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Nucleic Acids Res. 2001 January 1; 29(1): 137–140. | PMCID: PMC29787 |
RefSeq and LocusLink: NCBI gene-centered
resources Kim D. Pruitta and Donna
R. Maglott National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Building 38A Room 6N605, 8600 Rockville Pike, Bethesda, MD 20894 USA Received October 2, 2000; Accepted October 4, 2000. Thousands of genes have been painstakingly identified and characterized
a few genes at a time. Many thousands more are being predicted by
large scale cDNA and genomic sequencing projects, with levels of evidence
ranging from supporting mRNA sequence and comparative genomics to
computing ab initio models. This, coupled with
the burgeoning scientific literature, makes it critical to have
a comprehensive directory for genes and reference sequences for
key genomes. The NCBI provides two resources, LocusLink and RefSeq,
to meet these needs. LocusLink organizes information around genes
to generate a central hub for accessing gene-specific information
for fruit fly, human, mouse, rat and zebrafish. RefSeq provides
reference sequence standards for genomes, transcripts and proteins; human,
mouse and rat mRNA RefSeqs, and their corresponding proteins, are
discussed here. Together, RefSeq and LocusLink provide a non-redundant
view of genes and other loci to support research on genes and gene
families, variation, gene expression and genome annotation. Additional
information about LocusLink and RefSeq is available at http://www.ncbi.nlm.nih.gov/LocusLink/. LocusLink maintains descriptive information about loci including
nomenclature, database identifiers (ID), disease associations, map
positions and sequence accessions. These associations are then used
to compute connections to other NCBI resources, to both facilitate
navigation and enhance opportunities for new discoveries. LocusLink
data are continuously augmented and reviewed through the combined
efforts of NCBI staff and successful collaborations with the Human
Gene Nomenclature Committee (HGNC) ( 1),
Online Mendelian Inheritance in Man (OMIM) ( 2),
Mouse Genome Database (MGD) ( 3),
Rat Genome Database (RGD), FlyBase ( 4)
and Zebrafish (ZFIN) ( 5) groups.
This compilation is freely distributed via the LocusLink web site
and by FTP. LocusLink queries can be based on text terms (such as
a protein or disease name), gene symbols, sequence accessions and
database IDs (e.g., MIM or EC numbers). More complex operations
such as wild cards (e.g., ABC*), field restriction (e.g.,
123456[mim]) and booleans (e.g., ABC* AND
17[chr]) are also supported. The NCBI reference sequences (RefSeq) provide standards for
complete genomic nucleic acids, assembled contigs, transcripts and
proteins (see Table 1). RefSeq records
are derived from GenBank and the literature to provide a non-redundant set
of sequences that facilitate sequence identification and information
retrieval ( 6). Human, mouse and
rat RefSeq mRNAs, and their corresponding proteins, are the focus
of this discussion; these sequences can be accessed through the
NCBI Entrez retrieval system ( 7),
BLAST ( 8), FTP and LocusLink. | Table 1. RefSeq accessions, sequence type, processing method and
categories |
EXPANDED AND NEW FEATURES LocusLink The locus-to-sequence association maintained in LocusLink is used
to provide reciprocal connections among LocusLink, RefSeq and several
content-rich resources at NCBI including the Conserved Domain Database
(CDD), GenBank ( 9), Genes and
Disease, HomoloGene, Map Viewer, OMIM, PubMed, dbSNP ( 10),
dbSTS and UniGene ( 11) (Table 2). In addition, nucleotide and protein sequences
and OMIM records are linked to LocusLink reports via the NCBI LinkOut
service. Following ‘LinkOut’ at the upper right
side of an Entrez record is a convenient method to access a wealth
of information about that gene. Links between LocusLink and Genes
and Disease, HomoloGene, RefSeq, dbSNP and UniGene are based on shared
identifiers stored by these resources (e.g., MIM numbers or GenBank
accessions). Links to dbSTS and CDD are computed based on electronic
PCR (ePCR) ( 12) and BLAST, respectively.
And links to the NCBI Map Viewer are based on sequence identity,
cytogenetic location or genetic map data. URLs to these resources
are provided in Table 3. | Table 2. LocusLink: distributed data and links to additional information |
Several organisms and features have been added to the LocusLink
web site over the past year and are listed below. LocusLink provides
links to each resource whenever additional information is available. Conserved domains: CDD domains annotated on
RefSeq proteins are summarized in the product section of LocusLink reports.
