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MBE Advance Access originally published online on May 3, 2006
Molecular Biology and Evolution 2006 23(7):1414-1419; doi:10.1093/molbev/msl003
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© The Author 2006. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Research Article

Vertebrate DNA Transposon as a Natural Mutator: The Medaka Fish Tol2 Element Contributes to Genetic Variation without Recognizable Traces

Akihiko Koga*, Atsuo Iida*, Hiroshi Hori*, Atsuko Shimada{dagger} and Akihiro Shima{ddagger},1

* Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Japan; {dagger} Department of Biological Sciences, Graduate School of Sciences, University of Tokyo, Tokyo, Japan; and {ddagger} Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Japan

E-mail: koga{at}bio.nagoya-u.ac.jp.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
DNA-based transposable elements, or DNA transposons, transpose in a cut-and-paste fashion, involving excision from the chromosome. If this process affects the function of a host gene and the excision rate is high, any gene associated with such an element would clearly be in a genetically "unstable" state, and there are many examples of unstable genes in various organisms. However, none have hitherto been reported in vertebrates. We here document the finding of an unstable mutant gene in the medaka fish, Oryzias latipes, a useful model animal for vertebrate genetics and evolutionary studies. In an inbred strain, excision of the Tol2 element inserted in a pigmentation gene occurs spontaneously, giving rise to different heritable phenotypes and new mutant genes that carry different excision footprint sequences. The phenotypic mutation rate is as high as 2% per gamete, representing a 1000-fold increase from spontaneous mutation rates so far determined with the same organism. With mutations caused by insertion, and then excision, of transposons, one can no longer recognize participation of transposons in their generation. Thus, the impact of DNA transposons on vertebrate genomes may be, and may have been, larger than commonly supposed.

Key Words: DNA transposon • vertebrate • medaka • unstable mutation • genetic variation • genome evolution


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Transposable elements are thought to be factors contributing to genome evolution because of their transposition activity causing mutations and their repetitive nature giving rise to chromosomal rearrangements. DNA-based transposable elements, also called terminal-inverted-repeat elements or simply "DNA transposons," comprise one major class of transposable elements. They transpose in a cut-and-paste fashion, in contrast to RNA-mediated elements such as LINEs, SINEs, and retrovirus-like elements that move in a copy-and-paste manner. The cut process of DNA transposons involves excision from the chromosome. If this process affects the function of a host gene and the excision rate is high, the gene would be in a genetically unstable state. There are many examples of genetically unstable genes in various organisms such as Drosophila (Bryan et al. 1987Go), nematodes (Eide and Anderson 1985Go), maize (Wessler and Varagona 1985Go), and snapdragon (Coen et al. 1986Go). However, to our knowledge, such an event has hitherto not been reported in vertebrates. One reason might be the progression of decay of DNA transposons in vertebrate genomes, as indicated by genome sequencing projects (Crollius et al. 2000Go; IHGSC 2001Go; MGSC 2002Go). Vertebrate DNA transposons that have direct evidence for transposition activity so far reported are, except for those artificially reconstructed elements, only the Tzf element of zebrafish (Lam et al. 1996Go) and the Tol2 element of the medaka fish (Koga et al. 1996Go).

The Tol2 element is a member of the hAT transposable element family (Calvi et al. 1991Go) that includes hobo of Drosophila, Activator of maize, and Tam3 of snapdragon. It is 4.7 kb in length, has terminal inverted repeats of 17 and 19 bp, carries an internal gene, and is flanked by an 8-bp target site duplication (Koga et al. 1996Go; Koga and Hori 2001Go). The internal gene, consisting of 4 exons, encodes a transposase that catalyzes the transposition reaction of the Tol2 element (Koga et al. 1999Go, 2003Go). About 20 copies are present in the diploid genome of the medaka fish (Koga et al. 2000Go).

Tyrosinase (EC 1.14.18.1 [EC] ) is the key enzyme for melanin biosynthesis, and its deficiency is known to cause oculocutaneous albinism (Oetting et al. 2003Go). We have previously identified 3 naturally occurring mutant alleles for the medaka fish tyrosinase gene that carry transposon insertions (Koga et al. 1995Go; Koga et al. 1996Go; Iida et al. 2004Go). The i1 and ib alleles are 2 of these, where i represents color interferer, and the i1/i1 and ib/ib genotypes exhibit complete and weak oculocutaneous albino phenotypes, respectively, ib being dominant over i1 and recessive to the wild-type allele i+. The tyrosinase gene for the i1 allele (Tyr-i1) contains the Tol1 element in the first exon (Koga et al. 1995Go) and that for ib (Tyr-ib) carries the Tol2 element in the promoter region (Iida et al. 2004Go) (fig. 1). The Tol1 element is a DNA transposon similar in structure to, but different in nucleotide sequence from, the Tol2 element. We have recently reported an example of spontaneous, precise excision of the Tol2 element from the Tyr-ib gene that gave rise to the wild-type phenotype (Iida et al. 2005Go). Three i+/ib animals were then found among 63 offspring of a pair of fish of the ib/ib strain.


