Breakpoint diversity illustrates distinct mechanisms for Robertsonian translocation formation
Breakpoint diversity illustrates distinct mechanisms for Robertsonian translocation formationScott L. Page1, Jong-Chul Shin1,2, Jin-Yeong Han1,3, K. H. Andy Choo4 and Lisa G. Shaffer1,*
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, 2Department of Obstetrics and Gynecology, Catholic University Medical College, Seoul, Korea, 3Department of Clinical Pathology, College of Medicine, Dong-A University, Pusan, Korea and 4Murdoch Institute for Research into Birth Defects, Royal Children's Hospital, Parkville 3052, Australia
Received April 17, 1996;Revised and Accepted June 12, 1996
Robertsonian translocations are the most common chromosomal rearrangements in humans. The vast majority of the ten possible nonhomologous types of Robertsonian translocations ascertained are rob(13q14q) and rob(14q21q). Recombination between homologous sequences on nonhomologous chromosomes has been proposed as a mechanism leading to the preferential formation of rob(13q14q) and rob(14q21q). However, little evidence exists to indicate whether the remaining less common Robertsonian translocations form through a similar mechanism. To better elucidate the mechanisms involved in Robertsonian translocation formation, we have used fluorescence in situ hybridization to localize the breakpoints in 56 nonhomologous Robertsonian translocations. This study revealed highly variable locations of breakpoints in seven types of the less common Robertsonians, while nearly all rob(13q14q) and rob(14q21q) analyzed displayed breakpoints in the same locations. Therefore, this study provides direct evidence that rob(13q14q) and rob(14q21q) form through a specific mechanism, possibly involving homologous recombination, which is distinct from the mechanism(s) that contributes to the formation of the remaining types of Robertsonian translocations.
Chromosome translocations play significant roles in human fertility, birth defects, and cancer. Therefore, it is important to understand the mechanisms that contribute to their formation. The most common translocations in humans are whole arm exchanges between acrocentric chromosomes, termed Robertsonian translocations, which have an incidence of approximately 1/1000 individuals (1 ).
All ten possible pairwise combinations of the five acrocentrics (chromosomes 13, 14, 15, 21, and 22) resulting in nonhomologous Robertsonian translocations have been observed, but the distribution of these different types of translocations is highly nonrandom (1 ). Robertsonian (13q14q) and (14q21q) translocations are far more common than the remaining types of Robertsonians. In studies with unbiased ascertainment, such as consecutive newborn screening and prenatal testing for advanced maternal age, rob(13q14q) and rob(14q21q) comprise 75.6% (183/242) and 9.9% (24/242), respectively, of all nonhomologous Robertsonian translocations. Each of the other types make up only 0.8% to 3.7% of the total number of Robertsonian translocations ascertained in these studies (1 -7 ). The excess of rob(14q21q) is even more evident among Robertsonian translocations ascertained through Down syndrome. Although all of these Robertsonians involve chromosome 21, rob(14q21q) re- arrangements are observed ten times more often than any of the other nonhomologous translocations (1 ,8 -21 ). The high frequency of Robertsonian translocations and the relative excess of rob(13q14q) and rob(14q21q) over the remaining eight less common nonhomologous types have raised interest in the possible mechanisms leading to Robertsonian translocation formation.
The high overall frequency of Robertsonian translocation formation is thought to be influenced by the presence of nucleolar organizer regions (NOR), which contain ribosomal RNA genes (rDNA) at band p12 of each acrocentric chromosome (22 -25 ). The preferential association of these regions during the formation of nucleoli may result in an increased propensity for forming translocations that involve the centromere/short arm regions of acrocentric chromosomes (26 -29 ). However, analyses using chromosome staining and in situ hybridization have shown the vast majority of breakpoints in Robertsonian translocations to be located proximal to the NOR, resulting in structurally dicentric translocation chromosomes and deletion of the NOR (30 -44 ).
The p11 regions of human acrocentric chromosomes are known to contain several types of tandemly repeated DNA, including satellites I, II, III, and IV and [beta]-satellite (45 -53 ). Several subfamilies of satellite DNA specific to one or more of the acrocentric chromosomes have been isolated. These include the satellite III subfamilies pTRS-47, located on proximal 14p and 22p (ref. 54 ), and pTRS-63, specific to 14p and distal to pTRS-47 (refs. 39 ,55 ). The pTRI-6 satellite I subfamily is present on 13p and, to a lesser extent, on 21p (ref. 42 ). D15Z1, composed of satellite III DNA, is specific to 15p (ref. 56 ).
