44 research outputs found
Self-similarity of human protein interaction networks: a novel strategy of distinguishing proteins
The successful determination of reliable protein interaction networks (PINs) in several species in the
post-genomic era has hitherto facilitated the quest to understanding systems and structural properties of
such networks. It is envisaged that a clearer understanding of their intrinsic topological properties would
elucidate evolutionary and biological topography of organisms. This, in turn, may inform the
understanding of diseases’ aetiology. By analysing sub-networks that are induced in various layers identified
by zones defined as distance from central proteins, we show that zones of human PINs display self-similarity
patterns. What is observed at a global level is repeated at lower levels of inducement. Furthermore, it is
observed that these levels of strength point to refinement and specialisations in these layers. This may point
to the fact that various levels of representations in the self-similarity phenomenon offer a way of measuring
and distinguishing the importance of proteins in the network. To consolidate our findings, we have also
considered a gene co-expression network and a class of gene regulatory networks in the same framework. In
all cases, the phenomenon is significantly evident. In particular, the truly unbiased regulatory networks
show finer level of articulation of self-similarity.Web of Scienc
Human coronavirus OC43 3CL protease and the potential of ML188 as a broad-spectrum lead compound: Homology modelling and molecular dynamic studies
The coronavirus 3 chymotrypsin-like protease (3CLpro) is a validated target in the design of potential
anticoronavirus inhibitors. The high degree of homology within the protease’s active site and substrate conservation
supports the identification of broad spectrum lead compounds. A previous study identified the compound ML188,
also termed 16R, as an inhibitor of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) 3CLpro. This study
will detail the generation of a homology model of the 3CLpro of the human coronavirus OC43 and determine the
potential of 16R to form a broad-spectrum lead compound. MODELLER was used to generate a suitable
three-dimensional model of the OC43 3CLpro and the Prime module of SchrÓ§dinger predicted the binding
conformation and free energy of binding of 16R within the 3CLpro active site. Molecular dynamics further
confirmed ligand stability and hydrogen bonding networks
Computational characterization of iron metabolism in the tsetse disease vector, glossina morsitans: Ire stem-loops
Iron metabolism and regulation is an indispensable part of species survival, most importantly for
blood feeding insects. Iron regulatory proteins are central regulators of iron homeostasis, whose binding to iron
response element (IRE) stem-loop structures within the UTRs of genes regulate expression at the post-transcriptional level.
Despite the extensive literature on themechanism of iron regulation in human, less attention has been given to insect
and more specifically the blood feeding insects, where research has mainly focused on the characterization of ferritin and
transferrin. We thus, examined the mechanism of iron homeostasis through a genome-wide computational identification
of IREs and other enriched motifs in the UTRs of Glossina morsitans with the view to identify new IRE-regulated genes
Modelling human protein interaction networks as metric spaces has potential in disease research and drug target discovery
We have recently shown by formally modelling human protein interaction networks (PINs) as metric
spaces and classified proteins into zones based on their distance from the topological centre that hub proteins are
primarily centrally located. We also showed that zones closest to the network centre are enriched for critically
important proteins and are also functionally very specialised for specific ‘house keeping’ functions. We proposed that
proteins closest to the network centre may present good therapeutic targets. Here, we present multiple pieces of
novel functional evidence that provides strong support for this hypothesis. We found that the human PINs has a highly connected signalling core, with the majority of proteins
involved in signalling located in the two zones closest to the topological centre. The majority of essential, disease
related, tumour suppressor, oncogenic and approved drug target proteins were found to be centrally located.
