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PubMed2003

Genomic background drives the divergence of duplicated amylase genes at synonymous sites in Drosophila.

In some Drosophila species, there are two types of greatly diverged amylase (Amy) genes (Amy clusters 1 and 2), each encoding active amylase isozymes. Cluster 1 is located at the middle of its chromosomal arm, and the region has a normal local recombination rate. However, cluster 2 is near the centromere, and this region is known to have a reduced recombination rate. Although nonsynonymous substitutions follow a molecular clock, synonymous substitutions were accelerated in cluster 2 after gene duplications. This resulted in a higher GC content at the third codon position (GC3) and codon usage bias in cluster 1, and lower GC3 content and codon usage bias in the cluster 2. However, no systematic difference in GC content was observed in the first and second codon positions or the 3'-flanking regions. Therefore, differences in local recombination rate rather than mutation bias might explain the divergence at synonymous sites between the two Amy clusters within species (Hill-Robertson effect). Alternatively, the different patterns and levels of expression between the two clusters may imply that the reduced expression level in cluster 2 caused by chromatin potentiation decreased the codon bias. Both of these hypotheses imply the importance of the genomic background as a driving force of divergence between non-tandemly duplicated genes.

3' Flanking Region↗
PubMed1986

The biological significance of variation in satellite DNA and heterochromatin in newts of the genus Triturus: an evolutionary perspective.

The functional and evolutionary significance of highly repetitive, simple sequence (satellite) DNA is analysed by examining available information on the patterns of variation of heterochromatin and cloned satellites among newts (family Salamandridae), and particularly species of the European genus Triturus. This information is used to develop a model linking evolutionary changes in satellite DNAs and chromosome structure. In this model, satellites accumulate initially in large tandem blocks around centromeres of some or all of the chromosomes, mainly by repeated chromosomal exchanges in these regions. Centromeric blocks later become broken up and dispersed by small, random chromosome rearrangements in these regions. They are dispersed first to pericentric locations and then gradually more distally into the chromosome arms and telomeres. Dispersal of a particular satellite is accompanied by changes in sequence structure (for example, base substitutions, deletions, etc.) and a corresponding decrease in its detectability at either the molecular or cytological level. On the basis of this model, observed satellites in newt species may be classified as 'old', 'young', or of 'intermediate' phylogenetic age. The functions and effects of satellite DNA and heterochromatin at the cellular and organismal levels are also discussed. It is suggested that satellite DNA may have an impact on cell proliferation through the effect of late-replicating satellite-rich heterochromatin on the duration of S-phase of the cell cycle. It is argued that even small alterations in cell cycle time due to changes in heterochromatin amount may have magnified effects on organismal growth that may be of adaptive significance.

Animals↗
PubMed2001

Karyotypes and Giemsa C-banding patterns of Zebrina pendula, Z. purpusii and Setcreasea purpurea, compared with those of Tradescantia ohiensis.

It has been proposed that the genera Zebrina and Setcreasea of the family Commelinaceae should be united and reunited, respectively, with the genus Tradescantia, mainly based on morphological studies. In the present study, karyotypes and Giemsa C-banding patterns in the root-tip cells of three Zebrina and two Setcreasea clones were analyzed, and were compared with those of a triploid Tradescantia clone. Z. pendula and Z. purpusii (both 2n = 24) were found to have similar karyotypes (4 M + 6 ST + 14 T; M = meta-, ST = subtelo-, T = telocentric chromosomes), while Z. pendula cv Quadricolor (2n = 23) had a unique karyotype (6 M + 5 ST + 11 T + 1 SA; SA = short acrocentric chromosome). The only clear difference between Z. pendula and Z. purpusii was that one and two subtelocentric chromosomes, respectively, had satellites at the short arms. Two clones of S. purpurea (2n = 24) had karyotypes (8 M + 8 M' + 8 SM; M' = nearly meta-, SM = submetacentric chromosomes) similar to each other. T. ohiensis (2n = 18) had a symmetric karyotype (9 M + 9 SM) consisting of larger chromosomes than S. purpurea. Many clear Giemsa C-bands were detected, in addition to centromeric bands in all chromosomes of all clones. Z. pendula and Z. purpusii commonly had single clear interstitial bands in eight telocentric chromosomes each, but they also had unique telomeric and other interstitial bands, respectively. Z. pendula cv Quadricolor had a unique banding pattern, i.e., satellite bands in the unique short chromosome, telomeric bands at the long arms of all metacentric chromosomes, and single interstitial bands in six telocentric chromosomes. Two clones of S. purpurea had telomeric bands at many chromosome arms and satellite bands in two nearly metacentric and one submetacentric chromosomes, but some differences were found between them. On the other hand, all the chromosomes of T. ohiensis had telomeric bands at both arms, and three submetacentric chromosomes had satellite bands. These result prove structural differentiation of chromosomes occurred among the clones, especially in Zebrina, and show that S. purpurea is relatively close to T. ohiensis, while Zebrina is obviously distant from the other two genera. Therefore, there remains a question cytologically at least for uniting Zebrina with Tradescantia.

