Rfam

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Rfam
Rfam logo.png
Content
DescriptionThe Rfam database provides alignments, consensus secondary structures and covariance models for RNA families.
Data types
captured		RNA families
Organisms all
Contact
Research center EBI
Primary citation PMID   33211869
Access
Data format Stockholm format
Website rfam.org
Download URL FTP
Miscellaneous
License Public domain
Bookmarkable
entities		yes

Rfam is a database containing information about non-coding RNA (ncRNA) families and other structured RNA elements. It is an annotated, open access database originally developed at the Wellcome Trust Sanger Institute in collaboration with Janelia Farm, [1] [2] [3] [4] and currently hosted at the European Bioinformatics Institute. [5] Rfam is designed to be similar to the Pfam database for annotating protein families.

Contents

Unlike proteins, ncRNAs often have similar secondary structure without sharing much similarity in the primary sequence. Rfam divides ncRNAs into families based on evolution from a common ancestor. Producing multiple sequence alignments (MSA) of these families can provide insight into their structure and function, similar to the case of protein families. These MSAs become more useful with the addition of secondary structure information. Rfam researchers also contribute to Wikipedia's RNA WikiProject. [4] [6]

Uses

The Rfam database can be used for a variety of functions. For each ncRNA family, the interface allows users to: view and download multiple sequence alignments; read annotation; and examine species distribution of family members. There are also links provided to literature references and other RNA databases. Rfam also provides links to Wikipedia so that entries can be created or edited by users.

The interface at the Rfam website allows users to search ncRNAs by keyword, family name, or genome as well as to search by ncRNA sequence or EMBL accession number. [7] The database information is also available for download, installation and use using the INFERNAL software package. [8] [9] [10] The INFERNAL package can also be used with Rfam to annotate sequences (including complete genomes) for homologues to known ncRNAs.

Methods

A theoretical ncRNA alignment from 6 species. Secondary structure base pairs are coloured in blocks and identified in the secondary structure consensus sequence (bottom line) by the < and > symbols. Rfam alignment2.PNG
A theoretical ncRNA alignment from 6 species. Secondary structure base pairs are coloured in blocks and identified in the secondary structure consensus sequence (bottom line) by the < and > symbols.

In the database, the information of the secondary structure and the primary sequence, represented by the MSA, is combined in statistical models called profile stochastic context-free grammars (SCFGs), also known as covariance models. These are analogous to hidden Markov models used for protein family annotation in the Pfam database. [1] Each family in the database is represented by two multiple sequence alignments in Stockholm format and a SCFG.

The first MSA is the "seed" alignment. It is a hand-curated alignment that contains representative members of the ncRNA family and is annotated with structural information. This seed alignment is used to create the SCFG, which is used with the Rfam software INFERNAL to identify additional family members and add them to the alignment. A family-specific threshold value is chosen to avoid false positives.

Until release 12, Rfam used an initial BLAST filtering step because profile SCFGs were too computationally expensive. However, the latest versions of INFERNAL are fast enough [10] so that the BLAST step is no longer necessary. [11]

The second MSA is the “full” alignment, and is created as a result of a search using the covariance model against the sequence database. All detected homologs are aligned to the model, giving the automatically produced full alignment.

History

Version 1.0 of Rfam was launched in 2003 and contained 25 ncRNA families and annotated about 50 000 ncRNA genes. In 2005, version 6.1 was released and contained 379 families annotating over 280 000 genes. In August 2012, version 11.0 contained 2208 RNA families, while the current version (14.9, released in November 2022) annotates 4108 [7] families.

Major releases and publications

Problems

  1. The genomes of higher eukaryotes contain many ncRNA-derived pseudogenes and repeats. Distinguishing these non-functional copies from functional ncRNA is a formidable challenge. [2]
  2. Introns are not modeled by covariance models.

Related Research Articles

<span class="mw-page-title-main">Transfer-messenger RNA</span>

Transfer-messenger RNA is a bacterial RNA molecule with dual tRNA-like and messenger RNA-like properties. The tmRNA forms a ribonucleoprotein complex (tmRNP) together with Small Protein B (SmpB), Elongation Factor Tu (EF-Tu), and ribosomal protein S1. In trans-translation, tmRNA and its associated proteins bind to bacterial ribosomes which have stalled in the middle of protein biosynthesis, for example when reaching the end of a messenger RNA which has lost its stop codon. The tmRNA is remarkably versatile: it recycles the stalled ribosome, adds a proteolysis-inducing tag to the unfinished polypeptide, and facilitates the degradation of the aberrant messenger RNA. In the majority of bacteria these functions are carried out by standard one-piece tmRNAs. In other bacterial species, a permuted ssrA gene produces a two-piece tmRNA in which two separate RNA chains are joined by base-pairing.

