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Am J Hum Genet. Mar 3, 2008; 82(3): 763–771.
Published online Feb 29, 2008. doi:  10.1016/j.ajhg.2007.12.011
PMCID: PMC2427204

Phenotypically Concordant and Discordant Monozygotic Twins Display Different DNA Copy-Number-Variation Profiles


The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These findings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics.

Main Text

Monozygotic (MZ) twins represent an important resource in genetic studies related to normal development and disease. Numerous twin registries exist,1 often specializing in collection of phenotypically discordant MZ twins. Consequently, twin research has become a powerful tool for studying various diseases and endophenotypes, evaluating quantitative-trait loci, estimating heritability, studying differences in gene expression, and testing hypotheses regarding gene-environment interactions.1 It is generally presumed that MZ twins are genetically identical and that phenotypic differences between twins are mainly due to environmental factors. Examples of genetic and, more recently, epigenetic differences between MZ twins have, however, been described.2–5 The former are mainly related to aneuploidies. Somatic mosaicism is usually defined by the presence of genetically distinct populations of somatic cells in a single organism. Any genetic difference between MZ twins represents an extreme example of somatic mosaicism. Earlier reports have shown somatic mosaicism for mutations in specific disease-related genes or chromosomal aberrations that are connected with a disease and can, for instance, result in a milder disease phenotype.6–9 This steadily growing body of data indicates that somatic mosaicism for pathogenic mutations affecting known disease genes might be seen as a rule rather than as an exception. In addition, it was recently demonstrated that the frequency of inversions is altered between different populations of normal somatic cells in a healthy subject.10 However, the frequency of in vivo somatic mosaicism for copy-number variations (CNVs) in populations of apparently normal cells is so far unexplored.

A recent and important development in human genetics is the discovery of substantial large-scale structural variation (SV) changing the chromosomal architecture (such as deletions, duplications, insertions, inversions, and more complex rearrangements) and occurring both in phenotypically normal and in diseased subjects. The most explored subtype of SV involves changes affecting copy number of DNA segments (denoted here as Copy-Number Variation, [CNV]), often involving fragments of chromosomes that are considerable in size. Although approximately three years have passed since the initial reports,11,12 current publications still suggest that CNV is an underestimated aspect of the human genome in health and disease.13 In one comprehensive recent study,14 it has been suggested that the total amount of sequence variation involving CNVs between two normal subjects is actually higher than that for single-nucleotide polymorphisms (SNPs). This conclusion has been reinforced by the recent increase in resolution of CNV discovery.15 The advent of massively parallel sequencing will soon bridge the remaining gap between efficient global analysis of SNPs and assessments of SVs, so that in the next few years we will be able to fully explore the “SV plasticity” of our genome and its relation to normal and pathogenic variation.

The rationale of this study was to test whether phenotypically unselected and concordant MZ twins, as well as selected MZ twins discordant for a neurodegenerative phenotype, display CNVs. We used two different genome-wide platforms—the 32K BAC array and the Illumina HumanHap 300 Duo beadchip system—for cross-validation of the most salient findings. We present evidence for large-scale CNVs among MZ twins and suggest that these variations may be common, notably in somatic development. Our results question the long-standing notion that MZ twins are essentially genetically identical and open up new possibilities in the use of discordant MZ twins for identifying regions harboring disease- or trait-influencing loci.

