and H3. Gross energy digestibility was lower for RCGS than for GS at H2. Although cow performance was higher with RCGS treatment, the responses were variable between harvests, largely reflecting the changing proportion of RC in the swards as the season progresse

Effectiveness of Audio-Feedback in Postural Training for Adolescent Idiopathic Scoliosis Patients

The possibility of using learned physiological responses in control of progressive adolescent idiopathic scoliosis (AIS) was investigated. Sixteen (16) AIS patients with progressing or high-risk curves (Cobb's angle between 25° and 35° at start and reducible by lateral bending) were fitted with a device with tone alarm for poor posture. In the first 18 months of application, 3 patients defaulted and 4 showed curve progression > 10° (2 changed to rigid spinal orthoses and 2 underwent surgery). The curves for the other 9 patients were kept under control (within ±5° of Cobb's angle) and 5 of them have reached skeletal maturity and terminated the application. The remaining 4 patients were still using the devices until skeletal maturity or curve progression. The curve control rate was 69%. A long-lasting active spinal control could be achieved through the patient's own spinal muscles. Nevertheless, before the postural training device could become a treatment modality, a long-term study for more AIS patients was necessary. This project is ongoing in the Duchess of Kent Children's Hospital, Sandy Bay, Hong Kong.link_to_subscribed_fulltex