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Human Molecular Genetics Pages 1611-1618  

Position effect in human genetic disease
Introduction
Position Effect Cases
Mechanisms
The Study Of Human Position Effects
Acknowledgements
References

Position effect in human genetic disease

Position effect in human genetic disease

Dirk-Jan Kleinjan and Veronica van Heyningen*

MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK

Received May 18, 1998

The spatially, temporally and quantitatively correct expression of a gene requires the presence not only of intact coding sequence, free of adverse nucleotide changes, but also correctly functioning regulatory control. With the identification of an increasing number of disease-related genes, the molecular defect in many cases has been defined. It is becoming clear that it is not always the transcription unit that bears the defect: there are a number of cases where the regulation of gene expression has been compromised. Cases associated with chromosomal rearrangement outside the transcription and promoter regions are categorized as position effects. A number of different mechanisms may explain their aetiology. Here, we examine the human disorders where such position effects are implicated. Further study of such cases may lead to important insights into mechanisms of gene regulation and transcriptional control.

INTRODUCTION

Over the past few years the genes causing many human developmental disorders have been mapped and isolated. In a number of cases, patients with chromosomal rearrangements have facilitated the positional cloning of the disease-causing gene. Following unequivocal gene identification, however, in some instances translocation breakpoints were found to map outside the putative gene. These observations point to gene malfunction being caused in these cases by a `position effect'. For the purposes of this review a position effect is defined as a deleterious change in the level of gene expression brought about by a change in the position of the gene relative to its normal chromosomal environment, but not associated with an intragenic mutation or deletion. Thus, the transcription unit and minimal promoter of the rearranged gene are expected to remain intact.

There are broadly three categories of factors determining correct gene expression: (i) the promoter region-the site where the basal transcription machinery loads onto the DNA and initiation of transcription occurs; (ii) enhancer/silencer elements-short DNA regions containing binding sites for transcription factors which are often tissue-specific and aid in assembly of the transcription machinery on the promoter, independently of orientation and position with respect to the promoter; these elements are thought to work through increasing the frequency of successful transcription complex assembly on the promoter (1,2); and (iii) the local chromatin environment of the gene locus-enhancers and promoters can only function correctly in a permissive chromatin environment, which makes them accessible for protein interaction, as reflected by a greater general sensitivity of the locus to nuclease treatment. The active [beta]-globin locus, for instance, shows greater sensitivity to DNase I than the inactive locus (3,4). Although sharing some characteristics of enhancers, locus control regions (LCRs) are thought to work mainly at this third level of control. LCRs have been found associated with a number of highly expressed, spatially and temporally tightly controlled genes. They are thought to be instrumental in opening up the chromatin domain of the particular locus (5). LCRs appear to work in a tissue-dependent manner and are characterized by a number of tissue-specific DNase I hypersensitive sites. When assayed in transgenic mice, LCRs have been shown to confer position-independent, copy number-dependent expression on a linked gene (5,6).

Expression of a gene can be greatly influenced by its position in the genome. Chromatin organization can be roughly divided into a tightly wound heterochromatic structure and a more open and accessible euchromatic state (7). These two states are cytogenetically distinguishable with the aid of DNA-specific dyes. Euchromatin is decondensed during interphase, contains most of the genes and appears to replicate earlier in S phase. Heterochromatin exists in a more condensed state throughout the cell cycle, replicates later in S phase and is associated with several repeat sequences. The centromeric regions of chromosomes consist of constitutive heterochromatin. It has been estimated that ~15% of the mammalian genome and 30% of the Drosophila genome consists of heterochromatin (8).

