Outline Part 1 Introduction to Genomics Part 2 Visual Design for - - PowerPoint PPT Presentation

Visual Analytics for

Genomics

Cydney Nielsen!

BC Cancer Agency! Vancouver, BC, Canada!

Outline

Part 1 Introduction to Genomics Part 2 Visual Design for Genomics Part 3 Hands-On Design Exercise

Part 1

Introduction to Genomics

genome: the complete genetic material of a cell

Genomics Workflow

Part 1. Intro to Genomics

Sequencing Experiment

Part 1. Intro to Genomics

Sequencing Experiment

Part 1. Intro to Genomics

Sequencing Experiment

Part 1. Intro to Genomics

G - C! T - A!

sample data insight

Genomics Workflow

Part 1. Intro to Genomics

sample data insight

experiment

sequencing technology!

Genomics Workflow

Part 1. Intro to Genomics

sample data insight

experiment analysis

visualization! computation!

+

sequencing technology!

Genomics Workflow

Part 1. Intro to Genomics

sample data insight

experiment analysis

visualization! computation!

+

sequencing technology!

Genomics Workflow

Part 1. Intro to Genomics

sample data

experiment

sequencing technology!

Genomics Workflow

molecular biology

Part 1. Intro to Genomics

Genomics Workflow

computational biology / bioinformatics visual analytics

Part 1. Intro to Genomics

data insight

analysis

visualization! computation!

+

sample data

experiment

sequencing technology!

Genomics Workflow

molecular biology

Part 1. Intro to Genomics

Sequencing Experiment

Part 1. Intro to Genomics AAAAAAAAAAAAAAGATGT$ CACCAGTACACCGATA$ ACCAGATGGATTAGATGTA$ TACACCGATACACCAGA$ AAAGATGTATACCACCAG$ Sequencing machine! Millions of short sequences (“reads”)! e.g. 75 nt each compared to >3 billion nt in human genome!

Sequencing Experiment

Part 1. Intro to Genomics ~$5,000$ in$2001$ ~10¢$ in$2011$

Genomics Workflow

computational biology / bioinformatics visual analytics

Part 1. Intro to Genomics

data insight

analysis

visualization! computation!

+

De novo assembly!

AGCTTCAGATGGACAGATAA$ GGCATACAGACTTAGACATA$ CCAGACAAGACAGACACAGTA$ TACAAGACATAAGCAATACAGA$ CCAGACAAGACAGACACAGTA$

Genome$Assembly$

Sequencing Experiments

Part 1. Intro to Genomics

De novo assembly! Re-sequencing!

AGCTTCAGATGGACAGATAA$ GGCATACAGACTTAGACATA$ CCAGACAAGACAGACACAGTA$ TACAAGACATAAGCAATACAGA$ CCAGACAAGACAGACACAGTA$ AGCTTCAGATGGACAGATAA$ GGCATACAGACTTAGACATA$ CCAGACAAGACAGACACAGTA$ TACAAGACATAAGCAATACAGA$ CCAGACAAGACAGACACAGTA$

Reference$Genome$ Genome$Assembly$

Sequencing Experiments

Part 1. Intro to Genomics

De novo assembly! Re-sequencing! Enrichment!

AGCTTCAGATGGACAGATAA$ GGCATACAGACTTAGACATA$ CCAGACAAGACAGACACAGTA$ TACAAGACATAAGCAATACAGA$ CCAGACAAGACAGACACAGTA$ AGCTTCAGATGGACAGATAA$ GGCATACAGACTTAGACATA$ CCAGACAAGACAGACACAGTA$ TACAAGACATAAGCAATACAGA$ CCAGACAAGACAGACACAGTA$ AGCTTCAGATGGACAGATAA$ GGCATACAGACTTAGACATA$ CCAGACAAGACAGACACAGTA$ TACAAGACATAAGCAATACAGA$ CCAGACAAGACAGACACAGTA$

Reference$Genome$ Reference$Genome$ Genome$Assembly$

Sequencing Experiments

Part 1. Intro to Genomics

Sequencing Experiments

Part 1. Intro to Genomics

• What sequence variations appear in cancer patients,

but not in unaffected individuals?!

