Q J Med 2002; 95: 259-260
© 2002 Association of Physicians
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Variety
Until comparatively recently, genomes were thought to change slowly and by a limited number of mechanisms (single base pair mutations, chromosome rearrangements and sequence duplication). In mammals, the major factor in speciation appears to be duplication of parts of the genome, and although most of this type of change was thought to have occurred more than 450 million years ago, the sequencing of a number of genomes has recently made this assumption untenable.1
Around 5% of our genome is composed of segmental duplications that have arisen in the last 35 million years. These duplications are large in genetic terms (up to 200 kb) and maintain intron-exon structures that have a high sequence identity and no multiple repeats. They are found on all of the human chromosomes (the largest on chromosomes 15, 16, 17, 21 and 22) and are pericentromeric or subtelomeric.2 These are areas of lowered gene density, and it has been suggested that new material might be introduced there with less chance of deleterious effects. It has also been suggested that the lower rate of deletion of duplicated segments in these regions (because of the suppression of recombinations at these sites) is important. However, the likely explanation is that this is a targeted effect; duplications are favoured at these sites because of their sequence characteristics.3
What is the significance of these observations? There has not been a progressive expansion in animal (or plant) body plans in (evolutionary) recent times. There was a ‘sudden’ and massive reduction in the variability of the plans in the Pre-Cambrian and no new phyla have arisen since the Cambrian era (540–505 million years ago, see refererence 4 for discussion). Only seven animal phyla made the transition from water to land in the late Devonian, and it is interesting that no new phylum-level body plans emerged to ‘allow’ this migration. Valentine has suggested that pre-Cambrian genomes were simpler and more flexible, and that the development of multiple copies of many genes, which then diverged into a network of related functions, produced webs of interaction which were not easily broken. As development became more complex, the capacity to make effective change became restricted.5 This has always seemed plausible to me, but is clearly wrong. Although many duplicated segments are non-functional (lacking some exons or regulatory sequences that drive expression) there is evidence for ‘chimeric’ development, where transcripts run across adjacent duplications,6 providing a powerful mechanism for acquiring a new function without potentially losing an existing one. It was probably this type of change that allowed us to develop a head (or at least, a neural crest). We may speculate that the inhibitory actions that modify the basic body plan were permitted to develop by duplication, thus allowing normal morphogenesis to continue while variability appeared in specialist regions.
The cells of the neural crest form a transient population that exists only during development. They originate from the lateral tips of the dorsal neural tube, and migrate shortly after its closure, in a space between the dorsal tube and the dorsal somite. The migration is in phase with somite development; it is triggered by BMP4 and negatively regulated by noggin, which is itself induced by the epithelial tissue of the somites. Where noggin expression is high, neural crest cells do not migrate.
Organization of the neural crest differs in the head and neck. Segmentation of the mesoderm is absent (this determines the pattern of neural crest migration in the trunk) but a decade ago, Lumsden et al.7 showed that distinct segmental sub-populations of cranial neural-crest cells exist, matching the pattern of the rhombomeres. Early migrating cells populate the branchial arches, while later ones form the sensory ganglia, in association with cells which form the ectodermal placodes. These give rise in part to the ventro-medial neurons of the trigemminal ganglion, the neurones of all other cranial nerve sensory ganglia and the vestibulo-accoustic ganglion complex of the eighth cranial nerve.8 There are two crest-free segments, alternating with crest-producing ones, which thus produce three distinct streams between the mesencephalic-rhombencephalic boundary and the first somite. This pattern is determined by cellular outflow from rhombomeres 1 and 2, and 4 and 6, respectively. Graham et al.9 showed that apoptosis is marked in the dorsal midline in rhombomere 3 and 5 at the time when neural crest cells would be expected to emerge, apparently as a result of interaction with the epithelium and the expression of a homeobox gene (in the msx family). It is now clear that homeobox genes control most of the specificity in rhombomeric segmentation.
The mesodermal derivatives of the crest are extensive, and their patterning is clearly influenced by a segmentation of cellular outflow that ensures that the target muscle of a particular branchial arch is formed from connective tissue originating from the same rhombomere as its brachiomotor innervation (see reference 7).
Segmentation is thus evident in that part of the brain that develops from behind the node.10 What allowed us to develop a non-standard form (a head rather than a further strip of segments) was the acquisition of new genes. What allowed the development of the forebrain is still a mystery.
References
1.
Bailey JA, Yavor AM, Massa HF, Trask BJ, Eichler EE. Segmental duplications: organisation and impact within the current human gene project assembly. Genome Res2001; 11:1005–17.
2. Cheung VG, Nowak N, Jang W, et al. Integration of cytogenetic landmarks into the draft sequence of the human genome. Nature2001; 409:953–8.[Medline]
3.
Guy J, Spalluto C, McMurray A, et al. Genomic sequence and transcriptional profile of the boundary between pericentromeric satellites and genes on human chromosome arm 10q. Hum Mol Genet2000; 9:2029–42.
4. Berry C. Building an embryo with limited resources. Adv Pediatr1995; 41:343–58.
5. Valentine J. General patterns in Metazoan evolution. In: Hallam A, ed. Patterns of Evolution. New York, Elsevier Science Publishers, 1977.
6. Eichler EE. Recent duplication, domain accretion and the dynamic mutation of the human genome. Trends Genet2001; 17:661–9.[Web of Science][Medline]
7. Lumsden A, Sprawson N, Graham A. Segmental origin and migration of neural crest cells in the hindbrain region of the chick embryo. Development1991; 113:1281–91.[Abstract]
8. D'Amico Martel A, Noden DM. Contributions of placodal and neural crest cells to avian cranial peripheral ganglia. Am J Anat1983; 166:445–68.[Web of Science][Medline]
9. Graham A, Heyman I, Lumsden A. Even-numbered rhombomeres control the apoptotic elimination of neural crest cells from odd-numbered rhombomeres in the chick hindbrain. Development1993; 119:233–45.[Abstract]
10.
Berry C. Get ahead! Q J Med2002; 95:193–4.
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