advances in genomics since the publication of the human genome

Advances in Genomics Since the Publication of

the Human GenomeGreg Feero, M.D., Ph.D.

Faculty, Maine-Dartmouth FamilyPractice Residency Program, Fairfield, ME

Contributing editor, Journal of the American Medical Association

Disclosures• No financial or intellectual conflicts of

interest.

• I am a primary care doctor.

• For better or worse, my opinions are my own!!

Outline• Still waiting for the revolution?

• Discovery apace.

• An unsatisfying answer?

• The final word – education!

Science 4 Feb 2011

Degree of specialization

Impa

ct o

f gen

omic

s

February 2011NHGRI Published New Vision for Genomics

Understandingthe Structure of

Genomes

Understandingthe Biology of

Genomes

Understandingthe Biology of

Disease

Advancingthe Science of

Medicine

Improving theEffectivenessof Healthcare

1990-2003Human Genome Project

2004-2010

2011-2020

Beyond 2020

Genomic Accomplishments: Base Pairs to Bedside

Sequence from chromosome 7

GAAATAATTAATGTTTTCCTTCCTTCTCCTATTTTGTCCTTTACTTCAATTTATTTATTTATTATTAATATTATTATTTTTTGAGACGGAGTTTCACTCTTGTTGCCAACCTGGAGTGCAGTGGCGTGATCTCAGCTCACTGCACACTCCGCTTTCTGGTTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGACTACAGTCACACACCACCACGCCCGGCTAATTTTTGTATTTTTAGTAGAGTTGGGGTTTCACCATGTTGGCCAGACTGGTCTCGAACTCCTGACCTTGTGATCCGCCAGCCTCTGCCTCCCAAAGAGCTGGGATTACAGGCGTGAGCCACCGCGCTCGGCCCTTTGCATCAATTTCTACAGCTTGTTTTCTTTGCCTGGACTTTACAAGTCTTACCTTGTTCTGCCTTCAGATATTTGTGTGGTCTCATTCTGGTGTGCCAGTAGCTAAAAATCCATGATTTGCTCTCATCCCACTCCTGTTGTTCATCTCCTCTTATCTGGGGTCACATATCTCTTCGTGATTGCATTCTGATCCCCAGTACTTAGCATGTGCGTAACAACTCTGCCTCTGCTTTCCCAGGCTGTTGATGGGGTGCTGTTCATGCCTCAGAAAAATGCATTGTAAGTTAAATTATTAAAGATTTTAAATATAGGAAAAAAGTAAGCAAACATAAGGAACAAAAAGGAAAGAACATGTATTCTAATCCATTATTTATTATACAATTAAGAAATTTGGAAACTTTAGATTACACTGCTTTTAGAGATGGAGATGTAGTAAGTCTTTTACTCTTTACAAAATACATGTGTTAGCAATTTTGGGAAGAATAGTAACTCACCCGAACAGTGTAATGTGAATATGTCACTTACTAGAGGAAAGAAGGCACTTGAAAAACATCTCTAAACCGTATAAAAACAATTACATCATAATGATGAAAACCCAAGGAATTTTTTTAGAAAACATTACCAGGGCTAATAACAAAGTAGAGCCACATGTCATTTATCTTCCCTTTGTGTCTGTGTGAGAATTCTAGAGTTATATTTGTACATAGCATGGAAAAATGAGAGGCTAGTTTATCAACTAGTTCATTTTTAAAAGTCTAACACATCCTAGGTATAGGTGAACTGTCCTCCTGCCAATGTATTGCACATTTGTGCCCAGATCCAGCATAGGGTATGTTTGCCATTTACAAACGTTTATGTCTTAAGAGAGGAAATATGAAGAGCAAAACAGTGCATGCTGGAGAGAGAAAGCTGATACAAATATAAATGAAACAATAATTGGAAAAATTGAGAAACTACTCATTTTCTAAATTACTCATGTATTTTCCTAGAATTTAAGTCTTTTAATTTTTGATAAATCCCAATGTGAGACAAGATAAGTATTAGTGATGGTATGAGTAATTAATATCTGTTATATAATATTCATTTTCATAGTGGAAGAAATAAAATAAAGGTTGTGATGATTGTTGATTATTTTTTCTAGAGGGGTTGTCAGGGAAAGAAATTGCTTTTTTTCATTCTCTCTTTCCACTAAGAAAGTTCAACTATTAATTTAGGCACATACAATAATTACTCCATTCTAAAATGCCAAAAAGGTAATTTAAGAGACTTAAAACTGAAAAGTTTAAGATAGTCACACTGAACTATATTAAAAAATCCACAGGGTGGTTGGAACTAGGCCTTATATTAAAGAGGCTAAAAATTGCAATAAGACCACAGGCTTTAAATATGGCTTTAAACTGTGAAAGGTGAAACTAGAATGAATAAAATCCTATAAATTTAAATCAAAAGAAAGAAACAAACTGAAATTAAAGTTAATATACAAGAATATGGTGGCCTGGATCTAGTGAACATATAGTAAAGATAAAACAGAATATTTCTGAAAAATCCTGGAAAATCTTTTGGGCTAACCTGAAAACAGTATATTTGAAACTATTTTTAAA

About 2000 bases

Only about 3,000,000 more slides to go.

