Publications 2009
Abstract:
View this Publication:
Supplemental Data:
PubMed Link:
Abstract:
View this Publication:
Supplemental Data:
PubMed Link:
Abstract:
View this Publication:
Supplemental Data:
PubMed Link:
Abstract:
View this Publication:
Supplemental Data:
PubMed Link:
Abstract:
View this Publication:
Supplemental Data:
Supplemental Primers
Supplemental Alignments
PubMed Link:
Abstract:
View this Publication:
Supplemental Data:
PubMed Link:
Abstract:
View this Publication:
Supplemental Data:
PubMed Link:
Abstract:
View this Publication:
Supplemental Data:
PubMed Link:
Abstract:
View this Publication:
Supplemental Data:
PubMed Link:
Abstract:
SVA elements represent the youngest family of hominid non-LTR retrotransposons, which alter the human genome continuously. They stand out due to their organization as composite repetitive elements. To draw conclusions on the assembly process that led to the current organization of SVA elements and on their transcriptional regulation, we initiated our study by assessing differences in structures of the 116 SVA elements located on human chromosome 19. We classified SVA elements into seven structural variants, including novel variants like 39-truncated elements and elements with 59-flanking sequence transductions. We established a genome-wide inventory of 59-transduced SVA elements encompassing ;8% of all human SVA elements. The diversity of 59 transduction events found indicates transcriptional control of their SVA source elements by a multitude of external cellular promoters in germ cells in the course of their evolution and suggests that SVA elements might be capable of acquiring 59 promoter sequences. Our data indicate that SVA-mediated 59 transduction events involve alternative RNA splicing at cryptic splice sites. We analyzed one remarkably successful human-specific SVA 59 transduction group in detail because it includes at least 32% of all SVA subfamily F members. An ancient retrotransposition event brought an SVA insertion under transcriptional control of the MAST2 gene promoter, giving rise to the primal source element of this group. Members of this group are currently transcribed. Here we show that SVA-mediated 59 transduction events lead to structural diversity of SVA elements and represent a novel source of genomic rearrangements contributing to genomic diversity.
View this Publication:
Publication
Supplemental Data:
Supplemental Table 1
Supplemental Table 2
Supplemental Figure 1
PubMed Link:
Link
Abstract:
Transposable elements (TEs) are an important source of genome diversity and play a crucial role in genome evolution. A recent study by Zhao et al. describes novel patterns of TE diversification in the genome of the extinct mammoth Mammuthus primigenius. Analysis of Mammuthus has provided a unique genome landscape, a pivotal species for understanding TEs and genome evolution and hints at the diversity we verge on discovering by expanding our taxonomic sampling among genomes. Strategies based on this work might also revolutionize investigations of the interface between TE dynamics and genome diversity.
View this Publication:
Publication
Supplemental Data:
PubMed Link:
Link
Abstract:
Allelic differences of chemokine (C-C motif ) receptor 5 (CCR5) and CCR2, as well as the ligand for the chemokine receptor CXCR4, stromal-derived factor (SDF-1), are known to suppress HIV-1 transmission and to be involved in delay in HIV-1 disease progression. The aim of our study was to investigate the frequencies of four mutations that confer resistance to HIV-1: CCR5-Delta32, CCR5-m303, CCR2-64I, and SDF1-3'A among Bahrainis. We have studied the DNA polymorphisms in 304 unrelated healthy Bahraini individuals without any known history of HIV-1 infection or AIDS symptoms. The CCR5-Delta32 mutation was detected by PCR analysis, while the CCR5-m303, CCR2-64I, and SDF1-3'A mutations were detected by PCR-restriction fragment length polymorphism (PCR-RFLP) tests. Allele frequencies and the fit to the Hardy-Weinberg equilibrium were evaluated using the Arlequin population genetics application. The frequencies of the CCR5-Delta32, CCR2-64I, and SDF1-3'A alleles were 2.8%, 8.9%, and 26.5%, respectively. No mutant alleles were detected for the CCR5-m303 mutation in 304 individuals. We estimated the risk of AIDS onset (relative hazard), computed from the three-locus genotype data. This is the first report of these four mutations conferring resistance to HIV-1 in the Bahraini population. The presence of the CCR5-Delta32 allele among Bahrainis may be attributed to the admixture with people of European descent. The CCR2-64I allele and especially the SDF1-3'A allele are predominant in the Bahraini population and may be associated with resistance to fast HIV-1 infection in Bahrainis, and thus their genotyping can be used for prognosis in HIV-infected individuals.
