Preface. What Your Genes Are Wearing
1. Christian, Bixler, et al. (1971).
2. Schwanzel-Fukuda, Jorgenson, et al. (1992); Whitlock, Illing, et al. (2006).
3. See, for example, Bianco and Kaiser (2009) for a recent review of the genetics of Kallmann syndrome.
4. Hipkin, Casson, et al. (1990). French, Venu, et al. (2009) is another case study of twin discordance with respect to Kallmann syndrome, but this discordance is not as severe.
5. See, for example, Wong, Gottesman, et al. (2005).
6. This is a characterization of 9780393070057 in the narrow sense, which is the definition of 9780393070057 I will use throughout this book. 9780393070057 in the broad sense is not confined to alterations in DNA. See Jablonka and Lamb (2002) for a good historical and conceptual overview of the term.
7. See the following regarding epigenetic sources of discordance: for lupus, Ballestar, Esteller, et al. (2006); and for Alzheimer’s disease, Mastroeni, McKee, et al. (2009). Singh and O’Reilly (2009) provide evidence of epigenetic divergence in monozygotic twins discordant for schizophrenia; see also Kato, Iwamoto, et al. (2005).
Chapter 1. A Grandmother Effect
1. Stein and Susser (1975).
2. This ongoing longitudinal study is an international collaboration, involving several departments of the Academic Medical Center in Amsterdam and the MRC (Medical Research Council) at the University of Southampton in England.
3. Smith (1947).
4. Stein, Susser, et al. (1972); Ravelli, Stein, et al. (1976).
5. Hoch (1998). For the association between famine and depression, see Brown, van Os, et al. (2000); between famine and antisocial personality disorders in males, see Neugebauer, Hoek, et al. (1999).
6. Stein, Ravelli, et al. (1995); Lumey and Stein (1997); Lumey (1998).
7. Ravelli, van der Meulen, et al. (1998); Roseboom, van der Meulen, et al. (1999, 2000a, 2000b); Painter, Roseboom, et al. (2005).
8. Roseboom, de Rooij, et al. (2006).
9. Tobi, Lumey, et al. (2009).
10. Painter, Osmond, et al. (2008).
Chapter 2. Directors, Actors, Stagehands
1. Allen (1978) is an outstanding biography of Morgan from which this discussion benefited.
2. The original publications were Watson and Crick (1953a, 1953b). Watson subsequently wrote an account of this research—from his perspective—for a lay audience (Watson 1968), which is much more gossipy than most scientific memoirs of this sort.
3. The original formulation—of George Beadle and Edward Tatum—was actually “one gene = one enzyme” (Beadle and Tatum 1941). This was modified in the late 1950s to “one gene = one polypeptide (protein)” to include nonenzymatic proteins.
4. Posttranslational processing should actually be considered the third stage of protein synthesis since translation products are rarely functional. During posttranslational processing, many changes are made to the protoprotein to turn it into something that is physiologically useful. A goodexample is the protoprotein templated by the proopiomelanocortin (POMC) gene. The POMC protoprotein is cleaved into one of 20 different smaller protein hormones, depending on the type of cell in which the protoprotein finds itself. In the cells of one lobe of the pituitary gland (a small endocrine gland at the base of the brain), POMC is cleaved into adrenocorticotropic hormone (ACTH), which functions in the stress response. In cells of another part of the pituitary, POMC is cleaved into the opiate [.beta]-endorphin. In skin cells, POMC is cleaved into melanocyte stimulating hormone, which promotes production of the black pigment melanin. The protein product of the POMC gene is not a simple function of its base sequence, but rather is determined at the cellular level.
Other sorts of posttranslational processing take us even further from the DNA base sequence. Sometimes the amino acid that was coded is chemically converted into another amino acid that was not coded. In other cases, one amino acid is substituted for another amino acid in the protoprotein. Sometimes the substitute amino acid is not even one of the 20 amino acids for which there is a code. In these cases, the relationship between the DNA base sequence and the protein amino acid sequence is altered at the cellular level.
5. The executive cell view advocated here has a long history in biology. Mention should be made of Ernest Everett Just (1883–1941) among the early proponents; see, for example, Just (1939). Just formulated an idea of gene action and reaction (cytoplasm-nucleus interactions) very much along the lines advocated here (see, for example, Sapp 2009 and Newman 2009).
6. Even in the first two stages of protein synthesis, the process is shaped in a cell-dependent manner. Stage 1, transcription, is actually a two-step process. The first step is the formation of a pre–messenger RNA. The second step is the transformation of the pre-mRNA into the final mRNA, the mRNA that will actually serve as the template for protoprotein construction. A lot happens during this second step. Each gene actually consists of two or more separate coding regions called exons, separated by noncoding regions called introns. All of it—exons and introns—is transcribed into the pre-mRNA; then, following transcription, the intronic RNA bits are removed and the exons are spliced together. For many genes, the exons can be spliced together in different ways, each spliced variant constituting a different protein. This is called alternative splicing, which is another way that more than one protein can be constructed from one gene.