Figure 1
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  		FIG. 1.— Structure of the medaka fish tyrosinase gene. Exons are shown by boxes, in which the coding regions are stippled gray. With the Tyr-i1 and Tyr-ib mutant genes, the Tol1 and Tol2 transposons, respectively, are inserted at the positions indicated. The locations and directions of the PCR primers (P0–P5) are indicated by arrowheads.

 
With the results of this previous study, several questions concerning the activity of the Tol2 element were raised. 1) How high is the accurate excision frequency? 2) Does excision occur in females, males, or both? 3) At which stage of gametogenesis does excision occur? 4) Besides precise excision, does imprecise excision occur? 5) If yes, does imprecise excision lead to phenotypes other than the wild-type phenotype? 6) Is the highly frequent excision accompanied by a highly frequent reintegration into chromosomes? 7) What mechanisms underlie the sudden increase in the excision frequency or the transposition frequency?

To obtain answers to questions 1) to 6) and in preparation for solving 7) in future studies, we made large-scale crosses of fish, screened their offspring for new phenotypes, and analyzed the molecular structure and inheritance patterns of new mutant genes. The results clearly indicated mutator activity of the Tol2 element accompanied by a "transposition burst" of the element.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgements
 References
 
Fish Breeding
Medaka fish strains with i1/i1 and ib/ib genotypes were obtained from Y. Wakamatsu of the National Bioresource Project of Japan. With the ib/ib strain, we had conducted 3 generations of one-pair matings when it was used for our previous study (Iida et al. 2005Go). The ib/ib fish used in the present study were descendants of the subline in which eye color revertant fish had been found previously. Two more generations of one-pair matings were made before starting the present study. Fish of the Hd-rR strain, a highly inbred strain used for the Southern blot analysis, were provided by Y. Ishikawa of the National Bioresource Project of Japan.

Fish were maintained at 27 °C under a 14:10 h light:dark photoperiod cycle. One-pair sib matings for the present study were set up in plastic boxes containing about 400 ml of water. All live fertilized eggs were collected for 14 consecutive days. Fertilized eggs were collected within 3 h from spawning and incubated in petri dishes. Medaka fish hatch at 9 days postfertilization under these breeding conditions. Embryos were examined under a stereomicroscope for variation in the pigmentation pattern and density.

Molecular Techniques
This study is an extension of our previous work (Iida et al. 2004Go, 2005Go), and experimental procedures for the following molecular techniques were as earlier described: preparation of genomic DNA, polymerase chain reaction (PCR), cloning of PCR products, and DNA sequencing. The locations and directions of PCR primers are shown in figure 1, and the sequences are referenced in table 1. The PCR conditions are described for each case.


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  		Table 1 Information about Sequences of PCR Primers

 

   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgements
 References
 
We arranged 10 crosses, giving a mate of the i1/i1 genotype to each ib/ib fish (table 2). Offspring of new phenotypes were observed in 2 of the 5 "ib/ib female x i1/i1 male" crosses and 3 of the 5 "i1/i1 female x ib/ib male" crosses. Within each of these 5 crosses, there were no apparent differences in phenotype among siblings. However, differences were observed among the crosses (fig. 2).


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  		Table 2 Segregation among Offspring of Pair Matings

 

Figure 2
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  		FIG. 2.— Phenotypes of mutant fishes. Photographs of embryos were taken at 6 days postfertilization (DPF) under a light microscope. Dorsal and ventral views are shown for each embryo indicated on the left margin (A), and areas in white boxes are magnified for better comparison (B). Fish of the i+/i1 genotype (wild type) contain dense and heavily pigmented melanophores on the back skin (box a) and along the vessels on the yolk sac (box c). In fish of the ib/i1 genotype (weak albino phenotype), melanophores on the back skin are less pigmented and those along the vessels are absent. Fish of the i1/i1 genotype (complete albino phenotype) do not exhibit any melanin pigmentation. The differences between the i+/i1 and ib/i1 genotypes disappear by 15–18 DPF as the melanophores grow and the yolk is absorbed. Screening for new phenotypes (those with difference in the melanophore size and/or density from the ib/i1 phenotype detectable with naked eye) was performed by examining melanophores under a light microscope at 2, 4, 6, and 8 DPF. Of the 5 new phenotypes found, those from crosses 3, 6, and 8 did not apparently differ from the phenotype of i+/i1 (wild type). The new phenotype fish of cross 1 features discontinuity of melanophores on the yolk sac vessels (box d). The new phenotype fish of cross 7 exhibits round melanophores of a relatively uniform size on the back skin (box b). All the fish of these new phenotypes were morphologically normal and hatched without delay.

