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LiftOver is a necesary step to bring all genetical analysis to the same reference build.
LiftOver is a necesary step to bring all genetical analysis to the same reference build.
LiftOver can have three use cases:
(1) [[#Lift genomic positions | convert genomic position from one genome assembly to another genome assembly]]
In most scenarios, we have known genomic positions in NCBI build 36 (UCSC hg 18) and hope to lift them over to NCBI build 37 (UCSC hg19).
(2) [[#Lift dbSNP rs numbers | convert dbSNP rs number from one build to another]]
(3) [[#Lift Merlin/PLINK format |convert both genomic position and dbSNP rs number over different versions]]
It is likely to see such type of data in Merlin/PLINK format.
We will explain the work flow for the above three cases. In the rest of this article,
our example is to lift over from lower/older build to newer/higher build, as it is the common practice.
Using different tools, liftOver can be easy.
For example, UCSC liftOver tool is able to lift [http://genome.ucsc.edu/FAQ/FAQformat.html#format1 BED format] file between builds.
With our customized scripts, we can also lift rsNumber and Merlin/PLINK data files.
== Lift genomic positions ==
Genomic positions are best represented in [http://genome.ucsc.edu/FAQ/FAQformat.html#format1 BED format]. UCSC provides tools to convert BED file from one genome assembly to another.
=== Binary liftOver tool ===
=== Binary liftOver tool ===
We need [http://hgdownload.cse.ucsc.edu/admin/exe/linux.x86_64/liftOver liftOver binary] from UCSC and [http://hgdownload.cse.ucsc.edu/goldenPath/hg18/liftOver/hg18ToHg19.over.chain.gz hg18 to hg 19 chain file].
Provide BED format file (input.bed)
Provide BED format file (e.g. input.bed)
NOTE: Use the 'chr' before each chromosome name
NOTE: Use the 'chr' before each chromosome name
liftOver input.bed hg18ToHg19.over.chain.gz output.bed unlifted.bed
liftOver input.bed hg18ToHg19.over.chain.gz output.bed unlifted.bed
unlifted file will contain all genomic positions that cannot be lifted. The reason for that varies. See [[#Various reasons that lift over could fail | Various reasons that lift over could fail]]
unlifted.bed file will contain all genomic positions that cannot be lifted. The reason for that varies. See [[#Various reasons that lift over could fail | Various reasons that lift over could fail]]
=== Web interface ===
=== Web interface ===
be lifted if you click "Explain failure messages"
be lifted if you click "Explain failure messages"
== Lift Merlin format ==
== Lift dbSNP rs numbers ==
rs number is release by dbSNP. UCSC also make their own copy from each dbSNP version. Be aware that the same version of dbSNP from these two centers are not the same.
When we convert rs number from lower version to higher version, there are practically two ways.
=== Use RsMergeArch and SNPHistory ===
It is necessary to quickly summarize how dbSNP merge/re-activate rs number:
# when different rs number are found to refer to the same SNP, then higher rs number will be merged to lower rs number, and the merging will be recorded in RsMergeArch.bcp.gz.
# when rs number have to be retracted, rs number will be recorded in SNPHistory.bcp.gz
# a retracted SNP can be [http://www.ncbi.nlm.nih.gov/books/NBK44496/#Schema.rs4823903_which_has_merged_into re-activated] in SNPHistory.bcp.gz by adding comment
With the above in mind, we are able to combine these two tables to obtain the relationship between older rs number and new rs number.
We have developed a script (for internal use), named liftRsNumber.py [/net /dumbo/net/dumbo/home/zhanxw/amd/analyze/verifyBamID/] for lift rs numbers between builds.
This scripts require RsMergeArch.bcp.gz and SNPHistory.bcp.gz, those can be found in [[#Resources | Resources]].
Example input:
<pre>
3115860
12124819
2229002
1130683
</pre>
Command:
<pre>
python liftRsNumber.py input.rs > output.rs
</pre>
Example otuput:
<pre>
unchanged 3115860
unchanged 12124819
lifted 2229002
lifted 1130683
</pre>
== Lift Merlin/PLINK format ==
In Merlin/PLINK .map files, each line contains both genomic position and dbSNP rs number. Our goal here is to use both information to liftOver as many position as possible.
