Transcript Risk Assessment and Genetic Predisposition

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)
The Human Genome
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Human genome
Average chromosome
Average gene
Average coding sequence
Unit of the genetic code
Genetic variation
3 billion bp
150 million bp
50 thousand bp
3 thousand bp
3 bp
variable
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
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
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
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
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
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)
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
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.
The Practice of Genomic
Medicine
• Conditions
• Health Care and Health Care Providers
• Public Health Genetics
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.
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)
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
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
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
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
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)
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)
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
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
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
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
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
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
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.