Chromosome Banding↗
PubMed2000

The cytonuclear effects of facultative apomixis. II. Definitions and dynamics of disequilibria in tetraploid populations.

We develop a cytonuclear framework for tetraploid populations in which a diallelic nuclear marker exhibits tetrasomic inheritance. This system requires two separate parameterizations, with six cytonuclear disequilibria (nonrandom associations) in tetraploid individuals and four in their diploid gametes. Double reduction during meiosis adds further complexity by causing gametic output to vary with the distance of the nuclear locus from the centromere. We derive and analyze dynamical solutions for the disequilibria under generalized mixed mating, with any combination of apomixis, selfing, and outcrossing, with and without double reduction. As in comparable diploid systems, all disequilibria ultimately decay to zero, unless nuclear and cytoplasmic alleles are nonrandomly associated and outcrossing is absent, in which case permanent associations result. Selfing and apomixis retard the decay of disequilibria (or approach to equilibrium), and often to the same extent. In contrast, double reduction can accelerate the loss of tetraploid cytonuclear associations, but only negligibly in hybrid zones, and this loss is never faster than in diploids. Only in the absence of allelic associations or outcrossing is the asymptotic approach to equilibrium differentially affected by apomixis and selfing or slower under tetrasomic than disomic inheritance. To facilitate empirical applications, we also examine tetraploid hybrid zone dynamics and offer practical guidelines for experimental design and data analysis, showing how the consequences of the mating system alone provide a valuable baseline for drawing evolutionary inferences from the observed patterns of cytonuclear associations.

Evolution, Molecular↗
PubMed2004

Finishing the euchromatic sequence of the human genome.

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers approximately 99% of the euchromatic genome and is accurate to an error rate of approximately 1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human genome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead.

Amino Acid Sequence↗
PubMed1994

Diverse programs of ascus development in pseudohomothallic species of Neurospora, Gelasinospora, and Podospora.

Meiosis and ascospore development in the four-spored pseudohomothallic ascomycetes Neurospora tetrasperma, Gelasinospora tetrasperma, Podospora anserina, and P. tetraspora have been reexamined, highlighting differences that reflect independent origins of the four-spored condition in the different genera. In these species, as in the heterothallic eight-spored N. crassa, fusion of haploid nuclei is followed directly by meiosis and a postmeiotic mitosis. These divisions take place within a single unpartitioned giant cell, the ascus, which attains a length of > 0.1 mm before nuclei are enclosed by ascospore walls. Two basically different modes underlie the delivery of opposite mating type nuclei into each of the four ascospores in the different genera. In N. tetrasperma on the one hand, the mating type locus is closely centromere-linked. Mating types therefore segregate at the first meiotic division. The second-division spindles of N. tetrasperma overlap and are usually parallel to one another, in contrast to the their tandem arrangement in N. crassa. As a result, nonsister nuclei of opposite mating type are placed close together in each half-ascus and a pair is enclosed in each ascospore. In the Podospora and Gelasinospora species on the other hand, the second-division spindles are in tandem, with sister nuclei of opposite mating type associated as a pair in each half-ascus. It is established for P. anserina and inferred for P. tetraspora and G. tetrasperma that a single reciprocal crossing over almost always occurs in the mating type-centromere interval, ensuring that mating types segregate at the second meiotic division and that nuclei of opposite mating type are enclosed in each ascospore. Other differences are also seen that are less fundamental. Neurospora tetrasperma differs from the other species in the orientation of chromosomes and spindle pole body plaques at interphase II. Third-division spindles are oriented parallel to the ascus wall in Gelasinospora but across the ascus in Podospora and Neurospora. The two Podospora species differ from one another in nuclear behavior following mitosis in the young ascospores. In P. tetraspora, two of the four nuclei migrate into the tail cell, which degenerates, leaving one functional nucleus of each mating type. In P. anserina, by contrast, only one of the four nuclei moves into the tail cell, leaving the germinating ascospore with two functional nuclei of one mating type and one of the other. The pseudohomothallic condition with its heterokaryotic vegetative phase has significant consequences for both the individual organism and the breeding system. Genetic controls of development and recombination are complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Ascomycota↗
PubMed2002

