Lecture 9: Genetics and Heritable Disease

1. Lecture 9: Geneticsand Heritable Disease Objectives: Understand the basis of genetic inheritance Understand the basis of genetic variation Relate meiosis, to sex and haploid cells Understand chromosome structure and how it affects general health Explain how small changes in DNA information result metabolic changes Key Terms: Gene, Chromosome, Allele, Locus, loci, Mutation, Diploid and haploid, Phenotype and genotype, Homologous vs. heterozygous, Meiosis vs. Mitosis, Karyotype, X and Y chromosome, Sex determination, Linkage, linkage groups, Full and incomplete linkage, Genetic Markers, Crossover (Recombination), Pedigree, Autosomal and sex-linked, Recessive vs. Dominant, Duplication, Inversion and Translocation, Down Syndrome, Turner Syndrome, Klinefelter Syndrome, Prisoners Syndrome. Chapter 10 & 11 for background

2. Evidence of a Pluripotent Human Embryonic Stem Cell Line Derived from a Cloned Blastocyst Woo Suk Hwang et al. 1 College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea; • Somatic cell nuclear transfer. • Pluripotent embryonicstem cell line • Cloned human blastocyst. • Capable of differentiating into embryoidbodies • Containingcell derivatives from all three embryonic germ layers • Capable of continuous proliferation for >70 passages • Cells maintain normal karyotypes

3. inner cell mass oviduct uterus FERTILIZATION ovary IMPLANTATION endometrium Fig. 39.21a, p. 666

4. Start of amniotic cavity Start of embryonic disk Trophoblast (surface layer of cells of the blastoyst) Endometrium Blastocoel inner cell mass Start of yolk sac Uterine cavity DAYS 6-7 DAYS 10-11 Chorionic cavity Shorion Shorionic villi Blood-filled spaces Smniotic cavity Start of chorionic cavity Connecting stalk yolk sac DAY 14 DAY 12

5. Meiosis Nucleus of a diploid (2n) Reproductive cell with two pairs of homologous chromosomes OR Possible alignments of the two homologous chromosomes during metaphase I of meiosis A A a a A A a a B B b b b b B B A A a a A A a a The resulting alignments at metaphase II: B B b b b b B B B B b b b b B B allelic combinations possible in gametes: A A a a A A a a 1/4 AB 1/4 ab 1/4 Ab 1/4 aB Fig. 10.8, p. 158

6. FERTILIZATION Oviduct Ovary OVULATION Uterus Opening of cervix Zona pellucida Vagina Follicle cell Granules in cortex of cytoplasm Sperm enter vagina Nuclei fuse

8. Key Terms • Cloned human embryo • Embryonic stem cell • Blastula, Blastocyst • Pluripotent • Karyotype • How does cloning work: • Where does the egg come from • Where does the DNA come from • How many copies of each chromosome

9. BioethicsDestroying Embryos is the Basis of the Ethical Debate Questions: • What is the moral status of the developing embryo • Is this simply tissue or is it something more? • Is this a twin? The genetic make up is identical • What is the purpose? • Making donor tissue? • Making a baby? • Is regenerative medicine ethical?

10. Lecture 8: Geneticsand Heritable Disease Objectives: Understand the basis of genetic inheritance Understand the basis of genetic variation Relate meiosis, to sex and haploid cells Understand chromosome structure and how it affects general health Explain how small changes in DNA information result metabolic changes Key Terms: Gene, Chromosome, Allele, Locus, loci, Mutation, Diploid and haploid, Phenotype and genotype, Homologous vs. heterozygous, Meiosis vs. Mitosis, Karyotype, X and Y chromosome, Sex determination, Linkage, linkage groups, Full and incomplete linkage, Genetic Markers, Crossover (Recombination), Pedigree, Autosomal and sex-linked, Recessive vs. Dominant, Duplication, Inversion and Translocation, Down Syndrome, Turner Syndrome, Klinefelter Syndrome, Prisoners Syndrome. Chapter 11 for background

11. Lecture 9 Outline Intro to genetics Chromosomes and genes Karyotypes Variation Heridity Genetic disorders The big problems Extra and missing chromosomes The small problems Mutations Genetic Screening

12. Genes Units of information about heritable traits In eukaryotes, distributed among chromosomes Each gene has a particular locus(Location on a chromosome) Alleles Different molecular forms of a gene Arise through mutation Diploid cell has a pair of alleles at each locus Alleles on homologous chromosomes may be same or different Genetic Terminology

13. Genotype- the alleles a person has Phenotype- the observable trait a person has Dominant- Alleles affect masks the other allele it is paired with Recessive- Alleles affect is masked by the other allele it is paired with. Homozygous- Pair of alleles for a trait are identical Heterozygous- Pair of alleles for a trait are not identical Hybrid- Inherit non-identical alleles for a trait Genetic Terminology

