Download Inheritence Lecture

CHEME 355
Koshland, D.E. (2002) The seven pillars of life. Science 295: 2215-2216.
“The first pillar of life is a Program.
By program I mean an organized plan that describes both the
ingredients themselves and the kinetics of the interactions among
ingredients as the living system persists through time. For the living
systems we observe on Earth, this program is implemented by the
DNA that encodes the genes of Earth's organisms and that is
replicated from generation to generation, with small changes but
always with the overall plan intact. The genes in turn encode for
chemicals--the proteins, nucleic acids, etc.--that carry out the
reactions in living systems.
It is in the DNA that the program is summarized and maintained for
life on Earth.”
CHEME 355
Koshland, D.E. (2002) The seven pillars of life. Science 295: 2215-2216.
“The second pillar of life is IMPROVISATION.
Because a living system will inevitably be a
small fraction of the larger universe in which it
lives, it will not be able to control all the changes
and vicissitudes of its environment, so it must
have some way to change its program. If, for
example, a warm period changes to an ice age
so that the program is less effective, the system
will need to change its program to survive.
In our current living systems, such changes can
be achieved by a process of mutation plus
selection that allows programs to be optimized
for new environmental challenges that are to be
faced.”
CHEME 355
Koshland, D.E. (2002) The seven pillars of life. Science 295: 2215-2216.
“The third of the pillars of life is
COMPARTMENTALIZATION.
All the organisms that we consider living
are confined to a limited volume,
surrounded by a surface that we call a
membrane or skin that keeps the
ingredients in a defined volume and keeps
deleterious chemicals--toxic or diluting-on the outside. Moreover, as organisms
become large, they are divided into
smaller compartments, which we call cells
(or organs, that is, groups of cells), in
order to centralize and specialize certain
functions within the larger organism.”
CHEME 355
Koshland, D.E. (2002) The seven pillars of life. Science 295: 2215-2216.
“The fourth pillar of life is ENERGY.
Life as we know it involves movement--of chemicals, of the body, of components of
the body--and a system with net movement cannot be in equilibrium. It must be an
open and, in this case, metabolizing system. Many chemical reactions are going on
inside the cell, and molecules are coming in from the outer environment--O2, CO2,
metals, etc. The organism's system is parsimonious; many of the chemicals are
recycled multiple times in an organism's lifetime (CO2, for example, is consumed in
photosynthesis and then produced by oxidation in the system), but originally they
enter the living system from the outside, so thermodynamicists call this an open
system. Because of the many reactions and the fact that there is some gain of
entropy (the mechanical analogy would be friction), there must be a compensation to
keep the system going and that compensation requires a continuous source of
energy. The major source of energy in Earth's biosphere is the Sun--although life on
Earth gets a little energy from other sources such as the internal heat of the Earth-so the system can continue indefinitely by cleverly recycling chemicals as long as it
has the added energy of the Sun to compensate for its entropy changes.”
CHEME 355
Koshland, D.E. (2002) The seven pillars of life. Science 295: 2215-2216.
“The fifth pillar is REGENERATION.
Another system for regeneration is the
constant resynthesis of the constituents of
the living system that are subject to wear
and tear. For example, the heart muscle of
a normal human beats 60 times a minute-3600 times an hour, 1,314,000 times a year,
91,980,000 times a lifetime. No man-made
material has been found that would not
fatigue and collapse under such use,
which is why artificial hearts have such a
short utilization span. The living system,
however, continually resynthesizes and
replaces its heart muscle proteins as they
suffer degradation; the body does the
same for other constituents--its lung sacs,
kidney proteins, brain synapses, etc.”
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Koshland, D.E. (2002) The seven pillars of life. Science 295: 2215-2216.
“The sixth pillar is ADAPTABILITY.
Improvisation is a form of adaptability, but is too slow for many
of the environmental hazards that a living organism must face.
For example, a human that puts a hand into a fire has a painful
experience that might be selected against in evolution--but the
individual needs to withdraw his hand from the fire immediately
to live appropriately thereafter.
That behavioral response to pain (a reflex) is essential to survival
and is a fundamental response of living systems that we call
feedback.”
CHEME 355
Koshland, D.E. (2002) The seven pillars of life. Science 295: 2215-2216.
“Finally, and far from the least,
is the seventh pillar,
SECLUSION.
By seclusion, in this context, I
mean something rather like
privacy in the social world of our
universe.”
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Koshland, D.E. (2002) The seven pillars of life. Science 295: 2215-2216.
