Commit 5d4f3d84 authored by Laros's avatar Laros
Browse files

Updated prioritisation lecture.

parent 022489d7
../../submodules/presentation-pics/pics/lovd_plus/lovd_plus_analysis_3.png
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../../submodules/presentation-pics/pics/lovd_plus/lovd_plus_analysis_5.png
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......@@ -92,7 +92,7 @@
\begin{minipage}[t]{0.47\textwidth}
\begin{figure}
\includegraphics[width=\textwidth]{hiseq_2000}
\caption{HiSeq 2000.}
\caption{HiSeq 2500.}
\end{figure}
\end{minipage}
\hfill
......@@ -102,8 +102,8 @@
\item High throughput.
\item Paired end.
\item High accuracy.
\item Read length $2 \times 150$bp.
\item Relatively long run time.
\item Read length $2 \times 125$bp.
\item Relatively long run time (6 days).
\item Relatively expensive.
\end{itemize}
\end{minipage}
......@@ -168,6 +168,7 @@
Prioritisation is mainly done by filtering variants that we expect to be
irrelevant.
\bigskip
\pause
This can be because the variant does not follow the \emph{inheritance
pattern} of the disease.
......@@ -176,6 +177,7 @@
unaffected individual.
\end{itemize}
\bigskip
\pause
It can be because the \emph{predicted effect} of a variant does not fit in
the phenotype.
......@@ -286,27 +288,26 @@
\end{itemize}
\end{pframe}
\subsection{Databases}
\subsection{Variant Effect Predictor}
\begin{pframe}
In most cases we are not interested in common variants.
\begin{itemize}
\item dbSNP.
\item 1000 Genomes.
\item Exome Variant Server (EVS).
\end{itemize}
\medskip
A cut-off of $1\%$ is usually fine.
\bigskip
Databases containing detailed information about variants:
A selection of VEP annotation:
\begin{itemize}
\item \emph{Locus specific} databases.
\item Affected genes and transcripts.
\item Location of the variant.
\begin{itemize}
\item LOVD.
\item Upstream of a transcript, in coding sequence, in non-coding RNA,
in regulatory region.
\end{itemize}
\item Human Gene Mutation Database (HGMD).
\item Consequence on the protein sequence.
\begin{itemize}
\item Stop gained, missense, stop lost, frameshift.
\end{itemize}
\item Minor allele frequencies from the 1000 Genomes Project.
\item SIFT and PolyPhen scores for changes to protein sequence.
\end{itemize}
\vfill
\permfoot{\url{http://www.ensembl.org/info/docs/tools/vep/index.html}}
\end{pframe}
\subsection{Gene panels}
......@@ -316,6 +317,7 @@
\item Online Mendelian Inheritance in Man (OMIM).
\end{itemize}
\bigskip
\pause
To take it one step further, we can select the \emph{transcripts} that are
expressed in the tissue of interest.
......@@ -325,27 +327,36 @@
one expressed in muscle cells.
\vfill
\permfoot{http://www.omim.org/}
\permfoot{\url{http://www.omim.org/}}
\end{pframe}
\subsection{Location within a gene}
\subsection{Databases}
\begin{pframe}
A selection of VEP annotation:
In most cases we are not interested in common variants.
\begin{itemize}
\item Genes and transcripts affected by the variants.
\item Location of the variant.
\begin{itemize}
\item Upstream of a transcript, in coding sequence, in non-coding RNA,
in regulatory region.
\end{itemize}
\item Consequence of your variants on the protein sequence.
\item dbSNP.
\item 1000 Genomes.
\item Exome Variant Server (EVS).
\end{itemize}
\medskip
A cut-off of $1\%$ is usually fine.
\bigskip
\pause
Databases containing detailed information about variants:
\begin{itemize}
\item \emph{Locus specific} databases.
\begin{itemize}
\item Stop gained, missense, stop lost, frameshift.
\item LOVD.
\end{itemize}
\item Known variants that match yours, and associated minor allele
frequencies from the 1000 Genomes Project.
\item SIFT and PolyPhen scores for changes to protein sequence.
\item Human Gene Mutation Database (HGMD).
\end{itemize}
\vfill
\bs{\url{http://www.lovd.nl/}}
\bs{\url{http://www.hgmd.cf.ac.uk/}}
\end{pframe}
\subsection{Conservation}
......@@ -356,6 +367,36 @@
\end{center}
\caption{PhyloP scores based on $100$ vertebrate species.}
\end{figure}
\vfill
\permfoot{\url{http://compgen.bscb.cornell.edu/phast/}}
\permfoot{\phantom{.}}
\end{pframe}
\section{Putting it all together}
\subsection{Interactive filters}
\begin{pframe}
Prioritise your variants with interactive software like CLC~bio, NextGENe,
Cartagania, \ldots
\begin{figure}[]
\begin{center}
\includegraphics[trim=0.1cm 0.7cm 0.7cm 17cm, clip, width=\textwidth]
{lovd_plus_analysis_5}
\end{center}
\caption{Filtering with LOVD\raisebox{4pt}{+}.}
\end{figure}
\end{pframe}
\begin{pframe}
\begin{figure}[]
\begin{center}
\includegraphics[trim=0.1cm 0.7cm 0.7cm 16.6cm, clip, width=\textwidth]
{lovd_plus_analysis_3}
\end{center}
\caption{Results of an analysis.}
\end{figure}
\end{pframe}
\section{Phasing}
......@@ -401,6 +442,21 @@
\lastpagetemplate
\begin{pframe}
\begin{center}
Acknowledgements:
\bigskip
\bigskip
Ivo Fokkema
Sander Bollen
Gijs Santen
Claudia Ruivenkamp
Mari\"ette Hoffer
Johan den Dunnen
\end{center}
\end{pframe}
......
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