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Sample records for allele frequencies showed

  1. Bayesian Inference of Natural Selection from Allele Frequency Time Series.

    PubMed

    Schraiber, Joshua G; Evans, Steven N; Slatkin, Montgomery

    2016-05-01

    The advent of accessible ancient DNA technology now allows the direct ascertainment of allele frequencies in ancestral populations, thereby enabling the use of allele frequency time series to detect and estimate natural selection. Such direct observations of allele frequency dynamics are expected to be more powerful than inferences made using patterns of linked neutral variation obtained from modern individuals. We developed a Bayesian method to make use of allele frequency time series data and infer the parameters of general diploid selection, along with allele age, in nonequilibrium populations. We introduce a novel path augmentation approach, in which we use Markov chain Monte Carlo to integrate over the space of allele frequency trajectories consistent with the observed data. Using simulations, we show that this approach has good power to estimate selection coefficients and allele age. Moreover, when applying our approach to data on horse coat color, we find that ignoring a relevant demographic history can significantly bias the results of inference. Our approach is made available in a C++ software package. PMID:27010022

  2. Allele frequencies at microsatellite loci: The stepwise mutation model revisited

    SciTech Connect

    Valdes, A.M.; Slatkin, M. ); Freimer, N.B. )

    1993-03-01

    The authors summarize available data on the frequencies of alleles at microsatellite loci in human populations and compare observed distributions of allele frequencies to those generated by a simulation of the stepwise mutation model. They show that observed frequency distributions at 108 loci are consistent with the results of the model under the assumption that mutations cause an increase or decrease in repeat number by one and under the condition that the product Nu, where N is the effective population size and u is the mutation rate, is larger than one. It is also shown that the variance of the distribution of allele sizes is a useful estimator of Nu and performs much better than previously suggested estimators for the stepwise mutation model. In the data, there is no correlation between the mean and variance in allele size at a locus or between the number of alleles and mean allele size, which suggests that the mutation rate at these loci is independent of allele size. 39 refs., 6 figs., 4 tabs.

  3. Mutated tumor alleles are expressed according to their DNA frequency

    PubMed Central

    Castle, John C.; Loewer, Martin; Boegel, Sebastian; Tadmor, Arbel D.; Boisguerin, Valesca; de Graaf, Jos; Paret, Claudia; Diken, Mustafa; Kreiter, Sebastian; Türeci, Özlem; Sahin, Ugur

    2014-01-01

    The transcription of tumor mutations from DNA into RNA has implications for biology, epigenetics and clinical practice. It is not clear if mutations are in general transcribed and, if so, at what proportion to the wild-type allele. Here, we examined the correlation between DNA mutation allele frequency and RNA mutation allele frequency. We sequenced the exome and transcriptome of tumor cell lines with large copy number variations, identified heterozygous single nucleotide mutations and absolute DNA copy number, and determined the corresponding DNA and RNA mutation allele fraction. We found that 99% of the DNA mutations in expressed genes are expressed as RNA. Moreover, we found a high correlation between the DNA and RNA mutation allele frequency. Exceptions are mutations that cause premature termination codons and therefore activate nonsense-mediated decay. Beyond this, we did not find evidence of any wide-scale mechanism, such as allele-specific epigenetic silencing, preferentially promoting mutated or wild-type alleles. In conclusion, our data strongly suggest that genes are equally transcribed from all alleles, mutated and wild-type, and thus transcribed in proportion to their DNA allele frequency. PMID:24752137

  4. Mutated tumor alleles are expressed according to their DNA frequency.

    PubMed

    Castle, John C; Loewer, Martin; Boegel, Sebastian; Tadmor, Arbel D; Boisguerin, Valesca; de Graaf, Jos; Paret, Claudia; Diken, Mustafa; Kreiter, Sebastian; Türeci, Özlem; Sahin, Ugur

    2014-01-01

    The transcription of tumor mutations from DNA into RNA has implications for biology, epigenetics and clinical practice. It is not clear if mutations are in general transcribed and, if so, at what proportion to the wild-type allele. Here, we examined the correlation between DNA mutation allele frequency and RNA mutation allele frequency. We sequenced the exome and transcriptome of tumor cell lines with large copy number variations, identified heterozygous single nucleotide mutations and absolute DNA copy number, and determined the corresponding DNA and RNA mutation allele fraction. We found that 99% of the DNA mutations in expressed genes are expressed as RNA. Moreover, we found a high correlation between the DNA and RNA mutation allele frequency. Exceptions are mutations that cause premature termination codons and therefore activate nonsense-mediated decay. Beyond this, we did not find evidence of any wide-scale mechanism, such as allele-specific epigenetic silencing, preferentially promoting mutated or wild-type alleles. In conclusion, our data strongly suggest that genes are equally transcribed from all alleles, mutated and wild-type, and thus transcribed in proportion to their DNA allele frequency. PMID:24752137

  5. The frequency of HLA alleles in the Romanian population.

    PubMed

    Constantinescu, Ileana; Boșcaiu, Voicu; Cianga, Petru; Dinu, Andrei-Antoniu; Gai, Elena; Melinte, Mihaela; Moise, Ana

    2016-03-01

    Knowledge of human leukocyte antigen (HLA) allele frequencies is essential for bone marrow and kidney donor searches. The Romanian Caucasian population is heterogeneous and information on HLA polymorphism has not been well studied. We characterized the HLA genetic profile and allele frequencies of regional populations in Romania. HLA-A, B and DRB1 alleles were examined in 8252 individuals, belonging to the four main regions of Romania. The most common alleles found in the Romanian population are the following: HLA-A*01, A*02, A*03, A*11, A*24; HLA-B*18, B*35, B*44, B*51 and HLA-DRB1*01, DRB1*03, DRB1*07, DRB1*11, DRB1*13, DRB1*15, DRB1*16. More than half of the alleles are non-homogeneously spread in Romania. These results provide a starting point for future analyses of genetic heterogeneity in Romania. PMID:26711124

  6. Allele frequency of CODIS 13 in Indonesian population.

    PubMed

    Untoro, Evi; Atmadja, Djaja Surya; Pu, Chang-En; Wu, Fang-Chi

    2009-04-01

    Since the first application of DNA technology in 1985 in forensic cases, and the acceptance of this technology in 1988 at court, the DNA typing is widely used in personal identification, parentage cases and tracing the source of biological samples found in the crime scene. The FBI on 1990 had recommended the forensic labs to used 13 loci of Short Tandem Repeats (STR), known as CODIS 13, as the loci of choice for forensic use. The research on the population DNA database on these loci is extremely important for calculating the Paternity Index as well as Matching Probability for forensic application of DNA technology. As many as 402 unrelated persons, consisted of 322 from western part of Indonesia and 80 from eastern part of Indonesia, were chosen as the respondents of this research, after signing the informed consent. The peripheral blood sample was taken using sterile lancets and dropped onto FTA classic cards. The DNA was extracted by FTA purification solution (3x) and TE(-1) (2x), and amplified by PCR mix, either Cofiler or Profiler Plus (Perkin Elmers), followed by sequencing using ABI Prism type 3100 Avant Genetic Analyzer. The analysis showed that the alleles frequencies of Indonesian is specific, different with the other Asian populations with some specific alleles and microvariant were found. PMID:19261522

  7. Systematic Detection of Epistatic Interactions Based on Allele Pair Frequencies

    PubMed Central

    Ackermann, Marit; Beyer, Andreas

    2012-01-01

    Epistatic genetic interactions are key for understanding the genetic contribution to complex traits. Epistasis is always defined with respect to some trait such as growth rate or fitness. Whereas most existing epistasis screens explicitly test for a trait, it is also possible to implicitly test for fitness traits by searching for the over- or under-representation of allele pairs in a given population. Such analysis of imbalanced allele pair frequencies of distant loci has not been exploited yet on a genome-wide scale, mostly due to statistical difficulties such as the multiple testing problem. We propose a new approach called Imbalanced Allele Pair frequencies (ImAP) for inferring epistatic interactions that is exclusively based on DNA sequence information. Our approach is based on genome-wide SNP data sampled from a population with known family structure. We make use of genotype information of parent-child trios and inspect 3×3 contingency tables for detecting pairs of alleles from different genomic positions that are over- or under-represented in the population. We also developed a simulation setup which mimics the pedigree structure by simultaneously assuming independence of the markers. When applied to mouse SNP data, our method detected 168 imbalanced allele pairs, which is substantially more than in simulations assuming no interactions. We could validate a significant number of the interactions with external data, and we found that interacting loci are enriched for genes involved in developmental processes. PMID:22346757

  8. Microsatellite allele frequencies in humans and chimpanzees, with implications for constraints on allele size.

    PubMed

    Garza, J C; Slatkin, M; Freimer, N B

    1995-07-01

    The distributions of allele sizes at eight simple-sequence repeat (SSR) or microsatellite loci in chimpanzees are found and compared with the distributions previously obtained from several human populations. At several loci, the differences in average allele size between chimpanzees and humans are sufficiently small that there might be a constraint on the evolution of average allele size. Furthermore, a model that allows for a bias in the mutation process shows that for some loci a weak bias can account for the observations. Several alleles at one of the loci (Mfd 59) were sequenced. Differences between alleles of different lengths were found to be more complex than previously assumed. An 8-base-pair deletion was present in the nonvariable region of the chimpanzee locus. This locus contains a previously unrecognized repeated region, which is imperfect in humans and perfect in chimpanzees. The apparently greater opportunity for mutation conferred by the two perfect repeat regions in chimpanzees is reflected in the higher variance in repeat number at Mfd 59 in chimpanzees than in humans. These data indicate that interspecific differences in allele length are not always attributable to simple changes in the number of repeats. PMID:7659015

  9. Allelic disequilibrium and allele frequency distribution as a function of social and demographic history.

    PubMed Central

    Thompson, E A; Neel, J V

    1997-01-01

    Allelic disequilibrium between closely linked genes is a common observation in human populations and often gives rise to speculation concerning the role of selective forces. In a previous treatment, we have developed a population model of the expected distribution of rare variants (including private polymorphisms) in Amerindians and have argued that, because of the great expansion of Amerindian numbers with the advent of agriculture, most of these rare variants are of relatively recent origin. Many other populations have similar histories of striking recent expansions. In this treatment, we demonstrate that, in consequence of this fact, a high degree of linkage disequilibrium between two nonhomologous alleles <0.5 cM apart is the "normal" expectation, even in the absence of selection. This expectation is enhanced by the previous subdivision of human populations into relatively isolated tribes characterized by a high level of endogamy and inbreeding. We also demonstrate that the alleles associated with a recessive disease phenotype are expected to exist in a population in very variable frequencies: there is no need to postulate positive selection with respect to the more common disease-associated alleles for such entities as phenylketonuria or cystic fibrosis. PMID:8981963

  10. Distribution of forensic marker allelic frequencies in Pernambuco, Northestern Brazil.

    PubMed

    Santos, S M; Souza, C A; Rabelo, K C N; Souza, P R E; Moura, R R; Oliveira, T C; Crovella, S

    2015-01-01

    Pernambuco is one of the 27 federal units of Brazil, ranking seventh in the number of inhabitants. We examined the allele frequencies of 13 short tandem repeat loci (CFS1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, TH01, vWA, and TPOX), the minimum recommended by the Federal Bureau of Investigation and commonly used in forensic genetics laboratories in Brazil, in a sample of 609 unrelated individuals from all geographic regions of Pernambuco. The allele frequencies ranged from 5 to 47.2%. No significant differences for any loci analyzed were observed compared with other publications in other various regions of Brazil. Most of the markers observed were in Hardy-Weinberg equilibrium. The occurrence of the allele 47.2 (locus FGA) and alleles 35.1 and 39 (locus D21S11), also described in a single study of the Brazilian population, was observed. The other forensic parameters analyzed (matching probability, power of discrimination, polymorphic information content, paternity exclusion, complement factor I, observed heterozygosity, expected heterozygosity) indicated that the studied markers are very informative for human forensic identification purposes in the Pernambuco population. PMID:25966202

  11. High throughput automated allele frequency estimation by pyrosequencing.

    PubMed

    Doostzadeh, Julie; Shokralla, Shadi; Absalan, Farnaz; Jalili, Roxana; Mohandessi, Sharareh; Langston, James W; Davis, Ronald W; Ronaghi, Mostafa; Gharizadeh, Baback

    2008-01-01

    Pyrosequencing is a DNA sequencing method based on the principle of sequencing-by-synthesis and pyrophosphate detection through a series of enzymatic reactions. This bioluminometric, real-time DNA sequencing technique offers unique applications that are cost-effective and user-friendly. In this study, we have combined a number of methods to develop an accurate, robust and cost efficient method to determine allele frequencies in large populations for association studies. The assay offers the advantage of minimal systemic sampling errors, uses a general biotin amplification approach, and replaces dTTP for dATP-apha-thio to avoid non-uniform higher peaks in order to increase accuracy. We demonstrate that this newly developed assay is a robust, cost-effective, accurate and reproducible approach for large-scale genotyping of DNA pools. We also discuss potential improvements of the software for more accurate allele frequency analysis. PMID:18628978

  12. High Throughput Automated Allele Frequency Estimation by Pyrosequencing

    PubMed Central

    Absalan, Farnaz; Jalili, Roxana; Mohandessi, Sharareh; Langston, James W.; Davis, Ronald W.; Ronaghi, Mostafa; Gharizadeh, Baback

    2008-01-01

    Pyrosequencing is a DNA sequencing method based on the principle of sequencing-by-synthesis and pyrophosphate detection through a series of enzymatic reactions. This bioluminometric, real-time DNA sequencing technique offers unique applications that are cost-effective and user-friendly. In this study, we have combined a number of methods to develop an accurate, robust and cost efficient method to determine allele frequencies in large populations for association studies. The assay offers the advantage of minimal systemic sampling errors, uses a general biotin amplification approach, and replaces dTTP for dATP-apha-thio to avoid non-uniform higher peaks in order to increase accuracy. We demonstrate that this newly developed assay is a robust, cost-effective, accurate and reproducible approach for large-scale genotyping of DNA pools. We also discuss potential improvements of the software for more accurate allele frequency analysis. PMID:18628978

  13. Fast spatial ancestry via flexible allele frequency surfaces

    PubMed Central

    Rañola, John Michael; Novembre, John; Lange, Kenneth

    2014-01-01

    Motivation: Unique modeling and computational challenges arise in locating the geographic origin of individuals based on their genetic backgrounds. Single-nucleotide polymorphisms (SNPs) vary widely in informativeness, allele frequencies change non-linearly with geography and reliable localization requires evidence to be integrated across a multitude of SNPs. These problems become even more acute for individuals of mixed ancestry. It is hardly surprising that matching genetic models to computational constraints has limited the development of methods for estimating geographic origins. We attack these related problems by borrowing ideas from image processing and optimization theory. Our proposed model divides the region of interest into pixels and operates SNP by SNP. We estimate allele frequencies across the landscape by maximizing a product of binomial likelihoods penalized by nearest neighbor interactions. Penalization smooths allele frequency estimates and promotes estimation at pixels with no data. Maximization is accomplished by a minorize–maximize (MM) algorithm. Once allele frequency surfaces are available, one can apply Bayes’ rule to compute the posterior probability that each pixel is the pixel of origin of a given person. Placement of admixed individuals on the landscape is more complicated and requires estimation of the fractional contribution of each pixel to a person’s genome. This estimation problem also succumbs to a penalized MM algorithm. Results: We applied the model to the Population Reference Sample (POPRES) data. The model gives better localization for both unmixed and admixed individuals than existing methods despite using just a small fraction of the available SNPs. Computing times are comparable with the best competing software. Availability and implementation: Software will be freely available as the OriGen package in R. Contact: ranolaj@uw.edu or klange@ucla.edu Supplementary information: Supplementary data are available at

  14. Accounting for genotype uncertainty in the estimation of allele frequencies in autopolyploids.

    PubMed

    Blischak, Paul D; Kubatko, Laura S; Wolfe, Andrea D

    2016-05-01

    Despite the increasing opportunity to collect large-scale data sets for population genomic analyses, the use of high-throughput sequencing to study populations of polyploids has seen little application. This is due in large part to problems associated with determining allele copy number in the genotypes of polyploid individuals (allelic dosage uncertainty-ADU), which complicates the calculation of important quantities such as allele frequencies. Here, we describe a statistical model to estimate biallelic SNP frequencies in a population of autopolyploids using high-throughput sequencing data in the form of read counts. We bridge the gap from data collection (using restriction enzyme based techniques [e.g. GBS, RADseq]) to allele frequency estimation in a unified inferential framework using a hierarchical Bayesian model to sum over genotype uncertainty. Simulated data sets were generated under various conditions for tetraploid, hexaploid and octoploid populations to evaluate the model's performance and to help guide the collection of empirical data. We also provide an implementation of our model in the R package polyfreqs and demonstrate its use with two example analyses that investigate (i) levels of expected and observed heterozygosity and (ii) model adequacy. Our simulations show that the number of individuals sampled from a population has a greater impact on estimation error than sequencing coverage. The example analyses also show that our model and software can be used to make inferences beyond the estimation of allele frequencies for autopolyploids by providing assessments of model adequacy and estimates of heterozygosity. PMID:26607217

  15. How-To-Do-It: Multiple Allelic Frequencies in Populations at Equilibrium: Algorithms and Applications.

    ERIC Educational Resources Information Center

    Nussbaum, Francis, Jr.

    1988-01-01

    Presents an algorithm for solving problems related to multiple allelic frequencies in populations at equilibrium. Considers sample problems and provides their solution using this tabular algorithm. (CW)

  16. Cost-effective genome-wide estimation of allele frequencies from pooled DNA in Atlantic salmon (Salmo salar L.)

    PubMed Central

    2013-01-01

    Background New sequencing technologies have tremendously increased the number of known molecular markers (single nucleotide polymorphisms; SNPs) in a variety of species. Concurrently, improvements to genotyping technology have now made it possible to efficiently genotype large numbers of genome-wide distributed SNPs enabling genome wide association studies (GWAS). However, genotyping significant numbers of individuals with large number of SNPs remains prohibitively expensive for many research groups. A possible solution to this problem is to determine allele frequencies from pooled DNA samples, such ‘allelotyping’ has been presented as a cost-effective alternative to individual genotyping and has become popular in human GWAS. In this article we have tested the effectiveness of DNA pooling to obtain accurate allele frequency estimates for Atlantic salmon (Salmo salar L.) populations using an Illumina SNP-chip. Results In total, 56 Atlantic salmon DNA pools from 14 populations were analyzed on an Atlantic salmon SNP-chip containing probes for 5568 SNP markers, 3928 of which were bi-allelic. We developed an efficient quality control filter which enables exclusion of loci showing high error rate and minor allele frequency (MAF) close to zero. After applying multiple quality control filters we obtained allele frequency estimates for 3631 bi-allelic loci. We observed high concordance (r > 0.99) between allele frequency estimates derived from individual genotyping and DNA pools. Our results also indicate that even relatively small DNA pools (35 individuals) can provide accurate allele frequency estimates for a given sample. Conclusions Despite of higher level of variation associated with array replicates compared to pool construction, we suggest that both sources of variation should be taken into account. This study demonstrates that DNA pooling allows fast and high-throughput determination of allele frequencies in Atlantic salmon enabling cost

  17. Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project

    PubMed Central

    2010-01-01

    Background There is a lack of knowledge regarding the frequency of disease associated polymorphisms in populations and population attributable risk for many populations remains unknown. Factors that could affect the association of the allele with disease, either positively or negatively, such as race, ethnicity, and gender, may not be possible to determine without population based allele frequencies. Here we used a panel of 51 polymorphisms previously associated with at least one disease and determined the allele frequencies within the entire Personalized Medicine Research Project population based cohort. We compared these allele frequencies to those in dbSNP and other data sources stratified by race. Differences in allele frequencies between self reported race, region of origin, and sex were determined. Results There were 19544 individuals who self reported a single racial category, 19027 or (97.4%) self reported white Caucasian, and 11205 (57.3%) individuals were female. Of the 11,208 (57%) individuals with an identifiable region of origin 8337 or (74.4%) were German. 41 polymorphisms were significantly different between self reported race at the 0.05 level. Stratification of our Caucasian population by self reported region of origin revealed 19 polymorphisms that were significantly different (p = 0.05) between individuals of different origins. Further stratification of the population by gender revealed few significant differences in allele frequencies between the genders. Conclusions This represents one of the largest population based allele frequency studies to date. Stratification by self reported race and region of origin revealed wide differences in allele frequencies not only by race but also by region of origin within a single racial group. We report allele frequencies for our Asian/Hmong and American Indian populations; these two minority groups are not typically selected for population allele frequency detection. Population wide allele frequencies are

  18. Detection of Allelic Frequency Differences between the Sexes in Humans: A Signature of Sexually Antagonistic Selection.

