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PubMed2001

Methyl-CpG-binding protein 2 represses LINE-1 expression and retrotransposition but not Alu transcription.

In order to explore the defense mechanism by which retrotransposons are repressed, we assessed the ability of methyl-CpG-binding protein 2, MeCP2, to influence LINE-1 (L1) and Alu transcription and, furthermore, L1 retrotransposition. In transient transfection assays, targeting of the transcriptional-repression domain (TRD) of MeCP2 (via a linked Gal4 DNA-binding domain) to the transcriptional start site of L1 promoter-driven reporter constructs efficiently repressed transcription. The Gal4-linked TRD of the related methyl-CpG-binding protein MBD1 also repressed transcription but not that of MBD2. Furthermore, full-length MeCP2 effectively repressed transcription of a HpaII-methylated L1 reporter. Secondly, we used a genetic assay employing a full-length neo-marked L1 reporter construct to study L1 retrotransposition. We found the Gal4-linked TRD of MeCP2 to repress effectively L1 retrotransposition when targeted to the retrotransposition reporter. Retrotransposition was also reduced in response to in vitro HpaII methylation of the reporter and was further decreased by co-expressed full-length MeCP2. In striking contrast expression of the Gal4-linked TRD of MeCP2 had no inhibiting effect on transcription of an AluSx reporter tagged with a 7S-upstream sequence. Furthermore, full-length MeCP2 abrogated the methylation-induced repression of this reporter. Our results indicate that MeCP2 serves a role in repression of L1 expression and retrotransposition but has no inhibiting effect on Alu transcription.

Alu Elements↗
PubMed2002

Selective stimulation of translational expression by Alu RNA.

Human Alu and adenovirus VA1 RNAs each stimulate the translational expression of reporter genes in co-transient transfection assays without affecting either the rate of global protein synthesis or the abundance of the reporter mRNA. This selective, post-transcriptional stimulation of expression, which is observed in human and mouse cell lines and for three reporters, acts through a PKR- independent mechanism. The activity of Alu and VA1 RNAs in this assay is transient, causing a reduction in the lag time for the translational expression of the newly synthesized reporter mRNAs. The reduction in this lag time accounts for the relative selectivity of the effect upon the expression of the reporter and suggests novel roles for Alu and VA1 RNA in cell stress recovery and viral infection. Deletion analysis demonstrates that a specific region residing within the right monomer of the dimeric Alu consensus sequence is necessary for activity. Highly abundant left Alu monomer transcripts are inactive but the right Alu monomer is fully active, although its transcripts are scarce. Mouse B1 and B2 SINE RNAs stimulate reporter gene expression in mouse cells, suggesting that this activity is a general property of eucaryotic SINEs.

Adenoviridae↗
PubMed2004

Conserved tertiary base pairing ensures proper RNA folding and efficient assembly of the signal recognition particle Alu domain.

Proper folding of the RNA is an essential step in the assembly of functional ribonucleoprotein complexes. We examined the role of conserved base pairs formed between two distant loops in the Alu portion of the mammalian signal recognition particle RNA (SRP RNA) in SRP assembly and functions. Mutations disrupting base pairing interfere with folding of the Alu portion of the SRP RNA as monitored by probing the RNA structure and the binding of the protein SRP9/14. Complementary mutations rescue the defect establishing a role of the tertiary loop-loop interaction in RNA folding. The same mutations in the Alu domain have no major effect on binding of proteins to the S domain suggesting that the S domain can fold independently. Once assembled into a complete SRP, even particles that contain mutant RNA are active in arresting nascent chain elongation and translocation into microsomes, and, therefore, tertiary base pairing does not appear to be essential for these activities. Our results suggest a model in which the loop-loop interaction and binding of the protein SRP9/14 play an important role in the early steps of SRP RNA folding and assembly.

Alu Elements↗
PubMed2002

A two-hybrid screening of human Tau protein: interactions with Alu-derived domain.