Arrays constructed with genomic clones are widely used as a tool for CNV detection.14,16–18 The 32K BAC-array platform is a sensitive system to assess subtle imbalances and has been validated by use of a large number of samples with known genotypes. The samples used in this study were hybridized to the 32K BAC array and washed and scanned according to previously published protocols.19 All hybridizations were done in duplicate, with the dyes being swapped between the twins in the second hybridization to eliminate a possible dye-specific bias. The results were deposited in and analyzed with the Linnaeus Centre for Bioinformatics (LCB) environment for microarray-data management.20 Here, nonoptimal array features were filtered out, and spatial artifacts were addressed with the use of print-tip loess normalization.19 Comparative analysis was done in Microsoft Excel. Here, we excluded all clones that were not reliably scored in both hybridizations for each twin. We then calculated the global standard deviation (SD) of the remaining clones. Clones with an internal SD larger than the global SD were excluded for further analysis. Finally, we performed a t test to test whether the clones from the two duplicated experiments deviated significantly from the value of one, which is the theoretical value for a normal copy-number ratio. Computational analysis of statistical significance was carried out with the R statistical computing environment.21 We further applied the SNP-based Illumina HumanHap 300 Duo beadchip, which can also be used for copy-number analysis.22 The Illumina hybridizations were performed at the Leiden Genome Technology Center according to the manufacturer's instructions (Illumina, San Diego, CA). Image analysis was performed in Illumina's BeadStudio software, and the raw data were exported into Microsoft Access. Here, we filtered out all data that had allele frequency values representing homozygous SNPs. The absolute difference of the remaining heterozygous SNPs between the twins in each twin pair was then calculated and plotted. The data were finally deposited at the GEO main page at NCBI under the accession number GSE9609.

We studied a total of 19 pairs of MZ twins by using peripheral-blood-derived DNA (Table S1, available online). Nine MZ twin pairs were previously collected and assessed for Parkinson disease (PD [MIM 168600]), parkinsonism [MIM 168600], or Lewy body dementia [MIM 127750] by the Swedish Twin Registry (STR).23,24 Six of these nine MZ twin pairs were discordant for probable or possible PD, two pairs were discordant for parkinsonism of unknown cause, and one pair was discordant for Lewy body dementia. In two of the six MZ twin pairs discordant for PD, the co-twin had essential tremor, and in one pair, the co-twin had a mixed form of parkinsonism (Table S1). Ten phenotypically unselected and concordant normal Dutch MZ twins were collected as part of the Netherlands Twin Register (NTR).25 The monozygosity of the STR twins was determined on the basis of questionnaires, which alone have a 98% probability of correct zygosity establishment,23 and was further confirmed by genotyping with 13–18 SNPs distributed throughout the genome. On the basis of allele frequencies from 249 control subjects,26 the probability of being concordant at that number of unlinked loci, assuming dizygosity, was less than 0.03 (Table S1 and data not shown). The ten NTR MZ twins were genotyped on the SNP beadchip containing more than 300,000 SNPs, and genotypes were concordant for all SNPs.

The primary platform for analysis of STR twin pairs was the 32K BAC array. We compared one twin versus its co-twin and each twin against a genetically well-characterized normal female control (F1).19 The latter comparison serves to assess the true genotype of the twins (i.e., presence of putative shared CNV), whereas the former experiments show putative imbalance within each twin pair. BAC-array profiles from experiments between any twin versus F1 are consistently noisier, with higher standard deviations, compared to experiments using DNA from one twin versus another from the same pair (not shown). Comparisons within the STR twin pairs revealed a considerable number of loci suggestive of putative CNV. For instance, the profile from twin pair 291/292 points to a deletion encompassing 22 Mb of 11q in subject 292 on the basis of profiles from seven experiments (Figure 1). This finding was confirmed and refined on the Illumina beadchip (Figure 1). The centromeric breakpoint of the 22 Mb deletion, located at ~102 Mb, overlaps with a known intrachromosomal segmental duplication, and this deletion encompasses the ATM gene [MIM 607585] (see below). Comparing the BAC-array ratios with experiments in which all cells are affected by an imbalance (e.g., ratios for chromosome X in hybridization of male versus female), we estimated that the deletion in twin 292 is present in ~20% of nucleated blood cells.16 We also confirmed this CNV in quintuple in a high-resolution, repeat-free, nonredundant, PCR-based array (Figure 1), a test we previously developed for the detection of pathogenic gains and deletions and the discovery of CNV.27–29 Details regarding this confirmatory array are available from the authors upon request.