    PubMed

    Lucotte, Elise A; Laurent, Romain; Heyer, Evelyne; Ségurel, Laure; Toupance, Bruno

    2016-01-01

    Sexually antagonistic (SA) selection, a form of selection that can occur when both sexes have different fitness optima for a trait, is a major force shaping the evolution of organisms. A seminal model developed by Rice (Rice WR. 1984. Sex chromosomes and the evolution of sexual dimorphism. Evolution 38:735-742.) predicts that the X chromosome should be a hotspot for the accumulation of loci under SA selection as compared with the autosomes. Here, we propose a methodological framework designed to detect a specific signature of SA selection on viability, differences in allelic frequencies between the sexes. Applying this method on genome-wide single nucleotide polymorphism (SNP) data in human populations where no sex-specific population stratification could be detected, we show that there are overall significantly more SNPs exhibiting differences in allelic frequencies between the sexes on the X chromosome as compared with autosomes, supporting the predictions of Rice's model. This pattern is consistent across populations and is robust to correction for potential biases such as differences in linkage disequilibrium, sample size, and genotyping errors between chromosomes. Although SA selection is not the only factor resulting in allelic frequency differences between the sexes, we further show that at least part of the identified X-linked loci is caused by such a sex-specific processes. PMID:27189992

  19. Detection of Allelic Frequency Differences between the Sexes in Humans: A Signature of Sexually Antagonistic Selection

    PubMed Central

    Lucotte, Elise A.; Laurent, Romain; Heyer, Evelyne; Ségurel, Laure; Toupance, Bruno

    2016-01-01

    Sexually antagonistic (SA) selection, a form of selection that can occur when both sexes have different fitness optima for a trait, is a major force shaping the evolution of organisms. A seminal model developed by Rice (Rice WR. 1984. Sex chromosomes and the evolution of sexual dimorphism. Evolution 38:735–742.) predicts that the X chromosome should be a hotspot for the accumulation of loci under SA selection as compared with the autosomes. Here, we propose a methodological framework designed to detect a specific signature of SA selection on viability, differences in allelic frequencies between the sexes. Applying this method on genome-wide single nucleotide polymorphism (SNP) data in human populations where no sex-specific population stratification could be detected, we show that there are overall significantly more SNPs exhibiting differences in allelic frequencies between the sexes on the X chromosome as compared with autosomes, supporting the predictions of Rice’s model. This pattern is consistent across populations and is robust to correction for potential biases such as differences in linkage disequilibrium, sample size, and genotyping errors between chromosomes. Although SA selection is not the only factor resulting in allelic frequency differences between the sexes, we further show that at least part of the identified X-linked loci is caused by such a sex-specific processes. PMID:27189992

  20. Association of ABO Blood Group Phenotype and Allele Frequency with Chikungunya Fever

    PubMed Central

    Rujirojindakul, Pairaya; Chongsuvivatwong, Virasakdi; Limprasert, Pornprot

    2015-01-01

    Background. The objective of this study was to investigate the association of the ABO blood group phenotype and allele frequency with CHIK fever. Methods. A rural community survey in Southern Thailand was conducted in August and September 2010. A total of 506 villagers were enrolled. Cases were defined as individuals having anti-CHIK IgG by hemagglutination ≥1 : 10. Results. There were 314 cases (62.1%) with CHIK seropositivity. Females were less likely to have positive anti-CHIK IgG with odds ratio (OR) (95% CI) of 0.63 (0.43, 0.93). All samples tested were Rh positive. Distribution of CHIK seropositivity versus seronegativity (P value) in A, B, AB, and O blood groups was 80 versus 46 (0.003), 80 versus 48 (0.005), 24 versus 20 (0.55), and 130 versus 78 (<0.001), respectively. However, chi-square test between ABO and CHIK infection showed no statistical significance (P = 0.76). Comparison of the ABO blood group allele frequency between CHIK seropositivity and seronegativity was not statistically significant. Conclusion. This finding demonstrated no association of the ABO blood group phenotypes and allele frequencies with CHIK infection. PMID:25977691

  1. Global distribution of allele frequencies at the human dopamine D4 receptor locus

    SciTech Connect

    Chang, F.M.; Kidd, J.R.; Livak, K.J.

    1994-09-01

    The dopamine D4 receptor (DRD4) is a candidate gene for schizophrenia because the dopaminergic system has been implicated in this neuropsychiatric disorder. Several research groups have reported an association between allelic variants at DRD4 and schizophrenia, while others have been unable to replicate that finding. Knowledge of the appropriate gene frequencies in the underlying populations may resolve these inconsistencies. We have determined the frequencies of 8 different alleles of the 48 bp imperfect tandem repeat of exon 3 at the DRD4 locus in samples from 33 populations around the world. The frequencies vary considerably in the different populations with the most common allele ranging from 16% to 95%. Frequencies and Fst values will be presented for the 3 most common alleles (4-, 7-, and 2- repeat) by continental groupings, but the individual populations vary significantly around the averages. The populations averaged 4.3 alleles (range 2 to 7).

  2. HLA-G allele and haplotype frequencies in a healthy population of Iran.

    PubMed

    Kuroshli, Zahra; Gourabi, Hamid; Bazrgar, Masoud; Sanati, Mohammad Hossein; Bahraminejad, Elmira; Anisi, Khadije

    2014-06-01

    The human leukocyte antigen (HLA)-G molecule is expressed in cytotrophoblast cells, adult thymic epithelial cells, erythroblasts, pancreatic islets and mesenchymal stem cells. Although, HLA-G expression in allotransplanted patients is correlated with a better allograft acceptance, it is associated with an advanced grade of the tumor in cancer. In addition to the role on the immune system, HLA-G is also involved in successful pregnancy through the embryo implantation, fetal survival and the initial steps of hematopoiesis and angiogenesis. The aim of this study was determination of HLA-G allele frequencies in a healthy population of Iran. In this research, we selected 100 samples from healthy Iranian individuals and henceforth, we used polymerase chain reaction (PCR) followed by sequencing technique for exon 2, 3, 4 and intron 2 of the gene for evaluating the HLA-G alleles frequencies. Investigation of intronic (intron 2) variation is the novelty of our study. The obtained results indicated thirteen alleles of HLA-G in Iranian individuals including G*01:01:01:01, G*01:06, G*01:01:01:06, G*01:01:02, G*01:01:03, G*01:01:05, G*01:01:06, G*01:01:07, G*01:01:08, G*01:03, G*01:04:01, G*01:04:03, and G*01:04:04. According to this study, the most prevalent alleles in the Iranian population were G*01:01:01:01 (52.5%), G*01:01:02 (16%) and G*01:04:03 (14.5%) and also the lowest alleles regarding the frequency were G*01:01:01:06 (0.5%) and G*01:03 (0.5%). The results of G*01:01:01:01 and G*01:04:01 frequencies showed some similarities with the polish population. Our results were similar to the north Indian population for the frequencies of G*01:06 and G*01:01:02. PMID:24659125

  3. Combining allele frequency uncertainty and population substructure corrections in forensic DNA calculations.

    PubMed

    Cowell, Robert

    2016-07-01

    In forensic DNA calculations of relatedness of individuals and in DNA mixture analyses, at least two sources of uncertainty are present concerning the allele frequencies used for evaluating genotype probabilities when evaluating likelihoods. They are: (i) imprecision in the estimates of the allele frequencies in the population by using an inevitably finite database of DNA profiles to estimate them; and (ii) the existence of population substructure. Green and Mortera [6] showed that these effects may be taken into account individually using a common Dirichlet model within a Bayesian network formulation, but that when taken in combination this is not the case; however they suggested an approximation that could be used. Here we develop a slightly different approximation that is shown to be exact in the case of a single individual. We demonstrate the numerical closeness of the approximation using a published database of allele counts, and illustrate the effect of incorporating the approximation into calculations of a recently published statistical model of DNA mixtures. PMID:27231804

  4. Frequency of null allele of Human Leukocyte Antigen-G (HLA-G) locus in subjects to recurrent miscarriage

    PubMed Central

    Alizadeh, Nazila; Mosaferi, Elnaz; Farzadi, Laya; Majidi, Jafar; Monfaredan, Amir; Yousefi, Bahman; Baradaran, Behzad

    2016-01-01

    Background: Human leukocyte antigen-G (HLA-G) is a non-classical class I molecule highly expressed by extravillous cytotrophoblast cells. Due to a single base pair deletion, its function can be compensated by other isoforms. Investigating the frequency of null allele in Recurrent Miscarriage (RM) subjects could be useful in understanding the relationship between frequency of this allele and RM in a given population. Objective: This study aimed to determine the frequency of HLA-G*0105N null allele and its potential association with down-regulation of HLA-G in subjects with RM. Materials and Methods: Western blotting was used to assess the level of HLA-G protein expression. For investigating the frequency of HLA-G*0105N null allele in RM subjects, PCR-RFLP method was used. Exon 3 of HLA-G gene was amplified by polymerase chain reaction (PCR). Subsequently, PpuM-1 enzyme was employed to digest the PCR products and fragments were analyzed using gel electrophoresis. Results: Digestion using restriction enzyme showed the presence of heterozygous HLA-G*0105N null allele in 10% of the test population. Western blotting results confirmed the decrease in expression of HLA-G in the placental tissue of subjects with RM compared to subjects who could give normal birth. Conclusion: The frequency of heterozygous HLA-G*0105N null allele was high to some extent in subjects with RM. The mutation rate in subjects suggested that there is a significant association between RM and frequency of mutations in this allele. PMID:27525330

  5. Comparison of Prion Allele Frequency found in Suffolk and Targhee Sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Scrapie is a class of Transmissible Spongiform Encephalopathy that affects sheep and goats. The objective of this study was to compare genotypic and allelic frequencies among USSES Targhee and Suffolk sheep. A total of 122 sheep were genotyped for codon 171 with allele specific primers in 2 separate...

  6. Genotype and allele frequencies of isoniazid-metabolizing enzymes NAT2 and GSTM1 in Latvian tuberculosis patients.

    PubMed

    Igumnova, Viktorija; Capligina, Valentina; Krams, Alvils; Cirule, Andra; Elferts, Didzis; Pole, Ilva; Jansone, Inta; Bandere, Dace; Ranka, Renate

    2016-07-01

    Pharmacogenomic testing of tuberculosis drug-metabolizing enzyme genes was proposed as a strategy to identify patients at risk for suboptimal responses to medications. However, variations of the genotype frequencies among ethnic groups exist and new alleles are been identified. The aim of this study was to identify polymorphisms of genes encoding metabolic enzymes NAT2 and GSTM1 in tuberculosis patients in Latvia and to estimate the frequency of NAT2 slow acetylator and GSTM1 null genotypes. In total, 85 DNA samples were genotyped, all individuals were Caucasian. An ethnic heterogeneity reflecting the multiethnic population of the country was observed. 49 patients were Latvians, 30 were Russians and 6 of other ethnicity. In total, 7 NAT2 alleles were identified: *4, *5, *6, *7, *11, *12, * and *13. The most frequent was the slow acetylation allele NAT2*6 (frequency 0.388) followed by the slow acetylation allele NAT2*5 and the rapid acetylation allele NAT2*4 (frequencies 0.306 and 0.194, respectively). The predominance of slow (51.8%) and intermediate (43.5%) acetylators compared with rapid acetylators (4.7%) was observed. The GSTM1 null genotype was detected in 48.2% of tuberculosis patients. When subgroup analysis was performed according to ethnicity, the results showed that neither NAT2 allele frequencies nor GSTM1 null genotype frequency did not differ significantly in TB patients of Latvian or Russian ethnicity. Overall, genotyping results were similar with previous reports of a NAT2 gene variation and GSTM1 null genotype frequency in Caucasians. Our findings have a contribution for the pharmacogenetics-based tuberculosis therapy in Latvia in future. PMID:27236516

  7. The Equilibrium Allele Frequency Distribution for a Population with Reproductive Skew

    PubMed Central

    Der, Ricky; Plotkin, Joshua B.

    2014-01-01

    We study the population genetics of two neutral alleles under reversible mutation in a model that features a skewed offspring distribution, called the Λ-Fleming–Viot process. We describe the shape of the equilibrium allele frequency distribution as a function of the model parameters. We show that the mutation rates can be uniquely identified from this equilibrium distribution, but the form of the offspring distribution cannot itself always be so identified. We introduce an estimator for the mutation rate that is consistent, independent of the form of reproductive skew. We also introduce a two-allele infinite-sites version of the Λ-Fleming–Viot process, and we use it to study how reproductive skew influences standing genetic diversity in a population. We derive asymptotic formulas for the expected number of segregating sites as a function of sample size and offspring distribution. We find that the Wright–Fisher model minimizes the equilibrium genetic diversity, for a given mutation rate and variance effective population size, compared to all other Λ-processes. PMID:24473932

  8. A Generalized Approach for Estimating Effective Population Size from Temporal Changes in Allele Frequency

    PubMed Central

    Waples, R. S.

    1989-01-01

    The temporal method for estimating effective population size (N(e)) from the standardized variance in allele frequency change (F) is presented in a generalized form. Whereas previous treatments of this method have adopted rather limiting assumptions, the present analysis shows that the temporal method is generally applicable to a wide variety of organisms. Use of a revised model of gene sampling permits a more generalized interpretation of N(e) than that used by some other authors studying this method. It is shown that two sampling plans (individuals for genetic analysis taken before or after reproduction) whose differences have been stressed by previous authors can be treated in a uniform way. Computer simulations using a wide variety of initial conditions show that different formulas for computing F have much less effect on N(e) than do sample size (S), number of generations between samples (t), or the number of loci studied (L). Simulation results also indicate that (1) bias of F is small unless alleles with very low frequency are used; (2) precision is typically increased by about the same amount with a doubling of S, t, or L; (3) confidence intervals for N(e) computed using a χ(2) approximation are accurate and unbiased under most conditions; (4) the temporal method is best suited for use with organisms having high juvenile mortality and, perhaps, a limited effective population size. PMID:2731727

  9. Minor Allele Frequency Changes the Nature of Genotype by Environment Interactions.

    PubMed

    Verhulst, Brad; Neale, Michael C

    2016-09-01

    In the classical twin study, phenotypic variation is often partitioned into additive genetic (A), common (C) and specific environment (E) components. From genetical theory, the outcome of genotype by environment interaction is expected to inflate A when the interacting factor is shared (i.e., C) between the members of a twin pair. We show that estimates of both A and C can be inflated. When the shared interacting factor changes the size of the difference between homozygotes' means, the expected sibling or DZ twin correlation is .5 if and only if the minor allele frequency (MAF) is .5; otherwise the expected DZ correlation is greater than this value, consistent (and confounded) with some additional effect of C. This result is considered in the light of the distribution of minor allele frequencies for polygenic traits. Also discussed is whether such interactions take place at the locus level or affect an aggregated biological structure or system. Interactions with structures or endophenotypes that result from the aggregated effects of many loci will generally emerge as part of the A estimate. PMID:27105628

  10. HLA-B27 allele frequency in Sri Lankan patients with spondyloarthritides.

    PubMed

    Kidnapillai, S; Sirisena, N D; Dissanayake, V H

    2016-06-01

    This preliminary study aims to describe the HLA-B27 allele frequency in Sri Lankan patients with spondyloarthritides (SA). An anonymised database of 373 Sri Lankan patients with SA referred for HLA-B27 testing was retrospectively analysed. Eighty five (22.8%) patients were positive for the HLA-B27 allele. A male preponderance was observed among the positives. The HLA-B27 allele frequency in this sample of patients with SA was relatively low compared to published studies in other populations. Further research is needed to identify the predominant subtypes of the allele to determine which subtypes are the most prevalent in a larger sample of Sri Lankan patients with SA, and to define their association with the specific types of SA. PMID:27423748

  11. Effects of allele frequency estimation on genomic predictions and inbreeding coefficients

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic calculations often require estimating allele frequencies, which differ across time due to selection and drift. Data were 50,000 simulated markers and 39,985 actual markers for 2391 genotyped Holstein bulls. Gene content of relatives and gene frequencies in the base (founder) population were ...

  12. Geographical distribution of pyrethroid resistance allele frequency in head lice (Phthiraptera: Pediculidae) from Argentina.

    PubMed

    Toloza, Ariel Ceferino; Ascunce, Marina S; Reed, David; Picollo, María Inés

    2014-01-01

    The human head louse, Pediculus humanus capitis De Geer (Phthiraptera: Pediculidae), is an obligate ectoparasite that causes pediculosis capitis and has parasitized humans since the beginning of humankind. Head louse infestations are widespread throughout the world and have been increasing since the early 1990s partially because of ineffective pediculicides. In Argentina, the overuse of products containing pyrethroids has led to the development of resistant louse populations. Pyrethroid insecticides act on the nervous system affecting voltage-sensitive sodium channels. Three point mutations at the corresponding amino acid sequence positions M815I, T917I, and L920F in the voltage-gated sodium channel gene are responsible for contributing to knockdown resistance (kdr). The management of pyrethroid resistance requires either early detection or the characterization of the mechanisms involved in head louse populations. In the current study, we estimated the distribution of kdr alleles in 154 head lice from six geographical regions of Argentina. Pyrethroid resistance kdr alleles were found in high frequencies ranging from 67 to 100%. Of these, 131 (85.1%) were homozygous resistant, 13 (8.4%) were homozygous susceptible, and 10 (6.5%) were heterozygous. Exact tests for the Hardy-Weinberg equilibrium for each location showed that genotype frequencies differed significantly from expectation in four of the six sites studied. These results show that pyrethroid resistance is well established reaching an overall frequency of 88%, thus close to fixation. With 30 yr of pyrethroid-based pediculicides use in Argentina, kdr resistance has evolved rapidly among these head louse populations. PMID:24605463

  13. Molecular analysis of human leukocyte antigen class I and class II allele frequencies and haplotype distribution in Pakistani population

    PubMed Central

    Moatter, T.; Aban, M.; Tabassum, S.; Shaikh, U.; Pervez, S.

    2010-01-01

    AIM: Distribution of HLA class I and II alleles and haplotype was studied in Pakistani population and compared with the data reported for Caucasoid, Africans, Orientals and Arab populations. MATERIALS AND METHODS: HLA class I and II polymorphisms in 1000 unrelated Pakistani individuals was studied using sequence-specific primers and polymerase chain reaction and assay. RESULTS: The most frequent class I alleles observed were A*02, B*35 and CW*07, with frequencies of 19.2, 13.7 and 20%, respectively. Fifteen distinct HLA-DRB1 alleles and eight HLA-DQB1 alleles were recognized. The most frequently observed DRB1 alleles which represented more than 60% of the subjects were DRB1 *03, *07, *11 and *15. The rare DRB1 alleles detected in this study were HLADRB1 *08 and *09, having frequencies of 0.9 and 1.7%, respectively. In addition, at DRB1-DQB1 loci there were 179 different haplotypes and 285 unique genotypes and the most common haplotype was DRB1*15-DQB1*06 which represented 17% of the total DRB1-DQB1 haplotypes. In our population, haplotype A*33-B*58-Cw*03 comprised 2.8% of the total class I haplotypes observed. This haplotype was seen only in the oriental populations and has not been reported in the African or European Caucasoid. CONCLUSION: Our study showed a close similarity of HLA class I and II alleles with that of European Caucasoid and Orientals. In Pakistani population, two rare loci and three haplotypes were identified, whereas haplotypes characteristic of Caucasians, Africans and Orientals were also found, suggesting an admixture of different races due to migration to and from this region. PMID:21206703

  14. HLA Allele Frequencies in 5802 Koreans: Varied Allele Types Associated with SJS/TEN According to Culprit Drugs

    PubMed Central

    Park, Hye Jung; Kim, Young Joo; Kim, Dong Hyun; Kim, Junho; Park, Kyung Hee; Park, Jung-Won

    2016-01-01

    Purpose Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea. Materials and Methods We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01. Results HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03. Conclusion HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN. PMID:26632391

  15. HLA allele and haplotype frequencies in the Albanian population and their relationship with the other European populations.

