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  • 1
    Publication Date: 2007-04-14
    Description: The rhesus macaque (Macaca mulatta) is an abundant primate species that diverged from the ancestors of Homo sapiens about 25 million years ago. Because they are genetically and physiologically similar to humans, rhesus monkeys are the most widely used nonhuman primate in basic and applied biomedical research. We determined the genome sequence of an Indian-origin Macaca mulatta female and compared the data with chimpanzees and humans to reveal the structure of ancestral primate genomes and to identify evidence for positive selection and lineage-specific expansions and contractions of gene families. A comparison of sequences from individual animals was used to investigate their underlying genetic diversity. The complete description of the macaque genome blueprint enhances the utility of this animal model for biomedical research and improves our understanding of the basic biology of the species.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rhesus Macaque Genome Sequencing and Analysis Consortium -- Gibbs, Richard A -- Rogers, Jeffrey -- Katze, Michael G -- Bumgarner, Roger -- Weinstock, George M -- Mardis, Elaine R -- Remington, Karin A -- Strausberg, Robert L -- Venter, J Craig -- Wilson, Richard K -- Batzer, Mark A -- Bustamante, Carlos D -- Eichler, Evan E -- Hahn, Matthew W -- Hardison, Ross C -- Makova, Kateryna D -- Miller, Webb -- Milosavljevic, Aleksandar -- Palermo, Robert E -- Siepel, Adam -- Sikela, James M -- Attaway, Tony -- Bell, Stephanie -- Bernard, Kelly E -- Buhay, Christian J -- Chandrabose, Mimi N -- Dao, Marvin -- Davis, Clay -- Delehaunty, Kimberly D -- Ding, Yan -- Dinh, Huyen H -- Dugan-Rocha, Shannon -- Fulton, Lucinda A -- Gabisi, Ramatu Ayiesha -- Garner, Toni T -- Godfrey, Jennifer -- Hawes, Alicia C -- Hernandez, Judith -- Hines, Sandra -- Holder, Michael -- Hume, Jennifer -- Jhangiani, Shalini N -- Joshi, Vandita -- Khan, Ziad Mohid -- Kirkness, Ewen F -- Cree, Andrew -- Fowler, R Gerald -- Lee, Sandra -- Lewis, Lora R -- Li, Zhangwan -- Liu, Yih-Shin -- Moore, Stephanie M -- Muzny, Donna -- Nazareth, Lynne V -- Ngo, Dinh Ngoc -- Okwuonu, Geoffrey O -- Pai, Grace -- Parker, David -- Paul, Heidie A -- Pfannkoch, Cynthia -- Pohl, Craig S -- Rogers, Yu-Hui -- Ruiz, San Juana -- Sabo, Aniko -- Santibanez, Jireh -- Schneider, Brian W -- Smith, Scott M -- Sodergren, Erica -- Svatek, Amanda F -- Utterback, Teresa R -- Vattathil, Selina -- Warren, Wesley -- White, Courtney Sherell -- Chinwalla, Asif T -- Feng, Yucheng -- Halpern, Aaron L -- Hillier, Ladeana W -- Huang, Xiaoqiu -- Minx, Pat -- Nelson, Joanne O -- Pepin, Kymberlie H -- Qin, Xiang -- Sutton, Granger G -- Venter, Eli -- Walenz, Brian P -- Wallis, John W -- Worley, Kim C -- Yang, Shiaw-Pyng -- Jones, Steven M -- Marra, Marco A -- Rocchi, Mariano -- Schein, Jacqueline E -- Baertsch, Robert -- Clarke, Laura -- Csuros, Miklos -- Glasscock, Jarret -- Harris, R Alan -- Havlak, Paul -- Jackson, Andrew R -- Jiang, Huaiyang -- Liu, Yue -- Messina, David N -- Shen, Yufeng -- Song, Henry Xing-Zhi -- Wylie, Todd -- Zhang, Lan -- Birney, Ewan -- Han, Kyudong -- Konkel, Miriam K -- Lee, Jungnam -- Smit, Arian F A -- Ullmer, Brygg -- Wang, Hui -- Xing, Jinchuan -- Burhans, Richard -- Cheng, Ze -- Karro, John E -- Ma, Jian -- Raney, Brian -- She, Xinwei -- Cox, Michael J -- Demuth, Jeffery P -- Dumas, Laura J -- Han, Sang-Gook -- Hopkins, Janet -- Karimpour-Fard, Anis -- Kim, Young H -- Pollack, Jonathan R -- Vinar, Tomas -- Addo-Quaye, Charles -- Degenhardt, Jeremiah -- Denby, Alexandra -- Hubisz, Melissa J -- Indap, Amit -- Kosiol, Carolin -- Lahn, Bruce T -- Lawson, Heather A -- Marklein, Alison -- Nielsen, Rasmus -- Vallender, Eric J -- Clark, Andrew G -- Ferguson, Betsy -- Hernandez, Ryan D -- Hirani, Kashif -- Kehrer-Sawatzki, Hildegard -- Kolb, Jessica -- Patil, Shobha -- Pu, Ling-Ling -- Ren, Yanru -- Smith, David Glenn -- Wheeler, David A -- Schenck, Ian -- Ball, Edward V -- Chen, Rui -- Cooper, David N -- Giardine, Belinda -- Hsu, Fan -- Kent, W James -- Lesk, Arthur -- Nelson, David L -- O'brien, William E -- Prufer, Kay -- Stenson, Peter D -- Wallace, James C -- Ke, Hui -- Liu, Xiao-Ming -- Wang, Peng -- Xiang, Andy Peng -- Yang, Fan -- Barber, Galt P -- Haussler, David -- Karolchik, Donna -- Kern, Andy D -- Kuhn, Robert M -- Smith, Kayla E -- Zwieg, Ann S -- 062023/Wellcome Trust/United Kingdom -- R01 HG002939/HG/NHGRI NIH HHS/ -- U54 HG003068/HG/NHGRI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2007 Apr 13;316(5822):222-34.