human genetics to genomics: technology and innovation · human genetics to genomics: technology and...
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Human Genetics to Genomics:
Technology and Innovation
Megan Bowman, PhD
Bioinformatics and Biostatistics Core Manager
Van Andel Research Institute
@megbowman
megbowman
@varibbc
VAIBBC
Genetics vs. Genomics
Genetics is the study of heredity, or
how the characteristics of living
organisms are transmitted from one
generation to the next via DNA, the
substance that comprises genes, the
basic unit of heredity.
Genomics is the study of the entirety of an
organism’s genes – called the genome.
Using high-performance computing and
math techniques known as bioinformatics,
genomics researchers analyze enormous
amounts of DNA-sequence data to find
variations that affect health, disease or drug
response. In humans that means searching
through about 3 billion units of DNA across
23,000 genes.
(Jackson Laboratory) https://openi.nlm.nih.gov/detailedresult.php?img=PMC3663084_gb-
2013-14-4-111-1&req=4
Genetics vs. Genomics
http://pediaa.com/difference-between-gene-and-genome/
How do we study the genome?
Genomics comprises of two fundamental steps– generating the data
and analyzing it
How do we generate genomic data?
Microarrays and Next Generation Sequencing
https://www.eurofinsgenomics.eu/en/genotyping-gene-
expression/service-platforms/illumina-array-
platforms.aspx
https://www.illumina.com/content/dam/illumina-
marketing/documents/products/datasheets/novaseq-
6000-system-specification-sheet-770-2016-025.pdf
How do we study the genome?
Microarray
Solid surface (glass or silicon) where DNA is affixed in a grid fashion – “probes”
Extract RNA or DNA
https://www.nature.com/scitable/definition/microarray-202
Hybridize to allow DNA to bind
to probes
How do we study the genome?
High Throughput Sequencing
http://www.gendx.com/illumina-clonal-amplifiction
Short Read (50-150bp) Long Read (3rd Generation
Sequencing
https://commons.wikimedia.org/wiki/File:3rd_gen_Epigenetics.png
Advantages over microarrays
Unbiased detection
Broader dynamic rangeIncreased specificity and sensitivity
Portable Genomics
Oxford Nanopore MinION
Real-time, portable genome sequencing for
Ebola surveillance (Quick et al., Nature 2016
Genomics @VAI
Marie Adams, MS
VARI Genomics Core Manager
Illumina NextSeq 500 10X Genomics
Sequencing at VARI:
Whole genome and exome sequencing
RNA sequencing
ChIP sequencing
Single cell sequencing
Epigenetics related sequencing
Illumina iScan
https://genomicscore.vai.org/services/
Bioinformatics
So you have all these data….whats next?
Bioinformatics is the science of storing,
retrieving and analyzing large amounts
of biological information
http://nauacmrocks.azurewebsites.net/bio_lab.html
https://homepages.warwick.ac.uk/staff/D.Hebenstreit/
Bioinformatics and Biostatistics
@ VAI
Megan Bowman, PhD
BBC Core Manager
Ben Johnson, PhD
Bioinformatics Research
Scientist
Zach Madaj, MS
Biostatistician II
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BAX Tot
Cell Cycle/Apoptosis
BAK Tot
BCLXL Tot
MSK1 S360
ERK1/2
MAPK/ERK
p38MAPK T180/Y182 MEK1/2
Y527
PI3K/AKT
RTK
JAK/STAT
AXL Y702
Stimulates
Inhibits
MTOR
T70 T412T37/T46
Y279/216 T308
MDM2 S166
S155
p53 S15
Cyclin
Caspase
T359/S363
S380
PRAS40 T246
SRC Y416
IRS1 S612
Y1175
Protein Family
Protein Complex
AMPKb1 S108
AMPKa1 S485
T172
S240/244
mTOR S2448
4EBP1 S65
T389