Alternative splicing is but one way in which the initial transcript is modified according to the cellular environment. After all of the splicing comes RNA editing. During the editing process, some individual bases in the mRNA sequence undergo a chemical conversion into a different base, one that was not encoded in the DNA. So, even the correspondence between the DNA base sequence and the mRNA sequence is not always one-to-one.
7. See, for example, McClellan and King (2010) and Galvan, Falvella, et al. (2010).
8. See, for example, Rakyan, Blewitt, et al. (2002), and Hatchwell and Greally (2007).
9. Griffiths and Neumann-Held (1999); Beurton, Falk, et al. (2000); Stoltz, Griffiths, et al. (2004); Rheinberger (2008); Portin (2009).
10. Genes that don’t code for proteins are often referred to as “RNA genes.”
11. The term control panel is purely metaphoric, intended to aid the intuitions of nonbiologists regarding garden-variety gene regulation. Moreover, the regulatory elements that comprise the control panel need not be physically contiguous. Finally, some or all of the regulatory elements that comprise a control panel for a particular gene may also function in the regulation of other genes.
Chapter 3. What Roids Wrought
1. Guerriero (2009) summarizes what is known about the distribution of androgen receptors in the brain.
2. For an example from fish studies, see Hannes, Franck, et al. (1984). Burmeister, Kailasanath, et al. (2007) reported that androgen receptor levels dropped in response to a drop in social status. The best evidence of this effect in humans comes from studies of athletes after competition. For tennis players, Booth, Shelley, et al. (1989) reported a drop in testosterone levels in those who lost a match and an elevation of testosterone levels in winners. But the effect of competition outcome (or aggressive interactions in other animals) on testosterone levels is actually quite complex. See, for example, Suay, Salvador, et al. (1999). I am simplifying things here.
3. More precisely, pituitary GT levels are controlled by a small population of neurons within the hypothalamus called the preoptic area (POA); see, for example, Francis, Soma, et al. (1993).
4. In the scientific literature, the acronym for gonadotropin releasing hormone is GnRH, not GTRH. I use GTRH partly because it is easier for the uninitiated to assimilate, partly because it is more consistent with the standard abbreviation for gonadotropin (GT).
5. For more detailed accounts of the relationship between dominance, testosterone, and GTRH levels, see Francis, Jacobson, et al. (1992).
6. Francis, Soma, et al. (1993).
7. White, Nguyen, et al. (2002). Initially, though, there is a transient increase in the activity of the GTRH gene in males who are making a downward social transition (Parikh, Clement, et al. 2006), so the effect of social status on the GTRH gene itself is complicated. It may well be that transcription of this gene is affected less than its translation. Not all messenger RNAs get translated to protoproteins; it is often the case that more mRNAs are made than proteins (in this case, GTRH). The excess mRNA gets degraded. In the case of the GTRH gene, the rate of this degradation may be related to social status. GTRH mRNA may be degraded at a higher rate in nonterritorial males than in territorial males.
8. Renn, Aubin-Horth, et al. (2008).
9. For change in androgen receptor gene, see Burmeister, Kailasanath, et al. (2007); for change in GTRH receptor gene, see Au, Greenwood, et al. (2006).
Chapter 4. The Well-Socialized Gene
1. After viewing The Deer Hunter in March, 1979, Jan Scruggs, a Vietnam veteran, hit on the idea of a memorial with the names of all who were killed during the conflict (Ashabranner 1988).
2. Glucocorticoids such as cortisol, unlike testosterone, also exert effects through two nongenomic pathways—first by way of protein-protein interactions with other transcription factors (see, for example, Revollo and Cidlowski 2009), and second by way of nonnuclear receptors. This latter pathway is thought to underlie the most rapid responses to these hormones (Evanson, Tasker, et al. 2010).
3. Another good indicator of a pathological stress response is the neuropeptide arginine vasopressin (AVP); see, for example, Lightman (2008). Both CRH and AVP increase rapidly in response to an acute stressor, thoughchronic stress often results in a reduction in CRH over time. AVP increases with chronic stress, however.
4. Ventolini, Neiger, et al. (2008); Bevilacqua, Brunelli, et al. (2010).
5. Seckl and Holmes (2007); Drake, Tang, et al. (2007).
6. Kapoor, Leen, et al. (2008); Seckl (2008).
7. See, for example, Seckl and Meaney (2006), and Kapoor, Petropoulos, et al. (2008).
8. See PTSD Forum: Promoting Growth Through Healing, http://www.ptsdforum.org).
9. Laugharne, Janca, et al. (2007).
10. Yehuda, Bell, et al. (2008); Yehuda and Bierer (2007).
11. Yehuda, Engel, et al. (2005); Brand, Engel, et al. (2006).
12. Dean, Yu, et al. (2001). The effect of synthetic glucocorticoids is highly sex-specific and depends critically on the timing of the exposure (Kapoor and Matthews 2008; Kapoor, Kostaki, et al. 2009).
