MUTANTS
genetic variation in human development
Lecture 1
Fall 2006
Bennington College
Course description: An overview of the historical, social, and
scientific implications underlying mutations that affect “normal”
human embryogenesis, development, and growth.
Nepal boy claims to be shortest in world
Wed Aug 30, 7:17 AM ET
KATMANDU, Nepal - Nepal's shortest boy is waiting for word
from the Guinness World Records, where he has applied to be
named the shortest in the world, his supporters said on Wednesday.
Khagendra Thapa Magar, 14, is only 20 inches tall and weighs 10
pounds. According to Min Bahadur Thapa, president of the Khagendra
Thapa Magar Foundation, they are expecting to receive a reply from Londonbased Guinness World Records in the next few days. The foundation was set up
to collect funds for the boy. There was no listing on the Guinness World Records'
web site on a shortest boy category, but Thapa claimed their closest competitor
was 25 inches tall. The boy and family members are currently touring south
Nepal, seeking support for the foundation.
WE ARE ALL MUTANTS!
DNA sequence is, on average, 99.9% identical between ANY TWO PEOPLE
3 billion base pairs of DNA with variance of 0.1%…
a few million differences between any two people!
WE ARE ALL MUTANTS!
Each new embryo has, on average, ~100 mutations not found in the parents
These mutations are also called polymorphisms
Polymorphism: A naturally occurring variation among individuals in the
sequence of genetic information on a segment of DNA
polymorphisms underlie human diversity:
skin/eye/hair color
height
weight
facial features
temperament
intelligence
disease predisposition
advantageous polymorphisms drive natural selection/evolution
Researchers estimate that 10.8% of all South Africans over 2 years old were living with HIV in 2005.
Among those between 15 and 49 years old, the estimated HIV prevalence was 16.2% in 2005.
- data from http://www.avert.org/safricastats.htm
HIV infects CD4+ T cells
When the CCR5 gene contains a particular polymorphism called ∆32,
resistance to HIV infection is conferred
The mythology behind mutants
Before scientific knowledge was readily available, people used myth
and the supernatural (religion) to rationalize the occurrence of mutants
first cell viewed with light microscope - Robert Hooke, 1665
proposal of evolution - Charles Darwin, late 1850s
theory of inherited traits
(origin of modern genetics) - Gregor Mendel, 1860
physical changes in genes called mutations - 1927
structure of DNA revealed - 1953 (Watson, Crick, Franklin)
first
first complete
complete human
human genome
genome sequence
sequence -- 2001
2001 (a huge biotechnology company)
WE NOW KNOW THE SEQUENCE OF EVERY HUMAN GENE
- We have, essentially, the book of what makes humans humans
- While we understand the basic rules for reading the book,
we don’t yet have enough of a handle on the vocabulary
and grammar to fully understand the language of the book.
Things we know:
DNA (Deoxyribonucleic Acid) is composed of 4 bases or nucleotides
[ adenine, guanine, cytosine, and thymidine (A, G, C, T)]
DNA is double-stranded (so all bases are paired - A always pairs with T
and G always pairs with C)
We also can predict where genes begin and end ~30,000 genes predicted in human genome
Studies with organisms such as frogs, chicken, and mice
have revealed much about embryonic development, but
can only tell us so much about how this works in humans
-addition or removal of tissue
-addition or removal of organs
-addition or removal of genes
-Observation, observation, observation
-Documentation, documentation, documentation
HOW CAN WE STUDY THESE THINGS IN HUMANS???
Ordered dissection of pregnant slave
girls to follow embryo development
NOT A VIABLE OPTION!!!!!!!
The study of naturally occurring human mutations,
in combination with the use of lower organisms,
will lead the way to uncovering the mysteries encoded
in the human genome sequence, and how errors in the
sequence can have drastic effects on the final product.
Mutants throughout history - range from the absolutely fake
to the quite real, but are usually misinterpreted, misunderstood,
or misrepresented for the cause du jour…
Ancient Greece: The Minotaur (Myth)
The Minotaur
Ancient Greek mythology describes the minotaur,
a creature with the body of a man but the head of a bull,
that lived in a vast labyrinth on the island of Crete. The
creature was the child of Pasiphae, the wife of King Minos.
She became pregnant with the minotaur after mating with
a snow-white bull. After its birth the creature was locked
up in the labyrinth at the command of King Minos, but every
year the Athenians had to pay tribute to the King by sending
a sacrifice of seven young men and women who were fed to
the minotaur. Finally the creature was slain by a young
Athenian named Theseus.
Examples “borrowed” from http://www.museumofhoaxes.com/birth/birth.html
Mutants throughout history - range from the absolutely fake
to the quite real, but are usually misinterpreted, misunderstood,
or misrepresented for the cause du jour…
11th Century Italy: Maimo, Born of Ape and Woman (Status Unknown)
Gulielmus was an Italian count who owned a pet ape. As can happen, his wife fell in love
with the ape and mated with it. The resulting child was a curious half-man half-ape
creature which was given the name Maimo. Eventually the countess's ape lover grew
jealous of the Count and killed him. Maimo thereby came to the attention of Pope Alexander II,
who showed the creature to St. Peter Damian, who then wrote of it in his book De bono
religiosi status et variorum animatium tropologia. Perhaps influenced by the example of Maimo,
Pope Alexander II later decided to enforce the practice of clerical celibacy.
Examples “borrowed” from http://www.museumofhoaxes.com/birth/birth.html
Mutants throughout history - range from the absolutely fake
to the quite real, but are usually misinterpreted, misunderstood,
or misrepresented for the cause du jour…
December 1522: The Monk-Calf (Status Unknown)
The Monk-Calf
A deformed calf was born in the town of Freiburg.