Molecular fossils in the human genome: identification and analysis of the pseudogenes in chromosomes 21 and 22.

We have developed an initial approach for annotating and surveying pseudogenes in the human genome. We search human genomic DNA for regions that are similar to known protein sequences and contain obvious disablements (i.e., mid-sequence stop codons or frameshifts), while ensuring minimal overlap with annotations of known genes. Pseudogenes can be divided into "processed" and "nonprocessed"; the former are reverse transcribed from mRNA (and therefore have no intron structure), whereas the latter presumably arise from genomic duplications. We annotate putative processed pseudogenes based on whether there is a continuous span of homology that is >70% of the length of the closest matching human protein (i.e., with introns removed), or whether there is evidence of polyadenylation. We have applied our approach to chromosomes 21 and 22, the first parts of the human genome completely sequenced, finding 190 new pseudogene annotations beyond the 264 reported by the sequencing centers. In total, on chromosomes 21 and 22, there are 189 processed pseudogenes, 195 nonprocessed pseudogenes, and, additionally, 70 pseudogenic immunoglobulin gene segments. (Detailed assignments are available at http://bioinfo.mbb.yale.edu/genome/pseudogene or http://genecensus.org/pseudogene.) By extrapolation, we predict that there could be up to approximately 20,000 pseudogenes in the whole human genome, with a little more than half of them processed. We have determined the main populations and clusters of pseudogenes on chromosomes 21 and 22. There are notable excesses of pseudogenes relative to genes near the centromeres of both chromosomes, indicating the existence of pseudogenic "hot-spots" in the genome. We have looked at the distribution of InterPro families and Gene Ontology (GO) functional categories in our pseudogenes. Overall, the families in both processed and nonprocessed pseudogene populations occur according to a similar power-law distribution as that found for the occurrence of gene families, with a few big families and many small ones. The processed population is, in particular, enriched in highly expressed ribosomal-protein sequences (approximately 20%), which appear fairly evenly distributed across the chromosomes. We compared processed pseudogenes of different evolutionary ages, observing a high degree of similarity between "ancient" and "modern" subpopulations. This may be attributable to the consistently high expression of ribosomal proteins over evolutionary time. Finally, we find that chromosome 22 pseudogene population is dominated by immunoglobulin segments, which have a greater rate of disablement per amino acid than the other pseudogene populations and are also substantially more diverged.

Chromosome Mapping↗
PubMed2003

Myotonic dystrophy type 2: human founder haplotype and evolutionary conservation of the repeat tract.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19 (DM1) or 3 (DM2). In 2001, we demonstrated that DM2 is caused by a CCTG expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. To investigate the ancestral origins of the DM2 expansion, we compared haplotypes for 71 families with genetically confirmed DM2, using 19 short tandem repeat markers that we developed that flank the repeat tract. All of the families are white, with the majority of Northern European/German descent and a single family from Afghanistan. Several conserved haplotypes spanning >700 kb appear to converge into a single haplotype near the repeat tract. The common interval that is shared by all families with DM2 immediately flanks the repeat, extending up to 216 kb telomeric and 119 kb centromeric of the CCTG expansion. The DM2 repeat tract contains the complex repeat motif (TG)(n)(TCTG)(n)(CCTG)(n). The CCTG portion of the repeat tract is interrupted on normal alleles, but, as in other expansion disorders, these interruptions are lost on affected alleles. We examined haplotypes of 228 control chromosomes and identified a potential premutation allele with an uninterrupted (CCTG)(20) on a haplotype that was identical to the most common affected haplotype. Our data suggest that the predominant Northern European ancestry of families with DM2 resulted from a common founder and that the loss of interruptions within the CCTG portion of the repeat tract may predispose alleles to further expansion. To gain insight into possible function of the repeat tract, we looked for evolutionary conservation. The complex repeat motif and flanking sequences within intron 1 are conserved among human, chimpanzee, gorilla, mouse, and rat, suggesting a conserved biological function.