13. Kapoor, Petropoulos, et al. (2008); Emack, Kostaki, et al. (2008).
14. Liu, Diorio, et al. (1997); Francis and Meaney (1999); Francis, Champagne, et al. (2000).
15. Francis, Diorio, et al. (1999).
16. Liu, Diorio, et al. (1997).
17. Francis, Champagne, et al. (1999); Szyf, Weaver, et al. (2005).
18. Weaver, Cervoni, et al. (2004).
19. The methyl group does not attach just anywhere on the DNA, but rather specifically to a cytosine that is adjacent to a guanine. Since all of the bases in the DNA sequence are separated by a phosphorus molecule, the convention is to label these sites “CpG.”
20. Goldberg, True, et al. (1990); Kaminsky, Petronis, et al. (2008); Coventry, Medland, et al. (2009).
Chapter 5. Kentucky Fried Chicken in Bangkok
1. Neel (1962).
2. See, for example, Rothwell and Stock (1981), Speakman (2006, 2008), and Gibson (2007).
3. Neel (1999) abandoned the thrifty-genes hypothesis. Newer versions include Prentice, Hennig, et al. (2008), and Wells (2009).
4. See, for example, Hinney, Vogel, et al. (2010).
5. In this respect, obesity resembles many other complex traits (Petronis 2001; Smithies 2005).
6. For treatments of the story about the complexity of obesity genes, see Shuldiner and Munir (2003); Damcott, Sack, et al. (2003); Swarbrick and Vaisse (2003).
7. De Boo and Harding (2006) is a good summary of the diseases linked to birth weight.
8. Warner and Ozanne (2010). This is also called the developmental origins hypothesis to distinguish it from gene-centered theories (Mcmillen and Robinson 2005; Waterland and Michels 2007).
9. See, for example, Barker, Robinson, et al. (1997), and Hales and Barker (2001).
10. See, for example, Susser and Levin (1999).
11. For reviews, see Junien and Nathanielsz (2007) and Burdge, Hanson, et al. (2007).
12. Seckl (2004); Seckl and Holmes (2007).
13. Lillycrop, Slater-Jefferies, et al. (2007); Kim, Friso, et al. (2009). There are a number of DNA methyltransferases (Dnmt); the discussion in the text that follows concerns Dnmt1.
14. Bellinger and Langley-Evans (2005); Lillycrop, Phillips, et al. (2005).
15. Lillycrop, Slater-Jefferies, et al. (2007).
16. It is not only glucocorticoid receptor gene (GR) expression in the liver that influences these conditions. For example, GR expression in adipose tissue (fat) also plays an important role in the metabolic syndrome (see, for example, Walker and Andrew 2006). For an example of how GR expression in the liver is related to diabetes, see Simmons (2007). For a general overview of the relationship between GRexpression and the metabolic syndrome, see Witchel and DeFranco (2006). And for a good review of tissue-specific glucocorticoid action, see Gross and Cidlowski (2008).
17. Meaney, Szyf, et al. (2007).
18. Shively, Register, et al. (2009).
19. Bjorntorp and Rosmond (2000); Taylor and Poston (2007).
20. There are a number of histones, divided into five classes, which have combinatorial properties analogous to the bases in the genetic code, and hence comprise a “histone code” (Strahl and Allis 2000). This histone code would be an epigenetic code. But I don’t find this code talk helpful.
21. Aagaard-Tillery, Grove, et al. (2008); Delage and Dashwood (2008).
22. In the methylation of DNA, the methyl group is bonded to a cytosine base; in histone methylation, the methyl group is bonded to an amino acid, usually a lysine or arginine. As in DNA methylation usually (but not always), histone methylation has a suppressive effect on gene expression. There are a number of other sorts of posttranslational modifications of histones with epigenetic consequences, including acetylation, in which an acetyl group (CH3CO) is added to the lysine of the histone. Acetylation of histones usually (but not always) promotes gene expression.
23. Lillycrop, Slater-Jefferies, et al. (2007).
24. See, for example, Simmons (2007); Hess (2009); Zeisel (2009).
25. Kim, Friso, et al. (2009).
26. Rogers (2008); Leeming and Lucock (2009).
27. Jones, Skinner, et al. (2008); Currenti (2010); Ptak and Petronis (2010).
Chapter 6. Twigs, Trees, and Fruits
1. Beck and Power (1988); Porton and Niebrugge (2002). Not surprisingly, such sexually incompetent males also have reduced reproductive success (Meder 1993; Ryan, Thompson, et al. 2002). It is worse for hand-raised male chimps, however, almost half of which (46 percent) fail to exhibit “appropriate sexual behavior” (King and Mellen 1994).
2. I trace all work on social inheritance to the pioneering research of Denenberg and Rosenberg (1967) who demonstrated that manipulations of female rats as pups affected the emotionality (as open field activity, which is roughly a behavioral stress measure) and weight of their grand-offspring. This is the first grandmother effect that I am aware of. I believe this work went largely unappreciated until Michael Meaney and his colleagues recognized its importance.
