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PubMed2001

Spatial structure of lemming populations (Dicrostonyx groenlandicus) fluctuating in density.

The pattern and scale of the genetic structure of populations provides valuable information for the understanding of the spatial ecology of populations, including the spatial aspects of density fluctuations. In the present paper, the genetic structure of periodically fluctuating lemmings (Dicrostonyx groenlandicus) in the Canadian Arctic was analysed using mitochondrial DNA (mtDNA) control region sequences and four nuclear microsatellite loci. Low genetic variability was found in mtDNA, while microsatellite loci were highly variable in all localities, including localities on isolated small islands. For both genetic markers the genetic differentiation was clear among geographical regions but weaker among localities within regions. Such a pattern implies gene flow within regions. Based on theoretical calculations and population census data from a snap-trapping survey, we argue that the observed genetic variability on small islands and the low level of differentiation among these islands cannot be explained without invoking long distance dispersal of lemmings over the sea ice. Such dispersal is unlikely to occur only during population density peaks.

Animals↗
PubMed2005

Nuclear and mitochondrial evolutionary analyses of Collared, White-lipped, and Chacoan peccaries (Tayassuidae).

The three extant peccary species, the Chacoan (Catagonus wagneri), the White-lipped (Tayassu pecari) and the Collared (Pecari tajacu), are morphologically and chromosomally distinct and confined to the New World. There is ongoing paleontological, cytogenetic, and molecular debate about phylogenetic relationships among them. To contribute to the understanding of Tayassuidae phylogeny, three mitochondrial (control region, cytochrome b, and 12S rRNA) and five nuclear (K-casein, thyrotropin, tyrosinase, and swine short interspersed nuclear elements PRE-1 P27 and P642) peccary DNA fragments were amplified, cloned and sequenced from Chacoan, White-lipped, and Collared peccaries. Phylogenetic analyses were performed using maximum likelihood and neighbor joining methods. K-casein, thyrotropin, and tyrosinase sequences did not resolve the phylogeny, while control region, cytochrome b, 12S rRNA, and PRE-1 P27 and P642 sequences were more informative in deciphering phylogenetic relationships. When pig and warthog were used as an outgroup, Chacoan and White-lipped peccaries clustered distinct from Collared peccaries. Furthermore, control region and cytochrome b sequence variation within Collared peccaries was as extreme as that between White-lipped and Chacoan peccaries, supporting subspecific and possibly even specific variation within the widely distributed Collared peccary. This study supports the existence of two independent genera within the Tayassuidae family consisting of Collared and Chacoan/White-lipped peccaries, in contrast with classical morphological taxonomy which clusters White-lipped and Collared peccaries in the genus Tayassu or which alternatively clusters the Collared peccary in the genus Dicotyles as a related sister clade of the Chacoan peccary (genus Catagonus).

Animals↗
PubMed1997

Human histone acetyltransferase GCN5 exists in a stable macromolecular complex lacking the adapter ADA2.

Acetylation of core histones is an important regulatory step in transcriptional activation from chromatin templates. The yeast transcriptional coactivator protein GCN5 was recently shown to be a nuclear histone acetyltransferase (HAT). Genetic and biochemical studies in yeast suggest that GCN5 functions with the adapter proteins ADA1, ADA2, ADA3, and ADA5 in a heteromeric complex. We have established conditions for chromatographic fractionation of HATs and ADA2 from human K562 erythroleukemia cells. Gel-filtration chromatography revealed two populations of GCN5 with Stokes' radii of 67 and 33 A, consistent with a large macromolecular complex and a monomer, respectively. The GCN5-related HAT, PCAF, was resolved as a stable complex with a Stokes' radius of 74 A. The HAT complexes were resistant to 0.3 M NaCl and DNase I. ADA2 was characterized by a Stokes' radius of 35 A, consistent with a monomer. Thus, in contrast to the stable GCN5-adapter complex in yeast, human GCN5 and ADA2 are not stably associated with each other. The implications of this result are discussed vis-a-vis the mechanism of recruitment of GCN5 to regulatory regions of genes.

Acetyltransferases↗
PubMed1990

Human globin locus activation region (LAR): role in temporal control.

