Large Frequency Differences Research Articles

Follicular Lymphoma-Like B Cells In Healthy Individuals Are Released From Pretumoral Niches Established In Secondary Lymphoid Tissues

AbstractAbstract 466Follicular Lymphoma (FL) is a frequent mature B-cell neoplasia resulting from the malignant transformation of germinal center (GC) B-cells in secondary lymphoid organs. The t(14;18) translocation constitute both a genetic hallmark and a critical early event in the natural history of FL. t(14;18) is however not sufficient for malignant transformation, and further synergistic oncogenic events are clearly required. In line with this, t(14;18)+ cells can be detected in the blood of most healthy individuals (HI). However, large differences in frequencies can be observed between individuals with yet uncertain significance. We recently demonstrated that in HI carrying high t(14;18) frequencies, such circulating translocated cells constitute an expanding population of atypical B-cells displaying the geno/phenotypic features of FL. In particular, we found that in such individuals, these cells are “frozen” at a GC B-cell stage of differentiation, where sustained AID expression leads to constitutive somatic hypermutation (SHM), class switch recombination (CSR) and genomic instability. As such processes are responsible for the progressive acquisition of secondary oncogenic alteration in B-cell lymphomagenesis, we proposed that t(14;18)+ cells could represent bona fide FL precursors released from established premalignant niches in lymphoid organs (Roulland et al. JEM 2006, Agopian et al. 2009). To address this possibility, we now performed a systemic characterization of FL precursors in normal human biopsies: 20 paired blood/spleen/lymph nodes (LN) issued from organ donors, 10 blood/BM samples from patients undergoing cardiac surgery and 7 hyperplastic tonsils. Using a sensitive fluctuation PCR assay, we found that while children tonsils were negative, t(14;18)+ cells were very frequent in adult tissues (75% of spleens, 59% of LN and 30% of BM samples). The frequencies were distributed over a wide frequency spectrum (>500-fold), among which t(14;18)+ frequencies in spleen (up to 1/1000 cells) were surprisingly high, far above levels generally found in blood (from 1/100,000 to 1/10 million). To test the possibility that lymphoid organs (and in particular the spleen) constitute sanctuaries of FL precursors, we characterized t(14;18) cells in tissues at the molecular level, and evaluated if paired circulating and resident t(14;18)+ cells are clonally related. Using detailed molecular analysis of BCL2/IGH amplicons obtained by LR-PCR on coupled tissue samples or isolated splenic B-cell subsets discriminating naïve and GC/post-GC B-cells, we demonstrate that t(14;18) clones issued from spleen, LN and BM are the resident counterparts of the circulating pre-FL cells (including a «frozen» GC phenotype maintaining AID activity, with the presence of highly mutated Sμ regions, intra-Sμ deletions and for the most advanced clones, unusual stigmata of AID-mediated genomic instability linked to malignant progression). Furthermore, intraclonal variation (ICV) analysis of the upstream Sμ flanking region revealed the presence of an intense trafficking of the t(14;18)+ FL-like clones between lymphoid organs and/or blood. Indeed, clones presenting identical BCL2/IGH signature could be found in different organs and blood, and yet displayed systematic ICV, indicative of ongoing SHM and further supporting the derivation of such cells from GC derived B-cells with sustained AID activity. Collectively, these data establish a direct clonal relationship between resident t(14;18)+ cells and their circulating counterparts, and the early potential of such pre-FL GC-B cells to invade other reactive GC, and to disseminate in BM. These findings strongly impact on the current understanding of disease progression, and on the proper handling of t(14;18) frequency in blood as a potential early biomarker for lymphoma. Disclosures:No relevant conflicts of interest to declare.

Are substitution rates and RNA editing correlated?

