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PubMed1994

Mismatch repair and cancer susceptibility.

Mismatch-repair systems have been identified in organisms ranging from Escherichia coli to humans. They can repair almost all DNA base pair mismatches as well as small insertion/deletion mismatches. Molecular and biochemical analyses have shown that the core components of eukaryotic mismatch-repair systems are highly homologous to their bacterial counterparts. In humans, defects in four mismatch-repair genes have been linked both to hereditary non-polyposis colorectal cancer and to spontaneous cancers that exhibit rearrangements in DNA containing simple repeat sequences.

DNA Repair↗

PubMed1993

Microsatellite polymorphisms and the genetic linkage map of the human genome.

The use of simple sequence repeats as polymorphic genetic markers has significantly facilitated the construction of reference maps of the human chromosomes and the mapping of mendelian genetic diseases. These markers display major advantages over other systems, including restriction fragment length polymorphisms and satellites, but also have some limitations.

Animals↗

PubMed1999

Genetic diversity in parthenogenetic triploid Paragonimus westermani.

Paragonimus westermani is a medically important foodborne trematode occurring throughout southeast Asia. We have used molecular techniques to test the hypothesis that the parthenogenetic triploid form of P. westermani has arisen only once. Sources of data for comparison were: (a) restriction fragment length polymorphisms (RFLPs) of ribosomal internal transcribed spacers (ITS); and (b) 'fingerprint' patterns observed when genomic digests were probed with simple sequence repeats (ATT)10 and (ATGT)7. In all cases there were distinct differences among triploid isolates from southwest Japan, northeast China and Korea. These findings are considered in the context of previous cytogenetic, allozyme, mitochondrial-RFLP and partial cytochrome c-oxidase subunit I (COI) sequence studies and indicate that triploid lineages may have arisen independently on more than one occasion. We favour this view. An alternative explanation is that the triploids did have a single origin, but that different clonal lineages have undergone subsequent mutations.

Animals↗

PubMed1998

Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant.

We describe three families with hypoglycemia caused by familial hyperinsulinism (HI) in whom vertical transmission of the disorder occurred, suggesting autosomal dominant (AD) inheritance. We therefore examined the relationship between the apparent AD disorder and the more common autosomal recessive (AR) form of HI, which has recently been linked to the sulfonylurea receptor on chromosome 11p15.1. The clinical features of the 11 patients with AD HI were milder than those seen in 14 patients with AR HI. Hypoglycemia was readily controlled with either diet alone or with diazoxide in 10 of 11 patients with AD HI but in none of those with the AR form. In one large pedigree, analysis of genomic DNA with polymorphic simple sequence repeat markers excluded linkage of AD HI to the SUR locus in a dominant manner. The possibility of linkage to the SUR locus could not be absolutely excluded in the two smaller pedigrees. None of the published mutations of the SUR gene identified in patients with AR HI were detected in the patients with the AD form. We conclude that the AD form of hyperinsulinism is phenotypically different from the AR variant. The identification of more families with this form of HI may make it possible to locate the responsible gene by the use of linkage analysis.

Adolescent↗

PubMed1997

Frequent alterations in gene expression in colon tumor cells of the microsatellite mutator phenotype.

Tumors of the microsatellite mutator phenotype (MMP) are characterized by the accumulation of many thousands of somatic mutations in tracts of simple repeated sequences or microsatellites. Using arbitrarily primed PCR fingerprinting of RNA (RAP-PCR), we have comparatively analyzed the overall gene expression patterns of several colorectal tumor cell lines with and without the MMP. A reproducible pattern of 30-40 main products was obtained for each fingerprint with a total of about 200 cell transcripts analyzed. Differences in RAP-PCR fingerprints were detected between these tumor cell lines. Some of these expression polymorphisms appeared to be specific for tumor cells of the MMP because they were present in two or more different MMP+ cell lines but absent in all MMP- cell lines analyzed. We also analyzed RNAs prepared from single cell clones isolated from these tumor cell lines. Reproducible differences in the fingerprints were detected between single cell clones from each of the cell lines analyzed. Examples of single cell clone-specific fingerprint differences from one of the MMP tumor cell lines were cloned and sequenced. Differential expression of some of these sequences was confirmed by Northern analysis using the cloned fragments as probes. Similar fingerprint alterations were also observed among single cell clones derived from single cell clones from mutator tumor cell lines, which appeared to exhibit higher clonal variation in gene expression compared with MMP- cells. The detection of inter- and intra-tumor alterations in gene expression by unbiased RAP-PCR show that these fluctuations occur with high frequency in tumor cells of the MMP. These results indicate that the profound genomic instability of tumor cells of the MMP is also reflected in a high incidence of alterations in their patterns of gene expression.

