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1.
Primate Alu and rodent Alu-like elements comprise major families of mammalian small dispersed repetitive DNAs. These elements are repeated more than 10(5) times per haploid genome and are found between known genes, in introns and in satellite DNA. Their dispersion throughout the genome and the presence of directly repeated DNA sequences flanking the elements suggest, but do not prove, that they are capable of transposition. We describe here an allelic variation in the 5'-flanking region of the rat prolactin gene that offers the opportunity to examine the sequences of matching regions of two homologous chromosomes which differ in the presence of an Alu-like repetitive DNA element. Our findings support the hypothesis that these elements are integrated into the genome by generating short direct repeats of host DNA. 相似文献
2.
Mutation rates differ among regions of the mammalian genome 总被引:91,自引:0,他引:91
In the traditional view of molecular evolution, the rate of point mutation is uniform over the genome of an organism and variation in the rate of nucleotide substitution among DNA regions reflects differential selective constraints. Here we provide evidence for significant variation in mutation rate among regions in the mammalian genome. We show first that substitutions at silent (degenerate) sites in protein-coding genes in mammals seem to be effectively neutral (or nearly so) as they do not occur significantly less frequently than substitutions in pseudogenes. We then show that the rate of silent substitution varies among genes and is correlated with the base composition of genes and their flanking DNA. This implies that the variation in both silent substitution rate and base composition can be attributed to systematic differences in the rate and pattern of mutation over regions of the genome. We propose that the differences arise because mutation patterns vary with the timing of replication of different chromosomal regions in the germline. This hypothesis can account for both the origin of isochores in mammalian genomes and the observation that silent nucleotide substitutions in different mammalian genes do not have the same molecular clock. 相似文献
3.
A mammalian protein with specific demethylase activity for mCpG DNA 总被引:49,自引:0,他引:49
DNA-methylation patterns are important for regulating genome functions, and are determined by the enzymatic processes of methylation and demethylation. The demethylating enzyme has now been identified: a mammalian complementary DNA encodes a methyl-CpG-binding domain, bears a demethylase activity that transforms methylated cytosine bases to cytosine, and demethylates a plasmid when the cDNA is translated or transiently transfected into human embryonal kidney cells in vitro. The discovery of this DNA demethylase should provide a basis for the molecular and developmental analysis of the role of DNA methylation and demethylation. 相似文献
4.
Nucleosomes are the basic packaging units of chromatin, modulating accessibility of regulatory proteins to DNA and thus influencing eukaryotic gene regulation. Elaborate chromatin remodelling mechanisms have evolved that govern nucleosome organization at promoters, regulatory elements, and other functional regions in the genome. Analyses of chromatin landscape have uncovered a variety of mechanisms, including DNA sequence preferences, that can influence nucleosome positions. To identify major determinants of nucleosome organization in the human genome, we used deep sequencing to map nucleosome positions in three primary human cell types and in vitro. A majority of the genome showed substantial flexibility of nucleosome positions, whereas a small fraction showed reproducibly positioned nucleosomes. Certain sites that position in vitro can anchor the formation of nucleosomal arrays that have cell type-specific spacing in vivo. Our results unveil an interplay of sequence-based nucleosome preferences and non-nucleosomal factors in determining nucleosome organization within mammalian cells. 相似文献
5.
The transforming gene of Moloney murine sarcoma virus 总被引:31,自引:0,他引:31
A cleavage map of the Moloney murine sarcoma viral DNA was constructed and compared with that of a spontaneously occurring deletion mutant. By restriction enzyme analysis, it was shown that a region encompassing over 40% of the viral information was not essential for transformation or rescue of the deletion mutant. The transforming region was further localised by analysis of the transforming activity in tissue culture of isolated restriction fragments of linear duoble-stranded sarcoma viral DNA. In each case, DNA fragments that retained transforming activity preserved the cell-derived insertion sequences of the viral genome. Moreover, such transformants invariably expressed RNA specific to this region. By these two approaches, it was possible to demonstrate that the transforming region of the viral genome begins very near or within the cell-derived insertion sequences. Thus, the transforming gene of this mammalian sarcoma virus originates from within the mouse cell genome. 相似文献
6.
DNA甲基化是哺乳动物基因组最常见的修饰方式,它存在于生物体正常的生理过程,DNA异常甲基化和疾病的发生发展有关.该文综述了癌症中存在着的DNA的异常甲基化现象,即抑癌基因的高度甲基化,低表达,及癌基因的低甲基化,高表达,检测这些基因的甲基化状态可以为癌症的早期诊断及治疗提供参考依据. 相似文献
7.