A region of DNA located far upstream of the human beta-globin locus is critically involved in the regulation of the beta-globin gene family. Recent experiments in transgenic mice suggest that switching from fetal to adult globin gene expression during human development results from competition among individual globin gene family members for interaction with sequences in this region. The phenotypes of patients with defined hemoglobinopathies support this hypothesis.

Animals↗
PubMed2002

The kinetics of deregulation of expression by de novo methylation of the h19 imprinting control region in cancer cells.

Epigenetic lesions are common in neoplasia and range from hypermethylation of subsets of CpG islands to loss of imprinting. By exploiting an episomal model system and the strong de novo methylation capacity of a human cancer cell line, we show that an H19 minigene rapidly becomes methylated and silenced, mimicking the inactivation of the maternal H19 allele in a range of cancers. Although the H19 imprinting control region (ICR) initially displayed methylation protection, it eventually succumbed to the pressure mounted by the de novo methylation machinery of the JEG-3 cells. Importantly, we were able to visualize the kinetics of the loss of the H19 ICR chromatin insulator function in association with chromatin compaction. Our results document that a strong de novo methylation machinery leads to loss of methylation privilege states of H19 ICR to functionally manifest loss of insulator function in a matter of only a few days in human cancer cells.

Animals↗
PubMed2004

The 5'-HS4 chicken beta-globin insulator is a CTCF-dependent nuclear matrix-associated element.

The protein CTCF plays an essential role in the action of a widely distributed class of vertebrate enhancer-blocking insulators, of which the first example was found in a DNA sequence element, HS4, at the 5' end of the chicken beta-globin locus. HS4 contains a binding site for CTCF that is necessary and sufficient for insulator action. Purification of CTCF has revealed that it interacts with proteins involved in subnuclear architecture, notably nucleophosmin, a 38-kDa nucleolar phosphoprotein that is concentrated in nuclear matrix preparations. In this report we show that both CTCF and the HS4 insulator element are incorporated in the matrix; HS4 incorporation depends on the presence of an intact CTCF-binding site. However the DNA sequence in the neighborhood of HS4 is not like that of canonical matrix attachment regions, and its incorporation into the matrix fraction is not sensitive to ribonuclease, suggesting that the insulator is a distinct matrix-associated element.

Animals↗
PubMed2006

Role of the IBD5 susceptibility locus in the inflammatory bowel diseases.

The field of inflammatory bowel disease genetics plays a leading role in the genetics of complex traits. One of the first genetic loci for a complex trait to be identified by genome-wide linkage scans and confirmed by multiple studies was IBD1 for Crohn's disease. Shortly after this initial success, a second susceptibility locus, the IBD5 risk haplotype, was discovered and unequivocally replicated. In this review, we examine the genetics and potential functional implications of the IBD5 locus on disease susceptibility, prognosis, classification, and treatment. In addition, we discuss the challenges faced when the region identified by association contains multiple genes that are not easily separated by recombination-the primary tool of the human geneticist.

Chromosomes, Human, Pair 5↗
PubMed2006

A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus.

Despite the intense debate around the repeat instability reported on the large group of neurological disorders caused by trinucleotide repeat expansions, little is known about the mutation process underlying alleles in the normal range that, ultimately, expand to pathological size. In this study, we assessed the mutation mechanisms by which wild-type Machado-Joseph disease (MJD) alleles have been generated throughout human evolution. Haplotypes including the CAG repeat, six intragenic SNPs and four flanking microsatellites were analysed in 431 normal chromosomes of European, Asian and African origin. A bimodal CAG repeat length frequency distribution was found in the four most frequent wild-type lineages (H1-GCGGCA; H2-GTGGCA; H3-TTAGAC and H4-TTACAC). Based on flanking microsatellite haplotypes, the variance calculated by analysis of molecular variance between modal (CAG)n alleles was little or null in lineages H1, H2 and H4, as were the pairwise differences. Moreover, genetic distances among all the alleles from each lineage did not reflect the allele sizes differences, as expected if a stepwise mutation model was the main process of evolution. On the contrary, when exposed in maximum parsimonious phylogenetic trees, a large number of mutation steps separated same-size alleles, whereas several microsatellite haplotypes were shared by modal CAGs. In conclusion, our results suggest that the main mutation mechanism occurring in the evolution of the polymorphic CAG region at MJD/SCA3 locus is a multistep one, either by gene conversion or DNA slippage; repeats with 14, 21, 23 and 27 CAGs are the main alleles involved in this process.