Blotting, Northern↗

PubMed1998

Neuronal and behavioral differences between Mus musculus domesticus (C57BL/6JBy) and Mus musculus castaneus (CAST/Ei).

Previous studies have demonstrated that classical inbred strains of laboratory mice do not exhibit large genetic distances when simple sequence repeats (SSRs) are used to test for their polymorphisms whereas mice from wild origin exhibit high polymorphisms (more than 90%) for these sequence when compared with classical inbred strains of laboratory mice. The difference between Mus musculus castaneus and C57BL/6J reaches 98% and F1s male and female are fertile. These two properties pave the way for gene mapping derivating segregating generations between these strains. The phenotypical characteristics of Mus musculus castaneus have not been investigated, unfortunately. The first screening of Mus musculus castaneus and C57BL/6By was carried out for sensorial and motor development, spontaneous behavior in new environment, paw preference, maternal behavior, aggression in two different situations and time to learn escape in a water maze. Morphometry of hippocampus and weight of the male reproductive organs for measures that have been reported to be correlated with several of the examined behavior are also reported. The authors tested also reactivity to one drug (beta-CCM) revealing seizure proneness. The two strains differ for 69% of the reported measures. Comparison to other strains for the same measures obtained in the laboratory for identical tests with mice reared in identical situations provided the mean to compare Mus musculus castaneus with a large set of more or less traditional mice. This strain has the most extreme position for 80% of the comparisons.

Aggression↗

PubMed1998

Organisation and informational content of the Theileria parva genome.

When compared with other Apicomplexan organisms, Theileria parva has an exceptionally small, 10-12 Mbp, genome. There are only 4 chromosomes, each in the Mbp range, and a complete physical map, based on SfiI linking data, is available for each one. A number of genes and cDNAs have been mapped to specific SfiI fragments. Telomeres consist of the simple repeat sequence typical of chromosomal ends but sub-telomeric homologies do not extend beyond 5 kbp. The only dispersed repetitive sequences identified to date are minisatellites, but these are found on a subset of SfiI fragments. There are clusters of distinct multicopy sequences which contain ORFs. However, the majority of parasite protein coding genes are present in a single copy. They have a compact structure, exhibit a bias in codon usage and non-translated regions are small. Introns, if present, are unusually short. Overall, the genome contains remarkably little repetitive, non-coding DNA. The parasite mitochondrial DNA is linear in structure, has a limited protein coding capacity and fragmented rRNA genes and its telomeres contain inverted repeat sequences.

Animals↗

PubMed2000

Preliminary profile of the Cryptosporidium parvum genome: an expressed sequence tag and genome survey sequence analysis.

Cryptosporidium parvum is a protozoan enteropathogen that infects humans and animals and causes a pronounced diarrheal disease that can be life-threatening in immunocompromised hosts. No specific chemo- or immunotherapies exist to treat cryptosporidiosis and little molecular information is available to guide development of such therapies. To accelerate gene discovery and identify genes encoding potential drug and vaccine targets we constructed sporozoite cDNA and genomic DNA sequencing libraries from the Iowa isolate of C. parvum and determined approximately 2000 sequence tags by single-pass sequencing of random clones. Together, the 567 expressed sequence tags (ESTs) and 1507 genome survey sequences (GSSs) totaled one megabase (1 mb) of unique genomic sequence indicating that approximately 10% of the 10.4 mb C. parvum genome has been sequence tagged in this gene discovery expedition. The tags were used to search the public nucleic acid and protein databases via BLAST analyses, and 180 ESTs (32%) and 277 GSSs (18%) exhibited similarity with database sequences at smallest sum probabilities P(N)< or =10(-8). Some tags encoded proteins with clear therapeutic potential including S-adenosylhomocysteine hydrolase, histone deacetylase, polyketide/fatty-acid synthases, various cyclophilins, thrombospondin-related cysteine-rich protein and ATP-binding-cassette transporters. Several anonymous ESTs encoded proteins predicted to contain signal peptides or multiple transmembrane spanning segments suggesting they were destined for membrane-bound compartments, the cell surface or extracellular secretion. One-hundred four simple sequence repeats were identified within the nonredundant sequence tag collection with (TAA)(> or =6)/(TTA)(> or =6) and (TA)(> or = 10)/(AT)(> or =10 ) being the most prevalent, occurring 40 and 15 times, respectively. Various cellular RNAs and their genes were also identified including the small and large ribosomal RNAs, five tRNAs, the U2 small nuclear RNA, and the small and large virus-like, double-stranded RNAs. This investigation has demonstrated that survey sequencing is an efficient procedure for gene discovery and genome characterization and has identified and sequence tagged many C. parvum genes encoding potential therapeutic targets.

