Calculate genotype posterior probabilities given family and/or known population genotypes

Category Variant Evaluation and Refinement

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Overview

Calculate genotype posterior probabilities given family and/or known population genotypes

The tool calculates the posterior genotype probability for each sample genotype in a given VCF format callset. The input variants must present genotype likelihoods generated by HaplotypeCaller, UnifiedGenotyper or other source that provides unbiased genotype likelihoods.

The tool can use priors from three different data sources: (i) one or more supporting germline population callsets with specific annotation(s) if supplied , (ii) the pedigree for a trio if supplied and if the trio is represented in the callset under refinement, and/or (iii) the allele counts of the callset samples themselves given at least ten samples. It is possible to deactivate the contribution of the callset samples with the --ignore-input-samples flag.

For more background information and for mathematical details, see GATK forum article at https://software.broadinstitute.org/gatk/documentation/article?id=11074. Additional GATK mathematical notes are presented as whitepapers in the gatk GitHub repository docs section at https://github.com/broadinstitute/gatk/tree/master/docs.

Inputs

• A VCF with genotype likelihoods, and optionally genotypes, AC/AN fields, or MLEAC/AN fields. The tool will use MLEAC if available or AC if MLEAC is not provided. AN is also required unless genotypes are provided for all samples.
• (Optional) A PED pedigree file containing the description of the relationships between individuals. The tool considers only trio groups. A trio consists of mother-father-child.

Optionally, a collection of VCFs can be provided for the purpose of informing population allele frequency priors. Each of these resource VCFs must satisfy at least one of the following requirement sets:

• AC field and AN field
• MLEAC field and AN field
• Genotypes

Output

A new VCF with the following information:

• Genotype posteriors added to the FORMAT fields ("PP")
• Genotypes and GQ assigned according to these posteriors (note that the original genotype and GQ may change)
• Per-site genotype priors added to the INFO field ("PG")
• (Optional) Per-site, per-trio joint likelihoods (JL) and joint posteriors (JP) given as Phred-scaled probability of all genotypes in the trio being correct based on the PLs for JL and the PPs for JP. These annotations are added to the FORMAT fields.

Notes

By default, priors will be applied to each variant separately, provided each variant features data from at least 10 called samples (no-calls do not count). SNP sites in the input callset that have a SNP at the matching site in the supporting VCF will have priors applied based on the AC from the supporting samples and the input callset unless the --ignore-input-samples flag is used. If a site is not called in the supporting VCF, priors will be applied using the discovered AC from the input samples unless the --discovered-allele-count-priors-off flag is used. For any non-SNP sites in the input callset, flat priors are applied.

For versions of the tool 4.0.5.0+, the tool appropriately applies priors to indels.

If applying family priors, only diploid family genotypes are supported. In addition, family priors only apply to trios represented in both a supplied pedigree and in the callset under refinement. Note, if the pedigree is incomplete, the tools skips calculating family priors. In this case, and in the absence of other refinement, the results will be identical to the input.

Usage examples

Refine genotypes based on the discovered allele frequency in an input VCF containing many samples

 gatk --java-options "-Xmx4g" CalculateGenotypePosteriors \
   -V multisample_input.vcf.gz \
   -O output.vcf.gz
 

Inform the genotype assignment of a single sample using the 1000G phase 3 samples

 gatk --java-options "-Xmx4g" CalculateGenotypePosteriors \
   -V sample_input.vcf.gz \
   -O sample_output.1000G_PPs.vcf.gz \
   -supporting 1000G.phase3.integrated.sites_only.no_MATCHED_REV.hg38.vcf.gz
 

Apply only family priors to a callset

 gatk --java-options "-Xmx4g" CalculateGenotypePosteriors \
   -V input.vcf.gz \
   -O output.vcf.gz \
   -ped family.ped \
   --skip-population-priors
 

Apply frequency and HWE-based priors to the genotypes of a family without including the family allele counts in the allele frequency estimates

 gatk --java-options "-Xmx4g" CalculateGenotypePosteriors \
   -V input.vcf.gz \
   -O output.vcf.gz \
   --ignore-input-samples
 

Calculate the posterior genotypes of a callset, and impose that a variant *not seen* in the external panel is tantamount to being AC=0, AN=5008 within that panel

 gatk --java-options "-Xmx4g" CalculateGenotypePosteriors \
   -V input.vcf.gz \
   -O output.vcf.gz \
   -supporting 1000G.phase3.integrated.sites_only.no_MATCHED_REV.hg38.vcf.gz \
   --num-reference-samples-if-no-call 2504
 

Caveat

If applying family priors, only diploid family genotypes are supported

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Additional Information

Read filters

This Read Filter is automatically applied to the data by the Engine before processing by CalculateGenotypePosteriors.