Chromosomal rearrangements frequently lead to alteration of the gene's environment and this may be reflected in a change of expression, referred to as a position effect. A number of different mechanisms could account for observed changes in gene expression (Fig. 1). (i) The chromosomal rearrangement could separate the promoter/transcription unit from an essential distant regulatory element, thus removing the effect of this regulator on the gene. The absence of the enhancer element leads to reduction or absence of transcription from the gene in the appropriate tissue. Alternatively, if the element is involved in silencing the gene in a particular tissue, then its removal through rearrangement could lead to inappropriate activation of the gene (Fig. 1A and C). (ii) A rearrangement may also juxtapose the gene with an enhancer element from another gene, again leading to inappropriate gene expression. For instance, in Burkitt's lymphoma a translocation places the c-MYC gene under the control of an immunoglobulin enhancer (Fig. 1B; 9). This type of position effect also forms the basis of the `enhancer trap' technique, where a minimal promoter/reporter gene cassette is inserted at random in the genome and selected for activation of the reporter gene (10). (iii) The translocation could place the gene and its regulatory elements next to a second gene present at the site of translocation. Competition for the regulatory element between the disease gene and second gene may result in a reduction in expression levels (Fig. 1D). (iv) The rearrangement could give rise to classical position effect variegation (PEV) (Fig. 1E).


Figure 1. Possible mechanisms which may lead to a position effect. (A) The chromosomal rearrangement separates the promoter/transcription unit from a distant cis-acting regulatory element. The removal of an enchancer element will result in complete or partial silencing from the affected allele. Alternatively, if a silencer element is removed, inappropriate allele activation may occur. (B) Juxtaposition of the gene with an enhancer element from another gene may also lead to inappropriate gene expression. (C) Removal of a long-range insulator or boundary element may lead to inappropriate shutting down of the locus. Removal of an LCR will result in inactivation through a combination of (A) and (C). (D) Enhancer competition. A gene residing at the translocation site competes for interaction with the regulatory element(s) of the disease-causing gene, thereby reducing its level of expression. (E) PEV. PEV can occur when a chromosomal rearrangement causes the juxtaposition of a euchromatic gene with a region of heterochromatin. The heterochromatin DNA organization is thought to spread into the juxtaposed euchromatic region, thereby silencing the nearby gene in a stochastic manner.

The phenomenon of PEV was first recognized in Drosophila (11,12) and has been extensively studied both in Drosophila and in yeast (see ref. 13). More recently, PEV has also been demonstrated in mammalian systems (14,15). The study of PEV was initiated when a natural chromosomal inversion in Drosophila placed the white+ gene, which is required for normal red eye pigmentation, near centric heterochromatin, giving rise to a mosaic red and white eye pattern (see ref. 16). PEV describes the variable, but heritably stable, inhibition of gene expression due to the juxtaposition of a euchromatic gene with a region of heterochromatin through a chromosomal rearrangement. The heterochromatinized state of the DNA is thought to spread from the heterochromatin into the juxtaposed euchromatic region, thereby silencing the nearby gene. Initially this spreading is variable between individual cells, resulting in either repression or expression of the gene in a given cell, producing phenotypic mosaics due to differential gene expression in otherwise identical cells. At some point in development the expression status of the variegating gene becomes fixed and is clonally stable after that, so that clonal patches of similarly expressing cells are produced. The size and number of the differently coloured patches is a measure of the degree of variegation. The degree of variegation is dependent on the distance of the gene from the breakpoint, with shorter distances from the heterochromatic region giving rise to more frequent suppression. The spreading of heterochromatin is thought to occur via the formation of multiprotein complexes (17), whose components are now being defined. These multiprotein complexes somehow close the chromatin, in a way that is not very well understood at present, but which leads to inhibition of transcription. A correlation between PEV and altered chromatin structure was demonstrated in a study using a transgenic construct with the hsp26 promoter fused to heterologous sequences. Transgenes inserted in heterochromatin showed reduced levels of expression after heat shock induction compared with euchromatic insertions. In the heterochromatin-inserted constructs the hsp26 promoter region was shown to be less accessible to both restriction enzymes and micrococcal nuclease than the constructs that had inserted into euchromatin, indicating a less open chromatin structure over the transgenic promoter in heterochromatin (18). A number of genes have been shown to be capable of either enhancing or suppressing PEV. Several of these `modifiers of PEV' have been cloned and some have been found to encode chromatin structural proteins, while others may play a role in regulating chromatin assembly or modification (19). Among the chromatin modification mechanisms, histone acetylation/deacetylation has received much interest in recent years (20,21).

