Meiotic errors followed by two parallel postzygotic trisomy rescue events are a frequent cause of constitutional segmental mosaicism
© Robberecht et al; licensee BioMed Central Ltd. 2012
Received: 17 February 2012
Accepted: 10 April 2012
Published: 10 April 2012
Structural copy number variation (CNV) is a frequent cause of human variation and disease. Evidence is mounting that somatic acquired CNVs are prevalent, with mosaicisms of large segmental CNVs in blood found in up to one percent of both the healthy and patient populations. It is generally accepted that such constitutional mosaicisms are derived from postzygotic somatic mutations. However, few studies have tested this assumption. Here we determined the origin of CNVs which coexist with a normal cell line in nine individuals. We show that in 2/9 the CNV originated during meiosis. The existence of two cell lines with 46 chromosomes thus resulted from two parallel trisomy rescue events during postzygotic mitoses.
For decades, knowledge about copy number variation (CNV) in the human genome was limited to microscopically visible changes. Advances in technology have led to the discovery of submicroscopic CNVs, ranging from kilobases to megabases in size and covering up to 13% of the human genome [1, 2]. These CNVs can cause recurrent genomic disorders and sporadic disease, or they can represent benign changes found in the healthy population [3, 4]. Recent studies have revealed that CNVs are not only polymorphic between unrelated individuals, but also form a frequent source of somatic variation [5, 6].
Chromosomal mosaicism is defined as the coexistence of two or more chromosomally different cell lines in an organism which developed from a single zygote. The majority of those mosaicisms are aneuploidies. Several studies investigating in vitro fertilized embryos at the preimplantation stage demonstrated a very high number of chromosomal mosaicisms in early human embryos [7–9]. While many of these embryos will not reach the stage of implantation, some do continue to develop leading to fetal mosaicisms, confined placental mosaicism or mosaic infants. Postnatally, mosaicism is detected in 0.4-1% of patients referred for genetic diagnostic screening [10–12]. A recent study revealed that mosaic aberrations are present in about 0.8% of phenotypically normal adults . In addition, mosaicism appears to be variable amongst different tissues: chromosomal aneuploidies were detected in approximately 10% of normal human brain cells .
Segmental aneuploidies make up a significant part of mosaic chromosome anomalies. Analysis of several large series of prenatal samples by karyotyping has shown that, of the 0.25-2% mosaic cases that are detected, up to a third comprise segmental imbalances [15, 16]. In postnatal clinical diagnosis of patients with developmental anomalies this increases to about half of the mosaic cases [10, 17]. The majority of mosaic segmental imbalances are marker chromosomes . A smaller number of cases have been reported to consist of mosaic segmental deletions and/or duplications, ring chromosomes and translocations that have a 46,abnormal/46,normal karyotype. In recent years various case reports have been published [18–36]. The introduction of genome wide aneuploidy detection tools with a higher resolution such as array comparative genomic hybridisation (array CGH) or SNP arrays and the collection of large patient groups have also increased the detection rate of mosaic segmental abnormalities [10, 12, 17].
For mosaic aberrations, it is intuitively assumed that the rearrangement arose postzygotically. During embryogenesis, a mitotic rearrangement in an otherwise normal diploid embryo results in a second cell line carrying a chromosomal rearrangement. Nevertheless, evidence is mounting that such rearrangements can originate during meiosis. If so, a trisomic zygote carrying the abnormal chromosome has to be rescued twice, in parallel: once loosing the normal and once loosing the abnormal chromosome. Considering that the mitotic error rate is extremely high during early embryogenesis [7–9] and that most cases of mosaic aneuploidy detected in a large cohort of patients were of mitotic origin , we reasoned that the latter mechanism might be an important mechanism by which such mosaics arise. In this study we collected nine cases with mosaic structural imbalances to determine their origin and to ascertain whether a meiotic or postzygotic origin might be more prevalent.
