COMUS: Clinician-Oriented locus-specific MUtation detection and deposition System

Background: A disease-causing mutation refers to a heritable genetic change that is associated with a specific phenotype (disease). The detection of a mutation from a patient's sample is critical for the diagnosis, treatment, and prognosis of the disease. There are numerous databases and applications with which to archive mutation data. However, none of them have been implemented with any automated bioinformatics tools for mutation detection and analysis starting from raw data materials from patients. We present a Locus Specific mutation DB (LSDB) construction system that supports both mutation detection and deposition in one package. Results: COMUS (Clinician-Oriented locus specific MUtation detection and deposition System) is a mutation detection and deposition system for developing specific LSDBs. COMUS contains 1) a DNA sequence mutation analysis method for clinicians' mutation data identification and deposition and 2) a curation system for variation detection from clinicians' input data. To embody the COMUS system and to validate its clinical utility, we have chosen the disease hemophilia as a test database. A set of data files from bench experiments and clinical information from hemophilia patients were tested on the LSDB, KoHemGene http://www.kohemgene.org, which has proven to be a clinician-friendly interface for mutation detection and deposition. Conclusion: COMUS is a bioinformatics system for detecting and depositing new mutations from patient DNA with a clinician-friendly interface. LSDBs made using COMUS will promote the clinical utility of LSDBs. COMUS is available at http://www.comus.info. © 2009 Jho et al; licensee BioMed Central Ltdclose

Population Genetic Structure of Peninsular Malaysia Malay Sub-Ethnic Groups

Patterns of modern human population structure are helpful in understanding the history of human migration and admixture. We conducted a study on genetic structure of the Malay population in Malaysia, using 54,794 genome-wide single nucleotide polymorphism genotype data generated in four Malay sub-ethnic groups in peninsular Malaysia (Melayu Kelantan, Melayu Minang, Melayu Jawa and Melayu Bugis). To the best of our knowledge this is the first study conducted on these four Malay sub-ethnic groups and the analysis of genotype data of these four groups were compiled together with 11 other populations' genotype data from Indonesia, China, India, Africa and indigenous populations in Peninsular Malaysia obtained from the Pan-Asian SNP database. The phylogeny of populations showed that all of the four Malay sub-ethnic groups are separated into at least three different clusters. The Melayu Jawa, Melayu Bugis and Melayu Minang have a very close genetic relationship with Indonesian populations indicating a common ancestral history, while the Melayu Kelantan formed a distinct group on the tree indicating that they are genetically different from the other Malay sub-ethnic groups. We have detected genetic structuring among the Malay populations and this could possibly be accounted for by their different historical origins. Our results provide information of the genetic differentiation between these populations and a valuable insight into the origins of the Malay sub-ethnic groups in Peninsular Malaysia

Identification of Close Relatives in the HUGO Pan-Asian SNP Database

The HUGO Pan-Asian SNP Consortium has recently released a genome-wide dataset, which consists of 1,719 DNA samples collected from 71 Asian populations. For studies of human population genetics such as genetic structure and migration history, this provided the most comprehensive large-scale survey of genetic variation to date in East and Southeast Asia. However, although considered in the analysis, close relatives were not clearly reported in the original paper. Here we performed a systematic analysis of genetic relationships among individuals from the Pan-Asian SNP (PASNP) database and identified 3 pairs of monozygotic twins or duplicate samples, 100 pairs of first-degree and 161 second-degree of relationships. Three standardized subsets with different levels of unrelated individuals were suggested here for future applications of the samples in most types of population-genetics studies (denoted by PASNP1716, PASNP1640 and PASNP1583 respectively) based on the relationships inferred in this study. In addition, we provided gender information for PASNP samples, which were not included in the original dataset, based on analysis of X chromosome data

