The centromere of large, complex chromosomes is defined cytologically by the primary constriction and is required for proper chromosome segregation in both meiosis and mitosis. The kinetochore is located on either side of the centromere, and it is the centromere/kinetochore complex that is the location for the motor components responsible for chromosome movement in mitosis (1 -5 ). This complex can be split into three different regions, an inner pairing domain, a central domain and an outer kinetochore domain (2 ,6 ). The central domain is composed primarily of centromeric heterochromatin and is where centromere protein B (CENP-B) is localized (7 -10 ). CENP-B binds to a 17 bp motif (CENP-B boxes) within [alpha]-satellite DNA (11 ), the major class of DNA found at primate centromeres. Other proteins have also been localized to the kinetochore domain and have been implicated in chromosome movement. CENP-C has been localized to the inner plate of the kinetochore domain (12 ) and has been suggested to have a role in kinetochore assembly (13 ). Cytogenetic studies have indicated that, while CENP-B is present at both active and inactive centromeres, CENP-C is present only at active centromeres (5 ,7 ,14 ). CENP-E is found at the outer plate of the kinetochore structure and can be detected on either side of the centromere by late prometaphase (15 ,16 ). This protein is believed to function as a unique motor protein and is associated with microtubules and chromosomal movement (17 ,18 ).
One effective genetic approach to understanding mammalian centromeres and the role of centromeric proteins in the proper segregation of mitotic chromosomes is to examine structurally rearranged chromosomes with an abnormal number of centromeres. The most accessible rearrangements are Robertsonian translocations, which are the most common dicentric chromosomes in humans. Sullivan and Schwartz (5 ) studied 12 dicentric Robertsonian translocations and, using immunocytogenetic studies, demonstrated that while CENP-B was invariably present at both active and inactive centromeres, CENP-C and CENP-E were usually located only at active centromeres. These studies confirmed previous observations of CENP-C at active centromeres (7 ) and provided the first evidence that CENP-E is also found specifically at active centromeres, thus suggesting that at least two specific centromeric proteins are necessary for human centromeric function.
Small accessory unidentified chromosomes (`marker chromosomes') are estimated to occur in 0.05% of livebirths (19 ). Utilizing FISH, the majority of these can now be identified. In most instances, such chromosomes have been shown to contain [alpha]-satellite DNA and other pericentromeric material (20 ). However, a recently recognized class of marker chromosomes that lack detectable [alpha]-satellite DNA has been identified (21 ,22 ). In light of recent evidence that indicates a role for [alpha]-satellite DNA in centromere function (22 -24 ), this class of marker chromosomes raises the question of what DNA acts as a functional centromere in the absence of normal amounts of [alpha]-satellite DNA. In this study, we have investigated eight different marker chromosomes in which [alpha]-satellite DNA could not be detected by FISH with either pancentromeric or chromosome-specific [alpha]-satellite DNA probes. We explored the relationship between chromosome segregation, stability and the presence and identity of centromeric proteins in this unique set of marker chromosomes.
The eight cases were initially studied with high resolution chromosome analysis revealing the presence of a marker chromosome in all eight patients, and a concomitant deletion in three patients (Table 1 ). These markers were characterized using both G-banding and C-banding. No C-banded region was seen on any marker; however, a constriction was seen in each marker chromosome using G-banding. FISH with several different repetitive sequences was utilized to characterize each marker. FISH studies with [alpha]-satellite DNA, [beta]-satellite DNA and satellite III-DNA probes revealed no detectable signal on any of the markers (Table 1 ). Studies with chromosomal library probes revealed that three of these markers originated from chromosome 15, two from chromosome 9 (25 ), and one each from chromosomes 13, 11 and 10. Studies with a telomeric probe showed that seven of these markers had telomeres at each end, while one (Case 8) did not show any detectable hybridization.