3. Harlow and Zimmerman (1959).
4. Harlow, Harlow, et al. (1971).
5. Ruppenthal, Arling, et al. (1976); Champoux, Byrne, et al. (1992).
6. Champagne and Meaney (2001).
7. Champagne, Weaver, et al. (2006); Champagne and Curley (2009).
8. Champagne, Diorio, et al. (2001); Ross and Young (2009).
9. Champagne, Weaver, et al. (2006).
10. Bardi and Huffman (2006); McCormack, Sanchez, et al. (2006).
11. For maternal effects on Japanese macaques, see Bardi and Huffman (2002, 2006); for maternal effects on pigtail macaques, see Weaver, Richardson, et al. (2004).
12. Maestripieri (2003, 2005).
13. Greenfield and Marks (2010).
14. Bradley, Binder, et al. (2008).
15. Serbin and Karp (2004); Bailey, Hill, et al. (2009).
16. McGowan, Sasaki, et al. (2009). See also Weaver (2009).
17. Patton, Coffey, et al. (2001); DiBartolo and Helt (2007); Otani, Suzuki, et al. (2009). See Joyce, Williamson, et al. (2007), for effects of affectionless control on the stress axis.
18. Engert, Joober, et al. (2009); Kochanska, Barry, et al. (2009); Kaitz, Maytal, et al. (2010).
19. See, for example, Calatayud and Belzung (2001), Champagne and Meaney (2001), and Weaver (2009).
20. See, for example, Calatayud and Belzung (2001), and Champagne and Curley (2009).
21. Tyrka, Wier, et al. (2008).
22. Weaver, Meaney, et al. (2006).
23. Weaver, Champagne, et al. (2005).
Chapter 7. What Wright Wrought
1. Castle, Carpenter, et al. (1906). For a brief biography of Castle’s scientific life, see Snell and Reed (1993).
2. Provine (1986) is an excellent biography of Wright, with an emphasis on his contributions to population genetics and evolutionary biology.
3. Castle and Wright (1916); Wright (1916, 1927).
4. Voisey and van Daal (2002) is a detailed account of the physiological actions (at the molecular level) of the agouti protein and its regulation.
5. Wilson, Ollmann, et al. (1995).
6. Miltenberger, Mynatt, et al. (1997); Morgan, Sutherland, et al. (1999). The viable yellow mutation actually occurs somewhat upstream of the agouti locus itself. A mobile genetic element called a retrotransposon drives so-called ectopic expression of this gene (Duhl, Stevens, et al. 1994; Duhl,Vrieling, et al. 1994). The specific type of retrotransposon in this case is an intracisternal A particle (IAP). IAPs are involved in other dominant mutations at this locus as well. It is the IAP that is methylated, not the control panel of the agouti allele.
7. Wolff, Roberts, et al. (1986).
8. Wolff (1996).
9. Michaud, van Vugt, et al. (1994).
10. Morgan, Sutherland, et al. (1999).
11. Martin, Cropley, et al. (2008).
12. Morgan, Sutherland, et al. (1999).
13. Wolff, Kodell, et al. (1998); Dolinoy, Weidman, et al. (2006).
14. Cropley, Suter, et al. (2006). But see Waterland, Travisano, et al. (2007) for a different interpretation of these results. Blewitt, Vickaryous, et al. (2006) provides evidence that the methylation state itself is not the inherited epigenetic state in these experiments.
15. Rakyan, Preis, et al. (2001); Waterland, Travisano, et al. (2007).
16. See, for example, Reik, Dean, et al. (2001).
17. Rakyan, Chong, et al. (2003). Interestingly the Axinfu mutation, like the Avy mutation, involves an IAP (see Note 6).
18. Reviewed in Roemer, Reik, et al. (1997). Two of the best examples are studied in Rassoulzadegan, Grandjean, et al. (2006) and Rassoulzadegan, Grandjean, et al. (2007) involving Kit, another locus involved in coat coloration. This form of epigenetic inheritance appears to involve an RNA-based form of epigenetic regulation that I will discuss later.
19. Martin, Ward, et al. (2005); Morak, Schackert, et al. (2008). But see Chong, Youngson, et al. (2007).
20. Jablonka and Raz (2009). One reason that epigenetic inheritance is much more common in plants (and fungi) is that they don’t exhibit the early segregation of the germ line characteristic of muticellular animals. Jablonka and Raz further speculate that epigenetic inheritance is more adaptive in plants and fungi because they lack complex nervous systems and hence behavioral plasticity. These authors further speculate that epigenetic inheritance is actively selected against in highly mobile animals because they experience less-predictable environments, and as such there is less correlation between the environments of parent, offspring, and grand-offspring.
21. See Jablonka and Raz (2009) for a thorough review.
22. Richards (2006) and Henderson and Jacobsen (2007) are excellent reviews of epigenetic inheritance in plants.
23. Stokes, Kunkel, et al. (2002); Stokes and Richards (2002). This RNA-based form of epigenetic inheritance (see also Note 18) is often referred to as a paramutation, in which an epiallele in one generation affects the expression of the other allele at that locus in the next generation.