A second mechanism proposed to explain position effect silencing in Drosophila is based on the suggestion that the genome assumes a compartmentalized configuration in the nucleus, with subdivision into transcription-competent and -incompetent areas. Heterochromatic regions are assumed to locate to the transcription-incompetent areas, while euchromatin localizes in transcription-competent areas. When a gene is translocated to a heterochromatic region it is consequently dragged into a transcription-incompetent area of the nucleus, where it cannot be efficiently transcribed. Heterochromatin has been shown to be located in specific areas of the nucleus, in particular near the nuclear periphery (22). Recent reports suggest the existence of foci of heterochromatin in the nucleus and association of transcriptionally inactive genes with these (23-25).

Observations in Drosophila have also revealed that PEV-associated silencing is seen to work in two directions: not only when euchromatic genes are moved to regions of heterochromatin, but also when genes normally residing in heterochromatin are moved into euchromatin. This effect is shown by the rolled and light genes of Drosophila, which are normally located in heterochromatin. When they are moved far away from heterochromatin they show PEV (26,27). This suggests that genes have evolved to be expressed optimally in their home environment.

Are position effects observed in mammalian systems? Over the last few years a number of cases have been described of patients carrying chromosomal rearrangements that have breakpoints some distance from the gene implicated in the disease aetiology by recurrent point mutations, suggesting that the phenotype in these cases may be the result of a position effect. The genes involved in these putative position effect cases are listed in Table 1 and are discussed in greater detail below. For a phenotype to be ascribed to a position effect it is of course necessary that the nearby disease-causing gene has been clearly demonstrated to cause the phenotype, usually through loss-of-function intragenic mutations. Ideally, the absence of intragenic change in association with the chromosomal rearrangement should also be demonstrated, to strengthen the hypothesis that the rearrangement is solely responsible for the phenotype through transcriptional repression. Inspection of Table 1 reveals that all cases of proposed position effect in human disease are either in genes that are haplo-insufficient or sex chromosome linked. This can probably be attributed to the requirement for clear-cut ascertainment: a position effect is seen only where reduced expression from one allele causes a phenotype.

POSITION EFFECT CASES

The PAX6 gene was one of the first to provide a compelling argument that position effect could play a role in human genetic disease. Aniridia is a congenital malformation of the eye characterized by severe hypoplasia of the iris, usually accompanied by cataracts and corneal opacification. PAX6 haplo-insufficiency at chromosome 11p13 has been shown to be the cause of aniridia in deletion cases (28) and through loss-of-function point mutations (29). Two aniridia patients with translocation breakpoints mapping downstream of the PAX6 gene have been described (30). Detailed mapping of these breakpoints has placed them at 100 and 125 kb downstream of PAX6 (31). Three further aniridia patients with breakpoints 3[prime] of PAX6 have since been found (31; D.-J. Kleinjan et al., manuscript in preparation).

As in the case of PAX6, breakpoints have been found mapping downstream of the GLI3 and TWIST genes. The zinc finger gene GLI3 on chromosome 7p13 is involved in the embryonal development of limbs and the skull. Mutations in GLI3 lead to the development of the human Greig cephalopolysyndactyly syndrome (GCPS) (32). One potential position effect translocation has been described in a patient with a breakpoint 10 kb downstream of the last exon of GLI3 (33). Two dominant mutant alleles in the mouse, the extra toes (Xt and XtJ) phenotypes, are caused by mutations in murine Gli3 (34,35). The weak recessive Xt allele anterior digit deformity (add) is caused by a transgene integration combined with the deletion of an 80 kb region at ~40 kb upstream of Gli3 and thus represents a putative murine Gli3 position effect (36).

