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PubMed2000

Delineation of genetic zones in the European Norway spruce natural range: preliminary evidence.

We applied geostatistics to previously reported chloroplast simple sequence repeats (cpSSR) haplotype frequency data from 95 European Norway spruce populations to provide preliminary evidence about the following issues: (i) delineation of genetically homogeneous regions ('genetic zones'); (ii) prediction of their haplotype frequencies and definition of related criteria to be applied for provenance identification and certification of seedlots; (iii) identification of putative allochthonous stands; and (iv) construction of a continental-scale 'availability map' of the intraspecific biodiversity for Norway spruce. Direct evidence of large-scale geographical structure over the European natural range was obtained, detecting both geographical clines and stationary patterns. The increase of the mean genetic divergence by geographical distance (up to approximately 1800 km apart) provided a strong hint that geographical distance is a major factor of differentiation in Norway spruce. Haplotype frequency surfaces were obtained by applying ordinary kriging to sampling frequency data. Cluster analysis carried out on haplotype frequency surfaces revealed a fair discrimination among 16 genetic zones, with an accuracy of 0.916. Dendrogram analysis carried out on the predicted mean haplotype frequency confirmed a fairly good separability of the genetic zones detected. Reclassification of populations by discriminant analysis confirmed the robustness of the genetic subdivision obtained. Combining the information from discriminant analysis and cross-validation of sampling points, three populations likely to be of nonlocal origin were identified. The application of geostatistical analysis to genetic marker data is discussed in relation to breeding activities and to the formulation of appropriate conservation strategies.

Cluster Analysis↗
PubMed2001

Geographic pattern of genetic variation in Pinus resinosa: area of greatest diversity is not the origin of postglacial populations.

Genetic diversity is low in natural populations of red pine, Pinus resinosa, a species that has a vast range across north-eastern North America. In this study, we examined 10 chloroplast microsatellite or simple sequence repeats (cpSSR) loci in 136 individuals from 10 widespread populations. Substantial variation for the cpSSR loci was observed in the study populations. The contrast with red pine's lack of variation for other types of loci is likely to be due to the higher mutation rates typical of SSR loci. The amount of variation is lower than that generally found for cpSSR loci in other pine species. In addition, the variation exhibits a striking geographical pattern. Most of the genetic diversity is among populations, with little within populations, indicating substantial isolation of and genetic drift within many populations in the southern half of the species distribution. The greatest diversity now occurs in the north-eastern part of New England, which is especially intriguing because this entire area was glaciated. Thus the centre of diversity cannot be the origin of postglacial populations, rather it is likely caused by admixture, most probably because of influences from two separate refugia. Furthermore, the pattern indicates that the spread of red pine since the last glaciation is rather more complex than usually described, and it likely includes more than one refugia, complex migration routes, and postglacial-retreat isolation and genetic drift among shrinking populations in regions of the present southern range.

Chloroplasts↗
PubMed2001

Microsatellite diversity associated with ecological factors in Hordeum spontaneum populations in Israel.

Microsatellite diversity at 18 loci was analysed in 94 individual plants of 10 wild barley, Hordeum spontaneum (C. Koch) Thell., populations sampled from Israel across a southward transect of increasing aridity. Allelic distribution in populations was not distributed randomly. Estimates of mean gene diversity were highest in stressful arid-hot environments. Sixty-four per cent of the genetic variation was partitioned within populations and 36% between populations. Associations between ecogeographical variables and gene diversity, H(e), were established in nine microsatellite loci. By employing principle component analysis we reduced the number of ecogeographical variables to three principal components including water factors, temperature and geography. At three loci, stepwise multiple regression analysis explained significantly the gene diversity by a single principal component (water factors). Based on these observations it is suggested that simple sequence repeats are not necessarily biologically neutral.

Ecology↗
PubMed2002

Maternal inheritance of a chloroplast microsatellite marker in controlled hybrids between Fraxinus excelsior and Fraxinus angustifolia.

Restriction fragment length polymorphism, polymerase chain reaction-restriction fragment length polymorphism and simple sequence repeat (SSR or microsatellites) analyses were performed to detect chloroplast DNA polymorphisms between two ash species, Fraxinus excelsior and F. angustifolia. Only one SSR locus was found to be polymorphic, confirming the very close relatedness of these species. Inheritance of this marker was studied in hybrids obtained from controlled crosses between the two tree species. Results indicated, for the first time in Oleaceae, that chloroplasts are maternally inherited. This chloroplast SSR marker is now used concomitantly with nuclear markers to analyse ash populations in sympatric areas.