The European Bioinformatics Institute (EMBL-EBI) is an intergovernmental organization (IGO) which, as part of the European Molecular Biology Laboratory (EMBL) family, focuses on research and services in bioinformatics. It is located on the Wellcome Genome Campus in Hinxton near Cambridge, and employs over 600 full-time equivalent (FTE) staff. Institute leaders such as Rolf Apweiler, Alex Bateman, Ewan Birney, and Guy Cochrane, an adviser on the National Genomics Data Center Scientific Advisory Board, serve as part of the international research network of the BIG Data Center at the Beijing Institute of Genomics.

<span class="mw-page-title-main">Conserved sequence</span> Similar DNA, RNA or protein sequences within genomes or among species

In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids or proteins across species, or within a genome, or between donor and receptor taxa. Conservation indicates that a sequence has been maintained by natural selection.

<span class="mw-page-title-main">Pfam</span> Database of protein families

Pfam is a database of protein families that includes their annotations and multiple sequence alignments generated using hidden Markov models. The most recent version, Pfam 36.0, was released in September 2023 and contains 20,795 families.

Stockholm format is a multiple sequence alignment format used by Pfam, Rfam and Dfam, to disseminate protein, RNA and DNA sequence alignments. The alignment editors Ralee, Belvu and Jalview support Stockholm format as do the probabilistic database search tools, Infernal and HMMER, and the phylogenetic analysis tool Xrate. Stockholm format files often have the filename extension .sto or .stk.

<span class="mw-page-title-main">Richard M. Durbin</span> British computational biologist

Richard Michael Durbin is a British computational biologist and Al-Kindi Professor of Genetics at the University of Cambridge. He also serves as an associate faculty member at the Wellcome Sanger Institute where he was previously a senior group leader.

<span class="mw-page-title-main">DNA annotation</span> The process of describing the structure and function of a genome

In molecular biology and genetics, DNA annotation or genome annotation is the process of describing the structure and function of the components of a genome, by analyzing and interpreting them in order to extract their biological significance and understand the biological processes in which they participate. Among other things, it identifies the locations of genes and all the coding regions in a genome and determines what those genes do.

<span class="mw-page-title-main">Sean Eddy</span> American professor at Harvard University

Sean Roberts Eddy is Professor of Molecular & Cellular Biology and of Applied Mathematics at Harvard University. Previously he was based at the Janelia Research Campus from 2006 to 2015 in Virginia. His research interests are in bioinformatics, computational biology and biological sequence analysis. As of 2016 projects include the use of Hidden Markov models in HMMER, Infernal Pfam and Rfam.

αr7 is a family of bacterial small non-coding RNAs with representatives in a broad group of Alphaproteobacterial species from the order Hyphomicrobiales. The first member of this family was found in a Sinorhizobium meliloti 1021 locus located in the chromosome (C). Further homology and structure conservation analysis identified full-length homologs in several nitrogen-fixing symbiotic rhizobia, in the plant pathogens belonging to Agrobacterium species as well as in a broad spectrum of Brucella species. αr7 RNA species are 134-159 nucleotides (nt) long and share a well defined common secondary structure. αr7 transcripts can be catalogued as trans-acting sRNAs expressed from well-defined promoter regions of independent transcription units within intergenic regions (IGRs) of the Alphaproteobacterial genomes.

αr9 is a family of bacterial small non-coding RNAs with representatives in a broad group of α-proteobacteria from the order Hyphomicrobiales. The first member of this family (Smr9C) was found in a Sinorhizobium meliloti 1021 locus located in the chromosome (C). Further homology and structure conservation analysis have identified full-length Smr9C homologs in several nitrogen-fixing symbiotic rhizobia, in the plant pathogens belonging to Agrobacterium species as well as in a broad spectrum of Brucella species. αr9C RNA species are 144-158 nt long and share a well defined common secondary structure consisting of seven conserved regions. Most of the αr9 transcripts can be catalogued as trans-acting sRNAs expressed from well-defined promoter regions of independent transcription units within intergenic regions (IGRs) of the α-proteobacterial genomes.