In situ hybridization studies using molecular probes for these satellite DNA subfamilies have further localized the breakpoints of Robertsonian translocations but have mainly focused on the most commonly found types. The breakpoint on chromosome 14 for 17/17 rob(13q14q) and 12/12 rob(14q21q) was found to lie between pTRS-47 and pTRS-63 sequences (39 ,44 ). In 16 of 17 rob(13q14q), the chromosome 13 breakpoint was located distal to the pTRI-6 array in 13p11 (ref. 44 ). Similarly, the chromosome 21 breakpoint involved in 11/11 rob(14q21q) was also distal to pTRI-6 sequences in 21p11 (ref. 42 ). The consistent breakpoints observed in these translocations would be predicted from the hypothesis that rob(13q14q) and rob(14q21q) arise via recombination between homologous sequences shared by chromosomes 13 and 14 and by chromosomes 14 and 21, respectively, with the sequences on chromosome 14 being in opposite orientation as compared to the sequences on the other chromosomes (1 ,29 ,57 -59 ).
Little evidence exists to indicate the mechanisms that underlie the formation of other Robertsonians. The breakpoints in few of the less common Robertsonian translocations have been investigated using probes from the acrocentric short arm regions. In one study (41 ), [beta]-satellite was found to be deleted in 24 of 26 Robertsonian translocations analyzed, which included examples of rob(13q15q), rob(13q21q), rob(13q22q), rob(14q15q), rob(14q22q), and rob(21q22q), but no other proximal short arm probes were used.
In this study, we have used fluorescence in situ hybridization (FISH) to localize the breakpoints in 56 nonhomologous Robertsonian translocations, representing nine of the ten possible types. These included five rob(13q15q), two rob(13q21q), four rob(13q22q), five rob(14q15q), three rob(14q22q), two rob(15q21q), four rob(15q22q), eight rob(14q21q), and 23 rob(13q14q). Comparison of exchanges within and between types of Robertsonian translocations revealed highly variable locations of breakpoints in the less common Robertsonians, which suggests a different mechanism of formation from rob(13q14q) and rob(14q21q), in which specific breakpoints were observed.
Twenty-five of the 56 cases tested were of the less common types of nonhomologous Robertsonian translocations. The results using [alpha]-satellite and rDNA probes indicated that the majority of breakpoints were located in the proximal short arms of the chromosomes involved, resulting in structurally dicentric translocations in 23 of the 25 cases. The rDNA sequences were detected on only one of the 25 less common Robertsonian translocations. FISH data for [alpha]-satellite probes in cell lines GM00392, GM00479, and GM01296B have been published previously (41 ), and were confirmed by our study. Hybridization with the satellite DNA probes pTRS-47, pTRS-63, pTRI-6, and D15Z1 allowed us to further localize the breakpoints in these translocations (Table 1 ).
For five rob(13q15q), FISH with pTRI-6 showed positive hybridization signal on the translocation in each case, indicating that the chromosome 13 breakpoint lay distal to this satellite DNA sequence in 13p11. The breakpoints on chromosome 15 occurred either proximal or distal to the D15Z1 array (Fig. 1 ). D15Z1 was present on the translocation chromosomes in three cases (45737, 46700, GM02813), but was deleted in the other two cases (42115, GM01296B). Therefore, two different exchanges between chromosomes 13 and 15 were observed, which resulted in varying breakpoint locations on chromosome 15 (Table 1 ; Fig. 3 ).
Two rob(13q21q) were studied. The pTRI-6 probe hybridized to both translocations with intensity similar to the signal found on the free-lying chromosomes 13, suggesting that the array from chromosome 13 was retained on the translocation chromosomes. Chromosome 21 normally contains a smaller amount of pTRI-6 sequence than chromosome 13 (ref. 42 ). Analysis of interphase nuclei hybridized with pTRI-6 suggested that the array corresponding to chromosome 21 was also present on both translocations (Table 1 ; Fig. 3 ).
