About 1.3 MB of the GRCh38 reference was identified as falsely duplicated, including some medically relevant genes.
For details, see this paper: https://www.nature.com/articles/s41587-021-01158-1
To fix this the regions are masked in the reference genome by replacing the sequence with 'N'.
The regions are specified here.
Several regions are uniquely mappable after the masking (MAPQ>0), but were not before (MAPQ=0).
In these region, there will be new variant calls.
Mainly the regions also affected in CNV calling (see below) will contain changes in small variants.
Only when reference samples for CNV calling already exists, which were analyzed with the uncorrected reference genome, there is a problem with CNVs.
In that case you will see these artefacts:
- Masked regions will be shown with copy-number 0 after the change.
- New uniquely mappable regions are shown with copy-number 4.
This affects the following regions:
| chr | start | end | genes | OMIM genes and phenotypes |
|---|---|---|---|---|
| chr8 | 30393636 | 30407636 | RBPMS | |
| chr9 | 70701717 | 70737717 | TRPM3 | |
| chr11 | 1945622 | 2041622 | H19, LINC01219, MIR675, MRPL23, MRPL23-AS1 | |
| chr13 | 86253328 | 86269328 | ||
| chr13 | 111669328 | 111703328 | ||
| chr13 | 111754328 | 111793328 | ||
| chr16 | 19786345 | 19801345 | IQCK | |
| chr16 | 34339345 | 34500345 | ||
| chr16 | 34867345 | 34896345 | ||
| chr16 | 34960345 | 35072345 | CCNYL3, CLUHP11, LINC02184 | |
| chr21 | 5009983 | 5165983 | ||
| chr21 | 5966983 | 6160983 | ||
| chr21 | 6426983 | 6579983 | ||
| chr21 | 6789983 | 6933983 | ||
| chr21 | 7743983 | 7865983 | ||
| chr21 | 13713983 | 13718983 | ||
| chr21 | 13752983 | 13798983 | FAM207CP, FEM1AP1, TERF1P1 | |
| chr21 | 34374983 | 34494983 | C21ORF140, KCNE1, SMIM11, SMIM34 | KCNE1: Jervell and Lange-Nielsen syndrome 2, Long QT syndrome |
| chr21 | 43035983 | 43186983 | CBS, CRYAA, FRGCA, MRPL51P2, U2AF1 | CBS: Thrombosis, Homocystinuria; CRYAA:Cataract |
| chr21 | 43376983 | 43570983 | H2BC12L, HSF2BP, LINC00313, LINC00319, RPL31P1, SIK1 | SIK1: Developmental and epileptic encephalopathy; HSF2BP:Premature ovarian failure |
| chr21 | 44095983 | 44252983 | DNMT3L, DNMT3L-AS1, GATD3, ICOSLG, LINC01678, PWP2, TRAPPC10 | |
| chr22 | 18885468 | 18939468 | DGCR6, FAM230F, PRODH | PRODH: Schizophrenia, Hyperprolinemia |
| chrX | 37084895 | 37098895 |
To check if your genome is correctly masked, use this command:
> samtools faidx [genome] chr21:5010000-5166246
If the output consists of 'N' only, the genome is correctly masked.
To check if a genome/exome BAM/CRAM file was created with masked reference genome, use this command:
> samtools view [bam/cram] chr21:5966593-6161371
If the output is empty, a masked reference genome was used.
GitHub issue: #147
Benchmarks were performed in the folder: /mnt/storage2/users/ahsturm1/scripts/2022_09_12_grch38_false_duplications