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Mark A. Batzer - One of the best experts on this subject based on the ideXlab platform.
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Evolution of Alu Subfamily Structure in the Saimiri Lineage of New World Monkeys.
Genome biology and evolution, 2017Co-Authors: Jasmine N. Baker, Jerilyn A. Walker, Michael W. Denham, John A. Vanchiere, Kacie R. Phillippe, Corey P. St Romain, Paulina Gonzalez-quiroga, Jackson R. Mierl, Miriam K. Konkel, Mark A. BatzerAbstract:Squirrel monkeys, Saimiri, are commonly found in zoological parks and used in biomedical research. S. boliviensis is the most common species for research; however, there is little information about genome evolution within this primate lineage. Here, we reconstruct the Alu Element sequence amplification and evolution in the genus Saimiri at the time of divergence within the family Cebidae lineage. Alu Elements are the most successful SINE (Short Interspersed Element) in primates. Here, we report 46 Saimiri lineage specific Alu subfamilies. Retrotransposition activity involved subfamilies related to AluS, AluTa10, and AluTa15. Many subfamilies are simultaneously active within the Saimiri lineage, a finding which supports the stealth model of Alu amplification. We also report a high resolution analysis of Alu subfamilies within the S. boliviensis genome [saiBol1].
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a comparison of 100 human genes using an Alu Element based instability model
PLOS ONE, 2013Co-Authors: George W Cook, Jerilyn A. Walker, Miriam K. Konkel, Matthew G Bourgeois, Mitchell L Fullerton, John T Fussell, Heath D Herbold, Mark A. BatzerAbstract:The human retrotransposon with the highest copy number is the Alu Element. The human genome contains over one million Alu Elements that collectively account for over ten percent of our DNA. Full-length Alu Elements are randomly distributed throughout the genome in both forward and reverse orientations. However, full-length widely spaced Alu pairs having two Alus in the same (direct) orientation are statistically more prevalent than Alu pairs having two Alus in the opposite (inverted) orientation. The cause of this phenomenon is unknown. It has been hypothesized that this imbalance is the consequence of anomalous inverted Alu pair interactions. One proposed mechanism suggests that inverted Alu pairs can ectopically interact, exposing both ends of each Alu Element making up the pair to a potential double-strand break, or “hit”. This hypothesized “two-hit” (two double-strand breaks) potential per Alu Element was used to develop a model for comparing the relative instabilities of human genes. The model incorporates both 1) the two-hit double-strand break potential of Alu Elements and 2) the probability of exon-damaging deletions extending from these double-strand breaks. This model was used to compare the relative instabilities of 50 deletion-prone cancer genes and 50 randomly selected genes from the human genome. The output of the Alu Element-based genomic instability model developed here is shown to coincide with the observed instability of deletion-prone cancer genes. The 50 cancer genes are collectively estimated to be 58% more unstable than the randomly chosen genes using this model. Seven of the deletion-prone cancer genes, ATM, BRCA1, FANCA, FANCD2, MSH2, NCOR1 and PBRM1, were among the most unstable 10% of the 100 genes analyzed. This algorithm may lay the foundation for comparing genetic risks posed by structural variations that are unique to specific individuals, families and people groups.
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orangutan Alu quiescence reveals possible source Element support for ancient backseat drivers
Mobile Dna, 2012Co-Authors: Jerilyn A. Walker, Miriam K. Konkel, Brygg Ullmer, Christopher P Monceaux, Oliver A Ryder, Robert Hubley, Arian F A Smit, Mark A. BatzerAbstract:Background: Sequence analysis of the orangutan genome revealed that recent proliferative activity of Alu Elements has been uncharacteristically quiescent in the Pongo (orangutan) lineage, compared with all previously studied primate genomes. With relatively few young polymorphic insertions, the genomic landscape of the orangutan seemed like the ideal place to search for a driver, or source Element, of Alu retrotransposition. Results: Here we report the identification of a nearly pristine insertion possessing all the known putative hallmarks of a retrotranspositionally competent Alu Element. It is located in an intronic sequence of the DGKB gene on chromosome 7 and is highly conserved in Hominidae (the great apes), but absent from Hylobatidae (gibbon and siamang). We provide evidence for the evolution of a lineage-specific subfamily of this shared Alu insertion in orangutans and possibly the lineage leading to humans. In the orangutan genome, this insertion contains three orangutan-specific diagnostic mutations which are characteristic of the youngest polymorphic Alu subfamily, AluYe5b5_Pongo. In the Homininae lineage (human, chimpanzee and gorilla), this insertion has acquired three different mutations which are also found in a single human-specific Alu insertion. Conclusions: This seemingly stealth-like amplification, ongoing at a very low rate over millions of years of evolution, suggests that this shared insertion may represent an ancient backseat driver of Alu Element expansion.