Amino Acid Sequence↗

PubMed2000

Chasing behaviour genes into the next millennium.

Both linkage and association strategies are appropriate for the characterization of genes implicated in human behavioural dimensions and disorders. For the foreseeable future, association studies involving whole-genome scanning will combine strategies using both single-nucleotide and simple-sequence-repeat polymorphisms.

Genetic Linkage↗

PubMed1999

Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases.

Human bone marrow contains mesenchymal stem cells (MSCs) that can differentiate into various cells of mesenchymal origin. We developed an efficient method of isolating and culture expanding a homogenous population of MSCs from bone marrow and determined that MSCs express alpha-L-iduronidase, arylsulfatase-A and B, glucocerebrosidase, and adrenoleukodystrophy protein. These findings raised the possibility that MSCs may be useful in the treatment of storage disorders. To determine if donor derived MSCs are transferred to the recipients with lysosomal or peroxisomal storage diseases by allogeneic hematopoietic stem cell (HSC) transplantation, we investigated bone marrow derived MSCs of 13 patients 1-14 years after allogeneic transplantation. Highly purified MSCs were genotyped either by fluorescence in situ hybridization using probes for X and Y-chromosomes in gender mis-matched recipients or by radiolabeled PCR amplification of polymorphic simple sequence repeats. Phenotype was determined by the measurement of disease specific protein/enzyme activity in purified MSCs. We found that MSCs isolated from recipients of allogeneic HSC transplantation are not of donor genotype and have persistent phenotypic defects despite successful donor type hematopoietic engraftment. Whether culture expanded normal MSCs can be successfully transplanted into patients with storage diseases and provide therapeutic benefit needs to be determined.

Case-Control Studies↗

PubMed1999

Somatic mutation of the PTEN/MMAC1 gene in breast cancers with microsatellite instability.

The extent to which microsatellite instability (MI) contributes to the etiology of breast cancer has not been established in any large-scale studies. We examined 528 samples of tumor DNA from patients with primary breast cancer for MI, using 14 polymorphic CA-repeat markers. The frequency of MI in these tumors was unexpectedly low (10/528, 1.9%). The ten MI+ tumors were analyzed for mutations in five potential target genes that contain simple repeat sequences (TGFBIIR, IGF2R, hMSH6, BAX and PTEN/MMAC1). A somatic insertion of an extra adenine in the (A)6 region at codon 321-323 (exon 8) of the PTEN/MMAC1 gene, leading to a frame-shift, was identified in one tumor. This observation represented the first documented instance of PTEN/MMAC1 alteration in a MI+ primary breast cancer.

Breast Neoplasms↗

PubMed1998

Molecular-cytogenetic characterization of the Vicia faba genome--heterochromatin differentiation, replication patterns and sequence localization.

A comprehensive survey of the molecular-cytogenetic features of the Vicia faba chromosome complement (2n = 12) is given. It includes previous as well as new original data. Various Giemsa, restriction endonuclease and fluorochrome banding patterns, azacytidine-mediated segment extension, replication patterns, lateral A/T asymmetry and sequence localization data for tandemly arranged simple sequence repeats, dispersed repeats and coding sequences as well as histone acetylation patterns are considered. This allows not only to distinguish and characterize telomeres, subtelomeres, centromeres and the NOR, but also the structure of the 5S rRNA gene loci and two main types of interstitial heterochromatin. Additionally, it offers physical landmarks within euchromatic areas. Thus, the field bean genome, exemplified by the reconstructed karyotype ACB, belongs to the cytogenetically best investigated plant genomes.

Chromosome Banding↗

PubMed1989

Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops.