There are 3 methods to liftOver and we recommend the first 2 method. The first method is common, and it lifts most genomic positions, however, it does not reflect the dbSNP build change. The second method is more robust in the sense that each lifted rs number has valid genomic position, as its uses dbSNP as data source. The third method is not straigtforward, and we just briefly mention it.
=== Lift Merlin format ===
PLINK format and [http://www.sph.umich.edu/csg/abecasis/Merlin/tour/input_files.html Merlin format are nearly identical].
PLINK format and [http://www.sph.umich.edu/csg/abecasis/Merlin/tour/input_files.html Merlin format are nearly identical].
to obtain Merlin .map file.
to obtain Merlin .map file.
== Lift PLINK format ==
=== Lift PLINK format ===
[http://pngu.mgh.harvard.edu/~purcell/plink/data.shtml PLINK] format usually referrs to .ped and .map files.
[http://pngu.mgh.harvard.edu/~purcell/plink/data.shtml PLINK] format usually referrs to .ped and .map files.
We recommend split the jobs in several steps:
(1) convert .map to .bed file
==== Method 1 ====
We mainly use UCSC LiftOver binary tools to help lift over.
We have a script [[#Resources | liftMap.py]], however, it is recommended to understand the job step by step:
(1) Convert .map to .bed file
By rearrange columns of .map file, we obtain a standard BED format file.
By rearrange columns of .map file, we obtain a standard BED format file.
(2) liftOver .bed file
(2) LiftOver .bed file
Use method mentioned above to convert .bed file from one build to another.
Use method mentioned [[#Lift genomic positions | above]] to convert .bed file from one build to another.
(3) Convert lifted .bed file back to .map file
Rearrange column of .map file to obtain .bed file in the new build.
Rearrange column of .map file to obtain .bed file in the new build.
(4) modify .ped file
(4) Modify .ped file
.ped file have many column files. By convention, the first six columns are family_id, person_id, father_id, mother_id, sex, and phenotype.
.ped file have many column files. By convention, the first six columns are family_id, person_id, father_id, mother_id, sex, and phenotype.
From the 7th column, there are two letters/digits representing a genotype at the certain marker. In step (2), as some genomic positions cannot
From the 7th column, there are two letters/digits representing a genotype at the certain marker. In step (2), as some genomic positions cannot
(5) (optionally) change the rs number in the .map file
(5) (optionally) change the rs number in the .map file
Similar to the human reference build, dbSNP also have different versions. You may consider change rs number from the old dbSNP version to new dbSNP version
Similar to the human reference build, dbSNP also have different versions. You may consider change rs number from the old dbSNP version to new dbSNP version
depending on your needs Such steps are described in [#Lift dbSNP rs numbers | Lift dbSNP rs numbers].
depending on your needs Such steps are described in [#Lift dbSNP rs numbers | Lift dbSNP rs numbers].
(6) (optionally) additional method to lift dbSNP postion
==== Method 2 ====
NCBI dbSNP team has provided a provisional map for converting the genomic position of a larget set dbSNP from NCBI build 36 to NCBI build 37.
The idea is to use [[#Resources |LiftRsNumber.py]] to convert old rs number to new rs number, use the data file b132_SNPChrPosOnRef_37_1.bcp.gz (a data file containing each dbSNP and its positions in NCBI build 37), and adjust .map and .ped files accordingly.
(1) Extract and lift rs numbers
Use the tools [[#Use RsMergeArch and SNPHistory | LiftRsNumber.py]] to lift the rs number in the map file from old build to new build.
(2) Lookup SNP positions from rs number
dbSNP provides a file [[#Resources | joinb132_SNPChrPosOnRef_37_1.bcp.gz]] which contains rsNumber, chromosome and its position.
Use this file along with the new rsNumber obtained in the first step.
In practice, some rs numbers do not exist in build 132, or not suitable to be considered ( e.g. they do not reside on human reference, or they are mapped to multiple locations, these scenarios are noted by the chromosome column with values like "AltOnly", "Multi", "NotOn", "PAR", "Un"), we can drop them in the liftover procedure.
