An assessment of computational genotyping of SVs for clinical diagnosis

1. An assessment of computational
genotyping of Structural Variations for
clinical diagnosis
Fritz Sedlazeck
Oct, 16, 2018

2. Scientific interests
Detection of Variants
Clairvoyante
Lou et al. (in review)
Sniffles
Sedlazeck et. al. (2018)
SURVIVOR
Jeffares et. al. (2017)
Mapping/ Assembly reads
NextGenMap-LR
Sedlazeck et. al. (2018)
Falcon Unzip
Chin et.al. (2016)
NextGenMap
Sedlazeck et.al. (2013)
Benchmarking
Teaser
Smolka et.al. (2015)
Sequencing
Jünemann et.al. (2013)
Applications
Model organisms:
-Cancer (SKBR3) (in preparation)
-miRNA editing (Vesely et.al. 2012)
Non Model organisms:
-Cottus transposons (Dennenmoser
et. al. 2017)
-Clunio (Kaiser et. al. 2016)
-Seabass (Vij et.al. 2016)
-Pineapple (Ming et.al. 2015)
“moonlight”'

3. How to detect Structural Variations

4. Structural Variations
Genomic DisordersEvolution
Impact on regulation Impact on phenotypes
RegulatoryState
Cell Line
A
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0500100015002000
scale
affected#

5. Remaining Challenges for SVs calling
1. Accuracy of the calls
1. False positives
2. False negatives
2. Functional interpretation?
1. Population frequencies/ Curation
Illumina data
PacBio data
ONT data

6. Remaining Challenges for SVs calling
1. Accuracy of the calls
1. False positives
2. False negatives
2. Functional interpretation?
1. Population frequencies/ Curation
Illumina
PacBio
Nanopore

7. How to call SV in routine scans?
SV genotyping
• Advantages
• Low/no false positives
• False negatives ??
• Focus on variants that are know to have an impact.
• Disadvantages
• We cannot find novel SVs
Varuna Chander

8. Approaches
• DELLY: SV caller that also supports genotyping
• STIX: SV genotyper
• SVTyper: SV genotyper
• SV2: SV genotyper

9. Simulated data
1. We simulated SVs of different
types and sizes
2. Called SVs with Delly, Manta
and Lumpy
3. Merged calls with SURVIVOR
4. Used the merges as input to
the SV genotyper
5. Evaluated their results for SV
that they support.

10. Giab v0.5.0 deletions
• Most of the genotyper only
handle the DEL
• Constrain on the input
format/field
• Lack of sensitivity

11. Paragraph
• Graph based SV genotyper
• GiaB all types:
• Sensitivity: 82%
• Precision: 99%
• GT concordance: 80%
• Available:
github.com/Illumina/paragraph
P Krusche et al (in preparation)

12. Remaining Challenges for SVs calling
1. Accuracy of the calls
1. False positives
2. False negatives
2. Functional interpretation?
1. Population frequencies/ Curation

13. STIX: Population frequency
• Online framework to annotate
your SVs with allele
frequencies.
• ~0.1 sec / SV
• Storing informative reads
• (0.18% of BAM)
• Currently ~9000 samples
• Multiple ethnicities
Layer et al. (in preparation)

14. Acknowledgments
Varuna Chander
William Salerno
Richard Gibbs
Peter Krusche
Sai Chen,
Mike Eberle
Ryan Layer