Published by Oxford University Press 2008.
Germline Translocations in Mice: Unique Tools for Analyzing Gene Function and Long-Distance Regulatory Mechanisms
Affiliation of authors: Genome Biology, Lawrence Livermore National Laboratory, Livermore, CA
Correspondence to: Lisa Stubbs, Genome Biology, Lawrence Livermore National Laboratory, 7000 East Ave, L-452, Livermore CA 94550 (e-mail: ljstubbs{at}uiuc.edu).
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ABSTRACT |
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 Top Abstract IntroductionEfficient Induction and...Tying Genes to Mutant...Molecular Structure of...New Opportunities, Future...NotesReferences |
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Translocations have provided invaluable tools for identifying both cancer-linked genes and loci associated with heritable human diseases, but heritable human translocations are rare and few mouse models exist. Here we report progress on analysis of a collection of heritable translocations generated by treatment of mice with specific chemicals or radiation during late spermatogenic stages. The translocation mutants exhibit a range of visible phenotypes reflecting the disruption of coding sequences or the separation of genes from essential regulatory elements. The breakpoints of both radiation-induced and chemically induced mutations in these mice are remarkably clean, with very short deletions, duplications, or inversions in some cases, and ligation mediated by microhomology, suggesting nonhomologous end joining as the major path of repair. These mutations provide new tools for the discovery of novel genes and regulatory elements linked to human developmental disorders and new clues to the molecular basis of human genetic disease.
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INTRODUCTION |
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TopAbstractIntroductionEfficient Induction and...Tying Genes to Mutant...Molecular Structure of...New Opportunities, Future...NotesReferences |
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Discussions at this workshop have focused primarily on translocation events occurring in somatic tissues, particularly those associated with the development and progression of cancer. However, reciprocal translocations also occur at a low but significant frequency in germ cells; these germline rearrangements contribute to human infertility and have been linked to both spontaneous and heritable health disorders of many different types. Because of their cytogenetic visibility, translocations have provided invaluable tools for identifying genes mutated somatically in human cancer and for the same reasons they have also been a key to gene discovery in studies of inherited forms of cancer and other genetic disease (1–4).
Inherited translocations have also provided much of what we know about the locations and functions of long-distance regulatory elements in the human genome. These long-distance regulators are typically associated with genes encoding transcription factors or cell adhesion molecules with complex developmental expression patterns and functions critical to embryogenesis (5). Many genes of this type are found in isolated locations, surrounded by "gene deserts" that can span 1 million base pairs or more (6). These extended gene-sparse regions harbor enhancers and other regulatory elements that interact over large distances through chromatin loops to control gene expression in complex patterns that change throughout development (7). Although a number of different computational tools have arisen to predict the locations of noncoding sequences in recent years (8–10), identifying noncoding DNA sequences with the most important functions, especially those that act at significant distances, remains a major challenge.
Germline translocations provided the first clues to the existence of long-distance regulatory mechanisms for human genes and remain as one of the most efficient tools for their mapping and discovery. For example, patients inheriting translocations located several hundred kilobases (kb) downstream of the PAX6 gene develop Aniridia, a developmental defect of the eye that is also associated with PAX6 deletions and other types of null mutations. Certain other disorders associated with PAX6 null mutations, including specific abnormalities of the lens, cornea, brain, and pancreas, are not displayed by patients inheriting these distant translocations (11). These studies, coupled with data derived from mouse models, have led to the identification of DNA sequences that function specifically as critical regulators of PAX6 gene expression in the developing eye (12). In another classic example, patients who carry translocations breaking more than 1 million base pairs away from the sonic hedgehog (SHH) gene develop holoprosencephaly, a severe brain and craniofacial disorder that is associated with insufficient expression of SHH at critical developmental periods (4). Many additional examples have more recently been described, and it is clear that regulatory elements that act to control genes at long distances, sometimes located within or skipping over neighboring genes that are not affected by their activity, are not rare exceptions but relatively common features of mammalian genomes (5).