Mutations in the TWIST gene on 7p21 have been shown to cause the Saethre-Chotzen form of craniosynostosis. Saethre-Chotzen syndrome (acrocephalo-syndactyly type III), a common autosomal dominant craniosynostosis in humans, is characterized by brachydactyly, soft tissue syndactyly and facial dysmorphism, inluding ptosis, facial asymmetry and prominent ear crura. TWIST encodes a basic helix-loop-helix (bHLH) transcription factor (37). Expression of the murine homologue Twist is required in head mesenchyme for neural tube morphogenesis in mice. Mice heterozygous for a Twist null allele display skull defects and duplications of hind leg digits. In one study (38), a breakpoint 5 kb downstream of the gene was described, while in another study four breakpoints of balanced translocations 50-250 kb 3[prime] of the TWIST gene have been reported (39; P.Patel and S.Malcolm, personal communication).

It is noteworthy that all five of the aniridia-associated extra-genic breakpoints are located on the same (3[prime]) side of the PAX6 gene. If the aniridia phenotype were caused by PEV one might have expected to find breakpoints both 5[prime] and 3[prime] of the gene, as juxtaposition with heterochromatin would be equally likely to occur through breaks on either side of the gene. Although other factors may be involved in causing breaks to occur on one particular side, this observation appears to favour the case for disruption of a regulatory element from the gene. This is even more striking in the cases of PITX2, SOX9 and POU3F4.

Table 1. Position effect genes in human diseases
Affected gene Disease Distance of furthest reported breakpointa 3[prime] or 5[prime] side Reference
PAX6 Aniridia 125 kb 3[prime] 30
SOX9 Campomelic displasia 850 kb 5[prime] 46
POU3F4 X-Linked deafness 900 kb 5[prime] 48,49
PITX2 Rieger syndrome 90 kb 5[prime] 42
SHH Holoprosencephaly 265 kb 5[prime] 50,52
GLI3 Greig cephalopolysyndactyly 10 kb 3[prime] 33
TWIST Saethre-Chotzen syndrome 250 kb 3[prime] 38,39
[EEgr][Bgr][Bgr] complex [gamma][beta]-Thalassemia 50 kb 5[prime] 70,71
SRY Sex reversal 3 kb 5[prime]/3[prime] 54,55
FSHD Facioscapulohumural dystrophy 100 kb 3[prime] 64
SHFM1 Split hand/split foot malformation ~450 kb 5[prime]/3[prime] 61
aIn the case of 3[prime] breakpoints the distance refers to the distance from the breakpoint to the 3[prime]-end of the gene.

Rieger syndrome (RIEG) is an autosomal dominant disorder showing malformations of the anterior segment of the eye, dental hypoplasia and failure of the periumbilical skin to involute. The main locus for RIEG was mapped to 4q25-27 and recently the gene for a bicoid-related homeobox transcription factor, PITX2, was cloned from this region and point mutations in the gene were shown to cause RIEG (40,41). PITX2 is likely to be a transcription factor and its relatedness to Drosophila bicoid might explain its gene dosage sensitivity, as bicoid is important in setting up a gradient in the Drosophila embryo. In addition to deletions and mutations in the gene itself, a translocation break 90 kb upstream of the gene was found in one patient (42). Two further translocation breaks mapping between 15 and 90 kb upstream of PITX2 have been identified (43).

Campomelic dysplasia (CMPD1) is characterized by bowing of the long bones and other skeletal malformations and is associated with autosomal XY sex reversal (SRA1). Two-thirds of 46,XY CMPD1 patients develop as phenotypic females or intersexes. CMPD1 was mapped to chromosome 17q24.3-25.1, where SOX9 was subsequently assigned. SOX9 is an HMG-box protein related to the testis-determining gene SRY. Haplo-insufficient loss-of-function mutations in SOX9 were identified as the cause of CMPD1 in a number of patients (44,45). Eight cases of chromosomal rearrangements with breakpoints outside the SOX9 gene have now been identified. All map to the 5[prime] side of the SOX9 gene. The distance from breakpoint to the transcription start site ranges from 50 to an amazing 850 kb upstream of SOX9 (D. Pfeifer and G. Scherer, personal communication). It has been noted that patients with breakpoints outside the SOX9 gene appear to be less severely affected than patients with deletions or premature protein truncations (44,45).