Adult↗
PubMed2001

Meiotic and mitotic instability of two EMS-produced centric fragments in the haplodiploid wasp Nasonia vitripennis.

Terminal deletions that result in chromosomal fragments with centromeres (centric fragments) are relatively easy to generate and study in the haplodiploid insect Nasonia. We investigated the transmission stability of two chromosomal fragments generated by chemical mutagenesis. Visible mutations at the R locus (peach-233 and St-DR) and a linked body-colour mutant (purple) were used to track transmission of the centric fragments (which lack the purple locus and are wild-type at the R locus). Transmission rates in meiotic oogenesis were low (medians 0.15-0.18) and comparable to previous data on centric fragments in this species. The homologous chromosome genetic background strongly affected meiotic stability of one centric fragment (CF2) but not the other (CF1). Specifically, in peach/scarlet R locus heterozygous females, CF2 showed a normal segregation proportion with the chromosome bearing the scarlet allele (0.16), but near complete failure to segregate with peach (0.0002). Data show that this is due to loss of CF2 in eggs receiving peach, rather than to preferential segregation of CF2 with scarlet or mortality of CF2-bearing males. CF1 shows typical segregation ratios with both chromosomes. We hypothesize that deletions (or rearrangements) associated with the peach-233 mutant inhibit proper pairing and segregation of CF2. Consistent with the model, CF2 did segregate with chromosomes that had undergone recombination between peach and purple (a body-colour mutation 10 cM from peach), indicating that the domains inhibiting segregation are closely linked to peach. Mitotic instability also differed between the two fragments; reduced mitotic stability may relate to absence of telomeres on these centric fragments. Given the relative ease of generating and tracking terminal deletions in Nasonia, we propose this as a good system for studying mitotic and meiotic stability of centric fragments. Finally, results are discussed in relation to the evolution of B chromosomes from centric fragments.

Animals↗
PubMed2003

A high-density genetic recombination map of sequence-tagged sites for sorghum, as a framework for comparative structural and evolutionary genomics of tropical grains and grasses.

We report a genetic recombination map for Sorghum of 2512 loci spaced at average 0.4 cM ( approximately 300 kb) intervals based on 2050 RFLP probes, including 865 heterologous probes that foster comparative genomics of Saccharum (sugarcane), Zea (maize), Oryza (rice), Pennisetum (millet, buffelgrass), the Triticeae (wheat, barley, oat, rye), and Arabidopsis. Mapped loci identify 61.5% of the recombination events in this progeny set and reveal strong positive crossover interference acting across intervals of </=50 cM. Significant variations in DNA marker density are related to possible centromeric regions and to probable chromosome structural rearrangements between Sorghum bicolor and S. propinquum, but not to variation in levels of intraspecific allelic richness. While cDNA and genomic clones are similarly distributed across the genome, SSR-containing clones show different abundance patterns. Rapidly evolving hypomethylated DNA may contribute to intraspecific genomic differentiation. Nonrandom distribution patterns of multiple loci detected by 357 probes suggest ancient chromosomal duplication followed by extensive rearrangement and gene loss. Exemplifying the value of these data for comparative genomics, we support and extend prior findings regarding maize-sorghum synteny-in particular, 45% of comparative loci fall outside the inferred colinear/syntenic regions, suggesting that many small rearrangements have occurred since maize-sorghum divergence. These genetically anchored sequence-tagged sites will foster many structural, functional and evolutionary genomic studies in major food, feed, and biomass crops.

Biological Evolution↗
PubMed2001

A novel human gene (SARM) at chromosome 17q11 encodes a protein with a SAM motif and structural similarity to Armadillo/beta-catenin that is conserved in mouse, Drosophila, and Caenorhabditis elegans.

