Biomedical subjects

Peter F Arndt

Publications and source records attributed to Peter F Arndt.

15 recordsLinked to original sources

PubMed2006

HLA-class II haplotype associations with ovarian cancer.

The development of cancer is a multistep process that is characterized by the accumulation of genetic alterations in cells and changed cellular interactions with the surrounding healthy tissues. The human immune system is believed to be intrinsically involved in this process. The correlation of certain human leukocyte antigen (HLA)-class I and II haplotypes with tumorigenesis is documented in a variety of tumors. However, few data exist on the possible association of specific HLA-class II alleles or haplotypes with ovarian cancer. In our sample of 52 Caucasian patients with primary ovarian carcinoma and 239 female healthy local controls, we observed a significantly increased incidence of the HLA-class II haplotypes DRB1*0301 - DQA1*0501 - DQB1*0201 (p < 0.001) and DRB1*1001 - DQA1*0101 - DQB1*0501 (p < 0.001) in the patients. Our data suggest that HLA-class II loci or individual HLA-class II haplotypes may be involved in the pathogenesis of ovarian cancer.

Adult↗

PubMed2006

Reconstruction of ancestral nucleotide sequences and estimation of substitution frequencies in a star phylogeny.

Maximum likelihood phylogeny reconstruction methods are widely used in uncovering and assessing the evolutionary history and relationships of natural systems. However, several simplifying assumptions commonly made in this analysis limit the explanatory power of the results obtained. We present an algorithm that performs the phylogenetic analysis without making the common assumptions for sequence data from at least three leaf nodes in a star phylogeny. In particular, the underlying nucleotide substitution model does not have to be reversible and may include neighbor-dependent processes like the CpG methylation deamination process (CpG-effect). The base composition of the sequences at the external nodes and the one of the ancestral sequence may be different from each other and they do not have to be stationary state distributions of the corresponding substitution model. The algorithm is able to reconstruct the ancestral base composition and accurately estimate substitution frequencies in the branches of the star phylogeny. Extensive tests on simulated data validate the very favorable performance of the algorithm. As an application we present the analysis of aligned genomic sequences from human, mouse, and dog. Different substitution pattern can be observed in the three lineages.

Algorithms↗

PubMed2006

Minor shift in background substitutional patterns in the Drosophila saltans and willistoni lineages is insufficient to explain GC content of coding sequences.

BACKGROUND: Several lines of evidence suggest that codon usage in the Drosophila saltans and D. willistoni lineages has shifted towards a less frequent use of GC-ending codons. Introns in these lineages show a parallel shift toward a lower GC content. These patterns have been alternatively ascribed to either a shift in mutational patterns or changes in the definition of preferred and unpreferred codons in these lineages. RESULTS AND DISCUSSION: To gain additional insight into this question, we quantified background substitutional patterns in the saltans/willistoni group using inactive copies of a novel, Q-like retrotransposable element. We demonstrate that the pattern of background substitutions in the saltans/willistoni lineage has shifted to a significant degree, primarily due to changes in mutational biases. These differences predict a lower equilibrium GC content in the genomes of the saltans/willistoni species compared with that in the D. melanogaster species group. The magnitude of the difference can readily account for changes in intronic GC content, but it appears insufficient to explain changes in codon usage within the saltans/willistoni lineage. CONCLUSION: We suggest that the observed changes in codon usage in the saltans/willistoni clade reflects either lineage-specific changes in the definitions of preferred and unpreferred codons, or a weaker selective pressure on codon bias in this lineage.

Animals↗

PubMed2006

CorGen--measuring and generating long-range correlations for DNA sequence analysis.

CorGen is a web server that measures long-range correlations in the base composition of DNA and generates random sequences with the same correlation parameters. Long-range correlations are characterized by a power-law decay of the auto correlation function of the GC-content. The widespread presence of such correlations in eukaryotic genomes calls for their incorporation into accurate null models of eukaryotic DNA in computational biology. For example, the score statistics of sequence alignment and the performance of motif finding algorithms are significantly affected by the presence of genomic long-range correlations. We use an expansion-randomization dynamics to efficiently generate the correlated random sequences. The server is available at http://corgen.molgen.mpg.de.