Based upon both cytogenetic and FISH studies, the markers were subdivided into three groups (Table 1 ). Five of the cases (patients 1-5) had 46 normal chromosomes plus an additional supernumerary marker chromosome that appeared linear about a symmetrical point. This resulted in four copies of segments of 15q, 13q and 9p in cases 1-3, 4 and 5, respectively. Two cases (6 and 7) showed a terminal deletion in one chromosome along with a symmetrical mirror image marker resulting from duplication of the deleted segment. This resulted in three copies of segments of 9p and 11q in cases 7 and 6, respectively. The marker in case 8 resulted from an interstitial deletion of chromosome 10q. In this case, there was no duplication of the deleted chromosomal segment, leading to a net loss of material, because of mosaicism.
Table 1
The structure of each marker chromosome was examined with a series of cosmid and YAC probes. When possible, each marker was studied by FISH with at least two single-copy probes from the relevant chromosome. FISH with site-specific DNA probes revealed the presence of either two signals or no signal in markers 1-7. The information obtained by FISH, in conjunction with high resolution banding, suggests that markers 1-7 are linear `mirror image' rearrangements, which are symmetrical about a central point (Fig. 1 ). Only in case 8 was the inferred structure of the marker different. In this case, the marker was not symmetrical, appearing as the segment lost from an interstitial deletion in one chromosome 10 (Fig. 2 ).
When possible, mitotic stability of the markers was studied in lymphocyte, lymphoblast and fibroblast cultures (Table 1 ). Studies of lymphocyte cultures revealed that in three of the seven cases (cases 5-7), the marker chromosomes were seen in every cell examined. The marker was present in at least 74% of the cells from the other patients (cases 1-4). These findings suggest that the markers are stable in short-term lymphocyte cultures. The lymphoblast and fibroblast studies did not reveal the same high frequency of marker chromosomes (Table 1 ). While this may indicate that the marker is less stable in long-term cell culture, the lower frequencies may also be just a chance occurrence, as these lines are oligoclonal in origin.
Table 2
In order to understand how and why these chromosomes which lack detectable [alpha]-satellite DNA can segregate in culture, several antigens to centromere proteins were studied using indirect immunofluorescence in combination with FISH to evaluate each marker available for study. Consistent with the absence of detectable [alpha]-satellite DNA, CENP-B could not be detected in any of the five cases studied (Table 2 ; cases 1, 4, 6, 7 and 8). However, CENP-C was present on 5/5 cases studied, while CENP-E was present on 4/4 cases studied (Table 2 ; Figs 3 , 4 and 5 ). Neither CENP-C nor CENP-E was located in the center of the mirror image markers; however, only one antibody signal was detected on the chromosome.
Marker chromosomes occur in approximately one per 2000 livebirths. The vast majority of these markers can now be identified using FISH with either [alpha]-satellite DNA probes or with chromosome painting probes (20 ). In this study, we discuss a recently recognized type of marker chromosome in which the centromere is not detectable by C-banding, and [alpha]-satellite DNA is not detectable by FISH with either a pancentromeric probe or any chromosome-specific [alpha]-satellite DNA sequence (22 ). The identity of the marker in three of our cases (cases 6-8) was easily identified cytogenetically because of a concomitant deletion. However, in our other cases (cases 1-5), neither routine nor high resolution chromosome analysis identified the marker, and FISH with a series of DNA probes was required to identify the markers (Table 1 ).
Telomere probes confirmed that seven of these marker chromosomes (cases 1-7) were linear, with two telomeric segments. In addition, FISH with a series of single-copy cosmids and YACs indicated that all seven of these markers appeared to have a symmetrical mirror image organization. Because three different markers were found to originate from chromosome 15, single-copy cosmids and YACs were utilized to determine if these markers were identical in structure. This analysis clearly showed that each marker had a different breakpoint and involved different segments of chromosome 15q (Table 1 ).