Alleles↗
PubMed2003

The pedigree rate of sequence divergence in the human mitochondrial genome: there is a difference between phylogenetic and pedigree rates.

We have extended our previous analysis of the pedigree rate of control-region divergence in the human mitochondrial genome. One new germline mutation in the mitochondrial DNA (mtDNA) control region was detected among 185 transmission events (generations) from five Leber hereditary optic neuropathy (LHON) pedigrees. Pooling the LHON pedigree analyses yields a control-region divergence rate of 1.0 mutation/bp/10(6) years (Myr). When the results from eight published studies that used a similar approach were pooled with the LHON pedigree studies, totaling >2,600 transmission events, a pedigree divergence rate of 0.95 mutations/bp/Myr for the control region was obtained with a 99.5% confidence interval of 0.53-1.57. Taken together, the cumulative results support the original conclusion that the pedigree divergence rate for the control region is approximately 10-fold higher than that obtained with phylogenetic analyses. There is no evidence that any one factor explains this discrepancy, and the possible roles of mutational hotspots (rate heterogeneity), selection, and random genetic drift and the limitations of phylogenetic approaches to deal with high levels of homoplasy are discussed. In addition, we have extended our pedigree analysis of divergence in the mtDNA coding region. Finally, divergence of complete mtDNA sequences was analyzed in two tissues, white blood cells and skeletal muscle, from each of 17 individuals. In three of these individuals, there were four instances in which an mtDNA mutation was found in one tissue but not in the other. These results are discussed in terms of the occurrence of somatic mtDNA mutations.

Base Sequence↗
PubMed2002

Mitochondrial DNA variation along an altitudinal gradient in the greater white-toothed shrew, Crocidura russula.

The distribution of mitochondrial control region-sequence polymorphism was investigated in 15 populations of Crocidura russula along an altitudinal gradient in western Switzerland. High-altitude populations are smaller, sparser and appear to undergo frequent bottlenecks. Accordingly, they showed a loss of rare haplotypes, but unexpectedly, were less differentiated than lowland populations. Furthermore, the major haplotypes segregated significantly with altitude. The results were inconsistent with a simple model of drift and dispersal. They suggested instead a role for historical patterns of colonization, or, alternatively, present-day selective forces acting on one of the mitochondrial genes involved in metabolic pathways.

Altitude↗
PubMed2003

Evolution and genetic structure of the great tit (Parus major) complex.

The great tit complex is divided into four groups, each containing several subspecies. Even though the groups are known to differ markedly on morphological, vocal and behavioural characters, some hybridization occurs in the regions where they meet. The great tit has often been referred to as an example of a ring species, although this has later been questioned. Here, we have studied the genetic structure and phylogenetic relationships of the subspecies groups to clarify the evolutionary history of the complex using control region sequences of the mitochondrial DNA. The subspecies groups were found to be monophyletic and clearly distinct in mitochondrial haplotypes, and therefore must have had long-independent evolutionary histories. This conflicts with the ring species assignment and supports the formation of secondary contact zones of previously temporarily isolated groups. According to the phylogenetic species concept, all the subspecies groups could be considered as separate species, but if the definition of the biological species concept is followed, none of the subspecies groups is a true species because hybridization still occurs.

Animals↗
PubMedDate not supplied

BKV infection and hemorrhagic cystitis after allogeneic bone marrow transplant.

Hemorrhagic cystitis (HC) is a well-known complication after allogeneic bone marrow transplant (BMT) and can be related to adenovirus or human polyomavirus BK (BKV) infections. In this study a group of 20 patients after allogeneic BMT has been examined. BMT urine samples were analysed for the presence of Adenovirus and BKV DNAby means of polymerase chain reaction (PCR). 5/20 BMT patients developed HC after BMT. The presence of BKV DNA in urine samples was evident in 3/15 patients without HC and in 5/5 patients with HC. In 2/5 HC-patients the BKV DNA was not found after therapy with Cidofovir and Ribavirin. The search for adenovirus DNA in all samples was negative. The analysis of BKV non-coding control region (NCCR) isolated from urine samples revealed a structure very similar to the archetype in all samples. The RFLP (Restriction Fragment Length Polymorphism assay) showed the presence of BKV subtypes I and IV, with the prevalence of subtype I (4/5). This study supports the hypothesis that HC is mainly related to BKV rather than to adenovirus infection in BMT patients. Moreover, since BKV subtype I was predominant, it is reasonable to hypothesize that a specific BKV subtype could be associated with the development of HC.