Algorithms↗

PubMed2005

Identification of highly specific localized sequence motifs in human ribosomal protein gene promoters.

For ribosomal protein (RP) genes the start of transcription is rigidly controlled to maintain the 5'-TOP signal on the messenger RNA. The responsible regulatory mechanism is not yet fully understood. Careful comparative analysis of their proximal promoter sequences reveals common characteristics and thus provides clues to the underlying mechanism. We have extracted the proximal promoters of the 80 human cytosolic ribosomal protein genes together with the orthologous mouse sequences. After annotating the set with transcription factor binding sites based on the available literature, we searched for over-represented sequence motifs. We uncovered a novel motif that is localized at a fixed distance downstream to the transcription start. 31 out of the 80 promoters contain the motif in the same orientation around position +62 (standard deviation 6). A second evolutionary conserved and palindromic motif is found 13 times in the RP promoter set, 9 instances of which are located upstream around position -40. In addition, we see a characteristic profile of the GC-content and of the CpG dinucleotide frequencies. Our results support a model for the transcription of ribosomal protein genes in which the maintenance of the accurate start of transcription is provided by specific transcription factors. Such a factor binds the target DNA at a fixed location relative to the TSS, and possibly interacts directly with the basal transcription machinery.

Amino Acid Motifs↗

PubMed2005

A novel method distinguishes between mutation rates and fixation biases in patterns of single-nucleotide substitution.

Analysis of the genome-wide patterns of single-nucleotide substitution reveals that the human GC content structure is out of equilibrium. The substitutions are decreasing the overall GC content (GC), at the same time making its range narrower. Investigation of single-nucleotide polymorphisms (SNPs) revealed that presently the decrease in GC content is due to a uniform mutational preference for A:T pairs, while its projected range is due to a variability in the fixation preference for G:C pairs. However, it is important to determine whether lessons learned about evolutionary processes operating at the present time (that is reflected in the SNP data) can be extended back into the evolutionary past. We describe here a new approach to this problem that utilizes the juxtaposition of forward and reverse substitution rates to determine the relative importance of variability in mutation rates and fixation probabilities in shaping long-term substitutional patterns. We use this approach to demonstrate that the forces shaping GC content structure over the recent past (since the appearance of the SNPs) extend all the way back to the mammalian radiation approximately 90 million years ago. In addition, we find a small but significant effect that has not been detected in the SNP data-relatively high rates of C:G-->A:T germline mutation in low-GC regions of the genome.

Base Composition↗

PubMed2005

Substantial regional variation in substitution rates in the human genome: importance of GC content, gene density, and telomere-specific effects.

This study presents the first global, 1-Mbp-level analysis of patterns of nucleotide substitutions along the human lineage. The study is based on the analysis of a large amount of repetitive elements deposited into the human genome since the mammalian radiation, yielding a number of results that would have been difficult to obtain using the more conventional comparative method of analysis. This analysis revealed substantial and consistent variability of rates of substitution, with the variability ranging up to twofold among different regions. The rates of substitutions of C or G nucleotides with A or T nucleotides vary much more sharply than the reverse rates, suggesting that much of that variation is due to differences in mutation rates rather than in the probabilities of fixation of C/G vs. A/T nucleotides across the genome. For all types of substitution we observe substantially more hotspots than coldspots, with hotspots showing substantial clustering over tens of Mbp's. Our analysis revealed that GC-content of surrounding sequences is the best predictor of the rates of substitution. The pattern of substitution appears very different near telomeres compared to the rest of the genome and cannot be explained by the genome-wide correlations of the substitution rates with GC content or exon density. The telomere pattern of substitution is consistent with natural selection or biased gene conversion acting to increase the GC-content of the sequences that are within 10-15 Mbp away from the telomere.

Base Composition↗

PubMed2005

Solvable sequence evolution models and genomic correlations.

We study a minimal model for genome evolution whose elementary processes are single site mutation, duplication and deletion of sequence regions, and insertion of random segments. These processes are found to generate long-range correlations in the composition of letters as long as the sequence length is growing; i.e., the combined rates of duplications and insertions are higher than the deletion rate. For constant sequence length, on the other hand, all initial correlations decay exponentially. These results are obtained analytically and by simulations. They are compared with the long-range correlations observed in genomic DNA, and the implications for genome evolution are discussed.