In contrast, telomere studies on the chromosome 10 marker identified in case 8, revealed that this marker, in addition to having no detectable C-banding or [alpha]-satellite DNA, did not have any demonstrable telomeric regions. Most likely this marker was the result of an interstitial deletion not accompanied by duplication (see below). Based on the banding of both the deleted chromosome 10 and the marker, no material appeared lost from those cells with the marker. However, the patient did contain a cell line with the deletion but without the marker, thus resulting in a net loss of material.
Our cytogenetic analyses and FISH studies, revealed three different types of markers, all with no detectable [alpha]-satellite DNA. These included: (i) markers that originate as extra supernumerary chromosomes, such that the karyotype contained 46 normal chromosomes plus an accessory symmetrical mirror-image marker; (ii) markers that result from a terminal deletion of a chromosome with duplications of the deleted segment, leading to a symmetrical mirror-image marker; and (iii) markers that result from an interstitial deletion, leading to a non-duplicated marker. Our findings regarding these subtypes are consistent with previously reported cases. Magnani et al. (26 ) reported a marker chromosome derived from chromosome 14 with a concomitant deletion on one chromosome 14; this has been the only other case of a symmetrical marker chromosome in addition to the presence of a deletion. One case of an extra marker derived from chromosome 8, and three cases with an extra marker derived from chromosome 15 have been reported (21 ,27 ,28 ). Voullaire et al. (29 ) reported an unusual supernumerary marker chromosome resulting from an interstitial deletion. All of these marker chromosomes are similar to the eight cases described here in that none demonstrate C-banding nor contain detectable [alpha]-satellite DNA.
As described above, both FISH and DNA polymorphism studies were used to examine the mechanism of formation and the parental origin of marker chromosomes. In case 2, three individual alleles could be detected by PCR; thus the marker found in case 2 is probably the consequence of a meiotic error. In three of the cases, the proband's marker chromosome showed only two alleles, and therefore, were most likely the consequence of mitotic errors. These observations are consistent with our findings in routine cytogenetic studies of amniotic fluid cell cultures, where a survey of 400 amniotic fluid cultures revealed that 2.5% of the cases examined had an `acentric' symmetrical mirror image marker (data not shown). We believe that the majority of these markers were produced mitotically, are not stable in culture, and are most likely a tissue culture artifact.
Blennow et al. (21 ) have hypothesized that acentric markers derived from chromosome 15 are formed as reciprocal by-products of the formation of inv dup(15) chromosomes. While this is feasible, it is probably not the method of formation for the majority of these markers for several reasons. First, the markers reported here are much smaller than markers predicted as the acentric reciprocal event of the inv dup(15). Second, although there are several markers without normal centromeres derived from chromosome 15, this number is still very small and the breaks are very heterogeneous. In contrast, we have recently found that there are specific hotspots in proximal 15q involved in the formation of inv dup(15) chromosomes (Wandstrat et al., manuscript in preparation). Thirdly, our molecular data suggests that the majority of these markers most likely arise in mitosis, and therefore must be accounted for by a different mechanism than inv dup(15) markers which are the consequence of maternal meiotic errors (Wandstrat et al., manuscript in preparation). Therefore, it is unlikely that the marker chromosome studied in this report represents reciprocal events.
As demonstrated in our studies and in several previously reported cases by others (21 ,26 -29 ), this new class of markers has neither detectable [alpha]-satellite DNA nor detectable C-banding. Additionally in those cases studied, no CENP-B protein could be detected on these markers. This latter finding is not an unexpected result, as CENP-B binds to [alpha]-satellite DNA (2 ,7 ,9 ,11 ). Antibodies to CREST antigens were used in the study of three previous cases, and were shown to bind to these markers (27 ,29 ,30 ). As the antibodies present within each batch of CREST serum will vary and recognize several different centromeric proteins, information obtained using CREST serum is of limited value.
In order to better understand the relationship of centromeric proteins with these markers, we examined each of our markers for the presence or absence of specific centromeric proteins, CENP-C and CENP-E. In all five cases studied with CENP-C and the four studied with CENP-E, both proteins were detected. As described in previous studies of Robertsonian translocations (5 ), this suggests an important role for these proteins in the functional centromere and confirms earlier antibody microinjection studies that showed CENP-C to be required for the assembly of the kinetochore (13 ).