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Alu Element mutation spectra molecular clocks and the effect of dna methylation
Journal of Molecular Biology, 2004Co-Authors: Jinchuan Xing, Kyudong Han, Dale J Hedges, Hui Wang, Richard Cordaux, Mark A. BatzerAbstract:In primate genomes more than 40% of CpG islands are found within repetitive Elements. With more than one million copies in the human genome, the Alu family of retrotransposons represents the most successful short interspersed Element (SINE) in primates and CpG dinucleotides make up about 20% of Alu sequences. It is generally thought that CpG dinucleotides mutate approximately ten times faster than other dinucleotides due to cytosine methylation and the subsequent deamination and conversion of C-->T. However, the disparity of Alu subfamily age estimations based upon CpG or non-CpG substitution density indicates a more complex relationship between CpG and non-CpG substitutions within the Alu Elements. Here we report an analysis of the mutation patterns for 5296 Alu Elements comprising 20 subfamilies. Our results indicate a relatively constant CpG versus non-CpG substitution ratio of approximately 6 for the young (AluY) and intermediate (AluS) Alu subfamilies. However, a more complex non-linear relationship between CpG and non-CpG substitutions was observed when old (AluJ) subfamilies were included in the analysis. These patterns may be the result of the slowdown of the neutral mutation rate during primate evolution and/or an increase in the CpG mutation rate as the consequence of increased DNA methylation in response to a burst of retrotransposition activity approximately 35 million years ago.
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human dna quantitation using Alu Element based polymerase chain reaction
Analytical Biochemistry, 2003Co-Authors: Jerilyn A. Walker, Gail Kilroy, Jinchuan Xing, Jaiprakash G Shewale, Sudhir K Sinha, Mark A. BatzerAbstract:Human forensic casework requires sensitive quantitation of human nuclear DNA from complex sources. Widely used commercially available systems detect both nonhuman and human primate DNA, often require special equipment, and have a detection limit of approximately 0.1 ng. Multicopy Alu Elements include recently integrated subfamilies that are present in the human genome but are largely absent from nonhuman primates. Here, we present two Alu Element-based alternative methods for the rapid identification and quantitation of human DNA, inter-Alu PCR and intra-Alu PCR. Using SYBR green-based detection, the effective minimum threshold level for human DNA quantitation was 0.01 ng using inter-Alu- and 0.001 ng using intra-Alu-based PCR. Background cross-amplification with nonhuman DNA templates was detected at low levels using inter-Alu-based PCR, but was negligible using intra-Alu-based PCR. These Alu-based methods have several advantages over currently available systems. First, the assays are PCR based and no additional unique equipment is required. Second, the high copy number of subfamily-specific Alu repeats in the human genome makes these assays human specific within a very sensitive linear range. The introduction of these assays to forensic laboratories will undoubtedly increase the sensitivity and specificity of human DNA detection and quantitation from complex sources.
W F Reynolds - One of the best experts on this subject based on the ideXlab platform.
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an Alu Element in the myeloperoxidase promoter contains a composite sp1 thyroid hormone retinoic acid response Element
Journal of Biological Chemistry, 1996Co-Authors: F J Piedrafita, R B Molander, G Vansant, E A Orlova, M Pfahl, W F ReynoldsAbstract:An Alu Element preceding the myeloperoxidase gene (MPO) contains four hexamer motifs related to the consensus recognition sequence for nuclear hormone receptors (AGGTCA), arranged as direct repeats with spacing of 2, 4, and 2 nucleotides (DR-2-4-2). Gel shift experiments and transient transfection assays demonstrate that these sequences include binding sites for retinoic acid and thyroid hormone receptors and function in vivo to activate transcription of a chloramphenicol acetyltransferase reporter gene. The first DR-2 Elements of the series do not bind known receptors but do bind the SP1 transcription factor. Two alleles of the MPO gene exist that differ at one position within this Element, resulting in one allele with and one without a strong SP1 binding site. The Element with the SP1 site activates transcription by 25-fold in transient transfection assays, while the alternative allele confers severalfold less transcriptional activity. Most cases of acute myelocytic leukemia are homozygous for the allele with the SP1 binding site, suggesting this Element plays an important role in regulating the MPO gene in myeloid leukemias. This MPO-Alu is a representative of an Alu subclass numbering approximately 400,000 copies, suggesting many genes may be regulated by such Elements.