We will obtain the rs number and its position in the new build after this step.
(3) Lift .map file and .ped file
To lift over .map files, we can scan its content line by line, and skip those not lifted rs number.
Accordingly, it is necessary to drop the un-lifted SNP genotypes from .ped file.
==== Method 3 ====
NCBI dbSNP team has provided a [#Resources | provisional map] for converting the genomic position of a larget set dbSNP from NCBI build 36 to NCBI build 37.
In the second step, we have obtained unlifted genomic positions, so we can try to use the table to convert those unlfted dbSNPs.
In the second step, we have obtained unlifted genomic positions, so we can try to use the table to convert those unlfted dbSNPs.
After this step, there are still some SNPs that cannot be lifted, and they are mostly located on non-reference chromosome.
After this step, there are still some SNPs that cannot be lifted, as they are mostly located on non-reference chromosome.
Note: due to the limitation of the provisional map, some SNP can have multiple locations.
For example, we cannot convert rs10000199 to chromosome 4, 7, 12.
<pre>
10000199 A/G 4 166142415 166142415 2 3 G + 4 165922965 165922965 2 3 G +
10000199 A/G 7 4589694 4589694 2 3 C - 7 4623168 4623168 2 3 C -
10000199 A/G 12 57008620 57008620 2 3 C - 12 58722353 58722353 2 3 C -
10000199 A/G 5 156018406 156018406 2 3 C - 5 156085828 156085828 2 3 C -
</pre>
We can dissect this method into steps:
(1) Remove invalid record in dbSNP provisional map.
rs number is release by dbSNP. UCSC also make their own copy from each dbSNP version. Be aware that the same version of dbSNP from these two centers are not the same.
Provisional map have duplicated rs number or the chromsome in the new build can be "Unable to map"(UN), we need to clean this table.
(2) Use provisional map to update .map file
By joining .map file and this provisional map, we can obtain the new genomic position in the new build.
Note: provisional map uses 1-based chromosomal index. Things will get tricker if we want to lift non-single site SNP e.g. AA/GG
Since provisional map provides a range in this case, it is necessary to know the genomic position of that single base provided in the .map file,
and then we can look up the table, so it is not straigtforward.
(3) Adjust .map and .ped file
For those lifted dbSNP, we need to keep them in the .map files, otherwise, we need to delete them.
Accordingly, we need to deleted SNP genotypes for those cannot be lifted.
== Various reasons that lift over could fail ==
== Various reasons that lift over could fail ==
Thus it is probably not very useful to lift this SNP.
Thus it is probably not very useful to lift this SNP.
=== Cannot find rs number in newer dbSNP build ===
=== rs number changed in newer dbSNP build ===
It is possible that new dbSNP build does not have certain rs numbers.
It is possible that new dbSNP build does not have certain rs numbers.
When dbSNp release new build, higher rs number may be merged to lower rs number because of those rs numbers are actually the same SNP.
When dbSNp release new build, higher rs number may be merged to lower rs number because of those rs numbers are actually the same SNP.
</pre>
</pre>
== Resouces ==
== Resources ==
* liftRsNumber.py [[Media: liftRsNumber.py]]
* liftMap.py [[Media: liftMap.py]
* NCBI provisional map [ftp://ftp.ncbi.nih.gov:/snp/organisms/human_9606/misc/exchange/Remap_36_3_37_1.txt.gz file] and [ftp://ftp.ncbi.nih.gov:/snp/organisms/human_9606/misc/exchange/Remap_36_3_37_1.info info]
* NCBI provisional map [ftp://ftp.ncbi.nih.gov:/snp/organisms/human_9606/misc/exchange/Remap_36_3_37_1.txt.gz file] and [ftp://ftp.ncbi.nih.gov:/snp/organisms/human_9606/misc/exchange/Remap_36_3_37_1.info info]
* NCBI RgMergeArch file and [http://www.ncbi.nlm.nih.gov/SNP/snp_db_table_description.cgi?t=RsMergeArch schema]
* NCBI RgMergeArch file and [http://www.ncbi.nlm.nih.gov/SNP/snp_db_table_description.cgi?t=RsMergeArch schema]
