Welcome to the Genome. Michael Yudell
Читать онлайн книгу.
that genes were real and led genetics and molecular biology into a new and exciting realm. With the basics of heredity worked out, molecular biology became a driving force in science as the working characteristics of the gene came under scrutiny and study.
To complicate matters, research on and expansion of ideas about how phenotypes might be generated in a heritable fashion apart from genetics first formulated by C. H. Waddington and called epigenetics have made the biology of genes and inheritance even more complex and interesting. Epigenetics is what its name from the Greek implies—“beside genetics”. More precisely it concerns the expression of heritable phenotypes without changes in the DNA of the genome. In other words, epigenetic effects are heritable phenotypic effects without changes in genotype. The most famous case used to demonstrate this phenomenon is the Dutch Hunger Winter. A follow‐up study done on women who suffered through all or part of this 5‐month‐long famine that occurred near the end of World War II (the cause of the famine—which killed 20,000—was a Nazi blockade of food and fuel) revealed some important “heritable” problems. (82) It was reported that during the height of the famine, average caloric intake was less than 400 calories per day (the equivalent of say four pieces of toast). After the war a long‐term study of people who survived the famine was undertaken to determine the impact of famine on the offspring of women whose children were exposed prenatally to famine. As Laura C. Schultz puts it “the Dutch Hunger Winter study, from which results were first published in 1976, provides an almost perfectly designed, although tragic, human experiment in the effects of intrauterine deprivation on subsequent adult health.” (83)
The sad but remarkable results were that diabetes, obesity, microalbuminuria (a kidney malfunction), psychological and cognitive problems, and cardiovascular disease were seen in higher frequency in the offspring of women who lived through the famine than in the offspring of children of their siblings who were not exposed to famine. More remarkable was that women whose fetuses experienced the famine later in prenatal development were affected more severely than fetuses who experienced the famine earlier in their prenatal development (those fetuses that were conceived close to the end of the famine). Researchers could clearly show that this phenomenon was not due to DNA sequence changes. What then could cause this drastic change in the susceptibility to the offspring of women exposed to famine?
To understand this phenomenon completely we need first to describe the structure of DNA as it resides on our chromosomes. The DNA of our chromosomes is wrapped into what is called chromatin. First, the double helix is wrapped twice around a protein complex called a histone core. The histone cores have short parts of their proteins that “tail” off of the wrapped DNA. These “histone tails” are where the epigenetic action takes place, because these parts of the histone proteins can easily be modified by chemical reactions like the addition of methyl groups or acetyl groups. If a histone tail is methylated (or phosphorylated, acetylated, ubiquitylated, or sumoylated) this modification changes the shape of the histone core and disrupts the tightly wound chromatin altering the availability of the DNA in that region to transcription and hence gene expression of that region of the chromosome. Methylation can also occur on the DNA strand itself and this alters the availability of the region of DNA that is methylated to transcription.
Researchers were able to examine the methylation patterns of the DNA in an important gene called insulin‐like growth factor II (IGF2) of women who suffered through the Dutch Hunger Winter. Six decades after the famine, women exposed to it had much less methylation of IGF2 than women who escaped the famine. The implication of the study is that early mammalian development is an incredibly important stage where DNA sequences are highly prone to methylation tags as a result of some environmental shock like famine. Such methylation alters the gene expression of important genes involved in many phenotypes. More importantly, these methylation patterns can persist for long periods of time.
The Dutch Hunger Winter case is only one of many where epigenetic factors like DNA methylation and histone modification have an impact on human health. Epigenetic factors are also important in other organisms and have been implicated in many evolutionary phenomena. (83)
Figure 1.12 The mechanisms of epigenetics.
Credit: National Institutes of Health
REFERENCES
1 1. The Encode Project Consortium. 2012. “An Integrated Encyclopedia of DNA Elements in the Human Genome,” Nature 489: pp.57–74.
2 2. S. Anderson et al. 1981. “Sequence and Organization of the Human Mitochondrial Genome,” Nature 290: pp.457–465; https://www.mitomap.org/MITOMAP; Iakes Ezkurdia et al. 2014. “Multiple Evidence Strands Suggest That There May Be As FewAs 19,000 Human Protein‐Coding Genes,” Human Molecular Genetics 23: pp.5866–5878.
3 3. Kip A. West et al. 2003. “Rapid Akt Activation by Nicotine and a Tobacco Carcinogen Modulates the Phenotype of Normal Human Airway Epithelial Cells,” Journal of Clinical Investigation 111: pp.81–90; Kristine Novak. 2003. “Double Whammy,” Nature Reviews Cancer 3: p.83.
4 4. Peter J. Bowler. 1989. The Mendelian Revolution: The Emergence of Hereditarian Concepts in Modern Science and Society. Baltimore, MA: The Johns Hopkins University Press.
5 5. Euripides, Electra, as quoted in Conway Zirkle. 1951. “The Knowledge of Heredity Before 1900,” Genetics in the Twentieth‐Century: Essays on the Progress of Genetics During Its First 50 Years. L.C. Dunn ed. New York: The MacMillan Company, p.42.
6 6. Hans Stubbe. 1972. History of Genetics: From Prehistoric Times to the Rediscovery of Mendel’s Laws. Cambridge, MA: The MIT Press, pp.51–52.
7 7. Stubbe, 1972, pp.1–6.
8 8. Stubbe, 1972, p.33.
9 9. Ernst Mayr. 1982. The Growth of Biological Thought: Diversity, Evolution, and Inheritance. Cambridge, MA: The Belknap Press of the Harvard University Press, pp. 636–637; Ernst Mayr. 1988. Toward a New Philosophy of Biology: Observations of an Evolutionist. Cambridge, MA: The Belknap Press of Harvard University Press.
10 10. Stephen Jay Gould. 1977. Ontogeny and Phylogeny. Cambridge, MA: The Belknap Press of the Harvard University Press, pp.19–20.
11 11. Staffan Müller‐Wille and Hans‐Jorg Rheinberger. 2007. “Heredity—The Formation of an Epistemic Space,” in: Heredity Produced: At the Crossroads of Biology, Politics, and Culture, 1500–1870. Staffan Müller‐Wille et al. (eds). Cambridge, MA: MIT Press, pp.3–34.
12 12. Müller‐Wille and Rheinberger, 2007, p.12.
13 13. Müller‐Wille and Rheinberger, 2007, p.12.
14 14. Viterslav Orel. 1984. Mendel. New York: Oxford University Press, pp.19–23.
15 15. Robin Marantz Henig. 2000. The Monk in the Garden: The Lost and Found Genius of Gregor Mendel, the Father of Genetics. New York: A Mariner Book, pp.21–22.
16 16. Orel, 1984, pp.28–33.
17 17. Mayr, 1982, p.725.
18 18. Henig, 2000, pp.69–93.
19 19. Henig, 2000, p.86.
20 20. Henig, 2000, pp.85–86.
21 21. D. Peter Snustad and Michael J. Simmons. 2003. Principles of Genetics. New York: John Wiley & Sons, p.55.
22 22. Henig, 2000, p.140.
23 23. Orel, 1984, p.51.
24 24. Henig, 2000, p.140.
25 25. Henig, 2000, p.79.
26 26. Orel, 1984, p.92.
27 27. Ulf Lagerkvist. 1998. DNA Pioneers and Their Legacy. New Haven, CT: Yale University Press, pp.101–102.
28 28.