http://www.humgenomics.com The latest research articles published by Human Genomics 2013-05-15T00:00:00Z The Kelch-like (KLHL) gene family encodes a group of proteins that generally possess a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. BTB domains facilitate protein binding and dimerization. The BACK domain has no known function yet is of functional importance since mutations in this domain are associated with disease. Kelch domains form a tertiary structure of β-propellers that have a role in extracellular functions, morphology, and binding to other proteins. Presently, 42 KLHL genes have been classified by the HUGO Gene Nomenclature Committee (HGNC), and they are found across multiple human chromosomes. The KLHL family is conserved throughout evolution. Phylogenetic analysis of KLHL family members suggests that it can be subdivided into three subgroups with KLHL11 as the oldest member and KLHL9 as the youngest. Several KLHL proteins bind to the E3 ligase cullin 3 and are known to be involved in ubiquitination. KLHL genes are responsible for several Mendelian diseases and have been associated with cancer. Further investigation of this family of proteins will likely provide valuable insights into basic biology and human disease. http://www.humgenomics.com/content/7/1/13 Bajinder Dhanoa Tiziana Cogliati Akhila Satish Elspeth Bruford James Friedman Human Genomics 2013, null:13 2013-05-15T00:00:00Z doi:10.1186/1479-7364-7-13 /content/figures/1479-7364-7-13-toc.gif Human Genomics 1479-7364 ${item.volume} 13 2013-05-15T00:00:00Z XML The HUGO Gene Nomenclature Committee has approved gene symbols for the majority of protein-coding genes on the human reference genome. To adequately represent regions of complex structural variation, the Genome Reference Consortium now includes alternative representations of some of these regions as part of the reference genome. Here, we describe examples of how we name novel genes in these regions and how this nomenclature is displayed on our website, http://genenames.org. http://www.humgenomics.com/content/7/1/12 Ruth Seal Mathew Wright Kristian Gray Elspeth Bruford Human Genomics 2013, null:12 2013-05-01T00:00:00Z doi:10.1186/1479-7364-7-12 /content/figures/1479-7364-7-12-toc.gif Human Genomics 1479-7364 ${item.volume} 12 2013-05-01T00:00:00Z XML We sequenced 11 germline exomes from five families with familial pancreatic cancer (FPC). One proband had a germline nonsense variant in ATM with somatic loss of the variant allele. Another proband had a nonsense variant in PALB2 with somatic loss of the variant allele. Both variants were absent in a relative with FPC. These findings question the causal mechanisms of ATM and PALB2 in these families and highlight challenges in identifying the causes of familial cancer syndromes using exome sequencing. http://www.humgenomics.com/content/7/1/11 Robert Grant Wigdan Al-Sukhni Ayelet Borgida Spring Holter Zaheer Kanji Treasa McPherson Emily Whelan Stefano Serra Quang Trinh Vanya Peltekova Lincoln Stein John McPherson Steven Gallinger Human Genomics 2013, null:11 2013-04-05T00:00:00Z doi:10.1186/1479-7364-7-11 /content/figures/1479-7364-7-11-toc.gif Human Genomics 1479-7364 ${item.volume} 11 2013-04-05T00:00:00Z XML Background: Recent reports suggest the role of nonsynonymous single nucleotide polymorphisms (nsSNPs) in cyclin-dependent kinase 7 (CDK7) gene associated with defect in the DNA repair mechanism that may contribute to cancer risk. Among the various inhibitors developed so far, flavopiridol proved to be a potential antitumor drug in the phase-III clinical trial for chronic lymphocytic leukemia. Here, we described a theoretical assessment for the discovery of new drugs or drug targets in CDK7 protein owing to the changes caused by deleterious nsSNPs. Methods: Three nsSNPs (I63R, H135R, and T285M) were predicted to have functional impact on protein function by SIFT, PolyPhen2, I-Mutant3, PANTHER, SNPs&GO, PhD-SNP, and screening for non-acceptable polymorphisms (SNAP). Furthermore, we analyzed the native and proposed mutant models in atomic level 10 ns simulation using the molecular dynamics (MD) approach. Finally, with the aid of Autodock 4.0 and PatchDock, we analyzed the binding efficacy of flavopiridol with CDK7 protein with respect to the deleterious mutations. Results: By comparing the results of all seven prediction tools, three nsSNPs (I63R, H135R, and T285M) were predicted to have functional impact on the protein function. The results of protein stability analysis inferred that I63R and H135R exhibited less deviation in root mean square deviation in comparison with the native and T285M protein. The flexibility of all the three mutant models of CDK7 protein is diverse in comparison with the native protein. Following to that, docking study revealed the change in the active site residues and decrease in the binding affinity of flavopiridol with mutant proteins. Conclusion: This theoretical approach is entirely based on computational methods, which has the ability to identify the disease-related SNPs in complex disorders by contrasting their costs and capabilities with those of the experimental methods. The identification of disease related SNPs by computational methods has the potential to create personalized