The telomeric ends of eukaryotic chromosomes are composed of simple repeating sequences in which one DNA strand contains short tracts of guanine residues alternating with short tracts of A/T-rich sequences. The guanine-rich strand is always oriented in a 5'-3' direction towards the end of the chromosome and is extended to produce a 3' overhang of about two repeating units in species where the telomeric terminus is known. This overhang has been implicated in the formation of several unusual intra-and intermolecular DNA structures, although none of these structures has been characterized fully. We now report that oligonucleotides encoding Tetrahymena telomeres dimerize to form stable complexes in solution. This salt-dependent dimerization is mediated entirely by the 3'-terminal telomeric overhang (TT-GGGGTTGGGG) and produces complexes in which the N7 position of every guanine in the overhangs is chemically inaccessible. We therefore propose that telomeric DNA dimerizes by hydrogen bonding between two intramolecular hairpin loops, to form antiparallel quadruplexes containing cyclic guanine base tetrads. These novel hairpin dimers may be important in telomere association and recombination and could also provide a general mechanism for pairing two double helices in other recombinational processes.

Animals↗

PubMed1999

A telomerase component is defective in the human disease dyskeratosis congenita.

The X-linked form of the human disease dyskeratosis congenita (DKC) is caused by mutations in the gene encoding dyskerin. Sufferers have defects in highly regenerative tissues such as skin and bone marrow, chromosome instability and a predisposition to develop certain types of malignancy. Dyskerin is a putative pseudouridine synthase, and it has been suggested that DKC may be caused by a defect in ribosomal RNA processing. Here we show that dyskerin is associated not only with H/ACA small nucleolar RNAs, but also with human telomerase RNA, which contains an H/ACA RNA motif. Telomerase adds simple sequence repeats to chromosome ends using an internal region of its RNA as a template, and is required for the indefinite proliferation of primary human cells. We find that primary fibroblasts and lymphoblasts from DKC-affected males are not detectably deficient in conventional H/ACA small nucleolar RNA accumulation or function; however, DKC cells have a lower level of telomerase RNA, produce lower levels of telomerase activity and have shorter telomeres than matched normal cells. The pathology of DKC is consistent with compromised telomerase function leading to a defect in telomere maintenance, which may limit the proliferative capacity of human somatic cells in epithelia and blood.

Adult↗

PubMed1995

Microsatellite instability in squamous cell carcinoma of the head and neck.

Genomic instability or microsatellite instability (MI) in simple repeated sequences was initially recognised in colonic carcinomas and subsequently in other tumours. MI has been associated with mutations in genes concerned with replication and DNA repair. We investigated 34 microsatellite markers in squamous cell carcinoma of the head and neck (SCCHN). Fifty-six tumours, were studied, of which 25 were investigated with ten or more microsatellite markers. In this study we consider two or more microsatellite alterations in a tumour to be diagnostic of MI. We demonstrated that 7/25 (28%) of the tumours had MI at two or more loci and three of these tumours exhibited evidence of 20 or more loci with MI. No correlations were found between MI and previous treatment, site, histological differentiation, positive nodes at pathology, a history of alcohol intake or survival. MI has been demonstrated in T1N0 stage tumours, indicating that these changes may occur early in the disease process. A negative correlation was found between MI and a history of smoking (P = 0.02). Two or more markers of MI were found in three of four non-smokers compared with one of 13 in the smoking group of patients, which suggests a novel mechanism of carcinogenesis in non-smokers.

Carcinoma, Squamous Cell↗

PubMed1992

Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland.

Linkage disequilibrium mapping in isolated populations provides a powerful tool for fine structure localization of disease genes. Here, Luria and Delbrück's classical methods for analysing bacterial cultures are adapted to the study of human isolated founder populations in order to estimate (i) the recombination fraction between a disease locus and a marker; (ii) the expected degree of allelic homogeneity in a population; and (iii) the mutation rate of marker loci. Using these methods, we report striking linkage disequilibrium for diastrophic dysplasia (DTD) in Finland indicating that the DTD gene should lie within 0.06 centimorgans (or about 60 kilobases) of the CSF1R gene. Predictions about allelic homogeneity in Finland and mutation rates in simple sequence repeats are confirmed by independent observations.

Base Sequence↗

PubMed2026

EST-SSR based genetic polymorphism among Lablab (Lablab purpureus L. Sweet) accessions contrasting for drought stress at seedling stage.

