Error in Reference Genome UCSC
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Kathleen Klein
Sep 29, 2016, 11:55:41 AM9/29/16
to gen...@soe.ucsc.edu, cbs...@soe.ucsc.edu
I am not sure who I should contact, I have noticed that the UCSC for HG38, lists the reference allele at position chr13: 32355250 as T however this is the alternative allele and the reference should be C. This snap is located in the BRCA2 gene and therefore relevant to clinical genetic testing. The reference allele is classified as a missense variant when using a variant caller such as GATK or SOMATIC when indeed it is the reference allele.
Coding annotations by dbSNP:
BRCA2 (NM_000059): missense_variant A
(GCA) --> V (GTA)
If you need more information feel free to contact me.
Kathleen Klein
Cath Tyner
Oct 3, 2016, 5:03:49 PM10/3/16
to Kathleen Klein, gen...@soe.ucsc.edu, cbs...@soe.ucsc.edu
Hello Kathleen,
Thank you for using the UCSC Genome Browser and for inquiring about the reference allele at position chr13: 32355250, which is a T. You have noted that this is an alternative allele (and you are noting that the reference should be a C, the major allele).
In short, you are correct; the reference allele at this position is indeed a rare alternative allele. Since the reference genome is composed of sequence from multiple individuals, and all individuals contain rare alleles, some of these rare alleles are included in reference assemblies. My understanding is that there has been much discussion in the Genome Reference Consortium (GRC) about this issue. The UCSC Genome Browser displays the GRC reference sequence, but we cannot change it. However, our team may be discussing the possibility of adding a feature which helps to flag rare alleles like this.
Here is an interesting related article from 2016:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009343/
From the authors' conclusion (not necessarily the opinion of the Genome Browser team) :
Thank you for using the UCSC Genome Browser and for inquiring about the reference allele at position chr13: 32355250, which is a T. You have noted that this is an alternative allele (and you are noting that the reference should be a C, the major allele).
In short, you are correct; the reference allele at this position is indeed a rare alternative allele. Since the reference genome is composed of sequence from multiple individuals, and all individuals contain rare alleles, some of these rare alleles are included in reference assemblies. My understanding is that there has been much discussion in the Genome Reference Consortium (GRC) about this issue. The UCSC Genome Browser displays the GRC reference sequence, but we cannot change it. However, our team may be discussing the possibility of adding a feature which helps to flag rare alleles like this.
Here is an interesting related article from 2016:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009343/
From the authors' conclusion (not necessarily the opinion of the Genome Browser team) :
"By comparing the reference sequences of DNA, mRNA and protein, we observed a significantly high-level of consistency between them. We also observed that the differences between RefSeq mRNA and GRCh38 originated from minor reference alleles in GRCh38, which is expected from the vast majority of rare variants in current population genomics studies (24). In addition, many minor alleles still remain that are used as references by both GRCh38 and RefSeq mRNA. A comparison between GRCh37 and GRCh38 revealed that many of the inconsistent sequences observed between GRCh37 and RefSeq mRNA have been corrected between these versions of the genome. As the allele frequency data have become saturated for polymorphic sites, it will be beneficial for future genome analyses if the reference sequences are unified to represent the major alleles at as many sites as possible."
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