Adenoviridae↗
PubMed2005

Evidence for multiple reversals of asymmetric mutational constraints during the evolution of the mitochondrial genome of metazoa, and consequences for phylogenetic inferences.

Mitochondrial DNA (mtDNA) sequences are comonly used for inferring phylogenetic relationships. However, the strand-specific bias in the nucleotide composition of the mtDNA, which is thought to reflect assymetric mutational constraints, combined with the important compositional heterogeneity among taxa, are known to be highly problematic for phylogenetic analyses. Here, nucleotide composition was compared across 49 species of Metazoa (34 arthropods, 2 annelids, 2 molluscs, and 11 deuterosomes), and analyzed for a mtDNA fragment including six protein-coding genes, i.e., atp6, atp8, cox1, cox2, cox3, and nad2. The analyses show that most metazoan species present a clear strand assymetry, where one strand is biased in favor of A and C, whereas the other strand has reverse bias, i.e. in favor of T and G. the origin of this strand bias can be related to assymetric mutational constraints involving deaminations of A and C nucleotides during the replication and/or transcription processes. The analyses reveal that six unrelated genera are characterized by a reversal of the usual strand bias, i.e., Argiope (Araneae), Euscorpius (Scorpiones), Tigrioupus (Maxillopoda), Branchiostoma (Cephalochordata) Florometra (Echinodermata), and Katharina (Mollusca). It is proposed that assymetric mutational constraints have been independantly reversed in these six genera, through an inversion of the control region, i.e., the region that contains most regulatory elements for replication and transcription of the mtDNA. We show that reversals of assymetric mutational constraints have dramatic consequences on the phylogenetic analyses, as taxa characterized by reverse strand bias tend to group together due to long-branch attraction artifacts. We propose a new method for limiting this specific problem in tree reconstruction under the Bayesian approach. We apply our method to deal with the question of phylogenetic relationships of the major lineages of Arthropoda, This new approach provides a better congruence with nuclear analyses based on mtDNA sequences, our data suggest that Chelicerata, Crustacea, Myriapoda, Pancrustacea, and Paradoxopoda are monophyletic.

Animals↗
PubMed2005

Complete nucleotide sequence of the mitochondrial genome of Schlegel's tree frog Rhacophorus schlegelii (family Rhacophoridae): duplicated control regions and gene rearrangements.

The complete nucleotide sequence (21,359 bp) of the mitochondrial DNA of the rhacophorid frog Rhacophorus schlegelii was determined. The gene content, nucleotide composition, and codon usage of this genome corresponded to those typical of vertebrates. However, the Rh. schlegelii genome was unusually large due to the inclusion of two control regions and the accumulation of lengthy repetitive sequences in these regions. The two control regions had 97% sequence similarity over 1,510 bp, suggesting the occurrence of concerted sequence evolution. Comparison of the gene organizations among anuran species revealed that the mitochondrial gene arrangement of Rh. schlegelii diverged from that of typical vertebrates but was similar to that of Buergeria buergeri. The positions of the tRNA-Leu(CUN) and tRNA-Thr genes were exchanged between Rh. schlegelii and B. buergeri. Based on parsimonious consideration and the basal phylogenetic position of B. buergeri, these genes seemed to have been rearranged in an ancestral lineage leading to Rh. schlegelii.

Animals↗
PubMed2002

Multiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 imprinting control region.

The 5' region of the H19 gene harbors a methylation-sensitive chromatin insulator within an imprinting control region (ICR). Insertional mutagenesis in combination with episomal assays identified nucleosome positioning sequences (NPSs) that set the stage for the remarkably precise distribution of the four target sites for the chromatin insulator protein CTCF to nucleosome linker sequences in the H19 ICR. Changing positions of the NPSs resulted in loss of both CTCF target site occupancy and insulator function, suggesting that the NPSs optimize the fidelity of the insulator function. We propose that the NPSs ensure the fidelity of the repressed status of the maternal Igf2 allele during development by constitutively maintaining availability of the CTCF target sites.