Interestingly, one of the extragenic translocation patients was found to carry two different alleles for a known expressed nucleotide polymorphism in the SOX9 cDNA. This provides an opportunity to assess whether the two alleles are differentially expressed, as implied by the hypothesis of suppressed gene expression from the rearranged allele. Unfortunately, SOX9 is only expressed at very low basal transcription levels in lymphocytes and RT-PCR on a lymphoblastoid cell line from this patient revealed no differences in transcription level between the two alleles (46). However, it is conceivable that only high level tissue-specific expression is disrupted by position effects.

The argument for the suggestion that the dissociation of a regulatory element from the gene is the basis of the position effect is particularly strong for the chromosomal rearrangement cases involving POU3F4 in X-linked deafness (DFN3). DFN3 is characterized by fixation of the stapes and in most cases by conductive and sensorineural hearing loss. POU3F4 was cloned by homology to the mouse POU domain gene Brain4 and assigned to the Xq21.1 region, where the DFN3 locus maps (47). Mutations in the POU3F4 gene were found in nine unrelated male DFN3 patients. In four other patients the intronless POU3F4 gene was intact, but mini-deletions were found in a region >400 kb upstream of the gene (47,48). More recently five further DFN3 patients were found to have micro-deletions that overlap in an 8 kb fragment located 900 kb upstream of the POU3F4 gene (49). One of the patients appears to have an interstitial deletion of just this 8 kb fragment. As it is hard to imagine how an 8 kb deletion could make a difference in spreading of heterochromatin over a >900 kb distance, unless it contains a specific element, it seems unlikely that a simple PEV-like heterochromatin spreading mechanism is involved in the repression of the gene in this case of DFN3. The nature of the presumed element, for instance a regulatory element or a boundary element, remains to be determined, but its relatively small size makes the fragment suitable for more detailed analysis, perhaps through mouse transgenesis experiments.

In contrast, analysis of chromosome 7q36 translocation patients with holoprosencephaly seems to favour the classical PEV model. The sonic hedgehog (SHH) gene on chromosome 7q36 has been identified as the gene for one of the holoprosencephaly loci, HPE3 (50,51). Deletions of SHH and point mutations in the gene itself cause HPE, but translocations in a region from 15 to 265 kb upstream of SHH have been found in three unrelated HPE patients. A fourth translocation breakpoint has also been defined 315 kb upstream of SHH, but none of seven individuals carrying this rearrangement showed any HPE characteristics (52). Interestingly, all of the translocation patients are less severely affected than the patients with deletions of the SHH region. This genotype-phenotype correlation is especially prominent in a family of patients where the mother and two affected daughters, all with mild phenotype, carry a balanced translocation with a breakpoint 265 kb upstream of SHH. Two other daughters carry the same translocation in unbalanced form with deletion of 7q36-qter and are severely affected (50). The phenotype associated with another balanced translocation breakpoint mapped at 235 kb upstream of SHH is more variable, since three phenotypically normal carriers and one HPE individual have been reported with this breakpoint. The variable degree to which these patients are affected by HPE could be explained by a PEV mechanism. Interestingly, whereas haplo-insuffiency for SHH causes HPE in humans, no effects are observed in heterozygous SHH+/- mice (53). Thus, it may be that haplo-insufficiency of SHH is a borderline case and causes HPE only in some, but not all, individuals. Deletion of a regulatory element could cause a reduction in SHH expression which leads to HPE only in some cases.