Analysis of four rob(13q22q) showed two of these translocations to have unique combinations of breakpoints, while the last two shared the same breakpoint combination. Case 41863 was found to be a monocentric translocation which retained the chromosome 22 [alpha]-satellite array D22Z1, the satellite III probe pTRS-47, and rDNA. The chromosome 13 [alpha]-satellite array D13Z1 and short arm pTRI-6 sequences were not retained on this translocation. The other three cases were positive for both chromosome 13 and 22 [alpha]-satellite probes and negative for rDNA. The breakpoints were distal to the pTRI-6 array on chromosome 13 in these cases, but while case 46898 showed positive signals for the pTRS-47 probe on the translocation, cases 43397 and GM00392 lacked pTRS-47 sequences. Therefore, three exchanges resulting from different breakpoints were evident among the four rob(13q22q) studied (Table 1 ; Fig. 3 ).
The breakpoints in rob(14q15q) showed the greatest variability among the types of Robertsonian translocations analyzed in this study. Although the breakpoints were confined to the proximal short arms of the chromosomes involved, four different exchanges were found among the rob(14q15q) (Fig. 3 ). Case 43110 had breakpoints closest to the centromeres since the sequences detected by the proximal short arm probes, pTRS-47, pTRS-63, and D15Z1, were deleted. Conversely, case 44496 retained sequences detected by the three short arm probes for chromosome 14 and 15 and therefore had breakpoints closer to the rRNA gene clusters. GM00479, GM08827A, and GM08828A retained pTRS-47 sequences with deletion of the pTRS-63 array. In these three rob(14q15q), the chromosome 14 breakpoints lay between pTRS-47 and pTRS-63 sequences, with the chromosome 15 breakpoint either proximal (GM08827A) or distal (GM00479 and GM08828A) to the D15Z1 array (Table 1 ; Fig. 3 ).
. FISH results for the less common types of Robertsonian translocations
Case #
Karyotype
Sample type
Probe hybridization on Robertsonian translocation
13/21[alpha]
pTRA-20
pTRA-25
rDNA
pTRI-6
D15Z1
45737
45,XY,rob(13q15q)mat
L
+
+
+
-
+
+
46700
45,XX,rob(13q15q)mat
AF
+
+
+
-
+
+
GM02813
46,XX,-15,+rob(13q15q)mat
F
+
+
+
-
+
+
42115
45,XY,rob(13q15q)pat
AF
+
+
+
-
+
-
GM01296B
45,XX,rob(13q15q)
F
+a
+a
+
-
+
-
13/21[alpha]
rDNA
pTRI-6
49054
46,XY,-21,+rob(13q21q)pat
AF
2 signals
-
+
48728
45,XX,rob(13q21q)
PB
2 signals
-
+
13/21[alpha]
14/22[alpha]
rDNA
pTRI-6
pTRS-47
46898
45,XY,rob(13q22q)pat
L
+
+
-
+
+
41863
45,XX,rob(13q22q)
L
-
+
+
-
+
43397
45,XX,rob(13q22q)
L
+
+
-
+
-
GM00392
45,XX,rob(13q22q)
F
+a
+a
-
+
-
14/22[alpha]
pTRA-20
pTRA-25
rDNA
pTRS-47
pTRS-63
D15Z1
44496
45,XX,rob(14q15q)de novo
L
+
+
+
-
+
+
+
43110
45,XX,rob(14q15q)pat
AF
+
+
+
-
-
-
-
GM00479
45,XX,rob(14q15q)pat
F
+a
+a
+
-
+
-
+
GM08827A
45,XX,rob(14q15q)
L
+
+
+
-
+
-
-
GM08828A
45,XX,rob(14q15q)
L
+
+
+
-
+
-
+
14/22[alpha]
rDNA
pTRS-47
pTRS-63
43083
45,XX,rob(14q22q)de novo
AF
2 signals
-
+
-
48586
45,XX,rob(14q22q)
AF
1 signalb
-
+
-
GM00005
45,XX,rob(14q22q)
F
2 signals
-
-
-
13/21[alpha]
pTRA-20
pTRA-25
rDNA
pTRI-6
D15Z1
49307
46,XY,-15,+rob(15q21q)de novo
L
+
+
+
-
+
+
49306
46,XY,-15,+rob(15q21q)de novo
L
+
+
+
-
+
-
14/22[alpha]
pTRA-20
pTRA-25
rDNA
pTRS-47
D15Z1
46406
45,XY,rob(15q22q)de novo
F
+
+
+
-
+
+
48397
45,XX,rob(15q22q)pat
F
+
+
+
-
+
+c
48439
46,XY,-22,+rob(15q22q)
F
+
+
+
-
+
-
48729
45,XY,rob(15q22q)
AF
+
+
+
-
+
-
aPreviously reported by Wolff and Schwartz (41).bMonocentric translocation shown to retain the chromosome 22 centromere using probe p190.22 (see text).cReduced intensity.Abbreviations: AF, amniotic fluid; L, lymphoblasts; F, fibroblasts; PB, peripheral blood.