The microtubule associated protein tau has been implicated in several neurodegenerative diseases, grouped as tauopathies. To search for tau-associated proteins, the two-hybrid system was used with tau as a bait and an adult human brain cDNA library as a source of putative interacting proteins. We have identified two positive clones consisting of an Alu-derived amino acid sequence that binds to tau and show moderate homology with a motif found in several neuronal proteins related to neurodegenerative disorders. We have also demonstrated that the Alu-derived motif interacts in vitro with tau and may be involved in modulation of its phosphorylation. These findings suggest the existence of tau-binding proteins that are able to bind to tau through their Alu-derived sequence in a direct way. The possible interaction of these proteins with tau could play a role in its cellular localization, regulate the amount of phosphorylated tau and also be involved in the pathological processes of tauopathies.

Alu Elements↗
PubMed2001

Biased distribution of inverted and direct Alus in the human genome: implications for insertion, exclusion, and genome stability.

Alu sequences, the most abundant class of large dispersed DNA repeats in human chromosomes, contribute to human genome dynamics. Recently we reported that long inverted repeats, including human Alus, can be strong initiators of genetic change in yeast. We proposed that the potential for interactions between adjacent, closely related Alus would influence their stability and this would be reflected in their distribution. We have undertaken an extensive computational analysis of all Alus (the database is at http://dir.niehs.nih.gov/ALU) to better understand their distribution and circumstances under which Alu sequences might affect genome stability. Alus separated by <650 bp were categorized according to orientation, length of regions sharing high sequence identity, distance between highly identical regions, and extent of sequence identity. Nearly 50% of all Alu pairs have long alignable regions (>275 bp), corresponding to nearly full-length Alus, regardless of orientation. There are dramatic differences in the distributions and character of Alu pairs with closely spaced, nearly identical regions. For Alu pairs that are directly repetitive, approximately 30% have highly identical regions separated by <20 bp, but only when the alignments correspond to near full-size or half-size Alus. The opposite is found for the distribution of inverted repeats: Alu pairs with aligned regions separated by <20 bp are rare. Furthermore, closely spaced direct and inverted Alus differ in their truncation patterns, suggesting differences in the mechanisms of insertion. At larger distances, the direct and inverted Alu pairs have similar distributions. We propose that sequence identity, orientation, and distance are important factors determining insertion of adjacent Alus, the frequency and spectrum of Alu-associated changes in the genome, and the contribution of Alu pairs to genome instability. Based on results in model systems and the present analysis, closely spaced inverted Alu pairs with long regions of alignment are likely at-risk motifs (ARMs) for genome instability.

Alu Elements↗
PubMed2002

Patterns of human diversity, within and among continents, inferred from biallelic DNA polymorphisms.

Previous studies have reported that about 85% of human diversity at Short Tandem Repeat (STR) and Restriction Fragment Length Polymorphism (RFLP) autosomal loci is due to differences between individuals of the same population, whereas differences among continental groups account for only 10% of the overall genetic variance. These findings conflict with popular notions of distinct and relatively homogeneous human races, and may also call into question the apparent usefulness of ethnic classification in, for example, medical diagnostics. Here, we present new data on 21 Alu insertions in 32 populations. We analyze these data along with three other large, globally dispersed data sets consisting of apparently neutral biallelic nuclear markers, as well as with a beta-globin data set possibly subject to selection. We confirm the previous results for the autosomal data, and find a higher diversity among continents for Y-chromosome loci. We also extend the analyses to address two questions: (1) whether differences between continental groups, although small, are nevertheless large enough to confidently assign individuals to their continent on the basis of their genotypes; (2) whether the observed genotypes naturally cluster into continental or population groups when the sample source location is ignored. Using a range of statistical methods, we show that classification errors are at best around 30% for autosomal biallelic polymorphisms and 27% for the Y chromosome. Two data sets suggest the existence of three and four major groups of genotypes worldwide, respectively, and the two groupings are inconsistent. These results suggest that, at random biallelic loci, there is little evidence, if any, of a clear subdivision of humans into biologically defined groups.

Alleles↗
PubMed2005

Evolutionary mechanisms shaping the genomic structure of the Williams-Beuren syndrome chromosomal region at human 7q11.23.