tools for the diagnosis, prognosis, and treatment of diseases.Lay abstract: Cell cycle regulatory protein, CDK7, is linked with DNA repair mechanism which can contribute to cancer risk. The main aim of this study is to extrapolate the relationship between the nsSNPs and their effects in drug-binding capability. In this work, we propose a new methodology which (1) efficiently identified the deleterious nsSNPs that tend to have functional effect on protein function upon mutation by computational tools, (2) analyze d the native protein and proposed mutant models in atomic level using MD approach, and (3) investigated the protein-ligand interactions to analyze the binding ability by docking analysis. This theoretical approach is entirely based on computational methods, which has the ability to identify the disease-related SNPs in complex disorders by contrasting their costs and capabilities with those of the experimental methods. Overall, this approach has the potential to create personalized tools for the diagnosis, prognosis, and treatment of diseases. http://www.humgenomics.com/content/7/1/10 C George Priya Doss N Nagasundaram Chiranjib Chakraborty Luonan Chen Hailong Zhu Human Genomics 2013, null:10 2013-04-05T00:00:00Z doi:10.1186/1479-7364-7-10 /content/figures/1479-7364-7-10-toc.gif Human Genomics 1479-7364 ${item.volume} 10 2013-04-05T00:00:00Z PDF Hox genes encode transcription factors that regulate embryonic and post-embryonic developmental processes. The expression of Hox genes is regulated in part by the tight, spatial arrangement of conserved coding and non-coding sequences. The potential for evolutionary changes in Hox cluster structure is thought to be low among vertebrates; however, recent studies of a few non-mammalian taxa suggest greater variation than originally thought. Using next generation sequencing of large genomic fragments (>100 kb) from the red spotted newt (Notophthalamus viridescens), we found that the arrangement of Hox cluster genes was conserved relative to orthologous regions from other vertebrates, but the length of introns and intergenic regions varied. In particular, the distance between hoxd13 and hoxd11 is longer in newt than orthologous regions from vertebrate species with expanded Hox clusters and is predicted to exceed the length of the entire HoxD clusters (hoxd13–hoxd4) of humans, mice, and frogs. Many repetitive DNA sequences were identified for newt Hox clusters, including an enrichment of DNA transposon-like sequences relative to non-coding genomic fragments. Our results suggest that Hox cluster expansion and transposon accumulation are common features of non-mammalian tetrapod vertebrates. http://www.humgenomics.com/content/7/1/9 Stephen Voss Srikrishna Putta John Walker Jeramiah Smith Nobuyasu Maki Panagiotis Tsonis Human Genomics 2013, null:9 2013-04-05T00:00:00Z doi:10.1186/1479-7364-7-9 /content/figures/1479-7364-7-9-toc.gif Human Genomics 1479-7364 ${item.volume} 9 2013-04-05T00:00:00Z XML Na+/K+-ATPase alpha 2 (Atp1a2) is an integral plasma membrane protein belonging to the P-type ATPase family that is responsible for maintaining the sodium (Na+) and potassium (K+) gradients across cellular membranes with hydrolysis of ATP. Atp1a2 contains two subunits, alpha and beta, with each having various isoforms and differential tissue distribution. In humans, mutations in ATP1A2 are associated with a rare form of hereditary migraines with aura known as familial hemiplegic migraine type II. Genetic studies in mice have revealed other neurological effects of Atp1a2 in mice including anxiety, fear, and learning and motor function disorders. This paper reviews the recent findings in the literature concerning Atp1a2. http://www.humgenomics.com/content/7/1/8 Stephanie Gritz Richard Radcliffe Human Genomics 2013, null:8 2013-04-05T00:00:00Z doi:10.1186/1479-7364-7-8 /content/figures/1479-7364-7-8-toc.gif Human Genomics 1479-7364 ${item.volume} 8 2013-04-05T00:00:00Z XML The development (D in R&D) component for therapeutic protein products includes efforts to understand and improve bioprocessing methods (e.g., filling pump operation for vials and syringes; freeze drying to create more stable product), product degradation pathways and rational means to improve protein stability, new analytical methods, drug delivery methods and investigation of key product parameters affecting product safety and efficacy. Research in these areas occurs in pharmaceutical companies and in universities. Often in companies, the focus is on doing the work that is needed to get a given product into clinical trials and on the market. Whereas, in universities the focus in usually on more fundamental, mechanistic understanding of key issues such as factors causing protein aggregation and how to characterize and minimize this type of degradation. Therefore, there are numerous natural, synergistic collaborations between pharmaceutical companies and academic researchers, which provide for more rapid advancement of the field and relevant education of students, than if the two groups worked independently. There is a long tradition of such productive and valuable collaborations between industry scientists and professors in pharmaceutical sciences departments. For this commentary, based on my