Numerous databases and genome browsers allow users to gain information about the human genome, and this section will necessarily be selective. There are different electronic gateways to access information on the human genome, human genes, and the gene products (Table 1). If the starting point of interest is a gene or gene product, the HGNC portal organized by the HUGO Gene Nomenclature Committee has a simple, user-friendly architecture; we describe some features and components of that gateway below. More comprehensive coverage of electronic resources is available through NCBI’s Human Genome Resources (see Table 1).
Table1. SOME OF THE PRINCIPAL ELECTRONIC RESOURCES FOR INTERROGATING THE HUMAN GENOME, HUMAN GENES, AND GENE PRODUCTS
Gene nomenclature and the HGNC gateway
Gene symbols for human genes are allocated by the HGNC. They typically have between three and seven characters, and are displayed in italicized uppercase, such as HBB (hemoglobin beta subunit), CFTR (cystic fibrosis transmembrane regulator), or RN7SL (7SL RNA). Mitochondrial genes are prefixed by MT- (for example, MT-RNR1 is the mitochondrial 12S rRNA gene). Pseudogenes normally have a symbol that is the same as a related functional gene, but followed by a P, or by a P followed by a number (for example, CFTRP3 is one of three pseudogenes related to the CFTR gene). Note that gene symbols for mouse and rat genes have just the first letter in uppercase (for example, the mouse and rat orthologs of the human CFTR gene are each given the symbol Cftr).
The HGNC portal at www.genenames.org has links to many assorted databases and browsers. It can be interrogated by using as a query a gene symbol, if known, or descriptive text for an associated gene product or disease. For example, entering hemoglobin as the search term returns a list of genes encoding the different subunits of all forms of human hemoglobin, and entering cystic fibrosis yields different results with the first entry being the cystic fibrosis gene CFTR. Selecting a gene symbol such as CFTR opens the way to an extraordinary amount of related information through linked databases and genome browsers (Figure 1). The HGNC portal can also be used to identify members of gene families: see the Gene Families Index at https://www.genenames.org/cgi-bin/ genefamilies/
Fig1. Getting a wealth of information on a selected human gene starting from the HGNC portal at www. genenames.org. The figure shows the output displayed after selecting CFTR, the human cystic fibrosis gene. The box outlined in orange at top shows basic items of information maintained by HGNC, including related sequences (chloride channels of the same type as the CFTR protein, other members of the ATP binding cassette subfamily C) plus equivalent genes identified in other species by HCOP, the HGNC’s Comparison of Orthology Predictions tool. The “External links” section allows access to numerous databases and genome browsers. The former includes databases of nucleotide and protein sequences, and databases with associated clinical information (including the general OMIM resource and a locus-specific database, LSDB, that is devoted to cystic fibrosis). The genome browsers, which allow detailed examination of the structure of genes and their products and the ability to download selected sequence components, are listed under the “GENE RESOURCES” catalog. They include the NCBI’s Map Viewer available via the “Entrez Gene” subheading, the Ensembl browser, and the UCSC (University of California at Santa Cruz) Genome Browser—see text for more detail.
General databases storing nucleotide and protein sequences
In the example of Figure 1, the external link for “NUCLEOTIDE SEQUENCES” begins with general nucleotide sequence databases that are part of the International Nucleotide Sequence Database Collaboration (INSDC), comprising GenBank, the European Nucleotide Archive (ENA), and the DNA Database of Japan (DDBJ). The ID number for the CFTR mRNA sequence in these databases is M28668, and the 6129-nucleotide sequence is presented with coordinates for the coding sequence and a translation of the open reading frame presented in the single-letter amino acid code.
The general nucleotide sequence databases contain redundant sequences (with some times many entries for the same sequence from independent DNA clones, some having partial sequences, some full length). To make it easier to find a complete sequence of interest, the NCBI RefSeq database was established to provide a comprehensive, non redundant, and well-annotated set of reference sequences for different species. RefSeq reference transcripts have ID numbers beginning with NM_ for mRNA, and NR_ for non coding RNA; proteins associated with NM_ transcripts have ID numbers beginning with NP_ . The RefSeqGene database stores gene reference sequences.
Finding related nucleotide and protein sequences
Sequences evolutionarily related to a query sequence are identifiable by sequence com parison. The suite of BLAST programs at the NCBI can scan all nucleotide sequences in the general nucleotide databases and translations of nucleotide sequences to identify other nucleotide and protein sequences that are significantly related to a nucleotide or protein query. Significant homology may be apparent across the length of the query sequence or be limited to a region, such as a conserved protein domain or some other shared sequence.
The BLAT program, available at sites such as the UCSC (University of California at Santa Cruz) Genome Browser, allows rapid sequence searching across whole genomes. Query nucleotide sequences (up to a total of 25,000 nucleotides) and query protein sequences (up to 10,000 amino acids) can be entered to search for homologous sequences across the human genome, or the genome of any of multiple model organisms. The output lists significant hits, with given chromosome coordinates and sequence alignments.
The sequence comparisons include searching to find orthologs in other species using programs such as HCOP (the HGNC’s Comparison of Orthology Predictions tool) and HomoloGene. The latter provides pairwise and multisequence alignments of protein sequences from identified orthologs.
Protein characteristics and analyses
The “PROTEIN RESOURCES” component in Figure 1 provides access to programs that record or analyze different functional characteristics of the predicted protein of a gene of interest, including:
• UniProt—records associated functional information including presence of con served domains, disease-associated variants, expression characteristics, protein -protein interactions, and so on;
• InterPro—scans for the presence of related sequences including conserved domains and repeats that might be shared with other proteins, and seeks to assign proteins to membership of protein families.
Genome browsers
Navigating a sequenced genome is effectively assisted by programs with graphical user interfaces to portray genome information for selected chromosomes and sub chromosomal regions. The characteristics (genes, exons, transcripts, and so on) of a selected human chromosome or chromosome region can be tracked, moving from large scale to nucleotide scale, with click-over facilities to identify the characteristics and download the sequences of genes and associated exons, RNAs, and proteins. The principal browsers are listed in Table 1.
