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
  As, Ts, Gs, and Cs
• 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.