Similarly, the majority of proteins consistently expressed in 13 types of cancer are also predominantly located in zones
closest to the centre. Proteins from zones 1 and 2 were also found to comprise the majority of proteins in key KEGG
pathways such as MAPK-signalling, the cell cycle, apoptosis and also pathways in cancer, with very similar patterns
seen in pathways that lead to cancers such as melanoma and glioma, and non-neoplastic diseases such as measles,
inflammatory bowel disease and Alzheimer’s disease
Application of anin silicoapproach identifies a genetic locus withinITGB2,and itsinteractions withHSPG2 and FGF9,to be associated with anterior cruciateligament rupture risk
We developed a Biomedical Knowledge Graph model that is phenotype and biological function-aware through integrating knowledge from multiple domains in a Neo4j, graph database. Allknown human genes were assessed through the model to identify potential new risk genes foranterior cruciate ligament (ACL) ruptures and Achilles tendinopathy (AT). Genes were prioritisedand explored in a case–control study comparing participants with ACL ruptures (ACL-R),including a sub-group with non-contact mechanism injuries (ACL-NON), to uninjured controlindividuals (CON). After genefiltering, 3376 genes, including 411 genes identified throughprevious whole exome sequencing, were found to be potentially linked to AT and ACL ruptures.Four variants were prioritised:HSPG2:rs2291826A/G,HSPG2:rs2291827G/A,ITGB2:rs2230528C/TandFGF9:rs2274296C/T. The rs2230528 CC genotype was over-represented in the CON groupcompared to ACL-R (p< 0.001) and ACL-NON (p< 0.001) and the TT genotype and T allele wereover-represented in the ACL-R group and ACL-NON compared to CON (p< 0.001) group. Severalsignificant differences in distributions were noted for the gene-gene interactions: (HSPG2:rs2291826, rs2291827 andITGB2:rs2230528) and (ITGB2:rs2230528 andFGF9:rs2297429)
Protein interaction networks as metric spaces: A novel perspective on distribution of hubs
In the post-genomic era, a central and overarching question in the analysis of protein-protein
interaction networks continues to be whether biological characteristics and functions of proteins such as lethality,
physiological malfunctions and malignancy are intimately linked to the topological role proteins play in the network
as a mathematical structure. One of the key features that have implicitly been presumed is the existence of hubs,
highly connected proteins considered to play a crucial role in biological networks. We explore the structure of protein
interaction networks of a number of organisms as metric spaces and show that hubs are non randomly positioned
and, from a distance point of view, centrally located
Protein interaction networks as metric spaces: A novel perspective on distribution of hubs
In the post-genomic era, a central and overarching question in the analysis of protein-protein
interaction networks continues to be whether biological characteristics and functions of proteins such as lethality,
physiological malfunctions and malignancy are intimately linked to the topological role proteins play in the network
as a mathematical structure. One of the key features that have implicitly been presumed is the existence of hubs,
highly connected proteins considered to play a crucial role in biological networks. We explore the structure of protein
interaction networks of a number of organisms as metric spaces and show that hubs are non randomly positioned
and, from a distance point of view, centrally located
The African Coelecanth genome provides insights into tetrapod evolution
The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.Web of Scienc
Semantic interrogation of a multi knowledge domain ontological model of tendinopathy identifies four strong candidate risk genes
Tendinopathy is a multifactorial syndrome characterised by tendon pain and thickening, and impaired
performance during activity. Candidate gene association studies have identified genetic factors
that contribute to intrinsic risk of developing tendinopathy upon exposure to extrinsic factors.
Bioinformatics approaches that data-mine existing knowledge for biological relationships may assist
with the identification of candidate genes. The aim of this study was to data-mine functional annotation
of human genes and identify candidate genes by ontology-seeded queries capturing the features of
tendinopathy. Our BioOntological Relationship Graph database (BORG) integrates multiple sources of
genomic and biomedical knowledge into an on-disk semantic network where human genes and their
orthologs in mouse and rat are central concepts mapped to ontology terms. The BORG was used to
screen all human genes for potential links to tendinopathy. Following further prioritisation, four strong
candidate genes (COL11A2, ELN, ITGB3, LOX) were identified. These genes are differentially expressed
in tendinopathy, functionally linked to features of tendinopathy and previously implicated in other
connective tissue diseases. In conclusion, cross-domain semantic integration of multiple sources of
biomedical knowledge, and interrogation of phenotypes and gene functions associated with disease,
may significantly increase the probability of identifying strong and unobvious candidate genes in
genetic association studies
Exome sequencing identifies novel dysferlin mutation in a family with paucisymptomatic heterozygous carriers
BACKGROUND: We investigated a South African family of admixed ancestry in which the first generation (G1) developed
insidious progressive distal to proximal weakness in their twenties, while their offspring (G2) experienced severe
unexpected symptoms of myalgia and cramps since adolescence. Our aim was to identify deleterious mutations that
segregate with the affected individuals in this family.
METHODS: Exome sequencing was performed on five cases, which included three affected G1 siblings and two
pauci-symptomatic G2 offspring. As controls we included an unaffected G1 sibling and a spouse of one of the G1
affected individuals. Homozygous or potentially compound heterozygous variants that were predicted to be functional
and segregated with the affected G1 siblings, were further evaluated. Additionally, we considered variants in all genes
segregating exclusively with the affected (G1) and pauci-symptomatic (G2) individuals to address the possibility of a
pseudo-autosomal dominant inheritance pattern in this family.
RESULTS: All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF (dysferlin) mutation,
with their asymptomatic sibling and both pauci-symptomatic G2 offspring carrying only a single mutant allele. Sanger
sequencing confirmed segregation of the variant. No additional potentially contributing variant was found in the DYSF
or any other relevant gene in the pauci-symptomatic carriers.
CONCLUSION: Our finding of a truncating dysferlin mutation confirmed dysferlinopathy in this family and we propose
that the single mutant allele is the primary contributor to the neuromuscular symptoms seen in the second-generation
pauci-symptomatic carriers