CHEME 355
Genotype - Phenotype Correlation
4 Lectures
Oct 28:
Human Disease Patterns / Prenatal and Postnatal Disease (Examples)
Oct 30:
Gene / Etiology of Prenatal Disease (Osteogenesis Imperfecta)
Nov 6:
Genetic Flow of Information/ Intracellular Pathogenesis of
Osteogenesis Imperfecta
Nov 13 : Body Plan / Tissue Pathogenesis of Osteogenesis Imperfecta /
Adaptation
2 Labs
Nov 4:
Genotype-Phenotype Correlations and the Internet
Nov 18: Methodological Approaches to Studying Human Disease & Treatment
CHEME 355
Genotype - Phenotype Correlation
Biologists, as they consider the genome’s
impact on their work, are also moved by the
prospect of doing science in new ways.
…In vitro
…In vivo
There is now a third: in silico, meaning biology
that is done by querying genome data in
databases.
As a consequence of this revolution, biology in
the 21st century is rapidly becoming an
information science.
CHEME 355
Genotype - Phenotype Correlation
In a few years, genomics will make possible a test of
quite different power. The search for human gene
variants, and the technology of testing for thousands
of gene variants with a single microarray, are both
progressing so rapidly that it should soon be
possible to scan the entire human genome.
Such a scan in essence would predict all the
diseases a person might suffer in the course of a life,
with an implicit forecast of lifespan and likely cause
of death.
CHEME 355
Genotype - Phenotype Correlation
birth
genotype
“Personalized therapy is supported by an expanded
spectrum of drugs developed to target particular
disease subtypes on a particular genetic
background. Molecular profiling is used to monitor
the progress of the disease, and therapy may be
adjusted flexibly. This scenario is most likely to
apply to life-threatening diseases and to those for
which disease disposition and response to therapy
are known to vary considerably between individuals,
such as cancer and heart and brain disease. Overall,
the primary goal of personalized medicine should be
to increase the quality of life first, and life-span
second.”
Sander, C. (2000) Science 287:1977
database
Through a decision support system, the physician
may prescribe a personal immunization and screening
schedule or recommend specific preventive measures
CHEME 355
Genotype - Phenotype Correlation
“The April 1998 issue of Life magazine ran a
cover story, complete with a double-helix
spanning the length of the page, boldly titled
"Were You Born That Way?" The subtitle left no
doubt about the answer: "Personality,
temperament, even life choices. New studies
show it's mostly in your genes.””
Allen, G.E. (2001) Is a new eugenics afoot?
Science 294: 59-61.
CHEME 355
Genotype - Phenotype Correlation
With the human genome in hand, as well as those of
pathogenic viruses and bacteria, will any identifiable
barrier remain to curing all human disease?
If and when all disease is conquered, a great goal of
medicine will have been attained.
People will live out their natural lifespan in full health.
Genomic knowledge may show us not only how to
correct the degenerative diseases of aging from
which evolution has neglected to protect us, but also
how to unlock mechanisms that determine lifespan.
CHEME 355
McKeown, T. The Origins of Human Disease.
(Blackwell, Oxford, UK, 1988) pp. 233.
CHEME 355
Hunting and Gathering
Homo sapiens is identified ~600,000-years ago, about
the time when use of fire is discovered.
~100,000-years ago, archaic Homo sapiens merges into
Neanderthal man. About this time, cooperative hunting,
burial of the dead, use of tools, use of clothing, and use
of fire are commonly practiced.
Acquisition of these abilities/tools enlarges the human
habitat.
CHEME 355
Hunting and Gathering
Hunter-gatherers:
• Live in conditions that minimize exposure to human infection
(small groups of 25 to 50)
• Do not degrade environment
• Do not enhance environment
• Live as nomads: men obtaining food by hunting, women
obtained food by gathering
• Diet consists of insects, vegetables, fruit
CHEME 355
Hunting and Gathering
Hunter-gatherer populations may have been actively
restrained:
• It was common practice to eliminate a substantial
proportion (15- to 50%) of normal children.
• It also appears to be common to eliminate children who
were handicapped.
This may have been an attempt to titrate population size
with available resources, but the point is controversial.
CHEME 355
Hunting and Gathering
Hunter-gatherer health and disease:
• Life was short, death rates were high.
• Main causes of death include: accidents, food shortage, predation, parasitic disease.
TB from ~ 3000 BC
Leprosy from ~500 AD
Syphilis from ~1500 AD
Osteoarthritis
Osteomyelitis
Sinusitis
Colle’s fracture
• Relationship between food shortage and parasitic disease.