• WellformedReadFilter

CalculateGenotypePosteriors specific arguments

This table summarizes the command-line arguments that are specific to this tool. For more details on each argument, see the list further down below the table or click on an argument name to jump directly to that entry in the list.

Argument name(s)	Default value	Summary
Required Arguments
--output  -O	null	File to which variants should be written
--variant  -V	null	A VCF file containing variants
Optional Tool Arguments
--arguments_file	[]	read one or more arguments files and add them to the command line
--cloud-index-prefetch-buffer  -CIPB	-1	Size of the cloud-only prefetch buffer (in MB; 0 to disable). Defaults to cloudPrefetchBuffer if unset.
--cloud-prefetch-buffer  -CPB	40	Size of the cloud-only prefetch buffer (in MB; 0 to disable).
--de-novo-prior	1.0E-6	Prior for de novo mutations
--default-to-allele-count	false	Use AC rather than MLEAC
--disable-bam-index-caching  -DBIC	false	If true, don't cache bam indexes, this will reduce memory requirements but may harm performance if many intervals are specified. Caching is automatically disabled if there are no intervals specified.
--disable-sequence-dictionary-validation	false	If specified, do not check the sequence dictionaries from our inputs for compatibility. Use at your own risk!
--discovered-allele-count-priors-off	false	Do not use discovered allele count in the input callset for variants that do not appear in the external callset.
--gcs-max-retries  -gcs-retries	20	If the GCS bucket channel errors out, how many times it will attempt to re-initiate the connection
--gcs-project-for-requester-pays	""	Project to bill when accessing "requester pays" buckets. If unset, these buckets cannot be accessed.
--global-prior-indel	0.001	Global Dirichlet prior parameters for the indel allele frequency
--global-prior-snp	0.001	Global Dirichlet prior parameters for the SNP allele frequency
--help  -h	false	display the help message
--ignore-input-samples	false	Use external information only
--interval-merging-rule  -imr	ALL	Interval merging rule for abutting intervals
--intervals  -L	[]	One or more genomic intervals over which to operate
--num-reference-samples-if-no-call	0	Number of hom-ref genotypes to infer at sites not present in a panel
--pedigree  -ped	null	Pedigree file for samples
--reference  -R	null	Reference sequence
--sites-only-vcf-output	false	If true, don't emit genotype fields when writing vcf file output.
--skip-family-priors	false	Skip application of family-based priors
--skip-population-priors	false	Skip application of population-based priors
--supporting-callsets  -supporting	[]	Other callsets to use in generating genotype posteriors
--use-flat-priors-for-indels  -skipIndels	false	Use flat priors for indels
--version	false	display the version number for this tool
Optional Common Arguments
--add-output-sam-program-record	true	If true, adds a PG tag to created SAM/BAM/CRAM files.
--add-output-vcf-command-line	true	If true, adds a command line header line to created VCF files.
--create-output-bam-index  -OBI	true	If true, create a BAM/CRAM index when writing a coordinate-sorted BAM/CRAM file.
--create-output-bam-md5  -OBM	false	If true, create a MD5 digest for any BAM/SAM/CRAM file created
--create-output-variant-index  -OVI	true	If true, create a VCF index when writing a coordinate-sorted VCF file.
--create-output-variant-md5  -OVM	false	If true, create a a MD5 digest any VCF file created.
--disable-read-filter  -DF	[]	Read filters to be disabled before analysis
--disable-tool-default-read-filters	false	Disable all tool default read filters (WARNING: many tools will not function correctly without their default read filters on)
--exclude-intervals  -XL	[]	One or more genomic intervals to exclude from processing
--gatk-config-file	null	A configuration file to use with the GATK.
--input  -I	[]	BAM/SAM/CRAM file containing reads
--interval-exclusion-padding  -ixp	0	Amount of padding (in bp) to add to each interval you are excluding.
--interval-padding  -ip	0	Amount of padding (in bp) to add to each interval you are including.
--interval-set-rule  -isr	UNION	Set merging approach to use for combining interval inputs
--lenient  -LE	false	Lenient processing of VCF files
--QUIET	false	Whether to suppress job-summary info on System.err.
--read-filter  -RF	[]	Read filters to be applied before analysis
--read-index	[]	Indices to use for the read inputs. If specified, an index must be provided for every read input and in the same order as the read inputs. If this argument is not specified, the path to the index for each input will be inferred automatically.
--read-validation-stringency  -VS	SILENT	Validation stringency for all SAM/BAM/CRAM/SRA files read by this program. The default stringency value SILENT can improve performance when processing a BAM file in which variable-length data (read, qualities, tags) do not otherwise need to be decoded.
--seconds-between-progress-updates	10.0	Output traversal statistics every time this many seconds elapse
--sequence-dictionary	null	Use the given sequence dictionary as the master/canonical sequence dictionary. Must be a .dict file.
--tmp-dir	null	Temp directory to use.
--use-jdk-deflater  -jdk-deflater	false	Whether to use the JdkDeflater (as opposed to IntelDeflater)
--use-jdk-inflater  -jdk-inflater	false	Whether to use the JdkInflater (as opposed to IntelInflater)
--verbosity	INFO	Control verbosity of logging.
Advanced Arguments
--showHidden	false	display hidden arguments

