MUTANTSgenetic variation in human development

Lecture 1

Fall 2006Bennington 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 ETKATMANDU, 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 London-based Guinness World Records in the next few days. The foundation was set upto 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!

a few million differences between any two people!

DNA sequence is, on average, 99.9% identical between ANY TWO PEOPLE

3 billion base pairs of DNA with variance of 0.1%…

WE ARE ALL MUTANTS!

Polymorphism: A naturally occurring variation among individuals in the sequence of genetic information on a segment of DNA

Each new embryo has, on average, ~100 mutations not found in the parents

These mutations are also called polymorphisms

polymorphisms underlie human diversity: skin/eye/hair colorheightweightfacial featurestemperamentintelligencedisease 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

When the CCR5 gene contains a particular polymorphism called ∆32, resistance to HIV infection is conferred

HIV infects CD4+ T cells

The mythology behind mutants

Before scientific knowledge was readily available, people used mythand 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 complete human genome sequence - 2001 (a huge biotechnology company)first complete human genome sequence - 2001

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 Tand 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 micehave 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 encodedin the human genome sequence, and how errors in thesequence can have drastic effects on the final product.

Mutants throughout history - range from the absolutely faketo the quite real, but are usually misinterpreted, misunderstood, or misrepresented for the cause du jour…

Ancient Greece: The Minotaur (Myth)

The MinotaurAncient 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 faketo the quite real, but are usually misinterpreted, misunderstood, or misrepresented for the cause du jour…

Examples “borrowed” from http://www.museumofhoaxes.com/birth/birth.html

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.

Mutants throughout history - range from the absolutely faketo the quite real, but are usually misinterpreted, misunderstood, or misrepresented for the cause du jour…

Examples “borrowed” from http://www.museumofhoaxes.com/birth/birth.html

December 1522: The Monk-Calf (Status Unknown)

The Monk-CalfA 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)

March 1512: The Monster of Ravenna

In March 1512 an Italian woman in the town of Ravennagave 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 appearancesignified 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 intovery 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 scientificinquiry and conduct

normal natureaberrant natureman-manipulated nature

documenting/collecting oddities crucial to finding thecauses of these oddities - by finding the causes man canlearn 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

A linear sequence of amino acids:

Sequence determines Structure determines Function

mutation

Folds into a complex3-dimensional structure:

Protein A Protein B+

MutantProtein A Protein B+

Functional Protein Complex

NO Protein Complex!

MUTANT PROTEINS CANNOT FUNCTION CORRECTLY

example of Loss of function mutation

Protein A Protein B+

MutantProtein A Protein X+

Functional Protein Complex

MUTANT PROTEINS CANNOT FUNCTION CORRECTLY

example of Gain of function mutation

NEW Protein Complex!

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)

Meiosis reductive cell division(only for gametes)

chromosome duplication

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?

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 theinformation and also include references/citations (websites,

journal articles, etc.)

Short assignment: due in class Friday, 9/15

Weekly short essay: Due in class Friday 9/22

In the Mutants introduction, we see how fear of the unknownand lack of knowledge can have profound social consequences.Granted, the bulk of the introduction focuses on events andways of thinking from several centuries ago. However, thatdoes not mean it is not still happening today. Come up withan example of something we understand and can explaintoday that was still a mystery 100 years ago (or less). Whatwere the previously proposed explanations? What is the actualexplanation? How was it discovered and proven? Did any ofthe claims made before the phenomenon was explained haveany validity?

Please be sure to cite your sources (journal articles, books,websites, etc.).