“Measuring the Human Brain-Gut Microbiome- Immune System Dynamics: a Big Data Challenge” Plenary Talk 45 th Annual Meeting of the Behavior Genetics Association San Diego, CA June 18, 2015 Dr. Larry Smarr Director, California Institute for Telecommunications and Information Technology Harry E. Gruber Professor, Dept. of Computer Science and Engineering Jacobs School of Engineering, UCSD http://lsmarr.calit2.net 1
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“Measuring the Human Brain-Gut Microbiome-Immune System Dynamics: a Big Data Challenge” Plenary Talk 45 th Annual Meeting of the Behavior Genetics Association.
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“Measuring the Human Brain-Gut Microbiome-Immune System Dynamics: a Big Data Challenge”
Plenary Talk
45th Annual Meeting of the Behavior Genetics Association
San Diego, CA
June 18, 2015
Dr. Larry Smarr
Director, California Institute for Telecommunications and Information Technology
Harry E. Gruber Professor,
Dept. of Computer Science and Engineering
Jacobs School of Engineering, UCSD
http://lsmarr.calit2.net1
June 8, 2012 June 14, 2012
Interest in the Human MicrobiomeHas Moved Quickly From Frontier Science to Public Awareness
August 18, 2012June, 2012
To Understand the Interaction of Genetics and Human BehaviorWe Must Consider the Human Microbiome
Your Microbiome is Your “Near-Body” Environment
and its CellsContain 300x
as Many DNA GenesAs Your Human Cells
Your Body Has 10 Times As Many Microbe Cells As Human Cells
The Microbiome–Gut–Brain AxisProvides New Systemic Insights into Shifts in Behavior and Disease
Source: Montiel-Castro, et al. Frontiers in Integrative Neuroscience 2013
Many New Research Studies are Demonstrating Deep Relationships Between the Gut Microbiome and Behavioral Disorders
Gut Microbes Regulate Serotonin Production,90% of Which is in the Large Intestine
“It's almost unthinkable that the gut is not playing a critical role in mind states,"
says gastroenterologist Emeran Mayer, MD, director of the Center for Neurobiology of Stress at UCLA
Cell 161 264-276 (2015)
How Can One Combine Human Genetic GWASWith Gut Microbiome Metagenomics and Immune System Dynamics?
An N=1 Case Study of an Autoimmune Disease
I Have Turned My Body into a Genomic and Biomarker Observatory
One Blood DrawFor MeCalit2 64 Megapixel VROOM
Only One of My Blood Measurements Was Far Out of Range--Indicating Chronic Inflammation
Normal Range <1 mg/L
27x Upper Limit
Complex Reactive Protein (CRP) is a Blood Biomarker for Detecting Presence of Inflammation
Episodic Peaks in Inflammation Followed by Spontaneous Drops
Adding Stool Tests RevealedOscillatory Behavior in an Immune Variable Which is Antibacterial
Normal Range<7.3 µg/mL
124x Upper Limit for Healthy
Lactoferrin is a Protein Shed from Neutrophils -An Antibacterial that Sequesters Iron
TypicalLactoferrin Value for Active Inflammatory
Bowel Disease (IBD)
I Turned to SNP Analysis and GWAS to Understand My Human Genomic Predispositions
I Found I Had One of the Earliest Known SNPsAssociated with Crohn’s Disease
From www.23andme.com
SNPs Associated with CD
Polymorphism in Interleukin-23 Receptor Gene
— 80% Higher Risk of Pro-inflammatoryImmune Response
rs1004819
NOD2
IRGM
ATG16L1
There May Be a Correlation Between CD SNPsand Where and When the Disease Manifests
Me-MaleCD Onset
At 60-Years Old
Female CD Onset
At 20-Years Old
NOD2 (1)Rs2066844
2.08x Increased Risk
Il-23RRs1004819
1.8x Increased Risk
Subject withIleal Crohn’s
Subject withColonic Crohn’s
Source: Larry Smarr and 23andme
I Also Had an Increased Risk for Ulcerative Colitis,But a SNP that is Also Associated with Colonic CD
I Have a 33% Increased Risk for Ulcerative Colitis
HLA-DRA (rs2395185)
I Have the Same Level of HLA-DRA Increased Risk
as Another Male Who Has HadUlcerative Colitis for 20 Years
“Our results suggest that at least for the SNPs investigated [including HLA-DRA],
colonic CD and UC have common genetic basis.”-Waterman, et al., IBD 17, 1936-42 (2011)
So IBD May be Stratified by a Personalized Combinationof the 163 Known SNP Loci Associated with IBD
The width of the bar is proportional to the variance explained by that locus
“Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease,” Jostins, et al. Nature 491, 119-124 (2012)
Could Changes in the Microbiome Ecology and Genetic StructureProvide Some of the Missing Variance?
However, the Total Disease Variance Explained Is Only:• 13.6% for Crohn’s• 7.5% for Ulcerative Colitis
Why Did I Have an Autoimmune Disease like IBD?
Despite decades of research, the etiology of Crohn's disease
remains unknown. Its pathogenesis may involve a complex interplay between
host genetics, immune dysfunction,
and microbial or environmental factors.--The Role of Microbes in Crohn's Disease
Paul B. Eckburg & David A. RelmanClin Infect Dis. 44:256-262 (2007)
I Have Been Quantifying All Three
The Genetic Distance Between MicrobesVastly Exceeds That Among All Animals and Plants
You Are
Here
Source: Carl Woese, et al
Tree of Life Derived from 16S rRNA Sequences
For Deep Analysis of Changes in the Gut Microbiome EcologyOur Team Compared a Healthy Population with 3 Types of IBD
5 Ileal Crohn’s Patients, 3 Points in Time
2 Ulcerative Colitis Patients, 6 Points in Time
“Healthy” Individuals
Source: Jerry Sheehan, Calit2Weizhong Li, Sitao Wu, CRBS, UCSD
Total of 27 Billion ReadsOr 2.7 Trillion Bases
Inflammatory Bowel Disease (IBD) Patients
250 Subjects1 Point in Time
7 Points in Time
Each Sample Has 100-200 Million Illumina Short Reads (100 bases)
Larry Smarr(Colonic Crohn’s)
From Swedish Twin Study
To Map Out the Dynamics of Autoimmune Microbiome Ecology Couples Next Generation Genome Sequencers to Big Data Supercomputers
Illumina HiSeq 2000 at JCVI
SDSC Gordon Data Supercomputer
Example: Inflammatory Bowel Disease (IBD)
We used 25 CPU-yearsto compute
comparative gut microbiomesstarting from
7 trillion DNA bases of my samples,
255 healthy, and 20 IBD controls
Computational NextGen Sequencing Pipeline:From Sequence to Taxonomy and Function