αr14 is a family of bacterial small non-coding RNAs with representatives in a broad group of α-proteobacteria. The first member of this family (Smr14C2) was found in a Sinorhizobium meliloti 1021 locus located in the chromosome (C). It was later renamed NfeR1 and shown to be highly expressed in salt stress and during the symbiotic interaction on legume roots. Further homology and structure conservation analysis identified 2 other chromosomal copies and 3 plasmidic ones. Moreover, full-length Smr14C homologs have been identified in several nitrogen-fixing symbiotic rhizobia, in the plant pathogens belonging to Agrobacterium species as well as in a broad spectrum of Brucella species. αr14C RNA species are 115-125 nt long and share a well defined common secondary structure. Most of the αr14 transcripts can be catalogued as trans-acting sRNAs expressed from well-defined promoter regions of independent transcription units within intergenic regions (IGRs) of the α-proteobacterial genomes.

αr15 is a family of bacterial small non-coding RNAs with representatives in a broad group of α-proteobacteria from the order Rhizobiales. The first members of this family were found tandemly arranged in the same intergenic region (IGR) of the Sinorhizobium meliloti 1021 chromosome (C). Further homology and structure conservation analysis have identified full-length Smr15C1 and Smr15C2 homologs in several nitrogen-fixing symbiotic rhizobia, in the plant pathogens belonging to Agrobacterium species as well as in a broad spectrum of Brucella species. The Smr15C1 and Smr15C2 homologs are also encoded in tandem within the same IGR region of Rhizobium and Agrobacterium species, whereas in Brucella species the αr15C loci are spread in the IGRs of Chromosome I. Moreover, this analysis also identified a third αr15 loci in extrachromosomal replicons of the mentioned nitrogen-fixing α-proteobacteria and in the Chromosome II of Brucella species. αr15 RNA species are 99-121 nt long and share a well defined common secondary structure consisting of three stem loops. The transcripts of the αr15 family can be catalogued as trans-acting sRNAs encoded by independent transcription units with recognizable promoter and transcription termination signatures within intergenic regions (IGRs) of the α-proteobacterial genomes.

αr35 is a family of bacterial small non-coding RNAs with representatives in a reduced group of Alphaproteobacteria from the order Hyphomicrobiales. The first member of this family (Smr35B) was found in a Sinorhizobium meliloti 1021 locus located in the symbiotic plasmid B (pSymB). Further homology and structure conservation analysis have identified full-length SmrB35 homologs in other legume symbionts, as well as in the human and plant pathogens Brucella anthropi and Agrobacterium tumefaciens, respectively. αr35 RNA species are 139-142 nt long and share a common secondary structure consisting of two stem loops and a well conserved rho independent terminator. Most of the αr35 transcripts can be catalogued as trans-acting sRNAs expressed from well-defined promoter regions of independent transcription units within intergenic regions of the Alphaproteobacterial genomes.

αr45 is a family of bacterial small non-coding RNAs with representatives in a broad group of α-proteobacteria from the order Hyphomicrobiales. The first member of this family (Smr45C) was found in a Sinorhizobium meliloti 1021 locus located in the chromosome (C). Further homology and structure conservation analysis identified homologs in several nitrogen-fixing symbiotic rhizobia, in the plant pathogens belonging to Agrobacterium species as well as in a broad spectrum of Brucella species, in Bartonella species, in several members of the Xanthobactereacea family, and in some representatives of the Beijerinckiaceae family. αr45C RNA species are 147-153 nt long and share a well defined common secondary structure. All of the αr45 transcripts can be catalogued as trans-acting sRNAs expressed from well-defined promoter regions of independent transcription units within intergenic regions (IGRs) of the α-proteobacterial genomes.

<span class="mw-page-title-main">Alex Bateman</span> British bioinformatician

Alexander George Bateman is a computational biologist and Head of Protein Sequence Resources at the European Bioinformatics Institute (EBI), part of the European Molecular Biology Laboratory (EMBL) in Cambridge, UK. He has led the development of the Pfam biological database and introduced the Rfam database of RNA families. He has also been involved in the use of Wikipedia for community-based annotation of biological databases.

Non-coding RNAs have been discovered using both experimental and bioinformatic approaches. Bioinformatic approaches can be divided into three main categories. The first involves homology search, although these techniques are by definition unable to find new classes of ncRNAs. The second category includes algorithms designed to discover specific types of ncRNAs that have similar properties. Finally, some discovery methods are based on very general properties of RNA, and are thus able to discover entirely new kinds of ncRNAs.

DIMPL is a bioinformatic pipeline that enables the extraction and selection of bacterial GC-rich intergenic regions (IGRs) that are enriched for structured non-coding RNAs (ncRNAs). The method of enriching bacterial IGRs for ncRNA motif discovery was first reported for a study in "Genome-wide discovery of structured noncoding RNAs in bacteria".

An RNA motif is a description of a group of RNAs that have a related structure. RNA motifs consist of a pattern of features within the primary sequence and secondary structure of related RNAs. Thus, it extends the concept of a sequence motif to include RNA secondary structure. The term "RNA motif" can refer both to the pattern and to the RNA sequences that match it.