Figure 1
Copy-Number Variation (CNV) Analysis of Twin Pair 291/292

In addition to the 11q rearrangement, another large deletion, affecting 4p and a considerable part of 4q, was found in twin 292 by both 32K BAC analysis and Illumina beadchip (Figure 1). This ~85 Mb deletion was present in ~10–15% of cells. On the basis of the striking conjunction of two very large deletions, we searched the literature and found that chromosome 4 deletion and an 11q deletion, which targets the ATM gene, are common for chronic lymphocytic leukemia (CLL [MIM 151400]).30,31 We were not previously aware of any additional disease affecting twin 292, but consultation of the medical records confirmed that subject 292 had been diagnosed with CLL prior to sampling of his blood in the course of our study (Table S1). We have thus “rediagnosed” a clone of CLL cells containing two somatic and pathogenic CNVs in this twin. In this case, because we are studying the correct target tissue, we are confident that these two changes are truly pathogenic. The fact that we were able to detect this, in spite of a low percentage of cells containing aberrations, is a good illustration of the power of both genome-wide array platforms. As far as we are aware, the chromosome 4 aberration in subject 292 represents the lowest reported number of cells containing a change that has been detected via an array-based genome-wide platform for CNV screening. There are two main challenges in scoring “somatic CNVs” in monozygotic twins or other types of samples used for analysis of somatic mosaicism for copy-number changes. One concern is usually the small size of these CNVs. The second is that these aberrations will typically occur in only a proportion of cells. Both of these aspects make the analysis more challenging than scoring “germline CNVs” that are expected to be present in 100% of studied cells. The other eight STR MZ pairs also showed additional imbalances on the 32K BAC array, and this was replicated on the Illumina beadchip for two pairs. For instance, Figure 2 displays five small deviating loci, concordant between 32K array and Illumina, in twin pairs 491/492 and 701/702.

Figure 2
Parallel CNV Analysis with Two CNV Platforms

Several other putative CNV loci were found with the 32K arrays in six additional STR MZ pairs (Figures S1A and S1B). These loci were defined by two dye-swap experiments with at least two overlapping BAC clones deviating by >2 global standard deviations, the same criteria used when scoring the 11 Mb and 85 Mb deletions in twin 292. Tables S2–S4 further summarize the deviating loci, defined as single BACs or neighboring/overlapping BACs in all STR-twins with different cutoffs of statistical significance (difference of ≥2 or ≥3 global SDs). There were 31 loci that deviated in three phenotypically discordant MZ pairs and four loci that deviated in four such pairs (Tables S3 and S4). These can be viewed as candidates for containment of genes involved in the development of PD.

For the analysis of the ten phenotypically concordant twin pairs from NTR, the Illumina system was the primary platform used (Table S1). In addition to the concordant SNP genotypes (see above), including several CNVs that were shared by both twins of a pair, a few discordances in A and B allele frequencies were also found, suggesting putative de novo somatic CNV events. Figure 3 shows a clear example of a large CNV, which covers ~1.6 Mb on chromosome 2 in twin pair D and extends from SNPs rs2304429 to rs1662987, implying a deletion in twin D8. On the basis of the quantification, it too is found to be present in less than 100% of the cells. Two additional methods were applied to validate this finding: high-resolution Melting Curve Analysis and pyrosequencing (Figures 3C and 3D). Both methods confirmed the presence of the deletion and indicated that it was present in approximately 70–80% of blood cells from D8. Circumstantial evidence was obtained for other, posttwinning CNVs, but the statistics of identifying somatically mosaic (i.e., incomplete) CNVs by SNP concordance analysis requires further methodological development beyond the scope of this report.

Figure 3
CNV Analysis of Twin D8 Showing the 1.6 Mb Deletion on Chromosome 2

Analysis of CNVs is a generally understudied aspect of human genetic variation, particularly in somatic cells. MZ twins represent an excellent focus for such studies because any genotypic difference between twins derived from the same zygote highlights an irrefutable case of somatic variation. It is likely that the confirmed CNVs shown here represent only the “tip of an iceberg” of all CNVs that are actually present in the studied twins. The notion of somatic variation being far more common than previously assumed agrees well with our other, recent results showing CNVs between normal, fully differentiated tissues within an individual human subject (A.P., C.E.G.B., R.A., T.D.d.S., U.M., J.S., D.v.T., A.P., C.C., E.C.P., J.K., and J.P.D., unpublished data).