This section also includes the protein name, alternate names and
enzyme commission (EC) numbers. GeneRIF: LocusLink now supports community-generated functional
annotation. LocusLink reports display submitted GeneRIFs (Gene References Into Function)
and include a link to the submission form. Submissions consist of
a publication (PubMed ID) and brief comment summarizing the functional information
supported by the publication. HomoloGene: HomoloGene reports UniGene clusters
that are either calculated to be homologous, based on sequence identity,
or reported to be homologous. HomoloGene also reports the ‘best’ homologous
sequence pairs. HomoloGene includes all genomes in UniGene (human,
mouse, rat and zebrafish), as well as Drosophila melanogaster mRNAs. Maps: LocusLink now provides links to the Map
Viewer and the Human/Mouse Homology map, as appropriate.
The Map Viewer presents graphical views of various maps at the whole genome
and single chromosome levels. This resource is currently available
for D.melanogaster, Homo sapiens and Mus musculus. Views include presentation of genes,
STS markers, SNPs and disease phenotypes along the chromosomes.
The Human/Mouse Homology maps display genes, thought to
be orthologous, ordered by MGD’s genetic map and the human
sequence map. Organisms: LocusLink now includes fruit fly,
human, mouse, rat and zebrafish genes. The query interface supports
retrieving results for all species, restricting to a single organism
and displaying query results as a ‘Brief’ or expanded ‘Summary’ display. Reference sequences: The RefSeq section of the
LocusLink report has been expanded to include mitochondrial records, genomic
contigs and modeled transcripts and proteins produced by the NCBI
Human Genome Annotation effort. RefSeq data for a locus may include
curated RefSeq records representing known transcripts, a genomic
contig and modeled transcripts that overlap, but are distinct from,
the known transcripts. Table 1 indicates
the different accession number formats and categories they represent. RefSeq RefSeq transcript and corresponding protein records are now produced
through two independent processes. The first process, which relies
heavily on manual curation, provides a non-redundant dataset of
transcripts and proteins of known genes for human, mouse and rat;
these ‘known’ genes have some supporting evidence
for the existence of the gene although the protein function may
not be clear. The second process is NCBI’s Human Genome
Annotation project, which will be described in detail elsewhere.
Briefly, working draft and finished human genome sequence is assembled
into contigs ( 13); gene predictions
methods are used to produce the modeled mRNA and protein RefSeq
records (see Table 1). The modeled transcripts
and proteins may have different degrees of mRNA or EST evidence,
or may be predicted ab initio. RefSeq records include links to LocusLink where additional information
is often available. The organisms and features added to RefSeq records
over the past year are summarized below. Category: RefSeq mRNA and protein records are
now provided in four categories (previously termed ‘Status’ in LocusLink
reports): (i) genome annotation, (ii) predicted, (iii) provisional
and (iv) reviewed. The genome annotation category includes contigs,
modeled mRNAs and corresponding modeled proteins. Predicted records
represent genes of unknown function that are supported by mRNA sequence generated
in a full-length insert cDNA sequencing project, homology or ESTs;
the location of the protein product may be predicted in these records.
Provisional and reviewed RefSeq records largely represent genes
with known or inferred function. Provisional RefSeqs are not yet
reviewed, whereas reviewed RefSeq records have been individually
reviewed by NCBI staff and are richly annotated. Reviewed records
include publications, a gene description and annotation that may
not be on the provisional RefSeq or original GenBank records. Furthermore the
sequence may be modified, relative to the source GenBank sequence,
to extend the UTR, provide a transcript variant or remove contaminating
vector or linker sequence. By including sequence data derived from
more than one GenBank record and from the literature, reviewed RefSeq
records may provide a full-length mRNA sequence that is not available
in a single GenBank record. Conserved domains: BLAST analysis is used to
compare RefSeq proteins to the NCBI CDD; significant domain matches
are annotated on the protein record and are linked to the CDD resource
where additional information is available. Reviewed RefSeq proteins
may include additional domain annotation derived from the literature. Links: RefSeq records include links that facilitate
access to additional information. Links are provided to: (i) the
record(s) from which the mRNA (and hence protein) was derived, (ii) LocusLink,
(iii) OMIM, (iv) MGD, (v) RGD and (vi) CDD, as appropriate. In addition,
an overview of sequences that share sequence identity is available
through the ‘Related sequences’ link at the top
right of RefSeq (and GenBank) records. Organisms: The mRNA/protein RefSeq
resource now provides sequence standards for human, mouse and rat.
Review of all three organisms to verify the initial ‘gene
name-to-sequence’ association and to provide highly annotated
reviewed RefSeq records is ongoing. Variation: Variation features are automatically
added to Genome Annotation RefSeq records using the data available
in dbSNP. This expanded annotation will also be added to RefSeq records
representing known genes. The information available in LocusLink and RefSeq is continually being
reviewed and augmented. As illustrated in Figure , the number of RefSeq records tripled, and
LocusLink expanded ~5-fold over a 1-year period. New or updated
RefSeq records are made publicly available on a daily basis. The
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