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PubMed2003

Multicolor deconvolution microscopy of thick biological specimens.

One limitation in understanding disease at the cellular level has been the inability to efficiently analyze DNA on a cell-to-cell basis within the natural tissue context. However, DNA analyses at a single-cell resolution should be instrumental for the understanding of cancer cell biology, cancer evolution, for chromosomal mosaic analysis and rare cell events, and should provide otherwise inaccessible information on essential biological processes. Here we present a fluorescence in situ hybridization-based multicolor deconvolution technique for three-dimensional microscopy. We use up to seven different color channels for probe detection, which allows the simultaneous high-resolution localization of multiple point-like sources within a biological specimen with a thickness of up to 30 micro m. In addition, a DNA counterstain is used for volume labeling of the nuclei offering the opportunity for a simultaneous segmentation of nuclei. Furthermore, as the instrumentation consists of a standard fluorescence microscope it represents a low-cost method as compared to confocal microscopy.

Centromere↗
PubMed1990

Minichromosomes in Drosophila melanogaster derived from the transposing element TE1.

A minichromosome has originated from the transposing element TE1. This autonomously replicating chromosome contains the structural genes white and roughest, from the Drosophila X chromosome. It arose within a stock carrying TE1 at 45F on chromosome 2. In addition to the w and rst genes, the minichromosome may carry section 45C-45F from chromosome 2. It is inherited by 33%-47% of the offspring. By this criterion it carries a centromere, although the origin of the centromere is unknown. From this minichromosome a still smaller one has originated, probably through the loss of all material from chromosome 2 together with some heterochromatin. At the same time a duplication of white and roughest could have taken place. This chromosome has a strange morphology and is more frequently lost in meiosis than the larger one, but is still transmitted to about 29%-37% of the progeny of one parent heterozygous for the minichromosome. In both cases the flies have variegated eyes, probably as a result of position-effect variegation. The variegation pattern is influenced by factors in the X chromosome. The size of the smaller minichromosome is little more than 1 Mb as determined by pulsed field gel electrophoresis.

Animals↗
PubMed2001

The structure of duplications on human acrocentric chromosome short arms derived by the analysis of 15p.

We report the molecular analysis of a 130-kb DNA region containing a junction between beta and non-beta satellite DNA from chromosome 15p. The genomic region is characterized by beta satellite blocks intermingled with variants of the D4Z4 repeat, and duplicons from 4q24 and 4q35. Besides the p-arm of acrocentric chromosomes, the duplicons showed a wide genomespread involving pericentromeric, sub-telomeric, and interstitial regions. In this regard, the paralogous sequences were characterized by a high similarity index (96%), thus indicating a recent transposition during the evolution. The acrocentrics differedwith regard to the location of the 4q24 paralogous region, since it mapped on the p-arm of chromosomes 13-15 and 21, but only on 22q11.2. Conversely, the 4q35 duplication marked the p-arm of all the acrocentrics. In different individuals, the short arm of acrocentric chromosomes revealed a great variability of sequence representation and location at p11 and/or p13 for both the 4q24 and 4q35 duplications. The studied genomic region from chromosome 15p, of which a contig of approximately 200 kb has been derived, could lead to more detailed investigations into the sequence organization and possible biological function of chromosome regions that are located close to the rDNA array.

Alu Elements↗
PubMed1998

Genomic structure and domain organisation of the human Bak gene.

The Bcl-2 homologue, Bak, is a potent inducer of apoptosis. FISH data presented here located the gene to 6p21.3. Mapping was consistent with its location centromeric of the HSET locus and approximately 400kb from the MHC. The construction of a contig of genomic clones across the locus facilitated the sequencing of a PAC containing the gene. Comparison of the gene structure to functional and physical domains revealed a good agreement between the physical structure and the intron-exon organisation. The position of a single intron was conserved in comparison to other members of the Bcl-2 family, namely Bax, CED-9, Bcl-X and Bcl-2, but all other introns were displaced, consistent with a divergent phylogeny.

Amino Acid Sequence↗
PubMed1987

Chromosome-specific subsets of human alpha satellite DNA: analysis of sequence divergence within and between chromosomal subsets and evidence for an ancestral pentameric repeat.