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Efficient Induction and Phenotypic Characterization of Germline Translocations in Mice |
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TopAbstractIntroductionEfficient Induction and...Tying Genes to Mutant...Molecular Structure of...New Opportunities, Future...NotesReferences |
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Inherited translocations have proved invaluable in linking human genes and regulatory regions to disease-related phenotypes, but they are rare in the human population, and only a few mouse models exist. However, a long history of genetic toxicology studies have revealed specific regimes of chemical and radiation treatment that can induce heritable translocations in mice at very high efficiencies (13,14). One of the largest series of such experiments was conducted over several decades starting in the 1970s by our collaborator Walderico Generoso and his colleagues at the Oak Ridge National Laboratory. These studies revealed that translocations could be induced in the offspring of male mice exposed to ionizing radiation or alkylating chemicals during late stages of spermatogenesis. Fortunately, the translocation-bearing offspring of the mutagenized males were maintained and bred to establish permanent genetic lines. Our role in this story begins with the genetic and molecular characterization of this unique and precious collection of mutant mice.
More than 100 of the Generoso (Gso) translocations were mapped using cytogenetic methods, demonstrating that the mutations were well distributed throughout the genome with a bias toward gene-rich Geimsa light bands (13,14). A small number of translocations are associated with obvious dominant phenotypes, (15) but most of the carriers we examined, representing more than 300 different translocation-bearing strains, were phenotypically normal. In contrast, more than 20% of the mutations we screened were associated with obvious visible phenotypes in animals inheriting the translocations in homozyogous form (14). Because our screens were simple and focused on obvious defects detected in liveborn animals, this fraction of phenotype-linked translocations is certainly an underestimate. As years of knockout mouse studies have demonstrated, many mouse genes, including some with important developmental activities, can be completely ablated without obvious phenotypic consequences. The MyoD gene, encoding a major regulator of muscle development, is a classic example of genes of this type, many of which are gene family members with some level of functional redundancy (reviewed in 15–20; a fuller listing of mouse targeted mutations and phenotypes is available at the mouse genome database, http://www.informatics.jax.org/). Given the frequency with which reciprocal translocations were associated with visible mutant phenotypes and the proportion of genes that do not show a visible phenotype even when completely ablated, the data suggest that it is rare that this type of rearrangement in mammalian genomes does not disrupt function of at least one neighboring gene.
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Tying Genes to Mutant Phenotypes |
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TopAbstractIntroductionEfficient Induction and...Tying Genes to Mutant...Molecular Structure of...New Opportunities, Future...NotesReferences |
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In the past few years, we have focused on molecular and phenotypic characterization of a subset of 29 translocation mutant strains, including several with phenotypes that offer models for important unsolved problems in human health. One of our mutants, 67Gso, was essential to mapping a long sought-after gene associated with juvenile-onset–recessive polycystic kidney and liver disease in mice (22,23). Several other translocations have proved to be repeat mutations in genes with known phenotypic associations, including two independent translocations in the glutamate receptor gene, Grid2, which spans more than 1.5 million base pairs (Mb) of DNA (24). These two mutations were generated by different mutagens and are located more than 250-kb apart within different introns of the Grid2 locus; they can therefore be considered truly independent mutational events. Other Gso translocations have included new mutant alleles in the 100-kb RAR-related orphan receptor gene, Rora (26Gso), which is also mutated in the classical mouse mutation, staggerer (25), and the 140-kb calcium channel gene, Cacng2 (15Gso), associated with epilepsy in mouse stargazer mutants (26). The 26Gso and 15Gso translocations break within introns of the affected genes and create null mutations with phenotypes that are essentially identical to the known null mutations (C. Elso et al. unpublished data). The 14Gso translocation also breaks within an intron thereby creating a null mutation of the potassium channel gene, Kcnq1. Like targeted null mutations of Kcnq1 (27), the 14Gso mutation is associated with profound deafness and gastric hyperplasia. Our studies of the 14Gso translocation have further demonstrated a link between loss of Kcnq1 function, defective acid balance in the stomach, and severe gastritis with heightened susceptibility to gastric infections, mucosa-associated lymphoid tissue, and stomach cancer in the mutant mice (28).
