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Centromeres of Human Chromosomes Proc. Nail. Acad. Sci. USA Vol. 86, pp. 9394-9398, December 1989 Genetics Long-range organization of tandem arrays of a satellite DNA at the centromeres of human chromosomes: High-frequency array-length polymorphism and meiotic stability (pulsed-field gel electrophoresis/restriction fragment length polymorphism/human repetitive DNA/segregation) RACHEL WEVRICK AND HUNTINGTON F. WILLARD*t Department of Medical Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada Communicated by L. L. Cavalli-Sforza, August 14, 1989 ABSTRACT The long-range organization of arrays of a are organized into higher-order repeat units, which are tan- satellite DNA at the centromeres of human chromosomes was demly arranged to form arrays comprising up to millions of investigated by pulsed-field gel electrophoresis techniques. base pairs of DNA at human centromeres. At a molecular Both restriction-site and array-length polymorphisms were level, distinct chromosomal subsets from at least 12 auto- detected in multiple individuals and their meiotic segregation somes and the X and Y chromosomes have been identified was observed in three-generation families. Such variation was and are distinguished by characteristic long-range periodic- detected in all of the et satellite arrays examined (chromosomes ities revealed by restriction endonucleases that cleave once 1, 3, 7, 10, 11, 16, 17, X, and Y) and thus appears to be a per tandemly arranged higher-order repeat unit (8). Mecha- general feature of human centromeric DNA. The length of nisms for the generation and maintenance of tandem arrays individual centromeric arrays was found to range from an of repeated sequences have been postulated (9) and include average of =680 kilobases (kb) for the Y chromosome to :3000 recombinational events such as unequal sister-chromatid kb for chromosome 11. Furthermore, individual arrays appear exchange and sequence conversion. Misalignment and re- to be meiotically stable, since no changes in fragment lengths combination between higher-order a satellite repeat units (10, were observed. In total, we analyzed 84 meiotic events involv- 11) can lead to sequence homogenization and to spreading ing -191,000 kb of a satellite DNA from six autosomal and fixation ofpolymorphic variants (8). Further, such events centromeres without any evidence for recombination within an are predicted to result in contractions and expansions in the array. High-frequency array length variation and the potential overall length of the arrays of the chromosomes of chroma- to detect meiotic recombination within them allow direct tids involved and may lead to the generation of a distribution comparisons of genetic and physical distances in the region of of centromeric array sizes in a population (8). the centromeres of human chromosomes. The generation of Highly informative polymorphisms detected by chromo- primary consensus physical maps of a satellite arrays is a first some-specific a satellite probes should form the basis for a step in the characterization of the centromeric DNA of human series of centromere-based genetic linkage maps of the hu- chromosomes. man genome (12-16) and may also provide a set of molecular markers for investigating both the structure and the genetic Centromeres control the disjunction of homologous chromo- behavior of centromeres (17). Recent analyses of arrays of a somes in the first meiotic reductional division, and of sister satellite (18-21) and other satellite DNAs (22-25) by pulsed- chromatids in the second meiotic division and in mitosis. field gel electrophoresis techniques have demonstrated the Centromeric DNA forms a distinct site for interactions with potential of long-range mapping techniques for studies of the the spindle apparatus via the kinetochore, a complex pro- genomic organization of tandemly repeated DNA. In this teinaceous structure (1, 2). The properties of centromeric study, we have used chromosome-specific a satellite probes DNA are therefore expected to be somewhat different from and pulsed-field gel techniques to measure the sizes of a those of the rest of the chromosome in terms of replication, satellite arrays at the centromeres of several human chro- transcription, and recombination. Meiotic recombination is mosomes in different individuals. We have demonstrated reduced near the centromere in many organisms (3-6). In the array length polymorphism among different copies ofeach of budding yeast Saccharomyces cerevisiae, meiotic recombi- the centromeres examined and a high degree of restriction nation is reduced near the centromere both in wild-type yeast fragment length polymorphism within each array. Such cen- and in strains in which the cloned centromere has been tromere polymorphisms have been used to estimate the displaced to another position on the chromosome (4, 7). In meiotic stability of centromeric DNA by tracing individual the fission yeast Schizosaccharomyces pombe, the cen- restriction fragments contained in these megabase-sized ar- tromere of chromosome II is contained in a 60-kilobase (kb) rays through successive meioses. fragment containing