Genomics in Medicine
-
Upload
dan-gaston -
Category
Education
-
view
123 -
download
2
Transcript of Genomics in Medicine
![Page 1: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/1.jpg)
GENOMICS IN
MEDICINEThe Future of Healthcare
![Page 2: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/2.jpg)
Goal of Genomic Medicine
Identify genetic variation that causes or contributes to
disease (diagnostic), informs treatment options or patient
care (therapeutic/prognostic), or provides other useful
clinical information
![Page 3: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/3.jpg)
Research Drives Innovation in Healthcare
Healthcare
Research
Innovation
![Page 4: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/4.jpg)
Human Genome Project 1st Draft
![Page 5: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/5.jpg)
Personalized Medicine: Expectations and Reality
![Page 6: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/6.jpg)
Primary Clinical Applications
• Severe childhood genetic disorders
• Clinical Exome or Targeted Disease Panel
• Cheaper than 4 or 5 sequential gene tests
• Cystic Fibrosis Testing
• Oncology
• Classification
• Treatment Guidance
• Infectious disease
• Epidemiology/Outbreak monitoring
• Strain discrimination
![Page 7: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/7.jpg)
What Drives Genomic Innovation in Medicine?
Cost
Knowledge Utility
![Page 8: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/8.jpg)
![Page 9: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/9.jpg)
![Page 10: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/10.jpg)
![Page 11: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/11.jpg)
The Players
![Page 12: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/12.jpg)
![Page 13: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/13.jpg)
![Page 14: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/14.jpg)
Total Cost of Sequencing
• Whole Genome:
• Approximately $5000 - $10,000
• Technically $1000 Genome is “here” with Illumina 10X
![Page 15: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/15.jpg)
Total Cost of Sequencing
• Whole Genome:
• Approximately $5000 - $10,000
• Technically $1000 Genome is “here” with Illumina 10X
• Analysis cost >> Sequencing Cost
![Page 16: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/16.jpg)
Total Cost of Sequencing
• Whole Genome:
• Approximately $5000 - $10,000
• Technically $1000 Genome is “here” with Illumina 10X
• Analysis cost >> Sequencing Cost
• But, do we need the whole genome?
![Page 17: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/17.jpg)
Composition of the Human Genome
![Page 18: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/18.jpg)
Exome Sequencing
![Page 19: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/19.jpg)
Targeted Sequencing Panels
![Page 20: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/20.jpg)
What Drives Genomic Innovation in Medicine?
Cost
Knowledge Utility
![Page 21: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/21.jpg)
Bioinformatics Roles
• Support/Maintain Computational Infrastructure
•Raw data -> Genome/Exome
• Identify genetic variation
•Annotate genetic variation
•Quality Control
•Report to Stake Holders (Clinicians, Fellow
Scientists)
![Page 22: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/22.jpg)
Typical Bioinformatics Workflow
QC of Raw Data
Map to Reference
QC
Find Variants
QC
Annotate
Filter
![Page 23: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/23.jpg)
It Sounds simple but…
• For every stage there are multiple programs available and
published in the literature
![Page 24: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/24.jpg)
It Sounds simple but…
• For every stage there are multiple programs available and
published in the literature
• For every program there are a wide-variety of parameter
values and options. Defaults often “good enough” but
not always
![Page 25: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/25.jpg)
It Sounds simple but…
• For every stage there are multiple programs available and
published in the literature
• For every program there are a wide-variety of parameter
values and options. Defaults often “good enough” but
not always
• Best combinations of programs and options not well
understood
![Page 26: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/26.jpg)
It Sounds simple but…
• For every stage there are multiple programs available and
published in the literature
• For every program there are a wide-variety of parameter
values and options. Defaults often “good enough” but
not always
• Best combinations of programs and options not well
understood
• Protocols changing rapidly as new technologies and
methods developed
![Page 27: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/27.jpg)
Clinical Bioinformatics
Validate, validate, validate!
![Page 28: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/28.jpg)
Typical Bioinformatics Workflow
QC of Raw Data
Map to Reference
QC
Find Variants
QC
Annotate
Filter
![Page 29: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/29.jpg)
Clinical Genomics: Identify Clinically Relevant
Genetic Variation
![Page 30: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/30.jpg)
Discovering Disease-Causing Genetic Variants
4 million genetic variants
2 million associated with protein-coding genes
10,000 possibly of disease
causing type
1500 <1% frequency in population
Clinically
Relevant Genetic
Variants
![Page 31: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/31.jpg)
If a problem cannot be
solved, enlarge it.