GSK3aB S21/9 FOXO1/03aFOXO1 S256AKT S473
T56
S136
Casp 7 D198
Casp 6 D162Cyclin B1
Casp 3 D175Cyclin A
p90RSK S380
BRAF S445ARAF S299
CRAF S338 RAF S259
PTEN Tot
PI3K p85/p55
Y1289
MET Y1234/1235
Y877
STAT1 Y701
JAK2 Y1007JAK1 Y1022/23
Y705
IGF1R Y1135/36/50/51
Y996
AMPK Tot
S6RP S235/236
Y992
PDGFRa Y754
Y751
p70S6k S371
BAD S112
BCL S70
Y1197Y1248
STAT3 S727
VEGFR2 Y951
Y1173
PDGFRb Y716 ERBB3 TotERBB2 Tot
Y1148Y1068
EGFR Tot
Bioinformatics and Biostatistics Skill Set: Understanding of basic principles
of biology, mathematics, programming (R, Python, Perl, C++), Linux/Unix
Genomics Research in West
Michigan
Genomics has fundamentally changed how biomedical research is done and
has opened new avenues for patients
West Michigan has extraordinary ongoing research in genomics and
bioinformatics
Genomics Research
Patrick Grohar, MD., Ph.D
Translational Sarcoma
Therapeutics
Lurbinectedin Inactivates the Ewing Sarcoma Oncoprotein EWS-FLI1 by
Redistributing It within the Nucleus (Harlow et al., Cancer Research, 2016)
Examples
Genomic MET amplification occurs early in NF1-related malignant peripheral nerve
sheath tumor (MPNST) progression and is a potent therapeutic target (Biorxiv, 2017)
Matt Steensma, M.D
Musculoskeletal Oncology
Stand Up To Cancer
Peter Jones, Ph.D., D.Sc.
VARI Chief Scientific Officer
Epigenetic Therapies
Stephen Baylin, M.D.
VARI-SU2C Epigenetics
Dream Team
Six ongoing multi-institutional early phase trials involving epigenetics agents used in
combination in hematologic and solid tumor malignancies with robust correlative
research efforts
Genomics in the Clinic
Illumina MiSeqDx Cystic Fibrosis Clinical
Sequencing Assay
Illumina MiSeqDx Cystic Fibrosis
139-Variant Assay
Genomics in the Clinic
Clinical Applications of Next Generation
Sequencing
Whole Exome Sequencing = Analyzing the coding regions
of thousands of genes in a sample
Whole Genome Sequencing = Analyzing the entire genome
sequence
Clinical Genomics – Personal
Genomes
$1000 Genome - Illumina HiSeq X Ten Platform
Broad Institute (MA)
Baylor College of Medicine (TX)
HudsonAlpha (MS)
McDonnell Genome Institute (MO)
https://www.genome.gov/27541954/dna-sequencing-costs-data/
Personal Genomics
Broad Institute Clinical Research Sequencing Platform
https://www.broadinstitute.org/rare-disease
ExAC
http://exac.broadinstitute.org/
gnomAD
http://gnomad.broadinstitute.org/
Rare Variant Research @ VAI
Matt Steensma, M.D
Musculoskeletal Oncology
Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations
(Peacock et al., AJMG, 2015)
Changing the Genome-Gene
Editing
http://rna.berkeley.edu/crispr.html
CRISPR = Clustered Regularly Interspaced
Short Palindromic Repeats
Changing the Genome-Gene
Editing
Wang and Qi, Trends in Cell Biology 2016
Changing the Genome-Gene
Editing
• Accelerating Basic Research Science
• Generate cell lines and animals with specific mutations
• Model disease
• Remove defective genes
• Gene therapy
• Agriculture
• Non-transgenic crop improvement
• Genome editing in plant and animals
• Synthetic biology
• Non-transgenic crop improvement
• Genome editing in plant and animals
• Implications in human disease
• Two papers have been published modifying human embryos
https://www.slideshare.net/EkHanTanPhD/genome-editing-crisprcas9
http://rna.berkeley.edu/crispr.html
Thank you!
Contact the VARI Bioinformatics
and Biostatistics Team:
https://medium.com/towards-data-science/what-is-bioinformatics-703170763999