BackgroundRNA editing is a post-transcriptional process that, in seed plants, involves a cytosine to uracil change in messenger RNA, causing the translated protein to differ from that predicted by the DNA sequence. RNA editing occurs extensively in plant mitochondria, but large differences in editing frequencies are found in some groups. The underlying processes responsible for the distribution of edited sites are largely unknown, but gene function, substitution rate, and gene conversion have been proposed to influence editing frequencies.ResultsWe studied five mitochondrial genes in the monocot order Alismatales, all showing marked differences in editing frequencies among taxa. A general tendency to lose edited sites was observed in all taxa, but this tendency was particularly strong in two clades, with most of the edited sites lost in parallel in two different areas of the phylogeny. This pattern is observed in at least four of the five genes analyzed. Except in the groups that show an unusually low editing frequency, the rate of C-to-T changes in edited sites was not significantly higher that in non-edited 3rd codon positions. This may indicate that selection is not actively removing edited sites in nine of the 12 families of the core Alismatales. In all genes but ccmB, a significant correlation was found between frequency of change in edited sites and synonymous substitution rate. In general, taxa with higher substitution rates tend to have fewer edited sites, as indicated by the phylogenetically independent correlation analyses. The elimination of edited sites in groups that lack or have reduced levels of editing could be a result of gene conversion involving a cDNA copy (retroprocessing). If so, this phenomenon could be relatively common in the Alismatales, and may have affected some groups recurrently. Indirect evidence of retroprocessing without a necessary correlation with substitution rate was found mostly in families Alismataceae and Hydrocharitaceae (e.g., groups that suffered a rapid elimination of all their edited sites, without a change in substitution rate).ConclusionsThe effects of substitution rate, selection, and/or gene conversion on the dynamics of edited sites in plant mitochondria remain poorly understood. Although we found an inverse correlation between substitution rate and editing frequency, this correlation is partially obscured by gene retroprocessing in lineages that have lost most of their edited sites. The presence of processed paralogs in plant mitochondria deserves further study, since most evidence of their occurrence is circumstantial.

Genome-wide effects of long-term divergent selection.

To understand the genetic mechanisms leading to phenotypic differentiation, it is important to identify genomic regions under selection. We scanned the genome of two chicken lines from a single trait selection experiment, where 50 generations of selection have resulted in a 9-fold difference in body weight. Analyses of nearly 60,000 SNP markers showed that the effects of selection on the genome are dramatic. The lines were fixed for alternative alleles in more than 50 regions as a result of selection. Another 10 regions displayed strong evidence for ongoing differentiation during the last 10 generations. Many more regions across the genome showed large differences in allele frequency between the lines, indicating that the phenotypic evolution in the lines in 50 generations is the result of an exploitation of standing genetic variation at 100s of loci across the genome.

Abstract PL02-02: Profiling of prostate tumors to identify factors that contribute to health disparities

Abstract PL02-02: Profiling of prostate tumors to identify factors that contribute to health disparities

Stilbene and Its Derivatives for Multistate Spectral Sensing

Terahertz (THz) region in the vibrational spectra of a certain molecule reveals the intramolecular vibrations between weakly bonded or nonbonded groups. Additional information can be acquired by photoinduced transitions between metastable states of the target agent. Different isomers of stilbene and its derivatives can be utilized in order to obtain the spectral “THz fingerprint” using multistate spectral-sensing technology. Also, stilbene and its derivatives are able to form “capping” with DNA, thus making them a very important covalent linker with DNA terminus to increase the fidelity of DNA duplexes as oligonucleotide hybridization probes. We study photoinduced transitions of stilbene and its derivatives and the change of vibrational spectra as a result of these transitions. All derivatives have vibrational frequencies in the THz region with a large difference in frequencies between two isomers.

Evidence for a sharp structure variation inside a red-giant star

The availability of precisely determined frequencies of radial and non-radial oscillation modes in red giants is finally paving the way for detailed studies of the internal structure of these stars. We look for the seismic signature of regions of sharp structure variation in the internal structure of the CoRoT target HR7349. We analyse the frequency dependence of the large frequency separation and second frequency differences, as well as the behaviour of the large frequency separation obtained with the envelope auto-correlation function. We find evidence for a periodic component in the oscillation frequencies, i.e. the seismic signature of a sharp structure variation in HR7349. In a comparison with stellar models we interpret this feature as caused by a local depression of the sound speed that occurs in the helium second-ionization region. Using solely seismic constraints this allows us to estimate the mass (M=1.2^{+0.6}_{-0.4} Msun) and radius (R=12.2^{+2.1}_{-1.8} Rsun) of HR7349, which agrees with the location of the star in an HR diagram.

