96 And then there is Disorganisation. Disorganisation (223200). The Disorganisation mutation was first studied by Hummel (1958, 1959), then by Crosby et al. (1992). The possibility of a human homologue of Disorganisation was mooted by Winter and Donnai (1989) and Donnai and Winter (1989), who proposed its existence to explain children whose malformations had been previously attributed to a miscellany of other cause. Disorganisation is caused by a dominant mutation on mouse chromosome 14.
97 The power of the homeotic genes. The evolution of snake limblessness is discussed by Cohn and Tickle (1999). This explanation for the loss of fore-limbs in snakes does not account for the loss of the hind-limbs – which is due to a failure of the limb-buds to grow. Many studies have shown comparable changes in Hox gene expression patterns, particularly in arthropods. And some very recent studies have actually demonstrated that mutations in Hox genes are directly responsible for evolutionary changes in morphology (as a change in Hox gene expression, the snake example implies a mutation in some upstream regulatory factor). Mutations in Emx2 (600035), a human homologue of ems, is responsible for schizencephaly (269160). For a discussion of ems and other conserved brain genes see Reichert and Simeone (2001). Mutations in Pax6 (607108), a human homologue of eyeless, mutations cause aniridia (106210) (Ton et al. 1991). For a review of the conservation of eyeless/Pax6 in eye evolution see Gehring and Ikeo (1999).
99 In the cyclical way of intellectual fashion. Geoffroy’s major ideas on what we now call homology can be found in his Philosophic anatomique. Des organes respiratoires sous de la déermination et de l’dentité de leurs pièces osseuses (1818) and Considerations generates. Sur la vertèbre (1822) which have been collected by Le Guyader (1998) who also discusses the dispute with Cuvier as does Appel (1987). The revival of the dorso-ventral inversion hypothesis is due to, among others, De Robertis and Sasai (1996); for a sceptical update see Gerhart (2000).
CHAPTER IV: CLEPPIES
105 For the mark of Cain see Friedman (1981) pp.87–107. The football coach (p. 106) was Glenn Hoddle. He was sacked (The Times, London, 1 February 1999).
107 As recently as 1900. The story of the Cleppies is told by the British geneticist Karl Pearson (1908) in one of the first studies of a ‘lobster-claw’ family. Most British historians, Macaulay among them, accept that the Wigtown martyrs existed, but some such as Irving (1862) have noted that there are no eyewitness accounts and doubts that the whole thing happened, the graves notwithstanding. The best account is Fraser (1877). Irving and Fraser also note that another legend has another officer, the Provost, saying to maid Wilson, ‘Hech, my hearty! tak anither drink,’ only to find himself evermore afflicted with an unappeasable thirst. The uncertain nature of the story is made even clearer by the reference to ‘Good King Charlie’ – Charles II – who at the time of the execution, 11 May 1685, had been dead for two months. Historians generally blame his successor, the Roman Catholic James II, for unleashing the army on the Scottish Lowlands. The etymology of ‘clep’ is also confusing. W.A. Craigie, in his Dictionary of the older Scottish tongue(1931), gives ‘clep’ as ‘call’, but Pearson’s story suggests that ‘clepped’ also means to have a limb deformity. The clepped families themselves are described by Pearson (1908), McMullen and Pearson (1913) and Lewis and Embleton (1908). Pearson’s papers are of particular historical interest for he uses them to advance the agenda of the biometricians against the Mendelians by showing that this apparently dominant gene does not segregate in Mendelian ratios. While his campaign against Mendelianism proved futile, he was partly right about this trait: it looks as though at least one ectrodactyly allele is over-represented in male progeny, an apparent case of meiotic drive, the only one known in a human pathology (Jarvik et al. 1994).
109 The fragments of myth. Euterpe Bazopoulou-Kyrkanidou (1997) argues persuasively that Hephaestus’ lameness was usually represented as club-feet. Aterman (1999) proposes that Hephaestus’ deformity is related to the achondroplasia of the Egyptian deity Ptah – on which more in Chapter V – and, later, to arsenic neuritis, an acquired disease associated with smiths. These points of view are not necessarily inconsistent as the iconography clearly evolved over time. For the origins of the story of the Ostrich-Footed Wadoma see Gelfland et al. (1974); Roberts (1974); articles resurrecting the myth (e.g. Barrett and McCann 1980) and genetic investigations (Farrell 1984, Viljoen and Beighton 1984). Limb defects are second only to congenital heart defects in frequency (Bamshad et al. 1999).
111 One of the strange things about limbs. Pearson (1908) and Lewis and Embleton (1908) recount the manual dexterity of ‘lobster-claw’ families. See Hermann Unthan’s (1935) memoirs for an edifying account of armlessness. The goat is described by Slijper (1942).
113 What induces a limb-bud to grow out into space? The original description of the apical ectodermal ridge (or AER) and its experimental removal is described by Saunders (1948). Acheiropody (200500) is described by Freire-Maia (1975, 1981).
115 The apical ectodermal ridge is the sculptor of the limb. ‘Lobster-Claw syndrome’ and ‘ectrodactyly’ are both now less commonly used than ‘split-hand-split-foot-malformation’ syndrome (SHFM). The disorder occurs in 1 in 18,000 newborns; inheritance is usually dominant. There are at least three distinct SHFM loci in humans: SHFM1 at 7q21.3-q22.1 (183600); SHFM2 at Xq26 (313350), SHFM3 at 10q24 (600095), and we can add a fourth, ectrodactyly, ectodermal dysplasia and cleft lip syndrome (EEC) at 3q27 (129900) (Celli et al. 1999). There are many other related syndromes besides. Celli et al. (1999) identify the EEC gene as p63, a close relative of the tumor suppressor gene, P53; Yang et al. (1999) and Mills et al. (1999) study its function in mice. Another ectrodactyly gene in mice, Dactylplasia, encodes an F-box/WD40 family protein thought to be involved in protein destruction, and although the human homologue of this gene maps near to SHFM3, it has not yet been shown to be causually involved (Crackower et al. 1998; Sidow et al. 1999). The same is true for two distal-less related genes, DLX5 and DLX6, thought to be responsible for SHFM1 (Merlo et al. 2002). Both P63 and Dactylplasia are involved in the maintenance of the AER; among their many other skin defects, p63-homozyous mice have no limbs at all.
116 Action at a distance in the embryo. Developmental biologists will notice that the account given here, which focuses on the AER’s role in promoting the growth of the limb-bud, is not that given in textbooks. There is no mention of how the AER patters the proximo-distal axis of the limb-bud via the ‘Progress-Zone clock’ (Wolpert 1971). This is because a pair of recent papers (Sun et al. 2002; Dudley et al. 2002) have convincingly shown that the Progress-Zone clock model is wrong. This is fascinating, but a bit upsetting, since it seems to throw the question of proximo-distal patterning open again. Niswander et al. (1993) describe how beads soaked in FGF can replace the apical ectodermal ridge. Sun et al. (2002) also give the most recent account of what is now a plethora of engineered FGF mutations in mice which have shed light on how they work.