DNA↗

PubMed2005

Male-driven biased gene conversion governs the evolution of base composition in human alu repeats.

Regional biases in substitution pattern are likely to be responsible for the large-scale variation in base composition observed in vertebrate genomes. However, the evolutionary forces responsible for these biases are still not clearly defined. In order to study the processes of mutation and fixation across the entire human genome, we analyzed patterns of substitution in Alu repeats since their insertion. We also studied patterns of human polymorphism within the repeats. There is a highly significant effect of recombination rate on the pattern of substitution, whereas no such effect is seen on the pattern of polymorphism. These results suggest that regional biases in substitution are caused by biased gene conversion, a process that increases the probability of fixation of mutations that increase GC content. Furthermore, the strongest correlate of substitution patterns is found to be male recombination rates rather than female or sex-averaged recombination rates. This indicates that in addition to sexual dimorphism in recombination rates, the sexes also differ in the relative rates of crossover and gene conversion.

Alu Elements↗

PubMed2005

Identification and measurement of neighbor-dependent nucleotide substitution processes.

MOTIVATION: Neighbor-dependent substitution processes generated specific pattern of dinucleotide frequencies in the genomes of most organisms. The CpG-methylation-deamination process is, e.g. a prominent process in vertebrates (CpG effect). Such processes, often with unknown mechanistic origins, need to be incorporated into realistic models of nucleotide substitutions. RESULTS: Based on a general framework of nucleotide substitutions we developed a method that is able to identify the most relevant neighbor-dependent substitution processes, estimate their relative frequencies and judge their importance in order to be included into the modeling. Starting from a model for neighbor independent nucleotide substitution we successively added neighbor-dependent substitution processes in the order of their ability to increase the likelihood of the model describing given data. The analysis of neighbor-dependent nucleotide substitutions based on repetitive elements found in the genomes of human, zebrafish and fruit fly is presented. AVAILABILITY: A web server to perform the presented analysis is freely available at: http://evogen.molgen.mpg.de/server/substitution-analysis

Algorithms↗

PubMed2005

Comparative promoter region analysis powered by CORG.

BACKGROUND: Promoters are key players in gene regulation. They receive signals from various sources (e.g. cell surface receptors) and control the level of transcription initiation, which largely determines gene expression. In vertebrates, transcription start sites and surrounding regulatory elements are often poorly defined. To support promoter analysis, we present CORG http://corg.molgen.mpg.de, a framework for studying upstream regions including untranslated exons (5' UTR). DESCRIPTION: The automated annotation of promoter regions integrates information of two kinds. First, statistically significant cross-species conservation within upstream regions of orthologous genes is detected. Pairwise as well as multiple sequence comparisons are computed. Second, binding site descriptions (position-weight matrices) are employed to predict conserved regulatory elements with a novel approach. Assembled EST sequences and verified transcription start sites are incorporated to distinguish exonic from other sequences. As of now, we have included 5 species in our analysis pipeline (man, mouse, rat, fugu and zebrafish). We characterized promoter regions of 16,127 groups of orthologous genes. All data are presented in an intuitive way via our web site. Users are free to export data for single genes or access larger data sets via our DAS server http://tomcat.molgen.mpg.de:8080/das. The benefits of our framework are exemplarily shown in the context of phylogenetic profiling of transcription factor binding sites and detection of microRNAs close to transcription start sites of our gene set. CONCLUSION: The CORG platform is a versatile tool to support analyses of gene regulation in vertebrate promoter regions. Applications for CORG cover a broad range from studying evolution of DNA binding sites and promoter constitution to the discovery of new regulatory sequence elements (e.g. microRNAs and binding sites).

5' Untranslated Regions↗

PubMed2004

Genomic heterogeneity of background substitutional patterns in Drosophila melanogaster.