About 5% of the human genome consists of segmental duplications or low-copy repeats, which are large, highly homologous (>95%) fragments of sequence. It has been estimated that these segmental duplications emerged during the past approximately 35 million years (Myr) of human evolution and that they correlate with chromosomal rearrangements. Williams-Beuren syndrome (WBS) is a segmental aneusomy syndrome that is the result of a frequent de novo deletion at 7q11.23, mediated by large (approximately 400-kb) region-specific complex segmental duplications composed of different blocks. We have precisely defined the structure of the segmental duplications on human 7q11.23 and characterized the copy number and structure of the orthologous regions in other primates (macaque, orangutan, gorilla, and chimpanzee). Our data indicate a recent origin and rapid evolution of the 7q11.23 segmental duplications, starting before the diversification of hominoids (approximately 12-16 million years ago [Mya]), with species-specific duplications and intrachromosomal rearrangements that lead to significant differences among those genomes. Alu sequences are located at most edges of the large hominoid-specific segmental duplications, suggesting that they might have facilitated evolutionary rearrangements. We propose a mechanistic model based on Alu-mediated duplicated transposition along with nonallelic homologous recombination for the generation and local expansion of the segmental duplications. The extraordinary rate of evolutionary turnover of this region, rich in segmental duplications, results in important genomic variation among hominoid species, which could be of functional relevance and predispose to disease.

Alu Elements↗
PubMed1996

Comparative analysis of 1196 orthologous mouse and human full-length mRNA and protein sequences.

A large set of mRNA and encoded protein sequences, from orthologous murine and human genes, was compiled to analyze statistical, biological, and evolutionary properties of coding and noncoding transcribed sequences. Protein sequence conservation varied between 36% and 100% identity, with an average value of 85%. The average degree of nucleotide sequence identity for the corresponding coding sequences was also approximately 85%, whereas 5' and 3' untranslated regions (UTRs) were less conserved, with aligned identities of 67% and 69%, respectively. For some mouse and human genes, nucleotide sequences are more highly conserved than the encoded protein sequences. A subset of 32 sequences, consisting of only mouse/human protein pairs for which the human sequence represents a positionally cloned disease gene, had properties very similar to the larger data set, suggesting that our data are representative of the genome as a whole. With respect to sequence conservation, two interesting outliers are the breast cancer (BRCAI) gene product and the testis-determining factor (SRY), both of which display among the lowest degrees of sequence identity. The occurrence of both introns and repetitive elements (e.g., Alu, Bl) in 5' and 3' UTRs was also studied. These results provide one benchmark for the "comparative genomics" of mice and humans, with practical implications for the cross-referencing of transcript maps. Also, they should prove useful in estimating the additional sampling diversity provided by mouse EST sequencing projects designed to complement the existing human cDNA collection.

Amino Acid Sequence↗
PubMed2003

Genetic variation among world populations: inferences from 100 Alu insertion polymorphisms.

We examine the distribution and structure of human genetic diversity for 710 individuals representing 31 populations from Africa, East Asia, Europe, and India using 100 Alu insertion polymorphisms from all 22 autosomes. Alu diversity is highest in Africans (0.349) and lowest in Europeans (0.297). Alu insertion frequency is lowest in Africans (0.463) and higher in Indians (0.544), E. Asians (0.557), and Europeans (0.559). Large genetic distances are observed among African populations and between African and non-African populations. The root of a neighbor-joining network is located closest to the African populations. These findings are consistent with an African origin of modern humans and with a bottleneck effect in the human populations that left Africa to colonize the rest of the world. Genetic distances among all pairs of populations show a significant product-moment correlation with geographic distances (r = 0.69, P < 0.00001). F(ST), the proportion of genetic diversity attributable to population subdivision is 0.141 for Africans/E. Asians/Europeans, 0.047 for E. Asians/Indians/Europeans, and 0.090 for all 31 populations. Resampling analyses show that approximately 50 Alu polymorphisms are sufficient to obtain accurate and reliable genetic distance estimates. These analyses also demonstrate that markers with higher F(ST) values have greater resolving power and produce more consistent genetic distance estimates.

Africa↗
PubMed2001

A novel chromatin immunoprecipitation and array (CIA) analysis identifies a 460-kb CENP-A-binding neocentromere DNA.