--Dwight D. Eisenhower
Supreme Commander Allied Forces:
Second World War
34th President of the USA
4 million genetic variants
2 million associated with protein-coding genes
10,000 possibly of disease
causing type
1500 <1% frequency in population
![Page 32: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/32.jpg)
Knowledge Required
Variant
Gene
Population
Frequency
Pathways
Functions
Tissues
Variant
Type
Impact on
Protein
![Page 33: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/33.jpg)
Populations are Important
![Page 34: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/34.jpg)
2001 – Present: 14 years of Knowledge Building
Exome Variant Server
Exome Aggregation Consortium
![Page 35: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/35.jpg)
2001 – Present: 14 years of Knowledge Building
![Page 36: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/36.jpg)
2001 – Present: 14 years of Knowledge Building
![Page 37: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/37.jpg)
Building Knowledge Take-Away
•Clinical utility relies on:
• Knowledge of background variation from well
sampled populations
• Knowledge of function of as much genomic
sequence as possible
• Well defined workflows
• Knowledge of sources of error
![Page 38: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/38.jpg)
Variant Annotation Pipeline Example
![Page 39: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/39.jpg)
Variant Annotation Pipeline Example
![Page 40: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/40.jpg)
Genetic Variant Reporting
![Page 41: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/41.jpg)
Genetic Variant Reporting
![Page 42: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/42.jpg)
Genetic Variation Reporting
![Page 43: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/43.jpg)
Genetic Variation Reporting
![Page 44: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/44.jpg)
Genetic Variation Reporting
![Page 45: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/45.jpg)
Potential Pitfalls with Annotation Sources
• Databases often overlap and agree, but there may be
disagreements
• Source of information: Predicted versus experimental
• Incorrect and out-of-date information
• Large-scale un-validated versus manually curated datasets
![Page 46: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/46.jpg)
What Drives Genomic Innovation in Medicine?
Cost
Knowledge Utility
![Page 47: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/47.jpg)
Genomic Medicine: In the Clinic
• Rapid diagnosis of genetic disease in NICU cases
• Quicker and cheaper than sequential genetic testing (traditional
method)
• 50 hour diagnosis
![Page 48: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/48.jpg)
Genomic Medicine: In the Clinic
![Page 49: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/49.jpg)
Genomic Medicine: In the Clinic
![Page 50: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/50.jpg)
Genomic Medicine: In the Clinic
![Page 51: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/51.jpg)
Genomic Medicine: In the Clinic
![Page 52: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/52.jpg)
Genomic Medicine: In the Clinic
![Page 53: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/53.jpg)
Types of Next-Generation Sequencing
Experiments
•DNA-Seq
•RNA-Seq
•Methyl-Seq
•ChIP-Seq
•CLIP-Seq
![Page 54: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/54.jpg)
The Missing Pieces?
![Page 55: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/55.jpg)
The Missing Pieces?
![Page 56: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/56.jpg)
The Missing Pieces?
![Page 57: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/57.jpg)
The Missing Pieces?
![Page 58: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/58.jpg)
The Missing Pieces?
![Page 59: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/59.jpg)
The Missing Pieces?
![Page 60: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/60.jpg)
The Missing Pieces?
![Page 61: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/61.jpg)
The Missing Pieces?
Exon 1 Intron 1 Exon 2Reference
Patient
StartTAA
StopmRNA coding for protein
Exon 1 Intron 1 Exon 2
TAC
TyrSplice Site Loss
Missense/Frameshift Stop Gain
![Page 62: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/62.jpg)
Where Are We Going?
![Page 63: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/63.jpg)
Where Are We Going?
Do whole genome anyway, use bioinformatics to filter
down to reportable/actionable information
4 million genetic variants
2 million associated with protein-coding genes
10,000 possibly of disease
causing type
1500 <1% frequency in population
Clinically
Relevant Genetic
Variants
![Page 64: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/64.jpg)
Where Are We Going?
![Page 65: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/65.jpg)
Direct-to-Consumer
![Page 66: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/66.jpg)
New Technologies: Oxford Nanopore
![Page 67: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/67.jpg)
![Page 68: Genomics in Medicine](https://reader030.fdocuments.in/reader030/viewer/2022032616/55a5e35f1a28ab28368b46af/html5/thumbnails/68.jpg)
Summary of Key Points
• Clinical application possible when cost and applicable
knowledge reach critical point
• Personalized genomic medicine is here already
• The genome alone isn’t enough
• Large population surveys of healthy individuals
• Sample from diverse human populations globally
• Large-scale surveys of genes, genetic elements, and their
functions
• Data, data, and more data required