Argument details

Arguments in this list are specific to this tool. Keep in mind that other arguments are available that are shared with other tools (e.g. command-line GATK arguments); see Inherited arguments above.

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--add-output-sam-program-record / -add-output-sam-program-record

If true, adds a PG tag to created SAM/BAM/CRAM files.

boolean  true

---

--add-output-vcf-command-line / -add-output-vcf-command-line

If true, adds a command line header line to created VCF files.

boolean  true

---

--arguments_file / NA

read one or more arguments files and add them to the command line

List[File]  []

---

--cloud-index-prefetch-buffer / -CIPB

Size of the cloud-only prefetch buffer (in MB; 0 to disable). Defaults to cloudPrefetchBuffer if unset.

int  -1  [ [ -∞  ∞ ] ]

---

--cloud-prefetch-buffer / -CPB

Size of the cloud-only prefetch buffer (in MB; 0 to disable).

int  40  [ [ -∞  ∞ ] ]

---

--create-output-bam-index / -OBI

If true, create a BAM/CRAM index when writing a coordinate-sorted BAM/CRAM file.

boolean  true

---

--create-output-bam-md5 / -OBM

If true, create a MD5 digest for any BAM/SAM/CRAM file created

boolean  false

---

--create-output-variant-index / -OVI

If true, create a VCF index when writing a coordinate-sorted VCF file.

boolean  true

---

--create-output-variant-md5 / -OVM

If true, create a a MD5 digest any VCF file created.

boolean  false

---

--de-novo-prior / NA

Prior for de novo mutations
The de novo mutation prior -- i.e. the probability that a new mutation occurs. Sensitivity analysis on known de novo mutations suggests a default value of 10^-6.

double  1.0E-6  [ [ -∞  ∞ ] ]

---

--default-to-allele-count / NA

Use AC rather than MLEAC
By default the tool looks for MLEAC first, and then falls back to AC if MLEAC is not found. When this flag is set, the behavior is flipped and the tool looks first for the AC field and then fall back to MLEAC or raw genotypes.

boolean  false

---

--disable-bam-index-caching / -DBIC

If true, don't cache bam indexes, this will reduce memory requirements but may harm performance if many intervals are specified. Caching is automatically disabled if there are no intervals specified.

boolean  false

---

--disable-read-filter / -DF

Read filters to be disabled before analysis

List[String]  []

---

--disable-sequence-dictionary-validation / -disable-sequence-dictionary-validation

If specified, do not check the sequence dictionaries from our inputs for compatibility. Use at your own risk!