Centromere protein A (CENP-A) is an essential histone H3-related protein that constitutes the specialized chromatin of an active centromere. It has been suggested that this protein plays a key role in the epigenetic marking and transformation of noncentromeric genomic DNA into functional neocentromeres. Neocentromeres have been identified on more than two-thirds of the human chromosomes, presumably involving different noncentromeric DNA sequences, but it is unclear whether some generalized sequence properties account for these neocentromeric sites. Using a novel method combining chromatin immunoprecipitation and genomic array hybridization, we have identified a 460-kb CENP-A-binding DNA domain of a neocentromere derived from the 20p12 region of an invdup (20p) human marker chromosome. Detailed sequence analysis indicates that this domain contains no centromeric alpha-satellite, classical satellites, or other known pericentric repetitive sequence motifs. Putative gene loci are detected, suggesting that their presence does not preclude neocentromere formation. The sequence is not significantly different from surrounding non-CENP-A-binding DNA in terms of the prevalence of various interspersed repeats and binding sites for DNA-interacting proteins (Topoisomerase II and High-Mobility-Group protein I). Notable variations include a higher AT content similar to that seen in human alpha-satellite DNA and a reduced prevalence of long terminal repeats (LTRs), short interspersed repeats (SINEs), and Alus. The significance of these features in neocentromerization is discussed.

Alu Elements↗
PubMed2001

Statistical analysis of the DNA sequence of human chromosome 22.

We study statistical patterns in the DNA sequence of human chromosome 22, the first completely sequenced human chromosome. We find that (i). the 33.4 x 10(6) nucleotide long human chromosome exhibits long-range power-law correlations over more than four orders of magnitude, (ii). the entropies H(n) of the frequency distribution of oligonucleotides of length n (n-mers) grow sublinearly with increasing n, indicating the presence of higher-order correlations for all of the studied lengths 1<or=n<or=10, and (iii). the generalized entropies H(n)(q) of n-mers decrease monotonically with increasing q and the decay of H(n)(q) with q becomes steeper with increasing n<or=10, indicating that the frequency distribution of oligonucleotides becomes increasingly nonuniform as the length n increases. We investigate to what degree known biological features may explain the observed statistical patterns. We find that (iv). the presence of interspersed repeats may cause the sublinear increase of H(n) with n, and that (v). the presence of monomeric tandem repeats as well as the suppression of CG dinucleotides may cause the observed decay of H(n)(q) with q.

Algorithms↗
PubMed2003

Repeats and correlations in human DNA sequences.

We study the nucleotide-nucleotide mutual information function I(k) of the DNA sequences of the three completely sequenced human chromosomes 20, 21, and 22. We find in each human chromosome (i) the absence of the k=3 base pair (bp) sequence periodicity characteristic for protein coding regions, (ii) the absence of the k=10-11 bp sequence periodicity characteristic for both protein secondary structure and DNA bendability, and (iii) the presence of significant statistical dependencies at about k=135 bp and at about k=165 bp. We investigate to which degree the density and composition of interspersed repeats might explain these observed statistical patterns in all three human chromosomes. We use simple stochastic models to substitute known interspersed repeats and find by numerical studies that (iv) the presence of interspersed repeats dominates short-range correlations as measured by I(k) on the scale of several hundred base pairs in human chromosomes 20, 21, and 22. On the other hand, we find that (v) interspersed repeats contribute only weakly to long-range correlations due to the clustering of highly abundant Alu repeats.

Alu Elements↗
PubMed2003

Direct imaging of domains in the Lbeta' state of 1,2-dipalmitoylphosphatidylcholine bilayers.

A near-field scanning optical microscope was used to study domain formation and evolution in single-component supported lipid bilayers in the gel (L(beta') state. Results on 1,2-dipalmitoylphosphatidylcholine (DPPC) bilayers on glass substrates at room temperature are presented. The domain structure is determined by means of the optical anisotropy of the sample, which arises because DPPC molecules are tilted at theta approximately 32 degrees with respect to the bilayer normal [J. F. Nagle and S. Tristram-Nagle, Biochim. Biophys. Acta 1469, 159 (2000)]. From the measurements we obtain the difference in the index of refraction for the directions parallel and perpendicular to the acyl chains of the lipid molecules, Delta(n)=0.37+/-0.12, in good agreement with calculated and measured values. Direct evidence of the existence of domains in the L(beta') state is provided. These domains, defined as the correlation of the tilt angle theta, are found to be 1-2 microm across. Furthermore, it was found that they are robust under single-lipid-molecule diffusion, remaining unchanged over periods of hundreds of minutes.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2003

Nonlinear analysis of correlations in Alu repeat sequences in DNA.