Combined karyotypes after conventional and molecular cytogenetic analyses
Karyotype (ISCN 2009; Mb positions mapped in hg19)
46,XX,dup(13)(q31.3q33.1)dn/46,XX.arr 13q31.3q33.1 (RP11-319 L6-RP11-564 N10)x2 ~3
46,XX,dup(15)(q25q26.3)dn/46,XX.arr 15q25.2q26.3 (RP11-365 F16-CTB-154P1)2 ~3
46,XY,dup(11)(q12.1q13.3)dn/46,XY.arr 11q12.1q13.3 (RP11-131 J4-RP11-804 L21)2 ~3
46,XY,dup(1)(q12q32.1)dn/46,XY.arr 1q12q32.1 (RP11-417 J8-RP11-383 G10)2 ~3
46,XX,der(6)t(2;6)(p23.2;qter)dn/46,XX.arr 2p25.3p23.2 (GS1-68 F18-RP11-328 L16)2 ~3
25.56 Mb/124.2 Mb
46,XX,der(10)t(9;10)(p23;q26.13)dn/46,XX.arr 9p24.3p23(40,910-13,575,891)x2 ~3, 10q26.13q26.3 (124,007,108-135,422,505)x1 ~2
13.53 Mb/11.31 Mb
46,XX.ish del(11)(q14.1q14.2)(RP11-118 L16-,RP11-157B22-)dn[21/50].arr 11q14.1q14.2(83,122,844-86,794,856)x1 ~2
46,XX.ish del(1)(q43q44)(RP11-113O11-,RP11-370 K11-)dn[25/50].arr 1q43q44(242,916,876-243,920,382)x1 ~2
Results of the STR marker analysis
For two samples, three different alleles were detected within the duplicated region indicating a meiotic origin. Polymorphic marker analysis of sample 1 revealed the presence of three different alleles for marker D13S128 (Figure 3A). Two of the alleles were inherited from the father demonstrating the paternal origin of the segmental aneusomy. At marker D13S129, still within the duplication, two alleles with a 2:1 intensity ratio were detected, including only one of the two paternal alleles (Figure 3B). The remaining markers within the duplication were not informative. In case 6, carrier of an unbalanced translocation, two markers (D1S1653 and D1S1171) spread throughout the duplicated 1q region showed three different alleles (Figure 4). The other markers on 1q had either one or two alleles. Marker D20S117 in the deleted 20p region confirmed the deletion, with a 1:2 reduced peak intensity for one of both alleles.
For the other cases, only two different alleles were identified within the duplication region. Genotyping of cases 2 to 5 within the region of duplication showed in each case only two alleles. One of both alleles clearly had a higher intensity with about a 2:1 ratio (Figure 5). For sample 5, in which array CGH revealed that the rearrangement is only present in 10 to 20% (log2 value of 0.0888) of all cells, these peak intensity differences were still present, but to a lesser extent.
To determine the origin of the deletion in cases 8 and 9, again for the SNPs that were homozygous but with a different allele in both parents in the deletion, the A and B allele ratios were determined. The analysis showed that the signal of the paternal allele was reduced in case 8 and that a maternal allele was removed in case 9. To search for evidence of a potential meiotic event, the rest of the chromosome was screened for the presence of two paternal (case 8) or two maternal alleles (case 9). Hereto, the B-allele frequencies of SNPs on the affected chromosome, but outside the somatic CNV region, were evaluated for additional haplotypes. If the deletion resulted from a meiotic event, altered B-allele frequencies would be observed, with additional values between 0 and 0.5 as well as between 0.5 and 1. No such haplotypes were detected in the regions surrounding the deletion (Figure 6B).
The combination of a normal and an aberrant cell line in these cases could, aside from mosaicism, also result from chimerism: the fusion of two cell lineages from separate fertilization events. In samples 1 to 6, the presence of chimerism was evaluated by testing four STR markers spread over different chromosomes not involved in the aberrant region. in case of a mosaic all autosomal genotypes outside the duplicated region are expected to only contain two alleles (1 maternal & 1 paternal). For chimeras, some loci would have three or four alleles, or a skewed dosage of two alleles . None of the samples showed more than two alleles on any of the markers, confirming the mosaic status of the aberration (data not shown). In cases 7 to 9, the two different genotypes present in case of chimerism would be seen as aberrant B-allele frequencies in all autosomes, with an altered ratio between the two haplotypes. No alterations in the B-allele frequency were seen in the unaffected chromosomes, thereby ruling out the possibility of chimerism.
While the origin of mosaic segmental CNVs has only rarely been investigated, two case reports support our finding that pre-zygotic rearrangements followed by multiple postzygotic trisomy rescue events can underlie segmental mosaicisms. Blouin et al. detected a mosaic de novo direct tandem duplication of 21q11.2q22.2 that resulted from a meiosis I crossover followed by an unequal sister chromatid exchange and two trisomy rescue events, similar to our case 1. The mosaic de novo unbalanced translocation with partial trisomy 16p and maternal UPD 16 reported by Schinzel et al. likely originated from a maternal trisomy 16 (MI), a subsequent postzygotic translocation of the paternal 16p segment and finally loss of the paternal chromosomes 16 in the translocated and normal cell lines [18, 32]. Even after combining our results with previous mosaic segmental cases the total study population remains small, but future studies may be able to provide additional evidence for the high frequency of multiple independent trisomy rescue events.
In conclusion, we demonstrated that in 2/9 cases, the detected mosaic segmental aberrations resulted from meiotic errors followed by multiple parallel trisomy rescue events and not from postzygotic mitotic changes. In addition, we show that the use of sensitive array technology is especially suited for the detection of mosaicism, which is clinically relevant to a patient's diagnosis.