24. Koornneef, Hanhart, et al. (1991).
25. Zilberman and Henikoff (2005).
26. Here I am adopting the terminology of Youngson and Whitelaw (2008).
27. Moreover, grandsons of those who experienced plentiful food were more susceptible to diabetes (Pembrey, Bygren, et al. 2006). For a discussion of the role of sperm 9780393070057 in development, see Carrell and Hammoud (2010). For a mechanism of epigenetic inheritance via histones and chromatin remodeling, see Puri, Dhawan, et al. (2010).
Chapter 8. X-Women
1. As Dobyns, Filauro, et al. (2004) emphasize, most X-linked traits are neither dominant nor recessive but exhibit variable penetrance. There is evidence for such variability in color blindness as well.
2. Kraemer (2000). There are, of course, many other factors for this higher male mortality risk than just the male X deficit. For an interesting sociological study of how men and women tend to explain these differences, see Emslie and Hunt (2008).
3. This pioneering work in neurobiological genetics was conducted by Jeremy Nathans and his coworkers (Nathans, Piantanida, et al. 1986; Nathans, Thomas, et al. 1986). See also Nathans (1999).
4. Jordan and Mollon (1993); Jameson, Highnote, et al. (2001).
5. X-chromosome 9780393070057 can be traced to Mary Lyon’s discovery of X inactivation (Lyon 1961); see also Lyon (1971) and Lyon (1989). Susumu Ohno, a giant in the field of genetics, especially in sex chromosome research, was the first to propose methylation as a mechanism for inactivation (Ohno 1969). The important contribution of Ohno to this field is summarized in Riggs (2002). Lyon (1995) is a historical overview of research on X-chromosome inactivation. Chow, Yen, et al. (2005) is agood overview of what is known of the 9780393070057 of X inactivation. Urnov and Wolffe (2001) is a good history of 9780393070057 that covers the role of X inactivation in the development of the field (see also Holliday 2006). Jablonka (2004) provides an evolutionary perspective on the 9780393070057 of X inactivation.
6. Lyon (1961).
7. Brown and Greally (2003); Berletch, Yang, et al. (2010).
8. Namekawa, VandeBerg, et al. (2007); Deakin, Chaumeil, et al. (2009). There is some expression of paternal X genes in some tissues (VandeBerg, Johnston, et al. 1983).
9. Some features of autosomes appear to prevent complete inactivation; see, for example, Popova, Tada, et al. (2006).
10. Most dramatically, Cc completely lacked any of the orange coloration of Rainbow, indicating that an X-linked gene involved in the production of orange fur was randomly turned off early in Cc’s development.
11. This is certainly true of mice (Wagschal and Feil 2006); it is less clearly the case in humans (Moreira de Mello, de Araujo, et al. 2010).
12. Erwin and Lee (2008).
13. There is some evidence for this (Tiberio 1994; Loat, Asbury, et al. 2004; Haque, Gottesman, et al. 2009). Moreover, there is a report of female monozygotic twins discordant for red-green color deficiency who exhibit different X-inactivation patterns in their cone cells (Jorgensen, Philip, et al. 1992).
14. Pardo, Pérez, et al. (2007); Rodriguez-Carmona, Sharpe, et al. (2008).
15. Verriest and Gonella (1972); Cohn, Emmerich, et al. (1989).
16. Deeb (2005) is a nice summary of the molecular biology discussed here. See also Hayashi, Motulsky, et al. (1999).
17. Jordan and Mollon (1993).
18. Hunt, Williams, et al. (1993); Shyue, Hewett-Emmett, et al. (1995).
19. Tovee (1993).
20. Jacobs (1998, 2008); Jacobs and Deegan (2003).
Chapter 9. Horses Asses
1. I got this information online from The Mule Page, http://www.phudpucker.com/mules/mule.htm.
2. The Reivers (1962).
3. There is a characteristic cognitive deficit known as Turner neurocognitive phenotype (Ross, Roeltgen, et al. 2006), which is primarily restricted to spatial and mathematical reasoning. Turner syndrome is also associated with autism.
4. Parent-of-origin effects in Turner syndrome have been reported for growth (Hamelin, Anglin, et al. 2006; but see Ko, Kim, et al. 2010) and for cognition (see, for example, Skuse, James, et al. 1997, and Crespi 2008).
5. Cassidy and Ledbetter (1989).
6. Chen, Visootsak, et al. (2007).
7. Driscoll, Waters, et al. (1992); Williams, Angelman, et al. (1995).
8. Bittel, Kibiryeva, et al. (2005). This state of permanent paternal X inactivation is referred to as uniparental disomy.
9. Weksberg and Squire (1996); Delaval, Wagschal, et al. (2006).
10. Weksberg, Shuman, et al. (2005). Wilms’ tumor is an embryonic cancer. Embryonic cancers are rare, generally occurring only when there are major developmental problems.