Chimera↗
PubMed2000

Identification of new single-nucleotide polymorphisms in the thrombin receptor gene and their effects on coronary artery diseases in Koreans.

1. The thrombin receptor (the protease-activated receptor-1; PAR-1) is located on vascular cells as well as platelets and may play important roles in atherosclerotic disorders, such as coronary artery diseases (CAD). In the present study, we searched for genetic polymorphisms of the PAR-1 gene and evaluated their effects on CAD by association analysis. 2. We identified six polymorphisms in the 5'-untranslated region of the PAR-1 gene by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP); five single-nucleotide polymorphisms (SNP) at -2355 (A to G), -2333 (T to G), -1428 (G to A), -1071 (C to T) and -561 (A to G) and a simple sequence repeat (SSR) polymorphism between -1935 and -1841. Five SNP were in strong linkage disequilibrium with each other to make three major haplotypes, the frequency of which was over 90% of all possible haplotypes. 3. For association analysis, 150 patients who had CAD (CAD+), 58 subjects who had no stenosis on the coronary angiogram and 186 reference subjects who had no clinical evidence of CAD were used from the Korean population. The genotype frequencies of the SNP were in Hardy-Weinberg equilibrium, except A-561G in CAD+. The association of these SNP as well as of the SSR with CAD was not evident. This result suggests no major roles of the PAR-1 gene in CAD in Koreans.

5' Untranslated Regions↗
PubMed2000

Host genes controlling the susceptibility and resistance to squamous cell carcinoma of the tongue in a rat model.

Development of tongue carcinoma (TC) in rats by 4-nitroquinoline 1-oxide (4NQO), a potent carcinogen, is under host genetic control. The inbred Dark-Agouti (DA) strain rats showed a much higher susceptibility to TC than the Wistar-Furth (WF) strain. The author's previous study on crosses between two strains postulated a susceptibility gene in DA and a resistance gene in WF rats. This hypothesis was confirmed by the genetic analysis of the backcrosses to either parent and F2 with a simple sequence repeat polymorphism analysis. In the crosses between the DA and WF strains of rats, two major independently segregating host loci that influenced the cancer development by application of 4NQO positively or negatively were identified and mapped. DA rats had a semidominant susceptibility gene, Stc1, closely linked with D19Mit9 on chromosome 19, which was on the segment syntenic to human chromosome 16. In contrast, WF rats had a semidominant resistance gene, Rtc1, closely linked with D1Rat320 on chromosome 1, which is syntenic to human chromosome 11. The presence of other susceptibility and resistance genes on some chromosomes of both DA and WF rats was suspected, and they will be clarified in the near future. These findings provide powerful evidence that chemically induced tongue carcinogenesis is a multigenetic event.

4-Nitroquinoline-1-oxide↗
PubMed2000

Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution.

A remarkable instability at simple repeated sequences characterizes gastrointestinal cancer of the microsatellite mutator phenotype (MMP). Mutations in the DNA mismatch repair gene family underlie the MMP, a landmark for hereditary nonpolyposis colorectal cancer. These tumors define a distinctive pathway for carcinogenesis because they display a particular spectrum of mutated cancer genes containing target repeats for mismatch repair deficiency. One such gene is BAX, a proapoptotic member of the Bcl-2 family of proteins, which plays a key role in programmed cell death. More than half of colon and gastric cancers of the MMP contain BAX frameshifts in a (G)(8) mononucleotide tract. However, the functional significance of these mutations in tumor progression has not been established. Here we show that inactivation of the wild-type BAX allele by de novo frameshift mutations confers a strong advantage during tumor clonal evolution. Tumor subclones with only mutant alleles frequently appeared after inoculation into nude mice of single-cell clones of colon tumor cell lines with normal alleles. In contrast, no clones of BAX-expressing cells were found after inoculation of homozygous cell clones without wild-type BAX. These results support the interpretation that BAX inactivation contributes to tumor progression by providing a survival advantage. In this context, survival analyses show that BAX mutations are indicators of poor prognosis for both colon and gastric cancer of the MMP.

Animals↗
PubMed2001

Structure of linkage disequilibrium and phenotypic associations in the maize genome.