View this Publication:
Publication
Supplemental Data:
PubMed Link:
Link
Abstract:
Retrotransposons, specifically Alu and L1 elements, have been especially successful in their expansion throughout primate genomes. While most of these elements integrate through an endonuclease-mediated process termed target primed reverse transcription, a minority integrate using alternative methods. Here we present evidence for one such mechanism, which we term internal priming and demonstrate that loci integrating through this mechanism are qualitatively different from "classical" insertions. Previous examples of this mechanism are limited to cell culture assays, which show that reverse transcription can initiate upstream of the 3' poly-A tail during retrotransposon integration. To detect whether this mechanism occurs in vivo as well as in cell culture, we have analyzed the human genome for internal priming events using recently integrated L1 and Alu elements. Our examination of the human genome resulted in the recovery of twenty events involving internal priming insertions, which are structurally distinct from both classical TPRT-mediated insertions and non-classical insertions. We suggest two possible mechanisms by which these internal priming loci are created and provide evidence supporting a role in staggered DNA double-strand break repair. Also, we demonstrate that the internal priming process is associated with inter-chromosomal duplications and the insertion of filler DNA.
View this Publication:
Publication
Supplemental Data:
AIP Supplementary Sequences
L1IP Supplementary Sequences
Supplementary Primers
PubMed Link:
Link
Abstract:
Genus Macaca (Cercopithecidae: Papionini) is one of the most successful primate radiations. Despite previous studies on morphology and mitochondrial DNA analysis, a number of issues regarding the details of macaque evolution remain unsolved. Alu elements are a class of non-autonomous retroposons belonging to short interspersed elements that are specific to the primate lineage. Because retroposon insertions show very little homoplasy, and because the ancestral state (absence of the SINE) is known, Alu elements are useful genetic markers and have been utilized for analyzing primate phylogenentic relationships and human population genetic relationships. Using PCR display methodology, 298 new Alu insertions have been identified from ten species of macaques. Together with 60 loci reported previously, a total of 358 loci are used to infer the phylogenetic relationships of genus Macaca. With regard to earlier unresolved issues on the macaque evolution, the topology of our tree suggests that: 1) genus Macaca contains four monophyletic species groups; 2) within the Asian macaques, the silenus group diverged first, and members of the sinica and fascicularis groups share a common ancestor; 3) Macaca arctoides are classified in the sinica group. Our results provide a robust molecular phylogeny for genus Macaca with stronger statistical support than previous studies. The present study also illustrates that SINE-based approaches are a powerful tool in primate phylogenetic studies and can be used to successfully resolve evolutionary relationships between taxa at scales from the ordinal level to closely related species within one genus.
View this Publication:
Publication
Supplemental Data:
Primer Information and Identification Key
PubMed Link:
Link
Abstract:
Their ability to move within genomes gives transposable elements an intrinsic propensity to affect genome evolution. Non-long terminal repeat (LTR) retrotransposons — including LINE-1, Alu and SVA elements — have proliferated over the past 80 million years of primate evolution and now account for approximately one-third of the human genome. In this Review, we focus on this major class of elements and discuss the many ways that they affect the human genome: from generating insertion mutations and genomic instability to altering gene expression and contributing to genetic innovation. Increasingly detailed analyses of human and other primate genomes are revealing the scale and complexity of the past and current contributions of non-LTR retrotransposons to genomic change in the human lineage.
View this Publication:
Publication
Supplemental Data:
PubMed Link:
Link
Abstract:
Structural variants (SVs) are common in the human genome. Because approximately half of the human genome consists of repetitive, transposable DNA sequences, it is plausible that these elements play an important role in generating SVs in humans. Sequencing of the diploid genome of one individual human (HuRef) affords us the opportunity to assess, for the first time, the impact of mobile elements on SVs in an individual in a thorough and unbiased fashion. In this study, we systematically evaluated more than 8,000 SVs to identify mobile element-associated SVs as small as 100 bp and specific to the HuRef genome. Combining computational and experimental analyses, we identified and validated 706 mobile element insertion events (including Alu, L1, SVA elements and non-classical insertions), which added more than 305 kb of new DNA sequence to the HuRef genome compared to the Human Genome Project (HGP) reference sequence. We also identified 140 mobile element-associated deletions, which removed ~126 kb of sequence from the HuRef genome. Overall, ~10% of the HuRef-specific indels that are larger than 100 bp are caused by mobile element-associated events. More than one-third of the insertion/deletion events occurred in genic regions, and new Alu insertions occurred in exons of three human genes. Based on the number of insertions and the estimated time to the most recent common ancestor of HuRef and the HGP reference genome, we estimated the Alu, L1, and SVA retrotransposition rates to be one in 21 births, 212 births, and 916 births, respectively. This study presents the first comprehensive analysis of mobile element-related structural variants in the complete DNA sequence of an individual and demonstrates that mobile elements play an important role in generating inter-individual structural variation.
