The Human Genome

1. The Human Genome • the human genome consists of ~3 billion bp and 30,000-35,000 genes (haploid state) • it would fill about 150,000 phone book pages with A’s, T’s, G’s, and C’s • a disorder can be caused by variation in one or more base pairs (among the 3 billion) • the challenge is partly one of scale (needle in a haystack)

2. The Human Genome • Human genome 3 billion bp • Average chromosome 150 million bp • Average gene 50 thousand bp • Average coding sequence 3 thousand bp • Unit of the genetic code 3 bp • Genetic variation variable

3. The Human Genome Project • the largest biomedical research project ever • an international project that is ahead of schedule and under budget • from its beginning has set aside funds for its ethical, legal, and social implications (ELSI)--the largest single amount of money ever devoted to bioethics

4. The Human Genome Project About 90% of the human genome has been sequenced (the alphabet, so to speak; see web site). the sequence is a vital tool, but by itself will have little impact • the real impact will come when we figure out how the words/sentences are formed, and what they mean

5. The Human Genome Project and Related Technologies • impact on the practice of genomic medicine • impact on health (and health promotion/disease prevention) • impact on society

6. Genomic Medicine • about the interface between genomic and environmental (multifactorial) risk and protective factors • about conditions (e.g., heart disease, cancer, Alzheimer disease, mood disorders, etc.) caused or prevented, in part, by one or more variations in DNA • variations is a better word than mutations

7. Genomic Medicine These conditions: • are also of great importance to individuals and families who are affected by them • are quite common (affect virtually everyone) • cause genomics play a considerable role in health care and in society, in general

8. Genomic Medicine Thus far, most success in identifying genomic contributions to common disorders has been for low frequency, high penetrance alleles; for example: • HNPCC (colon cancer) • BRCA1 and 2 (breast and ovarian cancer) • MODY 1,2,3 (diabetes) • Alpha-synuclein (Parkinson Disease)

9. Genomic Medicine But, on a population basis, most genomic contributions to common disorders are from high frequency, low penetrance alleles; for example: • APC I1307K and colon cancer • ApoE and Alzheimer disease • Factor V Leiden and thrombosis • CCR5 and HIV resistance

10. Genetic Variation and Disease • Mendelian disorders are relatively rare--the DNA variation is necessary and sufficient to cause considerable phenotypic effects. • Complex disorders are caused by common DNA variations--any one of which may not be necessary or sufficient to produce a phenotypic effect, i.e., each variation has a small phenotypic effect.

11. The Practice of Genomic Medicine • Conditions • Health Care and Health Care Providers • Public Health Genetics

12. The Practice of Genomic Medicine Many chronic conditions are common enough such that genomic health care will be provided for the most part by primary care professionals from many health disciplines, with involvement of genomic health care specialists when appropriate/necessary.

13. The Practice of Genomic Medicine The practice of genomic medicine will change health care by: • providing a better understanding of non-genetic (environmental) factors in health and disease • providing a better understanding of the natural history of most rare and common conditions • emphasizing health maintenance rather than disease treatment • allowing for genetic therapies (engineering)

14. The Practice of Genomic Medicine These conditions are common enough such that: • genomics has and will continue be a primary focus for public health • might genomics be to public health in the 21st century what infectious diseases were to public health in the previous centuries

15. The Practice of Genomic Medicine The practice of genomic medicine will: • change the face of medicine and health care by providing knowledge of individual genomic predispositions • enable population-based screening, and more individualized testing for rare and common disorders with a genomic component • enable the practice of pharmacogenomics and other types of more individualized therapies

16. The Practice of Genomic Medicine Pharmacogenomics will allow for: • a wide variety of new medicines • more individualized use of new medications based on genetic variations/effects and side effects

17. Medical Genetics Time Line 2000 and beyond: • functional genomics and pathogenomics • genomic-based risk prediction • individualized therapy for genomic disorders/gene therapy • pharmacogenetics • public health genetics

18. Genetic Medicine and Research In terms of research: • the common, chronic conditions have and will continue to be of considerable interest because of their large impact on health and health care • in the next few decades, genomics will answer many basic biomedical questions, and provide better screening and testing methods, and interventions (many of them pre-symptomatic)

19. Genomics and Other Phenotypic (“Non-Disorder”) Characteristics The study of genomics will probably include characteristics that most do not see as “diseases,” and many do not consider to be innate (intelligence, growth and development, sexual orientation, alcoholism, violent behavior, happiness-sadness, confidence-anxiety, altruism-greed)

20. Genomics and Society Genomics will change our lives by: • allowing individuals and families (and maybe others) to know about their health and disease predispositions, and other characteristics and attributes • allowing for policy development/decisions at the local, state, national and international levels • showing that we are all MUTANTS! • showing how similar we are in some ways and different in others

21. Genomics and Society Genomics may change our lives through: • social stratification (employment, marital status, emigration status, etc.) • genetic/genomic engineering • cloning • euphenics (modifications in phenotype) rather than eugenics • discrimination against individuals and groups

22. Genomics and Society Genomics may change our lives through: • genetic determinism (will we have a false impression of our future?) • nature versus nurture, nature and nurture, nature over nurture, etc. • issues related to access to care • confidentiality/privacy of information • the right to know or not know, and not to act • informed consent • patenting and licensing

23. What Can Health Care Professionals Do To Prepare For Genomic Medicine? We need to learn to think “genomically” to: • realize how and when genomic factors play a role in patient care • be able to explain genomic concepts as they pertain to patient care • effectively use genomic screening (including family history-taking) and testing • deal with genomic risk and predisposition

24. What Can Health Care Professionals Do To Prepare For Genomic Medicine? We need to learn to think “genomically” to: • realize the personal/family and societal impacts of genomic information • protect genomic privacy • use genomics to individualize patient care • use genomics to promote health and prevent disease

25. What Can Society Do To Prepare For Genomic Medicine? We need to understand: • basic genomic concepts as they pertain to health, health promotion and disease prevention • the uses of genomics in health care • how to deal with genomics in health care including the right to say no • the societal impacts of genomics and genomic medicine--especially the ethical, social, legal, political and financial issues

26. Acknowledgment I would like to thank Alan Guttmacher, M.D., Special Assistant to the Director, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, for his help in preparing this presentation.