Animals↗
PubMed2006

Human papillomavirus E2 protein associates with nuclear receptors to stimulate nuclear receptor- and E2-dependent transcriptional activations in human cervical carcinoma cells.

Steroid hormones are proposed to act with human papillomaviruses (HPVs) as cofactors in the etiology of cervical cancer. Steroid hormone-activated nuclear receptors (NRs) are thought to bind to specific DNA sequences within transcriptional regulatory regions on the HPV DNA to either increase or suppress transcription of dependent genes. HPV-induced immortalization of epithelial cells usually requires integration of the viral DNA into the host cell genome. The integration event causes disruption of the E2 gene: the E2 protein is a transcription factor that regulates expression of the E6 and E7 oncoproteins by binding to four sites within the viral long control region (LCR). Our previous study suggested that E6 and E7 oncoproteins both directly bind to some NRs and serve as their cofactors. Here, we provide several lines of evidence demonstrating that the E2 protein is an NR coactivator through its physical interaction with NRs. In our study, the NR coactivator function of HPV E2 protein in human cervical carcinoma cells was independent of the type of E2, HPV transformation and the p53 status. Our observations also provide evidence suggesting regulatory mechanisms for the LCR involving interaction between the E2 protein and NRs in HeLa cells.

Alphapapillomavirus↗
PubMed2006

Further clinical and genetic characterization of SPG11: hereditary spastic paraplegia with thin corpus callosum.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders leading to progressive spasticity of the lower limbs. Clinically, HSPs are divided into "pure" and "complicated" forms. In pure HSP, the spasticity of the lower limbs is the sole symptom, whereas in complicated forms additional neurological and non-neurological features are observed. Genetically, HSPs are divided into autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) forms. Up to date, 30 different HSPs are linked to different chromosomal loci and 11 genes could be defined for AR-HSP, AD-HSP and XL-HSP. SPG11, an AR-HSP (synonym: HSP11), is a complicated HSP associated with a slowly progressive spastic paraparesis, mental impairment and the development of a thin corpus callosum (TCC) during the course of the disease. SPG11 has been previously linked to chromosomal region 15q13 - 15. First, we applied rigid diagnostic criteria to systematically examine 20 Turkish families with autosomal recessive HSP for characteristic features of SPG11. We detected four large Turkish families with AR-HSP and TCC consistent with SPG11. Subsequent genetic linkage analysis of those 4 families refines the SPG11 locus further down to a small region of 2.93 cM with a maximum lod score of 11.84 at marker D15S659 and will guide further candidate gene analysis.

Adolescent↗
PubMed1997

Repair pattern in the beta-globin gene cluster of human fibroblasts after ultraviolet irradiation.

We have developed a novel technique to determine repair of structurally different DNA lesions. It was used to address the question of whether DNA repair in the absence of transcription occurs in a uniformly random manner or with preferences for certain regions. Human fibroblasts were exposed to ultraviolet light (3-10 J/m2) and treated with 7.5 mM hydroxyurea to inhibit replicative DNA synthesis. During the first hours after irradiation cells were treated with 5-bromodeoxyuridine to label the regions undergoing repair, with the presumption that the regions that have been more efficiently repaired would incorporate more of the nucleoside. A 155-kb DNA sequence containing the entire human beta-globin domain was reconstructed using sequences deposited in the EMBL gene bank. Twelve uniformly long single-copy RNA probes spanning the beta-globin cluster were synthesised in vitro and immobilized on microtiter plates. They were hybridized with DNA from the irradiated cells. The amount of 5-bromodeoxyuridine, incorporated as a result of repair in the DNA fractions hybridized to the different RNA probes, was determined immunochemically using antibody to this nucleoside. By this technique we registered increased repair efficiency in the zone of the permanent scaffold attachment region at the 5'-end of the beta-globin domain during the first hours after ultraviolet irradiation. This result was confirmed and by the more conventional T4 endonuclease V technique detecting the removal of cyclobutane pyrimidine dimers.

Bromodeoxyuridine↗