Digital Analysis of Single-cell Genomes
Cheng-Zhong Zhang, Ph.D.
Monday, November 16, 2015
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Chapters
Introduction
Disclosure
Outline
Analysis of single-cell DNA amplification
Different amplification methods
Single-cell genome amplification
Analytical challenges
Analysis of coverage variation
Dominant bias at the amplicon level
Amplification non-uniformity
Sequencing depth and coverage
Depth and coverage
Graph
Predicting the depth-of-coverage
So far we are thinking of the haploid genome
Differential allelic bias
Allelic coverage and heterozygosity
Loss-of-heterozygosity detection
Detecting deletion by LOH
Haplotype-resolved single-cell analysis
Summary on single-cell sequencing analysis
Analysis of de novo mutations at the single-cell level
Mitotic aberrations
Micronucleation and DNA damage
Look into single-cell DNA damage by Sequencing
Single-cell sequencing metrics
Control daughters with no missegregation
Copy-number asymmetry due to missegregation
Chromosome missegregation creates copy- number asymmetry between sister cells
Haplotype copy number analysis
Haplotype copy number confirms 3:2 segregations
De novo chromosomal rearrangements are only concentrated on the missegregated chromosome
Association with the missegregated haplotype
A tale of two chromosomes
Binary distribution of a single chromatid
Summary of results
Summary
Profiling of heterogeneous tumors
Bulk and single-cell sequencing
Example: CLL-CW014
List of somatic alterations in CW014
Genotype sub-clonal mutations individually
Coverage and error rate at homozygous sites
Allelic amplification bias at heterozygous sites
Detection of allelic imbalance/loss-of-heterozygosity
Jointly probing LOH and SNVs by PCR
CW014: four different subclonal populations
CW011: two subclones of independent TP53 inactivations
CW236: subclonal evolution after clonal TP53 mutation
Conclusions
Acknowledgments
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