 
Using parent and offspring fish, PCR analysis of genomic DNAs obtained from tail biopsies was performed. Figure 3 shows the results in the case of cross 1, indicating the 2 offspring fish of the new phenotype to carry the i1 allele from their i1/i1 parents. The other allele, identical in size to the i+ allele, clearly originated from their ib/ib parent, in accordance with the expectation that the Tol2 element excision in the germ line was responsible for the new phenotype. Results indicating equivalent events concerning the origin and inheritance of new alleles were obtained with fish of crosses 3, 6, 7, and 8 (data not shown).


Figure 3
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  		FIG. 3.— PCR analysis of parents and offspring fish of cross 1. Genome DNA of each fish sample, indicated above the lanes, was used for PCRs with 4 different combinations of primers. The expected sizes of the PCR products are 1.0 kb with P0–P1 for Tyr-i1, 1.1 kb with P0–P2 for Tyr-ib, 1.1 kb with P0–P3 for Tyr-i+, and 0.8 kb with P4–P5 for all these alleles. The PCR conditions were 120 s at 94 °C; 30 cycles of 20 s at 94 °C, 20 s at 64 °C, and 50 s at 72 °C; and 180 s at 72 °C. The extension time of 50 s proved insufficient, with P0–P3, to produce a fragment containing the entire Tol1 or Tol2 element.

 
We cloned the PCR products with primers P0 and P3 into plasmids and sequenced them. Similar to the case of phenotypes, differences were observed among but not within crosses. It is therefore likely that animals of the new phenotype in each cross originated from a common excision event rather than through independent excisions. We designated the new alleles from crosses 1, 3, 6, 7, and 8 as ibE1, ibE3, ibE6, ibE7, and ibE8, respectively, where "E" stands for excision. Comparison of the sequences of these alleles with that of i+ revealed that differences were, when present, only in the vicinity of the Tol2 insertion point (fig. 4). In the cases of ibE3 and ibE8, the sequence was identical to that of i+. However, some nucleotides of the target site duplications had been left behind with ibE6 and ibE7, and a more complex change involving a Tol2 terminal region was observed with ibE1. The latter 3 cases are considered to be products of imprecise excision of the Tol2 element. The overall excision pattern was found to be essentially the same as what has previously been observed for the Tol2 element (Koga and Hori 2000Go; Koga 2004Go). Excision of the Tol2 element in the germ line of the ib/ib parent fish was thus confirmed.


Figure 4
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  		FIG. 4.— Nucleotide sequences of the region around the Tol2 insertion point. The top line is the sequence of Tyr-ib. The other lines are the sequences of excision products from the new mutant fish designated on the left margin. Blank spaces indicate the absence of corresponding nucleotides. TSD stands for target side duplication.

 
Whether the new alleles are inherited in the next generation can be examined by crossing new phenotype fish to i1/i1 fish and counting offspring of different phenotypes. This test was conducted with 3 new phenotype fish that had reached a reproductive maturation stage relatively early. The segregation patterns observed are consistent with the expectation that the new alleles are inherited by the next generation in the Mendelian fashion (table 3). Heterozygous fish that inherited the new alleles exhibited phenotypes identical to their heterozygous parents (data not shown).


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  		Table 3 Inheritance of New Mutant Alleles

 
To determine whether highly frequent reintegration into chromosomes had also occurred, we made a cross of another pair of ib/ib fish, raised their offspring to adults, and conducted a Southern blot analysis of the family (fig. 5A). Hybridization bands present in offspring but not in either parent indicate new insertions that had occurred in the germ line of the parents. A total of 13 such bands were observed among 10 offspring fish. Therefore, the insertion rate was estimated to be 13/20 = 0.65 (copies/gamete). It is interesting that 6 of the 13 new bands appeared in offspring 7. This may have occurred by chance or may have resulted from some unknown mechanism. However, the insertion rate of 0.65 is an adequate point estimate because the fish used were random samples of the offspring. Such a highly frequent insertion has hitherto not been observed: an example of the "usual" results is shown (fig. 5B).