Association studies based on linkage disequilibrium (LD) can provide high resolution for identifying genes that may contribute to phenotypic variation. We report patterns of local and genome-wide LD in 102 maize inbred lines representing much of the worldwide genetic diversity used in maize breeding, and address its implications for association studies in maize. In a survey of six genes, we found that intragenic LD generally declined rapidly with distance (r(2) < 0.1 within 1500 bp), but rates of decline were highly variable among genes. This rapid decline probably reflects large effective population sizes in maize during its evolution and high levels of recombination within genes. A set of 47 simple sequence repeat (SSR) loci showed stronger evidence of genome-wide LD than did single-nucleotide polymorphisms (SNPs) in candidate genes. LD was greatly reduced but not eliminated by grouping lines into three empirically determined subpopulations. SSR data also supplied evidence that divergent artificial selection on flowering time may have played a role in generating population structure. Provided the effects of population structure are effectively controlled, this research suggests that association studies show great promise for identifying the genetic basis of important traits in maize with very high resolution.

Chromosome Mapping↗
PubMed1993

Evidence for linkage of the apolipoprotein A-II locus to plasma apolipoprotein A-II and free fatty acid levels in mice and humans.

Although it has been hypothesized that the synteny between mouse and human genes provides an approach to the localization of genes that determine quantitative traits in humans, this has yet to be demonstrated. We tested this approach with two quantitative traits, plasma apolipoprotein A-II (apoAII) and free fatty acid (FFA) levels. ApoAII is the second most abundant protein of high density lipoprotein particles, but its function remains largely unknown. We now show that, in a backcross between strains Mus spretus and C57BL/6J, apoAII levels correlate with plasma FFA concentrations on both chow (P < 0.0001) and high-fat (P < 0.0003) diets and that apoAII levels are linked to the apoAII gene (P < 0.0002). To test whether variations of the apoAII gene influence plasma lipid metabolism in humans, we studied 306 individuals in 25 families enriched for coronary artery disease. The segregation of the apoAII gene was followed by using an informative simple sequence repeat in the second intron of the gene and two nearby genetic markers. Robust sib-pair linkage analysis was performed on members of these families using the SAGE linkage programs. The results suggest linkage between the human apoAII gene and a gene controlling plasma apoAII levels (P = 0.03). Plasma apoAII levels were also significantly correlated with plasma FFA levels (P = 0.007). Moreover, the apoAII gene exhibited linkage with a gene controlling FFA levels (P = 0.003). Evidence for nonrandom segregation was seen with markers as far as 6-12 centimorgans from the apoAII structural locus. These data provide evidence, in two species, that the apoAII gene is linked to a gene that controls plasma apoAII levels and that apoAII influences, by an unknown mechanism, plasma FFA levels. The results illustrate the utility of animal studies for analysis of complex traits.

Animals↗
PubMed1994

Extraordinarily polymorphic microsatellite DNA in barley: species diversity, chromosomal locations, and population dynamics.

This study was undertaken to assess the extent of genetic variation in barley simple sequence repeats (SSRs) and to study the evolutionary dynamics of SSR alleles. SSR polymorphisms were resolved by the polymerase chain reaction with four pairs of primers. In total, 71 variants were observed in a sample of 207 accessions of wild and cultivated barley. Analyses of wheat-barley addition lines and barley doubled haploids identified these variants (alleles) with four loci, each located on a different chromosome. The numbers of alleles detected at a locus corresponded to the number of nucleotide repeats in the microsatellite sequences. The numbers of alleles at two loci were 28 and 37; to our knowledge these are the largest numbers of alleles for single Mendelian loci reported in plants. Three alleles were resolved by each of the other two loci. Allelic diversity was greater in wild than in cultivated barley and surveys of two generations (F8 and F53) of Composite Cross II, an experimental population of cultivated barley, showed that few of the alleles present in the 28 parents survived into generation F53, whereas some infrequent alleles reached high frequencies. Such changes in frequency indicate that the chromosomal segments marked by the SSR alleles are under the influence of natural selection. The SSR variants allow specific DNA sequences to be followed through generations. Thus, the great resolving power of SSR assays may provide clues regarding the precise targets of natural and man-directed selection.

Alleles↗
PubMed1994

Loss of heterozygosity in cervical carcinoma: subchromosomal localization of a putative tumor-suppressor gene to chromosome 11q22-q24.