A novel human gene, SARM, encodes the orthologue of a Drosophila protein (CG7915) and contains a unique combination of the sterile alpha (SAM) and the HEAT/Armadillo motifs. The SARM gene was identified on chromosome 17q11, between markers D17S783 and D17S841 on BAC clone AC002094, which also included a HERV repeat and keratin-18-like, MAC30, TNFAIP1, HSPC017, and vitronectin genes in addition to three unknown genes. The mouse SARM gene was located on a mouse chromosome 11 BAC clone (AC002324). The SARM gene is 1.8 kb centromeric to the vitronectin gene, and the two genes share a promoter region that directs a high level of liver-specific expression of both the SARM and the vitronectin genes. In addition to the liver, the SARM gene was highly expressed in the kidney. A 0.4-kb antisense transcript was coordinately expressed with the SARM gene in the kidney and liver, while in the brain and malignant cell lines, it appeared independent of SARM gene transcription. The SARM gene encodes a protein of 690 amino acids. Based on amino acid sequence homology, we have identified a SAM motif within this derived protein. Structure modeling and protein folding recognition studies confirmed the presence of alpha-alpha right-handed superhelix-like folds consistent with the structure of the Armadillo and HEAT repeats of the beta-catenin and importin protein families. Both motifs are known to be involved in protein-protein interactions promoting the formation of diverse protein complexes. We have identified the same conserved SAM/Armadillo motif combination in the mouse, Drosophila, and Caenorhabditis elegans SARM proteins.

Amino Acid Motifs↗
PubMed2001

Ts65Dn -- localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome.

Fluorescent in situ hybridization (FISH) -- using mouse chromosome paints, probes for the mouse major centromeric satellite DNA, and probes for genes on chromosomes (Chr) 16 and 17 -- was employed to locate the breakpoint in a translocation used to produce a mouse model for Down syndrome. The Ts65Dn trisomy is derived from the reciprocal translocation T(16;17)65Dn. The Ts65Dn mouse carries a marker chromosome containing the distal segment of Chr 16, a region that shows linkage conservation with human Chr 21, and the proximal end of Chr 17. This chromosome confers trisomy for most of the genes in the Chr 16 segment and Ts65Dn mice show many of the phenotypic features characteristic of Down syndrome. We used FISH on metaphase chromosomes from translocation T65Dn/+ heterozygotes and Ts65Dn mice to show that the Chr 17 breakpoint is distal to the heterochromatin of Chr 17, that the Ts65Dn marker chromosome contains a small portion of Chr 17 euchromatin, that the Chr 16 breakpoint lies between the Ncam2 and Gabpa/App genes, and that the Ts65Dn chromosome contains >80% of the human Chr 21 homologs. The significance of this finding is discussed in terms of the utility of this mouse model.

Animal Diseases↗
PubMed2001

The genes encoding E-selectin (SELE) and lymphotactin (SCYC1) lie on separate chicken chromosomes although they are closely linked in human and mouse.

Three differentially expressed selectin genes (SELE, SELP, and SELL), important in the initial stages of leukocyte extravasation, have been reported in mammals. All three genes map close to the chemokine SCYC1 (small inducible cytokine subfamily C, member 1) in a large conserved chromosomal segment that extends from RXRG (retinoic acid receptor, gamma) to TNNT2 (troponin T2) on Chromosome (Chr) 1 in both human and mouse. In the mouse, we demonstrate that Sele is flanked by Prrx1 (paired-related homeobox gene 1) and Scyc1 and define the order of, and distances between, loci as centromere-Prrx1-(0.7+/-0.7 cM)-Sele-(1.2+/-0.9 cM)-Scyc1-telomere. In the chicken, we isolated BAC clones containing PRRX1, SELE, and SCYC1 and positioned them by fluorescent in situ hybridization. SELE and PRRX1 mapped to the short arm of chicken Chr 8 and SCYC1 mapped to the region equivalent to 1q11-1q13 on the long arm of chicken Chr 1. The location of SELE on chicken Chr 8 was independently established by linkage analysis of COM0185, an (AT)16 microsatellite locus identified in a BAC clone that contained SELE. COM0185 was linked to several loci that mapped to one end of chicken Chr 8, with the order of loci, and genetic distances (in cM) between them defined as MSU0435, MSU0325-(7.8+/-3.7)-COM0185-(5.8+/-3.2)-ROS0338-(9.6+/-4.0)-ABR0322-(3.8+/-2.6)-GLUL. We have therefore positioned an evolutionary breakpoint in mammals and chickens between SELE and SCYC1. Furthermore, comparative mapping analysis of the RXRG-TNNT2 chromosomal segment that is conserved on human and mouse Chr 1 indicates that it is divided into four segments in the chicken, each of which maps to a different chromosome.