Figure 5
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  		FIG. 5.— Southern blot analysis of 2 families for detection of new insertions. Panels (A) and (B) are results with the ib/ib strain and the Hd-rR strain, respectively. With each strain, genome DNA was extracted from a pair of fish and 10 of their offspring, digested with the restriction endonuclease PvuII, electrophoresed on a 1.0% agarose gel, transferred to nylon membranes, and then hybridized with a probe representing the 455-bp left terminal region of the Tol2 element. The 4682-bp element contains 4 PvuII cutting sites, the leftmost being between nucleotides 455 and 456. Because the distance to the nearest PvuII site in Tol2-flanking regions is expected to differ from copy to copy, the hybridization bands correspond to different Tol2 copies. The triangles on the right margin of panel (A) indicate hybridization bands that are present in offspring but not in the parents. These new bands are hemizygous, whereas most of the bands inherited from the parents are homozygous. Therefore, hybridization signals of the new bands are less intense. No new bands are to be found in the photograph for panel (B).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgements
 References
 
The results we have obtained in the present study give the following answers to questions 1) to 6) stated earlier. 1) The phenotypic mutation frequency obtained was 2.2% per gamete. The actual excision frequency would be the same but might be larger because there is a possibility of new alleles that were not found in the phenotype screening. 2) Excision occurs in the germ line of both females and males. 3) The stage of gametogenesis at which excision occurs cannot be determined with the present data, but the appearance of multiple offspring carrying the same footprint sequence in single pairs of parents suggests that excision can occur in premeiotic stages. 4) Both precise and imprecise excision occurs. 5) Imprecise excision can result in phenotypes different from that of precise excision. 6) Highly frequent reintegration into chromosomes occurs in parallel with highly frequent excision.

Our results indicate that the Tol2 element can act as a mutator for a host gene, the tyrosinase gene in this case. The phenotypic mutation rate is as high as 10–2, which represents a 1000-fold increase from "purely spontaneous" mutation rates determined by similar methods with the same organism (Shimada and Shima 1998Go; Shimada et al. 2005Go). In addition, the mutations observed here are not "loss of function" or simple "gain of function" but rather "diversification of function." Another important feature is that this situation was realized without any exogenous agents such as chemicals or radiation. At present, the trigger for the germ line transposition of the Tol2 element is not clear. Our speculation is that some specific conditions regarding the genetic conformation are required for the high transposition activity of the Tol2 element, and these were fulfilled in the particular materials we used. It is notable here that the parent fish had experienced 5 generations of one-pair sib matings (see Materials and Methods). We have not observed any new mutations among more than 2000 embryos of the original ib/ib mutant line and more than 1000 embryos of a subline that diverged after the second generation of inbreeding.

This report concerns the mutator activity of the Tol2 element by excision. However, mutations caused by insertion are also expected to occur. Because new mutations are presumed to be mostly recessive to wild-type genes, the possibility of revealing new mutations was low in the experimental system we used. However, we have a fish strain that is homozygous for several genes concerning the body color (Shimada et al. 2005Go), and we are now targeting detection of new mutations using this particular strain as a tester.

There are many examples of sudden increase in the transposition frequency of DNA transposons, and also resultant increase in the mutation frequency of host genes, in various organisms including animals and plants. However, to our knowledge, such an event has hitherto not been reported in vertebrates, possibly reflecting the progression of decay of DNA transposons in vertebrate genomes. A question to be answered in this context is whether the medaka fish is exceptional among vertebrates. It should be noted here that the Tol2 element is a recent invader of the medaka fish genome (Koga et al. 2000Go). The answer might thus be "yes" in that infection by an element happened to this organism "recently." The answer would probably be "no" if we consider the long timescale. Infection of DNA-based elements and subsequent proliferation appear to be possible also in other vertebrate species, as supported by our previous finding that the Tol2 element exhibits transposition activity when it is introduced into human, mouse, and chicken cells (Koga et al. 2003Go). Similar results have been reported with artificially reconstructed elements (Ivics et al. 1997Go; Miskey et al. 2003Go) and non-Tol2 elements originating from nonvertebrate species (Raz et al. 1997Go; Fadool et al. 1998Go; Zhang et al. 1998Go).

The present findings also have significance for the past of vertebrates. Although active DNA transposons are rare in present-day vertebrate genomes, large amounts of fossils are found there (Crollius et al. 2000Go; IHGSC 2001Go; MGSC 2002Go), indicating a greater prevalence in the past. An important feature related to this point is that, for mutations caused by insertion, and then excision, of transposons, one can no longer recognize participation of the transposons in their generation. Suppose, for example, that the ib allele is not known and the ibE7 allele was found in a natural population. In this case, a transposon would be unlikely to be regarded as the cause. Our results raise the possibility that DNA transposons may have been a factor in producing gene mutations, and even chromosomal rearrangements, without leaving recognizable traces. Such a possibility has been proposed earlier (Brookfield 2004Go), and our results provide supporting evidence for this view with a vertebrate.

As we report here, the Tol2 element acts as a natural mutator in its host organism. The role of DNA transposons in the genome evolution of vertebrates might be more significant than generally postulated.


   Acknowledgements
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
References
 
This work was supported by grant no. 16570002 to A.K. and A.S. from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a Basic Science Research Grant from the Sumitomo Foundation to A.K.


   Footnotes
 
1 Present address: Institute for Environmental Sciences, Rokkasho, Aomori, Japan. Back

Yoko Satta, Associate Editor


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 

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Accepted for publication April 27, 2006.


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