• Are these variations predictive of survival outcome?!
• Are these variations causal for the disease (driver

mutations) or not?! !

Part 1 - Summary

Part 1. Intro to Genomics

• 1. Large and ever increasing volume of sequencing

data!

• 2. Improved analysis techniques are essential for

biologists and clinicians to make the most of these data!

• 3. Great potential for visual analytics to facilitate

insight and understanding! !

Part 2

Visual Design for Genomics

Large number of samples for comparison! Challenge 1

Part 2. Visual Design for Genomics

Large number of samples for comparison!

“To systematically characterize the genomic changes in hundreds of tumors… and thousands of samples over the next five years”! ! The Cancer Genome Atlas! www.cancergenome.nih.gov!

Challenge 1

Part 2. Visual Design for Genomics

Stacked data tracks along a common genome x-axis!

Genome coordinate! Data samples!

Genome Browsers

Home Genomes Blat Tables Gene Sorter PCR PDF/PS Session FAQ Help

UCSC Cancer Genomics Heatmaps

Glioblastoma Copy Number Abnormality, Agilent 244A array (n=200)

Tumor vs normal G e n d e r

Genome coordinate! Data samples! Zhu et al., Nature Methods, 2009!

Genome Browsers

Part 2. Visual Design for Genomics

Large number of samples for comparison! ! ! ! Challenge 1

Critically consider what you need to display!

!

e.g. replace primary data with a biologically meaningful summary, such as significant changes between samples !

Part 2. Visual Design for Genomics

Genomic features are small and sparse! Challenge 2

Part 2. Visual Design for Genomics

LOCAL VIEW!

Genome Browsers

Part 2. Visual Design for Genomics

LOCAL VIEW!

Human chr1, 1 pt corresponds to 480 kb, which is larger than 98% of all human genes! !

Genome Browsers

Part 2. Visual Design for Genomics

a b

Chromatin states: Chromosome 3L 5′ 3′ 5′ 3′ 5′ 3′ 5′ 3′

Pericentromeric heterochromatin Cluster of small expressed genes PcG domains Heterochromatin- like domain Open chromatin domain

9 8 7 6 5 4 3 2 1

GLOBAL VIEW!

Kharchenko et al., Nature, 2011! Anders, Bioinformatics, 2009!

Hilbert Curve

Part 2. Visual Design for Genomics

Connect overview and detail!

Challenge 2 Genomic features are small and sparse!

Part 2. Visual Design for Genomics

Genomic features involve non-adjacent positions! Challenge 3

Part 2. Visual Design for Genomics

Challenge 3

• Kʹ

J J Jʹ Jʹ K Kʹ K Jʹ J Kʹ K’ K J Kʹ Jʹ K Reference Variant

c e a b d

J K Jʹ Kʹ

Structural rearrangements!

Part 2. Visual Design for Genomics

Challenge 3

• Kʹ

J J Jʹ Jʹ K Kʹ K Jʹ J Kʹ K’ K J Kʹ Jʹ K Reference Variant

c e a b d

J K Jʹ Kʹ

Structural rearrangements!

Part 2. Visual Design for Genomics

Challenge 3 Structural rearrangements!

Circos, Martin Krzywinski! Part 2. Visual Design for Genomics

Challenge 3

• Kʹ

J J Jʹ Jʹ K Kʹ K Jʹ J Kʹ K’ K J Kʹ Jʹ K Reference Variant

c e a b d

J K Jʹ Kʹ

Structural rearrangements!

Part 2. Visual Design for Genomics

Challenge 3 Structural rearrangements!

VISTA-Dot! Part 2. Visual Design for Genomics

Challenge 3

All these representations use a genomic coordinate system, which emphasizes base-pair distance between points. ! ! Is this the best use of positional information?!

Part 2. Visual Design for Genomics

• M. Krzywinski adapted from Mackinlay J (1986) ACM Trans Graph 5: 110-141.!