View this Publication:
Publication
Supplemental Data:
Supplemental Table 1
Supplemental Table 2
Supplemental Table 3
Supplemental Alignments
PubMed Link:
Link
Abstract:
PURPOSE: To examine the influence of a unilateral exercise training protocol on brachial artery reactivity (BAR) in 12 men (aged 81 +/- 5 yr). METHODS: Brachial artery diameters and blood flow parameters were assessed, in both arms, using high-resolution ultrasonography, before and after 5 min of forearm occlusion, before and at the end of each week of a 4-wk training program. Training consisted of a unilateral handgrip training protocol (nondominant arm) at 60% of maximal voluntary handgrip strength, performed for 4 wk, 4 d x wk(-1), 20 min per session, and a cadence of one contraction per 4 s. RESULTS: After training, handgrip strength increased 6.2% (baseline = 32.4 +/- 7.0 kg vs week 4 = 34.4 +/- 6.7 kg) in the trained arm only but failed to reach statistical significance (P = 0.10). No statistical changes were observed for blood pressure or resting HR. In contrast, BAR increased 45% (Pre = 2.9% vs Post = 4.1%, P = 0.05) in the trained arm only. Improvements in BAR were observed after the second week of training, without significant changes in the main vasodilatory trigger, defined as the relevant shear stimulus after forearm occlusion (P > 0.05). CONCLUSIONS: These data indicate that a localized short-term exercise program results in significant improvements in vascular function in the trained arm of elderly men compared with the control arm. Furthermore, the findings indicate a statistically significant increase in BAR at the end of the second week of training, despite a similar trigger for dilation versus before training.
View this Publication:
Supplemental Data:
PubMed Link:
Link
Abstract:
BACKGROUND: The angiotensin-converting enzyme (ACE) gene in humans has an insertion-deletion (I/D) polymorphic state in intron 16 on chromosome 17q23. This polymorphism has been widely investigated in different populations due to its association with the renin-angiotensin system. However, similar studies for Arab populations are limited. This study addresses the distribution of the ACE gene polymorphism in three Arab populations (Egyptians, Jordanians and Syrians). FINDINGS: The polymorphisms of ACE gene were investigated using polymerase chain reaction for detection of an I/D mutation. The results showed a high frequency of the ACE D allele among the three Arab populations, Egyptians (0.67), Jordanians (0.66) and Syrians (0.60), which is similar to those obtained from previous studies for Arab populations. CONCLUSIONS: The relationship between ACE alleles and disease in these three Arab populations is still not known, but the present results clearly suggest that geographic origin should be carefully considered in the increasing number of studies on the association between ACE alleles and disease etiology. This study adds to the data showing the wide variation in the distribution of the ACE alleles in different populations and highlights that great care needs to be taken when interpreting clinical data on the association of the ACE alleles with different diseases.
View this Publication:
Publication
Supplemental Data:
PubMed Link:
Link
Abstract:
BACKGROUND: The human platelet alloantigen system HPA-1 in the Egyptian population was examined by polymerase chain reaction using sequence-specific primers (PCR-SSP). The objectives of this study were to evaluate the allele frequency of HPA-1a and -1b in healthy Egyptian individuals and compare these with the international literature. Human platelet antigen (HPA) systems are associated with alloimmunization and organ transplantation rejection as well as the development of cardiovascular disease. Of the various HPA systems, HPA-1 specifically has been considered to be the most important antigenic system implicated in the Caucasian population. No study has yet examined this system in the Egyptian populations, however. We therefore investigated the allele frequency of the HPA-1 system in the Egyptian population. FINDINGS: To determine the allele frequency of the HPA-1a and -1b, we tested genomic DNAs from 206 healthy, unrelated Egyptian individuals using PCR-SSP. Our results showed that the 1a/1a genotype was the most predominant (59.22 %) followed by 1a/1b (34.95 %) and 1b/1b (5.83 %) with allele frequencies for 1a and 1b of 0.77 and 0.23, respectively, in the population. CONCLUSIONS: As compared with other geographic groups, a relatively high allele frequency of the HPA-1b in the Egyptian population may indicate a higher risk of alloimmunization. This study is the first to investigate the allele frequency of the HPA-1 system in the Egyptian population and serves as an outline for future clinical research associated with platelet disorders in this group.