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. agibbs@bcm.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17431167" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomedical Research ; *Evolution, Molecular ; Female ; Gene Duplication ; Gene Rearrangement ; Genetic Diseases, Inborn ; Genetic Variation ; *Genome ; Humans ; Macaca mulatta/*genetics ; Male ; Multigene Family ; Mutation ; Pan troglodytes/genetics ; Sequence Analysis, DNA ; Species Specificity
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2010-02-19
    Description: The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial and small sets of nuclear markers have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans. However, until now, fully sequenced human genomes have been limited to recently diverged populations. Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890430/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890430/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schuster, Stephan C -- Miller, Webb -- Ratan, Aakrosh -- Tomsho, Lynn P -- Giardine, Belinda -- Kasson, Lindsay R -- Harris, Robert S -- Petersen, Desiree C -- Zhao, Fangqing -- Qi, Ji -- Alkan, Can -- Kidd, Jeffrey M -- Sun, Yazhou -- Drautz, Daniela I -- Bouffard, Pascal -- Muzny, Donna M -- Reid, Jeffrey G -- Nazareth, Lynne V -- Wang, Qingyu -- Burhans, Richard -- Riemer, Cathy -- Wittekindt, Nicola E -- Moorjani, Priya -- Tindall, Elizabeth A -- Danko, Charles G -- Teo, Wee Siang -- Buboltz, Anne M -- Zhang, Zhenhai -- Ma, Qianyi -- Oosthuysen, Arno -- Steenkamp, Abraham W -- Oostuisen, Hermann -- Venter, Philippus -- Gajewski, John -- Zhang, Yu -- Pugh, B Franklin -- Makova, Kateryna D -- Nekrutenko, Anton -- Mardis, Elaine R -- Patterson, Nick -- Pringle, Tom H -- Chiaromonte, Francesca -- Mullikin, James C -- Eichler, Evan E -- Hardison, Ross C -- Gibbs, Richard A -- Harkins, Timothy T -- Hayes, Vanessa M -- R01 GM087472/GM/NIGMS NIH HHS/ -- R01 HG004909/HG/NHGRI NIH HHS/ -- R01GM087472/GM/NIGMS NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2010 Feb 18;463(7283):943-7. doi: 10.1038/nature08795.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Pennsylvania State University, Center for Comparative Genomics and Bioinformatics, 310 Wartik Lab, University Park, Pennsylvania 16802, USA. scs@bx.psu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20164927" target="_blank"〉PubMed〈/a〉
    Keywords: African Continental Ancestry Group/*genetics ; Asian Continental Ancestry Group/genetics ; Ethnic Groups/*genetics ; European Continental Ancestry Group/genetics ; Exons/genetics ; Genetics, Medical ; Genome, Human/*genetics ; Humans ; Phylogeny ; Polymorphism, Single Nucleotide/genetics ; South Africa/ethnology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-04-03
    Description: A tandem repeat’s (TR) propensity to mutate increases with repeat number, and can become very pronounced beyond a critical boundary, transforming it into a microsatellite (MS). However, a clear understanding of the mutational behavior of different TR classes and motifs and related mechanisms is lacking, as is a consensus on the existence of a boundary separating short TRs (STRs) from MSs. This hinders our understanding of MSs’ mutational properties and their effective use as genetic markers. Using indel calls for 179 individuals from 1000 Genomes Pilot-1 Project, we determined polymorphism incidence for four major TR classes, and formalized its varying relationship with repeat number using segmented regression. We observed a biphasic regime with a transition from a