Back to nature: ecological genomics of loblolly pine (Pinus taeda, Pinaceae)

Genetic variation is often arrayed in latitudinal or altitudinal clines, reflecting either adaptation along environmental gradients, migratory routes, or both. For forest trees, climate is one of the most important drivers of adaptive phenotypic traits. Correlations of single and multilocus genotypes with environmental gradients have been identified for a variety of forest trees. These correlations are interpreted normally as evidence of natural selection. Here, we use a genome-wide dataset of single nucleotide polymorphisms (SNPs) typed from 1730 loci in 682 loblolly pine (Pinus taeda L.) trees sampled from 54 local populations covering the full-range of the species to examine allelic correlations to five multivariate measures of climate. Applications of a Bayesian generalized linear mixed model, where the climate variable was a fixed effect and an estimated variance-covariance matrix controlled random effects due to shared population history, identified several well-supported SNPs associating to principal components corresponding to geography, temperature, growing degree-days, precipitation and aridity. Functional annotation of those genes with putative orthologs in Arabidopsis revealed a diverse set of abiotic stress response genes ranging from transmembrane proteins to proteins involved in sugar metabolism. Many of these SNPs also had large allele frequency differences among populations (F(ST) = 0.10-0.35). These results illustrate a first step towards a ecosystem perspective of population genomics for non-model organisms, but also highlight the need for further integration of the methodologies employed in spatial statistics, population genetics and climate modeling during scans for signatures of natural selection from genomic data.

GENETIC CHARACTERISTICS AND DISTANCES AMONGST SPANISH AND FRENCH RABBIT POPULATIONS

A total of 990 rabbits were tested using 18 blood electrophoretic markers. These animals belong to 6 breed populations presently breed in Spain (Spanish Common, Spanish Giant, Butterfly, Burgandy Fawn, New Zealand White and Californian), one Spanish cross-breed population, three French crossbreed populations originated from the INRA selected lines (1077, 2066 and 9077) and one Wild Spanish population. 12 markers were found to be polymorphic (Dia-2, 6-Pgd, Es-1, Es-2, Es-3, Es-7, Ada, Hp, Tf, Ca-2 and Hb), each one being controlled by one locus and showing autosomal co-dominant Mendelian inheritance. We have found large differences in gene frequencies of Dia-2, 6-Pgd, Ada, Es- 1, Es-2 and Es-3 loci in French populations. The genetic variabiliy estimated using the average degree of heterozygosity was lower in French than in Spanish populations. The results obtained from genetic distance analysis showed differences between French and Spanish populations. France 3 was the most divergent population. The genetic distance values obtained revealed that French populations are as different amongst themselves as they are between Spanish populations (the value obtained was corresponding to subspecie, NEI, 1987). These differences could have originated from the high selectiva pressure applied to parental lines. In the Spanish group, Spanish Giant was the most divergent population.

Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH2B3 as a Protective Factor against Bacterial Infection

Celiac disease (CD) is an intolerance to dietary proteins of wheat, barley, and rye. CD may have substantial morbidity, yet it is quite common with a prevalence of 1%-2% in Western populations. It is not clear why the CD phenotype is so prevalent despite its negative effects on human health, especially because appropriate treatment in the form of a gluten-free diet has only been available since the 1950s, when dietary gluten was discovered to be the triggering factor. The high prevalence of CD might suggest that genes underlying this disease may have been favored by the process of natural selection. We assessed signatures of selection for ten confirmed CD-associated loci in several genome-wide data sets, comprising 8154 controls from four European populations and 195 individuals from a North African population, by studying haplotype lengths via the integrated haplotype score (iHS) method. Consistent signs of positive selection for CD-associated derived alleles were observed in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, we also show a difference in allele frequency distribution (Fst) between HapMap phase II populations. Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504*A risk allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1200 and 1700 years ago.

