Arrival of the Fittest: Solving Evolution's Greatest Puzzle (35 page)

59
. Schultes and Bartel (2000).

60
. To be precise, in these walks they changed two residues at a time to preserve RNA secondary structures. One can think of such changes as a combination of a nucleotide change that disrupts secondary structure, followed by another one that restores it. Such pairs of mutations where one compensates for another are observed quite frequently in nature, and thus occur—although perhaps not simultaneously—in naturally evolving RNA molecules. See Kern and Kondrashov (2004). It is also relevant that these researchers had some inkling that their effort might be successful: They had managed to design a sequence that was intermediate between the starting enzymes and that had both activities.

61
. Their work also showed that a sequence that is intermediate between the starting fuser and splitter sequences can catalyze both reactions. See Schultes and Bartel (2000). Such phenotypic plasticity or promiscuity of RNA molecules further helps innovation, because it can make transitions between two genotype networks even easier. See Wagner (2011), chapter 13.

62
. The RNA polymerase that copies information in genes is a DNA-dependent RNA polymerase. (It uses a DNA template.) The RNA polymerase that replicates RNA is an RNA-dependent RNA polymerase.

63
. It is the so-called group I intron of a transfer RNA gene for isoleucine in the bacterium
Azoarcus.
See Tanner and Cech (1996), as well as Reinhold-Hurek and Shub (1992).

64
. The best-known form of the second process involves RNA and not DNA. It is called splicing and occurs when eukaryotes delete parts of a messenger RNA and splice the rest together to create a contiguous stretch of RNA that encodes a single polypeptide.

65
. See Hayden, Ferrada, and Wagner (2011). I simplified the description of several aspects of this experiment for brevity. Because of how the experiment was designed, the numbers of molecules fluctuated during different stages of the experiment between one hundred million molecules (after selection) and more than a trillion (10
¹²
) molecules. Also, during each generation, each molecule may replicate not just once but multiple times. An important aspect of the experiment’s first part was that the activity of the enzyme did not improve, nor did it deteriorate. The population only spread through genotype space without changing its phenotype. The population showed what geneticists call cryptic variation, variation that one cannot normally detect on the level of phenotypes, but that can become visible in a new environment, which involved in our experiment a change in the chemical target molecule of the RNA enzyme. In other words, if our experiment had generated phenotypic variation and this variation had fed the evolutionary process, we would not have been surprised—that is the standard Darwinian view—but the fact that cryptic variation can help evolutionary adaptation is more surprising, and best explained through the genotype network framework. The new substrate in the experiment’s second part could also be transformed by the original enzyme, but at a much slower rate. In other words, the experiment focused on how fast the average reaction rate of ribozymes in the two populations increases during laboratory evolution. In the first population, the rate increased up to eight times faster than in the second population.

66
. See Keats (1994).

67
. See also Dawkins (1998), where the author points out that there can be wonder and awe even in an unwoven rainbow.

CHAPTER FIVE: COMMAND AND CONTROL

1
. See Swallow (2003), as well as Bersaglieri et al. (2004) and Tishkoff et al. (2007).

2
. Any genetics textbook, such as Lewin (1997), describes some of their ingenious experimental tricks.

3
. There are several kinds of polymerases. The one I am discussing here is a DNA-dependent RNA polymerase.

4
. Strictly speaking, the RNA sequence is complementary to one strand of the gene and identical to the other strand, because DNA is a double-stranded molecule.

5
. β-galactosidases are enzymes that cleave the sugar β-galactose from larger sugars. Because lactose is one such sugar, lactase is a kind of β-galactosidase. For historical reasons, the gene encoding
E. coli
’s β-galactosidase is called the
lacZ
gene. See Lewin (1997), chapter 12.

6
. More precisely, the complete word is TGTGTGGGAATTGTGAGC-GATAACAATTTCACACA, and the regulator does not make specific contact with all the letters in this sequence. See also Lewin (1997), chapter 12. The word is very similar to a palindrome, a DNA word that when read in one direction on one strand gives the same letter sequence as read in the reverse direction on the opposite strand.

7
. For example, there may be up to twenty thousand elementary protein shapes or so-called domains. See Levitt (2009).

8
. The details of regulation are more complicated than I describe. For example, the regulator (called the
lac
repressor) is actually a complex of four polypeptides. And it regulates the expression of not just one but three adjacent genes, the so-called
lac
operon. But all these details leave the principles of regulation unchanged. See Lewin (1997), chapter 12.

9
. See Russell (2002), chapter 16. Yet another cost factor is that synthesizing a useless protein ties up ribosomes—the large complexes of molecules that translate proteins from RNA—which are thus not available to synthesize other, necessary proteins.

10
. See Dekel and Alon (2005).

11
. The interaction between activator and polymerase need not be direct. For example, an activator bound to DNA may change the conformation of DNA to open its double helix and thus make it easier for polymerase to start transcription. Nonetheless, the principle of complementarity is also important in transcriptional activation.

12
. With the exception of a few types of cells, such as red blood cells, which have shed their genome.

13
. See Poole et al. (2001), as well as Piatigorsky (1998) and Morano (1999).

14
. I am referring to type II collagen, encoded by the human COL2A1 gene. Other tissues, such as skin or hair, contain other types of collagen, made by different genes. Regarding motor proteins, I am referring to myosins, which are encoded by a large family of closely related genes in the human genome. Different tissues express different members of this family. Not all of them serve to contract muscles. Some, for example, transport molecules inside a cell.