Animals↗
PubMed1995

Localized gastric non-Hodgkin's lymphoma of high-grade malignancy in patients with pre-existing chronic lymphocytic leukemia or immunocytoma.

Analyses for clonality in cases of Richter's syndrome have provided evidence for a clonal evolution of high-grade lymphoma in most patients, while in others an independent cellular clone seems to exist in the secondary neoplasm. Richter's syndrome with an isolated high-grade lymphoma of the stomach has been rarely reported in patients with pre-existing B cell chronic lymphocytic leukemia (CLL). We investigated four cases of CLL or lymphoplasmacytoid immunocytoma (LPIC) with development of a localized high-grade B cell lymphoma in the stomach. Southern blotting showed different rearrangements of the immunoglobulin light and heavy chain genes in the tumor cells of the low-grade lymphoma and the gastric tumor in two cases. Comparison of the DNA sequences of the CDR3 region of the immunoglobulin genes revealed different clones in another case. By means of chromosomal in situ hybridization, trisomy 3 was detected in two cases of high-grade lymphoma of the stomach, but not in the cells of the associated low-grade tumor. Our findings indicate that high-grade non-Hodgkin's lymphomas arising localized in the stomach of patients with CLL or immunocytoma are not clonally related to the pre-existing low-grade lymphoma and, therefore indeed, present true secondary neoplasms.

Aged↗
PubMed2001

A novel human homolog of eosinophil major basic protein.

Eosinophil major basic protein (MBP) contributes to host defense and disease pathophysiology. Chromosome 11 contains the genes for human MBP1 (hMBP1) and a second novel MBP, hMBP2, in the centromere to 11q12 region. Interestingly, greater similarity exists between human and murine MBP1 and MBP2 orthologs, respectively, than between hMBP1 and hMBP2, suggesting a gene duplication event prior to the divergence of humans and mice. There is abundant mRNA for hMBP1 in both bone marrow (eosinophils and basophils) and placenta, but hMBP2 mRNA is present only in bone marrow (eosinophils). Comparison of proximal promoters for hMBP2, hMBP1, and murine MBP1 (mMBP1) shows a conserved GATA transcription factor binding site (functionally active in hMBP1). However, whether a C/EBP binding site common to hMBP1 and mMBP1 is functionally conserved in hMBP2 remains unresolved. Similarly, the role of conserved putative IK2 and STAT binding sites in MBP transcriptional control remains unknown. Like hMBP1, hMBP2 is in the eosinophil secondary granule. However, hMBP2 is two-fold less positively charged than hMBP (+8 versus +16 at neutral pH), and this difference may explain hMBP2's similar, but often less potent, in vitro biological activities. Overall, while conservation of hMBP2's amino acid sequence (63% identity with hMBP1) suggests a common function(s) with hMBP1, hMBP2's substantially reduced charge and the existence of the similar mMBP2 argue for additional, unique functions for hMBP2.

Amino Acid Sequence↗
PubMed2001

Evolutionary breakpoints on human chromosome 21.

Segments of the long arm of human chromosome 21 are conserved, centromere to telomere, in mouse chromosomes 16, 17, and 10. There have been 28 genes identified in human chromosome 21 between TMPRSS2, whose orthologue is the most distal gene mapped to mouse chromosome 16, and PDXK, whose orthologue is the most proximal gene mapped to mouse chromosome 10. Only 6 of these 28 genes have been mapped in mouse, and all are located on chromosome 17. To better define the chromosome 17 segment and the 16 to 17 transition, we used a combination of mouse radiation hybrid panel mapping and physical mapping by mouse: human genomic sequence comparison. We have determined the mouse chromosomal location of an additional 12 genes, predicted the location of 7 more,and defined the endpoints of the mouse chromosome 17 region. The mouse chromosome 16/chromosome 17 evolutionary breakpoint is between human genes ZNF295 and UMODL1, showing there are seven genes in the chromosome 16 segment distal to Tmprss2. The chromosome 17/chromosome 10 breakpoint seems to have involved a duplication of the gene PDXK, which on chromosome 21 lies immediately distal to the KIAA0179 gene. These data suggest that there may be as few as 21 functional genes in the mouse chromosome 17 segment. This information is important for defining existing and constructing more complete mouse models of Down syndrome.