11. See, for example, Reik (1989) and Shire (1989).
12. Reik, Dean, et al. (2001).
13. Santos and Dean (2004).
14. There is increasing evidence of defects in the reprogramming of imprinted genes in embryos generated through assisted reproductive technologies (ARTs); see, for example, Grace and Sinclair (2009), Laprise (2009), and Owen and Segars (2009). Defective reprogramming of imprinted genes is also thought to explain why mammal cloning is so hard to accomplish.
15. Lewis and Reik (2006).
16. When paternally imprinted genes are overexpressed, the result is often an abnormally large placenta; see, for example, Reik, Constancia, et al. (2003), and Fowden, Sibley, et al. (2006).
17. Overexpression of paternally imprinted genes often results in fetal overgrowth (Cattanach, Beechey, et al. 2006; Biliya and Bulla 2010).
18. The inhibitor of IGF2 under discussion here is called H19, which is an untranslated mRNA. The regulation of IGF2 is quite complex, and involves other loci and alleles.
19. Uniparental disomy of this sort is responsible for about 20 percent of the cases of Beckwith-Wiedemann syndrome (Cooper, Curley, et al. 2007).
20. See, for example, Bartholdi, Krajewska-Walasek, et al. (2009).
21. Kinoshita, Ikeda, et al. (2008).
22. The syndromes discussed here are but a tiny sample of what goes wrong health-wise when imprinting goes awry. See Amor and Halliday (2008) for a review of imprinting-related disorders. Wadhwa, Buss, et al. (2009) discuss imprinting disorders in the context of 9780393070057 and disease generally. Murphy and Jirtle (2003) discuss the costs of monoallelic expression in an evolutionary context.
23. See, for example, Vos, Dybing, et al. (2000), and Hayes, Stuart, et al. (2006).
24. For a discussion of the sexual plasticity of fishes relative to that of other vertebrates, see Francis (1992).
25. Gross-Sorokin, Roast, et al. (2006). Intersex males—that is, genetic males with ovarian features—are also common (Jobling, Williams, et al. 2006).
26. Milnes, Bermudez, et al. (2006).
27. Crews (2010) provides an excellent overview of endocrine disruptors and imprinted genes. See also Prins (2008) and Skinner, Manikkam, et al. (2010).
28. Virtanen, Rajpert-De Meyts, et al. (2005); Diamanti-Kandarakis, Bourguignon, et al. (2009); Wohlfahrt-Veje, Main, et al. (2009); Soto and Sonnenschein (2010). Some of these later-developing syndromes come by way of the agouti locus, which is maternally imprinted (Morgan, Sutherland, et al. 1999). Bisphenol A (BPA) shifts the coat color of Avy toward the yellow (and hence unhealthy) part of the spectrum through its hypomethylating effects (Dolinoy, Huang, et al. 2007). Interestingly, a high-folate diet reverses this effect. Bernal and Jirtle (2010) warn that BPA exposure could have significant health consequences for humans, both in this generation and, through epigenetic inheritance, future generations.
29. Anway, Cupp, et al. (2005).
30. Chang, Anway, et al. (2006); Stouder and Paoloni-Giacobino (2010).
31. Anway and Skinner (2008).
32. Shi, Krella, et al. (2005).
Chapter 10. Sea Urchins Are Not Just to Eat
1. Monroy (1986) is an excellent overview of the importance of the sea urchin in developmental biology.
2. See Bodemer (1964) for the early history of preformationism. Caspar Friedrich Wolf (1733–1794), considered one of the founders of embryology, decisively refuted the early forms of preformationism.
3. For more detailed discussions regarding the differences between preformationism and epigenesis, see Van Speybroeck, De Waele, et al. (2002), and Maienschein (2008).
4. This version of preformationism was first advocated by August Weismann and is known as the mosaic theory of development (see the references cited in Note 3).
5. Scott Gilbert provides a nice account of these experiments in his Developmental Biology (pp. 287–289, in the 3rd ed., 1991).
6. For my purposes here, self-organizing processes have two features: first, the relevant elements act in parallel (simultaneously) rather than serially; second, the executive function is distributed, not centralized. See ten Berge, Koole, et al. (2009) for a good example of self-organization during early development. In that study, the investigators focused on the activity of the gene Wnt and demonstrated the effects of undirected cellular interactions on its expression.
7. For this reason, Driesch could be considered the first proponent of the executive cell view advocated in this book.
8. Spooky notions like entelechy are generally subsumed under the term “vitalism” by biologists. Vitalism should be distinguished from organicism, which is a thoroughly materialist (nonspooky) but nonreductionist framework for understanding development and other complex phenomena. By nonreductionist, I mean a rejection of the notion that an explanation confined to a characterization of the properties of the parts is sufficient for explaining the whole. Put another way, reductionist explanations are entirely bottom-up, while nonreductionist explanations are both bottom-up and top-down.