Most of the Gso translocations disrupt a single gene on one of the two affected chromosomes, breaking the other chromosome within noncoding sequences without affecting the function of nearby genes. Several of these mutations give rise to transcripts that span two chromosomes, initiating at the promoter of a disrupted gene and continuing into DNA across the breakpoint site. For example, the T(7;10) 14Gso mutation yields a transcript that includes exons 1–9 of the 320-kb Kcnq1 gene and terminates in noncoding sequences from mouse chromosome 10 (Mmu10); the T(1;4) 153Gso mutation is associated with a transcript initiating from the Grid2 promoter in Mmu6 and terminating in noncoding DNA from Mmu4 (24,25). Although a small number of translocations disrupt genes within both breakpoint regions, none so far have given rise to transcripts that could potentially encode fusion proteins with novel function, as occurs frequently in association with cancer-linked somatic translocations (29).
All genes affected by the translocations we have analyzed fall into one of two major classes: 1) large genes, comprising exons that are spread out over exceptional genomic distances, or 2) genes embedded within large gene deserts, containing regulatory elements that cannot be separated from coding sequences without complete or partial loss of function. In each case, the regions disrupted represent "big targets", ie, lengthy sections of chromosomal DNA that must remain intact for proper biological function. We have not observed a bias towards any particular type of DNA sequence, repetitive element, or other structural feature of surrounding DNA. However, common features may emerge as additional breakpoints are sequenced and analyzed in future studies.
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Molecular Structure of Breakpoints |
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TopAbstractIntroductionEfficient Induction and...Tying Genes to Mutant...Molecular Structure of...New Opportunities, Future...NotesReferences |
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What do these mutations look like at the molecular level? Although breakpoints of many somatic translocations have been studied, very few mutation sites have been recovered and sequenced from germline translocations that can be associated with radiation treatment or specific chemical mutagens. At the time of this writing, we have cloned and sequenced breakpoints of nine induced translocations, including two that have been published in previous reports. The sequenced translocations were generated by very different mutagens, but surprisingly, their breakpoints share many common characteristics. All the translocation breaks we have examined so far are relatively clean and simple in structure, although most are associated with very short deletions, duplications, or inversions that directly abut the breakpoint sites. For example, the breakpoint of the T(1;6) 153Gso mutation, which arose in the offspring of a chlorambucil-treated male mouse, is associated with deletions of 3 base pairs (bp) on Mmu1 and 2 bp on Mmu6, with a 2-bp region of microhomology located directly at the site of chromosome breakage (24). In the analysis of the 14Gso mutation, which arose in an X-ray exposure experiment, we found short deletions at the site of breakage on both Mmu7 and Mmu10 (5 and 11 bp on each chromosome, respectively), and an 856-bp inversion of Mmu10 directly next to the breakpoint site. The site of chromosome fusion in this mutation also contains a 2-bp region of microhomology between the two chromosomes (28). The breakpoint of the T(4;15) 15Gso mutation, which also arose in offspring of an X-ray–treated male, displays short deletions at Mmu4 and Mmu15 breakpoints, together with a 20-bp duplication of Mmu15-related DNA and a 3-bp region of microhomology at the breakpoint sites (Figure 1). Other translocations, generated with a range of different chemicals or by exposure to ionizing radiation, exhibit very similar structures (C. Elso et al. unpublished data).
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The relative simplicity of the 14Gso and 15Gso translocations is surprising given the large size and complex structures of deletions, inversions, and other rearrangements associated with most of the X-ray–induced mutations described to date. The difference is almost certainly linked to the late stage of spermatogenesis in which the Gso translocations were induced; most X-ray–induced deletions and other complex rearrangements were generated by exposure to radiation in germ cells before the completion of the first meiotic division (30). Mutations induced at this stage would be repaired in the spermatocyte itself, whereas chromosome breaks induced in late spermatogenesis are repaired in the egg after fertilization (14). The structural differences observed in mutations generated during premeiotic or first-division germ cells vs these translocations, induced at late spermatogenic stages, indicates that different types of repair mechanisms are active in germ cells and the fertilized egg.