The centromeric regions of human chromosomes are characterized by diverged chromosome-specific subsets of a tandemly repeated DNA family, alpha satellite, which is based on a fundamental monomer repeat unit approximately 171 bp in length. We have compared the nucleotide sequences of 44 alphoid monomers derived from cloned representatives of the multimeric higher-order repeat units of human chromosomes 1, 11, 17, and X. The 44 monomers exhibit an average 16% divergence from a consensus alphoid sequence, and can be assigned to five distinct homology groups based on patterns of sequence substitutions and gaps relative to the consensus. Approximately half of the overall sequence divergence can be accounted for by sequence changes specific to a particular homology group; the remaining divergence appears to be independent of the five groups and is randomly distributed, both within and between chromosomal subsets. The data are consistent with the proposal that the contemporary tandem arrays on chromosomes 1, 11, 17, and X derive from a common multimeric repeat, consisting of one monomer each from the five homology groups. The sequence comparisons suggest that this pentameric repeat must have spread to these four chromosomal locations many millions of years ago, since which time evolution of the four, now chromosome-specific, alpha satellite subsets has been essentially independent.

Biological Evolution↗
PubMedDate not supplied

[Heterochromatin and chromosomal polymorphism].

The structure and sizes of different short deletions of Drosophila melanogaster X-chromosome: left break in the region of locus y-ac-sc, right break in different parts of the heterochromatic region (HR) near the centromere, of the nuclei of salivary glands and metaphases of oogonia were compared. It is suggested, that the development of large blocks of deoxynucleoproteins by a small number of loci of the HR, observed in mitotic chromosomes, is due to their ability to undergo additional replication, as it previously has been shown for locus bobbed. HR in human chromosomes provide high polymorphism of the chromosome sets. The same chromosome can appear in several varieties within a population. The varieties differ in sizes of the HR and their ability for intensive fluorescence. The appearance of these heredical varieties are conditioned by deletions, duplications and inversions in the HR. Studies on revealing boundaries between normal and pathological HR polymorphism of human chromosomes are in progress.

Animals↗
PubMed2003

Dimorphic Alu element located between the TFIIH and CDSN genes within the major histocompatibility complex.

Most Alu members of the large SINE family are fixed within the human genome but some younger mobile members are dimorphic, that is, they are either present or absent in the genome. Four different dimorphic Alu insertions have been identified and characterized previously within the class I region of the major histocompatibility complex (MHC). Here we report on (i) the identification and characterization of a new dimorphic Alu insertion, AluyTF, located between the transcription factor II H (TFIIH) and corneodesmosin (CDSN) genes within a region of the MHC that is telomeric of the human leukocyte antigen type B (HLA-B) locus and centromeric of the HLA-A locus, (ii) the haplotypic relationships between the AluyTF dimorphism and the HLA-A and -B loci within a panel of 48 IHW cell-lines representing at least 36 different HLA class I haplotypes, (iii) the AluyTF genotype, allele and haplotype frequencies present in the Australian caucasian and Japanese populations, and (iv) the frequency of association between the AluTF dimorphisms and HLA-A and -B alleles in 108 Australian caucasians and 99 Japanese. The AluyTF insertion was present at 27% in the IHW cell lines, and the gene frequency was 0.107 and 0.083 in the Australian caucasian and Japanese population, respectively. The Alu haplotype frequencies constructed from four different dimorphic Alu loci including AluyTF within the MHC were not significantly different (p > 0.05) between the two populations. There were no significant associations between the Alu insertion and either the HLA-A or -B alleles except for a moderately strong association with HLA-A29 in the Australians (71.7%). This polymorphic AluyTF element, along with the four other previously described polymorphic Alu elements within the class I region of the MHC, will be useful lineage and linkage markers in human population studies and for elucidating the evolution of HLA class I haplotypes.

Alu Elements↗
PubMed1997

Duplication and polymorphism in the MHC: Alu generated diversity and polymorphism within the PERB11 gene family.

The PERB11 gene family has at least five members within the telomeric region of the MHC. The PERB11.1 and PERB11.2 genes are approximately 40 kb and 160 kb centromeric of HLA-B, respectively. Using continuous genomic sequence encompassing PERB11.1 and PERB11.2, we have found a large (approximately 25 kb) segmental duplication extending beyond the genes themselves and other potential coding sequences. The major difference between the segments are large indels which are predominantly Alu sequences. The Alu sequences within the duplicated segments have created diversity via the internal and 3' poly A-rich region. A sequence comparison of an Alu sequence between two different human ancestral haplotypes shows a high level of polymorphism, particularly in the poly A-rich regions. This study characterises the Alu sequences within the peri-PERB11.1 and peri-PERB11.2 duplicated segments in relation to diversity and polymorphism and as evolutionary markers.