boolean  false

---

--disable-tool-default-read-filters / -disable-tool-default-read-filters

Disable all tool default read filters (WARNING: many tools will not function correctly without their default read filters on)

boolean  false

---

--discovered-allele-count-priors-off / NA

Do not use discovered allele count in the input callset for variants that do not appear in the external callset.
Don't add input sample ACs for variants not seen in the supporting panel. Default is to add discovered AC from input samples provided there are at least 10 input samples or if num-ref-samples-if-no-call is greater than zero.

boolean  false

---

--exclude-intervals / -XL

One or more genomic intervals to exclude from processing
Use this argument to exclude certain parts of the genome from the analysis (like -L, but the opposite). This argument can be specified multiple times. You can use samtools-style intervals either explicitly on the command line (e.g. -XL 1 or -XL 1:100-200) or by loading in a file containing a list of intervals (e.g. -XL myFile.intervals).

List[String]  []

---

--gatk-config-file / NA

A configuration file to use with the GATK.

String  null

---

--gcs-max-retries / -gcs-retries

If the GCS bucket channel errors out, how many times it will attempt to re-initiate the connection

int  20  [ [ -∞  ∞ ] ]

---

--gcs-project-for-requester-pays / NA

Project to bill when accessing "requester pays" buckets. If unset, these buckets cannot be accessed.

String  ""

---

--global-prior-indel / NA

Global Dirichlet prior parameters for the indel allele frequency
Prior indel pseudocounts for Dirichlet distribution of allele frequencies. The posterior distribution is a Dirichlet with parameters given by pseudocounts plus the number of occurrences in the resource vcfs.

double  0.001  [ [ -∞  ∞ ] ]

---

--global-prior-snp / NA

Global Dirichlet prior parameters for the SNP allele frequency
Prior SNP pseudocounts for Dirichlet distribution of allele frequencies. The posterior distribution is a Dirichlet with parameters given by pseudocounts plus the number of occurrences in the resource vcfs.

double  0.001  [ [ -∞  ∞ ] ]

---

--help / -h

display the help message

boolean  false

---

--ignore-input-samples / NA

Use external information only
When this flag is set, only the AC and AN calculated from external sources will be used, and the calculation will not use the discovered allele frequency in the callset whose posteriors are being calculated. Useful for callsets containing related individuals.

boolean  false

---

--input / -I

BAM/SAM/CRAM file containing reads

List[String]  []

---

--interval-exclusion-padding / -ixp

Amount of padding (in bp) to add to each interval you are excluding.
Use this to add padding to the intervals specified using -XL. For example, '-XL 1:100' with a padding value of 20 would turn into '-XL 1:80-120'. This is typically used to add padding around targets when analyzing exomes.

int  0  [ [ -∞  ∞ ] ]

---

--interval-merging-rule / -imr

Interval merging rule for abutting intervals
By default, the program merges abutting intervals (i.e. intervals that are directly side-by-side but do not actually overlap) into a single continuous interval. However you can change this behavior if you want them to be treated as separate intervals instead.

The --interval-merging-rule argument is an enumerated type (IntervalMergingRule), which can have one of the following values:

ALL

OVERLAPPING_ONLY

IntervalMergingRule  ALL

---

--interval-padding / -ip

Amount of padding (in bp) to add to each interval you are including.
Use this to add padding to the intervals specified using -L. For example, '-L 1:100' with a padding value of 20 would turn into '-L 1:80-120'. This is typically used to add padding around targets when analyzing exomes.

int  0  [ [ -∞  ∞ ] ]

---

--interval-set-rule / -isr

Set merging approach to use for combining interval inputs
By default, the program will take the UNION of all intervals specified using -L and/or -XL. However, you can change this setting for -L, for example if you want to take the INTERSECTION of the sets instead. E.g. to perform the analysis only on chromosome 1 exomes, you could specify -L exomes.intervals -L 1 --interval-set-rule INTERSECTION. However, it is not possible to modify the merging approach for intervals passed using -XL (they will always be merged using UNION). Note that if you specify both -L and -XL, the -XL interval set will be subtracted from the -L interval set.