The two rob(15q21q) analyzed had different breakpoints on chromosome 15. Case 49307 retained a positive signal for the D15Z1 probe, while this satellite DNA was deleted in case 49306. Both translocations retained a positive signal for the pTRI-6 probe, indicating that the chromosome 21 breakpoints were distal to this sequence in both cases (Table 1 ; Fig. 3 ).
The breakpoints in four cases of rob(15q22q) were localized using probes pTRS-47 and D15Z1. The pTRS-47 probe was retained on all of the translocations, which indicated that the breakpoints on chromosome 22 were located between pTRS-47 sequences and rDNA. Two translocations (46406 and 48397) retained D15Z1 signal, while detectable signal was not present in cases 48439 and 48729. The D15Z1 signal in case 48397, while present on the translocation, was consistently less intense than the average D15Z1 signal observed on free-lying chromosomes 15 (Fig. 2 ). While polymorphism in the size of the D15Z1 array cannot be excluded, the diminished signal may indicate partial deletion of D15Z1 sequences. The breakpoints on chromosome 15, therefore, were proximal to the D15Z1 array in two cases, and within or distal to D15Z1 sequences in two other cases of rob(15q22q) (Table 1 ; Fig. 3 ).
For comparison to the breakpoints observed in the less common Robertsonian translocations, we analyzed 23 rob(13q14q) and eight rob(14q21q) which had not previously been characterized (Table 2 ). The common rob(13q14q) and rob(14q21q) translocations have shown consistent localization of breakpoints in other studies (39 ,42 ,44 ). In this study, all 31 common Robertsonian translocations were dicentric and devoid of rDNA. In 30/31 of these translocations, the breakpoint on chromosome 14 appeared to be between the retained pTRS-47 sequences and the deleted pTRS-63 array. For one rob(13q14q) (case 48736), hybridization with the pTRS-63 probe produced a signal on the translocation, indicating that in this case, the chromosome 14 breakpoint lay distal to pTRS-63 sequences but proximal to rDNA. All rob(13q14q) were positive for the pTRI-6 array on chromosome 13, and all rob(14q21q) were positive for the pTRI-6 array on chromosome 21, which demonstrates that the breakpoints on chromosomes 13 or 21 were distal to the pTRI-6 domain in these translocations (Fig. 3 ). It was noted in case 48736, which had an unusual chromosome 14 breakpoint location, that the pTRI-6 signal was weaker than the signals usually seen on free-lying chromosomes 13. This unusually weak satellite DNA signal could indicate a breakpoint within that array or variability in the length of the array on the chromosome originally involved in the rearrangement. Nevertheless, the same breakpoint locations were observed in 96% (22/23) of rob(13q14q) and 100% (8/8) rob(14q21q) analyzed.
The mechanisms underlying Robertsonian translocation formation are completely unknown. The `mechanism' could include the precipitating factors leading up to the translocation event, as well as the translocation event itself. The factors setting the stage for translocation formation may or may not be the same for all Robertsonians and in fact, the actual translocation event may be different for specific classes of Robertsonian translocations. The breakpoint localization study presented here is largely directed toward understanding the nonrandom distribution of Robertsonian translocations, in which a disproportionately large number of rob(13q14q) and rob(14q21q) are ascertained (1 ).
A specific mechanism involving recombination between homologous sequences shared between the short arms of chromosomes 13, 14, and 21 has been proposed to explain the abundance of rob(13q14q) and rob(14q21q) (refs 1 ,29 ,57 -59 ). All translocations formed by such a mechanism would be expected to have breakpoints in the same relative locations. Previous breakpoint localization studies in rob(13q14q) and rob(14q21q) agree with this hypothesis and have identified subregions of the proximal short arms that contain the breakpoints in most cases (39 ,42 ,44 ). However, this type of study has not been performed for the less common types of Robertsonian translocations, so few clues exist to suggest the mechanism(s) forming these rearrangements. In this study, we localized the breakpoints in 56 Robertsonian translocations, including 25 from the less common types, 23 rob(13q14q), and eight rob(14q21q) using FISH. Localization of the breakpoints allowed us to elucidate the variability of exchanges involved in the formation of each type of Robertsonian translocation studied (Fig. 3 ).