“At the present time the way in which mutation and selection
(survival of the fittest) has worked over evolutionary time no
longer seems to apply to Homo sapiens. We have become more
compassionate, less demanding. Perhaps a newer approach-longer life and deliberate changes in the program by a supreme
council of wise Solomons--could be substituted for the cruder
survival-of-the-fittest scenario.
I do not necessarily advocate such a drastic change in the
current mechanism of improvisation, which has served us well
over the centuries, but am only pointing out that there is the
possibility to change particular mechanisms as long as we
maintain the pillars.”
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Engineering/Technology
"All around I see evidence of the impact of science on society.
This is so obvious and so well known that little more remains to
be said about it. Science and the technologies it has spawned
form the basis of all human activity, from the houses that we live
in, the food that we eat, the cars that we drive, to the electronic
gadgetry in almost every home that we use to remain informed
and entertained.”
Brenner, S. (1998) The impact of science on society. Science
282: 1411-1412.
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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.
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Geneticist: A gene is a trait
Phenotype.
In the mid-1800s, a monk named Gregor Mendel, working in
Brno in the Czech Republic, observed that the offspring of
certain plants had physical characteristics similar to the
physical characteristics of the plants' parents or ancestors.
Mendel set out to examine and quantify the physical traits
in pea plants (because of their speedy reproductive cycles)
in an attempt to predict the traits that would occur in future
generations.
Mendel counted many thousands of instances of seven
different traits, including plant height, flower color and
position, seed color and shape, and pod color and shape,
and concluded that certain particles or "factors" were being
transmitted from parent to offspring and so on, thus
providing a connection from one generation to the next.
Mendel suggested that these factors were directly
responsible for physical traits. His interpretation of the
experimental data further suggested that each individual
had not one, but two factors for each trait, and that these
factors interacted to produce the final physical
characteristics of the individual.
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Systems Biologist: A gene is a component in a network of reciprocal interactions
between cells and environment
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Evolutionary Biologist: A gene is an agent of change
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It is sequencing the genomes of other
animals to help biologists better understand
the construction of the human genome.
These genome databases are new
frameworks for organizing all biological and
medical knowledge, much as the periodic
table of elements organizes all of chemistry.
Humans have far fewer genes than was
generally expected to be the case. The fruit
fly has almost 14,000 genes, the roundworm
19,000, and humans only 30,000 or so.
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About the only thing humans have in common
with mice is that we are fellow mammals.
Yet, of the 26,000 confirmed human genes, only
300 had no counterpart in the mouse.
On this basis, the chimpanzee, our closest
relative, is expected to have essentially the same
set of genes as humans.
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Pathologist: A gene is a mutation
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Gerontologist: Aging may be caused by genes wearing out
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Biotechnology: A Gene is a Product to Manufacture at Scale
Recombinant DNA Technology.
A plasmid and the gene of interest are both cut with
the same restriction endonuclease. The plasmid and
gene now have complementary "sticky ends." They
are incubated with DNA ligase, which reforms the
two pieces as recombinant DNA.
Recombinant DNA is allowed to transform a
bacterial culture, which is then exposed to
antibiotics. All the cells except those which have
been encoded by the plasmid DNA recombinant are
killed, leaving a cell culture containing the desired
recombinant DNA.
DNA cloning allows a copy of any specific part of a
DNA (or RNA) sequence to be selected among many
others and produced in an unlimited amount. This
technique is the first stage of most of the genetic
engineering experiments: production of DNA
libraries, PCR, DNA sequencing, et al.
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Intellectual Property
A gene is a proprietary product
(research university)
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Society
A gene is a political issue
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Genetic flow of information
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Technological advances
The preceding fifty years has been a time of rapid and profound technological
change. Elucidation of the genetic flow of biological information (i.e. information flow
from DNA to RNA to protein) has provided for:
development of recombinant DNA technology
rise of molecular cell biology
advent of intellectual property (in biology and medicine)
development of the biotechnology industry
development of transgenic technologies (including human gene therapy)
elucidation of the modern definition of stem cells
advent of mammalian cloning technology
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The Requirements of Genetic Material
Once it had been accepted that there was genetic transmission of traits, the
search began for the factor that carried the information. It was established that
the following characteristics were required of genetic material:
It must be able to replicate, in order to be in each cell of a growing organism.
It must be able to control expression of traits:
traits are determined by the enzymes and proteins that act within us;
these proteins are determined by their sequences;
therefore, the genetic material must be able to encode the sequence of proteins.