faster to a slower exponential growth at 9, 5, 4, and 4 repeats for mono-, di-, tri-, and tetranucleotide TRs, respectively. We used an in vitro mutagenesis assay to evaluate the contribution of strand slippage errors to mutability. STRs and MSs differ in their absolute polymorphism levels, but more importantly in their rates of mutability growth. Although strand slippage is a major factor driving mononucleotide polymorphism incidence, dinucleotide polymorphism incidence is greater than that expected due to strand slippage alone, indicating that additional cellular factors might be driving dinucleotide mutability in the human genome. Leveraging on hundreds of human genomes, we present the first comprehensive, genome-wide analysis of TR mutational behavior, encompassing several motif sizes and compositions.
    Electronic ISSN: 1759-6653
    Topics: Biology
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  • 4
  • 5
    Publication Date: 2016-09-17
    Description: Transcript variation has important implications for organismal function in health and disease. Most transcriptome studies focus on assessing variation in gene expression levels and isoform representation. Variation at the level of transcript sequence is caused by RNA editing and transcription errors, and leads to nongenetically encoded transcript variants, or RNA–DNA differences (RDDs). Such variation has been understudied, in part because its detection is obscured by reverse transcription (RT) and sequencing errors. It has only been evaluated for intertranscript base substitution differences. Here, we investigated transcript sequence variation for short tandem repeats (STRs). We developed the first maximum-likelihood estimator (MLE) to infer RT error and RDD rates, taking next generation sequencing error rates into account. Using the MLE, we empirically evaluated RT error and RDD rates for STRs in a large-scale DNA and RNA replicated sequencing experiment conducted in a primate species. The RT error rates increased exponentially with STR length and were biased toward expansions. The RDD rates were approximately 1 order of magnitude lower than the RT error rates. The RT error rates estimated with the MLE from a primate data set were concordant with those estimated with an independent method, barcoded RNA sequencing, from a Caenorhabditis elegans data set. Our results have important implications for medical genomics, as STR allelic variation is associated with 〉40 diseases. STR nonallelic transcript variation can also contribute to disease phenotype. The MLE and empirical rates presented here can be used to evaluate the probability of disease-associated transcripts arising due to RDD.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
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  • 6
    Publication Date: 2014-10-29
    Description: The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 7
    Publication Date: 2013-03-21
    Description: Y chromosomes have long been dismissed as "graveyards of genes," but there is still much to be learned from the genetic relics of genes that were once functional on the human Y. We identified human X-linked genes whose gametologs have been pseudogenized or completely lost from the Y chromosome and inferred which evolutionary forces may be acting to retain genes on the Y. Although gene loss appears to be largely correlated with the suppression of recombination, we observe that X-linked genes with functional Y homologs evolve under stronger purifying selection and are expressed at higher levels than X-linked genes with nonfunctional Y homologs. Additionally, we support and expand upon the hypothesis that X inactivation is primarily driven by gene loss on the Y. Using linear discriminant analysis, we show that X-inactivation status can successfully classify 90% of X-linked genes into those with functional or nonfunctional Y homologs.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
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  • 8
    Publication Date: 2014-06-26