Comparison of breakpoints and exchanges in seven of the less frequently observed types of Robertsonian translocations revealed a high degree of variability. The most striking example of this variability was seen among the five rob(14q15q) analyzed, with four different exchanges identified (Fig. 3 ). Breakpoints occurred in three regions on chromosome 14p and in two regions on chromosome 15p. In addition, a previously reported rob(14q15q) was demonstrated by FISH to have retained rDNA sequences (38 ). This translocation would necessarily have resulted from an exchange not seen in the present study, further demonstrating the breakpoint variability in this type of Robertsonian translocation.
Likewise, for rob(13q15q), rob(13q22q), rob(14q22q), rob(15q21q), and rob(15q22q), several breakpoints were identified within each Robertsonian translocation type. Of the Robertsonians involving chromosome 15, the breakpoints occurred either proximal or distal to the D15Z1 array. However, no particular breakpoint on chromosome 15 was preferred during the formation of these translocations.
The rob(13q21q) studied did not show variation in breakpoints. However, since only two cases were available for analysis, and only one probe (pTRI-6) could be used which mapped to the proximal short arms of chromosomes 13 and 21, the likelihood of detecting variation in breakpoints may have been decreased. Nevertheless, other breakpoints apparently exist in rob(13q21q), as evidenced by three monocentric rob(13q21q) identified by FISH in other studies (38 ,41 ). Furthermore, one of the monocentric rob(13q21q) retained rDNA sequences (38 ), while another did not (41 ). Therefore, several breakpoints and exchanges seem to contribute to the formation of rob(13q21q).
No rob(21q22q) were available for the present study. However, FISH analysis of two rob(21q22q) by Wolff and Schwartz (41 ) showed the breakpoints to differ; one rob(21q22q) was monocentric and negative for [beta]-satellite DNA, while the other retained [beta]-satellite and [alpha]-satellite from both chromosomes 21 and 22. Therefore, this type of Robertsonian translocation also shows variable breakpoints.
In comparison to the less common types of Robertsonian translocations, the breakpoints in rob(13q14q) and rob(14q21q) were extremely consistent in location. Combined with previous data for rob(13q14q) (ref. 44 ), the breakpoints occurred between pTRI-6 sequences and rDNA on chromosome 13 and between pTRS-47 and pTRS-63 sequences on chromosome 14 in 95% (38/40) of translocations analyzed. For rob(14q21q), 100% of cases studied have demonstrated the same breakpoint locations (this study, refs 39 ,42 ), with the breakpoint on chromosome 14 located between pTRS-47 and pTRS-63 sequences and the chromosome 21 breakpoint distal to pTRI-6 sequences but proximal to rDNA. Furthermore, all other rob(13q14q) and rob(14q21q) studied using FISH (38 ,40 ,41 ) were dicentric and lacked rDNA. In contrast, several less common Robertsonian translocations were found to be monocentric or to have retained rDNA (this study, refs 38 ,41 ).
Although the less common Robertsonians have more variable breakpoints, much of this variation appears to be derived from chromosomes 14, 15, and 22 (Table 3 ). On chromosomes 15 and 22, the breakpoints are equally divided between the proximal and distal regions surrounding the array detected by the single satellite III probe for each short arm. For chromosome 14, the breakpoints in the less common types of Robertsonians were scattered throughout the proximal short arm, while over 98% (59/60) of the breakpoints seen in rob(13q14q) and rob(14q21q) lie between pTRS-47 and pTRS-63 sequences. Chromosomes 13 and 21 show very little variability in breakpoint location in the present study, although different breakpoints have been seen in other studies (38 ,41 ). This may indicate regions within proximal 13p and 21p that are preferentially involved in Robertsonian translocation formation. It should be considered that the proximal short arm probe for these chromosomes, pTRI-6, is a satellite I subfamily and thus differs from the satellite III probes used to study the other acrocentrics. Gravholt et al. (40 ) proposed that satellite III sequences are involved in Robertsonian formation. The satellite I sequences recognized by pTRI-6 may be in a region of the short arm proximal to the satellite III DNA, and therefore preferentially retained on the translocation, while satellite III sequences may often be deleted. Alternatively, if pTRI-6 were very close to the centromere, chance would favor its retention on the dicentric translocation chromosomes.
