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REPORT DATE (DD-MM-YYYY) 2. REPORT TYPE 3. DATES COVERED (From - To) December 15, 2010 Technical 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER The $100 Genome: Implications for the DoD 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 13109022 5e. TASK NUMBER PS 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER ANDThe ADDRESS(ES) MITRE Corporation JASON Program Office JSR-10-100 7515 Colshire Drive McLean, Virginia 22102 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) OSD/AT&L/DDR&E/PD Pentagon,Science and Rm Technology 38854 Directorate 11. SPONSOR/MONITOR’S REPORT RosslynWashington, VA 22209DC 2052820520 NUMBER(S) 12. DISTRIBUTION / AVAILABILITY STATEMENT 13. SUPPLEMENTARY NOTES 14. ABSTRACT Rapid advances in DNA sequencing and other technologies are ushering in an era of personal genomics. Soon it will be possible for every individual to have access to the complete DNA sequence of his or her genome for a modest cost. This development, coupled with the improving ability to predict how genetic variation affects susceptibility to disease, response to medical treatment, and other important phenotypes, will have a transformative effect on health care. This will be far reaching in civilian medical practice, and it could be used in the assessment of personnel at all stages of their military service. JASON was asked to consider the impact of anticipated advances in genome sequencing technology over the next decade, and to assess the relevant operational opportunities and challenges that will be presented by these technologies. 15. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF: 17. LIMITATION 18. NUMBER 19a. NAME OF RESPONSIBLE PERSON OF ABSTRACT OF PAGES Melissa Flagg 19b. TELEPHONE NUMBER (include area a. REPORT b. ABSTRACT c. THIS PAGE code) 703-614-9443 Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 Contents 1 EXECUTIVE SUMMARY ..................................................................................................1 2 INTRODUCTION.................................................................................................................7 2.1 Scope of the Study ...........................................................................................................8 2.2 The Challenge of Sequencing and Assembling Human Genomes ..................................9 3 DNA SEQUENCING TECHNOLOGY ASSESSMENT AND IMPLEMENTATION AND IMPLEMENTATION ..............................................................................................13 3.1 Current DNA Sequencing Technologies .......................................................................13 3.2 Future DNA Sequencing Technologies .........................................................................16 3.3 Who is Buying DNA Sequencing Machines and What are Their Goals? .....................20 4 THE ERA OF PERSONAL GENOMICS HAS ARRIVED ...........................23 5 CORRELATING GENOTYPE WITH PHENOTYPE ...................................27 5.1 Ongoing Efforts to Correlate Genotype with Phenotype ...............................................27 5.2 Issues that Confound Genotype/Phenotype Correlations ..............................................29 6 MICROBIOMICS – THE IMPORTANCE OF MICROBES ON HUMAN PHENOTYPES ...................................................................................................................35 6.1 The Diversity and Scale of a Personal Human Microbiome ..........................................35 6.2 Phenotypes Influenced by the Microbiome ...................................................................36 6.3 Potential Uses of Microbiome Data ...............................................................................37 7 GENOME DATA STORAGE, ANALYSIS AND SECURITY ....................39 7.1 Computational Costs for Genome Data Storage and Analysis ......................................39 7.2 Combining Personal Genome Data with Existing Health Records System ...................42 7.3 Implications of Computational Costs.............................................................................44 iii 8 PERSONAL GENOMICS DATA AND INFORMATION USEFUL FOR MEDICINE AND DEFENSE ........................................................................45 8.1 What Personal Genomics Data should be Collected......................................................45 8.2 Using Personal Genome Information.............................................................................46 9 CONCLUSIONS AND RECOMMENDATIONS ..............................................49 iv 1 EXECUTIVE SUMMARY Introduction Rapid advances in DNA sequencing and other technologies are ushering in an era of personal genomics. Soon it will be possible for every individual to have access to the complete DNA sequence of his or her genome for a modest cost. This development, coupled with the improving ability to predict how genetic variation affects susceptibility to disease, response to medical treatment, and other important phenotypes, will have a transformative effect on health care. This will be far reaching in civilian medical practice, and it could be used in the assessment of personnel at all stages of their military service. The U.S. military is a major consumer of medical services and has special medical needs compared to the general population. As the revolution in personal genomics proceeds, the military stands to benefit by implementing genomic technologies that enhance medical status and improve treatment outcomes. Furthermore, both offensive and defensive military operations may be impacted by the applications of personal genomics technologies through enhancement of the health, readiness, and performance of military personnel. It may be beneficial to know the genetic identities of an adversary and, conversely, to prevent an adversary from accessing the genetic identities of U.S. military personnel. Study Charge JASON was asked to consider the impact of anticipated advances in genome sequencing technology over the next decade, and to assess the relevant operational opportunities and challenges that will be presented by these technologies. The specific questions we sought to address in the study were: 1. What types of genetic information are likely to be most informative in personalized medicine relevant to military personnel? 2. What types of genetic information are likely to have tactical benefit in either offensive or defensive military operations? 3. What are the capabilities and costs of current technologies for assaying genetic variation, and are these capabilities sufficient to acquire the desired genetic information at reasonable cost? 1 4. How do recent research findings on the relative importance of different types of variation in human disease (e.g. common variants vs. rare variants; single-nucleotide polymorphisms vs. copy-number changes) affect the assessment of desired information and the technology needed to acquire it? 5. What new genomic technologies are emerging that are likely to benefit the military in the near term, and what is the likely roadmap for advances in genome sequencing technology over the next decade or so? 6. What capabilities will be required to analyze large sets of genomic data and accompanying phenotype data to derive information regarding the genetic basis for phenotypes of unique concern for force protection? 7. How should personal genomic information be handled to maintain the security of that information? Summary The first draft sequences of the human genome were published a decade ago at a cost of ~$300M. Although these data provided an unprecedented view of the genetic blueprint of humans, the prohibitive cost of DNA sequencing made difficult the correlation of genetic variations with specific traits. Successive improvements in “second-generation” DNA sequencing platforms over the last five years reduced the cost of sequencing by approximately an order of magnitude each year. An entire human genome can now be sequenced in a matter of days for a retail cost of $20,000, and “third-generation” DNA sequencing systems soon to be released will drive costs of reagents to below $100, although machines, labor and data processing expenses will add to the cost of each genome. Given technological developments, we believe that DNA sequencing costs will no longer be a factor limiting personal human genomics technologies. Therefore DNA sequencing information is likely to be broadly applied to health assessment, therapeutic decisions,