1. Exam #2 W 7/9 in class Today: Development and Genome Organization

2. Development: differentiating cells to become an organism

4. Cells function differently because they express different genes.

5. The proper control of gene expression is critical for proper development.

6. So development in animals is one way.

7. Inverse relationship between smoking and weight: more smoking : less weight

8. Effect of smoking on fetal development and how that can affect adults

9. Adults exposed to smoke as fetuses have higher risk of obesity and heart disease

10. What is the connection?

11. Obesity, Diabetes, Heart Disease, High Blood Pressure, Some Cancers all may have some origins during fetal development.

12. Adults metabolism may react to poor nutrition as fetuses… Adaptation of Thriftiness or Catch Up Growth.

13. Adults metabolism may react to poor nutrition as fetuses…Adaptation of Thriftiness or Catch Up Growth. Study of babies born during Dutch famine of 1944-45…

14. Adults metabolism may react to poor nutrition as fetuses…Adaptation of Thriftiness or Catch Up Growth. Study of babies born during Dutch famine of 1944-45… 20 years later found that these babies had higher rates of obesity.

15. Adults metabolism may react to poor nutrition as fetuses…Adaptation of Thriftiness or Catch Up Growth. Study of babies born during Dutch famine of 1944-45… 20 years later found that these babies had higher rates of obesity. Precise mechanism is not known

16. What about smoking? 17,000 births studied and checked at age 16 and 33. Fetuses exposed to smoking had increased rate of obesity.

17. What about smoking? 17,000 births studied and checked at age 16 and 33. Fetuses exposed to smoking had increased rate of obesity and more smoking meant more obesity.

18. What about smoking? 17,000 births studied and checked at age 16 and 33. Fetuses exposed to smoking had increased rate of obesity and more smoking meant more obesity. For Mom’s who abstained during pregnancy, no effect on fetus or as adult.

19. What about smoking? 17,000 births studied and checked at age 16 and 33. Fetuses exposed to smoking had increased rate of obesity and more smoking meant more obesity. Smoking during first trimester had same effect as during whole pregnancy.

20. What about smoking? For diabetes more than 10 cigarettes per day gave a 4 times greater risk of diabetes.

21. What about smoking? Risk of high blood pressure also increases with increased exposure to fetus of smoking during pregnancy

22. Why?

23. Nicotine can inhibit hunger and increase energy expenditure. This can lead to poor fetal nutrition.

24. Why? Nicotine causes constriction of blood vessels, and may limit blood flow to the fetus.

25. AAL 38.8 Mammalian circulation

26. Nicotine causes blood vessels to constrict

27. Why? CO in blood decreases delivery of O 2 to fetus.

28. Why? These are all indirect affects leading to “adaptation to thriftiness”… Nicotine can inhibit hunger and increase energy expenditure. Nicotine causes constriction of blood vessels, and may limit blood flow to the fetus. CO in blood decreases delivery of O 2 to fetus.

29. Why? Nicotine and other toxins in smoke may directly affect hormones that direct fetal development.

30. Hormones are molecules produced in one cell and signal another.

31. Why? Nicotine and other toxins in smoke may directly affect hormones that direct fetal development. Including hormones that direct brain development.

32. So, Smoking during pregnancy may have indirect and/or direct affects on fetal development, and these affects may manifest themselves in adults.

33. Correlation of weight (BMI)% Identical twins reared together80 Identical twins reared apart72 Fraternal twins reared together43 Biological siblings34 Parents and children living together26 Adopted children and parents 4 Unrelated children living together 1 Correlation of weight and relatedness The nature of environmental influences on weight and obesity: A behavior genetic analysis. Grilo, Carlos M.; Pogue-Geile, Michael F.; Psychological Bulletin, Vol 110(3), Nov 1991. pp. 520-537. And two books by Matt Ridley: Nature via Nurture (2003) and Genome: the Autobiography of a Species in 23 Chapters (1999)

34. Nature and Nurture: Are traits coded for by genes fixed while traits coded for by the environment are under our control?

35. So development in animals is one way. Why?

36. Fig 23.3 Developmental mutants of Drosophila melanogaster

37. Vertebrate Development: from zygote to adult

38. Early embryo development Fig 19.13

39. Totipotent: ability to differentiate into any cell-type

40. Totipotency is limited to early stages of animal development

41. Why do cells lose totipotency?

43. Mature, differentiated plant cells are totipotent

44. Why do cells lose totipotency?

45. Gene expression can be controlled at many points between DNA and making the final proteins. Changes in the various steps of gene expression control when and how much of a product are produced.

46. Why change gene expression? Different cells need different components Responding to the environment Replacement of damaged/worn-out parts

47. DNA packaging fluctuates… genes being expressed are unpackaged, genes not needed are tightly packaged. Fig 10.21

48. Normally DNA is loosely packaged During mitosis DNA is tightly packaged as chromosomes and individually visible Fig 3.8