    PubMed

    Sulcebe, G; Sanchez-Mazas, A; Tiercy, J-M; Shyti, E; Mone, I; Ylli, Z; Kardhashi, V

    2009-12-01

    Human leucocyte antigen (HLA) alleles are very interesting markers in identifying population relationships. Moreover, their frequency distribution data are important in the implementation of donor-recipient registry programs for transplantation purposes and also in determining the genetic predisposition for many diseases. For these reasons, we studied the HLA class I and II allele and haplotype frequencies in 160 healthy, unrelated Albanian individuals originating from all regions of the country. The HLA genotyping was performed through a 2-digit resolution SSOP method. The data were analysed with Arlequin and Phylip programs. No deviation was found from the Hardy-Weinberg equilibrium. A total of 17 A*, 30 B*, 12 Cw*, 13 DRB1* and 5 DQB1* alleles were identified. The six most frequent HLA-A-B-DRB1 haplotypes were A*02-B*18-DRB1*11 (5.60%), A*02-B*51-DRB1*16 (4.74%), A*01-B*08-DRB1*03 (3.48%), A*24-B*35-DRB1*11 (2.77%), A*02-B*51-DRB1*13 (2.21%), A*24-B*35-DRB1*14 (1.89%). Interestingly, 12 HLA-A-B-Cw-DRB1-DQB1 haplotypes occurred at a frequency >1%. When compared with the other populations, a close relationship was found with North Greek, Bulgarian, Macedonian, Romanian, Turkish, Cretan, Serbian, Croatian and Italian populations. A higher differentiation in allele frequency level was found with Western Europe populations. These data are the first report of HLA allele and haplotype distribution in an Albanian population inside this country. When compared with other populations, their distribution frequencies show close similarities with neighbouring populations of the entire Balkan area. PMID:19703234

  16. The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice.

    PubMed

    Cacciottolo, Mafalda; Christensen, Amy; Moser, Alexandra; Liu, Jiahui; Pike, Christian J; Smith, Conor; LaDu, Mary Jo; Sullivan, Patrick M; Morgan, Todd E; Dolzhenko, Egor; Charidimou, Andreas; Wahlund, Lars-Olof; Wiberg, Maria Kristofferson; Shams, Sara; Chiang, Gloria Chia-Yi; Finch, Caleb E

    2016-01-01

    The apolipoprotein APOE4 allele confers greater risk of Alzheimer's disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in 2 clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes (5XFAD (+/-) /human APOE(+/+)). At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy, plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and cerebral amyloid angiopathy increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds versus the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition. PMID:26686669

  17. A novel fluorescent quadruplex STR typing system and the allele frequency distributions in a Thai population.

    PubMed

    Yoshimoto, Takashi; Yamamoto, Toshimichi; Mizutani, Masaki; Uchihi, Rieko; Ohtaki, Hiroyuki; Katsumata, Yoshinao; Waiyawuth, Worawee; Songsivilai, Sirirurg

    2003-01-01

    We have previously reported a new triplex amplification and typing system by silver staining for three short tandem repeat (STR) loci, 9q2h2 (D2S3020), D15S233, and D14S299 without "microvariant" alleles such as .1, .2, and, .3 alleles in the Japanese population. In the present study, we established a new quadruplex system with an additional locus D7S809 using primer sets labeled with fluorescent multi-color dyes. Using this system, we genotyped 183 Thai people, found only one "microvariant" allele (allele 20.2) at D7S809, and calculated allele frequencies and some statistical properties at these four STR loci. From these allele frequencies at four STR loci, we performed three statistical analyses including a homozygosity test, a likelihood ratio test, and an exact test for Hardy-Weinberg equilibrium (HWE). Deviations from HWE (p < 0.05) were observed only in the two tests at the locus D7S809. In the present study, we compared the allele frequencies at these four loci in the Thai population to those in the Japanese population described previously. Consequently, all observed heterozygosities and power of discrimination (PD) at those loci in the Thai population were higher than 0.8 and 0.9, respectively, and all statistical values for discriminating power in the Thai population were slightly higher than those in the Japanese population. The combined paternity exclusion rate (combined PE) in the Thai population (0.978) was almost the same as that in the Japanese population (0.971). Therefore, this novel PCR amplification and typing system for four STR loci would be a convenient and informative DNA profiling system in the forensic field. PMID:12570210

  18. Allelic frequencies for the HLA-DQA1, D1S80, HUMTHO1, HUMTPOX, HUMCSF1PO and HUMVWA loci in Cantabria (middle north Spain).

    PubMed

    Sánchez-Molina, I; Calvet, R

    2000-01-01

    Allele frequencies for six DNA polymorphisms have been studied in a population sample from Cantabria (middle north Spain) using the polymerase chain reaction. The HLA-DQA1 locus was analyzed by the reverse dot-blot technique and the other five by polyacrylamide gel electrophoresis followed by silver staining. Six alleles were found for HLA-DQA1. 15 alleles for D1S80, 6 alleles for HUMTHO1 and HUMCSF1PO, 7 for HUMTPOX and 8 alleles for HUMVWA. The 21 repeat allele in HUMVWA had not previously been reported in a Spanish population. The genotype distributions met Hardy-Weinberg expectations for all the systems and some statistical parameters of forensic interest were calculated. Comparisons with other populations revealed significant differences for HLA-DQA1, HUMVWA and HUMTHO1, with interracial differences being more pronounced than between Spanish populations. The HUMVWA system showed the highest forensic efficiency of the six polymorphisms studied. PMID:10641932

  19. Natural Selection VS. Random Drift: Evidence from Temporal Variation in Allele Frequencies in Nature

    PubMed Central

    Mueller, Laurence D.; Barr, Lorraine G.; Ayala, Francisco J.

    1985-01-01

    We have obtained monthly samples of two species, Drosophila pseudoobscura and Drosophila persimilis, in a natural population from Napa County, California. In each species, about 300 genes have been assayed by electrophoresis for each of seven enzyme loci in each monthly sample from March 1972 to June 1975. Using statistical methods developed for the purpose, we have examined whether the allele frequencies at different loci vary in a correlated fashion. The methods used do not detect natural selection when it is deterministic (e.g., overdominance or directional selection), but only when alleles at different loci vary simultaneously in response to the same environmental variations. Moreover, only relatively large fitness differences (of the order of 15%) are detectable. We have found strong evidence of correlated allele frequency variation in 13–20% of the cases examined. We interpret this as evidence that natural selection plays a major role in the evolution of protein polymorphisms in nature. PMID:4054608

  20. Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants.

    PubMed

    Shearer, A Eliot; Eppsteiner, Robert W; Booth, Kevin T; Ephraim, Sean S; Gurrola, José; Simpson, Allen; Black-Ziegelbein, E Ann; Joshi, Swati; Ravi, Harini; Giuffre, Angelica C; Happe, Scott; Hildebrand, Michael S; Azaiez, Hela; Bayazit, Yildirim A; Erdal, Mehmet Emin; Lopez-Escamez, Jose A; Gazquez, Irene; Tamayo, Marta L; Gelvez, Nancy Y; Leal, Greizy Lopez; Jalas, Chaim; Ekstein, Josef; Yang, Tao; Usami, Shin-ichi; Kahrizi, Kimia; Bazazzadegan, Niloofar; Najmabadi, Hossein; Scheetz, Todd E; Braun, Terry A; Casavant, Thomas L; LeProust, Emily M; Smith, Richard J H

    2014-10-01

    Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) > 0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness. PMID:25262649

  1. Utilizing Ethnic-Specific Differences in Minor Allele Frequency to Recategorize Reported Pathogenic Deafness Variants

    PubMed Central

    Shearer, A. Eliot; Eppsteiner, Robert W.; Booth, Kevin T.; Ephraim, Sean S.; Gurrola, José; Simpson, Allen; Black-Ziegelbein, E. Ann; Joshi, Swati; Ravi, Harini; Giuffre, Angelica C.; Happe, Scott; Hildebrand, Michael S.; Azaiez, Hela; Bayazit, Yildirim A.; Erdal, Mehmet Emin; Lopez-Escamez, Jose A.; Gazquez, Irene; Tamayo, Marta L.; Gelvez, Nancy Y.; Leal, Greizy Lopez; Jalas, Chaim; Ekstein, Josef; Yang, Tao; Usami, Shin-ichi; Kahrizi, Kimia; Bazazzadegan, Niloofar; Najmabadi, Hossein; Scheetz, Todd E.; Braun, Terry A.; Casavant, Thomas L.; LeProust, Emily M.; Smith, Richard J.H.

    2014-01-01

    Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) >0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness. PMID:25262649

  2. Determination of permethrin resistance allele frequency of human head louse populations by quantitative sequencing.

    PubMed

    Kwon, Deok Ho; Yoon, Kyong Sup; Strycharz, Joseph P; Clark, J Marshall; Lee, Si Hyeock

    2008-09-01

    A quantitative sequencing (QS) protocol that detects the frequencies of sodium channel mutations (M815I, T917I, and L920F) responsible for knockdown resistance in permethrin-resistant head lice (Pediculus humanus capitis De Geer) was tested as a population genotyping method for use as a preliminary resistance monitoring tool. Genomic DNA fragments of the sodium channel a-subunit gene that encompass the three mutation sites were polymerase chain reaction (PCR)-1 amplified from individual head lice with either resistant or susceptible genotypes, and combined in various ratios to generate standard DNA template mixtures for QS. After sequencing, the signal ratios between resistant and susceptible nucleotides were calculated and plotted against the corresponding resistance allele frequencies. Quadratic regression coefficients of the plots were close to 1, demonstrating that the signal ratios are highly correlated with the resistance allele frequencies. Resistance allele frequencies predicted by QS, using either "pooled DNA" (DNA extracted from individual louse specimens and pooled) or "pooled specimen DNA" (DNA simultaneously extracted from multiple louse specimens), agreed well with those determined by individual sequencing, confirming the reliability and accuracy of QS as a population genotyping method and validating our approach of using the pooled specimen DNA as the DNA template for QS. Our protocol for QS was determined to be highly reliable for the prediction of resistance allele frequencies higher than approximately 7.4% at the 95% confidence level. According to the resistance allele frequencies determined by QS, pyrethroid resistance varies substantially among different geographical regions, emphasizing the importance of early resistance detection and proper management strategies. PMID:18826035

  3. Frequency of CCR5Δ32 allele in healthy Bosniak population

    PubMed Central

    Adler, Grażyna; Valjevac, Amina; Skonieczna-Żydecka, Karolina; Mackic-Djurovic, Mirela; Parczewski, Miłosz; Urbańska, Anna; Salkic, Nermin N

    2014-01-01

    Recent evidence has demonstrated the role of CCR5Δ32 in a variety of human diseases: from infectious and inflammatory diseases to cancer. Several studies have confirmed that genetic variants in chemokine receptor CCR5 gene are correlated with susceptibility and resistance to HIV infection. A 32-nucleotide deletion within the CCR5 reading frame is associated with decreased susceptibility to HIV acquisition and a slower progression to AIDS. Mean frequency of CCR5Δ32 allele in Europe is approximately 10%. The highest allele frequency is observed among Nordic populations (about 12%) and the lowest in the regions of Southeast Mediterranean (about 5%). Although the frequency of CCR5Δ32 was determined in numerous European populations, there is a lack of studies on this variant in the Bosnia and Herzegovina population. Therefore, the aim of our study was to assess the frequency of CCR5Δ32 allele in the cohort of Bosniaks and compare the results with European reports. CCR5Δ32 was detected by sequence-specific PCR in a sample of 100 healthy Bosniaks (DNA collected 2011-2013). Mean age of the cohort being 58.8 (±10.7) years, with 82% of women. We identified 17 heterozygotes and one mutant homozygote in study group, with mean ∆32 allele frequency of 9.5%. CCR5∆32 allele frequency among Bosniaks is comparable to that found in Caucasian populations and follows the pattern of the north-southern gradient observed for Europe. Further studies on larger cohorts with adequate female-to-male ratio are necessary. PMID:25172974

  4. Genotype and allelic frequencies of a newly identified mutation causing blindness in jordanian awassi sheep flocks.

    PubMed

    Jawasreh, K I Z; Ababneh, H; Awawdeh, F T; Al-Massad, M A; Al-Majali, A M

    2012-01-01

    A total of 423 blood samples were collected (during 2009 and 2010) from all the ram holdings at three major Jordanian governmental Awassi breeding stations (Al-Khanasry, Al-Mushairfa and Al-Fjaje) and two private flocks. All blood samples were screened for the presence of mutations at the CNGA3 gene (responsible for day blindness in Awassi sheep) using RFLP-PCR. The day blindness mutation was detected in all studied flocks. The overall allele and genotype frequencies of all studied flocks of the day blindness mutation were 0.088 and 17.49%, respectively. The genotype and allele frequencies were higher in station flocks than the farmer flocks (0.121, 24.15 and 0.012, 2.32, respectively). Al-Mushairfa and Al-Khanasry stations have the highest genotype and allele frequencies for the day blindness mutation that were 27.77, 30.00% and 0.14, 0.171, respectively. The investigated farmer flocks have low percentages (0.03, 5.88% at Al-Shoubak and 0.005 and 1.05%, at Al-Karak, respectively for genotype and allele frequencies) compared with the breeding stations. Ram culling strategy was applied throughout the genotyping period in order to gradually eradicate this newly identified day blindness mutation from Jordanian Breeding station, since they annually distribute a high percentage of improved rams to farmer's flocks. PMID:25049475

  5. Genotype and Allelic Frequencies of a Newly Identified Mutation Causing Blindness in Jordanian Awassi Sheep Flocks

    PubMed Central

    Jawasreh, K. I. Z.; Ababneh, H.; Awawdeh, F. T.; Al-Massad, M. A.; Al-Majali, A. M.

    2012-01-01

    A total of 423 blood samples were collected (during 2009 and 2010) from all the ram holdings at three major Jordanian governmental Awassi breeding stations (Al-Khanasry, Al-Mushairfa and Al-Fjaje) and two private flocks. All blood samples were screened for the presence of mutations at the CNGA3 gene (responsible for day blindness in Awassi sheep) using RFLP-PCR. The day blindness mutation was detected in all studied flocks. The overall allele and genotype frequencies of all studied flocks of the day blindness mutation were 0.088 and 17.49%, respectively. The genotype and allele frequencies were higher in station flocks than the farmer flocks (0.121, 24.15 and 0.012, 2.32, respectively). Al-Mushairfa and Al-Khanasry stations have the highest genotype and allele frequencies for the day blindness mutation that were 27.77, 30.00% and 0.14, 0.171, respectively. The investigated farmer flocks have low percentages (0.03, 5.88% at Al-Shoubak and 0.005 and 1.05%, at Al-Karak, respectively for genotype and allele frequencies) compared with the breeding stations. Ram culling strategy was applied throughout the genotyping period in order to gradually eradicate this newly identified day blindness mutation from Jordanian Breeding station, since they annually distribute a high percentage of improved rams to farmer’s flocks. PMID:25049475

  6. MHC allele frequency distributions under parasite-driven selection: A simulation model

    PubMed Central

    2010-01-01

    Background The extreme polymorphism that is observed in major histocompatibility complex (MHC) genes, which code for proteins involved in recognition of non-self oligopeptides, is thought to result from a pressure exerted by parasites because parasite antigens are more likely to be recognized by MHC heterozygotes (heterozygote advantage) and/or by rare MHC alleles (negative frequency-dependent selection). The Ewens-Watterson test (EW) is often used to detect selection acting on MHC genes over the recent history of a population. EW is based on the expectation that allele frequencies under balancing selection should be more even than under neutrality. We used computer simulations to investigate whether this expectation holds for selection exerted by parasites on host MHC genes under conditions of heterozygote advantage and negative frequency-dependent selection acting either simultaneously or separately. Results In agreement with simple models of symmetrical overdominance, we found that heterozygote advantage acting alone in populations does, indeed, result in more even allele frequency distributions than expected under neutrality, and this is easily detectable by EW. However, under negative frequency-dependent selection, or under the joint action of negative frequency-dependent selection and heterozygote advantage, distributions of allele frequencies were less predictable: the majority of distributions were indistinguishable from neutral expectations, while the remaining runs resulted in either more even or more skewed distributions than under neutrality. Conclusions Our results indicate that, as long as negative frequency-dependent selection is an important force maintaining MHC variation, the EW test has limited utility in detecting selection acting on these genes. PMID:20979635

  7. Frequency of Bt resistance alleles in H. armigera during 2006-2008 in Northern China.

    PubMed

    Gao, Yulin; Wu, Kongming; Gould, Fred

    2009-08-01

    Helicoverpa armigera is an important lepidopteran pest of cotton in China. From 2002, the frequency of Bt resistance alleles and quantitative shifts in larval Cry1Ac tolerance of field H. armigera population were monitored using bioassays of F(1) and F(2) offspring of isofemale lines from Xiajin County of Shandong Province (an intensive Bt cotton planting area) and Anci County of Hebei Province (a multiple-crop system including corn, soybean, peanut, and Bt cotton) in northern China. During 2006-2008, a total of 2,306 isofemale lines from the Xiajin population and a total of 1,270 isofemale lines from the Anci population were successfully screened on Cry1Ac diets. For each year, it was estimated that the major resistance gene frequency in Xiajin population in 2006, 2007, and 2008 was 0, 0.00022, and 0.00033, respectively. No major alleles conferring resistance to Cry1Ac were found in the Anci population; the frequency of resistance alleles for Cry1Ac was 0. Based on the relative average development rates (RADRs) of H. armigera larvae in F(1) tests, no substantial increase in Cry1Ac tolerance was found in either location over the 3-yr period. There were also significantly positive correlations between RADR of lines in the F(1) generation and the RADR of their F(2) offspring, indicating genetic variation in response to toxin. The low frequency of resistance alleles found in this study and in our previous results from 2002 to 2005 suggest the frequency of resistance alleles has remained low and that natural refugia resistance management strategy maybe effective for delaying resistance evolution in H. armigera to Bt cotton in northern China. PMID:19689916

  8. DNA-PKcs mutations in dogs and horses: allele frequency and association with neoplasia.

    PubMed

    Ding, Qi; Bramble, Lori; Yuzbasiyan-Gurkan, Vilma; Bell, Thomas; Meek, Katheryn

    2002-01-23

    Previously, spontaneous genetic immunodeficiencies in mice, Arabian foals, and recently in Jack Russell terriers have been ascribed to defects in DNA-PKcs (catalytic subunit of the DNA dependent protein kinase) expression. In severe combined immunodeficiency (SCID) foals, a 5 bp deletion at codon 9480 results in a frameshift and a 967 amino acid deletion from the C terminus (including the entire PI3 kinase domain) and an unstable mutant protein. In SCID mice, a single base pair mutation results in a premature stop codon and deletion of 83 amino acids; as in SCID foals, the mutant protein is unstable. Here, we define the mutation within the canine DNA-PKcs gene that results in SCID. In this case, a point mutation results in a stop codon at nucleotide 10,828 and premature termination at a position 517 amino acids before the normal C terminus resulting in a functionally null allele. Thus, this is the third documentation of a spontaneous germline mutation in the C terminus of DNA-PKcs. Emerging data implicate DNA repair factors as potential tumor suppressors. Here, we have ascertained the carrier frequency of the defective DNA-PKcs genes in Arabian horses and in Jack Russell terriers. Our data indicate (in good agreement with a previous report) that the carrier frequency of the equine SCID allele is approximately 8%; in contrast, the carrier frequency of the canine SCID allele is less than 1.1%. We also assessed the frequency of the equine SCID allele in a series of 295 tumors from Arabian horses. We find a statistically significant correlation between the development of a virally induced tumor (sarcoid) and heterozygosity for the equine SCID allele. These data provide further support for an emerging consensus: that DNA-PK may normally act as a tumor suppressor through its caretaker role in maintaining chromosomal stability. PMID:11867233

  9. Allele frequency data for 15 autosomal STR loci in eight Indonesian subpopulations.

    PubMed

    Venables, Samantha J; Daniel, Runa; Sarre, Stephen D; Soedarsono, Nurtami; Sudoyo, Herawati; Suryadi, Helena; van Oorschot, Roland A H; Walsh, Simon J; Widodo, Putut T; McNevin, Dennis

    2016-01-01

    Evolutionary and cultural history can affect the genetic characteristics of a population and influences the frequency of different variants at a particular genetic marker (allele frequency). These characteristics directly influence the strength of forensic DNA evidence and make the availability of suitable allele frequency information for every discrete country or jurisdiction highly relevant. Population sub-structure within Indonesia has not been well characterised but should be expected given the complex geographical, linguistic and cultural architecture of the Indonesian population. Here we use forensic short tandem repeat (STR) markers to identify a number of distinct genetic subpopulations within Indonesia and calculate appropriate population sub-structure correction factors. This data represents the most comprehensive investigation of population sub-structure within Indonesia to date using these markers. The results demonstrate that significant sub-structure is present within the Indonesian population and must be accounted for using island specific allele frequencies and corresponding sub-structure correction factors in the calculation of forensic DNA match statistics. PMID:26517173

  10. Validation of SNP Allele Frequencies Determined by Pooled Next-Generation Sequencing in Natural Populations of a Non-Model Plant Species

    PubMed Central

    Rellstab, Christian; Zoller, Stefan; Tedder, Andrew; Gugerli, Felix; Fischer, Martin C.