Important organicist developmental biologists include Karl Ernst von Baer (1792–1876), Charles Otis Whitman (1842–1910), Oskar Hertwig (1849-1922), Hans Spemann (1869–1941), Ross Granville Harrison (1870–1959), Ernest Everett Just (1883–1941), Paul Alfred Weiss (1898–1989), Viktor Hamburger (1900–2001), Joseph Needham (1900–1995), and Conrad Waddington (1905–1975). Scott Gilbert is a prominent contemporary organicist; see Gilbert and Sarkar (2000) for an excellent history of organicism. For a good account of contemporary organicism (under another name), see Kirschner, Gerhart, et al. (2000). Organicists reject the machine analogy for biological systems. Organicist developmental biologists reject preformationism.
9. Epigenesists do not deny the importance of these initial conditions (particularly the genome) in determining the adult form, only that these initial conditions do not comprise the adult form, however latently.
10. In contradistinction to the executive genome view, the executive cell perspective that I advocate falls into the category of organicist versions of epigenesis.
11. Ultimately, I would suggest, the directorial intuition in preformationism (and creationism) reflects a deep anthropomorphism that stems from the way we relate to our artifacts. I believe that this anthropomorphism is a major impediment to understanding complex processes such as development (and evolution).
12. This point is made especially well in Susan Oyama’s The Ontogeny of Information (1985). For insightful critiques of the “genome as recipe/program” metaphors, see Nijhout (1990), Atlan and Koppel (1990), Moss (1992), Fox Keller (1999, 2000), and Pigliucci (2010). Both Atlan and Koppel, and Fox Keller, note that there is a problem with the data-program distinction as well as the software-hardware distinction noted here. Nijhout advocates treating genes as material resources for the developing organism, as advocated here. This way of thinking about genes and genomes is also characteristic of advocates for developmental systems theory (I prefer the term “developmental systems perspective”). See, for example, Oyama (1985), and Griffiths and Gray (1994).
13. Here I am ignoring the fact that a small percentage of cells acquire slightly different genomes through somatic mutations. These somatic mutations do not, however, figure in normal cellular differentiation. I should also note that red blood cells do not have genomes when mature.
14. The canonical microRNA is lin-4, first identified in the nematode Caenorhabditis elegans (Horvitz and Sulston 1980). It is 22 nucleotides in length, with a hairpin structure characteristic of microRNAs. For good reviews, see Eddy (2001) and Storz, Altuvia, et al. (2005); see also Ying, Chang, et al. (2008).
15. Originally, the term RNA interference (RNAi) referred to the actionsof the related class of regulatory noncoding RNAs called small interfering RNAs (siRNAs); RNAi now encompasses the related microRNAs as well.
16. Schickel, Boyerinas, et al. (2008).
17. Georgantas, Hildreth, et al. (2007).
18. See, for example, Stocum (2004), and Straube and Tanaka (2006).
19. For dedifferentiation in repair of cartilage, see Schulze-Tanzil (2009). For dedifferentiation in repair of the peripheral nervous system, see Chen, Yu, et al. (2007). Bonventre (2003) discusses dedifferentiation in kidney repair.
20. Stocum (2002). Interestingly, biochemicals obtained from amphibians can boost regeneration in mammals, an indication that the mammalian genome can epigenetically respond in an ordered way to environmental influences to which it is never normally exposed.
21. Fibroblast cells were used in these experiments (see Takahashi, Okita, et al. 2007); see also Diez-Torre, Andrade, et al. (2009), and Lyssiotis, Foreman, et al. (2009). Kim, Zaehres, et al. (2008) used neural stem cells to generate pluripotent cells. The pluripotent cells generated in these experiments are called induced pluripotent stem cells (iPSCs) to distinguish them from actual embryonic stem cells (ESCs); iPSCs seem to have the essential properties of ESCs, including the capacity to differentiate into all three of the primary germ layers, but they may have subtle differences (Ou, Wang, et al. 2010). Araki, Jincho, et al. (2010) document the stages of dedifferentiation from adult fibroblast cell to iPSC.
22. Okano (2009). Fibroblasts can also be transformed into neurons without going through a pluripotent stage (Masip, Veiga, et al. 2010). This process is known as transdifferentiation (Collas and Hakelien 2003).
23. This line of research stems from an important study by Mintz and Illmensee (1975), which demonstrated that when malignant mouse teratocarcinoma cells are transplanted into the blastocyst (the mammalian form of blastula) of a mouse, they are normalized and contribute to the formation of a variety of normal cell types. Recently, Hochedlinger, Blelloch, et al. (2004) transplanted the genome of a mouse melanoma cell into an enucleated oocyte, from which they derived normal embryonic stem cells. From these stem cells, they generated normal-appearing mice.
24. Kulesa, Kasemeier-Kulesa, et al. (2006); Hendrix, Seftor, et al. (2007).
25. Collas (2010) is typical in this regard, in the context of cellular differentiation.
26. For the minimalist notion of programming in situated robotics, see Hendriks-Jansen (1996). Wolfram (2002) is an expanded, semi-mystical view of the significance of a minimalist program, motivated by Wolfram’s research on cellular automata.