Two possible cases for a position effect in humans with XY sex reversal have been reported for the sex-determining gene SRY on the short arm of the Y chromosome. The breakpoints in these two cases are on opposite sides of the SRY gene. In one case a deletion of 25-30 kb on the 5[prime] side of SRY has been found (54), while in the other case, which has been recorded as partial sex reversal, a deletion 3 kb downstream of the SRY gene and extending into the pseudo-autosomal region of Yp was found (55). The upstream position effect may well be due to a simple deletion of regulatory elements, as the deletion has been mapped to 1.7 kb upstream of the transcription initiation site and a number of conserved elements have recently been shown to reside in the SRY upstream region (56). The finding that the SRY gene can be subject to a position effect is corroborated by a study of induced Yp deletions in the mouse (57). Three fertile XY sex reversed female mice were shown to carry an intact SRY gene. Furthermore, a region of 36 kb surrounding the gene was found to be intact in all three lines. Significantly, this 36 kb region contains the 14 kb fragment that has been shown to be sufficient for female to male sex reversal in XX transgenic mice, indicating that the regulatory elements required for SRY expression are present in that fragment (58). Sry expression from the 14 kb fragment is, however, sensitive to the site of integration, as indicated by the fact that not all SRY transgenic mice were sex reversed. In the three sex-reversed mouse lines various deletions of the Sx1 repeat were demonstrated, at least 50 of which are found upstream of Sry, located between Sry and the centromere. The deletions bring Sry closer to the Y centromere and it has been suggested that the Sx1 repeats may provide a buffer or boundary to heterochromatinization of the SRY locus (59). The mice could be re-reversed back to a male phenotype with an Sry transgene, showing that their original sex reversal to female was caused by insufficient expression of Sry (59).

The last two examples in Table 1 are cases which are at this stage only suggestive of a position effect, but the role of the associated genes in causing the disease has not yet been identified by mutation or deletion within the coding region of a specific gene in patients with these disorders. In the case of the split hand/split foot malformation an extensive search of the SHFM1 locus, which has been mapped to 7q21.3-q22.1 on the basis of SHFM-associated chromosomal rearrangements (60), has resulted in the identification of three candidate genes, two genes of the Distal-less (dll) homeobox gene family, DLX5 and DLX6, and a novel gene, which was named DSS1 (deleted in split hand/split foot). No other candidate genes were found in a 500 kb region containing five of the seven known SHFM translocation breakpoints (61). SHFM is a heterogeneous limb developmental disorder, characterized by missing digits and fusion of remaining digits (ectrodactyly). The translocation breakpoints map around the DSS1 gene, but do not disrupt the gene itself, nor do they interrupt the DLX5 or DLX6 genes. The expression pattern of the mouse homologue Dss1 and the absence of other candidate genes in the region suggests the involvement of DSS1 in SHFM1 through a position effect, but no definite conclusions are possible at this stage.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder displaying progressive weakening and atrophy of the facial and shoulder girdle muscles. The FSHD locus has been mapped to the distal part of 4q35, in close proximity to the telomere and adjacent to sub-telomeric sequences. FSHD has been shown to be associated with the deletion of many interstitial copies of a 3.3 kb repeated unit from the 4q sub-telomeric region (62). These repeated units map very close to the telomere and belong to a repeat family associated with heterochromatic regions of the genome (63). A novel evolutionarily conserved gene, FRG1 (FSHD region gene 1), was identified ~100 kb proximal to the repeated units. Allele-specific transcriptional repression of this gene through heterochromatin spreading from the sub-telomeric region is a plausible mechanism for FSHD. The repeats contain homeobox-like sequences, but are apparently non-transcribed. They may, however, contain an element involved in insulating the FRG1 gene from PEV. The role of FRG1 in FSHD, however, awaits confirmation, as transcription levels appeared equal for both alleles of a FSHD patient heterozygous for a polymorphism in the first exon of FRG1 (64).

Natural position effect cases have also been described in mice. The Sx1 deletions at the Sry locus have already been mentioned and a number of other position effect cases exist which involve genes that are known to affect mouse coat colour. The best studied of these is the mast cell growth factor (Mgf), which is encoded by the Steel locus. Mgf is the ligand for the receptor tyrosine kinase c-kit, encoded by the W locus. Two mutant alleles of the Steel locus have been identified, Steel-panda and Steel-contrasted, that have breakpoints located 115 and 195 kb upstream of the Mgf coding sequences, respectively (65). It was shown that Mgf expression is repressed in a tissue- and development-specific manner and that both Steel-panda (SlPAN) and Steel-contrasted (SlCON) female mice are sterile due to arrest of ovarian follicle development. Two Steel alleles affecting only the Mgf coding sequences do not show complementation with the SlCON or SlPAN alleles, indicating that the gene encoding Mgf is the gene causing the phenotype (65). Other mouse mutants that are believed to be caused by position effects include the original allele, kr, at the kreisler locus, the W-sash (Wsh) and patch (Ph) alleles of the c-kit receptor tyrosine kinase at the W locus and the lethal nonagouti (ax) allele of the agouti coat colour locus (66-68).