    2013-01-01

    Sequencing of pooled samples (Pool-Seq) using next-generation sequencing technologies has become increasingly popular, because it represents a rapid and cost-effective method to determine allele frequencies for single nucleotide polymorphisms (SNPs) in population pools. Validation of allele frequencies determined by Pool-Seq has been attempted using an individual genotyping approach, but these studies tend to use samples from existing model organism databases or DNA stores, and do not validate a realistic setup for sampling natural populations. Here we used pyrosequencing to validate allele frequencies determined by Pool-Seq in three natural populations of Arabidopsis halleri (Brassicaceae). The allele frequency estimates of the pooled population samples (consisting of 20 individual plant DNA samples) were determined after mapping Illumina reads to (i) the publicly available, high-quality reference genome of a closely related species (Arabidopsis thaliana) and (ii) our own de novo draft genome assembly of A. halleri. We then pyrosequenced nine selected SNPs using the same individuals from each population, resulting in a total of 540 samples. Our results show a highly significant and accurate relationship between pooled and individually determined allele frequencies, irrespective of the reference genome used. Allele frequencies differed on average by less than 4%. There was no tendency that either the Pool-Seq or the individual-based approach resulted in higher or lower estimates of allele frequencies. Moreover, the rather high coverage in the mapping to the two reference genomes, ranging from 55 to 284x, had no significant effect on the accuracy of the Pool-Seq. A resampling analysis showed that only very low coverage values (below 10-20x) would substantially reduce the precision of the method. We therefore conclude that a pooled re-sequencing approach is well suited for analyses of genetic variation in natural populations. PMID:24244686

  11. Allele Frequencies Net Database: Improvements for storage of individual genotypes and analysis of existing data.

    PubMed

    Dos Santos, Eduardo Jose Melos; McCabe, Antony; Gonzalez-Galarza, Faviel F; Jones, Andrew R; Middleton, Derek

    2016-03-01

    The Allele Frequencies Net Database (AFND) is a freely accessible database which stores population frequencies for alleles or genes of the immune system in worldwide populations. Herein we introduce two new tools. We have defined new classifications of data (gold, silver and bronze) to assist users in identifying the most suitable populations for their tasks. The gold standard datasets are defined by allele frequencies summing to 1, sample sizes >50 and high resolution genotyping, while silver standard datasets do not meet gold standard genotyping resolution and/or sample size criteria. The bronze standard datasets are those that could not be classified under the silver or gold standards. The gold standard includes >500 datasets covering over 3 million individuals from >100 countries at one or more of the following loci: HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1 and -DRB1 - with all loci except DPA1 present in more than 220 datasets. Three out of 12 geographic regions have low representation (the majority of their countries having less than five datasets) and the Central Asia region has no representation. There are 18 countries that are not represented by any gold standard datasets but are represented by at least one dataset that is either silver or bronze standard. We also briefly summarize the data held by AFND for KIR genes, alleles and their ligands. Our second new component is a data submission tool to assist users in the collection of the genotypes of the individuals (raw data), facilitating submission of short population reports to Human Immunology, as well as simplifying the submission of population demographics and frequency data. PMID:26585775

  12. Predictable allele frequency changes due to habitat fragmentation in the Glanville fritillary butterfly.

    PubMed

    Fountain, Toby; Nieminen, Marko; Sirén, Jukka; Wong, Swee Chong; Hanski, Ilkka

    2016-03-01

    Describing the evolutionary dynamics of now extinct populations is challenging, as their genetic composition before extinction is generally unknown. The Glanville fritillary butterfly has a large extant metapopulation in the Åland Islands in Finland, but declined to extinction in the nearby fragmented southwestern (SW) Finnish archipelago in the 20th century. We genotyped museum samples for 222 SNPs across the genome, including SNPs from candidate genes and neutral regions. SW Finnish populations had significantly reduced genetic diversity before extinction, and their allele frequencies gradually diverged from those in contemporary Åland populations over 80 y. We identified 15 outlier loci among candidate SNPs, mostly related to flight, in which allele frequencies have changed more than the neutral expectation. At outlier loci, allele frequencies in SW Finland shifted in the same direction as newly established populations deviated from old local populations in contemporary Åland. Moreover, outlier allele frequencies in SW Finland resemble those in fragmented landscapes as opposed to continuous landscapes in the Baltic region. These results indicate selection for genotypes associated with good colonization capacity in the highly fragmented landscape before the extinction of the populations. Evolutionary response to habitat fragmentation may have enhanced the viability of the populations, but it did not save the species from regional extinction in the face of severe habitat loss and fragmentation. These results highlight a potentially common situation in changing environments: evolutionary changes are not strong enough to fully compensate for the direct adverse effects of environmental change and thereby rescue populations from extinction. PMID:26903642

  13. Predictable allele frequency changes due to habitat fragmentation in the Glanville fritillary butterfly

    PubMed Central

    Fountain, Toby; Nieminen, Marko; Sirén, Jukka; Wong, Swee Chong; Hanski, Ilkka

    2016-01-01

    Describing the evolutionary dynamics of now extinct populations is challenging, as their genetic composition before extinction is generally unknown. The Glanville fritillary butterfly has a large extant metapopulation in the Åland Islands in Finland, but declined to extinction in the nearby fragmented southwestern (SW) Finnish archipelago in the 20th century. We genotyped museum samples for 222 SNPs across the genome, including SNPs from candidate genes and neutral regions. SW Finnish populations had significantly reduced genetic diversity before extinction, and their allele frequencies gradually diverged from those in contemporary Åland populations over 80 y. We identified 15 outlier loci among candidate SNPs, mostly related to flight, in which allele frequencies have changed more than the neutral expectation. At outlier loci, allele frequencies in SW Finland shifted in the same direction as newly established populations deviated from old local populations in contemporary Åland. Moreover, outlier allele frequencies in SW Finland resemble those in fragmented landscapes as opposed to continuous landscapes in the Baltic region. These results indicate selection for genotypes associated with good colonization capacity in the highly fragmented landscape before the extinction of the populations. Evolutionary response to habitat fragmentation may have enhanced the viability of the populations, but it did not save the species from regional extinction in the face of severe habitat loss and fragmentation. These results highlight a potentially common situation in changing environments: evolutionary changes are not strong enough to fully compensate for the direct adverse effects of environmental change and thereby rescue populations from extinction. PMID:26903642

  14. Inference of Population Splits and Mixtures from Genome-Wide Allele Frequency Data

    PubMed Central

    Pickrell, Joseph K.; Pritchard, Jonathan K.

    2012-01-01

    Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In our model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data, we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and “ancient” Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.com. PMID:23166502

  15. PoMo: An Allele Frequency-Based Approach for Species Tree Estimation

    PubMed Central

    De Maio, Nicola; Schrempf, Dominik; Kosiol, Carolin

    2015-01-01

    Incomplete lineage sorting can cause incongruencies of the overall species-level phylogenetic tree with the phylogenetic trees for individual genes or genomic segments. If these incongruencies are not accounted for, it is possible to incur several biases in species tree estimation. Here, we present a simple maximum likelihood approach that accounts for ancestral variation and incomplete lineage sorting. We use a POlymorphisms-aware phylogenetic MOdel (PoMo) that we have recently shown to efficiently estimate mutation rates and fixation biases from within and between-species variation data. We extend this model to perform efficient estimation of species trees. We test the performance of PoMo in several different scenarios of incomplete lineage sorting using simulations and compare it with existing methods both in accuracy and computational speed. In contrast to other approaches, our model does not use coalescent theory but is allele frequency based. We show that PoMo is well suited for genome-wide species tree estimation and that on such data it is more accurate than previous approaches. PMID:26209413

  16. Genetically Determined Amerindian Ancestry Correlates with Increased Frequency of Risk Alleles for Systemic Lupus Erythematosus

    PubMed Central

    Sanchez, E; Webb, R; Rasmussen, A.; Kelly, J.A; Riba, L.; Kaufman, K.M.; Garcia-de la Torre, I.; Moctezuma, J.F.; Maradiaga-Ceceña, M.A.; Cardiel, M.; Acevedo, E.; Cucho-Venegas, M.; Garcia, M.A.; Gamron, S.; Pons-Estel, B.A.; Vasconcelos, C.; Martin, J.; Tusié-Luna, T.; Harley, J.B.; Richardson, B.; Sawalha, A.H.; Alarcón-Riquelme, M.E.

    2011-01-01

    Objectives To analyze if genetically determined Amerindian ancestry predicts the increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus. Methods Single nucleotide polymorphisms within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo normal healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation of the presence of risk alleles with ancestry was done using linear regression. Results A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4, STAT4, PDCD1, ITGAM, and IRF5 were associated with lupus in a Hispanic-Mestizo cohort enriched for European and Amerindian ancestry. In addition, two SNPs within the MHC region, previously associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression we predict an average increase of 2.34 risk alleles when comparing a lupus patient with 100% Amerindian ancestry to an SLE patient with 0% American Indian Ancestry (p<0.0001). SLE patients with 43% more Amerindian ancestry are predicted to carry one additional risk allele. Conclusion Amerindian ancestry increased the number of risk alleles for lupus. PMID:20848568

  17. Allelic frequencies and association with carcass traits of six genes in local subpopulations of Japanese Black cattle.

    PubMed

    Nishimaki, Takahiro; Ibi, Takayuki; Siqintuya; Kobayashi, Naohiko; Matsuhashi, Tamako; Akiyama, Takayuki; Yoshida, Emi; Imai, Kazumi; Matsui, Mayu; Uemura, Keiichi; Eto, Hisayoshi; Watanabe, Naoto; Fujita, Tatsuo; Saito, Yosuke; Komatsu, Tomohiko; Hoshiba, Hiroshi; Mannen, Hideyuki; Sasazaki, Shinji; Kunieda, Tetsuo

    2016-04-01

    Marker-assisted selection (MAS) is expected to accelerate the genetic improvement of Japanese Black cattle. However, verification of the effects of the genes for MAS in different subpopulations is required prior to the application of MAS. In this study, we investigated the allelic frequencies and genotypic effects for carcass traits of six genes, which can be used in MAS, in eight local subpopulations. These genes are SCD, FASN and SREBP1, which are associated with the fatty acid composition of meat, and NCAPG, MC1R and F11, which are associated with carcass weight, coat color and blood coagulation abnormality, respectively. The frequencies of desirable alleles of SCD and FASN were relatively high and that of NCAPG was relatively low, and NCAPG was significantly associated with several carcass traits, including carcass weight. The proportions of genotypic variance explained by NCAPG to phenotypic variance were 4.83 for carcass weight. We thus confirmed that NCAPG is a useful marker for selection of carcass traits in these subpopulations. In addition, we found that the desirable alleles of six genes showed no negative effects on carcass traits. Therefore, selection using these genes to improve target traits should not have negative impacts on carcass traits. PMID:26249527

  18. Microarray-based estimation of SNP allele-frequency in pooled DNA using the Langmuir kinetic model

    PubMed Central

    Yin, Bin-Cheng; Li, Honghua; Ye, Bang-Ce

    2008-01-01

    Background High throughput genotyping of single nucleotide polymorphisms (SNPs) for genome-wide association requires technologies for generating millions of genotypes with relative ease but also at a reasonable cost and with high accuracy. In this work, we have developed a theoretical approach to estimate allele frequency in pooled DNA samples, based on the physical principles of DNA immobilization and hybridization on solid surface using the Langmuir kinetic model and quantitative analysis of the allelic signals. Results This method can successfully distinguish allele frequencies differing by 0.01 in the actual pool of clinical samples, and detect alleles with a frequency as low as 2%. The accuracy of measuring known allele frequencies is very high, with the strength of correlation between measured and actual frequencies having an r2 = 0.9992. These results demonstrated that this method could allow the accurate estimation of absolute allele frequencies in pooled samples of DNA in a feasible and inexpensive way. Conclusion We conclude that this novel strategy for quantitative analysis of the ratio of SNP allelic sequences in DNA pools is an inexpensive and feasible alternative for detecting polymorphic differences in candidate gene association studies and genome-wide linkage disequilibrium scans. PMID:19087310

  19. Disparities in allele frequencies and population differentiation for 101 disease-associated single nucleotide polymorphisms between Puerto Ricans and non-Hispanic whites

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Variations in gene allele frequencies can contribute to differences in the prevalence of some common complex diseases among populations. Natural selection modulates the balance in allele frequencies across populations. Population differentiation (FST) can evidence environmental selection...

  20. Frequency and characterization of known and novel RHD variant alleles in 37 782 Dutch D-negative pregnant women.

    PubMed

    Stegmann, Tamara C; Veldhuisen, Barbera; Bijman, Renate; Thurik, Florentine F; Bossers, Bernadette; Cheroutre, Goedele; Jonkers, Remco; Ligthart, Peter; de Haas, Masja; Haer-Wigman, Lonneke; van der Schoot, C Ellen

    2016-05-01

    To guide anti-D prophylaxis, Dutch D- pregnant women are offered a quantitative fetal-RHD-genotyping assay to determine the RHD status of their fetus. This allowed us to determine the frequency of different maternal RHD variants in 37 782 serologically D- pregnant women. A variant allele is present in at least 0·96% of Dutch D- pregnant women The D- serology could be confirmed after further serological testing in only 54% of these women, which emphasizes the potential relevance of genotyping of blood donors. 43 different RHD variant alleles were detected, including 15 novel alleles (11 null-, 2 partial D- and 2 DEL-alleles). Of those novel null alleles, one allele contained a single missense mutation (RHD*443C>G) and one allele had a single amino acid deletion (RHD*424_426del). The D- phenotype was confirmed by transduction of human D- erythroblasts, consolidating that, for the first time, a single amino acid change or deletion causes the D- phenotype. Transduction also confirmed the phenotypes for the two new variant DEL-alleles (RHD*721A>C and RHD*884T>C) and the novel partial RHD*492C>A allele. Notably, in three additional cases the DEL phenotype was observed but sequencing of the coding sequence, flanking introns and promoter region revealed an apparently wild-type RHD allele without mutations. PMID:27018217

  1. Semantic Web-based integration of cancer pathways and allele frequency data.

    PubMed

    Holford, Matthew E; Rajeevan, Haseena; Zhao, Hongyu; Kidd, Kenneth K; Cheung, Kei-Hoi

    2009-01-01

    We demonstrate the use of Semantic Web technology to integrate the ALFRED allele frequency database and the Starpath pathway resource. The linking of population-specific genotype data with cancer-related pathway data is potentially useful given the growing interest in personalized medicine and the exploitation of pathway knowledge for cancer drug discovery. We model our data using the Web Ontology Language (OWL), drawing upon ideas from existing standard formats BioPAX for pathway data and PML for allele frequency data. We store our data within an Oracle database, using Oracle Semantic Technologies. We then query the data using Oracle's rule-based inference engine and SPARQL-like RDF query language. The ability to perform queries across the domains of population genetics and pathways offers the potential to answer a number of cancer-related research questions. Among the possibilities is the ability to identify genetic variants which are associated with cancer pathways and whose frequency varies significantly between ethnic groups. This sort of information could be useful for designing clinical studies and for providing background data in personalized medicine. It could also assist with the interpretation of genetic analysis results such as those from genome-wide association studies. PMID:19458791

  2. Semantic Web-Based Integration of Cancer Pathways and Allele Frequency Data

    PubMed Central

    Holford, Matthew E.; Rajeevan, Haseena; Zhao, Hongyu; Kidd, Kenneth K.; Cheung, Kei-Hoi

    2009-01-01

    We demonstrate the use of Semantic Web technology to integrate the ALFRED allele frequency database and the Starpath pathway resource. The linking of population-specific genotype data with cancer-related pathway data is potentially useful given the growing interest in personalized medicine and the exploitation of pathway knowledge for cancer drug discovery. We model our data using the Web Ontology Language (OWL), drawing upon ideas from existing standard formats BioPAX for pathway data and PML for allele frequency data. We store our data within an Oracle database, using Oracle Semantic Technologies. We then query the data using Oracle’s rule-based inference engine and SPARQL-like RDF query language. The ability to perform queries across the domains of population genetics and pathways offers the potential to answer a number of cancer-related research questions. Among the possibilities is the ability to identify genetic variants which are associated with cancer pathways and whose frequency varies significantly between ethnic groups. This sort of information could be useful for designing clinical studies and for providing background data in personalized medicine. It could also assist with the interpretation of genetic analysis results such as those from genome-wide association studies. PMID:19458791

  3. Allele frequency distribution of 13 X-chromosomal STR loci in Pakistani population.

    PubMed

    Tariq, Muhammad Akram; Ullah, Obaid; Riazuddin, S Amer; Riazuddin, Sheikh

    2008-11-01

    Short tandem repeat (STR) markers are extensively being used for human identification as well as paternity and forensic case work. X-chromosome STR (X-STR) markers are a powerful complementary system especially in deficiency paternity testing. Many X-linked microsatellites have been evaluated but further studies are required to determine population specific statistics. Here, we report allele frequencies of 13 X-linked microsatellites (DXS8378, DXS9902, DXS6810, DXS7132, DXS981, DXS6793, DXS6801, DXS6789, GATA172D05, HPRTB, GATA31E08, DXS8377, and DXS7423) in the Pakistani population. Blood samples were collected from individuals representing all major ethnic groups of the Pakistan population. A total of 5-18 alleles were observed for each locus and altogether 109 alleles for all 13 X-STR loci. Heterozygosity in females ranged from 0.524 to 0.884. No significant deviation was observed from Hardy-Weinberg equilibrium for all 13 microsatellites. In addition, there was no evidence of linkage disequilibrium in any pairs of these markers. These results strongly suggest that the X-linked microsatellites described here can potentially serve as an extension to autosomal systems currently used in parentage analysis and forensic case work. PMID:18629532

  4. Initial frequency of alleles conferring resistance to Bacillus thuringiensis poplar in a field population of Chrysomela tremulae.

    PubMed Central

    Génissel, Anne; Augustin, Sylvie; Courtin, Claudine; Pilate, Gilles; Lorme, Philippe; Bourguet, Denis

    2003-01-01

    Globally, the estimated total area planted with transgenic plants producing Bacillus thuringiensis (Bt) toxins was 12 million hectares in 2001. The risk of target pests becoming resistant to these toxins has led to the implementation of resistance-management strategies. The efficiency and sustainability of these strategies, including the high-dose plus refuge strategy currently recommended for North American maize, depend on the initial frequency of resistance alleles. In this study, we estimated the initial frequencies of alleles conferring resistance to transgenic Bt poplars producing Cry3A in a natural population of the poplar pest Chrysomela tremulae (Coleoptera: Chrysomelidae). We used the F(2) screen method developed for detecting resistance alleles in natural pest populations. At least three parents of the 270 lines tested were heterozygous for a major Bt resistance allele. We estimated mean resistance-allele frequency for the period 1999-2001 at 0.0037 (95% confidence interval = 0.00045-0.0080) with a detection probability of 90%. These results demonstrate that (i) the F(2) screen method can be used to detect major alleles conferring resistance to Bt-producing plants in insects and (ii) the initial frequency of alleles conferring resistance to Bt toxin can be close to the highest theoretical values that are expected prior to the use of Bt plants if considering fitness costs and typical mutation rates. PMID:12737656

  5. Estimation of population allele frequencies from next-generation sequencing data: pool-versus individual-based genotyping.