14. VISUAL REPRESENTATION Pair of Chromosomes Gene Locus (loci) Alleles Heterozygous Homozygous A pair of homologous chromosomes, each in the unduplicated state (most often, one from a male parent and its partner from a female parent) Heterozygous Homozygous A gene locus (plural, loci), the location for a specific gene on a specific type of chromosome A pair of alleles (each being a certain molecular form of a gene) at corresponding loci on a pair of homologous chromosomes Three pairs of genes (at three loci on this pair of homologous chromosomes); same thing as three pairs of alleles

15. Homologous Chromosomes • Homologous autosomes are identical in length, size, shape, and gene sequence • Sex chromosomes are nonidentical but still homologous • Homologous chromosomes interact, then segregate from one another during meiosis DNA DNA and proteins arranged as cylindrical fiber Nucleosome Histone

16. Human Karyotype 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 XX (or XY)

17. Karyotype Preparation • Cultured cells are arrested at metaphase • This is when cells are most condensed and easiest to identify Arrested cells are broken open • Metaphase chromosomes are fixed and stained (how many copies of each chromosome in one cell?) • Chromosomes are photographed through microscope • Photograph of chromosomes is cut up and arranged to form a karyotype diagram

18. Karyotypes • The Alaskan king crab has 208 chromosomes. • The fruit fly has 4. • Number has nothing to do with complexity of the organism Cotton Rat (Sigmodon hipsidus) Pied Kingfisher (Ceryle rudis) Carrion Beetle (Phosphuga atrata)

19. Sex Chromosomes • Discovered in late 1800s • Mammals, fruit flies • XX is female, XY is male • Human X and Y chromosomes function as homologues during meiosis (In some organisms XX is male, XY female but for this class XX is female and XY is male, no tricky stuff)

20. X X X Y Y X X X XX XX XY XY Sex Determination eggs sperm Female germ cell Male germ cell sex chromosome combinations possible in new individual

21. The Y Chromosome Fewer than two dozen genes identified One is the master gene for male sex determination SRY gene (Sex-determining region of Y) SRY present, testes form SRY absent, ovaries form The X Chromosome Carries more than 2,300 genes Most genes deal with nonsexual traits Genes on X chromosome can be expressed in both males and females The Sex Chromosomes

22. appearance of structures that will give rise to external genitalia appearance of “uncommitted” duct system of embryo at 7 weeks Effect of YChromosome 7 weeks Y present Y absent Y present Y absent testes ovaries 10 weeks ovary testis birth approaching

23. Genetic Variation Why aren’t there just two types of people? Recombination Duplication Inversion Deletion Transversion

24. A A A A a B B B B B C C C C C a A a a a b b b b b c c c c c Recombination(homologus recombination) • Chromosomes Mix • The ends of homologus chromosomes are exchanged Fig. 11.3, p. 172

25. animation

26. Duplication • Gene sequence that is repeated several to hundreds of times • Duplications occur in normal chromosomes • May have adaptive advantage • Useful mutations may occur in copy normal chromosome one segment repeated three repeats

27. Inversion A linear stretch of DNA is reversed within the chromosome

28. Translocation • A piece of one chromosome becomes attached to another nonhomologous chromosome • Most are reciprocal (switch ends) Chromosome Nonhomologous chromosome Reciprocal translocation

29. Translocation Chromosome Nonhomologous chromosome Reciprocal translocation

30. Deletion • Loss of some segment of a chromosome • Most are lethal or cause serious disorder

31. Genetic Inheritance

32. Monogenetic Inheritance

33. Pedigree • Chart that shows genetic connections among individuals • Standardized symbols • Knowledge of probability and Mendelian patterns used to suggest basis of a trait • Conclusions most accurate when drawn from large number of pedigrees

34. I II III IV V *Gene not expressed in this carrier. Pedigree for Polydactly female male 5,5 6,6 * 5,5 6,6 6,6 5,5 6,6 5,5 6 7 5,5 6,6 5,5 6,6 5,5 6,6 5,5 6,6 5,6 6,7 12 6,6 6,6

35. Autosomal Recessive Inheritance Patterns • If parents are both heterozygous, child will have a 25% chance of being affected

36. Galactosemia • Caused by autosomal recessive allele • Gene specifies a mutant enzyme in the pathway that breaks down lactose enzyme 1 enzyme 2 enzyme 3 GALACTOSE-1- PHOSOPHATE GALACTOSE-1- PHOSOPHATE LACTOSE GALACTOSE +glucose intermediate in glycolysis

37. Autosomal Dominant Inheritance Trait typically appears in every generation

38. Huntington Disorder • Autosomal dominant allele • Causes involuntary movements, nervous system deterioration, death • Symptoms don’t usually show up until person is past age 30 • People often pass allele on before they know they have it

39. X-Linked Recessive Inheritance • Males show disorder more than females • Son cannot inherit disorder from his father

40. Examples of X-Linked Traits • Color blindness • Inability to distinguish among some of all colors • Hemophilia • Blood-clotting disorder • 1/7,000 males has allele for hemophilia A • Was common in European royal families