The --interval-set-rule argument is an enumerated type (IntervalSetRule), which can have one of the following values:

UNION

Take the union of all intervals

INTERSECTION

Take the intersection of intervals (the subset that overlaps all intervals specified)

IntervalSetRule  UNION

---

--intervals / -L

One or more genomic intervals over which to operate

List[String]  []

---

--lenient / -LE

Lenient processing of VCF files

boolean  false

---

--num-reference-samples-if-no-call / NA

Number of hom-ref genotypes to infer at sites not present in a panel
When a variant is not seen in a panel, this argument controls whether to infer (and with what effective strength) that only reference alleles were observed at that site. E.g. "If not seen in 1000Genomes, treat it as AC=0, AN=2000", where AN=2*nSamples for human autosomes.

int  0  [ [ -∞  ∞ ] ]

---

--output / -O

File to which variants should be written

R File  null

---

--pedigree / -ped

Pedigree file for samples
See https://software.broadinstitute.org/gatk/documentation/article.php?id=7696 for more details on the PED format. Note that each -ped argument can be tagged with NO_FAMILY_ID, NO_PARENTS, NO_SEX, NO_PHENOTYPE to tell the GATK PED parser that the corresponding fields are missing from the ped file.

File  null

---

--QUIET / NA

Whether to suppress job-summary info on System.err.

Boolean  false

---

--read-filter / -RF

Read filters to be applied before analysis

List[String]  []

---

--read-index / -read-index

Indices to use for the read inputs. If specified, an index must be provided for every read input and in the same order as the read inputs. If this argument is not specified, the path to the index for each input will be inferred automatically.

List[String]  []

---

--read-validation-stringency / -VS

Validation stringency for all SAM/BAM/CRAM/SRA files read by this program. The default stringency value SILENT can improve performance when processing a BAM file in which variable-length data (read, qualities, tags) do not otherwise need to be decoded.

The --read-validation-stringency argument is an enumerated type (ValidationStringency), which can have one of the following values:

STRICT

LENIENT

SILENT

ValidationStringency  SILENT

---

--reference / -R

Reference sequence

String  null

---

--seconds-between-progress-updates / -seconds-between-progress-updates

Output traversal statistics every time this many seconds elapse

double  10.0  [ [ -∞  ∞ ] ]

---

--sequence-dictionary / -sequence-dictionary

Use the given sequence dictionary as the master/canonical sequence dictionary. Must be a .dict file.

String  null

---

--showHidden / -showHidden

display hidden arguments

boolean  false

---

--sites-only-vcf-output / NA

If true, don't emit genotype fields when writing vcf file output.

boolean  false

---

--skip-family-priors / NA

Skip application of family-based priors
Skip application of family-based priors. Note: if pedigree file is absent, family-based priors will always be skipped.

boolean  false

---

--skip-population-priors / NA

Skip application of population-based priors
Skip application of population-based priors

boolean  false

---

--supporting-callsets / -supporting

Other callsets to use in generating genotype posteriors
Supporting external panels. Allele counts from these panels (taken from AC,AN or MLEAC,AN or raw genotypes) will be used to inform the frequency distribution underlying the genotype priors. These files must be VCF 4.2 spec or later.

List[FeatureInput[VariantContext]]  []

---

--tmp-dir / NA

Temp directory to use.

GATKPathSpecifier  null

---

--use-flat-priors-for-indels / -skipIndels

Use flat priors for indels
Use flat priors for indels (can be used to replicate the legacy CalculateGenotypePosteriors behavior) If an input variant contains an indel allele, flat priors will be applied to that site. If a reference panel variant contains an indel allele, flat priors will be applied instead.

boolean  false

---

--use-jdk-deflater / -jdk-deflater

Whether to use the JdkDeflater (as opposed to IntelDeflater)

boolean  false

---

--use-jdk-inflater / -jdk-inflater

Whether to use the JdkInflater (as opposed to IntelInflater)

boolean  false

---

--variant / -V

A VCF file containing variants

R String  null

---

--verbosity / -verbosity

Control verbosity of logging.

The --verbosity argument is an enumerated type (LogLevel), which can have one of the following values:

ERROR

WARNING

INFO

DEBUG

LogLevel  INFO

---

--version / NA

display the version number for this tool

boolean  false

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GATK version 4.1.4.1 built at Thu, 5 Dec 2019 09:51:56 -0500.