Challenge 3

Part 2. Visual Design for Genomics

Challenge 3

• Kʹ

J J Jʹ Jʹ K Kʹ K Jʹ J Kʹ K’ K J Kʹ Jʹ K Reference Variant

c e a b d

J K Jʹ Kʹ

Structural rearrangements!

Part 2. Visual Design for Genomics

Genomic features involve non-adjacent positions! Challenge 3

Encode important information in position!

Part 2. Visual Design for Genomics

Challenge 4 Large number of data types!

Part 2. Visual Design for Genomics

Genomic location (Mb) 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 2 4 1 Copy number Allelic ratio 100 Non-inverted

• rientation

Inverted

• rientation

Deletion-type Tandem dup-type Head-to-head inverted Tail-to-tail inverted

SNU-C1 (colorectal): Chr 15

A

Stephens et al., Cell, 2011!

Genomic rearrangement in cancer

Part 2. Visual Design for Genomics

CAST/EiJ WSB/EiJ PWK/PhJ

b a

SPRET/EiJ 1 2 9 P 2 / O l a H s d 1 2 9 S 1 / S v I m J 1 2 9 S 5 / S v E v

A / J A K R / J B A L B / c J C 3 H / H e J C 5 7 B L / 6 N J C B A / J D B A / 2 J L P / J N O D / S h i L t J N Z O / H I L t J

17 mouse genomes

Part 2. Visual Design for Genomics Keane et al., Nature, 2011!

Challenge 4 Large number of data types!

Exploit domain-specific details in your design!

Part 2. Visual Design for Genomics

Challenge 5 No longer one genome but many!

Part 2. Visual Design for Genomics

Challenge 5 No longer one genome but many!

Part 2. Visual Design for Genomics

Ossowski et al. Genome Research, 2008!

Single nucleotide variation

Part 2. Visual Design for Genomics

Integrative Genomics Viewer (IGV)!

Robinson et al. Nature Biotechnology, 2011!

Single nucleotide variation

Part 2. Visual Design for Genomics

Challenge 5 No longer one genome but many!

Be open to change (genomics is evolving quickly)!

Part 2. Visual Design for Genomics

• 1. Cri<cally$consider$what$you$need$to$display$
• 2. Connect$overview$and$detail$
• 3. Encode$important$informa<on$in$posi<on$
• 4. Exploit$domainIspecific$details$in$your$design$
• 5. Be$open$to$change$(genomics$is$evolving$quickly)$

Part 2 - Summary

Part 2. Visual Design for Genomics

Part 3

Hands-On Design Exercise

Genome Assembly

Part 3. Hands-On Design Exercise AAAAAAAAAAAAAAGATGT$ CACCAGTACACCGATA$ ACCAGATGGATTAGATGTA$ TACACCGATACACCAGA$ AAAGATGTATACCACCAG$

Input!

Genome Assembly

Part 3. Hands-On Design Exercise AAAAAAAAAAAAAAGATGT$ CACCAGTACACCGATA$ ACCAGATGGATTAGATGTA$ TACACCGATACACCAGA$ AAAGATGTATACCACCAG$ AAAAAAAAAAAAAAGATGT$ AAAGATGTATACCACCAG$ CACCAGTACACCGATA$ TACACCGATACACCAGA$ ACCAGATGGATTAGATGTA$

Input! Aligned!

Genome Assembly

Part 3. Hands-On Design Exercise AAAAAAAAAAAAAAGATGT$ CACCAGTACACCGATA$ ACCAGATGGATTAGATGTA$ TACACCGATACACCAGA$ AAAGATGTATACCACCAG$ AAAAAAAAAAAAAAGATGTATACCACCAGTACACCGATACACCAGATGGATTAGATGTA$ AAAAAAAAAAAAAAGATGT$ AAAGATGTATACCACCAG$ CACCAGTACACCGATA$ TACACCGATACACCAGA$ ACCAGATGGATTAGATGTA$

Input! Aligned! Consensus!