Base Sequence↗
PubMed1989

Comparison of the chromosomal localization of murine and human glucocerebrosidase genes and of the deduced amino acid sequences.

To study structure-function relationships and molecular evolution, we determined the nucleotide sequence and chromosomal location of the gene encoding murine glucocerebrosidase (glucosylceramidase; D-glucosyl-N-acylsphingosine glucohydrolase, EC 3.2.1.45). In the protein coding region of the murine cDNA, the nucleotide sequence and the corresponding deduced amino acid sequences were 82% and 86% identical to the respective human sequences. All five amino acids presently known to be essential for normal enzymatic activity were conserved between mouse and man. The murine enzyme had a single deletion relative to the human enzyme at amino acid number 273. One ATG translation initiation signal was present in the mouse sequence in contrast to the human sequence, where two start codons have been reported. Nucleotide sequencing of a clone derived from murine genomic DNA revealed that the murine signal for translation initiation was located in exon 2. The locations of all 10 introns were conserved among mouse and man. We mapped the genetic locus for glucocerebrosidase to mouse chromosome 3, at a position 7.6 +/- 3.2 centimorgans from the locus for the beta subunit of nerve growth factor. Comparison of linkage relationships in the human and murine genome indicates that these closely linked mouse genes are also syntenic on human chromosome 1 but in positions that span the centromere.

Amino Acid Sequence↗
PubMed2006

Chromosomal instability in Barrett's esophagus is related to telomere shortening.

Barrett's esophagus is a useful model for the study of carcinogenesis, as the metaplastic columnar epithelium that replaces squamous esophageal epithelium is at elevated risk for development of adenocarcinoma. We examined telomere length and chromosomal instability (CIN) in Barrett's esophagus biopsies using fluorescence in situ hybridization. To study CIN, we selected centromere and locus-specific arm probes to chromosomes 17/17p (p53), 11/11q (cyclin D1), and 9/9p (p16 INK4A), loci reported to be involved in early stages of Barrett's esophagus neoplasia. Telomere shortening was observed in Barrett's esophagus epithelium at all histologic grades, whereas CIN was highest in biopsies with dysplastic changes; there was, however, considerable heterogeneity between patients in each variable. Alterations on chromosome 17 were strongly correlated with telomere length (r = 0.55; P < 0.0001) and loss of the 17p arm signal was the most common event. CIN on chromosome 11 was also associated with telomere shortening (r =0.3; P = 0.05), although 11q arm gains were most common. On chromosome 9p, arm losses were the most common finding, but chromosome 9 CIN was not strongly correlated with telomere length. We conclude that CIN is related to telomere shortening in Barrett's esophagus but varies by chromosome. Whether instability is manifested as loss or gain seems to be influenced by the chromosomal loci involved. Because telomere shortening and CIN are early events in Barrett's esophagus neoplastic progression and are highly variable among patients, it will be important to determine whether they identify a subset of patients that is at risk for more rapid neoplastic evolution.

Adenocarcinoma↗
PubMed2000

A physical map, including a BAC/PAC clone contig, of the Williams-Beuren syndrome--deletion region at 7q11.23.

Williams-Beuren syndrome (WBS) is a developmental disorder caused by haploinsufficiency for genes in a 2-cM region of chromosome band 7q11.23. With the exception of vascular stenoses due to deletion of the elastin gene, the various features of WBS have not yet been attributed to specific genes. Although >/=16 genes have been identified within the WBS deletion, completion of a physical map of the region has been difficult because of the large duplicated regions flanking the deletion. We present a physical map of the WBS deletion and flanking regions, based on assembly of a bacterial artificial chromosome/P1-derived artificial chromosome contig, analysis of high-throughput genome-sequence data, and long-range restriction mapping of genomic and cloned DNA by pulsed-field gel electrophoresis. Our map encompasses 3 Mb, including 1.6 Mb within the deletion. Two large duplicons, flanking the deletion, of >/=320 kb contain unique sequence elements from the internal border regions of the deletion, such as sequences from GTF2I (telomeric) and FKBP6 (centromeric). A third copy of this duplicon exists in inverted orientation distal to the telomeric flanking one. These duplicons show stronger sequence conservation with regard to each other than to the presumptive ancestral loci within the common deletion region. Sequence elements originating from beyond 7q11.23 are also present in these duplicons. Although the duplicons are not present in mice, the order of the single-copy genes in the conserved syntenic region of mouse chromosome 5 is inverted relative to the human map. A model is presented for a mechanism of WBS-deletion formation, based on the orientation of duplicons' components relative to each other and to the ancestral elements within the deletion region.