Entanglement generation via full-resonant four-wave mixing

We present to use a full-resonant four-level atomic system to generate the steady-state entanglement. This scheme is based on the nondegenerate four-wave mixing process with the four fields being resonant with the corresponding bare atomic transitions, unlike the previous mixing schemes, where the entanglement is achieved under the condition of off-resonance. Another feature of such a mixing is that four fields are coupled to the different atomic transitions, respectively. By choosing the atoms appropriately, entanglement occurs between the fields with the large frequency difference.

Interleukin 10 polymorphisms differentially influence the risk of gastric cancer in East Asians and Caucasians

Background: Although a number of association studies of gastric cancer (GC) risk have been conducted worldwide, their results have been inconsistent among different populations. The association between GC incidence and Helicobacter pylori ( H. pylori) infection is somewhat of an enigma that has yet to be clearly explained. Geographically-restricted positive selection due to unique environmental pressures often result in large allele frequency differences between populations. Thus, population differences need to be investigated when attempting to identify genes that contribute to phenotypes that differ greatly between populations. Methods: We analyzed population differences in 18 polymorphisms of 12 GC-associated or immune response-related genes from 3 ethnic groups comprising 50 Koreans, 46 Indians, and 60 Caucasians; these groups differed in H. pylori seropositivity and susceptibility to GC. Results: An interleukin 10 ( IL10) polymorphism demonstrated a significantly different genotype distribution ( F ST = 0.306, P = 0.014), indicating a large difference between the Korean and Caucasian populations. The odds ratio of IL10 polymorphism allele between the populations was 38.32 (95% confidence interval, 11.49–127.83). Conclusion: This finding, taken together with previous evidence, provides a possible explanation for previous discrepant association results and supports the idea that IL10 gene polymorphisms can differentially affect GC development among populations.

Association of Polymorphisms in Genes Regulating the Corticotropin-Releasing Factor System With Antidepressant Treatment Response

The corticotropin-releasing factor (CRF, or corticotropin-releasing hormone) and arginine vasopressin systems have been implicated in the pathophysiology of anxiety and depressive disorders and response to antidepressant treatment. To study the association of genetic variants in 10 genes that regulate the CRF and arginine vasopressin systems with treatment response to citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) sample (N = 1768). Pharmacogenetic association study derived from the STAR*D study, a multicenter, prospective, open, 12-week effectiveness trial. Outpatient primary care and psychiatric clinics. Patients Individuals with nonpsychotic major depressive disorder for whom DNA was available who were subsequently treated with citalopram hydrobromide for 4 to 12 weeks. Intervention Flexible doses of citalopram. Main Outcome Measure Association of genetic polymorphisms in genes encoding the CRF system with response and remission to citalopram treatment at exit visit. One single-nucleotide polymorphism (SNP) (rs10473984) within the CRHBP locus showed a significant association with both remission (P = 6.0 x 10(-6); corrected, P = .0026) and reduction in depressive symptoms (P = 7.0 x 10(-7); corrected, P = .00031) in response to citalopram. The T allele of this SNP was associated with poorer treatment outcome in 2 of the 3 ethnic subsamples (African American and Hispanic), despite large differences in minor allele frequency. This association was more pronounced in patients with features of anxious depression (P = .008). The nonresponse allele was shown to be associated with overall higher plasma corticotropin levels and more pronounced dexamethasone suppression of corticotropin. These data indicate that a genetic variant within the CRHBP locus affects response to citalopram in African American and Hispanic patients, suggesting a role for this gene and for the CRF system in antidepressant treatment response.

QTL mapping for two commercial traits in farmed saltwater crocodiles (Crocodylus porosus)

