Page 59 - Genetics_From_Genes_to_Genomes_6th_FULL_Part3

10.2 Genome Architecture and Evolution 353

Combinatorial strategies at the DNA level the proliferation of T cells that have particular V-D-J rear-
T-cell receptor genes, among the best-studied examples of rangements encoding the best receptors for the antigen to
DNA-level combinatorial amplification, are encoded by a which the individual was exposed.
multiplicity of gene segments that become rearranged in
one type of somatic cells—T cells—but not in the germ Combinatorial strategies at the RNA level
line or any other type of cell (Fig. 10.16). The human T-cell The splicing together of RNA exons in different orders—
receptor family has 45 functional variable (V) gene seg- alternative splicing—is another way in which combinato-
ments, two functional diversity (D) gene segments, 11 func- rial strategies can increase information and generate
tional joining (J) gene segments, and two almost identical diversity. Further diversity results from the initiation of
constant (C) segments. In an individual T cell, any D ele- transcription at distinct promoter regions, which creates
ment may first join to any J element by deletion of the transcripts with different numbers of exons.
intervening DNA. This joined D-J element may, in turn, The three neurexin genes, which encode proteins that
join to any V element—once again by deletion of the inter- help bind neurons together at synapses, illustrate both of
vening DNA—to generate a complete V-D-J exon. This these combinatorial RNA strategies (Fig. 10.17). Each
combinatorial process can generate 990 different V-D-J neurexin gene contains two promoter regions (producing
exons (45 × 2 × 11 = 990), although in a given T cell, only α- and β-class mRNAs) and five sites at which alternative
one such functional rearrangement occurs. Thus, from splicing can occur. Together, these three genes can proba-
58 gene elements (45 + 2 + 11) within a single gene, a bly generate more than 2000 alternatively spliced forms of
combinatorial joining mechanism can generate 990 differ- mRNA. Key questions include how many of the splice vari-
ent kinds of T-cell receptor proteins. ants encode functionally distinct proteins (rather than pro-
T-cell receptors are capable of interacting with foreign
molecular structures, which are termed antigens. T cells teins with the same function), and whether different
variants represent different addresses for telling neurons
are driven by contact with antigens to divide and expand where to go during embryonic development. By looking at
their numbers 1000-fold or more. This antigen-triggered the sequences of many cDNA clones, scientists have de-
expansion by mitosis to a clone of genetically identical tected some splice variants that are specific for particular
cells is a key part of every immune response. The particular subsets of nerve tissue, suggesting the importance of this
combinatorial gene arrangements in a few of the original combinatorial strategy for nervous system organization.
population of T cells by chance produce T-cell receptors
fitted more precisely to a specific antigen. Binding with the
antigen then triggers the clonal expansion of the cells that Posttranslational modification of proteins
carry the tightly fitting receptors, amplifying the useful Human proteins may be modified by more than 400 differ-
combinatorial information. The specificity and strength of ent chemical reactions, each capable of altering the pro-
the immune response thus increases over time because of teins’ functions. Some examples of these posttranslational
modifications were shown in Fig. 8.26, and they include
reactions such as protein cleavage and protein phosphory-
Figure 10.16 Gene for the human β T-cell receptor lation. Thus, the typical human cell might have perhaps
chain. In the germ line and in most somatic cells, the gene is 50,000 different types of mRNAs (the primary transcripts
composed of about 45 V elements, 2 D segments, about 11 J of many genes are alternately spliced in a single cell type)
elements, and 2 nearly identical C (constant) regions. During T cell but perhaps 1 million different proteins. Human cells can
development, any D may join with any J. Subsequently, any V may
join with any D-J. Finally, the rearranged V-D-J exon is spliced to a make more types of protein modifications than can cells of
C exon. As a result of these sequential rearrangements of a single their simpler model-organism counterparts.
gene, different T cells can express one of almost 1000 different
kinds of ß receptor chains.
Germ-line DNA Figure 10.17 The organization of the human neurexin
genes. The human genome has three genes encoding neurexin.
Each gene has two promoters (α and β) to initiate mRNA synthesis
V1 V2 V3 V45 D1 J1...... J5 C1 D2 J6......... J11 C2
and five sites at which alternative RNA splicing can occur. The blue
rectangles indicate exons affected by alternative splicing. Numbers
at the top of the figure designate individual exons.
promoter promoter
1 2 3 4 5 67 8 910 11 12 13 14151617 1 18 19 20 21 222324
Intron Intron
V28 D1 J4 C1 V3 D2 J9 C2
Alternative Site2 Site 3 Site 4 Site 5
Rearranged DNA in T cell #1 Rearranged DNA in T cell #2 splice site 1