Oko

Proto-e

Proto-P

Conversion of 8 by P ' inactivation of 8

Triplication Goat

Figure 6.9 Evolution of p globin cluster. Complex gene duplications, conversions, and inactivation events have occurred in different mammalian lineages. Redrawn with permission from Strachan and Read (2004).

subsequent observation that for tandemly repeated ribosomal RNA genes (Box 6.4) the sequence between genes was more similar within a species than between two related species, led to a concerted model of evolution with all members of a multigene family assumed to evolve in a concerted manner rather than independently. Homogeneity between member genes is promoted by repeated unequal crossover events and gene conversion (Box 6.5) allowing a mutation to spread across the gene members of the family. The availability of sequence data

Box 6.6 CASP12 gene duplication and selective advantage of an inactive pseudogene

A single nucleotide polymorphism (SNP) in exon 4 of the duplicated copy of the CASP12 gene creates a pseudogene by converting an arginine codon (CGA) to a stop codon (TGA), truncating the protein to half its normal length and rendering it inactive. The ancestral state appears to be the active gene encoding the full length protein and is found in a range of primate and rodent species. Among present-day human populations, the active ancestral copy is found almost exclusively on chromosomes of African ancestry, its presence on chromosomes of non-African descent being less than 1%. Highest frequencies of the ancestral version are seen among present-day San (75%) and Mbuti (60%) pygmies; the average amongst present-day sub-Saharan

African populations is 28% (Xue et al. 2006). There is evidence that those individuals with the ancestral active form of CASP12 produce lower amounts of cytokines on stimulation with lipopolysacchar-ide and are at greater risk of severe sepsis (Saleh et al. 2004). It is postulated that there was selection against the active form of the CASP12 gene, seen at the level of an individual as resistance to sepsis in those carrying the protein-truncating mutation. It is thought that the mutation arose in Africa some 100 000-500 000 years ago, and that it was initially neutral or nearly neutral, and then subject to strong positive selection over the last 60 000-100 000 years which has driven the polymorphism to near fixation in non-African populations (Xue et al. 2006).

has more recently led to a model of 'birth and death' evolution by which duplicated genes may be maintained in the genome for a long time, or be deleted, or lose function through deleterious mutations (Nei and Hughes 1992).

The 'birth and death' evolution model appeared particularly applicable to immune genes such as immunoglobulin gene families (Section 6.4.3) and the MHC on chromosome 6 (Chapter 12). Mutations occurring in the duplicated copy may lead to deleterious consequences for the encoded gene but an overall selective advantage, as illustrated by a recent mutation affecting the CASP12 gene, encoding caspase-12 (Box 6.6) (Saleh et al. 2004; Xue et al. 2006).

6.4.3 Immunoglobulin gene families

Gene families for the constant and variable regions of immunoglobulin light (X and k) and heavy chains are found clustered in the genome, with 50-100 genes identified in each of the variable region gene families. Immunoglobulin molecules comprise heavy and light chains joined by disul-phide bonds leading to two variable region antigen binding sites and a constant region (C) (Fig. 6.11) (Janeway et al. 2005). Immunoglobulins on B cells are a critical component in our defence against infection, with diversity in the variable regions essential to being able to respond to a great diversity of possible foreign antigens. Diversity in the variable region is achieved by a number of mechanisms, key to which is the fact that it is encoded by a number of different gene segments that are subject to somatic recombination in developing lymphocytes to randomly bring together a complete variable region sequence (Weigert et al. 1978; Tonegawa 1983; Janeway et al. 2005).

For light chains, there are V gene segments (comprising the bulk of the variable region domain) and J gene segments (joining segment); in heavy chains there are in addition diversity gene segments (D) (Fig. 6.11) (Early et al. 1980). A very high degree of potential combinatorial diversity can be achieved by such gene rearrangements: for the X light chain locus at chromosome 22q11.2, 30 functional VX gene segments and four JX gene segments could generate 120 possible X variable regions; for the k light chain locus at chromosome 2p11.2, 200 variable regions are possible (40 Vk X 5 Jk) . There is also evidence of a large inverted duplication spanning the Vk cluster which is restricted to humans, thought to have occurred about 5 million years ago (Kawasaki et al. 2001). At the heavy chain locus on chromosome 14q32.3, 40 VH segments combined with 25 DH segments and six JH segments provide in principle 6000 possible different variable heavy chain regions. Combinatorial diversity based on the 320 light chain peptides (120+200) with each of the ~6000 heavy chains gives a theoretical 1.9 X 106 different antibody specificities (Janeway et al. 2005).

Further somatic diversity is achieved through the joining process of somatic recombination: so-called junctional diversity involves both shortening of the gene segments (as joining ends is imprecise) and the insertion of one or several nucleotides between the segments during joining. Finally, once B cells have been activated by encountering antigen, somatic mutation of the rearranged variable region light and heavy chain genes occurs at a very high rate throughout the coding sequences (Weigert et al. 1970).

The remarkable diversity of immunoglobulin proteins is thus achieved by a series of different somatic events from a starting point of distinct multigene families encoding segments of the variable region of the protein, which have arisen through gene duplication and been subject to 'birth and death' evolution (Ota and Nei 1994; Sitnikova and Nei 1998).

6.5 Segmental duplication, deletion, and gene conversion

6.5.1 Lessons from the study of the genetics of colour vision

Genes encoding the photoreceptor pigments found in photoreceptor cells are thought to have arisen by gene duplication events, with analysis of gene sequences

Light chain

Light chain

_ Heavy chain

Variable region

Constant region

Germline DNA

Somatic recombination

Light chain

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