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an Alu Element in the myeloperoxidase promoter contains a composite sp1 thyroid hormone retinoic acid response Element
Journal of Biological Chemistry, 1996Co-Authors: Javier F Piedrafita, R B Molander, G Vansant, E A Orlova, M Pfahl, W F ReynoldsAbstract:Abstract An Alu Element preceding the myeloperoxidase gene (MPO) contains four hexamer motifs related to the consensus recognition sequence for nuclear hormone receptors (AGGTCA), arranged as direct repeats with spacing of 2, 4, and 2 nucleotides (DR-2-4-2). Gel shift experiments and transient transfection assays demonstrate that these sequences include binding sites for retinoic acid and thyroid hormone receptors and function in vivo to activate transcription of a chloramphenicol acetyltransferase reporter gene. The first DR-2 Elements of the series do not bind known receptors but do bind the SP1 transcription factor. Two alleles of the MPO gene exist that differ at one position within this Element, resulting in one allele with and one without a strong SP1 binding site. The Element with the SP1 site activates transcription by 25-fold in transient transfection assays, while the alternative allele confers severalfold less transcriptional activity. Most cases of acute myelocytic leukemia are homozygous for the allele with the SP1 binding site, suggesting this Element plays an important role in regulating the MPO gene in myeloid leukemias. This MPO-Alu is a representative of an Alu subclass numbering ∼400,000 copies, suggesting many genes may be regulated by such Elements.
Jian-min Chen - One of the best experts on this subject based on the ideXlab platform.
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Severe infantile isolated exocrine pancreatic insufficiency caused by the complete functional loss of the SPINK1 gene
Human Mutation, 2017Co-Authors: Théa Venet, Emmanuelle Masson, Cécile Talbotec, Kareen Billiemaz, Renaud Touraine, Claire Gay, Sylvie Destombe, David Cooper, Hugues Patural, Jian-min ChenAbstract:Exocrine pancreatic insufficiency (EPI) is rare in children, with most if not all cases occurring as part of syndromic conditions such as cystic fibrosis and Shwachman-Diamond syndrome. Here we report two cases, both presenting with severe EPI around 5 months of age. Characterized by diffuse pancreatic lipomatosis, they otherwise exhibited no remarkable deficiencies in other organs. Novel non-identical homozygous variants (a deletion removing the entire SPINK1 gene and an insertion of a full-length inverted Alu Element into the 3'-untranslated region of the SPINK1 gene) resulting in the complete functional loss of the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) were identified in each patient. Having correlated our findings with current knowledge of SPINK1's role in exocrine pancreas pathophysiology, we propose that complete and partial functional losses of the SPINK1 gene are associated with quite distinct phenotypes, the former causing a new pediatric disease entity of severe infantile isolated EPI.
Wei Shi - One of the best experts on this subject based on the ideXlab platform.
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detection of serum Alu Element hypomethylation for the diagnosis and prognosis of glioma
Chinese journal of experimental surgery, 2013Co-Authors: Mingjie Gong, Jian Chen, Liang Xia, Jinlong Shi, Q I Jing, Wei ShiAbstract:Objective To investige the roles of measuring hypomethylation of serum Alu Elements (Alu) in glima.Methods Tumor tissues and matched serum specimens from 65 glioma patients and serum samples from 30 healthy controls were examined for Alu hypomethylation by bisulfite sequencing.Results The median serum Alu methylation level was 47.30％ in patients [interquartile range (IQR),(35.40 ± 54.25) ％] and 57.90％ in the controls [IQR,(55.25 ± 61.45) ％].The median Alu methylation level in tumor samples was 40.30％ [IQR,(36.80 ± 54.20) ％],which showed the correlation of Alu hypomethylation between tumor and serum samples (r =0.882) in the study group.The methylation level was higher in the low-grade glioma group than in the high-grade group in tumor and serum samples.A correlation between high methylation level and longer survival time was detected in tumor and serum samples.Receiver operating characteristic (ROC) curve analysis revealed that the area-under-the-curve (AUC) for diagnosis was 0.861 (95％ confidence interval:0.789 ± 0.933),suggesting that Alu hypomethylation in serum may be of diagnostic vAlue.Conclusion Our results indicate that the detection of Alu hypomethylation in serum may be clinically useful for the diagnosis and prognosis of glioma. Key words: Glioma; Serum; Methylation
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detection of serum Alu Element hypomethylation for the diagnosis and prognosis of glioma
