Advances in Genomics Since the Publication of the Human Genome Greg Feero, M.D., Ph.D. Faculty, Maine-Dartmouth Family Practice 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 Impact of genomics

February 2011 NHGRI Published New Vision for Genomics

Understanding the Structure of Genomes Understanding the Biology of Genomes Understanding the Biology of Disease Advancing the Science of Medicine Improving the Effectiveness of Healthcare Human Genome Project Beyond 2020 Genomic Accomplishments: Base Pairs to Bedside

Sequence from chromosome 7 GAAATAATTAATGTTTTCCTTCCTTCTCCTATTTTGTCCTTTACTTCAATTTATTTATTTATTATTAATATTATTATTTTTT GAGACGGAGTTTCACTCTTGTTGCCAACCTGGAGTGCAGTGGCGTGATCTCAGCTCACTGCACACTCCGCTTTCTG GTTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGACTACAGTCACACACCACCACGCCCGGCTAATTTT TGTATTTTTAGTAGAGTTGGGGTTTCACCATGTTGGCCAGACTGGTCTCGAACTCCTGACCTTGTGATCCGCCAGCC TCTGCCTCCCAAAGAGCTGGGATTACAGGCGTGAGCCACCGCGCTCGGCCCTTTGCATCAATTTCTACAGCTTGTTT TCTTTGCCTGGACTTTACAAGTCTTACCTTGTTCTGCCTTCAGATATTTGTGTGGTCTCATTCTGGTGTGCCAGTAGC TAAAAATCCATGATTTGCTCTCATCCCACTCCTGTTGTTCATCTCCTCTTATCTGGGGTCACATATCTCTTCGTGATTG CATTCTGATCCCCAGTACTTAGCATGTGCGTAACAACTCTGCCTCTGCTTTCCCAGGCTGTTGATGGGGTGCTGTTC ATGCCTCAGAAAAATGCATTGTAAGTTAAATTATTAAAGATTTTAAATATAGGAAAAAAGTAAGCAAACATAAGGAACA AAAAGGAAAGAACATGTATTCTAATCCATTATTTATTATACAATTAAGAAATTTGGAAACTTTAGATTACACTGCTTTTA GAGATGGAGATGTAGTAAGTCTTTTACTCTTTACAAAATACATGTGTTAGCAATTTTGGGAAGAATAGTAACTCACCC GAACAGTGTAATGTGAATATGTCACTTACTAGAGGAAAGAAGGCACTTGAAAAACATCTCTAAACCGTATAAAAACAA TTACATCATAATGATGAAAACCCAAGGAATTTTTTTAGAAAACATTACCAGGGCTAATAACAAAGTAGAGCCACATGT CATTTATCTTCCCTTTGTGTCTGTGTGAGAATTCTAGAGTTATATTTGTACATAGCATGGAAAAATGAGAGGCTAGTTT ATCAACTAGTTCATTTTTAAAAGTCTAACACATCCTAGGTATAGGTGAACTGTCCTCCTGCCAATGTATTGCACATTTG TGCCCAGATCCAGCATAGGGTATGTTTGCCATTTACAAACGTTTATGTCTTAAGAGAGGAAATATGAAGAGCAAAACA GTGCATGCTGGAGAGAGAAAGCTGATACAAATATAAATGAAACAATAATTGGAAAAATTGAGAAACTACTCATTTTCT AAATTACTCATGTATTTTCCTAGAATTTAAGTCTTTTAATTTTTGATAAATCCCAATGTGAGACAAGATAAGTATTAGTG ATGGTATGAGTAATTAATATCTGTTATATAATATTCATTTTCATAGTGGAAGAAATAAAATAAAGGTTGTGATGATTGTT GATTATTTTTTCTAGAGGGGTTGTCAGGGAAAGAAATTGCTTTTTTTCATTCTCTCTTTCCACTAAGAAAGTTCAACT ATTAATTTAGGCACATACAATAATTACTCCATTCTAAAATGCCAAAAAGGTAATTTAAGAGACTTAAAACTGAAAAGTT TAAGATAGTCACACTGAACTATATTAAAAAATCCACAGGGTGGTTGGAACTAGGCCTTATATTAAAGAGGCTAAAAAT TGCAATAAGACCACAGGCTTTAAATATGGCTTTAAACTGTGAAAGGTGAAACTAGAATGAATAAAATCCTATAAATTTA AATCAAAAGAAAGAAACAAACTGAAATTAAAGTTAATATACAAGAATATGGTGGCCTGGATCTAGTGAACATATAGTA AAGATAAAACAGAATATTTCTGAAAAATCCTGGAAAATCTTTTGGGCTAACCTGAAAACAGTATATTTGAAACTATTTT TAAA 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

Understanding the Structure of Genomes Understanding the Biology of Genomes Understanding the Biology of Disease Advancing the Science of Medicine Improving the Effectiveness of Healthcare Human Genome Project Beyond 2020 Genomic Accomplishments: Base Pairs to Bedside

Progress in Mendelian disease gene discovery Known Unknown, suspected Mendelian Sources: Lander, E. Nature, Feb Feb 2011

Cystic fibrosisAdult onset diabetesAIDS

Diabetes Unaffected SNP A SNP B

Affymetrix 500K Illumina 317K Illumina 550K Illumina 650Y Continued Progress in Genotyping Technology Courtesy S. Gabriel, Broad/MIT July 2005Oct 2006 Cost per person (USD)

NHGRI Catalog of Published Genome- Wide Association Studies (GWAS) > 5619 SNPs!!

Equation of a Variant’s Predictive Potential Effect size X = Association Strength Predictive Potential

Classical genetic study “mutation” Effect size X = Association Strength Predictive Potential Association => Causality

Genome Wide Association Study “SNP” Effect size X = Association Strength Predictive Potential

Genome Wide Association Study “SNPs” Effect size ? X = Association Strength Predictive Potential

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 = Association Strength Predictive Potential

Frequency vs. Effect Frequency in population Effect size 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?

Understanding the Structure of Genomes Understanding the Biology of Genomes Understanding the Biology of Disease Advancing the Science of Medicine Improving the Effectiveness of Healthcare Human Genome Project Beyond 2020 Genomic Accomplishments: Base Pairs to Bedside

2011Medical Education Issue 9/7/2011

Genomics theme issues: JAMA Archives of: Dermatology Facial Plastic Surgery General Psychiatry Internal Medicine Neurology Ophthalmology Otolaryngology—Head & Neck Surgery Pediatrics & Adolescent Medicine Surgery Coming April 2013!

2012 – The rising tide of genomics… – 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!