MECHANISMS

If the case for the existence of position effects in human disease is accepted, the question of the mechanism(s) involved still remains to be answered. An obvious explanation which is frequently suggested is that another gene is present and disrupted at the site of the breakpoint. However, in most cases there are a number of arguments against this possibility. The simplest general argument is the unlikelihood of two genes with similar haplo-insufficient phenotypes repeatedly mapping close together in all the diseases discussed. In the case of the 5[prime] breakpoint cases, the possibility of alternative 5[prime] exons cannot be formally excluded, even though searches for such alternative upstream exons in some of these cases have been negative. A novel first exon was identified at a later stage in the human dystrophin gene >500 kb upstream of its previously known promoter (69).

Proposed mechanisms for position effects have been listed in the Introduction. Basically, two different possibilities can be envisaged. Firstly, in a mechanism analogous with Drosophila PEV, the transposition of a gene from its accustomed chromatin environment to a novel site may lead to suppression of gene expression and therefore to a haplo-insufficiency phenotype. The spreading of a repressive chromatin structure at the new site causes PEV of the gene and results in silencing of the gene in a percentage (or all) of the cells. Secondly, the chromosomal rearrangement may separate the transcribed body of the gene from cis-acting regulatory elements. This option is clearly different, but may nevertheless in its subsequent effects be linked to the first mechanism. Displacement of an insulator or boundary element, for instance, is predicted to lead to reduced expression through altered chromatin organization. Displacement of an enhancer is expected to result in a reduced level of expression in all cells in key tissues where the enhancer normally functions. Finally, if the deleted element is an LCR, then its displacement would potentially result in a combination of the two options. Although not discussed in the previous section, [gamma][beta]-thalassaemias, caused by translocations upstream of the globin genes, also constitute a position effect. The cause of the disease in those cases, however, has long been known to be due to deletion of the [beta]-globin LCR (70,71). Disrupted LCR activity may well be at the root of most of the human position effect cases. A final possible mechanism is competition for regulatory elements between the disease gene and genes present at its new translocated site. This possibility has mainly emerged from work on the [beta]-globin locus, where at embryonic/fetal stages the different globin genes compete for interaction with the LCR (72). In the murine HoxB cluster competition for a shared enhancer element was found between the HoxB4 and HoxB5 genes (73).

There are relatively few naturally occurring cases of human or murine disorders where a position effect may be involved. The occurrence of position effects in mammalian systems has become clearer from studies of gene regulation in transgenic mice. Assays for promoter and enhancer sequences of developmentally regulated genes often involve microinjection into mouse oocytes of constructs containing such sequences linked to a reporter gene. Typically, only a proportion of the resulting transgenic lines will express the reporter and in these cases the expression level is not usually proportional to transgene copy number. This variability in the expression of transgenic constructs is a function of the integration site of the construct. Recently it was shown that inclusion of an appropriate LCR in the construct can overcome this expression level variability. Insertion of an incomplete LCR fails to prevent PEV when the transgene integrates into or near a heterochromatic region, but the presence of a complete intact LCR in the construct can protect against PEV and leads to copy number-dependent, site of integration-independent expression (14,15).