    PubMed

    Gautier, Mathieu; Foucaud, Julien; Gharbi, Karim; Cézard, Timothée; Galan, Maxime; Loiseau, Anne; Thomson, Marian; Pudlo, Pierre; Kerdelhué, Carole; Estoup, Arnaud

    2013-07-01

    Molecular markers produced by next-generation sequencing (NGS) technologies are revolutionizing genetic research. However, the costs of analysing large numbers of individual genomes remain prohibitive for most population genetics studies. Here, we present results based on mathematical derivations showing that, under many realistic experimental designs, NGS of DNA pools from diploid individuals allows to estimate the allele frequencies at single nucleotide polymorphisms (SNPs) with at least the same accuracy as individual-based analyses, for considerably lower library construction and sequencing efforts. These findings remain true when taking into account the possibility of substantially unequal contributions of each individual to the final pool of sequence reads. We propose the intuitive notion of effective pool size to account for unequal pooling and derive a Bayesian hierarchical model to estimate this parameter directly from the data. We provide a user-friendly application assessing the accuracy of allele frequency estimation from both pool- and individual-based NGS population data under various sampling, sequencing depth and experimental error designs. We illustrate our findings with theoretical examples and real data sets corresponding to SNP loci obtained using restriction site-associated DNA (RAD) sequencing in pool- and individual-based experiments carried out on the same population of the pine processionary moth (Thaumetopoea pityocampa). NGS of DNA pools might not be optimal for all types of studies but provides a cost-effective approach for estimating allele frequencies for very large numbers of SNPs. It thus allows comparison of genome-wide patterns of genetic variation for large numbers of individuals in multiple populations. PMID:23730833

  6. On the Bayesness, minimaxity and admissibility of point estimators of allelic frequencies.

    PubMed

    Martínez, Carlos Alberto; Khare, Kshitij; Elzo, Mauricio A

    2015-10-21

    In this paper, decision theory was used to derive Bayes and minimax decision rules to estimate allelic frequencies and to explore their admissibility. Decision rules with uniformly smallest risk usually do not exist and one approach to solve this problem is to use the Bayes principle and the minimax principle to find decision rules satisfying some general optimality criterion based on their risk functions. Two cases were considered, the simpler case of biallelic loci and the more complex case of multiallelic loci. For each locus, the sampling model was a multinomial distribution and the prior was a Beta (biallelic case) or a Dirichlet (multiallelic case) distribution. Three loss functions were considered: squared error loss (SEL), Kulback-Leibler loss (KLL) and quadratic error loss (QEL). Bayes estimators were derived under these three loss functions and were subsequently used to find minimax estimators using results from decision theory. The Bayes estimators obtained from SEL and KLL turned out to be the same. Under certain conditions, the Bayes estimator derived from QEL led to an admissible minimax estimator (which was also equal to the maximum likelihood estimator). The SEL also allowed finding admissible minimax estimators. Some estimators had uniformly smaller variance than the MLE and under suitable conditions the remaining estimators also satisfied this property. In addition to their statistical properties, the estimators derived here allow variation in allelic frequencies, which is closer to the reality of finite populations exposed to evolutionary forces. PMID:26271891

  7. Allele and genotype frequencies of metabolic genes in Native Americans from Argentina and Paraguay.

    PubMed

    Bailliet, G; Santos, M R; Alfaro, E L; Dipierri, J E; Demarchi, D A; Carnese, F R; Bianchi, N O

    2007-03-01

    Interethnic differences in the allele frequencies of CYP2D6, NAT2, GSTM1 and GSTT1 deletions have been documented for Caucasians, Asians, and Africans population. On the other hand, data on Amerindians are scanty and limited to a few populations from southern areas of South America. In this report we analyze the frequencies of 11 allele variants of CYP2D6 and 4 allele variants of NAT2 genes, and the frequency of GSTM1 and GSTT1 homozygous deleted genotypes in a sample of 90 donors representing 8 Native American populations from Argentina and Paraguay, identified as Amerindians on the basis of their geographic location, genealogical data, mitochondrial- and Y-chromosome DNA markers. For CYP2D6, 88.6% of the total allele frequency corresponded to *1, *2, *4 and *10 variants. Average frequencies for NAT2 *4, *5, *6 and *7 alleles were 51.2%, 25%, 6.1%, and 20.1%, respectively. GSTM1 deletion ranged from 20% to 66%, while GSTT1 deletion was present in four populations in less than 50%. We assume that CYP2D6 *2, *4, *10, *14; NAT2 *5, *7 alleles and GSTM1 and GSTT1 *0/*0 genotypes are founder variants brought to America by the first Asian settlers. PMID:17194620

  8. GST M1-T1 null Allele Frequency Patterns in Geographically Assorted Human Populations: A Phylogenetic Approach

    PubMed Central

    Ramasamy, Thirumurugan; Ayyavoo, Jayachitra

    2015-01-01

    Genetic diversity in drug metabolism and disposition is mainly considered as the outcome of the inter-individual genetic variation in polymorphism of drug-xenobiotic metabolizing enzyme (XME). Among the XMEs, glutathione-S-transferases (GST) gene loci are an important candidate for the investigation of diversity in allele frequency, as the deletion mutations in GST M1 and T1 genotypes are associated with various cancers and genetic disorders of all major Population Affiliations (PAs). Therefore, the present population based phylogenetic study was focused to uncover the frequency distribution pattern in GST M1 and T1 null genotypes among 45 Geographically Assorted Human Populations (GAHPs). The frequency distribution pattern for GST M1 and T1 null alleles have been detected in this study using the data derived from literatures representing 44 populations affiliated to Africa, Asia, Europe, South America and the genome of PA from Gujarat, a region in western India. Allele frequency counting for Gujarat PA and scattered plot analysis for geographical distribution among the PAs were performed in SPSS-21. The GST M1 and GST T1 null allele frequencies patterns of the PAs were computed in Seqboot, Gendist program of Phylip software package (3.69 versions) and Unweighted Pair Group method with Arithmetic Mean in Mega-6 software. Allele frequencies from South African Xhosa tribe, East African Zimbabwe, East African Ethiopia, North African Egypt, Caucasian, South Asian Afghanistan and South Indian Andhra Pradesh have been identified as the probable seven patterns among the 45 GAHPs investigated in this study for GST M1-T1 null genotypes. The patternized null allele frequencies demonstrated in this study for the first time addresses the missing link in GST M1-T1 null allele frequencies among GAHPs. PMID:25867025

  9. GST M1-T1 null allele frequency patterns in geographically assorted human populations: a phylogenetic approach.

    PubMed

    Kasthurinaidu, Senthilkumar Pitchalu; Ramasamy, Thirumurugan; Ayyavoo, Jayachitra; Dave, Dhvani Kirtikumar; Adroja, Divya Anantray

    2015-01-01

    Genetic diversity in drug metabolism and disposition is mainly considered as the outcome of the inter-individual genetic variation in polymorphism of drug-xenobiotic metabolizing enzyme (XME). Among the XMEs, glutathione-S-transferases (GST) gene loci are an important candidate for the investigation of diversity in allele frequency, as the deletion mutations in GST M1 and T1 genotypes are associated with various cancers and genetic disorders of all major Population Affiliations (PAs). Therefore, the present population based phylogenetic study was focused to uncover the frequency distribution pattern in GST M1 and T1 null genotypes among 45 Geographically Assorted Human Populations (GAHPs). The frequency distribution pattern for GST M1 and T1 null alleles have been detected in this study using the data derived from literatures representing 44 populations affiliated to Africa, Asia, Europe, South America and the genome of PA from Gujarat, a region in western India. Allele frequency counting for Gujarat PA and scattered plot analysis for geographical distribution among the PAs were performed in SPSS-21. The GST M1 and GST T1 null allele frequencies patterns of the PAs were computed in Seqboot, Gendist program of Phylip software package (3.69 versions) and Unweighted Pair Group method with Arithmetic Mean in Mega-6 software. Allele frequencies from South African Xhosa tribe, East African Zimbabwe, East African Ethiopia, North African Egypt, Caucasian, South Asian Afghanistan and South Indian Andhra Pradesh have been identified as the probable seven patterns among the 45 GAHPs investigated in this study for GST M1-T1 null genotypes. The patternized null allele frequencies demonstrated in this study for the first time addresses the missing link in GST M1-T1 null allele frequencies among GAHPs. PMID:25867025

  10. Frequency of alleles and haplotypes of the human leukocyte antigen system in Bauru São Paulo, Brazil

    PubMed Central

    Salvadori, Luana de Cassia; Santana, Fabiana Covolo de Souza; Marcos, Elaine Valim Camarinha

    2014-01-01

    Background HLA allele identification is used in bone marrow transplant programs as HLA compatibility between the donor and recipient may prevent graft rejection. Objective This study aimed to estimate the frequency of alleles and haplotypes of the HLA system in the region of Bauru and compare these with the frequencies found in other regions of the country. Methods HLA-A*, HLA-B*, and HLA-DRB1* allele frequencies and haplotypes were analyzed in a sample of 3542 volunteer donors at the National Registry of Voluntary Bone Marrow Donors (REDOME) in Bauru. HLA low resolution typing was performed using reverse line blot with the Dynal Reli™ SSO-HLA Typing Kit and automated Dynal AutoReli™48 device (Invitrogen, USA). Results Twenty, 36, and 13 HLA-A*, HLA-B*, and HLA-DRB1* allele groups, respectively, were identified. The most common alleles for each locus were HLA-A*02, HLA-B*35, and HLA-DRB1*07. The most frequent haplotype was A*01-B*08-DRB1*03. Allele and haplotype frequencies were compared to other regions in Brazil and the similarities and differences among populations are shown. Conclusion The knowledge of the immunogenic profile of a population contributes to the comprehension of the historical and anthropological aspects of different regions. Moreover, this helps to find suitable donors quickly, thereby shortening waiting lists for transplants and thus increasing survival rates among recipients.

  11. Allelic frequencies and statistical data obtained from 15 STR loci in a population of the Goiás State.

    PubMed

    Vieira, T C; Silva, D M; Gigonzac, M A D; Ferreira, V L; Gonçalves, M W; da Cruz, A D

    2013-01-01

    Due to the miscegenation of the Brazilian population, the central region of Brazil was colonized by internal migration of individuals from different origins, who contributed to the genetic diversity existing in this population. The purpose of this study was to estimate population parameters based on the allele frequencies for 15 polymorphic autosomal short-tandem repeat (STR) loci present in the population of the State of Goiás in the central region of Brazil, and to compare the results with those of others from different Brazilian populations. DNA was obtained from a sample of 986 unrelated individuals by a commercial reagent kit and was quantified by spectrometry for later amplification in the thermocycler. These loci, commonly used in forensics and paternity testing, reflected Hardy-Weinberg equilibrium in this population. The D18S51 and Penta E loci had the highest number of alleles, while the observed heterozygosity reached the highest rates in FGA (0.920), D7S820 (0.870), and vWA (0.867) markers. Genetic diversity reached the highest levels in Penta E (0.906), Penta D (0.873), and D18S51 (0.860) markers, and the investigated forensic parameters showed high average values, with 93% power of discrimination, polymorphism information content of 78%, gene diversity of 79%, and observed heterozygosity of 79%. Similar to the other populations of Brazil, the population of the Midwest is derived from the admixture of 3 main parental groups: Amerindian, European, particularly Portuguese, and Africans from sub-Saharan Africa. In this context, the overall distribution of allele frequencies in the STR markers of various Brazilian populations is quite similar to the data obtained in this study. PMID:23359020

  12. Testing for Ancient Selection Using Cross-population Allele Frequency Differentiation.

    PubMed

    Racimo, Fernando

    2016-02-01

    A powerful way to detect selection in a population is by modeling local allele frequency changes in a particular region of the genome under scenarios of selection and neutrality and finding which model is most compatible with the data. A previous method based on a cross-population composite likelihood ratio (XP-CLR) uses an outgroup population to detect departures from neutrality that could be compatible with hard or soft sweeps, at linked sites near a beneficial allele. However, this method is most sensitive to recent selection and may miss selective events that happened a long time ago. To overcome this, we developed an extension of XP-CLR that jointly models the behavior of a selected allele in a three-population tree. Our method - called "3-population composite likelihood ratio" (3P-CLR) - outperforms XP-CLR when testing for selection that occurred before two populations split from each other and can distinguish between those events and events that occurred specifically in each of the populations after the split. We applied our new test to population genomic data from the 1000 Genomes Project, to search for selective sweeps that occurred before the split of Yoruba and Eurasians, but after their split from Neanderthals, and that could have led to the spread of modern-human-specific phenotypes. We also searched for sweep events that occurred in East Asians, Europeans, and the ancestors of both populations, after their split from Yoruba. In both cases, we are able to confirm a number of regions identified by previous methods and find several new candidates for selection in recent and ancient times. For some of these, we also find suggestive functional mutations that may have driven the selective events. PMID:26596347

  13. The allele frequency spectrum in genome-wide human variation data reveals signals of differential demographic history in three large world populations.

    PubMed Central

    Marth, Gabor T; Czabarka, Eva; Murvai, Janos; Sherry, Stephen T

    2004-01-01

    We have studied a genome-wide set of single-nucleotide polymorphism (SNP) allele frequency measures for African-American, East Asian, and European-American samples. For this analysis we derived a simple, closed mathematical formulation for the spectrum of expected allele frequencies when the sampled populations have experienced nonstationary demographic histories. The direct calculation generates the spectrum orders of magnitude faster than coalescent simulations do and allows us to generate spectra for a large number of alternative histories on a multidimensional parameter grid. Model-fitting experiments using this grid reveal significant population-specific differences among the demographic histories that best describe the observed allele frequency spectra. European and Asian spectra show a bottleneck-shaped history: a reduction of effective population size in the past followed by a recent phase of size recovery. In contrast, the African-American spectrum shows a history of moderate but uninterrupted population expansion. These differences are expected to have profound consequences for the design of medical association studies. The analytical methods developed for this study, i.e., a closed mathematical formulation for the allele frequency spectrum, correcting the ascertainment bias introduced by shallow SNP sampling, and dealing with variable sample sizes provide a general framework for the analysis of public variation data. PMID:15020430

  14. Initial frequency of alleles for resistance to Bacillus thuringiensis toxins in field populations of Heliothis virescens

    PubMed Central

    Gould, F.; Anderson, A.; Jones, A.; Sumerford, D.; Heckel, D. G.; Lopez, J.; Micinski, S.; Leonard, R.; Laster, M.

    1997-01-01

    The risk of rapid pest adaptation to an insecticide is highly dependent on the initial frequency of resistance alleles in field populations. Because we have lacked empirical estimates of these frequencies, population–genetic models of resistance evolution have relied on a wide range of theoretical estimates. The recent commercialization of genetically engineered cotton that constitutively produces an insecticidal protein derived from the biocontrol agent, Bacillus thuringiensis (Bt) has raised concern that we lack data needed to quantify the risk of insect pests such as Heliothis virescens rapidly adapting to this ecologically valuable class of toxins. By individually mating over 2,000 male H. virescens moths collected in four states to females of a Bt toxin-resistant laboratory strain, and screening F1 and F2 offspring for tolerance of the toxic protein, we were able to directly estimate the field frequency of alleles for resistance as 1.5 × 10−3. This high initial frequency underscores the need for caution in deploying transgenic cotton to control insect pests. Our single-pair mating technique greatly increases the efficiency of detecting recessive resistance alleles. Because alleles that decrease target site sensitivity to Bt toxins and other insecticides are often recessive, this technique could be useful in estimating resistance allele frequencies in other insects exposed to transgenic insecticidal crops or conventional insecticides. PMID:11038613

  15. Determination of knockdown resistance allele frequencies in global human head louse populations using the serial invasive signal amplification reaction

    PubMed Central

    Hodgdon, Hilliary E.; Yoon, Kyong Sup; Previte, Domenic J.; Kim, Hyo Jeong; Aboelghar, Gamal E.; Lee, Si Hyeock; Clark, J. Marshall

    2010-01-01

    BACKGROUND Pediculosis is the most prevalent parasitic infestation of humans. Resistance to pyrethrin- and pyrethroid-based pediculicides is due to knockdown (kdr)-type point mutations in the voltage-sensitive sodium channel α-subunit gene. Early detection of resistance is crucial for the selection of effective management strategies. RESULTS Kdr allele frequencies of lice from 14 countries were determined using serial invasive signal amplification reaction. Lice collected from Uruguay, UK and Australia had kdr allele frequencies of 100% while lice from Ecuador, Papua New Guinea, South Korea and Thailand had kdr allele frequencies of 0%. The remaining 7 countries investigated, including seven US populations, two Argentina, Brazil, Denmark, Czech Republic, Egypt and Israel, displayed variable kdr allele frequencies, ranging from 11% to 97%. CONCLUSION The newly developed and validated SISAR method is suitable for accurate monitoring of kdr allele frequencies in head lice. Proactive management is needed where kdr-type resistance is not yet saturated. Based on sodium channel insensitivity and its occurrence in louse populations resistant to pyrethrin- and pyrethroid-based pediculicides, the T917I mutation appears a key marker for resistance. Results from the Egyptian population, however, indicate that phenotypic resistance of lice with single or double mutations (M815I and/or L920F) should also be determined. PMID:20564731

  16. Population-ethnic group specific genome variation allele frequency data: a querying and visualization journey.

    PubMed

    Viennas, Emmanouil; Gkantouna, Vassiliki; Ioannou, Marina; Georgitsi, Marianthi; Rigou, Maria; Poulas, Konstantinos; Patrinos, George P; Tzimas, Giannis

    2012-08-01

    National/ethnic mutation databases aim to document the genetic heterogeneity in various populations and ethnic groups worldwide. We have previously reported the development and upgrade of FINDbase (www.findbase.org), a database recording causative mutations and pharmacogenomic marker allele frequencies in various populations around the globe. Although this database has recently been upgraded, we continuously try to enhance its functionality by providing more advanced visualization tools that would further assist effective data querying and comparisons. We are currently experimenting in various visualization techniques on the existing FINDbase causative mutation data collection aiming to provide a dynamic research tool for the worldwide scientific community. We have developed an interactive web-based application for population-based mutation data retrieval. It supports sophisticated data exploration allowing users to apply advanced filtering criteria upon a set of multiple views of the underlying data collection and enables browsing the relationships between individual datasets in a novel and meaningful way. PMID:22659238

  17. Population genetics of nine short tandem repeat loci: allele frequency distribution in a Brazilian population sample.

    PubMed

    Soares-Vieira, José Arnaldo; Billerbeck, Ana Elisa C; Pinto, Emília Modolo; Iwamura, Edna S M; Bilharinho de Mendonça, Berenice; Otto, Paulo A

    2002-06-01

    Gene and genotype frequencies in relation to the D3S1358, vWA, FGA, TH01, TPOX, CSF1PO, D5S818, D13S317, and D7S820 loci were determined in a sample of 290 unrelated individuals (204 Caucasians and 86 mulattoes) living in the city of São Paulo, Brazil. The sex test Amelogenin was also performed in all subjects from our sample, revealing the expected sex in all instances. Allele frequency data obtained from the analysis of these samples were in the usual range of other population groups with similar racial background. In the sample of Caucasian individuals, panmictic proportions were ruled out in relation to TPOX and CSF1PO loci, but only in the latter was the overall frequency of heterozygotes significantly less than expected. In the sample of mulattoes, Hardy-Weinberg proportions were rejected in relation to FGA and CSF1PO loci, but in no instance were the overall numbers of heterozygotes different from the corresponding expected ones under panmixia. Taking into account all this and also the number of tests performed, the degree of genetic heterogeneity of Brazilian populations, and the critical level reached by the significant results (1% < alpha<5%), the departures from panmixia here observed can be considered to be negligible in altering significantly biologic relationship odds calculated under the assumption of random matings. PMID:12040266

  18. Relationship between allozymes, heterozygosity and morphological characters in red deer (Cervus elaphus), and the influence of selective hunting on allele frequency distribution.