References

  1. 1 2 3 Griffiths-Jones S, Bateman A, Marshall M, Khanna A, Eddy SR (2003). "Rfam: an RNA family database". Nucleic Acids Res. 31 (1): 439–41. doi:10.1093/nar/gkg006. PMC   165453 . PMID   12520045.
  2. 1 2 3 Griffiths-Jones S, Moxon S, Marshall M, Khanna A, Eddy SR, Bateman A (2005). "Rfam: annotating non-coding RNAs in complete genomes". Nucleic Acids Res. 33 (Database issue): D121–4. doi:10.1093/nar/gki081. PMC   540035 . PMID   15608160.
  3. 1 2 3 Gardner PP, Daub J, Tate JG, et al. (October 2008). "Rfam: updates to the RNA families database". Nucleic Acids Research. 37 (Database issue): D136–D140. doi:10.1093/nar/gkn766. PMC   2686503 . PMID   18953034.
  4. 1 2 3 Gardner PP, Daub J, Tate J, Moore BL, Osuch IH, Griffiths-Jones S, Finn RD, Nawrocki EP, Kolbe DL, Eddy SR, Bateman A (2011). "Rfam: Wikipedia, clans and the "decimal" release". Nucleic Acids Res. 39 (Database issue): D141–5. doi:10.1093/nar/gkq1129. PMC   3013711 . PMID   21062808.
  5. ↑ "Moving to xfam.org". Xfam Blog. Retrieved 3 May 2014.
  6. 1 2 Daub J, Gardner PP, Tate J, Ramsköld D, Manske M, Scott WG, Weinberg Z, Griffiths-Jones S, Bateman A (December 2008). "The RNA WikiProject: community annotation of RNA families". RNA. 14 (12): 2462–4. doi: 10.1261/rna.1200508 . PMC   2590952 . PMID   18945806.
  7. 1 2 "Rfam families". rfam.xfam.org.
  8. ↑ Eddy SR, Durbin R (June 1994). "RNA sequence analysis using covariance models". Nucleic Acids Research. 22 (11): 2079–88. doi:10.1093/nar/22.11.2079. PMC   308124 . PMID   8029015.
  9. ↑ Eddy SR (2002). "A memory-efficient dynamic programming algorithm for optimal alignment of a sequence to an RNA secondary structure". BMC Bioinformatics. 3: 18. doi: 10.1186/1471-2105-3-18 . PMC   119854 . PMID   12095421.
  10. 1 2 Nawrocki EP, Eddy SR (2013). "Infernal 1.1: 100-fold faster RNA homology searches". Bioinformatics. 29 (22): 2933–5. doi:10.1093/bioinformatics/btt509. PMC   3810854 . PMID   24008419.
  11. ↑ Nawrocki EP, Burge SW, Bateman A, Daub J, Eberhardt RY, Eddy SR, Floden EW, Gardner PP, Jones TA, Tate J, Finn RD (January 2015). "Rfam 12.0: updates to the RNA families database". Nucleic Acids Res. 43 (Database issue): D130–7. doi:10.1093/nar/gku1063. PMC   4383904 . PMID   25392425.
  12. ↑ Burge SW, Daub J, Eberhardt R, Tate J, Barquist L, Nawrocki EP, Eddy SR, Gardner PP, Bateman A (January 2013). "Rfam 11.0: 10 years of RNA families". Nucleic Acids Res. 41 (Database issue): D226–32. doi: 10.1093/nar/gks1005 . PMC   3531072 . PMID   23125362.
  13. ↑ Kalvari I, Argasinska J, Quinones-Olvera N, Nawrocki EP, Rivas E, Eddy SR, Bateman A, Finn RD, Petrov AI (January 2018). "Rfam 13.0: shifting to a genome-centric resource for non-coding RNA families". Nucleic Acids Res. 46 (D1): D335–D342. doi:10.1093/nar/gkx1038. PMC   5753348 . PMID   29112718.
  14. ↑ Kalvari I, Nawrocki EP, Ontiveros-Palacios N, Argasinska J, Lamkiewicz K, Marz M, Griffiths-Jones S, Toffano-Nioche C, Gautheret D, Weinberg Z, Rivas E, Eddy SR, Finn RD, Bateman A, Petrov AI (January 2021). "Rfam 14: expanded coverage of metagenomic, viral and microRNA families". Nucleic Acids Res. 49 (D1): D192–D200. doi: 10.1093/nar/gkaa1047 . PMC   7779021 . PMID   33211869.
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