Animals↗
PubMed1988

Karyotypic conservation in the mammalian order monotremata (subclass Prototheria).

The order Monotremata, comprising the platypus and two species of echidna (Australian and Nuigini) is the only extant representative of the mammalian subclass Prototheria, which diverged from subclass Theria (marsupials and placental mammals) 150-200 million years ago. The 2n = 63 male, 64 female karyotype (newly described here) of the Nuigini echidna is almost identical in morphology and G-band pattern to that of the Australian echidna, from which it diverged about a million years ago. The karyotype of the platypus (2n = 52) has several features in common with those of the echidna species; six pairs of large autosomes, many pairs of small (but not micro-) chromosomes, and a series of small unpaired chromosomes which form a multivalent at meiosis. Comparison of the G-band patterns of platypus and echidna autosomes reveals considerable homology. Chromomycin banding demonstrates GC-rich heterochromatin at the centromeres of many platypus and echidna chromosomes, and at the nucleolar organizing regions; some of this heterochromatin C-bands weakly in platypus (but not echidna) spreads. Late replication banding patterns resemble G-banding patterns and confirm the homologies between the species. Striking heteromorphism between chromosomes of some of the large autosomal pairs can be accounted for in the echidna by differences in amount of chromomycin-bright, late replicating heterochromatin. The sex chromosomes in all three species also bear striking homology, despite the difference in sex determination mechanism between platypus (XX/XY) and the echidna species (X1X1X2X2/X1X2Y). The platypus X and echidna X1 each represent about 5.8% of haploid chromosome length, and are G-band identical. Y chromosomes are similar between species, and are largely homologous to the X (or X1).

Animals↗
PubMed2002

Origin of an apparent B chromosome by mutation, chromosome fragmentation and specific DNA sequence amplification.

The present study documents the de novo origin of an apparent B chromosome in Plantago lagopus. The origin was associated with mutation (aneuploidy), chromosome fragmentation, specific DNA sequence amplification, addition of telomeric repeats, and centromeric misdivision. It originated in the progeny of trisome 2, from the excision of 5S rDNA and 18S, 5.8S, 25S rDNA sequences located on chromosome 2, and within a few generations acquired many characteristics of an apparent B chromosome. The B chromosome has preferential transmission through the male (41%, P<0.025) and female gametes (42%, P<0.01) but does not affect plant phenotype. The B chromosome is completely heterochromatic, has a functional centromere and does not pair at meiosis with any A chromosomes of the standard complement. Fluorescence in situ hybridization analysis showed that it arose from massive amplification of 5S rDNA sequences, has 18S, 5.8S, 25S rDNA sequences at the ends of both arms and telomeric repeats at both termini. Ag-NOR-banding and determination of the maximum number of nucleoli in interphase cells indicate that the nucleolar organizer regions at the ends of both arms of the B chromosome are active in organizing nucleoli. RNA blot analysis showed that the 5S rDNA sequences are not transcribed. To our knowledge, this is the first report that fully documents one of the mechanisms by which B chromosomes may arise in nature.

Base Sequence↗
PubMed2006

Analysis of kinesin motor function at budding yeast kinetochores.

Accurate chromosome segregation during mitosis requires biorientation of sister chromatids on the microtubules (MT) of the mitotic spindle. Chromosome-MT binding is mediated by kinetochores, which are multiprotein structures that assemble on centromeric (CEN) DNA. The simple CENs of budding yeast are among the best understood, but the roles of kinesin motor proteins at yeast kinetochores have yet to be determined, despite evidence of their importance in higher eukaryotes. We show that all four nuclear kinesins in Saccharomyces cerevisiae localize to kinetochores and function in three distinct processes. Kip1p and Cin8p, which are kinesin-5/BimC family members, cluster kinetochores into their characteristic bilobed metaphase configuration. Kip3p, a kinesin-8,-13/KinI kinesin, synchronizes poleward kinetochore movement during anaphase A. The kinesin-14 motor Kar3p appears to function at the subset of kinetochores that become detached from spindle MTs. These data demonstrate roles for structurally diverse motors in the complex processes of chromosome segregation and reveal important similarities and intriguing differences between higher and lower eukaryotes.