15
. In the evolution of some new cell types, multiple kinds of innovations may be involved, for example because some new cell types require both new regulation of existing proteins and new proteins.

16
. See Gilbert (2010), 42–43, for the regulation of the chick δ1 crystallin gene by Pax6, and for the regulation of Pax6 itself. Pax6 stands for “paired box 6,” which refers to a 120-amino-acid-long element of the protein’s structure that is similar among Pax6 proteins of different organisms.

17
. I simplify again for brevity. For example, the polymerase itself is not one protein, but a complex of more than a dozen proteins, some of which can interact with transcriptional regulators, whereas others cannot. Each transcriptional regulator may also comprise more than one protein, and there may be more than one binding site—and sometimes many—for any one regulator near the same gene. Some DNA-bound regulators act alone, whereas others need to physically interact with other proteins to regulate transcription.

18
. For Pax6 and its role in eye disease and development see Hingorani, Hanson, and van Heyningen (2012), as well as Tzoulaki, White, and Hanson (2005) and Ashery-Padan et al. (2000). For its relationship to eyeless and fruit fly eye development see Gehring and Ikeo (1999).

19
. A wiring diagram is an abstraction that allows our eyes to grasp a circuit’s genotype at a glance. It is easily augmented through equations that describe the interactions of circuit genes encoded in DNA in great detail, but such equations are less easy on the eyes.

20
. Some gene expression patterns may not reach an equilibrium but may vary cyclically, which can be important to maintain rhythmic behavior, such as the circadian clocks that regulate day-night activity cycles.

21
. The prize was awarded to Christiane Nüsslein-Volhard, Edward B. Lewis, and Eric Wieschaus. See Lewis (1978) and Nüsslein-Volhard and Wieschaus (1980). Development does not sculpt bodies in the same way for all insects. For example, in fruit flies all segments are laid down early in the embryo, whereas in grasshoppers, posterior segments form in a posterior proliferation zone during development. Thus any one species can serve as a model of development only for a restricted group of other species.

22
. To be precise, in the early fly embryo not cells but nuclei divide, which makes the spreading of signals among them easier. And here are some further simplifications: Diffusion and transport of some RNA molecules is facilitated by cytoskeletal elements. Some RNA molecules, such as that of the regulator
hunchback,
do not show a gradient like bicoid but are uniformly distributed throughout the embryo. Hunchback’s translation is inhibited by another regulator,
nanos,
concentrated at the posterior pole, which contributes to a hunchback gradient. Moreover, while all these molecules are regulators, not all of them are transcriptional regulators. Nanos, for example, affects the translation of other RNAs.

23
. See Carroll, Grenier, and Weatherbee (2001).

24
. At this stage, nuclei have become separated by cell membranes, regulators can no longer diffuse freely through the embryo, and cells need to communicate in ways that can overcome membranes.

25
. The actual sequence of events is again more complicated. Upon hormone binding, so-called heat shock proteins bound to the receptor dissociate from it, the receptor gets transported into the cell nucleus, and it dimerizes, that is, it forms a complex of two proteins.

26
. This might happen if the regulator gene suffers a mutation. See Reinitz, Mjolsness, and Sharp (1995), as well as Jäger et al. (2004) and Mjolsness, Sharp, and Reinitz (1991).

27
. I here focus mostly on one aspect of limb formation, that is, how limbs get structured along their proximodistal axis—the one that extends from the part of a structure closer to the body to the part farther away from the body. There are several other well-studied questions, such as how limbs “know” where to sprout along the head-tail axis, and how they are patterned along the axis running from back to front, the dorsoventral axis. See Carroll et al. (2001).

28
. See Lewis (1978). See also Gilbert (1997), chapter 14.

29
. See Cohn and Tickle (1999). An expanding region of thoracic identity is only part of the explanation for why snakes have more (thoracic) vertebrae. The other comes from a segmentation clock—driven by yet another regulation circuit that determines segment and vertebrae number. See Gomez and Pourquie (2009).

30
. See Davis, Dahn, and Shubin (2007), as well as Sordino, Vanderhoeven, and Duboule (1995).

31
. See Zakany and Duboule (2007). For Hox genes and human limb malformations see Goodman (2002). Human birth defects involving Hox genes are rarely as clear-cut as these examples, because of partial redundancies involving several Hox genes.

32
. See Stevens, Stubbins, and Hardman (2008), as well as Stevens, Hardman, and Stubbins (2008) and Stevens (2005), for the adaptive role of eyespots. The gene
distalless
derives its name from the fact that mutations in it eliminate the distal-most part of a fly’s legs, that is, the part farthest away from the body. See Panganiban and Rubenstein (2002), as well as Dong, Dicks, and Panganiban (2002) and Carroll et al. (2001).

33
. See Brakefield et al. (1996) and Keys et al. (1999).

34
. See Kenrick (2001), as well as Beerling, Osborne, and Chaloner (2001) and Gottschlich and Smith (1982). Not all plants have dissected leaves, because leaf dissection has a price: A greater surface area also means greater water loss, which is a disadvantage in dry climates.

35
. See Bharathan et al. (2002).

36
. See Hay and Tsiantis (2006) and Bharathan et al. (2002). Strictly speaking, KNOX, which stands for class I KNOTTED1-like homeobox proteins, is not just one regulator but a family of similar regulator proteins that act in different plants. I also note that dissected leaves may have originated through additional changes in one or more of the other genes in this circuit, but none of that takes away from the importance of regulatory change for their origin.