Mapping human genetic diversity in Asia

Asia harbors substantial cultural and linguistic diversity, but the geographic structure of genetic variation across the continent remains enigmatic. Here we report a large-scale survey of autosomal variation from a broad geographic sample of Asian human populations. Our results show that genetic ancestry is strongly correlated with linguistic affiliations as well as geography. Most populations show relatedness within ethnic/linguistic groups, despite prevalent gene flow among populations. More than 90% of East Asian (EA) haplotypes could be found in either Southeast Asian (SEA) or Central-South Asian (CSA) populations and show clinal structure with haplotype diversity decreasing from south to north. Furthermore, 50% of EA haplotypes were found in SEA only and 5% were found in CSA only, indicating that SEA was a major geographic source of EA populations

Molecular Recognition by Synthetic Receptors in Biomimetic and Cellular Systems

A deep water-soluble cavitand, a synthetic host molecule that can selectively recognize small molecules of the correct size, shape and charge, shows notable selectivity for trimethylammonium (R-NMe3+) salts through cation-π interactions in water. The cavitand possesses a negatively charged hydrophilic rim and a hydrophobic aromatic pocket, and can self-assemble into a vase-like conformation in aqueous solution via intramolecular hydrogen bonding. This host can be incorporated into supported lipid bilayers (SLBs) and retain its binding selectivity.To study the scope of guests that can be recognized, several proteins were functionalized with R-NMe3+ binding handles and the recognition event between the functionalized proteins and cavitand:SLB system was monitored by Surface Plasmon Resonance (SPR) Spectroscopy. The binding was monovalent, and displayed a binding affinity of >105 M-1, showing that the cavitand is capable of recognizing suitably labeled large proteins via cavity-based recognition.Underivatized proteins with high isoelectric points also showed strong binding to the cavitand:bilayer system under high salt conditions. This unique binding is due to charge-based interactions between the negatively charged rim of cavitand and the positively charged surfaces of proteins. Moreover, immobilized trypsin on the cavitand:SLB interface maintains its enzymatic function: the adhered trypsin is capable of digestion of insulin B. This indicates that the cavitand:SLB system is tolerant to enzymatic reactions.From preliminary results on artificial SLBs, our interest has moved on to molecular recognition processes using cavitands in living cells. Shape-based molecular recognition with a synthetic receptor in living cells is far more challenging than in biomimetic membrane systems, simply due to the vast array of competitive species in a living cell. It was observed that the cavitand is capable of selective guest recognition and transmembrane transport in living cells despite the complexity of the environment. The host was combined with a R-NMe3+ labeled fluorescent guest in human cervical cancer cells (HeLa), and selective transport of the guest into the cells was observed. In the absence of cavitands minimal transport was observed, and no transport of fluorescein itself (without a R-NMe3+ binding handle) was observed. This was the first biological application of cavitands in cellular systems

Cell and Protein Recognition at a Supported Bilayer Interface via In Situ Cavitand-Mediated Functional Polymer Growth

Water-soluble deep cavitands embedded in a supported lipid bilayer are capable of anchoring ATRP initiator molecules for the in situ synthesis of primary amine-containing polymethacrylate patches at the water:membrane interface. These polymers can be derivatized in situ to incorporate fluorescent reporters, allow selective protein recognition, and can be applied to the immobilization of nonadherent cells at the bilayer interface. [Image: see text

Labeled protein recognition at a membrane bilayer interface by embedded synthetic receptors.

Self-folding deep cavitands embedded in a supported lipid bilayer are capable of recognizing suitably labeled proteins at the bilayer interface. The addition of a choline derived binding "handle" to a number of different proteins allows their selective noncovalent recognition, with association constants on the order of 10(5) M(-1). The proteins are displayed at the water:bilayer interface, and a single binding handle allows recognition of the large, charged protein by a small molecule synthetic receptor via complementary shape and charge interactions

Labeled Protein Recognition at a Membrane Bilayer Interface by Embedded Synthetic Receptors

Self-folding deep cavitands embedded in a supported lipid bilayer are capable of recognizing suitably labeled proteins at the bilayer interface. The addition of a choline derived binding “handle” to a number of different proteins allows their selective noncovalent recognition, with association constants on the order of 10⁵ M^–1. The proteins are displayed at the water:bilayer interface, and a single binding handle allows recognition of the large, charged protein by a small molecule synthetic receptor via complementary shape and charge interactions