At one slide per second, this lecture will be done in about 35 days!

The human genome is pretty darn big.

“The race was to sequence the human genome, all 3 billion genetic letters of it… a race not to the finish but to the starting line. Moreover, … the new race marked by that starting line was a marathon.”

Circa 2000

Circa 2012

Understandingthe Structure of

Genomes

Understandingthe Biology of

Genomes

Understandingthe Biology of

Disease

Advancingthe Science of

Medicine

Improving theEffectivenessof Healthcare

1990-2003Human Genome Project

2004-2010

2011-2020

Beyond 2020

Genomic Accomplishments: Base Pairs to Bedside

Progress in Mendelian disease gene discovery

KnownUnknown, suspected Mendelian

1990 2011

Sources: Lander, E. Nature , Feb. 2011www.genetests.org, Feb 2011

Cystic fibrosis Adult onset diabetes AIDS

Diabetes Diabetes

Unaffected Unaffected

SNP A SNP B

0

300

600

900

1200

1500

1800

Jul-05 Oct-05 Jan-06 Apr-06 Jul-06 Oct-06

Affymetrix 500K

Illumina 317K

Illumina 550K Illumina

650Y

Continued Progress in Genotyping Technology

Courtesy S. Gabriel, Broad/MITJuly 2005 Oct 2006

Cost

per

per

son

(USD

)

NHGRI Catalog of Published Genome-Wide Association Studies (GWAS)

> 5619 SNPs!!

Equation of a Variant’s Predictive Potential

Effect size

X =AssociationStrength

PredictivePotential

Classical genetic study“mutation”

Effect size

X =AssociationStrength

PredictivePotential

Association => Causality

Genome Wide Association Study“SNP”

Effect size

X =AssociationStrength

PredictivePotential

Genome Wide Association Study“SNPs”

Effect size

?X =AssociationStrength

PredictivePotential

Nature, April 2003

Quantum Leaps in Technology:

.….Genome sequencing at $1000 or less for a

mammalian genome…..

Advances in Genome Biology and Technology Conference

February 2012

genome.gov/sequencingcosts

Sequencing

???

Effect size

X =AssociationStrength

PredictivePotential

Frequency vs. Effect

Frequency in population

Effe

ct s

ize Classical

mutation

SNP-like variation

?

Published online April 2, 2012

Nature 9/23/12

30 JUNE 2011

16 June 2011

You are not alone in there….

Genomics

Personalized Medicine

Quality Health Care

JAMA, March 14,2012

Solutions – primary care style…

• 33% of diabetics are undiagnosed --- blood glucose. (Almanac, 2008)

• 24% of hypertensives undiagnosed --- blood pressure measurements. (Almanac, 2008)

• 37% of high cholesterol undiagnosed --- fasting lipid panel. (Almanac, 2008)

• Universal health care, better screening programs, smoking cessation, exercise programs, improved nutrition etc…

WSJ, Nov. 2, 2013

$1,600,000!!!!!!

Are the expenses of targeted treatments sustainable?

For:Patients?Insurers?

State budgets?National economies?

Understandingthe Structure of

Genomes

Understandingthe Biology of

Genomes

Understandingthe Biology of

Disease

Advancingthe Science of

Medicine

Improving theEffectivenessof Healthcare

1990-2003Human Genome Project

2004-2010

2011-2020

Beyond 2020

Genomic Accomplishments: Base Pairs to Bedside

2011Medical Education Issue9/7/2011

Genomics theme issues:JAMAArchives of:DermatologyFacial Plastic SurgeryGeneral PsychiatryInternal MedicineNeurologyOphthalmologyOtolaryngology—Head & Neck SurgeryPediatrics & Adolescent MedicineSurgery

Coming April 2013!

2012 – The rising tide of genomics….2000 – The genomic tsunami

Conclusions• The revolution is here, and happening all about

you.

• The front lines are in specialty care, but not for long.

• Considerably more basic, clinical, and translational research will be need to answer the “cost curve” question.

Some slides courtesy of:

Eric Green, NHGRI

Jean Jenkins, NHGRI

Teri Manolio, NHGRI

THANKS!