• Non-communicable diseases (cancer, ASCVD, obesity, diabetes, hypertension) are rare to
non-existent.
• Early nomads lived in small bands, infrequently contacting others. Numbers were not large
enough -- and bands were not dense enough -- to maintain (spread) acutely infectious
diseases, e.g. measles, smallpox, whooping cough, polio, enteric infections, respiratory
infections, either by fomites or by zoonoses.
CHEME 355
Agriculture
The switch from hunter-gatherer to agriculturalist occurred over a period
of ~8,000-years.
Agriculture is thought to have offered one principle advantage —
providing a greater amount of food per unit area of land — which could
feed a larger population.
Pattern of events in various parts of the world is consistent with a
picture of continuous population growth and population pressure. Was
expansion a stimulus for technological change?
Beginning about 6000-years ago, man’s first attempts to control the
environment — the domestication of plants and animals — is associated
with (a) transition from a nomadic to a settled way of life, (b) an increase
in food supply, (c) expansion of populations, and (d) creation of first
‘urban’ areas with large populations in continuous close contact.
CHEME 355
Agriculture
Agriculturalists:
• Lacked mechanized power
• Were physically active
• Domesticated plants and animals
Diet was different from that of hunter-gatherer,
but still based mainly on unrefined plant foods.
Dairy products consumed for the first time.
CHEME 355
Agriculture
Population growth:
• 10,000-years ago, < 10 mil.
• 1800, 1 bil.
• Even allowing for gross inaccuracy of the figures, there
is little doubt that human populations grew more rapidly
in the first few thousand years following the agricultural
revolution than in the few million years preceding it.
CHEME 355
Agriculture
Agriculturalist health and disease:
• Life was short, death rates were high.
• Main causes of death include: acute infectious disease, accidents,
food shortage, parasitic disease, dietary insufficiency.
• Relationship between food shortage and parasitic/infectious
disease.
• Non-communicable diseases (cancer, ASCVD, obesity, diabetes,
hypertension) are rare to non-existent.
• Acutely infectious diseases, e.g. measles, smallpox, whooping
cough, polio, enteric infections, respiratory infections, are spread
either by fomites or by zoonoses.
• Connection between public health and infection control/spread.
CHEME 355
Industry
Change from agriculture to industry takes place over a
few hundred years. Effect on health is profound, with
the decline of infectious disease and the rise on noncommunicable disease.
Modern rise in population is distinguished from all
previous increases by its size, continuity and duration.
A major contributor is the decline in death rate -increase in normal longevity -- of modern man.
CHEME 355
Industry
Population Growth
Mortality Rate
CHEME 355
Industry
Industrialists:
• Sedentary lifestyle
• Longer life
• Abundant food
• Processed food
• Degraded environment
• Increase in medical technology
CHEME 355
Industry
Industrialist health and disease:
• Life is extended, death rates fall significantly. For the first time
in history a mother knows that the loss of one of her children
before maturity is an unlikely event.
• Main causes of death include: non-communicable diseases
(cancer, ASCVD, obesity, diabetes, hypertension) .
• Although much in decline, acutely infectious diseases are
spread either by fomites or by zoonoses.
• Connection between public health and infection control/spread.
• Acute infections decline because of improved public health,
improved medical treatment, increased resistance to infection.
CHEME 355
Industry
CHEME 355
Disease origins
Classification scheme that includes:
• Diseases determined at the time of fertilization. Genes
(gene defects) are both necessary and sufficient
requirements for disease manifestations to arise.
• Diseases that require environmental influences for their
manifestation. These include diseases of poverty and
diseases of affluence. Concept of diseases due to
maladaption.
Prenatal diseases are considered separately from postnatal
diseases because experience suggests that they are
essentially different in character, e.g. prenatal diseases do
not respond to improvements in living conditions.
CHEME 355
Prenatal diseases
Common gene abnormalities are said to be determined at
fertilization:
• Chromosomal defects
- Can be seen in the microscope
- 7- to 10% of embryos
- 5- to 6-per 1000 births
(e.g. Down’s Syndrome)
• Single-gene disorders
- Inheritance can be predicted on Mendelian principles
- Autosomal dominant, autosomal recessive, X-linked
- 2- to 9-per 1000 births
(e.g. Thalassemia, PKU, cystic fibrosis, muscular dystrophy,
osteogenesis imperfecta)
CHEME 355
Postnatal diseases
Postnatal diseases are multifactorial, which
means that disease is caused by the interaction
over time of multiple environmental and genetic
influences.
