Genomics and Health Studies: Insights and Discoveries

This paper proposes that the transposons and long non-coding DNA in the genome define the detailed three-dimensional structures of animals and plants in a digital structure encoding that is manipulated by the transposons.

Background A group of inherited disorders that are attributed to defects in the primary cilium or the ‘cell’s antenna’ are called primary ciliopathies. In 2012, Genomics England or GE spearheaded the 100,000 Genomes Project and recruited National Health Service or NHS patients with eligible rare diseases and cancer. The sequence data from this project were associated with Human Phenotype Ontology or HPO terms entered by recruiting clinicians. With that, the objective of this study is to optimize strategies to improve molecular diagnostic rates for probands recruited to the CMC category within the 100,000 Genomes Project. Method The researchers recruited 83 prescreened probands, which are assumed to have congenital anomalies and malformations caused by ciliopathies in the following disease categories: Bardet-Biedl syndrome, Joubert syndrome, and ‘Rare Multisystem Ciliopathy Disorders.’ The researchers implemented bespoke variant filtering and analysis strategy in order to enhance molecular diagnostic rates for participants. In addition, first-pass analysis was blinded to previous results, and then verified against the GEL reported findings in the GMC exit questionnaires. These were completed by regional NHS GMCs for each analysed participant. According to researchers, study analysis workflow comprised steps to filter genomic data, assess putative pathogenic variants then classify and assign diagnostic confidence. Key Findings The researchers established a research molecular diagnosis for half of probands and it appeared to be 20% higher than previously reported by GEL. According to researchers, a high proportion of diagnoses are correlated to variants in non-ciliopathy disease genes. These can hamper the clinical recognition of ciliopathies. Additionally, 13% of probands acquired at least one causative variant outside the tiers 1 and 2 variant prioritisation categories, however these are not included in standard 100,000 Genomes Project diagnostic strategies. These include four structural variants and three predicted to cause non-canon-ical splicing defects. The researchers also stated that two unrelated participants have biallelic likely pathogenic variants in LRRC45, a putative novel ciliopathy disease gene Conclusions and Recommendations The researchers therefore concluded that large-scale genomic sequencing and phenotyping, such as the 100,000 Genomes Project, have immense influence over the data that could offer huge opportunities to improve diagnostics, understanding of disease mechanisms and identification of novel drug targets. The researchers highlighted the need to improve strategies to analyse sequence data to provide the maximum benefit for patients and the scientific community.

Background This study analyzes genome-wide epigenome in patients with nociceptive and neuropathic chronic pain subtypes. Chronic pain itself and the transition from acute to chronic pain may be epigenetically controlled. Method The authors conducted a cross-sectional study of a genome-wide DNA methylation analysis. It was performed using the blood DNA reduced representation bisulfite sequencing technique. The prospective patients include those with chronic nociceptive pain, chronic neuropathic pain, and healthy controls. Three prospective cohorts were compared at both the single CpG and differentially methylated region levels. Key findings The study reported that chronic nociceptive pain and chronic neuropathic pain differ in their etiology. However, they have a common main symptom, pain, although it has different characteristics. Epigenetic disturbances accompanying nociceptive pain are very different from those accompanying neuropathic pain. In nociceptive pain, the epigenetic disturbance observed would affect the function of the opioid analgesic system. In neuropathic pain, it would affect that of the GABAergic reward system. Conclusion In conclusion, an epigenome-wide study identified CpGs methylation signatures in the blood, discriminating nociceptive from neuropathic types of chronic pain. Genes associated with these signatures appear to have essential functions in the neuro-musculoskeletal system. The new targets identified in our study might help to discover more specific treatments for these pains.

Background Patients with Meier-Gorlin syndrome typically present a short stature, small ear, and deficient or absent patella. Genome sequencing can be used to identify new Mendelian genes. This also presents a chance for easy sequencing with informative-phased variants. The sequencing is efficient for recessive disorders when there is no parental DNA. The study aimed to explain the use of linked-read Chromium genome sequencing technology to determine biallelic pathogenic genetic variations. Methods The researchers used the linked-read whole genome sequencing to determine reasons for the Meier-Gorlin syndrome. There were 8 genes linked to the Meier-Gorlin syndrome, which were all programming important parts for DNA replication. The DNA was extracted from the subjects’ whole blood through conventional clinical laboratory procedures. The Chromium genome sequencing was done for the samples. Moreover, amino acid sequences for DONSON from various organisms were aligned through default parameters. The site-guided mutagenesis was employed to have the variants of interest into the fluorescent protein-DONSON molecule. These were confirmed through Sanger sequencing. Key Findings The researchers reported that the effective phasing of the linked-read information of the proponents resulted in the determination of biallelic rare variations in 4 subjects in DONSON. This was a newly recognized DNA replication fork surveillance factor. The genetic variations had 5 new missense and 1 deep intronic variations. These were all recognized as harmful to function. The missense variations interrupted DONSON’s nuclear localization. Whereas the intronic variation had a new splice site where an abnormal transcript with no remaining highly expressed transcript was made. Conclusion The researchers concluded that the genetic findings expand the range of traits linked with DONSON variants. This also raised the new question of the part of DONSON in DNA replication. The determination of the disease gene for Meier-Gorlin syndrome exemplifies the use of linked-read whole genome sequencing. This was an effective equipment to be taken into account in studying the genetics of recessive diseases and conditions.