The high degree of breakpoint variability observed among non-rob(13q14q) and non-rob(14q21q) translocations suggests that these translocations arise through a different mechanism than the majority of rob(13q14q) and rob(14q21q). A mechanism involving pairing and recombination between specific sequences shared between the acrocentrics is unlikely in the less common Robertsonians, since this mechanism should produce consistent breakpoints. The variable breakpoints seen could be the result of random breakage and exchange. The close association of the acrocentric short arms at nucleoli may increase the chances of erroneous repair after DNA breakage, resulting in translocation formation. However, this model would require the proximal region of the short arm to be more prone to breakage than other parts of the chromosome, since this is the location of most breakpoints in Robertsonian translocations (30 -44 ). There is no indication at the present time that DNA in this region is especially susceptible to breakage, and Robertsonian translocations rarely form following exposure to ionizing radiation (61 -63 ).
. Distribution of breakpoints by chromosome among rob(13q14q), rob(14q21q), and the less common types of Robertsonian translocations
rob(13q14q) &
Chromosome
Region
rob(14q21q)a
Others
13
13qter - D13Z1
0/40
1/11
D13Z1 - pTRI-6
1/40
0/11
pTRI-6 - rDNA
39/40
10/11
14
14qter - D14Z1
0/60
1/8
D14Z1 - pTRS-47
0/60
2-3/8b
pTRS-47 - pTRS-63
59/60
3-4/8b
pTRS-63 - rDNA
1/60
1/8
15
pTRA-20 - D15Z1
-
7/16
D15Z1 - rDNA
-
9/16
21
D21Z1 - pTRI-6
0/19
0/4
pTRI-6 - rDNA
19/19
4/4
22
D22Z1 - pTRS-47
-
3-4/11b
pTRS-47 - rDNA
-
6-7/11b
rDNA-22pter
-
1/11
aIncludes data from the present study and translocations characterized previously (39,42,44).bThe breakpoint locations in one rob(14q22q) (case 43083) could not be fully determined due to pTRS-47 localization on both chromosomes 14 and 22 (ref. 54).
An alternative model takes into account molecular data from certain other constitutional chromosome translocation breakpoints. Analysis of DNA sequences at the breakpoints of two X;autosome translocations has revealed short motifs (4-5 bp) present in the corresponding normal sequences of both chromosomes involved (64 ,65 ). Although similar motifs have not been found in all X;autosome breakpoints that have been sequenced (66 ), it was suggested that these very short homologous sequences in regions otherwise lacking homology may play a role in forming translocations. The proximal short arms of all acrocentrics are rich in repetitive DNA, including satellite III, which has been suggested to be involved in Robertsonian translocation formation (40 ). Several subfamilies of satellite III DNA have been cloned and shown to contain divergent sequences, but they all contain copies of the consensus 5'-GGAAT-3' monomer (54 -56 ,67 ,68 , McQuillan,C. and Choo,K.H.A., unpublished data). It is conceivable that this or similar motifs may be involved in the formation of Robertsonian translocations. In fact, the motif found at the breakpoint of a t(X;4) was GGAAT (65 ). The presence of repeated sequence motifs throughout the proximal acrocentric short arms is consistent with breakpoints that are variable, yet usually confined to this region. A mechanism such as this would be capable of forming any Robertsonian translocation, and could be responsible for the two rob(13q14q) reported with breakpoints that do not correspond with the usual locations (this study, ref. 44 ).
The regions into which the breakpoints in rob(13q14q) and rob(14q21q) have been localized have not been fully defined, so the possibility that the breakpoints vary within those regions cannot be excluded at this time. However, the observation of consistent breakpoints in the vast majority of common Robertsonian translocations supports the hypothesis of a specific mechanism of formation for most rob(13q14q) and rob(14q21q) which is distinct from the mechanism that gives rise to other Robertsonian translocations. Several authors have suggested that pairing and recombination between homologous sequences present on 13 and 14 or 14 and 21 would most likely account for the high frequencies of rob(13q14q) and rob(14q21q) occurrence (1 ,29 ,57 -59 ). The homologous sequences involved in translocation formation would have to be in opposite orientation on chromosome 14 as to facilitate recombination resulting in rob(13q14q) and rob(14q21q), but not rob(13q21q) (refs 1 ,58 ,59 ). A similar mechanism apparently underlies the formation of t(X;Y)(p22.3;q11) translocations (69 -72 ). Xp22.3 and Yq11 contain homologous sequences believed to have once been pseudoautosomal but moved by a rearrangement on an ancestral Y chromosome. Abnormal pairing of the X and Y in these regions followed by recombination would result in translocation formation. Evidence exists for pairing and recombination between the ribosomal RNA genes on the short arms of nonhomologous acrocentric chromosomes (73 ,74 ). If homologous sequences were present in opposite orientation in the proximal short arms, recombination leading to translocation formation may occur.