two decades of experience with such collaborations, I will describe my views on the advantages of such partnerships and some of the pitfalls. http://www.humgenomics.com/content/7/1/7 John Carpenter Human Genomics 2013, null:7 2013-03-05T00:00:00Z doi:10.1186/1479-7364-7-7 /content/figures/1479-7364-7-7-toc.gif Human Genomics 1479-7364 ${item.volume} 7 2013-03-05T00:00:00Z XML Background: Microsatellites are nucleotide sequences of tandem repeats occurring throughout the genome, which have been widely used in genetic linkage analysis, studies of loss of heterozygosity, determination of lineage and clonality, and the measurement of genome instability or the emergence of drug resistance reflective of mismatch repair deficiency. Such analyses may involve the parallel evaluation of many microsatellite loci, which are often limited by sample DNA, are labor intensive, and require large data processing. Results: To overcome these challenges, we developed a cost-effective high-throughput approach of microsatellite analysis, in which the amplifications of microsatellites are performed in miniaturized, multiplexed polymerase chain reaction (PCR) adaptable to 96 or 384 well plates, and accurate automated allele identification has been optimized with a collective reference dataset of 5,508 alleles using the GeneMapper software. Conclusions: In this investigation, we have documented our experience with the optimization of multiplex PCR conditions and automated allele identification, and have generated a unique body of data that provide a starting point for a cost-effective, high-throughput process of microsatellite analysis using the studied markers. http://www.humgenomics.com/content/7/1/6 Truc Nguyen Shaheen Lakhan Barry Finette Human Genomics 2013, null:6 2013-03-05T00:00:00Z doi:10.1186/1479-7364-7-6 /content/figures/1479-7364-7-6-toc.gif Human Genomics 1479-7364 ${item.volume} 6 2013-03-05T00:00:00Z XML The global healthcare industry is undergoing substantial changes and adaptations to the constant decline of approved new medical entities. This decrease in internal research productivity is resulting in a major decline of patent-protected sales (patent cliff) of most of the pharmaceutical companies. Three major global adaptive trends as driving forces to cope with these challenges are evident: cut backs of internal research and development jobs in the western hemisphere (Europe and USA), following the market growth potential of Asia by building up internal or external research and development capabilities there and finally, ‘early innovation hunting’ with an increased focus on identifying and investing in very early innovation sources within academia and small start-up companies. Early innovation hunting can be done by different approaches: increased corporate funding, establishment of translational institutions to bridge innovation, increasing sponsored collaborations and formation of technology hunting groups for capturing very early scientific ideas and concepts. This emerging trend towards early innovation hunting demands special adaptations from both the pharmaceutical industry and basic researchers in academia to bridge the translation into new medicines which deliver innovative medicines that matters to the patient. This opinion article describes the different modalities of cross-fertilisation between basic university or publicly funded institutional research and the applied research and development activities within the pharmaceutical industry. Two key factors in this important translational bridge can be identified: preparation of both partnering organisations to open up for new and sometime disruptive ideas and creation of truly trust-based relationships between the different groups allowing long-term scientific collaborations while acknowledging that value-creating differences are an essential factor for successful collaboration building. http://www.humgenomics.com/content/7/1/5 Paul Germann Alexander Schuhmacher Juan Harrison Ronald Law Kevin Haug Gordon Wong Human Genomics 2013, null:5 2013-03-05T00:00:00Z doi:10.1186/1479-7364-7-5 /content/figures/1479-7364-7-5-toc.gif Human Genomics 1479-7364 ${item.volume} 5 2013-03-05T00:00:00Z XML The RGD Pathway Portal provides pathway annotations for rat, human and mouse genes and pathway diagrams and suites, all interconnected via the pathway ontology. Diagram pages present the diagram and description, with diagram objects linked to additional resources. A newly-developed dual-functionality web application composes the diagram page. Curators input the description, diagram, references and additional pathway objects. The application combines these with tables of rat, human and mouse pathway genes, including genetic information, analysis tool and reference links, and disease, phenotype and other pathway annotations to pathway genes. The application increases the information content of diagram pages while expediting publication. http://www.humgenomics.com/content/7/1/4 G Hayman Pushkala Jayaraman Victoria Petri Marek Tutaj Weisong Liu Jeff Pons Melinda Dwinell Mary Shimoyama Human Genomics 2013, null:4 2013-02-05T00:00:00Z doi:10.1186/1479-7364-7-4 /content/figures/1479-7364-7-4-toc.gif Human Genomics 1479-7364 ${item.volume} 4 2013-02-05T00:00:00Z XML