Because both CENP-C and CENP-E are present on the marker chromosomes, we can hypothesize that these chromosomes must contain functional kinetochore, thus explaining why the markers are stable in vivo. However, it is unclear how and where these proteins bind, as no conventional centromere is present. It is possible that a small undetectable amount of [alpha]-satellite DNA is present and provides the basis for a functioning centromere, but that the amount of [alpha]-satellite DNA present is below our methods of detection. This would be consistent with several studies over the past few years that have shown that by introducing [alpha]-satellite DNA into primate and human cell lines, these sequences will provide the necessary requirements for certain aspects of centromere function (24 ,31 ). Additionally, Wevrick et al. (32 ) and Andersen et al. (33 ) have shown that a partial deletion of [alpha]-satellite DNA, while associated with reduced amounts of CENP-B, is consistent with the presence of a mitotically stable human chromosome. However, it seems unlikely that this is the best model for explaining the markers reported here. Our analyses showed that these markers are symmetrical, do not include a typical centromeric sequence, and originated from chromosomal segments distant from the centromeric region. The inclusion of [alpha]-satellite into the markers would require an extensive chromosomal rearrangement, a complex event that appears unlikely. An alternative explanation would be the activation of small amounts of `ectopic' [alpha]-satellite DNA at non-centromeric positions in these rearrangements (29 ). Although this is possible, there is no evidence for such `ectopic' [alpha]-satellite DNA from extensive physical mapping studies except on chromosome 2q, which is the site of the ancient primate centromere (34 -36 ).
The most likely explanation for our finding is that marker chromosome formation is accompanied by activation of non-centromeric sequences at non-centromeric sites. Such sequences could be normal euchromatic DNA that, in the absence of [alpha]-satellite DNA and/or other centromeric DNA, is capable of being activated to form a `neo-centromere' (37 ). The activation may be sequence-specific, but the sequence-specificity must be broader than currently recognized. The activation may alternatively be sequence-independent or conformation-dependent, in which case the centromere/kinetochore forms at a particular site because the chromatin achieves a proper conformation at that site which permit CENP-C and CENP-E association to form a kinetochore. Based on our studies and previously reported studies, there is a selection bias in the patient samples. Therefore, while these markers are not frequent, they can be formed and become stable if selected for phenotypically.
Eight patients with de novo supernumerary marker chromosomes were collected from five different genetics centers. Seven of these patients were ascertained because of mental retardation and/or development delay or because of structural anomalies detected at birth; one (case 8) was ascertained through routine prenatal diagnosis studies.
Metaphase chromosomes were prepared from phytohemagglutinin (PHA)-stimulated blood cultures, from fibroblast cultures and/or lymphoblast cultures by using standard procedures. When possible, leukocytes from peripheral blood of the probands were cultured for high resolution chromosome studies (38 ,39 ). To attain high resolution chromosomes, PHA-stimulated blood leukocytes were cultured for ~72 h in RPMI 1640 with 17% fetal bovine serum. The cultures were synchronized by addition of thymidine for the last 16.5 h of culture and harvested after the addition of ethidium bromide and colcemid for the last 45 and 25 min of culture, respectively. The cells were treated for 8 min with 0.075 M KCl and fixed in 3:1 methanol:acetic acid prior to staining. Chromosomes were GTG- and C-banded, and at least 20 chromosomal spreads were examined from two cultures.
Polyclonal antibodies to CENP-B, CENP-C and CENP-E were generated in the laboratories of two of the co-authors (W.E. and H.F.W.) (24 ). In addition, monoclonal antibodies to CENP-E were provided by Dr Tim Yen (Philadelphia, PA) (15 ,16 ). Both monolayer and suspension cultures of cells were used to obtain unfixed metaphase preparations for immunofluorescence. Modifications of the method of Earnshaw (7 ) were applied to the preparation of metaphase chromosomes for antibody detection (5 ). Lymphoblastoid cells were grown on polylysine-coated slides and harvested as monolayer cell cultures. The method of Sullivan and Schwartz (5 ) was used for the visualization of CENP-C and CENP-E.