Poverty vs. Affluence
CHEME 355
Postnatal diseases -- diseases of poverty
‘Third world’ & Diseases of Poverty:
• Natural resource development
• New diseases
• Civil war
• Public health
• Lack of food
• Political instability
• Population growth
CHEME 355
Postnatal diseases -- diseases of affluence
Striking replacement of infectious disease that kills early in life with
non-communicable disease that kills late.
New diseases in human history caused by conditions of life arising
during the industrial period (smoking example).
Small changes in genome; large changes in environment/living
conditions, e.g. population growth, cities, technology, diet,
reproductive patterns, habits, exercise, substance abuse
(maladaptation idea).
‘Wear and tear’ idea: The programmed end is often preceded by a
period of ill health caused by the breakdown of non-essential
organs such as the eyes, ears and joints, or by the partial collapse
of an essential organ such as brain, heart, kidney.
Examples include cancer, ASCVD, obesity, diabetes, hypertension,
osteoporosis, etc.
CHEME 355
Summary: Genotype - phenotype correlations
birth
genotype
“Personalized therapy is supported by an expanded
spectrum of drugs developed to target particular
disease subtypes on a particular genetic
background. Molecular profiling is used to monitor
the progress of the disease, and therapy may be
adjusted flexibly. This scenario is most likely to
apply to life-threatening diseases and to those for
which disease disposition and response to therapy
are known to vary considerably between individuals,
such as cancer and heart and brain disease. Overall,
the primary goal of personalized medicine should be
to increase the quality of life first, and life-span
second.”
Sander, C. (2000) Science 287:1977
database
Through a decision support system, the physician
may prescribe a personal immunization and screening
schedule or recommend specific preventive measures
CHEME 355
Postnatal and Prenatal
Disease Examples
CHEME 355
Atherosclerotic Cardiovascular Disease
Survival curves and life expectancy at birth for females in
the United States (1900, 1995, and projected).
CHEME 355
Atherosclerotic Cardiovascular Disease
1900
1910
1948
1949
CHEME 355
Atherosclerotic Cardiovascular Disease
1960
1970
1980
1990
CHEME 355
Atherosclerotic Cardiovascular Disease
The reduction in cardiovascular mortality in the past three
decades has increased the life expectancy in the United
States by an average of five years.
Cardiovascular disease remains by far the leading cause of
death in industrialized nations. It has been projected that
cardiovascular disease worldwide will climb from the 2nd
most common cause of death to 1st, with >36% of all deaths
in 2020. Thus, for the first time in human history,
cardiovascular disease is likely to become the most
common cause of death worldwide.
Two new epidemics of cardiovascular disease are
emerging: heart failure and atrial fibrillation.
CHEME 355
Atherosclerotic Cardiovascular Disease
Atherosclerosis is an inflammatory disease. The
lesion of atherosclerosis results from several
highly specific cellular and molecular
responses to injury of the artery wall.
Atherosclerosis is a progressive disease
characterized by the accumulation of lipid and
fibrous extracellular matrix in large- and
medium-sized arteries.
CHEME 355
Atherosclerotic Cardiovascular Disease
CHEME 355
Atherosclerotic Cardiovascular Disease
LDL Cholesterol
OX-LDL
Endothelial
dysfunction
Inflammation
Thrombosis
Loss of control of vascular tone
Macrophage
activation
CHEME 355
Atherosclerotic Cardiovascular Disease
CHEME 355
Osteogenesis imperfecta
Clinical Forms
OI Type I
OI Type II
OI Type III
OI Type IV
CHEME 355
Osteogenesis imperfecta
Demographics
Incidence
Gender
Distribution
CHEME 355
Phenotype, OI type II
Post-mortem photo
Post-mortem x-ray image
CHEME 355
Bone structure & function
A decalcified bone
Post-mortem x-ray
OI type II
Human femur
CHEME 355
Collagen structure & biosynthesis / biomineralization
Structure
Biosynthesis
CHEME 355
Two Classes of Mutation
Structural and Null
CHEME 355
Glycine mutations are the most common structural mutations
-Gly - X - Y - Gly - X - Y
Ala, Asp, Arg, Ser, Cyc, Trp, Val, Tyr, Term
Gly
GATC
Asp
GATC
CHEME 355
Gly
Asp
?
GATC GATC
Post-mortem x-ray image