Infection of cervical epithelial cells with so-called "aggressive" subtypes of human papilloma virus (HPV) appears to be an important factor in the etiology of cervical carcinoma. However, mounting evidence suggests that additional genetic changes are required for progression to an invasive carcinoma. Functional studies have shown that human chromosome 11 contains a gene or genes capable of suppressing tumorigenicity in cell lines derived from different histopathological types of cervical carcinoma, suggesting that aberration of this gene(s) may represent at least one of the additional changes required for tumorigenic progression. To identify the likely chromosomal position of this gene(s), we have carried out a systematic genetic analysis of chromosome 11 in the primary tumors of 32 patients with cervical carcinoma. Sixteen highly polymorphic markers, 10 of which were based on simple sequence repeats typed by PCR, were used to compare matched DNA samples from noninvolved tissue and portions of tumor tissue highly enriched for neoplastic cells by the cryostat-sectioning technique. Of the 32 patients examined, 14 (44%) demonstrated clonal genetic alterations resulting in loss of heterozygosity for one or more markers. Seven of the clonal genetic alterations on chromosome 11 were specific to the long arm, and the overlap between these and other allelic deletions suggests that a suppressor gene(s) relevant to cervical carcinoma maps to chromosome 11q22-q24.

Alleles↗
PubMed1994

Allelotyping of butadiene-induced lung and mammary adenocarcinomas of B6C3F1 mice: frequent losses of heterozygosity in regions homologous to human tumor-suppressor genes.

To identify the potential involvement of tumor-suppressor gene inactivation during neoplastic development in B6C3F1 mice, genetic losses were determined from allelotypes of butadiene-induced lung and mammary adenocarcinomas. By using length polymorphisms in restriction fragments and simple sequence repeats, or "microsatellites," markers on each autosome were analyzed for allele losses in tumor DNAs. Losses of heterozygosity on chromosome 11 were observed at several loci surrounding the p53 tumor-suppressor gene (Trp53) in 12 of 17 mammary tumors and 2 of 8 lung tumors. Although most of these alterations appeared to result from nondisjunction, at least two examples of somatic recombination or deletion were also observed. Southern analysis revealed a homozygous deletion of the remaining Trp53 allele of one of these mammary tumors. Losses of heterozygosity were also detected at the Rb-1 tumor-suppressor gene in 7 of 17 mammary tumors and 1 lung tumor. Finally, frequent allele losses were observed on chromosome 4 in lung tumors. Analysis of nine chromosome 4 loci defined an interstitial deletion containing the Ifa gene cluster in one of the lung tumors. A tumor-suppressor gene was previously mapped to this region of chromosome 4 in studies with somatic cell hybrids. In addition, homozygous deletions have been reported in a homologous region of human chromosome 9p for acute lymphocytic leukemias, glioblastomas, melanomas, and lung carcinomas. These findings suggest that the inactivation of tumor-suppressor genes including Trp53, Rb-1, and an unidentified gene on chromosome 4 plays a significant role during carcinogenesis in mice.

Adenocarcinoma↗
PubMed1994

Genetic analysis of the NZB contribution to lupus-like autoimmune disease in (NZB x NZW)F1 mice.

Lupus-like autoimmunity in (NZB x NZW)F1 mice is frequently marked by the development of a severe and fatal renal disease. Genes from both NZB and NZW parents are required for the full expression of disease. We applied a mapping technique based on polymorphism in simple sequence repeats to the analysis of (NZB x NZW)F1 x NZW backcross mice to determine the NZB genetic contribution to disease. The results show that a single NZB locus or tightly linked group of loci on the distal part of chromosome 4 provides the strongest association with renal disease and death. This locus, designated here as nba-1 (New Zealand Black autoimmunity), lies distal to the locus elp-1, 60-70 centimorgans from the centromere. It is of interest that a gene encoding a receptor for tumor necrosis factor maps to the vicinity of this disease-associated gene.

Animals↗
PubMed1998

The reverse transcriptase component of the Tetrahymena telomerase ribonucleoprotein complex.

Telomerase is a eukaryotic reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. We describe here the identification of a Tetrahymena telomerase protein with reverse transcriptase motifs, p133. This subunit is associated with the previously identified Tetrahymena telomerase RNA and the telomerase proteins p80 and p95 in immunoprecipitation assays. Therefore, all four known Tetrahymena telomerase components are present in a single complex. Expressed in rabbit reticulocyte lysate, recombinant p133 and telomerase RNA alone catalyze a reverse transcriptase activity with some similarities to and some differences from native Tetrahymena telomerase. These experiments suggest a complexity of telomerase structure and function.

Amino Acid Sequence↗
PubMed1999

The onset and extent of genomic instability in sporadic colorectal tumor progression.