Several new satellite III subfamilies from the acrocentric short arms, including sequences that are common to chromosomes 13, 14, and 21, may be candidates for sequences involved in rob(13q14q) and rob(14q21q) formation (McQuillan,C. and Choo,K.H.A., unpublished data). Given the breakpoint data, such candidate sequences would be expected to be located between the pTRS-47 and pTRS-63 arrays in 14p11 and distal to pTRI-6 sequences in 13p11 and 21p11. Further mapping of short arm sequences and analysis of rob(13q14q) and rob(14q21q) will be necessary to identify the breakpoints involved in these translocations and to determine their role in translocation formation.
Robertsonian translocation carriers were ascertained through the Kleberg Cytogenetics Laboratory (Baylor College of Medicine) and several other cytogenetic centers. Cell lines GM00005, GM00392, GM00479, GM01296B, GM02813, GM03044, GM03417, GM03786, GM04890, GM07964, GM08827A, and GM08828A were obtained from Coriell Cell Repositories (Camden, NJ). Except for GM00392, GM00479, and GM01296B, for which [alpha]-satellite data were published (41 ), breakpoint localization had not been previously performed nor published on any of the cases studied.
The DNA probes used in this study are listed in Table 4 . The Oncor D13Z1/D21Z1 probe and [alpha]RI (ref. 75 ) both detect [alpha]-satellite DNA at the centromeres of chromosomes 13 and 21. The Oncor D14Z1/D22Z1 probe and [alpha]XT (ref. 76 ) both detect [alpha]-satellite DNA at the centromeres of chromosomes 14 and 22. The Oncor [alpha]-satellite probes were used in most of the experiments, but were replaced by [alpha]RI and [alpha]XT in the remaining experiments. Two [alpha]-satellite probes specific to separate arrays at the centromere of chromosome 15 were used. These were pTRA-20 and pTRA-25 (ref. 77 ), which were hybridized separately in the FISH experiments. The plasmids pA (ref. 78 ) and pU6.2 (ref. 79 ) contain 28S and 18S rRNA genes, respectively, which are normally present at band p12 of each acrocentric chromosome. These two plasmids were co-hybridized as the rDNA probe. The satellite III DNA subfamily pTRS-47 is present in the p11 regions of chromosomes 14 and 22 (ref. 54 ). The pTRS-47 probe was used for FISH on translocations involving chromosomes 14 or 22. The plasmid pTRS-63 contains a subfamily of satellite III DNA that is specific for the p11 region of chromosome 14 (ref. 55 ) and was used in the analysis of translocations involving chromosome 14. A probe specific for a satellite I subfamily, pTRI-6, was used under high stringency conditions (50% formamide/2* SSC, 43oC and 0.1* SSC, 43oC) to uniquely identify the presence of this array on chromosome 13 at band p11 and chromosome 21 at band p11 (ref. 42 ) for translocations involving chromosomes 13 or 21. Previous reports have used this probe to identify other satellite I subfamilies with similar sequence homology under low stringency conditions (42 ,80 ). Under the conditions presented here, pTRI-6 did not hybridize to these other satellite I subfamilies located at 13p13 and 21q. D15Z1 is a satellite III subfamily specific to 15p11 (ref. 56 ). The D15Z1 probe was purchased from Oncor and used with translocations involving chromosome 15.
. Probes used for breakpoint localization in Robertsonian translocations
Chromosome
Probe
Type of DNA
location
Reference
D13Z1/D21Z1
[alpha]-satellite
13,21
Oncor
[alpha]RI
[alpha]-satellite
13,21
75
D14Z1/D22Z1
[alpha]-satellite
14,22
Oncor
[alpha]XT
[alpha]-satellite
14,22
76
pTRA-20
[alpha]-satellite
15
77
pTRA-25
[alpha]-satellite
15
77
pTRI-6
satellite I
13,21
42
pTRS-47
satellite III
14,22
54
pTRS-63
satellite III
14
55
D15Z1
satellite III
15
56
pA *
28S rRNA gene
13,14,15,21,22
78
pU6.2 *
18S rRNA gene
13,14,15,21,22
79
*pA and pU6.2 were co-hybridized as the rDNA probe.