Journal of Molecular Neuroscience, 2013Co-Authors: Jian Chen, Mingjie Gong, Futian Liu, Liang Xia, Dekang Nie, Feihui Zou, Jinlong Shi, Longxiang Zhao, Hao Zuo, Wei ShiAbstract:Global genomic hypomethylation is a hallmark of cancer in humans. In the present study, the feasibility of measuring hypomethylation of Alu Elements (Alu) in serum and its clinical utility were investigated. Tumor tissues and matched serum specimens from 65 glioma patients and serum samples from 30 healthy controls were examined for Alu hypomethylation by bisulfite sequencing. The median serum Alu methylation level was 47.30 % in patients (interquartile range (IQR), 35.40–54.25 %) and 57.90 % in the controls (IQR, 55.25–61.45 %). The median Alu methylation level in tumor samples was 40.30 % (IQR, 36.80–54.20 %), which shows the correlation of Alu hypomethylation between tumor and serum samples (r = 0.882) in the study group. The methylation level was higher in the low-grade glioma group than in the high-grade group both in tumor and serum samples. A correlation between high methylation level and longer survival time was detected in tumor and serum samples. Receiver operating characteristic curve analysis showed that the area under the curve for diagnosis was 0.861 (95 % confidence interval, 0.789–0.933), suggesting that Alu hypomethylation in serum may be of diagnostic vAlue. Our results indicate that the detection of Alu hypomethylation in serum may be clinically useful for the diagnosis and prognosis of glioma.
E A Orlova - One of the best experts on this subject based on the ideXlab platform.
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an Alu Element in the myeloperoxidase promoter contains a composite sp1 thyroid hormone retinoic acid response Element
Journal of Biological Chemistry, 1996Co-Authors: F J Piedrafita, R B Molander, G Vansant, E A Orlova, M Pfahl, W F ReynoldsAbstract:An Alu Element preceding the myeloperoxidase gene (MPO) contains four hexamer motifs related to the consensus recognition sequence for nuclear hormone receptors (AGGTCA), arranged as direct repeats with spacing of 2, 4, and 2 nucleotides (DR-2-4-2). Gel shift experiments and transient transfection assays demonstrate that these sequences include binding sites for retinoic acid and thyroid hormone receptors and function in vivo to activate transcription of a chloramphenicol acetyltransferase reporter gene. The first DR-2 Elements of the series do not bind known receptors but do bind the SP1 transcription factor. Two alleles of the MPO gene exist that differ at one position within this Element, resulting in one allele with and one without a strong SP1 binding site. The Element with the SP1 site activates transcription by 25-fold in transient transfection assays, while the alternative allele confers severalfold less transcriptional activity. Most cases of acute myelocytic leukemia are homozygous for the allele with the SP1 binding site, suggesting this Element plays an important role in regulating the MPO gene in myeloid leukemias. This MPO-Alu is a representative of an Alu subclass numbering approximately 400,000 copies, suggesting many genes may be regulated by such Elements.
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an Alu Element in the myeloperoxidase promoter contains a composite sp1 thyroid hormone retinoic acid response Element
Journal of Biological Chemistry, 1996Co-Authors: Javier F Piedrafita, R B Molander, G Vansant, E A Orlova, M Pfahl, W F ReynoldsAbstract:Abstract An Alu Element preceding the myeloperoxidase gene (MPO) contains four hexamer motifs related to the consensus recognition sequence for nuclear hormone receptors (AGGTCA), arranged as direct repeats with spacing of 2, 4, and 2 nucleotides (DR-2-4-2). Gel shift experiments and transient transfection assays demonstrate that these sequences include binding sites for retinoic acid and thyroid hormone receptors and function in vivo to activate transcription of a chloramphenicol acetyltransferase reporter gene. The first DR-2 Elements of the series do not bind known receptors but do bind the SP1 transcription factor. Two alleles of the MPO gene exist that differ at one position within this Element, resulting in one allele with and one without a strong SP1 binding site. The Element with the SP1 site activates transcription by 25-fold in transient transfection assays, while the alternative allele confers severalfold less transcriptional activity. Most cases of acute myelocytic leukemia are homozygous for the allele with the SP1 binding site, suggesting this Element plays an important role in regulating the MPO gene in myeloid leukemias. This MPO-Alu is a representative of an Alu subclass numbering ∼400,000 copies, suggesting many genes may be regulated by such Elements.