We report on a nonlinear analysis of deterministic structures in Alu repeats, one of the richest repetitive DNA sequences in the human genome. Alu repeats contain the recognition sites for the restriction endonuclease AluI, which is what gives them their name. Using the nonlinear prediction method developed in chaos theory, we find that all Alu repeats have novel deterministic structures and show strong nonlinear correlations that are absent from exon and intron sequences. Furthermore, the deterministic structures of Alus of younger subfamilies show panlike shapes. As young Alus can be seen as mutation free copies from the "master genes," it may be suggested that the deterministic structures of the older subfamilies are results of an evolution from a "panlike" structure to a more diffuse correlation pattern due to mutation.

Alu Elements↗
PubMed2006

Quasiperiodic property in Alu repeats.

We investigate the possible quasiperiodic property in the sequences of Alu repeats, one of typical noncoding DNA sequences. We calculated the quasiperiods of the right and left monomers of Alu repeats of different families with quasiperiodic matrix algorithm. It is interesting that the right monomers of all families show significant quasiperiod 8 in their sequences while the left monomers show quasiperiods 8 or 5. Our results indicate that there exist common quasiperiods in most Alu repeats. This may be helpful to further explore possible functions of Alu repeats.

Algorithms↗
PubMed2001

ARP/wARP and molecular replacement.

The aim of ARP/wARP is improved automation of model building and refinement in macromolecular crystallography. Once a molecular-replacement solution has been obtained, it is often tedious to refine and rebuild the initial (search) model. ARP/wARP offers three options to automate that task to varying extents: (i) autobuilding of a completely new model based on phases calculated from the molecular-replacement solution, (ii) updating of the initial model by atom addition and deletion to obtain an improved map and (iii) docking of a structure onto a new (or mutated) sequence, followed by rebuilding and refining the side chains in real space. A few examples are presented where ARP/wARP made a considerable difference in the speed of structure solution and/or made possible refinement of otherwise difficult or uninterpretable maps. The resolution range allowing complete autobuilding of protein structures is currently 2.0 A, but for map improvement considerable advances over more conventional refinement techniques are evident even at 3.2 A spacing.

Alu Elements↗
PubMed2005

PROGINS Alu sequence insertion is associated with hyperprolactinaemia but not leiomyoma susceptibility.

OBJECTIVE: Leiomyoma and hyperprolactinaemia are both progesterone-dependent diseases. Hormone-related genes, such as the progesterone receptor (PGR), might be involved in their pathogenesis. DESIGN AND MEASUREMENTS: Subjects were divided into three groups: (i) leiomyoma (n = 120); (ii) hyperprolactinaemia (n = 101); (iii) normal controls (n = 140). We investigated the Alu (306-bp DNA) insertion in intron G of the PGR gene in all individuals. PGR gene polymorphisms [T1 (wild-type); T2 (PROGINS, with Alu insertion)] were determined by PCR and electrophoresis. Genotype and allele frequencies of the PROGINS in each group were detected and compared. RESULTS: We observed no significant difference of the PGR*T1/T2 genotypes and allele frequencies between leiomyoma and other two groups. The proportions of T1 homozygote/heterozygote/T2 homozygote in each group were (i) 90/8.3/1.7%; (ii) 84.2/9.9/5.9%; (iii) 92.9/6.4/0.7%. In contrast, a higher percentage of T2-related genotype and allele were noted in hyperprolactinaemic women compared to other two groups. The proportions of T1/T2 alleles in each group were: (i) 94.2/5.8%; (ii) 89.1/10.9%; (iii) 96.1/3.9%. CONCLUSIONS: The PROGIN*T2-related genotype and allele are related to a higher susceptibility to hyperprolactinaemia. The PROGINS polymorphism is not associated with leiomyoma development.

Adult↗