Long-range restriction site mapping of mammalian genomic DNA 总被引:3,自引:0,他引:3
Molecular analysis of many problems in genetics would be facilitated by the ability to construct restriction site maps of long stretches of genomic DNA and to directly place genes on these maps. Pulsed-field gradient gel electrophoresis allows measurement of the size of DNA fragments up to at least 2,000 kilobase pairs (kb) long and we have used this technique here to map sites for one class of infrequently cutting restriction enzyme over a total of 1,500 kb of mouse genomic DNA. The sites for these enzymes tend to be clustered in the genome. These clusters may correspond to the short stretches of C + G-rich unmethylated DNA often associated with mammalian genes. 相似文献
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A physical map of the mouse genome 总被引:1,自引:0,他引:1
Gregory SG Sekhon M Schein J Zhao S Osoegawa K Scott CE Evans RS Burridge PW Cox TV Fox CA Hutton RD Mullenger IR Phillips KJ Smith J Stalker J Threadgold GJ Birney E Wylie K Chinwalla A Wallis J Hillier L Carter J Gaige T Jaeger S Kremitzki C Layman D Maas J McGrane R Mead K Walker R Jones S Smith M Asano J Bosdet I Chan S Chittaranjan S Chiu R Fjell C Fuhrmann D Girn N Gray C Guin R Hsiao L Krzywinski M Kutsche R Lee SS Mathewson C McLeavy C Messervier S Ness S Pandoh P Prabhu AL Saeedi P 《Nature》2002,418(6899):743-750
A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human-mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy. 相似文献
10.
Modular regulatory principles of large non-coding RNAs 总被引:3,自引:0,他引:3
11.
A transposon-like element in human DNA 总被引:3,自引:0,他引:3
K E Paulson N Deka C W Schmid R Misra C W Schindler M G Rush L Kadyk L Leinwand 《Nature》1985,316(6026):359-361
12.
Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project 总被引:2,自引:0,他引:2
ENCODE Project Consortium Birney E Stamatoyannopoulos JA Dutta A Guigó R Gingeras TR Margulies EH Weng Z Snyder M Dermitzakis ET Thurman RE Kuehn MS Taylor CM Neph S Koch CM Asthana S Malhotra A Adzhubei I Greenbaum JA Andrews RM Flicek P Boyle PJ Cao H Carter NP Clelland GK Davis S Day N Dhami P Dillon SC Dorschner MO Fiegler H Giresi PG Goldy J Hawrylycz M Haydock A Humbert R James KD Johnson BE Johnson EM Frum TT Rosenzweig ER Karnani N Lee K Lefebvre GC Navas PA Neri F Parker SC Sabo PJ 《Nature》2007,447(7146):799-816
13.
When telomeres are rendered dysfunctional through replicative attrition of the telomeric DNA or by inhibition of shelterin, cells show the hallmarks of ataxia telangiectasia mutated (ATM) kinase signalling. In addition, dysfunctional telomeres might induce an ATM-independent pathway, such as ataxia telangiectasia and Rad3-related (ATR) kinase signalling, as indicated by the phosphorylation of the ATR target CHK1 in senescent cells and the response of ATM-deficient cells to telomere dysfunction. However, because telomere attrition is accompanied by secondary DNA damage, it has remained unclear whether there is an ATM-independent pathway for the detection of damaged telomeres. Here we show that damaged mammalian telomeres can activate both ATM and ATR and address the mechanism by which the shelterin complex represses these two important DNA damage signalling pathways. We analysed the telomere damage response on depletion of either or both of the shelterin proteins telomeric repeat binding factor 2 (TRF2) and protection of telomeres 1 (POT1) from cells lacking ATM and/or ATR kinase signalling. The data indicate that TRF2 and POT1 act independently to repress these two DNA damage response pathways. TRF2 represses ATM, whereas POT1 prevents activation of ATR. Unexpectedly, we found that either ATM or ATR signalling is required for efficient non-homologous end-joining of dysfunctional telomeres. The results reveal how mammalian telomeres use multiple mechanisms to avoid DNA damage surveillance and provide an explanation for the induction of replicative senescence and genome instability by shortened telomeres. 相似文献
14.
A Rad26-Def1 complex coordinates repair and RNA pol II proteolysis in response to DNA damage 总被引:11,自引:0,他引:11
Woudstra EC Gilbert C Fellows J Jansen L Brouwer J Erdjument-Bromage H Tempst P Svejstrup JQ 《Nature》2002,415(6874):929-933
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Warren WC Hillier LW Marshall Graves JA Birney E Ponting CP Grützner F Belov K Miller W Clarke L Chinwalla AT Yang SP Heger A Locke DP Miethke P Waters PD Veyrunes F Fulton L Fulton B Graves T Wallis J Puente XS López-Otín C Ordóñez GR Eichler EE Chen L Cheng Z Deakin JE Alsop A Thompson K Kirby P Papenfuss AT Wakefield MJ Olender T Lancet D Huttley GA Smit AF Pask A Temple-Smith P Batzer MA Walker JA Konkel MK Harris RS Whittington CM Wong ES Gemmell NJ Buschiazzo E Vargas Jentzsch IM Merkel A 《Nature》2008,453(7192):175-183
We present a draft genome sequence of the platypus, Ornithorhynchus anatinus. This monotreme exhibits a fascinating combination of reptilian and mammalian characters. For example, platypuses have a coat of fur adapted to an aquatic lifestyle; platypus females lactate, yet lay eggs; and males are equipped with venom similar to that of reptiles. Analysis of the first monotreme genome aligned these features with genetic innovations. We find that reptile and platypus venom proteins have been co-opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypus biology. Expansions of protein, non-protein-coding RNA and microRNA families, as well as repeat elements, are identified. Sequencing of this genome now provides a valuable resource for deep mammalian comparative analyses, as well as for monotreme biology and conservation. 相似文献
17.