    PubMed

    Hartl, G B; Lang, G; Klein, F; Willing, R

    1991-06-01

    Morphological characters in red deer (Cervus elaphus), which serve as criteria for selective hunting, were examined in relation to electrophoretic variation in three populations from the Vosges in eastern France. From the polymorphic loci examined, certain alleles at Idh-2, Me-1 and Acp-1 showed significant associations with a special development of body and antler characters selected for by hunters. Idh-2(125) was associated with larger hind foot length in females and a higher number of antler points in males. Me-1(90) and Acp-1(100) were associated with small spikes. The populations studied differed from one another in the duration and intensity of selective hunting and the increase or decrease in the respective allele frequencies could be explained by selection for large body size, a high number of antler points and against small spikes in yearlings, rather than by genetic drift. Among other morphological characters examined, the length of the main beam was significantly associated with the allele Acp-2(100). In contrast, no associations could be detected between overall heterozygosity and the development or the degree of asymmetry (in paired structures) of any of the morphological traits in question. Although no obvious differences in the overall values of polymorphism or heterozygosity were found between the populations, selective hunting leads towards a change in allele frequencies and eventually to the loss of one or the other rare allele. PMID:1880046

  19. Knockdown resistance allele frequencies in North American head louse (Anoplura: Pediculidae) populations.

    PubMed

    Yoon, Kyong Sup; Previte, Domenic J; Hodgdon, Hilliary E; Poole, Bryan C; Kwon, Deok Ho; El-Ghar, Gamal E Abo; Lee, Si Hyeock; Clark, J Marshall

    2014-03-01

    The study examines the extent and frequency of a knockdown-type resistance allele (kdr type) in North American populations of human head lice. Lice were collected from 32 locations in Canada and the United States. DNA was extracted from individual lice and used to determine their zygosity using the serial invasive signal amplification technique to detect the kdr-type T917I (TI) mutation, which is most responsible for nerve insensitivity that results in the kdr phenotype and permethrin resistance. Previously sampled sites were resampled to determine if the frequency of the TI mutation was changing. The TI frequency was also reevaluated using a quantitative sequencing method on pooled DNA samples from selected sites to validate this population genotyping method. Genotyping substantiated that TI occurs at high levels in North American lice (88.4%). Overall, the TI frequency in U.S. lice was 84.4% from 1999 to 2009, increased to 99.6% from 2007 to 2009, and was 97.1% in Canadian lice in 2008. Genotyping results using the serial invasive signal amplification reaction (99.54%) and quantitative sequencing (99.45%) techniques were highly correlated. Thus, the frequencies of TI in North American head louse populations were found to be uniformly high, which may be due to the high selection pressure from the intensive and widespread use of the pyrethrins- or pyrethroid-based pediculicides over many years, and is likely a main cause of increased pediculosis and failure of pyrethrins- or permethrin-based products in Canada and the United States. Alternative approaches to treatment of head lice infestations are critically needed. PMID:24724296

  20. Knockdown Resistance Allele Frequencies in North American Head Louse (Anoplura: Pediculidae) Populations

    PubMed Central

    Yoon, Kyong Sup; Previte, Domenic J.; Hodgdon, Hilliary E.; Poole, Bryan C.; Kwon, Deok Ho; El-Ghar, Gamal E. Abo; Lee, Si Hyeock; Clark, J. Marshall

    2014-01-01

    The study examines the extent and frequency of a knockdown-type resistance allele (kdr type) in North American populations of human head lice. Lice were collected from 32 locations in Canada and the United States. DNA was extracted from individual lice and used to determine their zygosity using the serial invasive signal amplification technique to detect the kdr-type T917I (TI) mutation, which is most responsible for nerve insensitivity that results in the kdr phenotype and permethrin resistance. Previously sampled sites were resampled to determine if the frequency of the TI mutation was changing. The TI frequency was also reevaluated using a quantitative sequencing method on pooled DNA samples from selected sites to validate this population genotyping method. Genotyping substantiated that TI occurs at high levels in North American lice (88.4%). Overall, the TI frequency in U.S. lice was 84.4% from 1999 to 2009, increased to 99.6% from 2007 to 2009, and was 97.1% in Canadian lice in 2008. Genotyping results using the serial invasive signal amplification reaction (99.54%) and quantitative sequencing (99.45%) techniques were highly correlated. Thus, the frequencies of TI in North American head louse populations were found to be uniformly high, which may be due to the high selection pressure from the intensive and widespread use of the pyrethrins- or pyrethroid-based pediculicides over many years, and is likely a main cause of increased pediculosis and failure of pyrethrins- or permethrin-based products in Canada and the United States. Alternative approaches to treatment of head lice infestations are critically needed. PMID:24724296

  1. Allelic frequencies and statistical data obtained from 12 codis STR loci in an admixed population of the Brazilian Amazon

    PubMed Central

    da Costa Francez, Pablo Abdon; Rodrigues, Elzemar Martins Ribeiro; Frazão, Gleycianne Furtado; dos Reis Borges, Nathalia Danielly; dos Santos, Sidney Emanuel Batista

    2011-01-01

    The allelic frequencies of 12 short tandem repeat loci were obtained from a sample of 307 unrelated individuals living in Macapá, a city in the northern Amazon region, Brazil. These loci are the most commonly used in forensics and paternity testing. Based on the allele frequency obtained for the population of Macapá, we estimated an interethnic admixture for the three parental groups (European, Native American and African) of, respectively, 46%, 35% and 19%. Comparing these allele frequencies with those of other Brazilian populations and of the Iberian Peninsula population, no significant distances were observed. The interpopulation genetic distances (FST coefficients) to the present database ranged from FST = 0.0016 between Macapá and Belém to FST = 0.0036 between Macapá and the Iberian Peninsula. PMID:21637540

  2. Evaluation of DNA pooling for the estimation of microsatellite allele frequencies: a case study using striped bass (Morone saxatilis).

    PubMed

    Skalski, Garrick T; Couch, Charlene R; Garber, Amber F; Weir, Bruce S; Sullivan, Craig V

    2006-06-01

    Using striped bass (Morone saxatilis) and six multiplexed microsatellite markers, we evaluated procedures for estimating allele frequencies by pooling DNA from multiple individuals, a method suggested as cost-effective relative to individual genotyping. Using moment-based estimators, we estimated allele frequencies in experimental DNA pools and found that the three primary laboratory steps, DNA quantitation and pooling, PCR amplification, and electrophoresis, accounted for 23, 48, and 29%, respectively, of the technical variance of estimates in pools containing DNA from 2-24 individuals. Exact allele-frequency estimates could be made for pools of sizes 2-8, depending on the locus, by using an integer-valued estimator. Larger pools of size 12 and 24 tended to yield biased estimates; however, replicates of these estimates detected allele frequency differences among pools with different allelic compositions. We also derive an unbiased estimator of Hardy-Weinberg disequilibrium coefficients that uses multiple DNA pools and analyze the cost-efficiency of DNA pooling. DNA pooling yields the most potential cost savings when a large number of loci are employed using a large number of individuals, a situation becoming increasingly common as microsatellite loci are developed in increasing numbers of taxa. PMID:16582444

  3. Detection of MPLW515L/K Mutations and Determination of Allele Frequencies with a Single-Tube PCR Assay

    PubMed Central

    Takei, Hiraku; Morishita, Soji; Araki, Marito; Edahiro, Yoko; Sunami, Yoshitaka; Hironaka, Yumi; Noda, Naohiro; Sekiguchi, Yuji; Tsuneda, Satoshi; Ohsaka, Akimichi; Komatsu, Norio

    2014-01-01

    A gain-of-function mutation in the myeloproliferative leukemia virus (MPL) gene, which encodes the thrombopoietin receptor, has been identified in patients with essential thrombocythemia and primary myelofibrosis, subgroups of classic myeloproliferative neoplasms (MPNs). The presence of MPL gene mutations is a critical diagnostic criterion for these diseases. Here, we developed a rapid, simple, and cost-effective method of detecting two major MPL mutations, MPLW515L/K, in a single PCR assay; we termed this method DARMS (dual amplification refractory mutation system)-PCR. DARMS-PCR is designed to produce three different PCR products corresponding to MPLW515L, MPLW515K, and all MPL alleles. The amplicons are later detected and quantified using a capillary sequencer to determine the relative frequencies of the mutant and wild-type alleles. Applying DARMS-PCR to human specimens, we successfully identified MPL mutations in MPN patients, with the exception of patients bearing mutant allele frequencies below the detection limit (5%) of this method. The MPL mutant allele frequencies determined using DARMS-PCR correlated strongly with the values determined using deep sequencing. Thus, we demonstrated the potential of DARMS-PCR to detect MPL mutations and determine the allele frequencies in a timely and cost-effective manner. PMID:25144224

  4. Real-time PCR genotyping assay for canine progressive rod-cone degeneration and mutant allele frequency in Toy Poodles, Chihuahuas and Miniature Dachshunds in Japan

    PubMed Central

    KOHYAMA, Moeko; TADA, Naomi; MITSUI, Hiroko; TOMIOKA, Hitomi; TSUTSUI, Toshihiko; YABUKI, Akira; RAHMAN, Mohammad Mahbubur; KUSHIDA, Kazuya; MIZUKAMI, Keijiro; YAMATO, Osamu

    2015-01-01

    Canine progressive rod-cone degeneration (PRCD) is a middle- to late-onset, autosomal recessive, inherited retinal disorder caused by a substitution (c.5G>A) in the canine PRCD gene that has been identified in 29 or more purebred dogs. In the present study, a TaqMan probe-based real-time PCR assay was developed and evaluated for rapid genotyping and large-scale screening of the mutation. Furthermore, a genotyping survey was carried out in a population of the three most popular breeds in Japan (Toy Poodles, Chihuahuas and Miniature Dachshunds) to determine the current mutant allele frequency. The assay separated all the genotypes of canine PRCD rapidly, indicating its suitability for large-scale surveys. The results of the survey showed that the mutant allele frequency in Toy Poodles was high enough (approximately 0.09) to allow the establishment of measures for the prevention and control of this disorder in breeding kennels. The mutant allele was detected in Chihuahuas for the first time, but the frequency was lower (approximately 0.02) than that in Toy Poodles. The mutant allele was not detected in Miniature Dachshunds. This assay will allow the selective breeding of dogs from the two most popular breeds (Toy Poodle and Chihuahua) in Japan and effective prevention or control of the disorder. PMID:26549343

  5. Real-time PCR genotyping assay for canine progressive rod-cone degeneration and mutant allele frequency in Toy Poodles, Chihuahuas and Miniature Dachshunds in Japan.

    PubMed

    Kohyama, Moeko; Tada, Naomi; Mitsui, Hiroko; Tomioka, Hitomi; Tsutsui, Toshihiko; Yabuki, Akira; Rahman, Mohammad Mahbubur; Kushida, Kazuya; Mizukami, Keijiro; Yamato, Osamu

    2016-03-01

    Canine progressive rod-cone degeneration (PRCD) is a middle- to late-onset, autosomal recessive, inherited retinal disorder caused by a substitution (c.5G>A) in the canine PRCD gene that has been identified in 29 or more purebred dogs. In the present study, a TaqMan probe-based real-time PCR assay was developed and evaluated for rapid genotyping and large-scale screening of the mutation. Furthermore, a genotyping survey was carried out in a population of the three most popular breeds in Japan (Toy Poodles, Chihuahuas and Miniature Dachshunds) to determine the current mutant allele frequency. The assay separated all the genotypes of canine PRCD rapidly, indicating its suitability for large-scale surveys. The results of the survey showed that the mutant allele frequency in Toy Poodles was high enough (approximately 0.09) to allow the establishment of measures for the prevention and control of this disorder in breeding kennels. The mutant allele was detected in Chihuahuas for the first time, but the frequency was lower (approximately 0.02) than that in Toy Poodles. The mutant allele was not detected in Miniature Dachshunds. This assay will allow the selective breeding of dogs from the two most popular breeds (Toy Poodle and Chihuahua) in Japan and effective prevention or control of the disorder. PMID:26549343

  6. Alarmingly High Segregation Frequencies of Quinolone Resistance Alleles within Human and Animal Microbiomes Are Not Explained by Direct Clinical Antibiotic Exposure

    PubMed Central

    Field, Wesley; Hershberg, Ruth

    2015-01-01

    Antibiotic resistance poses a major threat to human health. It is therefore important to characterize the frequency of resistance within natural bacterial environments. Many studies have focused on characterizing the frequencies with which horizontally acquired resistance genes segregate within natural bacterial populations. Yet, very little is currently understood regarding the frequency of segregation of resistance alleles occurring within the housekeeping targets of antibiotics. We surveyed a large number of metagenomic datasets extracted from a large variety of host-associated and non host-associated environments for such alleles conferring resistance to three groups of broad spectrum antibiotics: streptomycin, rifamycins, and quinolones. We find notable segregation frequencies of resistance alleles occurring within the target genes of each of the three antibiotics, with quinolone resistance alleles being the most frequent and rifamycin resistance alleles being the least frequent. Resistance allele frequencies varied greatly between different phyla and as a function of environment. The frequency of quinolone resistance alleles was especially high within host-associated environments, where it averaged an alarming ∼40%. Within host-associated environments, resistance to quinolones was most often conferred by a specific resistance allele. High frequencies of quinolone resistance alleles were also found within hosts that were not directly treated with antibiotics. Therefore, the high segregation frequency of quinolone resistance alleles occurring within the housekeeping targets of antibiotics in host-associated environments does not seem to be the sole result of clinical antibiotic usage. PMID:26019163

  7. Allelic frequency and genotypes of prion protein at codon 136 and 171 in Iranian Ghezel sheep breeds

    PubMed Central

    Zadeh, Reza Ashrafi; Omrani, Mir Davood; Ramezani, Fatemeh; Amniattalab, Amir

    2011-01-01

    PrP genotypes at codons 136 and 171 in 120 Iranian Ghezel sheep breeds were studied using allele-specific PCR amplification and compared with the well-known sheep breeds in North America, the United States and Europe. The frequency of V allele and VV genotype at codon 136 of Ghezel sheep breed was significantly lower than AA and AV. At codon 171, the frequency of allele H was significantly lower than Q and R. Despite the similarities of PrP genotypes at codons 136 and 171 between Iranian Ghezel sheep breeds and some of the studied breeds, significant differences were found with others. Planning of effective breeding control and successful eradication of susceptible genotypes in Iranian Ghezel sheep breeds will not be possible unless the susceptibility of various genotypes in Ghezel sheep breeds to natural or experimental scrapie has been elucidated. PMID:21778818

  8. Frequency of Bt resistance alleles in Helicoverpa armigera in the Xinjiang cotton-planting region of China.

    PubMed

    Li, Guoping; Feng, Hongqiang; Gao, Yulin; Wyckhuys, Kris A G; Wu, Kongming

    2010-10-01

    Helicoverpa armigera Hübner (Lepidoptera: Noctuidae) is a key insect pest of cotton in Xinjiang cotton-planting region of northwest China. In this region, cotton is grown on average ≈ 1.65 million ha (1.53 ≈ 1.80 million ha) annually in largely monoculture agricultural landscapes, similarly to cropping systems in the United States or Australia. Under such cropping regimes, naturally occurring refuges (with non-Bt crops) may be insufficient to prevent H. armigera resistance development to Bt toxins. Therefore, we assessed frequency of alleles conferring resistance to Cry1Ac toxin of F(1) and F(2) offspring of H. armigera isofemale lines from two distinct localities in the region during 2005-2009. More specifically, a total of 224 isofemale lines was collected from Korla County (≈ 70% Bt cotton adoption) and 402 lines from Shache County (≈ 5% Bt cotton planting). Subsequent offspring was screened on Cry1Ac artificial diet. From 2005 to 2009, resistance gene frequency in Korla fluctuated between 0.0000 and 0.0040, while being 0.0000-0.0008 in individuals collected from Shache, and there were no significant increases in both counties from 2005 to 2009. Relative average development rates (RADRs) of larvae in F(1) tests showed significant increases from Korla, but not in Shache. RADR of F(1) larvae is significantly correlated with RADR of F(2) offspring, indicating genetic variation in response to toxin in field H. armigera population. Although the occurrence of Cry1Ac resistance alleles was low in Xinjiang cotton-planting region of China, particular attention should be given to H. armigera resistance development in Korla County. PMID:22546469

  9. Mapping Bias Overestimates Reference Allele Frequencies at the HLA Genes in the 1000 Genomes Project Phase I Data

    PubMed Central

    Brandt, Débora Y. C.; Aguiar, Vitor R. C.; Bitarello, Bárbara D.; Nunes, Kelly; Goudet, Jérôme; Meyer, Diogo

    2015-01-01

    Next-generation sequencing (NGS) technologies have become the standard for data generation in studies of population genomics, as the 1000 Genomes Project (1000G). However, these techniques are known to be problematic when applied to highly polymorphic genomic regions, such as the human leukocyte antigen (HLA) genes. Because accurate genotype calls and allele frequency estimations are crucial to population genomics analyses, it is important to assess the reliability of NGS data. Here, we evaluate the reliability of genotype calls and allele frequency estimates of the single-nucleotide polymorphisms (SNPs) reported by 1000G (phase I) at five HLA genes (HLA-A, -B, -C, -DRB1, and -DQB1). We take advantage of the availability of HLA Sanger sequencing of 930 of the 1092 1000G samples and use this as a gold standard to benchmark the 1000G data. We document that 18.6% of SNP genotype calls in HLA genes are incorrect and that allele frequencies are estimated with an error greater than ±0.1 at approximately 25% of the SNPs in HLA genes. We found a bias toward overestimation of reference allele frequency for the 1000G data, indicating mapping bias is an important cause of error in frequency estimation in this dataset. We provide a list of sites that have poor allele frequency estimates and discuss the outcomes of including those sites in different kinds of analyses. Because the HLA region is the most polymorphic in the human genome, our results provide insights into the challenges of using of NGS data at other genomic regions of high diversity. PMID:25787242

  10. A note on the change in gene frequency of a selected allele in partial full-sib mating populations

    SciTech Connect

    Caballero, A.

    1996-02-01

    The change in gene frequency of a selected allele in partial full-sib mating populations was analyzed. The implications of these papers is important in terms of the fixation probability of genes because, for the same equilibrium inbreeding coefficient, fixation rates of mutant genes would be larger for partial full-sib mating than for partial selfing. 4 refs.

  11. Finite frequency tomography shows a variety of plumes

    NASA Astrophysics Data System (ADS)

    Nolet, G.; Montelli, R.; Masters, G.; Dahlen, F. A.; Hung, S.

    2003-04-01

    The new technique of finite-frequency tomography (see abstract by Montelli et al., this meeting) is very powerful in imaging objects of small dimension in the lower mantle. The first global images of P velocity anomalies obtained by using this technique to invert a small but very accurate data set of long period P arrivals bottoming in the lower mantle show 18 low velocity anomalies in excess of -0.5%, all but two of which are associated with a known hotspot at the surface, and they serve as an unprecented glimpse into the deep mechanisms that give rise to hotspots. The following synopsis is given under the caveat that we have not yet incorporated high frequency waves into the interpretation, nor completed a full resolution analysis at the time of writing of this abstract (both will be presented at the meeting). We observe six or seven hotspots fed by a plume extending to the core-mantle boundary: Cap Verde, Easter Island, Hawaii, Kerguelen, St Helena, Tahiti, and perhaps also Azores. Several hotspots, among which are Bouvet, Bowie, and Mount Erebus, seem to originate at mid-mantle depth, while others (Afar, Ascension, Galapagos, Iceland, la Reunion and others) seem to be mostly confined to the upper mantle. Many renowned hotspots (such as Eifel, Samoa and Yellowstone) have only very weak low velocity anomalies at depth and may be the result of superficial processes confined to the top of the upper mantle. We confirm the existence of the two superplumes which both have Δ V_P < -0.5% extending as high as 2000 km depth. It is clear that no one plume/hotspot model can explain the variety in deep expressions of hotspots in the mantle. If midmantle plume origins represent originally deep plumes in their end stage, while the two unidentified anomalies are either beginning new plumes (Greenland) or plumes cut off in their initial ascent (W. Pacific), the large number of plumes caught in this phase would point to lengthy rise times of the order of tens of millions of

  12. Frequencies of 23 functionally significant variant alleles related with metabolism of antineoplastic drugs in the chilean population: comparison with caucasian and asian populations.

