To ensure that each LRG record is kept current, the curators update all existing LRGs twice a year and when a new genome build is released. The LRG is aligned to the reference genome to determine its mapping coordinates. Each area of contiguous alignment is described separately, along with any differences between the LRG and the reference. Both detail the official names and synonyms of genes, transcripts and proteins contained within the LRG region.
Mapping of these sequences in LRG coordinates and any mapping discrepancies are included. Furthermore, there are links from the sequences to the NCBI or Ensembl browsers where additional information, such as expression patterns or biological evidence for each sequence, can be found.
The transcript s included in the fixed section are also listed in the updatable section, but marked with a note to distinguish them from the other transcripts included in the record. Alternate or legacy numbering systems exon and amino acid , determined prior to the existence of the LRG and widely used by the community, may also be included in this part of the updatable section to enable easy comparison between different numbering systems.
Any genes partially or completely overlapping the LRG are annotated. The Ensembl data include protein-coding genes from the Ensembl transcript annotation process 7. The Ensembl gene set also includes automatically-annotated pseudogenes and non-coding RNAs.
Once the review process is complete, a pending LRG is made public and requesters are notified. From this point, sequences included in the fixed section will not change. Additional transcripts can be added to the fixed section of a public LRG in the future should this be necessary for reporting variants at the locus.
If this should happen, the original information in this section, e. LRGs are established to provide a consistent reporting framework. Because of this policy, should an error in an LRG sequence be identified after release, the sequence in the LRG will not be changed.
Instead, a second LRG for the locus will be created if the community so requests, with an independent accession number, and the updatable layer of the problematic LRG will be annotated to inform users of the discrepancy. All sequences in the LRG fixed section can be used for stable reporting of variants using their stable identifiers. GlyAla coordinates. Should the need arise in the future to create multiple LRGs for the same locus, these will have different accession numbers, rather than versions of the same accession number.
Therefore, this will eliminate the ambiguity caused by versioning in variant reporting. A submission template was designed to capture the essential elements to describe genotypic variation and its impact on phenotype and disease. Submissions are loaded to ClinVar. These data are then reported to the submitter and are made publicly available. An authentication key is required to access the web service, which can be freely requested from gro. LRGs are also supported by external software: the Variant Effect Predictor 14 for variation analysis, e.
Detailed manual curation and extensive collaboration with experts enable the creation of custom-made records that are optimal for reporting variants. Several case studies are described in the Supplementary Data to illustrate how the LRG project has addressed these challenging regions. Communication is an essential part of the LRG project. News items can be received via e-mail by subscribing to the mailing list e-mail gro.
The LRG website also contains background information on the project and the complete LRG specification, along with instructions on how to request an LRG and submit variants. Creation of LRGs is being prioritized according to demand, with LRGs directly requested by the diagnostic community taking precedence. Ongoing collaborations are underway to create LRGs for the genes involved in inherited bleeding and platelet disorders and for the genes included in the United Kingdom National External Quality Assessment Service scheme.
LRGs are also being created for genes organized by type of disease as included in commercial diagnostic testing panels, e. Whenever a new genome assembly is available, and the NCBI and Ensembl databases have been updated, the mapping information and annotation of all LRGs will be updated to the new assembly.
Mapping of the LRG genomic sequence to both the current and penultimate assembly will be included. Development of this will enable retrieval of LRG data through specific URLs without the need for an authentication key. Supplementary Data are available at NAR online, including [18—25]. Funding for open access charge: The Wellcome Trust.
The authors would like to thank the requesters and collaborators of all LRGs. National Center for Biotechnology Information , U. Journal List Nucleic Acids Res v. Nucleic Acids Res. Published online Nov Jacqueline A. Ray E. Elspeth A. Donna R. Author information Article notes Copyright and License information Disclaimer. Published by Oxford University Press. For commercial re-use, please contact journals. This article has been cited by other articles in PMC.
Open in a separate window. Figure 1. Figure 2. Figure 3. Reporting variants on LRGs All sequences in the LRG fixed section can be used for stable reporting of variants using their stable identifiers. Case studies Detailed manual curation and extensive collaboration with experts enable the creation of custom-made records that are optimal for reporting variants. Further information Communication is an essential part of the LRG project. Conflict of interest statement. None declared. Genome Med.
Ensembl Created specifically for clinical reporting by manual curation. Include a minimum set of transcripts for reporting at a locus ideally one Manually curated by expert scientists. Include transcript sequences that are stable and independent of changes to transcript models RefSeq and GENCODE Establish a coordinate system that is independent from upgrades to the reference genome assembly, and provides mappings to present and past assemblies Use a unique and stable identifier that is not versioned.
Flexible and collaborative. Allow inclusion of legacy or community-requested reference sequences Individual records created at the request of the clinical community and in collaboration with gene-specific experts.
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