Sequence Alignment Rules

Part 3. Hands-On Design Exercise

1.$Maximize$sequence$overlap:$ $ This$overlap$is$BETTER…& $

AAAAAAAAAAAAAAGATGTATACCACCAGTACACCGATACACCAGATG

$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$GATGTATACCACCAGTACACCGATACACCAGATGGATTAGATGTAGGGG $ …than$this$overlap:$ $

AAAAAAAAAAAAAAGTATGTATACCACCAGTACACCGATACACCAGATG

$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$GATGTATACCACCAGTACAC $

Sequence Alignment Rules

Part 3. Hands-On Design Exercise

1.$Maximize$sequence$overlap:$ $ This$overlap$is$BETTER…& $

AAAAAAAAAAAAAAGATGTATACCACCAGTACACCGATACACCAGATG

$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$GATGTATACCACCAGTACACCGATACACCAGATGGATTAGATGTAGGGG $ …than$this$overlap:$ $

AAAAAAAAAAAAAAGTATGTATACCACCAGTACACCGATACACCAGATG

$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$GATGTATACCACCAGTACAC $ 2.$Align$leUers$rightIsideIup,$reading$leV$to$right$(just$like$wriUen$English):$ $ NOT$a$valid&overlap $: $ $ $ $ $ $Valid$overlap:$

$

CACCAGTACATTTTTAAAGGG CACCAGTACATTTTTAAAGGG

Sequence Alignment Rules

Part 3. Hands-On Design Exercise

GTACACCGGGAAATTTTTA ATTTTTAAAGGGCCACATG

Sequence Alignments

Part 3. Hands-On Design Exercise AGCAGATC…AAAAAAAA AAAAAAAA…TACTTACA …TACTTACA…GGGGGGGG GGGGGGGG…GGGGGGGG GGGGGGGG…GACAGATA AAAAAAAA…AAAAAAAA

Yellow set!

Sequence Alignments

Part 3. Hands-On Design Exercise GATAGA…AAAAAA AAAAAA…CAGATG …CAGATG…GGGGGG GGGGGG…GGGGGG GGGGGG…ATAGAC

Blue set!

…ATAGAC…AAAAAA AAAAAA…GGACAT AAAAAA…AAAAAA

Sequence Alignments

Part 3. Hands-On Design Exercise GATAGA…AAAAAA AAAAAA…CAGATG …CAGATG…GGGGGG GGGGGG…ATAGAC

Both sets together (pretend you don’t know colour)!

…ATAGAC…AAAAAA AAAAAA…GGACAT AGCAGA…AAAAAA AAAAAA…CTTACA …CTTACA…GGGGGG GGGGGG…CAGATA Ambiguous –! could belong to multiple sequences:! AAAAAA…AAAAAA GGGGGG…GGGGGG

Sequence Alignments

Part 3. Hands-On Design Exercise GATAGA…AAAAAA AAAAAA…CAGATG …CAGATG…GGGGGG GGGGGG…ATAGAC …ATAGAC…AAAAAA AAAAAA…GGACAT AGCAGA…AAAAAA AAAAAA…CTTACA …CTTACA…GGGGGG GGGGGG…CAGATA

Choosing a representation

Part 3. Hands-On Design Exercise

Choosing a representation

Part 3. Hands-On Design Exercise

Choosing a representation

Part 3. Hands-On Design Exercise

ABySS-Explorer

Part 3. Hands-On Design Exercise

ABySS-Explorer

(a) (b)

Nielsen et al. 2009! ! ABySS-Explorer: visualizing genome sequence assemblies.! ! IEEE Trans Vis Comput Graph! VisWeek Proceedings! (Best paper award)! !

Part 3. Hands-On Design Exercise

Resources

The&Cartoon&Guide&to&Gene5cs& Larry$Gonick$and$Mark$Wheelis$(1991)$$ The&Processes&of&Life:&An&Introduc5on&to&Molecular&Biology& Lawrence$E.$Hunter$(2009)$ Nature&Methods&special&issue&on&Visualizing&Biological&Data&(2010)& hUp://www.nature.com/nmeth/journal/v7/n3s$ $ Bang&Wong’s&monthly&Points&of&View&column& hUp://bang.clearscience.info$