Mutation is the underlying force that provides the variation upon which evolutionary forces can act. It is important to understand how mutation rates vary within genomes and how the probabilities of fixation of new mutations vary as well. If substitutional processes across the genome are heterogeneous, then examining patterns of coding sequence evolution without taking these underlying variations into account may be misleading. Here we present the first rigorous test of substitution rate heterogeneity in the Drosophila melanogaster genome using almost 1500 nonfunctional fragments of the transposable element DNAREP1_DM. Not only do our analyses suggest that substitutional patterns in heterochromatic and euchromatic sequences are different, but also they provide support in favor of a recombination-associated substitutional bias toward G and C in this species. The magnitude of this bias is entirely sufficient to explain recombination-associated patterns of codon usage on the autosomes of the D. melanogaster genome. We also document a bias toward lower GC content in the pattern of small insertions and deletions (indels). In addition, the GC content of noncoding DNA in Drosophila is higher than would be predicted on the basis of the pattern of nucleotide substitutions and small indels. However, we argue that the fast turnover of noncoding sequences in Drosophila makes it difficult to assess the importance of the GC biases in nucleotide substitutions and small indels in shaping the base composition of noncoding sequences.

Animals↗

PubMed2004

Regional and time-resolved mutation patterns of the human genome.

MOTIVATION: Substantial regional variations of substitutional processes have recently been reported from human/mouse comparisons. However, several features including the C + G dependence and the CpG-based transition effect remain obscure. RESULTS: Utilizing the vast amount of transposable elements in the human genome, we performed detailed analysis of the substitutional and insertion/deletion patterns along the human lineage in a regional and time-resolved fashion. We observed a drastic increase in the CpG-based transition frequency at about the time of the mammalian radiation. We also observed clear regional biases of substitution patterns, most notably a bias to enrich the C+G content toward the telomeres. AVAILABILITY: The programs used are available upon request from the authors.

Algorithms↗

PubMed2003

Distinct changes of genomic biases in nucleotide substitution at the time of Mammalian radiation.

Differences in the regional substitution patterns in the human genome created patterns of large-scale variation of base composition known as genomic isochores. To gain insight into the origin of the genomic isochores, we develop a maximum-likelihood approach to determine the history of substitution patterns in the human genome. This approach utilizes the vast amount of repetitive sequence deposited in the human genome over the past approximately 250 Myr. Using this approach, we estimate the frequencies of seven types of substitutions: the four transversions, two transitions, and the methyl-assisted transition of cytosine in CpG. Comparing substitutional patterns in repetitive elements of various ages, we reconstruct the history of the base-substitutional process in the different isochores for the past 250 Myr. At around 90 MYA (around the time of the mammalian radiation), we find an abrupt fourfold to eightfold increase of the cytosine transition rate in CpG pairs compared with that of the reptilian ancestor. Further analysis of nucleotide substitutions in regions with different GC content reveals concurrent changes in the substitutional patterns. Although the substitutional pattern was dependent on the regional GC content in such ways that it preserved the regional GC content before the mammalian radiation, it lost this dependence afterward. The substitutional pattern changed from an isochore-preserving to an isochore-degrading one. We conclude that isochores have been established before the radiation of the eutherian mammals and have been subject to the process of homogenization since then.

CpG Islands↗

PubMed2003

DNA sequence evolution with neighbor-dependent mutation.

We introduce a model of DNA sequence evolution which can account for biases in mutation rates that depend on the identity of the neighboring bases. An analytic solution for this class of models is developed by adopting well-known methods of nonlinear dynamics. Results are presented for the CpG-methylation-deamination process, which dominates point substitutions in vertebrates. The dinucleotide frequencies generated by the model (using empirically obtained mutation rates) match the overall pattern observed in noncoding DNA. A web-based tool has been constructed to compute single- and dinucleotide frequencies for arbitrary neighbor-dependent mutation rates. Also provided is the backward procedure to infer the mutation rates using maximum likelihood analysis given the observed single- and dinucleotide frequencies. Reasonable estimates of the mutation rates can be obtained very efficiently, using generic noncoding DNA sequences as input, after masking out long homonucleotide subsequences. Our method is much more convenient and versatile to use than the traditional method of deducing mutation rates by counting mutation events in carefully chosen sequences. More generally, our approach provides a more realistic but still tractable description of noncoding genomic DNA and may be used as a null model for various sequence analysis applications.

DNA↗