Siena Borsani - Unisi.it - Università degli Studi di Siena

28 Maggio 2009 - Università degli Studi di Siena
Personal genomics: dream or reality?
Giuseppe Borsani
Universita’ degli Studi di Brescia
Dipartimento di Scienze Biomediche
e Biotecnologie
[email protected]
Year 2001
Stargate
Year 2007
Genomics goes
personal
Get ready…… the voyage is about to begin
Sequence variations between two aploid genomes
∿3.000.000 bp
∿1.000.000 bp
∿10.000.000 bp
Individual genomes vary in several respects. The types of variability in inheritance include:
variations in single nucleotides (SNPs); insertion or deletion of several nucleotides; insertion
or deletion of thousands of nucleotides (structural variation); and duplication or multiplication
of DNA segments more than 1,000 nucleotides long (copy-number variation).
A minimum of 0.5% variation exists between two haploid genomes
“All men are (not)
created equal”
Left: Verne Troyer, American
actor and stunt performer
Right: Yao Ming, professional
basketball player
How to build a
Homo sapiens
How to build a
Homo sapiens
Identical twins
Jim
Jim
- Jim and Jim had each been married twice. Their first wives were named Linda; their second,
Betty.
- Each twin had a son with the same name, but spelled differently: James Alan and James Allan.
- As children, each twin had a dog named Toy.
- Both had taken family vacations independently to the same three-block strip of Florida beach,
called Pas-Grille, without ever meeting. They both arrived in light blue Chevrolets.
- Each had worked part-time in law enforcement as sheriffs.
- Both smoked Salems, and both savored an occasional Miller Lite beer.
- Both bit their fingernails, and since age eighteen both suffered from mixed headache
syndrome, a combined tension and migraine headache.
- Both scattered love notes to their wives around the house.
A Life Decoded: My Genome - My Life
PLoS Biology October 2007 | Volume 5 | Issue 10 | e254
Gene-based variation in Venter’s genome
- 44% of genes (10,208 / 23,224) have at least one
heterozygous variant in the UTR or coding region
T
ATG
Stop
G
PLoS Biology October 2007 | Volume 5 | Issue 10 | e254
Gene-based variation in Venter’s genome
- 4,107 genes have one or more nonsynonymous SNPs
indicating that at least 17% (4,107 / 23,224) of genes
encode differential proteins
Leu
TTA
ATG
Stop
TTC
Phe
PLoS Biology October 2007 | Volume 5 | Issue 10 | e254
Predisposition status for multifactorial diseases
Craig Venter and Alzheimer's disease
e3/e4
- Craig Venter is heterozygous for variants in the APOE gene
(e3/e4)
- Lifetime risk of developing Alzheimer's disease is three times
higher for carriers of one APOE epsilon4 allele
- Approximately 1 in 7 people carry the epsilon4 variant of
APOE
Houston, TX - 31 May 2007,
Richard Gibbs and Jim Watson
12 SNPs correspond to mutations in genes
causing disease or other phenotypes
✝Coverage at these SNP positions is greater than 5. Both would
produce severe phenotypes if they were truly homozygous
* Coverage at these SNP positions is less than 5. However, both
produce benign phenotypes
Usher Syndrome
The entire Watson sequence, with the exception of
the APOE gene, has been released to the public
APOE
?
http://jimwatsonsequence.cshl.edu/
7,648 protein
coding changes
James Watson
3,766 protein
coding changes
Craig Venter
3,882 protein
coding changes
Quicker, smaller, cheaper
NATURE, Vol 452, 17 April 2008
Personal genomics targets
- Many scientists are competing in a challenge issued by the NIH to
produce a sequencing method that costs:
$100,000 less than per genome by 2009
$1,000 or less by 2014
- X-Prize Foundation is offering $10 million - the largest medical
prize in history - for the first private team that can decode 100
human genomes in 10 days
Second
generation
DNA
sequencing
technologies
Roche
ABI
Illumina
The Genome
Sequencer FLX™
Titanium System
SOLiD 3 System
Illumina Genome
Analyzer
~ 400 million highquality reads/run
~ 1,5 gigabases of
data/run
~ 2 gigabases of
data/day
~ 400 bases/read
~ 50 bases/read
~ 75 bases/read
Who’s next?
1
2
3
3
October 2007 - The
sequencing of the first
genome of a Han
Chinese (a researcher)
was finished in by the
Beijing Genomics
Institute (BGI). BGI will
sequence the genomes of
100 Chinese volunteers
for scientific purposes
4
5
March 2008 - Scientists
from Applied Biosystems
have resequenced a
human DNA sample that
was included in the
International HapMap
Project (an anonymous
African male of the
Yoruba people of Ibadan,
Nigeria) for less than
$60,000
May 2008 - Geneticists
of Leiden University
Medical Centre (LUMC)
are the first to determine
the DNA sequence of a
woman (Dr. Marjolein
Kriek, a clinical
geneticist at LUMC). The
DNA sequencing was
done with the Illumina
1G equipment.