Cancer cell genomes contain alterations beyond known etiologic events, but their total number has been unknown at even the order of magnitude level. By sampling colorectal premalignant polyp and carcinoma cell genomes through use of the technique inter-(simple sequence repeat) PCR, we have found genomic alterations to be considerably more abundant than expected, with the mean number of genomic events per carcinoma cell totaling approximately 11,000. Colonic polyps early in the tumor progression pathway showed similar numbers of events. These results indicate that, as with certain hereditary cancer syndromes, genomic destabilization is an early step in sporadic tumor development. Together these results support the model of genomic instability being a cause rather than an effect of malignancy, facilitating vastly accelerated somatic cell evolution, with the observed orderly steps of the colon cancer progression pathway reflecting the consequences of natural selection.

Adenomatous Polyps↗
PubMed1995

Structure, organization, and expression of the human band 7.2b gene, a candidate gene for hereditary hydrocytosis.

Band 7.2b is an integral membrane phosphoprotein absent from the erythrocyte membranes of patients with hereditary hydrocytosis, a hemolytic anemia inherited in an autosomal dominant fashion and characterized by stomatocytic red blood cells with abnormal permeability to Na+ and K+. The precise role of band 7.2b is unknown, but it may interact with other proteins of the junctional complex of the membrane skeleton. To gain additional insight into the structure and function of this protein and to provide the necessary tools for further genetic studies of hydrocytosis patients, we determined the sequence of the full-length human band 7.2b cDNA, characterized the genomic structure of the band 7.2b gene, studied its pattern of expression in different tissues, and characterized the promoter of the gene. The composite band 7.2b gene cDNA was 3047 base pairs in length. Northern blot analysis revealed a wide tissue distribution of expression of the band 7.2b gene, with utilization of alternative polyadenylation signals generating transcripts of 2.2 and 3.1 kilobases. Cloning of the band 7.2b chromosomal gene revealed that it is composed of seven exons distributed over 40 kilobases of DNA. The band 7.2b gene promoter was identified as a TATA-less, (G+C)-rich promoter with a typical InR recognition sequence and a single transcription initiation site. It directed high level expression of a reporter gene in both erythroid and nonerythroid cells. An imperfect simple sequence repeat polymorphism was identified in the 5'-flanking DNA, and an assay was developed for its analysis by PCR.

3T3 Cells↗
PubMed2002

Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC).

The hereditary non-polyposis colorectal cancer (HNPCC)-syndrome is the most common form of hereditary colorectal cancers, and accounts for 2-7% of the total colorectal cancer burden. Since there are no single clinical features specific for HNPCC, diagnosis is based on family history (Amsterdam or Bethesda criteria) and is confirmed by the detection of a mutation in one of the responsible mismatch repair (MMR) genes. Two types of HNPCC-families can be distinguished. Type I HNPCC tumors are exclusively located in the colon, whereas in Type II HNPCC patients, extracolonic tumors are present in the stomach, endometrium, ovary, and urinary tract. The identification of the human homologues of yeast mismatch repair genes hMSH2, hMSH3, hMSH6, hMLH1, hMLH3, hPMS1 (scMLH2), and hPMS2 (scPMS1) offered the prospect of genetic screening leading to an extensive search for mutations in HNPCC-families. The majority of the alterations have been found in hMSH2 (40%) and hMLH1 (40%) genes. Mutations in the other MMR genes appear rare, absent, and/or associated with atypical families (1-5%). As a result of the mismatch repair deficiency, replication misincorporation errors accumulate, resulting in a mutator phenotype. Diagnosis of HNPCC-associated replication errors is most easily determined by the examination of a panel of the National Cancer Institute (NCI)-recommended simple repeated sequences (microsatellites), combined with immunohistochemical analysis. Although the exact molecular mechanism of the tumor development in these patients remains poorly understood, the identification of tumors that harbor a microsatellite instability has clinical and prognostic implications.

Base Pair Mismatch↗
PubMed2000

Rare etiology of autosomal recessive disease in a child with noncarrier parents.

A child with maple syrup urine disease type 2 (MSUD2) was found to be homozygous for a 10-bp MSUD2-gene deletion on chromosome 1. Both purported parents were tested, and neither carries the gene deletion. Polymorphic simple-sequence repeat analyses at 15 loci on chromosome 1 and at 16 loci on other chromosomes confirmed parentage and revealed that a de novo mutation prior to maternal meiosis I, followed by nondisjunction in maternal meiosis II, resulted in an oocyte with two copies of the de novo mutant allele. Fertilization by a sperm that did not carry a paternal chromosome 1 or subsequent mitotic loss of the paternal chromosome 1 resulted in the propositus inheriting two mutant MSUD2 alleles on two maternal number 1 chromosomes.

Alleles↗