49. DNA packaging fluctuates… Some of the tight packaging of DNA is irreversible. Fig 10.21

50. Irreversible packaging of DNA partially explains the loss of totipotency.

51. Stem cells still have totipotency Fig 19.13

52. Embryonic Stem Cells are totipotent Adult Stem Cells are pluripotent (only form some cell types) Fig 19.14

53. What genetic mechanisms regulate/allow development?

54. Increases in cell number play a role… Fig 23.1

55. …so does cell death. Fig 23.1

56. CB 21.19 Development of a mouse paw: yellow areas show dying cells

57. All humans are female for the first nine weeks of development

58. Fig 23.27

59. All humans are female for the first nine weeks of development

60. Flower parts: Complexity from a few simple genes 4 whorls of a flower Fig 23.23

61. Each whorl expresses a specific combination of three genes Fig 23.24

62. Fig 23.23

63. Changing expression of A, B, or C genes changes organ identity Fig 23.24

64. Flower parts: Complexity from a few simple genes 4 whorls of a flower Fig 23.23

65. How does a cell know where it is? Fig 23.2

66. Drosophila Development Fig 23.4

67. Polarity development by mRNA localization Fig 23.5

68. Hox genes regulate the identity of body parts Fig 23.11

69. Expression of hox genes in the embryo give rise to different adult body parts. embryo adult Fig 23.11

70. The order of Hox genes parallels the order of body parts in which they are expressed Fig 23.17

71. Drosophila and vertebrate Hox protein show striking similarities (500 million years since common ancestor) Fig 23.16

72. Many hox proteins have common sequences (these are from Drosophila) Fig 23.13

73. helix-turn-helix: a common DNA-binding motif Fig 23.13

74. Many developmental genes are transcription factors these are from Drosophila

75. “Introduction to Genetic Analysis” 9 th ed. ©2008 by Griffiths et al Fig 12.18 Interaction of genes can set gradients in cells/organisms that signal how different regions should develop.

76. Reporter gene: protein coding region promoter reporter gene (luciferase, etc) easily visualized protein promoter “Introduction to Genetic Analysis” 9 th ed. ©2008 by Griffiths et al Fig 12.19

77. Interaction of genes can set gradients in cells/organisms that signal how different regions should develop. “Introduction to Genetic Analysis” 9 th ed. ©2008 by Griffiths et al Fig 12.18

78. Why change gene expression? Different cells need different components Responding to the environment Replacement of damaged/worn-out parts

79. The order of Hox genes parallels the order of body parts in which they are expressed Fig 23.17

80. 25,00012 How are genomes organized? Tbl 20.2

81. http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=human&CHR=X&MAPS=i deogr[Xpter:Xqter],genes[1.00:153692391.00] Map of human chromosome 20 How does the organization of a genome affect its function?

82. Figure 7-113 Molecular Biology of the Cell, 4th ed by Alberts et al (Adapted from S. Baxendale et al., Nat. Genet. 10:67–76, 1995.) Comparison of Fugu and human huntingtin gene: 7.5 X bigger both have 67 exons, connected by lines (green indicates transposons prevalent in human version) (puffer fish)

83. Some genes have several similar sequences within the genome: known as a gene family Fig 8.7

84. Hemoglobin (carries O 2 in the blood) is comprised of a gene family in humans Fig 8.7

85. Different members of the hemoglobin gene family are expressed at different developmental stages

86. Fetal Hb binds O 2 more strongly than maternal Hb

87. Pseudogenes have the structure of a gene, but are not expressed.

88. Most cells in an organism have the same DNA. Which cells have different DNA?

89. DNA is rearranged in B-cells during antibody production Fig 17.9

90. Each B-cell produces a unique antibody

91. DNA rearrangements in B-cells allow each B-cell to produce a unique antibody Fig 17.9

92. Recently Mobilized Transposons in the Human and Chimpanzee Genomes (2006) Ryan E. Mills et al. The American Journal of Human Genetics 78: 671-679 and Which transposable elements are active in the human genome? (2007) Ryan E. Mills et al. Trends in Genetics 23: 183-191

93. Transposons: mobile DNA

94. Transposons comprise much of human DNA

95. Fig 17.12C Retro-transposons move via an RNA intermediate

96. Tbl 1 Recently Mobilized Transposons in the Human and Chimpanzee Genomes (2006) Ryan E. Mills et al. The American Journal of Human Genetics 78: 671-679

97. Humans and chimpanzees shared a common ancestor about 6 million years ago

98. human chimp Fig 3 Recently Mobilized Transposons in the Human and Chimpanzee Genomes (2006) Ryan E. Mills et al. The American Journal of Human Genetics 78: 671-679 Humans have more transposons than chimps

99. Conclusions: Transposons may play a role in evolution More abundant transposons in humans show “recent” transposon activity

100. Conclusions: Transposons may play a role in evolution More abundant transposons in humans show “recent” transposon activity What affect do transposons have in humans?

101. Fig 3 Recently Mobilized Transposons in the Human and Chimpanzee Genomes (2006) Ryan E. Mills et al. The American Journal of Human Genetics 78: 671-679

102. Tbl 1 Which transposable elements are active in the human genome? (2007) Ryan E. Mills et al. Trends in Genetics 23: 183-191 Does transposition cause disease?

103. An active copy of the L1 transposon ‘jumped’ into the factor VIII gene and caused hemophilia

104. Diseases caused by transposon insertion: Duchenne muscular dystrophy Coffin-Lowry syndrome Fukuyama-type congenital muscular dystrophy (FCMD) colon cancer chronic granulomatous disease X-linked dilated cardiomyopathy familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism neurofibromatosis type 1

105. Active human transposons have been estimated to generate about one new insertion per 10–100 live births Which transposons are mobile?

106. Tbl 1 Which transposable elements are active in the human genome? (2007) Ryan E. Mills et al. Trends in Genetics 23: 183-191 Which transposons are mobile?

107. Comparative genomics also has been used to identify recently mobilized transposons in genetically diverse humans. For example, over 600 recent transposon insertions were identified by examining DNA resequencing traces from 36 genetically diverse humans.

108. Conclusions: Transposons may play a role in evolution More abundant transposons in humans show “recent” transposon activity Transposons are still active, and can cause mutations and disease.

109. Exam #2 W 7/9 in class