Our findings influence the understanding of phenotypic and genotypic diversity in MZ twins. First, we wish to stress that although our data seem to suggest a difference, it is not justified to conclude that phenotypically discordant MZ twins are more frequently affected by CNV than are concordant MZ twins. To assess this question, larger cohorts of both twin categories need to be analyzed, preferably by use of DNA extracted from multiple tissues. On the other hand, some of the CNVs in twins discordant for Parkinson disease, parkinsonism, or Lewy body dementia might be pathogenic for these phenotypes, especially when they would also be present in the affected cells of the central nervous system. Indeed, a frequent limitation of CNV analyses as generally performed in the context of somatic disorders is that the genotype of one tissue analyzed (usually blood) might not always be relevant to the genotype of the tissue responsible for the disease, a phenomenon well known for other disorders.32 Second, our findings issue a note of caution. Because genome-wide tools show de novo CNVs in healthy individuals, we should expect such changes when analyzing patients. The detection of de novo aberrations has so far been considered evidence for a causal link between mutation and disease status of a patient. We show that one should be careful when drawing such conclusions.

Finally, estimating the frequency with which de novo CNVs occur is currently difficult. On the basis of the detection of one megabase-range, confirmed CNV among ten unselected, phenotypically concordant MZ twin pairs next to several potential ones with a lower degree of cellular mosaicism and/or smaller size, the de novo posttwinning CNV frequency could be as high as 5% on a per-individual basis or 10% per twinning event. The detection rate among the discordant Parkinson twins suggests an even higher figure, but this is within a selected, discordant group and thus might represent a mixture of phenotypically relevant, as well as random, and phenotypically neutral CNV events. This figure is clearly only a first approximation, and a larger cohort of MZ twins needs to be studied in order to more accurately define the frequency. It is not straightforward to derive supporting evidence from other studies, because parents were typically not analyzed in these studies. One such estimate, based on the de novo deletion frequency in the DMD gene [MIM 300377], which lacks conspicuous low-copy repeats (segmental duplications) enhancing propensity for rearrangements, arrives at one de novo deletion per eight newborns and one duplication per 50 newborns.33 Sebat et al.34 mention the detection of one de novo deletion when 28 CEPH individuals were studied, an essentially similar frequency. We note that the frequency of de novo CNVs strongly depends on the cutoff criteria set to detect these, especially when the size of an aberration and the number of cells affected by it diminish. In the above circumstances, the confirmation of CNVs via alternative techniques becomes particularly challenging. Our work clearly suggests a need for new, better methods for confirmatory analyses, of which massively parallel sequencing seems promising.15 On the other hand, our results also point to the feasibility of studies targeting larger cohorts of MZ twins discordant for various phenotypes as a way to characterize genetic factors predisposing one to disease. Future studies should ideally be performed with the use of DNA extracted from more than one tissue, or from cells derived from the same developmental lineage as the target tissue that is responsible for generation of the discordant phenotype.

Figure 4
Statistical Analysis of Two Dye-Swap Experiments from Twin 291 versus 292


This study was supported by funds from the Health Services Foundation and the General Endowment Fund (HSF, GEF) from the University of Alabama at Birmingham Medical School, the Swedish Cancer Society, the Swedish Children's Cancer Foundation, and the U.S. Army Medical Research and Materiel Command (award no. W81XWH-04-1-0269 to J.P.D), as well as by Netherlands Genomics Initiative funds to the Center for Medical Systems Biology supporting A.A.C.H.G., J.T.d.D., D.I.B., and G.J.B.v.O. The twin specimens and phenotypic data were collected with the support of National Institutes of Health (NIH) grant ES10758 to N.L.P. S.E. acknowledges the support of NIH grant 5T32HL072757-04, and D.B.A. acknowledges the support of NIH grants 3P30DK056336-05S2 and 5R01ES009912-08.We thank Drs. Eline Slagboom and Claudia Ruivenkamp for sample contribution, guidance, and discussions, as well as Drs. Bruce A. Korf, Lisa Guay-Woodford, Jay McDonald, and Marco Marra for critical comments on the manuscript. We also thank Dr. Doug Horsman for valuable advice about the genetics of CLL.

Supplemental Data

Document S1. Two Figures:

Web Resources

The URLs for data presented herein are as follows:

Accession Numbers

The array data were deposited at the GEO main page at NCBI under the accession number GSE9609.


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