The Oncor D13Z1/D21Z1, D14Z1/D22Z1, and D15Z1 probes were purchased labeled with biotin or digoxigenin. All other probes were labeled with biotin or digoxigenin by nick translation. The labeled DNA was ethanol precipitated and resuspended in hybridization solution containing 50% or 65% formamide, 10% dextran sulfate, and 2* SSC. The 13/21 [alpha]-satellite, 14/22 [alpha]-satellite, and D15Z1 probes were each hybridized at a final concentration of 0.5 ng/[mu]l. Final concentrations of 1.75 ng/[mu]l and 2.0 ng/[mu]l were used for pTRA-20 and pTRA-25, respectively. For pTRI-6, probe concentrations ranged from 4 to 20 ng/[mu]l, while pTRS-47, pTRS-63, and each of the two plasmids in the rDNA probe were used at final concentrations of 20 ng/[mu]l.
Metaphase chromosomes were prepared according to standard methods. Procedures for FISH were performed as described elsewhere (44 ,81 ) with minor modifications. The 2* SSC wash following hybridization was extended from 5 to 8 min at 43oC. In some experiments, amplification of pTRS-47 and pTRS-63 signals was omitted. If cross-hybridization was encountered, the slide washes and detection were repeated, which usually removed the cross-hybridizing probe. The slides were analyzed with a Zeiss Axiophot fluorescence microscope equipped with single and triple band pass filter sets. Images were captured and enhanced using a PSI Powergene 810 probe system and printed using a Tektronix color/monochrome Phaser II SDX printer.
Only probes that map to the chromosomes involved in the translocation were used to analyze each case. These probes were hybridized alone or in dual-color combination with a second probe, usually an [alpha]-satellite probe, to identify the translocation. Since [alpha]-satellite probes may occasionally disguise nearby weak signals, single band pass filter sets were used to confirm deletions in two-color experiments. In cases 45737, 46898, 47095, 47747, and 47929, chromosomes from a second related carrier of the translocation were tested with all probes to confirm the FISH data. The satellite DNA arrays detected by these probes can occasionally show polymorphisms in FISH signal intensity that may affect the interpretation of experimental results. Therefore, in cases of de novo translocations where parental samples were available [42062, 43083, 44496, 46406, 47138, 47196 (father only), 48582, 48720], the parents were tested with satellite DNA probes that were deleted from the translocations, to confirm that these sequences were present in the chromosomes that potentially formed the translocations. The determination of probe hybridization on the translocations was based on observation of at least ten metaphases in most cases. In some cases, analysis of interphase nuclei was also performed. Dicentric rob(13q21q) and rob(14q22q) were identified either by two closely spaced 13/21 or 14/22 [alpha]-satellite signals on the translocations at metaphase or interphase nuclei showing the appropriate number of signals, two for the translocation and one for each free-lying chromosome homologue.
We wish to thank Catherine Kashork, Sandy Steakley, and Melinda Rosenkrantz for technical assistance and Dr A. Baldini (Baylor College of Medicine, Houston, TX) and Dr A.L. Jørgensen (Aarhus University, Aarhus, Denmark) for generously providing DNA probes. We also thank the following colleagues for providing patient samples: Dr C. Bacino (Baylor College of Medicine, Houston, TX), Dr R. Best (University of South Carolina, Columbia, SC), Dr S.W. Cheung (Laboratory for Genetic Services, Houston, TX), V. Corson, M.S. (Johns Hopkins University, Baltimore, MD), Dr A. Donnenfeld (Pennsylvania Hospital, Philadelphia, PA), Dr L. Estabrooks (Integrated Genetics, Santa Fe, NM), Dr R. Habibian (Alfigen, Pasadena, CA), Dr C. Jackson-Cook (Medical College of Virginia, Richmond, VA), Dr P. Mamunes (Alfigen, Fort Lauderdale, FL), Dr J. Mascarello (Children's Hospital, San Diego, CA), Dr J. Priest (Shodair Hospital, Helena, MT), Dr D. Van Dyke (Henry Ford Hospital, Detroit, MI), Dr J. Zenger-Hain (Oakwood Hospital, Dearborn, MI). S.L.P. was supported by a National Science Foundation Graduate Fellowship #92-9255674.
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