Lablab is a multipurpose and the most drought-tolerant (DT) crop compared with its relatives. Despite its potential, Lablab is still an underutilized crop with a lack of improved varieties in many countries. The DT (D349, D147, HA4, D363, D352, D359, D348, D311, D55 and D250) and drought-susceptible (DS) (D271, D66, D106, D6, D26, D255, D28, D186, D95, and D258) accessions were earlier identified according to their morphological and biochemical responses to moisture stress at the seedling stage. These accessions were used to establish genetic polymorphism among the accessions contrasting for drought stress based on the Expressed Sequence Tag-Simple Sequence Repeats (EST-SSR) markers. The CTAB protocol was employed for the genomic DNA extraction. After DNA quality and quantity verification, the PCR was conducted using 16 EST-SSR primer pairs specific to the Lablab. The products were separated through the horizontal polyacrylamide gel electrophoresis (hPAGE). Discriminating ability of the markers and primers' efficiency were evaluated based on various genetic parameters. Principal Coordinate Analysis (PCoA) was performed to estimate the distance matrix among the population and among the accessions. While cluster analysis was processed to trace the genetic relationship among the accessions, dendrogram was constructed to decipher their genetic relationship. Analysis of Molecular Variance (AMOVA) was finally computed to quantify the diversity level and genetic relationship among the population, and among the accessions. A low polymorphism (GD = 0.19) was observed between the DT and DS accessions, likely due to limited discriminatory power of the EST-SSR markers. However, the PCoA, cluster analysis and AMOVA identified DT (D147, HA4, and D349) and DS (D106, D95, and D271) accessions as strongly contrasting populations under drought stress, with D147, HA4, D349, D363, D359, D352, and D348 further recommended as DT accessions. Given the low polymorphism observed, further validation using more informative molecular markers and advanced genomic approaches is recommended to improve the identification of drought-tolerance genes and related QTLs to support Lablab breeding programs.

Expressed Sequence Tags↗

PubMed1997

Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23).

We report the cloning and characterization of the entire AFX gene which fuses to MLL in acute leukemias with a t(X;ll)(q13;q23). AFX consists of two exons and encodes for a protein of 501 amino acids. We found that normal B- and T-cells contain similar levels of AFX mRNA and that both the MLL/AFX as well as the AFX/MLL fusion transcripts are present in the cell line and the ANLL sample with a t(X;11)(q13;q23). The single intron of the AFX gene consists of 3706 nucleotides. It contains five simple sequence repeats with lengths of at least 12 bps, a chi-like octamer sequence (GCA/TGGA/TGG) and several immunoglobulin heptamer-like sequences (GATAGTG) that are distributed throughout the entire AFX intron sequence. In the KARPAS 45 cell line the breakpoints occur at nucleotides 2913/2914 of the AFX intron and at nucleotides 4900/4901 of the breakpoint cluster region of the MLL gene. The AFX protein belongs to the forkhead protein family. It is highly homologous to the human FKHR protein, the gene of which is disrupted by the t(2;13)(q35;q14), a chromosome rearrangement characteristic of alveolar rhabdomyosarcomas. It is noteworthy that the t(X;11)(q13;q23) in the KARPAS 45 cell line and in one acute nonlymphoblastic leukemia (ANLL) disrupts the forkhead domain of the AFX protein exactly at the same amino acids as does the t(2;13)(q35;q14) in case of the FKHR protein. In addition, the 5'-part of the AFX protein contains a conserved hexapeptide motif (QIYEWM) that is homologous to the functionally important conserved hexapeptide QIYPWM upstream of the homeobox domain in Hox proteins. This motif mediates the co-operative DNA binding of Pbx family members and Hox proteins and, therefore, plays an important role in physiologic and oncogenic processes. In acute leukemias with a t(X;11)(q13;q23), this hexapeptide motif is separated from the remaining forkhead domain within the AFX protein. The predicted amino acid sequence of AFX differs significantly from the partial AFX protein sequence published previously (Genes, Chromosomes and Cancer, 1994, 11, 79-84). This discrepancy can be explained by the occurrence of two sequencing errors in the earlier work at nucleotide number 783 and 844 (loss of a cytosine residue or guanosine residue, respectively) that lead to two reading frame shifts.

Acute Disease↗