Animals↗
PubMed1994

Fluorescence in situ hybridization improves the detection of monosomy 7 in myelodysplastic syndromes.

We performed conventional cytogenetic (CC) and interphase fluorescence in situ hybridization (FISH) analysis with an alpha satellite chromosome 7 specific DNA centromeric probe (p alpha 7t1) on bone marrow material prepared for CC in 11 controls and 80 cases of myelodysplastic syndromes (MDS). In controls, a mean of 4.3 +/- 1% of the 700 cells examined showed only one FISH signal for chromosome 7, and the finding of > 6.3% (mean +2 standard deviations) of cells with one FISH signal was considered to indicate the presence of a clone with -7. By CC, clonal -7 was found in 11 patients, whereas two patients had -7 in only one mitose (non-clonal -7). In eight of the 11 cases of clonal -7 by CC, interphase FISH confirmed -7. In the remaining three patients, 5.1%, 6.3% and 18.4% respectively of the cells had one signal. Those three patients had, in addition to -7 by CC, a marker chromosome which was shown to be constituted of chromosome 7 pericentromeric material by FISH analysis on metaphase spreads (metaphase FISH). Of the two patients with non-clonal -7 by CC, one had a -7 clone by interphase FISH whereas the other patient had normal FISH results. Five of the 67 patients with no -7 mitose by CC had clonal -7 by interphase FISH, with one chromosome 7 signal in 14.4 to 39% of the cells examined. At least three mitoses with -7 were found in two of them by metaphase FISH. Three of the five patients were reexamined 12 to 17 months later: CC and metaphase FISH found no -7, whereas interphase FISH still showed a -7 clone. Three of the patients with clonal -7 by CC and by FISH were reexamined in complete hematological remission after intensive therapy. CC found no -7 and interphase FISH was normal in all three patients. Our findings suggest that interphase FISH may improve the detection of -7 in MDS. Conventional cytogenetics should still be performed in parallel to FISH, however, because of possible false negative FISH results when a pericentromeric chromosome 7 marker is present in patients with -7. Larger numbers of cases with minor -7 clones, detectable by FISH only, and longer follow-up in those cases will be necessary to determine the significance of this finding, the evolution of this minor clone, and the outcome of the patients.

Bone Marrow↗
PubMed1985

Evolution of primary Raynaud's phenomenon (Raynaud's disease) to connective tissue disease.

Eighty-seven patients diagnosed as having primary Raynaud's phenomenon (Raynaud's disease) were reexamined after this symptom had been present for a mean of 8.8 years (range 2.0-34.5). One or more additional clinical feature(s) suggesting an underlying connective tissue disease were found in 12 patients (14%) at first evaluation, and in 23 (26%) by the last evaluation. The most frequent findings were puffy fingers (10 patients), digital tip pitting scars (8 patients), and digital tip ulcerations (6 patients). Distal esophageal hypomotility and/or decreased pulmonary diffusing capacity for carbon monoxide were found in 12 patients. Only 4 individuals (5%) developed clear evidence of a connective tissue disease, and in all cases, the diagnosis was the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) syndrome variant of systemic sclerosis. This condition became obvious 8-17 years after the onset of Raynaud's phenomenon. One or more serologic test values were initially abnormal in 2 of these CREST syndrome patients, as well as in 12 patients who continued to have primary Raynaud's phenomenon at the last evaluation. The combination of puffy fingers, digital pitting scars, and serum anticentromere antibody, all consistent with CREST syndrome, occurred in a small group of patients. None of the 78 patients whose serologic tests were repeated during followup had a change in the serologic profile. These results suggest that only a small proportion of patients with primary Raynaud's phenomenon develop one of the connective tissue diseases during the first decade after onset. When such a disorder does appear, systemic sclerosis with the CREST syndrome variant is the most likely eventual diagnosis.

Adolescent↗