41. Alcoholism Intelligence Homosexuality???? Polygenetic inheritance (familial)

42. Children of alcoholics are 4 times as likely to become alcoholics as children of nonalcoholic parents… D2, a dopamine receptor in the brain, has been linked to alcohol sensitivity in mice = mechanism/disease theory Contemporary moral standards Correlation factor ~ 0.32, considered a weak Association Alcoholism Scientific Ideology & Therapeutic View of humans -They learn to be alcoholics from watching mom or dad? Behavior/imprint/condition theory B. F. Skinner & Pavlov -Society made him do it: poverty, culture, education… -Genetics: my genes made me do it… • Alcohol dehydrogenase (ADH) affects the amount of alcohol in the bloodstream. • Alcoholics have higher levels of ADH in their blood than do non-alcoholics. • This suggests that genetically predisposed people have a reduced or less functional ADH or ALDH enzyme.

43. Heredity factor = anywhere from .4 to .7 Headstart programs can increase IQ Twin studies: shared environment mediates genetic factors until adulthood

44. A Mystery of Heritable traits: What is this condition? Here are the clues: 1) The trait is referred to by biologists as a "stable bimorphism, expressed behaviorally." 2) Its exists in the form of two basic internal, invisible orientations, over 90% of the population accounting for the majority orientation and under 10% (one reliable study puts the figure at 7.89%) for the minority orientation, though there is still debate about actual percentages. 3) Only a very small number of people are truly equally oriented both ways. 4) Evidence from art history suggests the incidence of the two different orientations has been constant for five millennia. 5) A person's orientation cannot be identified simply by looking at him or her; those with the minority orientation are just as diverse in appearance, race, religion, and all other characteristics as those with the majority orientation. 6) Since the trait itself is internal and invisible, the only way to identify an orientation in someone else is by observing in them the behavior or reflex that express it. However-- 7) --The trait itself is not a "behavior." It is the neurological orientation expressed, at times, behavioraly. A person with the minority orientation can engage, usually due to coercion or social pressure, in behavior that seems to express the majority orientation--several decades ago, those with the minority orientation were frequently forced to behave as if they had the majority orientation--but internally the orientation remains the same. As social pressures have lifted, the minority orientation has become more commonly and openly expressed in society.

45. 8) Neither orientation is a disease or mental illness. Neither is pathological. 9) Neither orientation is chosen. 10) Signs of one's orientation are detectable very early in children, often, researchers have established, by age two or three, and one's orientation has probably been defined at the latest by age two, and quite possibly before birth. These first intriguing observations began to catch the attention of researchers. The trait looked biological in origin. The data was indicating that the trait had a genetic source: 11) Adoption studies show that the orientation of adopted children is unrelated to the orientation of their parents, demonstrating that the trait is not environmentally rooted. 12) Twin studies show that pairs of identical (monozygotic) twins, with their identical genes, have a higher-than-average chance of sharing the same orientation compared to pairs of randomly selected individuals; the average (or "background") rate of the trait in any given population is just under 8%, while the twin rate is just over 12%, over 30% higher. 13) The incidence of the minority orientation is strikingly higher in the male population-- about 27% higher-- than it is in the female population, a piece of information that gives indications to the biological conditions creating the trait. 14) Like the trait eye color, familial studies show no direct parent-offspring correlation for the two versions of the trait, but the minority orientation clearly "runs in families," handed down from parent to child in a loose but genetically characteristic pattern. 15) This pattern shows a "maternal effect," a classic telltale of a genetically-loaded trait. The minority orientation, when it is expressed in men, appears to be passed down through the mother. That’s the clinical profile for this trait. What are we talking about???

46. Scientific ideology Human handedness! (Were you fooled?) Despite what some would like you to believe, however, this is not a good analogy for what is currently known about the habitability of homosexuality. Current research (up to 2001) suggests a very weak correlation of homosexual behavior and genetic traits (<0.25). Despite much $, effort and social pressure, the correlation data remain very low. Contemporary moral standards Because of great social pressure, no doubt, more work will be forthcoming soon. Given what you know about objective and subjective science, how can you judge the validity of this work? Homosexuality

47. Genetic Disorders Big Changes

48. Aneuploidy Individuals have one extra or less chromosome (2n + 1 or 2n - 1) Major cause of human reproductive failure Most human miscarriages are aneuploids Polyploidy Individuals have three or more of each type of chromosome (3n, 4n) Common in flowering plants Lethal for humans 99% die before birth Newborns die soon after birth Chromosome Number Problems

49. Nondisjunction n + 1 n + 1 n - 1 n - 1 chromosome alignments at metaphase I nondisjunction at anaphase I alignments at metaphase II anaphase II

50. Down Syndrome • Trisomy of chromosome 21 • Mental impairment and a variety of additional defects • Can be detected before birth • Risk of Down syndrome increases dramatically in mothers over age 35