Chromosome Segregation↗
PubMed2006

Molecular refinement of gibbon genome rearrangements.

The gibbon karyotype is known to be extensively rearranged when compared to the human and to the ancestral primate karyotype. By combining a bioinformatics (paired-end sequence analysis) approach and a molecular cytogenetics approach, we have refined the synteny block arrangement of the white-cheeked gibbon (Nomascus leucogenys, NLE) with respect to the human genome. We provide the first detailed clone framework map of the gibbon genome and refine the location of 86 evolutionary breakpoints to <1 Mb resolution. An additional 12 breakpoints, mapping primarily to centromeric and telomeric regions, were mapped to approximately 5 Mb resolution. Our combined FISH and BES analysis indicates that we have effectively subcloned 49 of these breakpoints within NLE gibbon BAC clones, mapped to a median resolution of 79.7 kb. Interestingly, many of the intervals associated with translocations were gene-rich, including some genes associated with normal skeletal development. Comparisons of NLE breakpoints with those of other gibbon species reveal variability in the position, suggesting that chromosomal rearrangement has been a longstanding property of this particular ape lineage. Our data emphasize the synergistic effect of combining computational genomics and cytogenetics and provide a framework for ultimate sequence and assembly of the gibbon genome.

Animals↗
PubMed1998

Structural and evolutionary characterization of the human sorbitol dehydrogenase gene duplication.

We have established that two very closely homologous human sorbitol dehydrogenase sequences lie within 0.5 Mb on Chromosome 15. We have defined the relative orientation of SORD1 and SORD2 genes with respect to both the centromere and each other and established their exact chromosome location. In addition, we have identified polymorphic variants in the locus, which may be useful, in association studies to predict predisposition to clinical problems resulting from decreased conversion of cellular sorbitol to fructose. To define the evolutionary relationship of these human genes, SORD from the marmoset was also sequenced for comparison. Marmoset SORD, which appears to be a single gene in this species, shows significantly less homology with either SORD1 or SORD2 than they do with each other, suggesting that the human homologs represent a recent gene duplication event. A hypothesis is presented to explain the retention of the redundant SORD2 sequence in the human genome.

Amino Acid Sequence↗
PubMed2003

BAGE genes generated by juxtacentromeric reshuffling in the Hominidae lineage are under selective pressure.

In this paper, we show that the BAGE (B melanoma antigen) gene family was generated by chromosome rearrangements that occurred during the evolution of hominoids. An 84-kb DNA fragment derived from the phylogenetic 7q36 region was duplicated in the juxtacentromeric region of either chromosome 13 or chromosome 21. The duplicated region contained a fragment of the MLL3 gene, which, after juxtacentromeric reshuffling, generated the ancestral BAGE gene. Then, this ancestral gene gave rise to several independent genes through successive rounds of inter- and intrachromosome duplications. Comparison of synonymous and nonsynonymous mutations in putative coding regions shows that BAGE genes, but not the BAGE gene fragments, are under selective pressure. Our data strongly suggest that BAGE proteins have a function and that juxtacentromeric regions, whose plasticity is now largely proved, are not a simple junkyard of gene fragments, but may be the birth site of novel genes.

Animals↗
PubMed2002

Variation in recombination rate across the genome: evidence and implications.

Recent data from humans and other species provide convincing evidence of variation in recombination rate in different genomic regions. Comparison of physical and genetic maps reveals variation on a scale of megabases, with substantial differences between sexes. Recombination is often suppressed near centromeres and elevated near telomeres, but neither of these observations is true for all chromosomes. In humans, patterns of linkage disequilibrium and experimental measures of recombination from sperm-typing reveal dramatic hotspots of recombination on a scale of kilobases. Genome-wide variation in the amount of crossing-over may be due to variation in the density of hotspots, the intensity of hotspots, or both. Theoretical models of selection and linkage predict that genetic variation will be reduced in regions of low recombination, and this prediction is supported by data from several species. Heterogeneity in rates of crossing-over provides both an opportunity and a challenge for identifying disease genes: as associations occur in blocks, genomic regions containing disease loci may be identified with relatively few markers, yet identifying the causal mutations is unlikely to be achieved through associations alone.

Animals↗