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New section describing familial PEDIGREE headers #413

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New section describing familial PEDIGREE headers #413

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0e7b06a
[DRAFT] Outline of new familial ##PEDIGREE section
jmarshall Apr 10, 2019
2fcd817
Restructured where is PEDIGREE meta explained
Jul 24, 2019
a35d422
Add example of PED to VCF conversion
jmmut Nov 14, 2019
36b3918
VCF: add references in pedigree example
jmmut Dec 1, 2019
f1bc982
VCF: add siblings to pedigree section
jmmut Dec 2, 2019
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38 changes: 30 additions & 8 deletions VCFv4.3.tex
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Original file line number Diff line number Diff line change
Expand Up @@ -238,6 +238,7 @@ \subsubsection{Contig field format}


\subsubsection{Sample field format}
\label{meta-sample}
It is possible to define sample to genome mappings as shown below:
{\scriptsize
\begin{verbatim}
Expand All @@ -256,13 +257,38 @@ \subsubsection{Pedigree field format}
##PEDIGREE=<ID=SomaticNonTumour,Original=GermlineID>
##PEDIGREE=<ID=ChildID,Father=FatherID,Mother=MotherID>
##PEDIGREE=<ID=SampleID,Name_1=Ancestor_1,...,Name_N=Ancestor_N>
##PEDIGREE=<ID=ChildID,MonozygoticTwin=OtherChildID>
##PEDIGREE=<ID=ChildID,DizygoticTwin=AnotherChildID>
##PEDIGREE=<ID=ChildID,Sibling=SiblingChildID>
\end{verbatim}
\noindent or a link to a database:

The first two lines assert that the DNA in genomes TumourSample and SomaticNonTumour is asexually or clonally derived with mutations from the DNA in genome OriginalID.
The third line describes a family relationship between genomes.
A VCF will therefore contain one entry per trio.
The fourth line is an example of the most general form of a pedigree line.
It means that the genome SampleID is derived from the N $\ge$ 1 genomes Ancestor1, ..., AncestorN.
The fifth and sixth lines describe relationships between twins.
Regular siblings can be inferred implicitly from trios like the third line, but if the parents are unknown, the seventh line describes a sibling relationship explicitly.

Mother and Father are optional (e.g.\ if unknown) and have the same meaning as in PED files. Consider the following example PED line (the columns are Family ID, Individual ID, Paternal ID, Maternal ID, Sex, Phenotype, Genotypes):
\begin{verbatim}
FAM001 9 7 8 1 2 A A
\end{verbatim}

The family described in that line can be expressed in VCF as:

\begin{verbatim}
##PEDIGREE=<ID=9,Father=7,Mother=8>
\end{verbatim}

Phenotypes can be expressed as explained in Section \ref{meta-sample}, and genotypes as in Section \ref{genotype-fields}.

If samples and the relationships between them are described in an external resource such as a database or PED file, is it also possible to provide a link:
\begin{verbatim}
##pedigreeDB=URL
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This is not the line I'm interested in but I can't comment on the other one. PED does not support more than 2 ancestors, do we want to do it in VCF? I have never seen this used so I don't think a lot of people will miss it if we drop it. That will make trivial to add some examples for trios.

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@pd3 @lbergelson what should we do about this? Dropping support for more than 2 ancestors would render some files incorrect, but as I said in my previous comment I have never seen that syntax being used.

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I don't think there would be a lot of pushback against dropping multiple ancestor lines because they seem pretty ambiguously defined at the moment and I haven't ever seen one used... That said, we should maybe not be making breaking changes to an existing spec?

Are they intended only for asexual ancestry where each is the parent of the next? Or are they just an unsorted bag of ancestors that could represent any tree of parentage?

i.e does <ID=SampleID,Name_1=Ancestor_1,...,Name_N=Ancestor_N>
imply

SampleID -> Ancestor_1 -> Ancestor 2

or could it also mean

 Ancestor_1 <- SampleID -> Ancestor_2

I lean towards removing or deprecating it if we don't know exactly what it means and no one seems to be using it.

I'm also not clear on which of these are controlled vocabulary. Is there a specific ontology of relationships that are allowed? Are we allowed to specify something like Sibling in the case where we don't have parent in the vcf or is that handled with dummy trios that point to unique but not present parents ID's

Are you allowed to include only 1 parent or are trios required?

I assume the example would address some of these questions.

\end{verbatim}

\noindent See \ref{PedigreeInDetail} for details.
\noindent See Section \ref{ClonalPedigree} for more details about clonal relationships.


\subsection{Header line syntax}
Expand Down Expand Up @@ -390,6 +416,7 @@ \subsubsection{Fixed fields}
\end{itemize}

\subsubsection{Genotype fields}
\label{genotype-fields}
If genotype information is present, then the same types of data must be present for all samples.
First a FORMAT field is given specifying the data types and order (colon-separated FORMAT keys matching the regular expression \texttt{\^{}[A-Za-z\_][0-9A-Za-z\_.]*\$}, duplicate keys are not allowed).
This is followed by one data block per sample, with the colon-separated data corresponding to the types specified in the format.
Expand Down Expand Up @@ -1261,7 +1288,7 @@ \subsubsection{Sample mixtures}
\normalsize

\subsubsection{Clonal derivation relationships}
\label{PedigreeInDetail}
\label{ClonalPedigree}
In cancer, each VCF file represents several genomes from a patient, but one genome is special in that it represents the germline genome of the patient.
This genome is contrasted to a second genome, the cancer tumor genome.
In the simplest case the VCF file for a single patient contains only these two genomes.
Expand All @@ -1281,11 +1308,6 @@ \subsubsection{Clonal derivation relationships}
\end{verbatim}

This line asserts that the DNA in genome DerivedID is asexually or clonally derived with mutations from the DNA in genome OriginalID.
This is the asexual analog of the VCF format that has been proposed for family relationships between genomes, i.e., there is one entry per trio of the form:

\begin{verbatim}
##PEDIGREE=<ID=ChildID,Mother=MotherID,Father=FatherID>
\end{verbatim}

Let's consider a cancer patient VCF file with 4 genomes: germline, primary\_tumor, secondary\_tumor1, and secondary\_tumor2 as illustrated in Figure 10.
The primary\_tumor is derived from the germline and the secondary tumors are each derived independently from the primary tumor, in all cases by clonal derivation with mutations.
Expand Down