FISH was performed utilizing a variety of probes (YACs, cosmids, satellite DNA or chromosomal libraries) on unstained slides according to the technique of Pinkel et al. (40 ) with minor modifications, depending on the probe (41 ).
In each case at least 10, and in most cases 20, metaphases were analyzed for the presence of probe utilized on both the normal and the derived chromosome.
Digital images were captured using a confocal microscope and/or Zeiss epifluorescence microscope equipped with a cooled CCD camera (Photometrics CH250) controlled by an Apple Macintosh computer. Gray scale source images were captured separately with DAPI, fluorescein and rhodamine filter sets, merged and pseudocolored using Gene Join software (Yale University).
Highly polymorphic microsatellite markers within the duplicated region of the derived chromosome found in each patient were analyzed by PCR using standard techniques (42 ). Primer sequences for microsatellite analysis (Operon Technologies, Inc., Alameda, CA, or Research Genetics, Inc., Huntsville, AL) were obtained from the Genome DataBase.
We wish to acknowledge Laurie Becker, Bruce Tyler, J. Marie Haren and Jeffrey Conroy in the Cytogenetics and Molecular Laboratories at the Center for Human Genetics for expert technical assistance. We wish to thank Dr John Harrington for the antibodies for CENP-B, CENP-C and CENP-E. We also thank Drs Terry Hassold and Stephanie Sherman for critical comments on the manuscript. This work was supported in part by NIH grant PO1 HD 32111, and by a grant from the Willson Foundation to the Center for Human Genetics at University Hospitals of Cleveland. W.C.E. is supported by a Principal Research Fellowship from the Wellcome Trust.
Human Molecular Genetics
Pages
Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA
Introduction
Results
Cytogenetic studies
Structural analysis
Mitotic stability
Centromere proteins
Timing and parental origin
Discussion
Identification and delineation of structure
Previous studies
Origin and mechanism of formation
Centromere function
Materials and Methods
Clinical population
Cytogenetic studies
Centromere protein antibodies
FISH studies
Molecular studies
Acknowledgements
References
Patient #
[alpha]-Sat
Telomere
Type of
Karyotype
Stability
abnormality
lymphocyte
lymphoblast
fibroblast
1
-
++
Mirror image duplication
47,XX,+der(15)(qter -> q25.3::q25.3 -> qter)
82%
33%
NA
2
-
++
Mirror image duplication
47,XY,+der(15)(qter -> q25.3::q25.3 -> qter)
74%
3%
NA
3
-
++
Mirror image duplication
47,XY,+der(15)(qter -> q26.1::q26.1 -> qter)
86%
0%
NA
4
-
++
Mirror image duplication
47,XY,+der(13)(qter -> q32::q32 -> qter)
98%
32%
8%
5
-
++
Mirror image duplication
47,XY,+der(9)(pter -> p21.2::p21.2 -> pter)
100%
NA
NA
6
-
++
Terminal deletion; mirror image duplication
47,XY,del(11)(q22),+der(11)(qter -> q22::q22 -> qter)
100%
100%
100%
7
-
++
Terminal deletion; mirror image duplication
47,XY,del(9)(p12),+der(9)(pter -> p12::p12pter)
100%
100%
NA
8
-
-
Interstitial deletion and marker
47,XX,del(10)(q11q23),+der(10)(q11q23)
62%a
NA
80%
Patient #
CENP-B
CENP-C
CENP-E
1
-
+
NA
2
NA
NA
NA
3
NA
NA
NA
4
-
+
+
6
-
+
+
7
-
+
+
8
-
+
+
REFERENCES
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Oxford University Press, 1996
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