repetitive DNA, in which meiotic re- combination is greatly reduced (5). Limited data based on mapping of chiasmata suggest that this may also be the case MATERIALS AND METHODS in human chromosomes (6). Cell Lines and Probes. Lymphoblastoid cell lines used for The mammalian centromere is cytogenetically defined as the family analysis of restriction fragment length polymor- the primary constriction in metaphase chromosomes. The phisms were obtained from the National Institute of General human a satellite DNA family is the predominant class of Medical Sciences Mutant Cell Repository (Camden, NJ). DNA located at the centromere of each human chromosome These cell lines were derived from 13 individuals in a three- and, in total, constitutes several percent of the genome (8). generation family (K-1333). High molecular weight DNA Multiple 171-base-pair (bp) monomer units of a satellite DNA Abbreviation: CHEF, contour-clamped homogeneous electric field. The publication costs of this article were defrayed in part by page charge *To whom reprint requests should be addressed. payment. This article must therefore be hereby marked "advertisement" tPresent address: Department of Genetics, Stanford University, in accordance with 18 U.S.C. §1734 solely to indicate this fact. Stanford, CA 94305. 9394 Downloaded by guest on September 30, 2021 Genetics: Wevrick and Willard Proc. Natl. Acad. Sci. USA 86 (1989) 9395 from these cell lines and other established cell lines, including satellite arrays on chromosome 7 (27) or with satellite III near somatic cell hybrids containing a limited number of human the Y chromosome centromere (35). chromosomes (e.g., see ref. 26), was prepared as described below. Cloned a satellite probes specific for the following chromosomes were used: chromosome 1 [probe pSD1-1 RESULTS (DJZS), ref. 18]; 3 [probe p3-5 (D3ZI), ref. 21]; 7 [probes Long-Range Polymorphisms in a Sateilite DNA. Previous pMGB7 (D7Z2) and pa7tl (D7ZJ), ref. 27]; 10 [probe experiments suggested the presence of a satellite polymor- palORP8 (DIOZI), ref. 28]; 11 [probe pLC11A (DIIZI), ref. phisms involving large DNA fragments (12, 18-21, 28). To 29]; 16 [probe pSE16.2 (D16Z2); ref. 36]; 17 [probe p17H8 investigate the frequency of these polymorphisms in a num- (DI7ZI), ref. 26]; X [probe pBamX7 (DXZI), ref. 30]; and Y ber of different a satellite arrays (from chromosomes 1, 3, 7, [probes Y97 (DYZ3), ref. 31, or pYCS-1c (DYZ3), C. Sharp 10, 11, 16, 17, X, and Y), we screened DNA fom multiple and H.F.W., unpublished work]. individuals with enzymes not expected to cut in the higher- DNA Preparation and Electrophoresis. High molecular order repeat unit in CHEF gels. A pattern of multiple weight DNA was isolated from cultured lymphoblasts essen- hybridizing bands ofvarying, apparently random lengths was tially as described (32). S. cerevisiae chromosome size mark- seen in most of the arrays investigated with multiple en- ers were strain YNN265 (Bio-Rad). Sch. pombe chromosome zymes, with examples shown in Fig. 1 A and B for probes size markers were prepared from strain 972 by the method of from the centromeres of chromosomes 11 and 16. For ex- Vollrath and Davis (33). Contour-clamped homogeneous ample, an a satellite probe for the centromere ofchromosome 16 detected fragments ranging in size from 40 to 1200 kb in Bgl electric field (CHEF) gel electrophoresis (ref. 34; apparatus II-digested DNA from six unrelated individuals, with a dif- from Bio-Rad) was used in the mapping experiments. CHEF ferent pattern in each individual examined (Fig. 1B). Probes electrophoresis was performed in 0.5x TBE buffer (45 mM associated with larger arrays may leave some fragments Tris/45 mM boric acid/1 mM EDTA, pH 7.6) at 15TC, as unresolved under these running conditions (e.g., Fig. 1B). specified in the figure legends. After ethidium bromide stain- DNA from a large three-generation family (K-1333) was ing and photography, pulsed-field gels were treated with 0.25 analyzed by CHEF electrophoresis in order to investigate the M HCl for 10 min prior to transfer of DNA. Methods of segregation of restriction site and array length polymor- transfer to nylon filters, prehybridization, and chromosome- phisms (Fig. 2); these data demonstrate Mendelian inheri- specific hybridization with 32P-labeled a satellite probes have tance of the arrays and their associated polymorphisms. been described (26). Array Length Polymorphisms and Size Estimates. The Choice of Restriction Enzymes. The repetitive nature of a smaller arrays, found in the centromeric DNA of the Y satellite DNA requires the choice of appropriate restriction chromosome (Fig. 1C) and in domain I of chromosome 7 enzymes for each array under investigation. Enzymes chosen centromeric a satellite array (data not shown), yield only one for these experiments, as for previous a satellite polymor- or two hybridizing fragments respectively upon digestion phism studies (12, 28), were those that cut frequently in with a number of enzymes, presumably representing the nonrepetitive DNA but infrequently within the a satellite entirety of each array in a single fragment.
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