Bioinformatics

Figure 2.7 Entries in the RefSeq protein database corresponding to the original Srour et al. (2010) entry in Figure 2.3. Entries can be accessed and examined by clicking on any of the accession numbers. See text for details.

Figure 2.8 The RefSeq entry for the netrin receptor, the protein product of the human DCC gene. The FASTA link at the top of the entry provides quick access to the protein sequence in FASTA format, while the Graphics link provides access to a graphical view of all of the individual elements captured within the entry's feature table (see Figure 2.9). See text for details.

Figure 2.9 The same RefSeq entry for the netrin receptor shown in Figure 2.8, now rendered in graphical format. The user can learn more about individual elements displayed in this view by simply hovering the cursor over any of the elements in the display; one such example is shown in the pop-up box at the bottom right, for the phosphorylation site at position 1267 of the sequence. Zoom and navigational controls are at the top of the view window, allowing the user to understand this gene within its broader genomic context.

From here, the user can also enter the structural realm by examining the protein structures that are available through the Discovery Column. Clicking on the See all 9 structures link takes the user to the view shown in Figure 2.10, listing structural entries related to the netrin receptor. The second entry is for the crystal structure of a fragment of netrin-1 complexed with the DCC receptor (PDB:4URT; Finci et al. 2014), and clicking on the title of that entry takes the user to the structure summary page shown in Figure 2.11. Starting on the right, the Interactions window shows the relationships between the individual elements in this biological unit, here consisting of the netrin-1 protein (circle A), the DCC receptor (circle B), and five different chemical entities (diamonds 1–5). The three-dimensional structure is shown in the left panel, and the structure can be further interrogated by clicking on the square with the diagonal arrow in the bottom left of that panel. This action will launch iCn3D (for “I see in three-D”), a web-based viewer that allows the structure to be rotated, provides coloring and rendering options to enhance visualization, and provides a wide variety of additional options; the reader is referred to the iCn3D online documentation for specifics. In the upper right of the 4URT structure summary page is a link to similar structures, as determined by VAST+. Clicking on the VAST+ link produces the output shown in Figure 2.12, here showing the first 10 of 256 structures deemed to have similar biological units to the query (4URT); the table shown here is sorted by RMSD of all aligned residues (in Å), from smallest to largest.

Figure 2.10 Protein structures associated with the RefSeq entry for the human netrin receptor shown in Figures 2.8and 2.9. The description of each structure is hyperlinked, allowing the user to access the structure summary page for that entry (see Figure 2.11). Individual links below each entry allow quick access to related structures and proteins, information on conserved domains, and the iCn3D viewer.

Figure 2.11 The structure summary page for pdb:4URT, the crystal structure of a fragment of netrin-1 complexed with the DCC receptor (Finci et al. 2014). The entry shows header information from the corresponding Molecular Modeling Database (MMDB) entry, a link to the paper reporting this structure, and the methodology used to determine this structure (here, X-ray diffraction with a resolution of 3.1 Å). See text for details.

Although the focus of many investigators is on sequence-based data, database cataloging and organizing sequence information are not the only kinds of databases useful to the biomedical research community. An excellent example of such a database that is tremendously useful in genomics is called Online Mendelian Inheritance in Man (OMIM), the electronic version of the venerable catalog of human genes and genetic disorders originally founded by Victor McKusick and first published in 1966 (McKusick 1966, 1998; Amberger et al. 2014). OMIM, which is authored and maintained at The Johns Hopkins University School of Medicine, provides concise textual information from the published literature on most human conditions having a genetic basis, as well as pictures illustrating the condition or disorder (where appropriate), full citation information, and links to a number of useful external resources, some of which will be described below. As will become obvious through the following example, a basic knowledge of OMIM should be part of the armamentarium of physician-scientists with an interest in the clinical aspects of genetic disorders.

Figure 2.12 A list of structures deemed similar to pdb:4URT using VAST+. The table is sorted by the root-mean-square deviation of all aligned residues (in Å), from smallest to largest. Details on each individual structure in the list can be found by clicking on its Protein Data Bank (PDB) ID number.

OMIM has a defined numbering system in which each entry is assigned a unique number – a “MIM number” – that is similar to an accession number, with certain positions within that number indicating information about the genetic disorder itself. The first digit represents the mode of inheritance of the disorder: 1, 2, and 6 stand for autosomal loci or phenotypes, 3 for X-linked loci or phenotype, 4 for Y-linked loci or phenotype, and 5 for mitochondrial loci or phenotypes. An asterisk (*) preceding a MIM number indicates a gene, a hash sign (#) indicates an entry describing a phenotype, a plus sign (+) indicates that the entry describes a gene of known sequence and phenotype, and a percent sign (%) describes a confirmed Mendelian phenotype or locus for which the underlying molecular basis is unknown. If no Mendelian basis has been clearly established for a particular entry, no symbol precedes the MIM number.

Figure 2.13 Online Mendelian Inheritance in Man (OMIM) entries related to the DCC gene. The hash sign (#) preceding the first entry indicates that it is an entry describing a phenotype – here, mirror movements. The second entry is preceded by an asterisk (*), indicating that it is a gene entry – here, for the DCC gene.