Discussion of LCR function sometimes invokes the presence of insulator or boundary elements that block the spreading of heterochromatin. Such elements have been identified in Drosophila. The 87A7 heat shock locus is flanked on both sides by a pair of nuclease hypersensitive sites bordering a 250-300 bp DNA fragment. These elements, which have been called 5[prime] and 3[prime] specialized chromatin structures (scs and scs[prime] elements, respectively), are believed to establish a domain of independent gene activity, but are neither stimulatory nor inhibitory within the domain (74,75). When placed between an enhancer and a promoter the scs elements were shown to block communication between the two. Another example of a putative insulator in Drosophila is the complex formed by the Suppressor of Hairy-Wing protein [Su(Hw)] on a gypsy retrotransposon element (76-78). The existence of insulator elements in the mammalian genome is not clear. Although elements from the human and chicken [beta]-globin LCRs have been reported to be able to function as insulators in some assays, this has not so far been confirmed by animal studies (79,80). The deletion of insulator elements might, however, be involved in some of the mammalian position effect cases. In both SRY and FSHD the deletion of repeats between the gene and a presumed heterochromatic region is involved.

THE STUDY OF HUMAN POSITION EFFECTS

The study of position effects in human patients is severely hampered by the inability to look at the correct tissues. Many of the affected genes are tissue-specific transcription factors involved in early development and therefore one would have to study the effect of the translocations on expression of the gene in the affected early embryo. The creation of mouse models may overcome this problem, but this requires the generation of YAC transgenic mice with the relevant human locus (which may be too large even for YAC transgenesis, e.g. SOX9 with breakpoints 850 kb upstream). To assess function, the transgenic mice need to be crossed onto a mouse null background. In the case of PAX6, a YAC containing the human PAX6 locus and extending beyond the furthest position effect breakpoint has been shown to rescue the Smalleye phenotype, which is caused by a mutation in the murine Pax6 gene (81), whereas a truncated YAC with an intact PAX6 gene was not able to rescue the phenotype (82).

In most proposed position effect cases little is known about the chromatin structure of the DNA segment into which the disease gene locus has translocated. Constitutive heterochromatin occurs in the human genome only at the centromeres and part of the long arm of the Y chromosome. Other regions which assume the characteristics of heterochromatin in a developmentally controlled manner, as for instance the inactive X chromosome, are usually referred to as facultative heterochromatin (83). Telomeres are not constitutively condensed, but they share the repetitive structure of yeast and Drosophila telomeres and might likewise repress juxtaposed genes. Their (hetero)chromatin structure, however, may well be different from centric heterochromatin, as, at least in Drosophila, variegating genes near telomeres do not respond to known modifiers of PEV. Analysis of the heterochromatic end of three variegating Drosophila breakpoints revealed the presence of middle repetitive sequences. However, re-inversion of one of these cases in which the heterochromatic sequences at the initial breakpoint were retained restored wild-type expression, indicating that the sequences at the breakpoint by themselves were insufficient to cause PEV (84). Other cases of revertant chromosome rearrangements have been found where some PEV was still detectable, but only in the presence of enhancers of variegation (85). Thus, it might be that repeat sequences are involved in PEV, but that a threshold of repetitive DNA is required or a combination of repeats and other more specific sequences. Analysis and comparison of the trans-breakpoint regions in the human position effect cases where no specific regulatory elements are involved may therefore be helpful in the identification of elements that are involved in heterochromatin formation.

In conclusion, position effect phenomena are clearly a mechanism to be considered in human genetic disease. The realization that position effects could be involved in many human genetic disorders may horrify those involved in positional cloning efforts aimed at identifying disease genes through translocation breaks. The actual mechanism behind each of the position effect cases described above remains to be established, but further research is likely to improve our understanding of long-range effects on gene regulation. The existence of position effects must be borne in mind, in particular for the design of gene therapy constructs, where transgene expression control is critical. We cannot expect to be able to manipulate the genome effectively until we understand chromatin organization and its effect on gene expression much more thoroughly.

ACKNOWLEDGEMENTS

We would like to thank Jacky Guy and Beth Sullivan for critical reading of the manuscript and D. Pfeifer, G. Scherer, P. Patel and S. Malcolm for providing information on unpublished SOX9 and TWIST breakpoints. D.A.K. is supported by EC project BMH4-CT96-1428.

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*To whom correspondence should be addressed. Tel:+44 131 332 2471; Fax: +44 131 343 2620; Email: vervan@hgu.mrc.ac.uk

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