View this Publication:
Publication
Supplemental Data:
PubMed Link:
Link
Abstract:
DNA double-strand breaks (DSBs) are a common form of cellular damage that can lead to cell death if not repaired promptly. Experimental systems have shown that DSB repair in eukaryotic cells is often imperfect and may result in the insertion of extra chromosomal DNA or the duplication of existing DNA at the breakpoint. These events are thought to be a source of genomic instability and human diseases, but it is unclear whether they have contributed significantly to genome evolution. Here we developed an innovative computational pipeline that takes advantage of the repetitive structure of genomes to detect repair-mediated duplication events (RDs) that occurred in the germline and created insertions of at least 50 bp of genomic DNA. Using this pipeline we identified over 1,000 probable RDs in the human genome. Of these, 824 were intra-chromosomal, closely linked duplications of up to 619 bp bearing the hallmarks of the synthesis-dependent strandannealing repair pathway. This mechanism has duplicated hundreds of sequences predicted to be functional in the human genome, including exons, UTRs, intron splice sites and transcription factor binding sites. Dating of the duplication events using comparative genomics and experimental validation revealed that the mechanism has operated continuously but with decreasing intensity throughout primate evolution. The mechanism has produced species-specific duplications in all primate species surveyed and is contributing to genomic variation among humans. Finally, we show that RDs have also occurred, albeit at a lower frequency, in non-primate mammals and other vertebrates, indicating that this mechanism has been an important force shaping vertebrate genome evolution.
View this Publication:
Publication
Supplemental Data:
PubMed Link:
Link
Abstract:
This study assessed cardiovascular disease risk factors in three groups of human subjects aged 20-34 [young, 20 male (M)/33 female (F)], 60-74 (aged, 29M/29F), and > 90 years (nonagenarian, 47M/50F). Components of the metabolic syndrome, cardiovascular disease, and markers of inflammation and oxidative stress were assessed. Nonagenarians weighed less than the two other groups (P < 0.001); however, there was no difference in percent fat among the three groups. Aged individuals had the highest prevalence of the metabolic syndrome (P < 0.001) according to the Adult Treatment Panel III classification. Both fibrinogen and homocysteine concentrations were significantly higher in the nonagenarians compared to younger groups. However, there were no significant differences between groups in fasting insulin, high sensitive C-reactive protein, and plasminogen activator inhibitor 1 concentrations. There were also no relationships between inflammation/ oxidative stress and the metabolic syndrome or cardiovascular disease although nonagenarians appear to be protected from oxidative damage to DNA.
View this Publication:
Publication
Supplemental Data:
PubMed Link:
Link
Abstract:
The Alu family is a highly successful group of non-LTR retrotransposons ubiquitously found in primate genomes. Similar to the L1 retrotransposon family, Alu elements integrate primarily through an endonuclease-dependent mechanism termed target site-primed reverse transcription (TPRT). Recent studies have suggested that, in addition to TPRT, L1 elements occasionally utilize an alternative endonucleaseindependent pathway for genomic integration. To determine whether an analogous mechanism exists for Alu elements, we have analyzed three publicly available primate genomes (human, chimpanzee and rhesus macaque) for endonuclease-independent recently integrated or lineage specific Alu insertions. We recovered twenty-three examples of such insertions and show that these insertions are recognizably different from classical TPRT-mediated Alu element integration. We suggest a role for this process in DNA double-strand break repair and present evidence to suggest its association with intra-chromosomal translocations, in-vitro RNA recombination (IVRR), and synthesis-dependent strand annealing (SDSA).
View this Publication:
Publication
Supplemental Data:
Cover
Supplemental Primers
Supplemental Sequences
PubMed Link:
Link
Abstract:
View this Publication:
Publication
Supplemental Data:
PubMed Link:
Link