Five cases were referred for cytogenetic/molecular investigations after clinical evaluation for dysmorphic features, whereas cases 4, 6, 8 and 9 were ascertained during prenatal diagnosis (CVS and/or amniocentesis).
Cytogenetic analyses were performed on GTG-banded metaphase chromosomes from PHA-stimulated peripheral blood lymphocytes or from CVS cells or amniocytes after standard culture and chromosome preparation protocols. Twenty metaphases with a resolution of 550 bands per haploid genome were karyotyped (ISCN 2009).
BAC microarray analysis was performed as described elsewhere . Briefly, CodeLink Bioarray System slides (Amersham Biosciences, Chalfont St.Giles, UK) were used for array construction using a 1 Mb clone set of 3 683 BAC and PAC clones. Genomic DNA from the index patient and two other patients was labelled in Cy3 and Cy5, respectively (Amersham Biosciences, Chalfont St.Giles, UK) with random prime labelling (Bioprime array CGH, Invitrogen, Sunnydale, CA) and hybridized in a 3-way experiment. Hybridization and post-hybridization washing steps were performed as previously described . Slides were scanned at 532 nm (Cy3) and 635 nm (Cy5) using a GenePix 4000B microarray scanner (Axon Instruments, Union City, CA) with the software GenePixPro 6.0. Data analysis was performed with Excel (Microsoft Inc.; Diegem, Belgium) as described . The percentage of mosaicism was calculated by dividing the mean log2 ratio of the BAC clones in the duplicated region by the log2 of a non-mosaic aberration (0.5849).
SNP array analysis was performed on Affymetrix GeneChip® Human Mapping 250 K NspI arrays (Affymetrix, Inc., Santa Clara CA, USA) containing 25-mer oligonucleotides representing a total of 262 264 SNPs. DNA digestion, labeling and hybridization were performed according to the manufacturer's protocol. After hybridization, arrays were washed and stained on the Affymetrix GeneChip fluidics station 450 and scanned using the Affymetrix GeneChip® Scanner 3000 7 G. Data analysis was performed using Copy Number Analyzer for GeneChip version 2.0 (CNAG 2.0)  and Genotyping Console™ Software (Affymetrix, Inc.).
Fluorescent in situ hybridization
To confirm aberrations found by microarray, FISH was performed with BAC probes as described , using an optical fluorescence microscope (Olympus U-SPT, BX51, Japan) with selective filters equipped with CytoVision® software (Applied Imaging, Genetix, Gateshead, UK).
SNP cluster determination
For determining the parental origin of the DNA copy number aberrations by a SNP-cluster strategy, normalized SNP A and B allele intensities as well as SNP genotype calls were computed using Affymetrix power tools (APT-1.10.1) in combination with the Birdseed command . Besides the described trio datasets, in-house produced Affymetrix 250 K SNP NspI data from 102 additional DNA samples were co-processed for accurate SNP cluster and genotype determination. Subsequently, the probe intensities and genotype calls for SNPs within the regions of interest were retrieved for all DNA samples and interpreted by custom R-code  in which patient and parental SNP-probe intensities are visualised in the Birdseed SNP clusters from the 102 individuals.
B-allele frequency plots
To generate the B-allele frequency (BAF) plots, copy number analysis of the SNP array data was performed using the Affymetrix power tools BRLMM, a modified version of RLMM  and the pennCNV  algorithm. These data were subsequently further interpreted and visualized in BAF and logR ratio plots by the genoCN algorithm .
Polymorphic microsatellite marker analysis
Polymorphic microsatellite markers made up of dinucleotide (CA)n repeats (short tandem repeats or STRs) were selected from the Ensembl  and UCSC  genome browser databases and the oligonucleotides were purchased from Eurogentec S.A. (Seraing, Belgium) and Pharmacia Biotech (Uppsala, Sweden). Genomic DNA was extracted from peripheral blood leukocytes, amniocytes or CVS cells of the patients and their parents according to standard procedures and CA repeats spaced along the involved chromosomes were amplified by polymerase chain reaction (PCR). DNA extracted from skin fibroblasts was also included in the analysis in case the mosaicism was encountered in fibroblasts.
After PCR amplification of the STRs, fragments were analyzed by gel electrophoresis. Automated fragment sizing was performed on the ABI Prism 3100 Genetic Analyzer (Applied Biosystems, Nieuwerkerk a/d Ijssel, the Netherlands), using software GeneScan or Genemapper v4.0 (Applied Biosystems, Nieuwerkerk a/d Ijssel, The Netherlands).
This work has been made possible by an IWT (SBO 60848) and FWO grant G.0320.07.
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