Steering Committee
Richard Durbin (co-chair) Sanger Institute
David Altshuler (co-chair) Broad / MGH / Harvard
Goncalo Abecasis University of Michigan
Aravinda Chakravarti Johns Hopkins
Andrew Clark Cornell University
Francis Collins National Human Genome Research Institute
Peter Donnelly Oxford University
Paul Flicek European Bioinformatics Institute
Stacey Gabriel Broad Institute
Richard Gibbs Baylor College of Medicine
Bartha Knoppers University of Montreal
Eric Lander Broad Institute
Elaine Mardis Washington University in St. Louis
Gil McVean Oxford University
Debbie Nickerson University of Washington
Leena Peltonen Sanger Institute
Stephen Sherry National Center for Biotechnology Information
Rick Wilson Washington University in St. Louis
Huanming (Henry) Yang Beijing Genomics Institute
http://www.1000genomes.org/
1000 Genomes Project
1) Sequencing the genomes of two nuclear
families (both parents and an adult child) at deep
coverage (20 passes of each genome)
2) Sequencing the genomes of 180 people at low
coverage (2 passes of each genome)
3) Sequencing the exons of about 1,000 genes in
about 1,000 people
The project will deliver sequence data at an
average rate of about 8.2 billion bases per day,
the equivalent of more than two human genomes
every 24 hours
The Personal Genome Project (PGP) aims to publish the complete genomes
and medical records of 100,000 volunteers, in order to enable research into
personalized medicine. It was initiated by Harvard University's George
Church and announced in January 2006
Data will be freely available over the Internet, so that researchers can test
various hypotheses about the relationships among genotype, environment
and phenotype.
All data will be published along with the volunteer's name. An important
part of the project will be the exploration of the resulting risks to the
participants, such as possible discrimination by insurers and employers if
the genome shows a predisposition for certain diseases
November 2007
PGP-10
The first ten volunteers are referred to as the "PGP-10".
So far, nine volunteers in the PGP-10 have given
permission to release their names:
1. Misha Angrist, Duke Institute for Genome Sciences and Policy
2. Keith Batchelder, Genomic Healthcare Strategies
3. George Church, Harvard
4. Esther Dyson, EDventure Holdings
5. Rosalynn Gill-Garrison, Sciona
6. John Halamka, Harvard Medical School
7. Stan Lapidus, Helicos BioSciences
8. Kirk Maxey, Cayman Chemical
9. James Sherley, Boston stem cell researcher
John D. Halamka, M.D. M.S
Chief Information Officer of the
CareGroup Health System, Chief
Information Officer and Dean for
Technology at Harvard Medical
School, Chairman of the New
England Health Electronic Data
Interchange Network (NEHEN),
CEO of MA-SHARE (the
Regional Health Information
Organization), Chair of the US
Healthcare Information Technology Standards Panel (HITSP),
and a practicing Emergency
Physician.
http://www.personalgenomes.org/public/2.html
Third generation DNA sequencing
technologies: toward the $1000 genome
Complete Genomics will sequence your entire
genome for $5,000 starting in 2009
October 6, 2008
First Human Genome sequence from Complete
Genomics
February 2009 - Scientists at the Company have successfully
sequenced a Caucasian HapMap sample (Coriell catalog #
NA07022; cell line DNA) generating 91x average read coverage
of the genome in a matter of days using Complete Genomics
third-generation genome sequencing technology. Sequencing of
this genome was conducted at the Company’s commercial-scale
genome center.
Complete Genomics’ sequencing system provided unprecedented
throughput. ~ 254 Gigabases (Gb) of mapped bases were
generated, the largest ever for one human genome. The average
run rate was more than 70 billion mapped bases (70 Gb) per run
or 8.8 Gb per machine run per day.
Single-molecule DNA sequencing
4 APRIL 2008 VOL 320
SCIENCE
Per$onal
Genomic$
Con$umer
Genomic$
Genotyping using DNA chips
Genotyping is the process of determining which genetic
variants an individual possesses. Genotyping can be
performed through a variety of different methods, depending
on the variants of interest and resources available. A good
way of looking at hundred thousands SNPs in a single
individual is a technology called a “DNA chip.”
Age-related macular degeneration,
Alcohol Flush Reaction, Alzheimer's
disease, Asthma, Atrial fibrillation, Bitter
Taste Perception, Breast Cancer, Coeliac
Disease, Colorectal Cancer, Crohn's
disease, Exfoliation Glaucoma, Heart
Attack, Hemochromatosis, Lactose
Intolerance, Lung cancer, Male Pattern
Baldness, Multiple sclerosis, Nicotine
Dependence, Obesity, Peripheral Arterial
Disease, Prostate cancer, Psoriasis,
Restless legs, Rheumatoid arthritis, Type
1 Diabetes, Type 2 Diabetes
Order now…
?