    PubMed

    Roco, Angela; Quiñones, Luis; Agúndez, José A G; García-Martín, Elena; Squicciarini, Valentina; Miranda, Carla; Garay, Joselyn; Farfán, Nancy; Saavedra, Iván; Cáceres, Dante; Ibarra, Carol; Varela, Nelson

    2012-01-01

    Cancer is a leading cause of death worldwide. The cancer incidence rate in Chile is 133.7/100,000 inhabitants and it is the second cause of death, after cardiovascular diseases. Most of the antineoplastic drugs are metabolized to be detoxified, and some of them to be activated. Genetic polymorphisms of drug-metabolizing enzymes can induce deep changes in enzyme activity, leading to individual variability in drug efficacy and/or toxicity. The present research describes the presence of genetic polymorphisms in the Chilean population, which might be useful in public health programs for personalized treatment of cancer, and compares these frequencies with those reported for Asian and Caucasian populations, as a contribution to the evaluation of ethnic differences in the response to chemotherapy. We analyzed 23 polymorphisms in a group of 253 unrelated Chilean volunteers from the general population. The results showed that CYP2A6*2, CYP2A6*3, CYP2D6*3, CYP2C19*3, and CYP3A4*17 variant alleles are virtually absent in Chileans. CYP1A1*2A allele frequency (0.37) is similar to that of Caucasians and higher than that reported for Japanese people. Allele frequencies for CYP3A5*3(0.76) and CYP2C9*3(0.04) are similar to those observed in Japanese people. CYP1A1*2C(0.32), CYP1A2*1F(0.77), CYP3A4*1B(0.06), CYP2D6*2(0.41), and MTHFR T(0.52) allele frequencies are higher than the observed either in Caucasian or in Japanese populations. Conversely, CYP2C19*2 allelic frequency (0.12), and genotype frequencies for GSTT1 null (0.11) and GSTM1 null (0.36) are lower than those observed in both populations. Finally, allele frequencies for CYP2A6*4(0.04), CYP2C8*3(0.06), CYP2C9*2(0.06), CYP2D6*4(0.12), CYP2E1*5B(0.14), CYP2E1*6(0.19), and UGT2B7*2(0.40) are intermediate in relation to those described in Caucasian and in Japanese populations, as expected according to the ethnic origin of the Chilean population. In conclusion, our findings support the idea that ethnic variability must be

  13. Frequencies of 23 Functionally Significant Variant Alleles Related with Metabolism of Antineoplastic Drugs in the Chilean Population: Comparison with Caucasian and Asian Populations

    PubMed Central

    Roco, Ángela; Quiñones, Luis; Agúndez, José A. G.; García-Martín, Elena; Squicciarini, Valentina; Miranda, Carla; Garay, Joselyn; Farfán, Nancy; Saavedra, Iván; Cáceres, Dante; Ibarra, Carol; Varela, Nelson

    2012-01-01

    Cancer is a leading cause of death worldwide. The cancer incidence rate in Chile is 133.7/100,000 inhabitants and it is the second cause of death, after cardiovascular diseases. Most of the antineoplastic drugs are metabolized to be detoxified, and some of them to be activated. Genetic polymorphisms of drug-metabolizing enzymes can induce deep changes in enzyme activity, leading to individual variability in drug efficacy and/or toxicity. The present research describes the presence of genetic polymorphisms in the Chilean population, which might be useful in public health programs for personalized treatment of cancer, and compares these frequencies with those reported for Asian and Caucasian populations, as a contribution to the evaluation of ethnic differences in the response to chemotherapy. We analyzed 23 polymorphisms in a group of 253 unrelated Chilean volunteers from the general population. The results showed that CYP2A6*2, CYP2A6*3, CYP2D6*3, CYP2C19*3, and CYP3A4*17 variant alleles are virtually absent in Chileans. CYP1A1*2A allele frequency (0.37) is similar to that of Caucasians and higher than that reported for Japanese people. Allele frequencies for CYP3A5*3(0.76) and CYP2C9*3(0.04) are similar to those observed in Japanese people. CYP1A1*2C(0.32), CYP1A2*1F(0.77), CYP3A4*1B(0.06), CYP2D6*2(0.41), and MTHFR T(0.52) allele frequencies are higher than the observed either in Caucasian or in Japanese populations. Conversely, CYP2C19*2 allelic frequency (0.12), and genotype frequencies for GSTT1 null (0.11) and GSTM1 null (0.36) are lower than those observed in both populations. Finally, allele frequencies for CYP2A6*4(0.04), CYP2C8*3(0.06), CYP2C9*2(0.06), CYP2D6*4(0.12), CYP2E1*5B(0.14), CYP2E1*6(0.19), and UGT2B7*2(0.40) are intermediate in relation to those described in Caucasian and in Japanese populations, as expected according to the ethnic origin of the Chilean population. In conclusion, our findings support the idea that ethnic variability must be

  14. DRD4 long allele carriers show heightened attention to high-priority items relative to low-priority items.

    PubMed

    Gorlick, Marissa A; Worthy, Darrell A; Knopik, Valerie S; McGeary, John E; Beevers, Christopher G; Maddox, W Todd

    2015-03-01

    Humans with seven or more repeats in exon III of the DRD4 gene (long DRD4 carriers) sometimes demonstrate impaired attention, as seen in attention-deficit hyperactivity disorder, and at other times demonstrate heightened attention, as seen in addictive behavior. Although the clinical effects of DRD4 are the focus of much work, this gene may not necessarily serve as a "risk" gene for attentional deficits, but as a plasticity gene where attention is heightened for priority items in the environment and impaired for minor items. Here we examine the role of DRD4 in two tasks that benefit from selective attention to high-priority information. We examine a category learning task where performance is supported by focusing on features and updating verbal rules. Here, selective attention to the most salient features is associated with good performance. In addition, we examine the Operation Span (OSPAN) task, a working memory capacity task that relies on selective attention to update and maintain items in memory while also performing a secondary task. Long DRD4 carriers show superior performance relative to short DRD4 homozygotes (six or less tandem repeats) in both the category learning and OSPAN tasks. These results suggest that DRD4 may serve as a "plasticity" gene where individuals with the long allele show heightened selective attention to high-priority items in the environment, which can be beneficial in the appropriate context. PMID:25244120

  15. Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.

    PubMed

    Sallman, D A; Komrokji, R; Vaupel, C; Cluzeau, T; Geyer, S M; McGraw, K L; Al Ali, N H; Lancet, J; McGinniss, M J; Nahas, S; Smith, A E; Kulasekararaj, A; Mufti, G; List, A; Hall, J; Padron, E

    2016-03-01

    Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53 VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53 VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53 VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2 VAF predicted for monocytosis (P=0.003), RUNX1 VAF with thrombocytopenia (P=0.01) and SF3B1 with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS. PMID:26514544

  16. Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies.

    PubMed Central

    Falush, Daniel; Stephens, Matthew; Pritchard, Jonathan K

    2003-01-01

    We describe extensions to the method of Pritchard et al. for inferring population structure from multilocus genotype data. Most importantly, we develop methods that allow for linkage between loci. The new model accounts for the correlations between linked loci that arise in admixed populations ("admixture linkage disequilibium"). This modification has several advantages, allowing (1) detection of admixture events farther back into the past, (2) inference of the population of origin of chromosomal regions, and (3) more accurate estimates of statistical uncertainty when linked loci are used. It is also of potential use for admixture mapping. In addition, we describe a new prior model for the allele frequencies within each population, which allows identification of subtle population subdivisions that were not detectable using the existing method. We present results applying the new methods to study admixture in African-Americans, recombination in Helicobacter pylori, and drift in populations of Drosophila melanogaster. The methods are implemented in a program, structure, version 2.0, which is available at http://pritch.bsd.uchicago.edu. PMID:12930761

  17. Rapid genotyping assays for the 4-base pair deletion of canine MDR1/ABCB1 gene and low frequency of the mutant allele in Border Collie dogs.

    PubMed

    Mizukami, Keijiro; Chang, Hye-Sook; Yabuki, Akira; Kawamichi, Takuji; Hossain, Mohammad A; Rahman, Mohammad M; Uddin, Mohammad M; Yamato, Osamu

    2012-01-01

    P-glycoprotein, encoded by the MDR1 or ABCB1 gene, is an integral component of the blood-brain barrier as an efflux pump for xenobiotics crucial in limiting drug uptake into the central nervous system. Dogs homozygous for a 4-base pair deletion of the canine MDR1 gene show altered expression or function of P-glycoprotein, resulting in neurotoxicosis after administration of the substrate drugs. In the present study, the usefulness of microchip electrophoresis for genotyping assays detecting this deletion mutation was evaluated. Mutagenically separated polymerase chain reaction (MS-PCR) and real-time PCR assays were newly developed and evaluated. Furthermore, a genotyping survey was carried out in a population of Border Collies dogs in Japan to determine the allele frequency in this breed. Microchip electrophoresis showed advantages in detection sensitivity and time saving over other modes of electrophoresis. The MS-PCR assay clearly discriminated all genotypes. Real-time PCR assay was most suitable for a large-scale survey due to its high throughput and rapidity. The genotyping survey demonstrated that the carrier and mutant allele frequencies were 0.49% and 0.25%, respectively, suggesting that the mutant allele frequency in Border Collies is markedly low compared to that in the susceptible dog breeds such as rough and smooth Collies. PMID:22362942

  18. Colloquium paper: human adaptations to diet, subsistence, and ecoregion are due to subtle shifts in allele frequency.

    PubMed

    Hancock, Angela M; Witonsky, David B; Ehler, Edvard; Alkorta-Aranburu, Gorka; Beall, Cynthia; Gebremedhin, Amha; Sukernik, Rem; Utermann, Gerd; Pritchard, Jonathan; Coop, Graham; Di Rienzo, Anna

    2010-05-11

    Human populations use a variety of subsistence strategies to exploit an exceptionally broad range of ecoregions and dietary components. These aspects of human environments have changed dramatically during human evolution, giving rise to new selective pressures. To understand the genetic basis of human adaptations, we combine population genetics data with ecological information to detect variants that increased in frequency in response to new selective pressures. Our approach detects SNPs that show concordant differences in allele frequencies across populations with respect to specific aspects of the environment. Genic and especially nonsynonymous SNPs are overrepresented among those most strongly correlated with environmental variables. This provides genome-wide evidence for selection due to changes in ecoregion, diet, and subsistence. We find particularly strong signals associated with polar ecoregions, with foraging, and with a diet rich in roots and tubers. Interestingly, several of the strongest signals overlap with those implicated in energy metabolism phenotypes from genome-wide association studies, including SNPs influencing glucose levels and susceptibility to type 2 diabetes. Furthermore, several pathways, including those of starch and sucrose metabolism, are enriched for strong signals of adaptations to a diet rich in roots and tubers, whereas signals associated with polar ecoregions are overrepresented in genes associated with energy metabolism pathways. PMID:20445095

  19. Investigator HDplex markers: allele frequencies and mutational events in a North Italian population.

    PubMed

    Turrina, Stefania; Ferrian, Melissa; Caratti, Stefano; De Leo, Domenico

    2015-07-01

    Autosomal short tandem repeats (STRs) analysis represents the method of election in forensic genetics and up to now, 23 STRs are available for these purposes. However, in particular circumstances such as human identification or complex kinship cases, examination of additional STRs may be required in order to obtain reliable conclusions. For this purpose, a new multiplex STR system, namely Investigator® HDplex kit (QIAGEN) that coamplifies a set of 12 autosomal loci, 9 of which, represents novel supplementary STRs, was recently developed. A population sample of 359 unrelated healthy subjects residing in North Italy was typed to determine allele frequencies, forensic parameters and genetic distances among European populations. Furthermore, to evaluate the suitability of the HDplex kit as an auxiliary tool for paternity testing, mutation rates were estimated on 84 confirmed family trios. The 12 loci resulted highly informative with a combined power of discrimination of 0.999998 and no departures from Hardy-Weinberg equilibrium were observed with the sole exception of locus D4S2366. From the comparison of our population sample and European reference populations, a single significant difference was revealed with the Poland population at D4S2366 locus. With regard to the mutation rate study, on a total of 2,016 meioses considered, six single-step mutational events were observed and the average mutation rate calculated was of 2.94 × 10(-3) per locus per generation (95% confidence interval, 1.08 × 10(-3)-6.39 × 10(-3)). PMID:25205546

  20. Prion protein genotype survey confirms low frequency of scrapie-resistant K222 allele in British goat herds.

    PubMed

    Goldmann, W; Marier, E; Stewart, P; Konold, T; Street, S; Langeveld, J; Windl, O; Ortiz-Pelaez, A

    2016-02-13

    Scrapie in goats is a transmissible, fatal prion disease, which is endemic in the British goat population. The recent success in defining caprine PRNP gene variants that provide resistance to experimental and natural classical scrapie has prompted the authors to conduct a survey of PRNP genotypes in 10 goat breeds and 52 herds to find goats with the resistant K222 allele. They report here the frequencies in 1236 tested animals of the resistance-associated K222 and several other alleles by breed and herd. Eight animals were found to be heterozygous QK222 goats (0.64 per cent genotype frequency, 95 per cent CI 0.28 to 1.27 per cent) but no homozygous KK222 goats were detected. The K222 allele was found in Saanen, Toggenburg and Anglo-Nubian goats. The fact that only a few goats with the K222 allele have been identified does not preclude the possibility to design and implement successful breeding programmes at national level. PMID:26755614

  1. Prion protein genotype survey confirms low frequency of scrapie-resistant K222 allele in British goat herds

    PubMed Central

    Goldmann, W.; Stewart, P.; Konold, T.; Street, S.; Langeveld, J.; Windl, O.; Ortiz-Pelaez, A.

    2016-01-01

    Scrapie in goats is a transmissible, fatal prion disease, which is endemic in the British goat population. The recent success in defining caprine PRNP gene variants that provide resistance to experimental and natural classical scrapie has prompted the authors to conduct a survey of PRNP genotypes in 10 goat breeds and 52 herds to find goats with the resistant K222 allele. They report here the frequencies in 1236 tested animals of the resistance-associated K222 and several other alleles by breed and herd. Eight animals were found to be heterozygous QK222 goats (0.64 per cent genotype frequency, 95 per cent CI 0.28 to 1.27 per cent) but no homozygous KK222 goats were detected. The K222 allele was found in Saanen, Toggenburg and Anglo-Nubian goats. The fact that only a few goats with the K222 allele have been identified does not preclude the possibility to design and implement successful breeding programmes at national level. PMID:26755614

  2. Case-control study of allele frequencies of 15 short tandem repeat loci in males with impulsive violent behavior

    PubMed Central

    Yang, Chun; Ba, Huajie; Gao, Zhiqin; Zhao, Hanqing; Yu, Haiying; Guo, Wei

    2013-01-01

    Background Analysis of genetic polymorphisms in short tandem repeats (STRs) is an accepted method for detecting associations between genotype and phenotype but it has not previously been used in the study of the genetics of impulsive violent behavior. Objective Compare the prevalence of different polymorphisms in 15 STR loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818 and FGA) between men with a history of impulsive violence and male control subjects without a history of impulsive violence. Methods The distributions of the alleles of the 15 STR loci were compared between 407 cases with impulsive violent behavior and 415 controls using AmpFlSTR® Identifiler™ kits. Results Compared to controls, the average frequencies of the following alleles were significantly lower in individuals with a history of violent behavior: allele 10 of TH01 (OR=0.29, 95%CI=0.16-0.52, p<0.0001,), allele 8 of TPOX (OR=0.71, 95%CI=0.58-0.86, p=0.0005), allele 9 of TPOX (OR=0.65, 95%CI=0.47-0.89, p=0.0072) and allele 14 of CSF1PO (OR=0.27, 95%CI=0.11-0.68, p=0.0035). One allele was significantly higher in cases than controls: allele 11 of TPOX (OR=1.79, 95%CI=1.45-2.22, p<0.0001). Conclusions To the best of our knowledge, this is the first behavioral genetic study that clearly demonstrates a close relationship between specific genetic markers and impulsive aggression in non-psychiatric offenders. Further prospective work will be needed to determine whether or not the alleles identified can be considered risk factors for impulsive aggression and, if so, the underlying mechanisms that result in this relationship. PMID:24991178

  3. Allele frequency-based analyses robustly map sequence sites under balancing selection in a malaria vaccine candidate antigen.

    PubMed Central

    Polley, Spencer D; Chokejindachai, Watcharee; Conway, David J

    2003-01-01

    The Plasmodium falciparum apical membrane antigen 1 (AMA1) is a leading candidate for a malaria vaccine. Here, within-population analyses of alleles from 50 Thai P. falciparum isolates yield significant evidence for balancing selection on polymorphisms within the disulfide-bonded domains I and III of the surface accessible ectodomain of AMA1, a result very similar to that seen previously in a Nigerian population. Studying the frequency of nucleotide polymorphisms in both populations shows that the between-population component of variance (F(ST)) is significantly lower in domains I and III compared to the intervening domain II and compared to 11 unlinked microsatellite loci. A nucleotide site-by-site analysis shows that sites with exceptionally high or low F(ST) values cluster significantly into serial runs, with four runs of low values in domain I and one in domain III. These runs may map the sequences that are consistently under the strongest balancing selection from naturally acquired immune responses. PMID:14573469

  4. High Resolution Human Leukocyte Antigen Class I Allele Frequencies and HIV-1 Infection Associations in Chinese Han and Uyghur Cohorts

    PubMed Central

    Liu, Yanhou; Zhao, Zhongfang; Li, Tianyi; Liao, Qi; Kushner, Nicholas; Touzjian, Neal Y.; Shao, Yiming; Sun, Yongtao; Strong, Amie J.; Lu, Yichen

    2012-01-01

    Background Host immunogenetic factors such as HLA class I polymorphism are important to HIV-1 infection risk and AIDS progression. Previous studies using high-resolution HLA class I profile data of Chinese populations appeared insufficient to provide information for HIV-1 vaccine development and clinical trial design. Here we reported HLA class I association with HIV-1 susceptibility in a Chinese Han and a Chinese Uyghur cohort. Methodology/Principal Findings Our cohort included 327 Han and 161 Uyghur ethnic individuals. Each cohort included HIV-1 seropositive and HIV-1 seronegative subjects. Four-digit HLA class I typing was performed by sequencing-based typing and high-resolution PCR-sequence specific primer. We compared the HLA class I allele and inferred haplotype frequencies between HIV-1 seropositive and seronegative groups. A neighbor-joining tree between our cohorts and other populations was constructed based on allele frequencies of HLA-A and HLA-B loci. We identified 58 HLA-A, 75 HLA-B, and 32 HLA-Cw distinct alleles from our cohort and no novel alleles. The frequency of HLA-B*5201 and A*0301 was significantly higher in the Han HIV-1 negative group. The frequency of HLA-B*5101 was significantly higher in the Uyghur HIV-1 negative group. We observed statistically significant increases in expectation-maximization (EM) algorithm predicted haplotype frequencies of HLA-A*0201-B*5101 in the Uyghur HIV-1 negative group, and of Cw*0304-B*4001 in the Han HIV-1 negative group. The B62s supertype frequency was found to be significantly higher in the Han HIV-1 negative group than in the Han HIV-1 positive group. Conclusions At the four-digit level, several HLA class I alleles and haplotypes were associated with lower HIV-1 susceptibility. Homogeneity of HLA class I and Bw4/Bw6 heterozygosity were not associated with HIV-1 susceptibility in our cohort. These observations contribute to the Chinese HLA database and could prove useful in the development of HIV-1 vaccine

  5. Frequency of HLA-DRB1 gene alleles in patients with multiple sclerosis in a Lithuanian population.

    PubMed

    Balnytė, Renata; Rastenytė, Daiva; Mickevičienė, Dalia; Vaitkus, Antanas; Skrodenienė, Erika; Vitkauskienė, Astra

    2012-01-01

    The aim of the present study was to investigate the influence of HLA-DRB1 alleles on the genetic susceptibility to multiple sclerosis in the Lithuanian population. MATERIAL AND METHODS. A total of 120 patients with multiple sclerosis and 120 unrelated healthy controls were enrolled in this case-control study. Allelic frequencies were compared between the groups. HLA-DRB1 alleles were genotyped using the polymerase chain reaction. RESULTS. HLA-DRB1*15 was present in 55.8% of the patients with multiple sclerosis and 10.0% of the controls (OR, 5.58; 95% CI, 3.19-9.77; P<0.0001). The protective alleles that were found to be more prevalent among the controls compared with the patients with multiple sclerosis were HLA-DRB1*01 (26.7% vs. 7.5%, P<0.0001), *03 (17.5% vs. 8.3%, P=0.034), and *16 (11.7% vs. 3.3%, P=0.014). HLA-DRB1*15 was more common among the female patients with multiple sclerosis than among the male patients (68.4% vs. 34.1%; OR, 4.18; 95%, CI 1.90-9.22; P=0.001). The heterozygous inheritance of HLA-DRB1*15 allele was more common in the patients with a history of maternal multiple sclerosis than in those with a history of paternal multiple sclerosis (29.4% vs. 9.8%; P=0.045). CONCLUSIONS. HLA-DRB1*15 was found to be associated with multiple sclerosis in the Lithuanian population. This allele was more prevalent among the female patients with multiple sclerosis. Maternal multiple sclerosis was more common than paternal multiple sclerosis, but the relationship with HLA-DRB1*15 allele was not established. HLA-DRB1*01, *03, and *16 appeared to be the protective alleles in this series. PMID:22370504