The creature had a bony head, was missing an eye,
and had a fold of skin on its back that looked rather
like a cape, or a cowl. In the active imagination of
local protestants, the calf resembled a monk, so they
dubbed it the monk-calf. The next year Martin Luther
described the creature in a pamphlet, claiming that its
birth symbolized the sin of the Roman Catholic Church.
The Catholic Church responded that its birth actually
symbolized the sin of the Protestant Reformation (and
began referring to the monk-calf by the name of Luther)
Examples “borrowed” from http://www.museumofhoaxes.com/birth/birth.html
March 1512: The Monster of Ravenna
In March 1512 an Italian woman in the town of Ravenna
gave birth to a severely deformed child, and in the
Popular imagination of the time the poor child instantly
was transformed into a fearsome monster. The monster
was said to have a large horn sticking out of its head, it
was armless, on its chest were the letters XYV, and its
scaly leg had an eye affixed to its knee. News of the child
was quickly communicated to Rome, and soon all of Europe
had heard of it. Of course, what was significant about the
child was not its actual appearance, but what that appearance
signified. Some said its birth foretold the defeat of the Italian
army at the Battle of Ravenna. Others said its appearance
signified the sin of the Italian people. According to legend it
grew to adulthood and proceeded to terrorize peasants in the
Italian countryside. More likely, the child died soon after birth.
Roberts syndrome
-shortened limbs
-cleft palate/lip
-genital abnormalities
In the late 1500’s, started to see a more scientific, and less supernatural,
approach to understanding the occurrence of human mutants.
Ambroise Paré - Des monstres et prodiges (1573)
tried to come up with causes of mutations occurring (other than “wrath of God”)
- mating with animals
- mating during menstruation
- too much semen
- too little semen
- narrow womb
- bad posture
- MATERNAL IMPRESSIONS
all, of course, incorrect, but at least testable hypotheses
and therefore moving toward a scientific approach
Sir Thomas Browne - Pseudodoxia epidemica, or, enquiries into
very many received tenents and commonly presumed truths (1646)
Some myths busted:
- the feathers of a dead kingfisher always indicate wind direction
-there were no rainbows before The Flood
-the legs of badgers are shorter on one side than the other
William Harvey - Generation of animals (1651)
foundation of modern developmental biology
- chicken embryos (Aristotle did this ~340 BC!!!)
- developing deer embryos
Francis Bacon
champion of modern scientific learning and thinking
wanted to establish guiding principles for scientific
inquiry and conduct
normal nature
aberrant nature
man-manipulated nature
documenting/collecting oddities crucial to finding the
causes of these oddities - by finding the causes man can
learn the secrets of nature and manipulate it to his whim.
WE NOW KNOW THE SEQUENCE OF EVERY HUMAN GENE
a single mutation can have multiple consequences
one mutated gene = multiple effects
-red hair/overweight
-albinism/deafness/constipation
- short fingers and toes/malformed genitalia
Central Dogma of Molecular Biology
PROTEIN FOLDING
Sequence determines Structure determines Function
A linear sequence of amino acids:
mutation
Folds into a complex
3-dimensional structure:
MUTANT PROTEINS CANNOT FUNCTION CORRECTLY
Functional Protein Complex
Protein A
+
Protein B
NO Protein Complex!
Mutant
Protein A
+
Protein B
example of Loss of function mutation
MUTANT PROTEINS CANNOT FUNCTION CORRECTLY
Functional Protein Complex
Protein A
+
Protein B
NEW Protein Complex!
Mutant
Protein A
+
Protein X
example of Gain of function mutation
Robert’s syndrome
-cleft lip and palate
-shortened limbs (resemble those of babies whose mothers took thalidomide during pregnancy)
-incidence greater if parents are closely related (first cousins, etc.)
-very rare
-autosomal recessive inheritance
autosomal recessive inheritance refers to genetic conditions that occur
only when mutations are present in both copies of a given gene (therefore,
both parents must carry a mutant copy of the gene)
Mitosis (normal cell division)
chromosome
duplication
Meiosis
reductive cell division
(only for gametes)
Autosomal recessive trait only expressed if both egg
and sperm have the mutant version of the gene
What is the percent chance of this occurring?
Short assignment: due in class Friday, 9/15
What is the name of the gene that, when mutated,
causes Roberts syndrome?
What happens to cells when this gene is mutated?
Choose 5 words that you were previously unfamiliar
with that you encounter in your research and define them
Please include a brief description of how you found the
information and also include references/citations (websites,
journal articles, etc.)
Weekly short essay: Due in class Friday 9/22
In th e Mu tant s in tro du cti on , we see ho w fear of th e u n know n
a nd lack of k n owle dg e ca n ha ve p ro fou nd soc ia l con s e q ue n ces .
Gra n te d, th e bul k of the in tro du cti on foc u se s on e ven ts an d
wa ys of th in kin g fro m se vera l ce n t u ries ago . Howe ver , t h at
d oes n ot m ea n i t is n ot s t ill h ap p e ni n g to da y. Co m e u p wit h
a n exa mpl e o f s ome thi n g we u n d e rs ta nd an d can ex pl a in
to d a y th a t was s t ill a m ys ter y 1 00 ye ars a g o (or less ). Wh a t
were th e p re vio u s ly pr o p ose d ex p lan at io n s ? Wh a t i s the a ct u a l
ex pl a n a ti on ? How wa s it di sco vere d a nd p ro ven ? Did an y of
the c la im s m a d e b efore th e ph e n ome n on w as ex pl a ine d h a ve
a n y va lidi t y?
Ple a se b e s u re to cite yo u r s o u rces (jo u rn al ar ticles , book s ,
we b s ite s, et c.).