Sergey Brin
Anne Wojcicki
Incredible but…
true
When you share chemistry with someone, you significantly increase
your chances of realizing these amazing benefits:
- You'll love their natural body fragrance -they'll smell “sexier” than
other people
- You'll have a more satisfying sex life
- If you’re a woman, you'll have a higher rate of orgasms
- There will be less cheating in your exclusive relationship
- As a couple, you'll be more fertile
- Your children will be healthier
http://www.genebase.com/node/rudolph
KNOME COMMENCES WHOLE-GENOME
SEQUENCING PROCESS FOR FIRST CLIENTS
First individuals in history to have genome sequenced by a
personal genomics firm CAMBRIDGE, Mass.
Jan. 22, 2008 Knome and the Beijing Genomics Institute
(BGI), announced today that they have initiated the process
to sequence the entire genomes of two private individuals.
These clients are expected to be the first individuals in the
world to have their genome sequenced by a personal
genomics firm.
Knome is currently offering a limited number of clients the
opportunity to participate in its 2008 sequencing programs.
Pricing starts at $350,000 and includes both sequencing and
a comprehensive analysis from a team of leading
geneticists, clinicians and bioinformaticians.
For $1 per gene, Knome launches $24,500
exome sequencing service
May 18, 2009 / Personal genomics outfit Knome, which until now
has specialized in offering a whole-genome sequencing service to
wealthy consumers for $99,500 and up, has launched the first $1/
gene comprehensive gene sequencing service. The exome
sequencing service, called KnomeSELECT, will cost $24,500 for
individuals, with a $10,000 discount for couples ($19,500 per
person for couples and families).
Direct-to-consumer (DTC) genetic tests
vs classical genetic testing
- Personal genomics test are offered directly to consumers over
the web and are thereby initiated directly by consumers,
outside of a defined clinical context and often without the
involvement of a healthcare provider.
- Rather than focusing on selected genes or traits, these
genomics services examine and inform customers about huge
amounts of genetic information which might be meaningless in
most part today but in the future could turn out to be
highly informative for a large range of clinical, physical
and behavioral traits.
Genetic Exhibitionism
ACGTACGCATTCAGC
GGATAGAGCATATGC
ATGTCAGGCAGTCAT
CGATATCGATGCATG
CATGACGATCAGACG
TGTATGACCACCGCG
CTGTCTCTTCGTCCT
AATCGATCGACGACA
TCAGTCATGCACGAC
GATACACAGCGTACG
TACGTACTGACGTAC
Shopping in New York
Genetic screening firm Navigenics is
coming to Greene St. 73 for 10 days to
promote their services. For a sample of
saliva (and $2500 + annual fees), they
will provide a personalized risk
assessment for 17 different diseases
bases on your DNA
Curiosity killed the cat…
ACTN3 (Actinin-alpha-3) exon 15 polymorphism
mRNA position: 1747
CGA ⇒ TGA
Protein position: 577
Arg[R] ⇒ STOP[X]
ACTN3 is absent in more than one billion people worldwide!!!
How is ACTN3 gene involved with sporting performance?
BioEssays 26:786–795, 2004
1747 C>T
577X
WT
DdeI recognition
sequence
...CTNAG...
...GANTC...
TGACCGAGAGC
ACTGGCTCTCG
TGACTGAGAGC
ACTGACTCTCG DdeI
DdeI
Homozygote wild type (R,R): 188 and 485 bp products
Homozygote mutant (X,X): 100, 188 and 385 bp products
Heterozygote (R,X):
100, 188, 385 and 485 products
577RR genotype (2 DdeI fragments)
Individuals that do not carry the 577X variant in either copy of the
ACTN3 gene may have a natural predisposition for speed / power
sports such as football, weight lifting and sprint events
???
Final thoughts
Tarot cards for the 21st
century
-  Love & Relationship
- Karmic & Spirit
- Past Life
- Predictions
- Body & Health
-  Business, Career & Success
- Money
Tarot
reader
How to ruin your life for
$1000*
“Last year two online services, deCODEme
and 23andMe, started offering DNA
analysis and calculating your risk of
developing
20
diseases,
including
Alzheimer’s”
“If you find out you’ve an increased risk of diabetes and heart
diseases, the advice you’d be given is exactly the same as if you
didn’t have an increased risk: eat well, exercise, don’t smoke, don’t
get too fat, have a test if you get symptoms”
* Now less than $400
Dr Ann Robinson
Your long-lost twin…
"Having one's genome
decoded is like finding
out that you have an
identical twin who was
reared somewhere else”
"It lets you see the
possibilities your genes
provided you with, the
selves you might have
become, but didn't”
Dan Jones, NewScientist, 19 August 2006
Do we really
want to know
the sequence of
our genome….?
Personal
Genome
Two Lovers
The story revolves
around Joaquin Phoenix
who becomes suicidal after
breaking up with his
girlfriend after finding out
they were both carriers of
Tay Sachs disease
Prisoners of our own DNA
Genetic counseling
2009
Soon
?
Small % of population
Large % of population
Few diseases-genes/
patient
Hundreds diseases-genes/
patient
Genome hackers
New Scientist, 25 March 2009
The end
Rene Magritte: “Art evokes the mystery without which the
world would not exist”