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The Search for Genetic Material
1860
1940
1900
1952
1953
1943
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Hereditary Material is Bound on Chromosomes
At the turn of the century, two developments in technology allowed scientists to observe
material inside the cell nucleus: the construction of increasingly powerful microscopes
and the discovery of dyes or stains that selectively colored the various components of the
cell. Long, thin, rod-like structures, which tended to become colored when the cell was
treated with certain stains, called chromosomes were observed in the nucleus.
In addition:
• The number of chromosomes in any cell appeared to double immediately prior to
mitosis.
• Germ cells appeared to have exactly half of the number of chromosomes found in
somatic cells.
• The fertilization of an egg with a sperm cell produces a diploid cell called a zygote,
which has the same number of chromosomes as the somatic cells of that organism.
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Proof that the chromosomes were Mendel's hereditary factors did not come until 1905.
Microscopic observations discovered the sex chromosomes. These chromosomes were
named "X" and "Y." Gender was shown to be the direct result of a specific combination of
chromosomal material, and sex became the first phenotype (physical characteristic) to be
assigned a chromosomal location - specifically the X and Y chromosomes.
Quantitative analysis of chromosomes showed a composition of about 40% DNA and 60%
protein. At first, it seemed that protein must be responsible for carrying hereditary
information, since not only is protein present in larger quantities than DNA, but protein
molecules are composed of twenty different subunits while DNA molecules are composed
of only four. It seemed clear that a protein molecule could encode not only more
information, but a greater variety of information, because it possessed a substantially
larger collection of ingredients with which to work.
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DNA is the genetic material, Avery et al. 1943
The Transforming Principle DNA Might be the Genetic
Material
DNA was first identified in 1868 by Friedrich
Miescher, a Swiss biologist. He called the
substance nuclein, noted the presence of
phosphorous, and separated the substance
into a basic part (which we now know is
DNA) and an acidic part (a class of acidic
proteins that bind to basic DNA).
In 1943, Oswald Avery, Colin Macleod, and
Maclyn McCarty, at the Rockefeller Institute,
discovered that different strains of the
bacterium Strepotococcus pneumonae
could have different effects on a mouse.
One virulent strain could kill an injected
mouse, and another avirulent strain had no
effect.
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DNA is the genetic material, transfection
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DNA is the genetic material, mutation
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Genetic flow of information is carried out inside of cells
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Genetic flow of information is carried out inside of cells
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Chromosomal defects; point mutations
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Genotype-phenotype
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Post-mortem
x-ray
OI type II
OSTEOGENESIS IMPERFECTA
Definition
Clinical syndromes
Demographics
Prominent phenotype
- bone weakness
- abnormal mineralization
Likely candidate for mutation?
Type I collagen!
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Collagen structure & biosynthesis / biomineralization
Structure
Biosynthesis
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Initial Studies
Penttinen, R.P., Lichtenstein, J.R., Martin, G.R., and McKusick, V.A. (1975)
Abnormal collagen metabolism in cultured cells in osteogenesis imperfecta.
Proc Natl Acad Sci U S A 72:586.
Barsh, G.S., and Byers, P.H.(1981)
Reduced secretion of structurally abnormal type I procollagen in a form of osteogenesis imperfecta.
Proc Natl Acad Sci U S A 78:5142.
Barsh, G.S., David, K.E., and Byers, PH. (1982)
Type I osteogenesis imperfecta: a nonfunctional allele for pro alpha 1 (I) chains of type I procollagen.
Proc Natl Acad Sci U S A 79:3838.
Chu, M.L., Williams, C.J., Pepe, G., Hirsch, J.L., Prockop, D.J., Ramirez, F. (1983)
Internal deletion in a collagen gene in a perinatal lethal form of osteogenesis imperfecta.
Nature 304:78.
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Two Classes of Mutation
Structural and Null
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Glycine mutations are the most common structural mutations
Gly - X - Y - Gly - X - Y
Ala, Asp, Arg, Ser, Cyc, Trp, Val, Tyr, Term
Gly
Asp
Asp
Gly
Gly
Gly
Gly
Normal
Gly
Abnormal
G A T C G A T C
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Inheritance patterns
New Accident
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Inheritance patterns
OI IV
OI II
Somatic Mosaicism
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Inheritance patterns
OI II
OI II
Gonadal Mosaicism
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Gly
Asp
?
G A T C G A T C
Post-mortem x-ray image