The recent generation of a genetic linkage map for the saltwater crocodile (Crocodylus porosus) has now made it possible to carry out the systematic searches necessary for the identification of quantitative trait loci (QTL) affecting traits of economic, as well as evolutionary, importance in crocodilians. In this study, we conducted genome-wide scans for two commercially important traits, inventory head length (which is highly correlated with growth rate) and number of scale rows (SR, a skin quality trait), for the existence of QTL in a commercial population of saltwater crocodiles at Darwin Crocodile Farm, Northern Territory, Australia. To account for the uncommonly large difference in sex-specific recombination rates apparent in the saltwater crocodile, a duel mapping strategy was employed. This strategy employed a sib-pair analysis to take advantage of our full-sib pedigree structure, together with a half-sib analysis to account for, and take advantage of, the large difference in sex-specific recombination frequencies. Using these approaches, two putative QTL regions were identified for SR on linkage group 1 (LG1) at 36 cM, and on LG12 at 0 cM. The QTL identified in this investigation represent the first for a crocodilian and indeed for any non-avian member of the Class Reptilia. Mapping of QTL is an important first step towards the identification of genes and causal mutations for commercially important traits and the development of selection tools for implementation in crocodile breeding programmes for the industry.

Rapid Assessment of Genetic Ancestry in Populations of Unknown Origin by Genome-Wide Genotyping of Pooled Samples

As we move forward from the current generation of genome-wide association (GWA) studies, additional cohorts of different ancestries will be studied to increase power, fine map association signals, and generalize association results to additional populations. Knowledge of genetic ancestry as well as population substructure will become increasingly important for GWA studies in populations of unknown ancestry. Here we propose genotyping pooled DNA samples using genome-wide SNP arrays as a viable option to efficiently and inexpensively estimate admixture proportion and identify ancestry informative markers (AIMs) in populations of unknown origin. We constructed DNA pools from African American, Native Hawaiian, Latina, and Jamaican samples and genotyped them using the Affymetrix 6.0 array. Aided by individual genotype data from the African American cohort, we established quality control filters to remove poorly performing SNPs and estimated allele frequencies for the remaining SNPs in each panel. We then applied a regression-based method to estimate the proportion of admixture in each cohort using the allele frequencies estimated from pooling and populations from the International HapMap Consortium as reference panels, and identified AIMs unique to each population. In this study, we demonstrated that genotyping pooled DNA samples yields estimates of admixture proportion that are both consistent with our knowledge of population history and similar to those obtained by genotyping known AIMs. Furthermore, through validation by individual genotyping, we demonstrated that pooling is quite effective for identifying SNPs with large allele frequency differences (i.e., AIMs) and that these AIMs are able to differentiate two closely related populations (HapMap JPT and CHB).

A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci

Previous genome-wide association studies (GWASs) have identified several loci associated with human height; however, such evidence was mostly reported in Caucasian populations. Since the different distributions of height between populations suggest their different genetic backgrounds, analysis in different populations would be useful. Here, we present the results of a GWAS for adult height in 19 633 Japanese subjects. We found eight significantly associated loci that satisfied the genome-wide significance level (P < 5.0 x 10(-8)). Of these, the association to the LHX3-QSOX2 locus was entirely novel (rs12338076, P = 2.2 x 10(-8)). We also identified the association to the IGF1 locus (rs17032362, P = 8.1 x 10(-9)). Conditional association analysis in the IGF1 locus with rs17032362 suggested the existence of an additional independent association with height to this locus (rs1457595, P = 1.2 x 10(-5)). We observed large differences in the allele frequencies of rs17032362 and rs1457595 between Japanese (34 and 9%, respectively) and Caucasian (1.7 and 0%, respectively) populations, thereby suggesting weak statistical powers for the IGF1 locus in the previous Caucasian GWASs for height. We extensively compared our results with those of previous reports on the Caucasian and Korean populations. We were able to replicate all four loci previously reported in Koreans (EFEMP1, ZBTB38, HMGA1 and PLAG1, P < 5.0 x 10(-8)) and 15 loci identified in Caucasians (P < 0.001). The combination of the height-associated loci identified in our study and the previous GWASs demonstrated an effect size of 1.26 cm (95% confidence interval: 1.18-1.34) per 1.0 increase of the normalized Z score for height-increasing alleles, explaining 4.6% of the total variance of adult height.

