This review is based on a thorough description of the structure and sequence organization of tandemly organized repetitive DNA sequence families in the human genome; it is aimed at revealing the locusspecific sequence organization of tandemly repetitive sequence structures as a highly conserved DNA sequence code. These repetitive so-called “super-structures” or “higher-order” structures are able to attract specific nuclear proteins. I shall define this code therefore as a “chromatin folding code”. Since locus-specific superstructures of tandemly repetitive sequence units are present not only in the chromosome centromere or telomere region but also on the arms of the chromosomes, I assume that their chromatin folding code may contribute to, or even organize, the folding pathway of the chromatin chain in the nucleus. The “chromatin folding code” is based on its specific “chromatin code”, which describes the sequence dependence of the helical pathway of the DNA primary sequence (i.e., secondary structure) entrapping the histone octamers in preferential positions. There is no periodicity in the distribution of the nucleosomes along the DNA chain. The folding pathway of the nucleosomal chromatin chain is however still flexible and determined by e.g., the length of the DNA chain between the nucleosomes. The fixation and stabilization of the chromatin chain in the space of the nucleus (i.e., its “functional state”) may be mediated by additionally unique DNA protein interactions that are dictated by the “chromatin folding code”. The unique DNA-protein interactions around the centromeres of human chromosomes are revealed for example by their “C-banding”. I wish to stress that it is not my aim to relate each block of repetitive DNA sequences to a specific “chromatin folding code”, but I shall demonstrate that there is an inherent potential for tandem repeated sequence units to develop a locus-specific repetitive higher order structure; this potential may create a specific chromatin folding code whenever a selection force exists at the position of this repetitive DNA structure in the genome.

Potential genetic functions of tandem repeated DNA sequence blocks in the human genome are based on a highly conserved “chromatin folding code”

Changes in the morphology of human and murine chromosomes during the different stages of mitosis have been examined by scanning electron microscopy. Two important findings have emerged from this study. The first is that prophase chromosomes do not become split into pairs of chromatids until late prophase or early metaphase. This entails two distinct processes of condensation, the earlier one starting as condensations of chromosomes into chromomeres which then fuse to form a cylindrical body. After this cylindrical body has split in two longitudinally, further condensation occurs by mechanisms that probably include coiling of the chromatids as well as other processes. The second finding is that the centromeric heterochromatin does not split in two at the same time as the rest of the chromosome, but remains undivided until anaphase. It is proposed that the function of centromeric heterochromatin is to hold the chromatids together until anaphase, when they are separated by the concerted action of topoisomerase II acting on numerous similar sites provided by the repetitive nature of the satellite DNA in the heterochromatin. A lower limit to the size of blocks of centromeric heterochromatin is placed by the need for adequate mechanical strength to hold the chromatids together, and a higher limit by the necessity for rapid splitting of the heterochromatin at anaphase. Beyond these limits malsegregation will occur, leading to aneuploidy. Because the centromere remains undivided until anaphase, it cannot undergo the later stage of condensation found in the chromosome arms after separation into chromatids, and therefore the centromere remains as a constriction.

Scanning electron microscopy of mammalian chromosomes from prophase to telophase.

Review and hypothesis: Alzheimer disease and Down syndrome--chromosome 21 nondisjunction may underlie both disorders.

Fourteen cases of mosaic variegated aneuploidy (MVA) syndrome have been reported in the last 10 years. The phenotype of this rare condition has been quite consistent: severe microcephaly, growth deficiency, mild physical anomalies, and mental retardation. We describe here a young boy in whom MVA syndrome is associated to myelodysplasia with a monosomy 7 bone marrow clone. At the age of 3 years, myelodysplasia progressed to an acute lymphoblastic leukemia, and the patient died soon after. Several syndromes with short stature and severe microcephaly, such as the Seckel and Nijmegen syndromes, comprise hematological findings and chromosome instability. However, chromosome instability was not confirmed in our patient. MVA with hematological findings has not been reported before, but 3 patients of 14 (21%) have developed a malignancy (rhabdomyosarcoma, acute lymphoblastic leukemia, and nephroblastoma). Therefore, we propose that MVA is a condition predisposing to neoplasia.

High risk of malignancy in mosaic variegated aneuploidy syndrome.

Separation of chromatids of all mitotic chromosomes, here called total premature chromatid separation (total PCS), was observed in 67 to 87.5% of repeated cultures of peripheral blood lymphocytes from two unrelated infants. Also noted was a variety of mosaic aneuploidies, especially trisomies, double trisomies, and monosomies, to be called mosaic variegated aneuploidy. The infants both showed severe pre- and postnatal growth retardation, profound developmental retardation, uncontrollable seizures, severe microcephaly, hypoplasia of the brain, Dandy-Walker anomaly, abnormal facial appearance, and bilateral cataract. Patient 1, a girl, in addition had a cleft palate, multiple renal cysts, and Wilms tumor of the left kidney. Whereas patient 2, a boy, had ambiguous external genitalia. They both died within 2 years of age. In the two families of the infants, their parents and three other members showed 2.5 to 47% lymphocytes with total PCS but without mosaic variegated aneuploidy or phenotypic abnormalities. Another 10 relatives studied showed 0 to 1% cells with total PCS and so were judged negative for the total PCS trait. It was deduced that the total PCS trait in the two families was transmitted in an autosomal-dominant fashion, and the two affected infants were homozygous for the trait.

Mosaic variegated aneuploidy with multiple congenital abnormalities: homozygosity for total premature chromatid separation trait.

We describe a family with an increased frequency of cells with premature centromere division (PCD) of all chromosomes in four phenotypically normal individuals. This familial PCD phenomenon is apparently different from the well-described PCD of the X chromosome and from the centromere splitting in cells of patients with Roberts syndrome. Implications for genetic counseling are discussed.

Premature centromere division (PCD): a dominantly inherited cytogenetic anomaly.

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Premature centromere division (PCD): a dominantly inherited cytogenetic anomaly.