    Description: The integration and fixation preferences of DNA transposons, one of the major classes of eukaryotic transposable elements, have never been evaluated comprehensively on a genome-wide scale. Here, we present a detailed study of the distribution of DNA transposons in the human and bat genomes. We studied three groups of DNA transposons that integrated at different evolutionary times: 1) ancient (〉40 My) and currently inactive human elements, 2) younger (〈40 My) bat elements, and 3) ex vivo integrations of piggyBat and Sleeping Beauty elements in HeLa cells. Although the distribution of ex vivo elements reflected integration preferences, the distribution of human and (to a lesser extent) bat elements was also affected by selection. We used regression techniques (linear, negative binomial, and logistic regression models with multiple predictors) applied to 20-kb and 1-Mb windows to investigate how the genomic landscape in the vicinity of DNA transposons contributes to their integration and fixation. Our models indicate that genomic landscape explains 16–79% of variability in DNA transposon genome-wide distribution. Importantly, we not only confirmed previously identified predictors (e.g., DNA conformation and recombination hotspots) but also identified several novel predictors (e.g., signatures of double-strand breaks and telomere hexamer). Ex vivo integrations showed a bias toward actively transcribed regions. Older DNA transposons were located in genomic regions scarce in most conserved elements—likely reflecting purifying selection. Our study highlights how DNA transposons are integral to the evolution of bat and human genomes, and has implications for the development of DNA transposon assays for gene therapy and mutagenesis applications.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
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  • 9
    Publication Date: 2013-09-04
    Description: Many studies have demonstrated that divergence levels generated by different mutation types vary and covary across the human genome. To improve our still-incomplete understanding of the mechanistic basis of this phenomenon, we analyze several mutation types simultaneously, anchoring their variation to specific regions of the genome. Using hidden Markov models...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 10
    Publication Date: 2013-03-09
    Description: Dinucleotide microsatellites are dynamic DNA sequences that affect genome stability. Here, we focused on mature microsatellites, defined as pure repeats of lengths above the threshold and unlikely to mutate below it in a single mutational event. We investigated the prevalence and mutational behavior of these sequences by using human genome sequence data, human cells in culture, and purified DNA polymerases. Mature dinucleotides (≥10 units) are present within exonic sequences of 〉350 genes, resulting in vulnerability to cellular genetic integrity. Mature dinucleotide mutagenesis was examined experimentally using ex vivo and in vitro approaches. We observe an expansion bias for dinucleotide microsatellites up to 20 units in length in somatic human cells, in agreement with previous computational analyses of germ-line biases. Using purified DNA polymerases and human cell lines deficient for mismatch repair (MMR), we show that the expansion bias is caused by functional MMR and is not due to DNA polymerase error biases. Specifically, we observe that the MutSα and MutLα complexes protect against expansion mutations. Our data support a model wherein different MMR complexes shift the balance of mutations toward deletion or expansion. Finally, we show that replication fork progression is stalled within long dinucleotides, suggesting that mutational mechanisms within long repeats may be distinct from shorter lengths, depending on the biochemistry of fork resolution. Our work combines computational and experimental approaches to explain the complex mutational behavior of dinucleotide microsatellites in humans.
    Electronic ISSN: 2160-1836
    Topics: Biology
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