14.10: Evolutionary Roles of Transposition in Genetic Diversity
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\(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)Here we’ll see how transposition can affect genes and genetic diversity. We’ll also look at parallels between transposition and the generation of immunological diversity, and we’ll consider the provocative notion that our immune system owes at least some of its evolutionary history to transposons, or at least to mechanisms of transposition!
14.10.1 Transposons and Exon Shuffling
A role for unequal recombination in moving exons in and out of eukaryotic split genes was described earlier. This kind of exon shuffling could happen when short DNA sequences in two different introns misalign during meiotic synapsis, allowing unequal crossing over. Expression of a gene with a “new” exon produces a protein with a new domain and a new activity. If the new domain is not harmful (e.g., found in only one of two alleles of a gene), the mutation need not be lethal, and genetic diversity and the potential for evolution is increased!
Transposons embedded in introns are long regions of DNA similarity that can stabilize synapsis, increasing opportunities for unequal alignment of chromosomal DNA and therefore, chances for recombination and exon shuffling. For example, Alu (SINE) elements often integrate within introns with no ill effect. The similarity of Alu elements in the introns of unrelated genes seems to account for exon shuffling by unequal crossing over between the different genes that share domains and, thus, specific functions.
Another way in which transposons facilitate germline-cell exon shuffling is more direct. Imagine a pair of transposons in introns of a gene on either side of an exon. Should such transposons behave like the two outer IS elements in a bacterial Tn element (discussed earlier), they might be excised as a single, large transposon containing an exon.
The paired transposons flanking the exon might then insert in an intron of a completely different gene! The general pathway of exon shuffling involving paired proximal DNA transposons is illustrated in Figure 14.28.
In this generic example of exon shuffling, exon 2 of gene 1 has been inserted (along with flanking transposons) into another gene (gene 2). Transposon-mediated exon shuffling can explain the insertion of exon-encoded domains of epidermal growth factor (EGF) into several otherwise-unrelated genes. The mitogen EGF was discovered because it stimulated skin cells to start dividing. The gene for TPA (tissue plasminogen activator, a blood-clot dissolving protease) shares domains with the EGF gene. TPA is a treatment for heart attack victims, and if it is administered rapidly after the attack, it can dissolve the clot and allow coronary artery blood flow to heart muscle to resume. Other genes that contain EGF domains include those for Neu and Notch proteins, both involved in cellular differentiation and development.
Explain how insertion of a “foreign” exon (not to mention the two transposable elements!) need not kill a cell, an organism, or its progeny.
Some exon shuffling mutations may have been mediated by LINE transposition and by a special group of recently discovered transposons called helitrons. Helitrons replicate by a rolling-circle mechanism. If you are curious about helitrons, do a Google search to learn more about them and what role they may have had in refashioning and reconstructing genomes in evolution.
14.10.2 Transposon Genes and Immune-System Genes Have History
Several important eukaryotic genes may have been derived from transposons. Perhaps the most intriguing example of this is to be found in the complex vertebrate immune system. Our immune system includes immunoglobulins (antibodies). You inherited genes for immunoglobulin proteins from your parents. These genes contain multiple variant V, D, and J regions linked to a C region. V, D, J, and C are defined as variable, joining, diversity, and constant DNA regions, respectively. These regions recombine to create many diverse V-D-J-C immunoglobulin antibody molecules (although the D region is not always included in the final recombined gene). The gene rearrangements occur during the maturation of stem cells in bone marrow that will become immune cells (B or T lymphocytes). In response to a challenge by foreign antigens, (e.g., proteins on a bacterial surface or toxins released by invading cells), our immune system will select B or T lymphocytes that contain rearranged immunoglobulin genes, which are able to make immunoglobulins that can recognize, bind, and eliminate the invading antigens.
A discussion of the molecular biology of the immune system is beyond our scope here. Suffice it to say that the recombinational immunoglobulin gene rearrangements include enzymatic activities very similar to those of transposition. In fact, the so-called “RAG1 enzyme” active in immunoglobulin gene rearrangement is closely related to genes in a family of transposons (Transib) found in invertebrates and fungi. It looks like immune-gene rearrangement might have origins in transposition!