MUTANTS genetic variation in human development Lecture 1 Fall 2006 Bennington College

1. MUTANTS genetic variation in human development Lecture 1 Fall 2006 Bennington College

2. 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 London- based 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. Course description: An overview of the historical, social, and scientific implications underlying mutations that affect “normal” human embryogenesis, development, and growth.

3. 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!

4. 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

5. polymorphisms underlie human diversity: skin/eye/hair color height weight facial features temperament intelligence disease predisposition

6. HIV infects CD4+ T cells 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

7. 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 complete human genome sequence - 2001 (a huge biotechnology company) first complete human genome sequence - 2001

8. 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.

9. 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

10. 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

11. 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.

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. William Harvey - Generation of animals (1651) • foundation of modern developmental biology • chicken embryos (Aristotle did this ~340 BC!!!) • - developing deer embryos

19. 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.

20. 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

21. Central Dogma of Molecular Biology

22. A linear sequence of amino acids: mutation Folds into a complex 3-dimensional structure: PROTEIN FOLDING Sequence determines Structure determines Function

23. Mutant Protein A Functional Protein Complex ACTIVE + Protein A Protein B Protein B NO Protein Complex! INACTIVE + MUTANT PROTEINS CANNOT FUNCTION CORRECTLY example of Loss of function mutation

24. Mutant Protein A Functional Protein Complex + Protein A Protein B NEW Protein Complex! altered activity + Protein X MUTANT PROTEINS CANNOT FUNCTION CORRECTLY ACTIVE example of Gain of function mutation

25. 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)

26. chromosome duplication Mitosis (normal cell division) Meiosis reductive cell division (only for gametes)

27. 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?

28. 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.)

29. Weekly short essay: Due in class Friday 9/22