The lesions found at breakpoints in the mutagen-induced germline translocations are remarkably similar to those noted at breakpoints of rearrangements arising in somatic cells. The microrearrangements and stretches of microhomology found at breakpoint sites in our heritable mutations are also observed at translocation breakpoints in somatic cells and are signatures of nonhomologous end joining (NHEJ) double-strand break repair (31). These observations provide the first clear indication that NHEJ pathways also function in repair events leading to translocations in mammalian germline cells.
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New Opportunities, Future Challenges, and Links to Human Cancer |
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TopAbstractIntroductionEfficient Induction and...Tying Genes to Mutant...Molecular Structure of...New Opportunities, Future...NotesReferences |
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We continue to analyze new mutations, including several mutations that map outside the boundaries of known transcription units but ablate or substantially alter the functions of known or novel neighboring genes. These translocations, including some that are located tens or hundreds of kilobases away, hold promise to define the locations of novel regulatory elements that act at a distance to control the expression of conserved mouse and human genes.
What can these mouse mutations teach us about human gene function and the molecular basis of genetic disease? First, they tell us that induced and "spontaneous" translocations occur by common routes and may be indistinguishable on the molecular level. Secondly, they promise to expand the known base of critical genes and noncoding elements that must be intact for complete human health and well-being. Because the cost of DNA resequencing from individual patients is still relatively high, most searches for disease-linked mutations are focused on coding sequences, intron–exon junctions, and promoters of known genes. However, the human genome is filled with functional sequences including critical regulatory elements that have not been identified and tied to disease-related functions. In a small number of cases, deletions or other types of mutations in distant regulatory elements have been identified as the underlying cause of human disease (5,32), but specific mutations in these elusive elements are difficult to find. Translocations that disrupt gene function but lie outside the boundaries of transcription units can signal the locations of distant elements that are critical to gene function, as they have for PAX6 (5), SHH (4), and other important developmental loci. Because the functions and gene expression patterns of these ancient developmental genes are typically conserved, transgenic mouse models can be used to efficiently map the most important functional elements (12,32,33). Once identified, these critical noncoding elements can be included for resequencing, increasing the number of human patients that might be diagnosed accurately through DNA-based screens.
And more specifically, how can this line of study benefit scientists focused on human cancer? Many of the genes that are disrupted or co-opted to create protein fusion products in human cancer are deeply conserved genes with critical roles in early development. In a number of cases these genes are dysregulated, through epigenetic modification of regulatory sequences or through DNA rearrangements that fuse active protein-coding modules to regulatory elements from elsewhere in the genome (eg, 34–37). Most known cancer-related regulatory element mutations involve promoters, almost certainly because those elements are the easiest to find. However, many cancer-linked loci, including Myc, are embedded within large conserved "gene desert" regions and a thorough search for dysregulating mutations may therefore require consideration of potential regulatory elements located some distance from the genes.
Developing methods to identify long-distance regulators and to determine their in vivo functions is therefore likely to open doors to the study of noncoding mutations with new roles in the initiation or progression of cancer. Significant efforts are now underway to identify the most deeply conserved regulatory elements in the human genome, blending computational and experimental approaches to predict and test their function in transgenic systems (38). However, linking these elements to the activities of specific genes and identifying the small fraction of those elements with crucial, nonredundant, and disease-related functions will still require in vivo models or the direct identification of loss-of-function mutations in these regulatory sequences in human patients. By flagging the identities of large genomic regions that must remain intact for normal gene function, germline translocations provide a useful tool in this challenging quest.
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NOTES |
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We thank our collaborators W. Generoso, N. Cacheiro, and K. T. Cain for their foundational studies and the important role they played in inspiring our current work and Laurie Gordon for critical comments on the manuscript. This study was performed under the auspices of the US Department of Energy Office of Biological and Environmental Research by the University of California, Lawrence Livermore National Laboratory under contract no. W-7405-ENG-48.
Present address: Institute of Genomic Biology, University of Illinois, 1206 W. Gregory Drive, IGB-2402, Urbana, IL
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