27. Passier and Mummery (2003).
28. Moreover, there are subtle differences between embryonic stem cells (ESCs) and induced embryonic stem cells (iPSCs) that are clinically relevant. For example, ESCs have proved much more efficient in promoting neuronal redifferentiation than iPSCs have (Tokumoto, Ogawa, et al. 2010).
29. This is how Conrad Waddington, who coined the term epigenetic, describes its derivation: “Some years ago I introduced the word ‘epigenetic,’ derived from the Aristotelian word ‘epigenesis,’ which had more or less passed into disuse, as a suitable name for the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being” (Waddington 1968).
30. In essence, Waddington’s goal was a synthesis of what was then known as “embryology” and genetics; we now call this synthesis developmental biology. I consider Waddington the father of modern developmental biology.
31. With respect to the causal primacy of genome or cytoplasm within a cell, Waddington said, “Of course, to insist on pursuing the argument ad infinitum leads to a ridiculous question, like asking whether the hen or the egg came first, because finally the gene and the cytoplasm are dependent on each other and neither could exist alone” (Waddington 1935/1946). This is a good encapsulation of the executive cell view.
32. The responsiveness of the genome is conveyed in the following quote from Waddington (1962): “…the almost universal occurrence in higher organisms of feedback between cytoplasm and genes, such that the nature of the cytoplasm determines the intensity of the syntheses controlled by the various genes in the nucleus.” This description is also a nice characterization of modern 9780393070057.
33. See, for example, Gurdon and Melton (2008), and de Souza (2010).
Chapter 11. Pray for the Devil
1. This was Hobbes’s assessment—in his magnum opus, Leviathan—of the human condition in the state of nature, that is, prior to the civilizinginfluence of the state. In my edition (edited by R. Tuck), the actual quote is “And the life of man, solitary, poore, nasty, brutish and short.” (Hobbes, 1651/1996).
2. Wroe, McHenry, et al. (2005).
3. McCallum (2008).
4. This mechanism by which cancer cells are directly transmitted from one individual to another is called allografting (Pearse and Swift 2006).
5. The poor immune recognition has been attributed to low diversity at major histocompatibility complex (MHC) loci, the protein products of which, in certain immune cells, are responsible for recognizing the difference between self and nonself (Siddle, Kreiss, et al. 2007). Low genetic variation at these sites makes a seeming match between self and nonself more likely. Murgia, Pritchard, et al. (2006) have proposed that the reason for high MHC diversity typically found in most animals is to prevent contagious cancers.
6. For the bottleneck in cheetah populations, see O’Brien, Wildt, et al. (1983). For tolerance of skin allografts, see Sanjayan and Crooks (1996).
7. Murgia, Pritchard, et al. (2006).
8. Hsiao, Liao, et al. (2008).
9. Pearse and Swift (2006).
10. See, for example, Daley (2008).
11. Loh, Hayes, et al. (2006). Murchison, Tovar, et al. (2010), however, proposed that DFTD cells are derived from Schwann cells, a type of glia (support cells in the nervous system) that supply nutrients to axons in the peripheral nervous system.
12. Tu, Lin, et al. (2002); Sales, Winslet, et al. (2007); Trosko (2009).
13. Schulz and Hatina (2006).
14. Johnsen, Malene Krag, et al. (2009).
15. Curtis (1965); Frank and Nowak (2004). Gatenby and Vincent (2003) is a good summarization of SMT.
16. Hisamuddin and Yang (2006).
17. Duesberg (2005); Duesberg, Li, et al. (2005); Nicholson and Duesberg (2009).
18. Bharadwaj and Yu (2004); Pathak and Multani (2006).
19. Duesberg, Li, et al. (2000); Pezer and Ugarkovic (2008).
20. DFTD is a clonal cell line that originated in a single individual some time prior to 1996.
21. CTVT originated between two hundred and fifty and twenty-five hundred years ago (Murgia, Pritchard, et al. 2006). Frank (2007) considers CTVT a distinct genomic species, the “malignant dog.”
22. Feinberg, Ohlsson, et al. (2006); Suijkerbuijk, van der Wall, et al. (2007).
23. Feinberg, Ohlsson, et al. (2006).
24. Gaudet, Hodgson, et al. (2003).
25. Feinberg, Ohlsson, et al. (2006).
26. Lotem and Sachs (2002).
27. Feinberg, Ohlsson, et al. (2006).
28. See, for example, Ganesan, Nolan, et al. (2009).
29. Fassati and Mitchison (2010).
30. Capp (2005) is a good introduction to this approach. See also Ingber (2002), Soto and Sonnenschein (2004), and Chung, Baseman, et al. (2005).
31. Kenny and Bissell (2003). See also Bissell and Labarge (2005), Nelson and Bissell (2006), and Kenny, Lee, et al. (2007).