On the Madden–Julian Oscillation–Atlantic Hurricane Relationship

Abstract The large-scale equatorial circulation known as the Madden–Julian oscillation (MJO) has been shown to impact tropical cyclone activity in several basins around the globe. In this paper, the author utilizes an MJO index created by Wheeler and Hendon to examine its impacts on tropical genesis and intensification in the Atlantic. Large differences in frequency and intensity of tropical cyclone activity are seen, both in the tropical Atlantic as well as in the northwest Caribbean and Gulf of Mexico depending on the MJO phase. Coherent changes in upper- and lower-level winds and relative humidity are likely responsible for these differences. Since the MJO shows potential predictability out to about two weeks, the relationships discussed in this paper may be useful for short-term predictions of the probability of tropical cyclone activity in the Atlantic as a complement to the already available longer-term seasonal predictions.

Characterization of X-Linked SNP genotypic variation in globally distributed human populations

An analysis of X-linked genetic variation in human populations provides insights into population structure and demographic patterns.

双腔大频差双频全固态激光器设计与实验研究

双腔大频差双频全固态激光器设计与实验研究

Genomic and Geographic Distribution of Private SNPs and Pathways in Human Populations

AIMS: Geography-based genetic differentials operating on entire biochemical pathways may reflect different adaptive evolutionary processes that separated populations may have undergone. They may also influence treatment outcome for a variety of drugs - an emerging and important area of study. This research article leverages the International HapMap Consortium data to identify pathway components that differ in genotype frequency for four populations: individuals of Northern European descent from the USA (CEU), individuals from West Africa (YRI), Japan (JPT) and China (CHB). MATERIALS #ENTITYSTARTX00026; METHODS: By identifying loci with fixed or large frequency differences (δ = 1) between paired population samples (CEU vs YRI, CEU vs CHB, CEU vs JPT, YRI vs CHB, YRI vs JPT and CHB vs JPT), and reconstructing the physiological functions of genes at these loci, we report a list of pathways affected by natural selection during human evolution. RESULTS: Of the 3.7 million HapMap SNPs, 463 loci (which mapped to 38 genes) were fixed (δ = 1) in at least one population pair. These private loci included four nonsynonymous coding SNPs: rs4536103 (NEUROG3), rs1385699 (EDA2R), rs11946338 (ARHGAP24) and rs4422842 (CACNA1B). A total of four additional genes demonstrated evidence of recent positive selection: three genes in European subjects (IER5L, NPNT and SESTD1) and a single gene in Asian subjects (EXOC6B). DISCUSSION: Gene ontology and pathway analyses suggest that cellular differentiation, apoptosis and activation of the NF-κB transcription factor vary between populations in genomic regions of fixed (private) SNPs identified in this study. Variability in these pathways may provide important clues into the mechanisms of human adaptation to different environments. An improved understanding of their variability may also help to explain race-specific differences in the treatment outcomes observed for a variety of modern drugs.

Plant regeneration in Stone pine (Pinus pinea L.) by somatic embryogenesis

Regeneration of plants by somatic embryogenesis (SE) was achieved in Stone pine (Pinus pinea), one of the most characteristic tree species of the Mediterranean ecosystem. The initial explants were megagametophytes containing zygotic embryos from five selected half-sib families collected at different dates over 2 consecutive years. Rates of extrusion and initiation of SE differed in both years. However, qualitative patterns were very similar: for most families, the responsive developmental window was from late cleavage polyembryony to early cotyledonary stage. The highest overall mean frequencies of extrusion and SE initiation (7 and 0.9%, respectively, for the five families and the eight 2006 collections) were obtained on a modified Litvay’s medium with 9 μM 2,4-D and 4.5 μM BAP, supplemented with L-glutamine and casein hydrolysate. Families showed large differences in frequencies of SE initiation from year to year. Only seven embryogenic lines were induced in 2005, representing three of the five families tested, whereas 34 lines from all the families were obtained in 2006. Proliferation of embryonal masses (EM) was significantly improved when they were subcultured after dispersing in liquid medium and collected on filter paper disks, instead of being subcultured as small clumps. This effect showed a significant interaction with genotype. Several preconditioning treatments and culture media combinations were tested for embryo development and maturation. The high proliferation rate of EM hampered somatic embryo development. However, up to 42 mature embryos from different lines of three of the five families were obtained, 23 of them germinated and seven converted into somatic seedlings.