DNA methylation is highly dynamic during mammalian embryogenesis. It is broadly accepted that the paternal genome is actively depleted of 5-methylcytosine at fertilization, followed by passive loss that reaches a minimum at the blastocyst stage. However, this model is based on limited data, and so far no base-resolution maps exist to support and refine it. Here we generate genome-scale DNA methylation maps in mouse gametes and from the zygote through post-implantation. We find that the oocyte already exhibits global hypomethylation, particularly at specific families of long interspersed element 1 and long terminal repeat retroelements, which are disparately methylated between gametes and have lower methylation values in the zygote than in sperm. Surprisingly, the oocyte contributes a unique set of differentially methylated regions (DMRs)--including many CpG island promoters--that are maintained in the early embryo but are lost upon specification and absent from somatic cells. In contrast, sperm-contributed DMRs are largely intergenic and become hypermethylated after the blastocyst stage. Our data provide a genome-scale, base-resolution timeline of DNA methylation in the pre-specified embryo, when this epigenetic modification is most dynamic, before returning to the canonical somatic pattern. 相似文献
18.
Molecular basis of xeroderma pigmentosum group C DNA recognition by engineered meganucleases 总被引:1,自引:0,他引:1
Redondo P Prieto J Muñoz IG Alibés A Stricher F Serrano L Cabaniols JP Daboussi F Arnould S Perez C Duchateau P Pâques F Blanco FJ Montoya G 《Nature》2008,456(7218):107-111
Xeroderma pigmentosum is a monogenic disease characterized by hypersensitivity to ultraviolet light. The cells of xeroderma pigmentosum patients are defective in nucleotide excision repair, limiting their capacity to eliminate ultraviolet-induced DNA damage, and resulting in a strong predisposition to develop skin cancers. The use of rare cutting DNA endonucleases-such as homing endonucleases, also known as meganucleases-constitutes one possible strategy for repairing DNA lesions. Homing endonucleases have emerged as highly specific molecular scalpels that recognize and cleave DNA sites, promoting efficient homologous gene targeting through double-strand-break-induced homologous recombination. Here we describe two engineered heterodimeric derivatives of the homing endonuclease I-CreI, produced by a semi-rational approach. These two molecules-Amel3-Amel4 and Ini3-Ini4-cleave DNA from the human XPC gene (xeroderma pigmentosum group C), in vitro and in vivo. Crystal structures of the I-CreI variants complexed with intact and cleaved XPC target DNA suggest that the mechanism of DNA recognition and cleavage by the engineered homing endonucleases is similar to that of the wild-type I-CreI. Furthermore, these derivatives induced high levels of specific gene targeting in mammalian cells while displaying no obvious genotoxicity. Thus, homing endonucleases can be designed to recognize and cleave the DNA sequences of specific genes, opening up new possibilities for genome engineering and gene therapy in xeroderma pigmentosum patients whose illness can be treated ex vivo. 相似文献
19.
Gene targeting in normal and amplified cell lines 总被引:25,自引:0,他引:25
Targeted recombination in mammalian cells is rare compared with non-homologous integration. In Saccharomyces cerevisiae the reverse is true. Differences in targeting efficiency could arise because a target of unique DNA is 200 times more dilute in mammalian genomes than it is in yeast. We tested this possibility by measuring gene targeting in normal CHO cells with two copies of the dihydrofolate reductase (DHFR) gene and in amplified CHOC 400 cells, which carry 800 copies. If the concentration of the target gene is critical, amplified cells should show an enhanced frequency of targeted recombination relative to non-homologous integration. Using a positive/negative selection protocol, we demonstrated that the efficiency of targeting into DHFR genes is indistinguishable in normal and amplified CHO cells. As targeting does not depend on the number of targets, the search for homology is not a rate-limiting step in the mammalian pathway of gene targeting. Thus, the difference in genome size is not the basis for the different outcomes of targeting experiments in S. cerevisiae and mammals. 相似文献
20.
Genome-wide analysis reveals novel molecular features of mouse recombination hotspots 总被引:1,自引:0,他引:1
Smagulova F Gregoretti IV Brick K Khil P Camerini-Otero RD Petukhova GV 《Nature》2011,472(7343):375-378