  6. Frequency of the CCR5-delta32 allele in Brazilian populations: A systematic literature review and meta-analysis.

    PubMed

    Silva-Carvalho, Wlisses Henrique Veloso; de Moura, Ronald Rodrigues; Coelho, Antonio Victor Campos; Crovella, Sergio; Guimarães, Rafael Lima

    2016-09-01

    The CCR5 is a chemokine receptor widely expressed by several immune cells that are engaged in inflammatory responses. Some populations have individuals exhibiting a 32bp deletion in the CCR5 gene (CCR5-delta32) that produces a truncated non-functional protein not expressed on the cell surface. This polymorphism, known to be associated with susceptibility to infectious and inflammatory diseases, such as osteomyelitis, pre-eclampsia, systemic lupus erythematous, juvenile idiopathic arthritis, rheumatoid arthritis and HIV/AIDS, is more commonly found in European populations with average frequency of 10%. However, it is also possible to observe a significant frequency in other world populations, such as the Brazilian one. We performed a systematic review and meta-analysis of CCR5-delta32 genetic association studies in Brazilian populations throughout the country to estimate the frequency of this polymorphism. We also compared CCR5-delta32 frequencies across Brazilian regions. The systematic literature reviewed studies involving delta32 allele in Brazilian populations published from 1995 to 2015. Among the reviewed literature, 25 studies including 30 Brazilian populations distributed between the North, Northeast, South and Southeast regions were included in our meta-analysis. We observed an overall allelic frequency of 4% (95%-CI, 0.03-0.05), that was considered moderate and, notably, higher than some European populations, such as Cyprus (2.8%), Italy (3%) and Greece (2.4%). Regarding the regional frequency comparisons between North-Northeast (N-NE) and South-Southeast (S-SE) regions, we observed an allelic frequency of 3% (95%-CI, 0.02-0.04) and 4% (95%-CI, 0.03-0.05), respectively. The populations from S-SE regions had a slightly higher CCR5-delta32 frequency than N-NE regions (OR=1.41, p=0.002). Although there are several studies about the CCR5-delta32 polymorphism and its effect on the immune response of some infectious diseases, this report is the first meta

  7. Maximum likelihood model based on minor allele frequencies and weighted Max-SAT formulation for haplotype assembly.

    PubMed

    Mousavi, Sayyed R; Khodadadi, Ilnaz; Falsafain, Hossein; Nadimi, Reza; Ghadiri, Nasser

    2014-06-01

    Human haplotypes include essential information about SNPs, which in turn provide valuable information for such studies as finding relationships between some diseases and their potential genetic causes, e.g., for Genome Wide Association Studies. Due to expensiveness of directly determining haplotypes and recent progress in high throughput sequencing, there has been an increasing motivation for haplotype assembly, which is the problem of finding a pair of haplotypes from a set of aligned fragments. Although the problem has been extensively studied and a number of algorithms have already been proposed for the problem, more accurate methods are still beneficial because of high importance of the haplotypes information. In this paper, first, we develop a probabilistic model, that incorporates the Minor Allele Frequency (MAF) of SNP sites, which is missed in the existing maximum likelihood models. Then, we show that the probabilistic model will reduce to the Minimum Error Correction (MEC) model when the information of MAF is omitted and some approximations are made. This result provides a novel theoretical support for the MEC, despite some criticisms against it in the recent literature. Next, under the same approximations, we simplify the model to an extension of the MEC in which the information of MAF is used. Finally, we extend the haplotype assembly algorithm HapSAT by developing a weighted Max-SAT formulation for the simplified model, which is evaluated empirically with positive results. PMID:24491253

  8. Frequency of alleles conferring resistance to the Bt toxins Cry1Ac and Cry2Ab in Australian populations of Helicoverpa armigera (Lepidoptera: Noctuidae).

    PubMed

    Mahon, R J; Olsen, K M; Downes, S; Addison, S

    2007-12-01

    Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) is an important lepidopteran pest of cotton (Gossypium spp.) in Australia and the Old World. From 2002, F2 screens were used to examine the frequency of resistance alleles in Australian populations of H. armigera to Bacillus thuringiensis (Bt) CrylAc and Cry2Ab, the two insecticidal proteins present in the transgenic cotton Bollgard II. At that time, Ingard (expressing Cry1Ac) cotton had been grown in Australia for seven seasons, and Bollgard II was about to be commercially released. The principal objective of our study was to determine whether sustained exposure caused an elevated frequency of alleles conferring resistance to Cry1Ac in a species with a track record of evolving resistance to conventional insecticides. No major alleles conferring resistance to Cry1Ac were found. The frequency of resistance alleles for Cry1Ac was <0.0003, with a 95% credibility interval between 0 and 0.0009. In contrast, alleles conferring resistance to Cry2Ab were found at a frequency of 0.0033 (0.0017, 0.0055). The first isolation of this allele was found before the widespread deployment of Bollgard II. For both toxins the experiment-wise detection probability was 94.4%. Our results suggest that alleles conferring resistance to Cry1Ac are rare and that a relatively high baseline frequency of alleles conferring resistance to Cry2Ab existed before the introduction of Bt cotton containing this toxin. PMID:18232402

  9. Vestibular function is associated with residual low-frequency hearing loss in patients with bi-allelic mutations in the SLC26A4 gene.

    PubMed

    Jung, Jinsei; Seo, Young Wook; Choi, Jae Young; Kim, Sung Huhn

    2016-05-01

    DFNB4 is non-syndromic, autosomal recessive type of hearing loss with an enlarged vestibular aqueduct (EVA) caused by mutations in SLC26A4/pendrin. Although the characteristics of hearing loss are well known in DFNB4, vestibular function remains inconclusive. We evaluated the vestibular function of 31 patients with bi-allelic mutations in SLC26A4/pendrin and analyzed genetic, radiological, and audiological correlations with vestibular function. In a caloric test, unilateral and bilateral vestibulopathies were detected in 45.2% and 6.4% of patients, respectively; however, only 22.6% had subjective vertigo symptoms. While vestibular phenotype was not significantly associated with specific mutations in genetic alleles or the sizes of the endolymphatic sac and vestibular aqueduct, a residual hearing threshold at a low frequency (500 Hz) was definitely correlated with vestibular function in DFNB4 (p = 0.005). These findings may indicate that vestibular function in DFNB4 deteriorates unilaterally in ears when hearing loss occurs. In conclusion, DFNB4 shows vestibular dysfunction, which is strongly linked to hearing loss at low frequencies without any allelic or anatomical predisposing factor. PMID:26900070

  10. Genetic Adaptation to Climate in White Spruce Involves Small to Moderate Allele Frequency Shifts in Functionally Diverse Genes

    PubMed Central

    Hornoy, Benjamin; Pavy, Nathalie; Gérardi, Sébastien; Beaulieu, Jean; Bousquet, Jean

    2015-01-01

    Understanding the genetic basis of adaptation to climate is of paramount importance for preserving and managing genetic diversity in plants in a context of climate change. Yet, this objective has been addressed mainly in short-lived model species. Thus, expanding knowledge to nonmodel species with contrasting life histories, such as forest trees, appears necessary. To uncover the genetic basis of adaptation to climate in the widely distributed boreal conifer white spruce (Picea glauca), an environmental association study was conducted using 11,085 single nucleotide polymorphisms representing 7,819 genes, that is, approximately a quarter of the transcriptome. Linear and quadratic regressions controlling for isolation-by-distance, and the Random Forest algorithm, identified several dozen genes putatively under selection, among which 43 showed strongest signals along temperature and precipitation gradients. Most of them were related to temperature. Small to moderate shifts in allele frequencies were observed. Genes involved encompassed a wide variety of functions and processes, some of them being likely important for plant survival under biotic and abiotic environmental stresses according to expression data. Literature mining and sequence comparison also highlighted conserved sequences and functions with angiosperm homologs. Our results are consistent with theoretical predictions that local adaptation involves genes with small frequency shifts when selection is recent and gene flow among populations is high. Accordingly, genetic adaptation to climate in P. glauca appears to be complex, involving many independent and interacting gene functions, biochemical pathways, and processes. From an applied perspective, these results shall lead to specific functional/association studies in conifers and to the development of markers useful for the conservation of genetic resources. PMID:26560341

  11. Genotype and allele frequencies of drug-metabolizing enzymes and drug transporter genes affecting immunosuppressants in the Spanish white population.

    PubMed

    Bosó, Virginia; Herrero, María J; Buso, Enrique; Galán, Juan; Almenar, Luis; Sánchez-Lázaro, Ignacio; Sánchez-Plumed, Jaime; Bea, Sergio; Prieto, Martín; García, María; Pastor, Amparo; Sole, Amparo; Poveda, José Luis; Aliño, Salvador F

    2014-04-01

    Interpatient variability in drug response can be widely explained by genetically determined differences in metabolizing enzymes, drug transporters, and drug targets, leading to different pharmacokinetic and/or pharmacodynamic behaviors of drugs. Genetic variations affect or do not affect drug responses depending on their influence on protein activity and the relevance of such proteins in the pathway of the drug. Also, the frequency of such genetic variations differs among populations, so the clinical relevance of a specific variation is not the same in all of them. In this study, a panel of 33 single nucleotide polymorphisms in 14 different genes (ABCB1, ABCC2, ABCG2, CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, MTHFR, NOD2/CARD15, SLCO1A2, SLCO1B1, TPMT, and UGT1A9), encoding for the most relevant metabolizing enzymes and drug transporters relating to immunosuppressant agents, was analyzed to determine the genotype profile and allele frequencies in comparison with HapMap data. A total of 570 Spanish white recipients and donors of solid organ transplants were included. In 24 single nucleotide polymorphisms, statistically significant differences in allele frequency were observed. The largest differences (>100%) occurred in ABCB1 rs2229109, ABCG2 rs2231137, CYP3A5 rs776746, NOD2/CARD15 rs2066844, TPMT rs1800462, and UGT1A9 rs72551330. In conclusion, differences were recorded between the Spanish and other white populations in terms of allele frequency and genotypic distribution. Such differences may have implications in relation to dose requirements and drug-induced toxicity. These data are important for further research to help explain interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy. PMID:24232128

  12. ACTN3 Allele Frequency in Humans Covaries with Global Latitudinal Gradient

    PubMed Central

    Lek, Monkol; North, Kathryn N.; Organ, Chris L.

    2013-01-01

    A premature stop codon in ACTN3 resulting in α-actinin-3 deficiency (the ACTN3 577XX genotype) is common in humans and reduces strength, muscle mass, and fast-twitch fiber diameter, but increases the metabolic efficiency of skeletal muscle. Linkage disequilibrium data suggest that the ACTN3 R577X allele has undergone positive selection during human evolution. The allele has been hypothesized to be adaptive in environments with scarce resources where efficient muscle metabolism would be selected. Here we test this hypothesis by using recently developed comparative methods that account for evolutionary relatedness and gene flow among populations. We find evidence that the ACTN3 577XX genotype evolved in association with the global latitudinal gradient. Our results suggest that environmental variables related to latitudinal variation, such as species richness and mean annual temperature, may have influenced the adaptive evolution of ACTN3 577XX during recent human history. PMID:23359641

  13. Polymorphism discovery and allele frequency estimation using high-throughput DNA sequencing of target-enriched pooled DNA samples

    PubMed Central

    2012-01-01

    Background The central role of the somatotrophic axis in animal post-natal growth, development and fertility is well established. Therefore, the identification of genetic variants affecting quantitative traits within this axis is an attractive goal. However, large sample numbers are a pre-requisite for the identification of genetic variants underlying complex traits and although technologies are improving rapidly, high-throughput sequencing of large numbers of complete individual genomes remains prohibitively expensive. Therefore using a pooled DNA approach coupled with target enrichment and high-throughput sequencing, the aim of this study was to identify polymorphisms and estimate allele frequency differences across 83 candidate genes of the somatotrophic axis, in 150 Holstein-Friesian dairy bulls divided into two groups divergent for genetic merit for fertility. Results In total, 4,135 SNPs and 893 indels were identified during the resequencing of the 83 candidate genes. Nineteen percent (n = 952) of variants were located within 5' and 3' UTRs. Seventy-two percent (n = 3,612) were intronic and 9% (n = 464) were exonic, including 65 indels and 236 SNPs resulting in non-synonymous substitutions (NSS). Significant (P < 0.01) mean allele frequency differentials between the low and high fertility groups were observed for 720 SNPs (58 NSS). Allele frequencies for 43 of the SNPs were also determined by genotyping the 150 individual animals (Sequenom® MassARRAY). No significant differences (P > 0.1) were observed between the two methods for any of the 43 SNPs across both pools (i.e., 86 tests in total). Conclusions The results of the current study support previous findings of the use of DNA sample pooling and high-throughput sequencing as a viable strategy for polymorphism discovery and allele frequency estimation. Using this approach we have characterised the genetic variation within genes of the somatotrophic axis and related pathways, central to mammalian post

  14. High frequency of the apolipoprotein E *4 allele in African pygmies and most of the African populations in sub-Saharan Africa.

    PubMed

    Zekraoui, L; Lagarde, J P; Raisonnier, A; Gérard, N; Aouizérate, A; Lucotte, G

    1997-08-01

    Apolipoprotein E genotypes (alleles *2, *3, and *4) have been determined in 70 Aka Pygmies and 470 unrelated African sub-Saharan subjects. Allele frequencies for Pygmies are 5.7% for APOE*2, 53.6% for APOE*3, and 40.7% for APOE*4, and the global proportions for sub-Saharan subjects are 11.6% for APOE*2, 70.6% for APOE*3, and 17.8% for APOE*4. The frequencies in some ethnic groups are statistically different from the overall mean in the Afar and the Isa, the Ewe (Togo), the Malinke (Guinea), and the Mossi; three ethnic groups have a higher allele frequency of APOE*4 (Fon, 29.4%; Zairians, 33.3%; Tutsi, 38.5%). The APOE*4 allele is considered the ancestral form because of its high frequency in African Pygmies and other aboriginal populations. PMID:9198315

  15. Skewed allele frequencies of an Mx gene mutation with potential resistance to avian influenza virus in different chicken populations.

    PubMed

    Li, X Y; Qu, L J; Yao, J F; Yang, N

    2006-07-01

    The Mx gene is considered to confer positive antiviral responses to the orthomyxovirus in many organisms. In the chicken, 1 nonsynonymous single nucleotide polymorphism (G to A) at position 2,032 of Mx cDNA was demonstrated to confer positive antiviral activity in vitro to avian influenza virus in a previous study. In the current study, 15 Chinese native chicken breeds, 4 highly selected commercial lines, and the Red Jungle Fowl were selected to detect allele frequencies of the Mx mutation. The frequencies of the favorable allele A in native breeds were 0.7241 to 0.9554, which were much higher than those (0.0565 to 0.2742) found in the commercial populations. Whereas most native breeds were in Hardy-Weinberg equilibrium at this locus (P > 0.01), 3 out of 4 commercial populations were not in Hardy-Weinberg equilibrium (P < 0.01). Selection, environment, and negative correlations between production and disease resistant traits could contribute to highly skewed frequencies of the mutation among native breeds and commercial populations. The results suggested that further studies are needed with regard to the genetic resistance to avian influenza in different populations with various domestication background and selection history. PMID:16830876

  16. Fish scales and SNP chips: SNP genotyping and allele frequency estimation in individual and pooled DNA from historical samples of Atlantic salmon (Salmo salar)

    PubMed Central

    2013-01-01

    Background DNA extracted from historical samples is an important resource for understanding genetic consequences of anthropogenic influences and long-term environmental change. However, such samples generally yield DNA of a lower amount and quality, and the extent to which DNA degradation affects SNP genotyping success and allele frequency estimation is not well understood. We conducted high density SNP genotyping and allele frequency estimation in both individual DNA samples and pooled DNA samples extracted from dried Atlantic salmon (Salmo salar) scales stored at room temperature for up to 35 years, and assessed genotyping success, repeatability and accuracy of allele frequency estimation using a high density SNP genotyping array. Results In individual DNA samples, genotyping success and repeatability was very high (> 0.973 and > 0.998, respectively) in samples stored for up to 35 years; both increased with the proportion of DNA of fragment size > 1000 bp. In pooled DNA samples, allele frequency estimation was highly repeatable (Repeatability = 0.986) and highly correlated with empirical allele frequency measures (Mean Adjusted R2 = 0.991); allele frequency could be accurately estimated in > 95% of pooled DNA samples with a reference group of at least 30 individuals. SNPs located in polyploid regions of the genome were more sensitive to DNA degradation: older samples had lower genotyping success at these loci, and a larger reference panel of individuals was required to accurately estimate allele frequencies. Conclusions SNP genotyping was highly successful in degraded DNA samples, paving the way for the use of degraded samples in SNP genotyping projects. DNA pooling provides the potential for large scale population genetic studies with fewer assays, provided enough reference individuals are also genotyped and DNA quality is properly assessed beforehand. We provide recommendations for future studies intending to conduct high-throughput SNP

  17. Genetic comparison of lake sturgeon populations: Differentiation based on allelic frequencies at seven microsatellite loci

    USGS Publications Warehouse

    McQuown, E.; Krueger, C.C.; Kincaid, H.L.; Gall, G.A.E.; May, B.

    2003-01-01

    The lake sturgeon (Acipenser fulvescens) has recently become a high priority for restoration management because of the near extinction of the species from many areas of North America. The identification of the level of population differentiation that naturally exists among lake sturgeon populations will be useful in the development of management plans to conserve and restore diversity, and in the choice of donor populations to use for re-introduction. Genetic variation among and within 210 lake sturgeon collected from seven locations (St. Lawrence River, Des Prairies River (tributary to the St. Lawrence River), Mattagami River (Hudson Bay drainage), Menominee River (Lake Michigan drainage), Wolf River (Lake Michigan drainage), Niagara River, and Lake Erie) was examined based on allelic variation at seven microsatellite loci (four disomic and three putative tetrasomic). High levels of variability were detected at these loci. Analyses revealed an average of 8.6 alleles per locus (range 5 to 12 alleles per locus) and heterozygosity values at the four disomic loci ranging from 0.46 to 0.66. Multivariate factor analysis of Nei's genetic distance values produced three distinct population groups that were organized by geography: 1) Mattagami (northern Quebec), 2) Menominee/ Wolf (Lake Michigan - Wisconsin), and 3) St. Lawrence/ Des Prairies/ Niagara/ Erie (lower Great Lakes). Differences based on G-tests summed over all loci occurred between all possible paired comparisons of the collections (P < 0.01). These analyses indicated that lake sturgeon populations are differentiated within the Great Lakes basin. Managers of this species will need to identify individual populations in their jurisdictions and provide separate consideration for their conservation and rehabilitation.

  18. Real-Time PCR Genotyping Assay for GM2 Gangliosidosis Variant 0 in Toy Poodles and the Mutant Allele Frequency in Japan

    PubMed Central

    RAHMAN, Mohammad Mahbubur; YABUKI, Akira; KOHYAMA, Moeko; MITANI, Sawane; MIZUKAMI, Keijiro; UDDIN, Mohammad Mejbah; CHANG, Hye-Sook; KUSHIDA, Kazuya; KISHIMOTO, Miori; YAMABE, Remi; YAMATO, Osamu

    2013-01-01

    ABSTRACT GM2 gangliosidosis variant 0 (Sandhoff disease, SD) is a fatal, progressive neurodegenerative lysosomal storage disease caused by mutations of the HEXB gene. In canine SD, a pathogenic mutation (c.283delG) of the canine HEXB gene has been identified in toy poodles. In the present study, a TaqMan probe-based real-time PCR genotyping assay was developed and evaluated for rapid and large-scale genotyping and screening for this mutation. Furthermore, a genotyping survey was carried out in a population of toy poodles in Japan to determine the current mutant allele frequency. The real-time PCR assay clearly showed all genotypes of canine SD. The assay was suitable for large-scale survey as well as diagnosis, because of its high throughput and rapidity. The genotyping survey demonstrated a carrier frequency of 0.2%, suggesting that the current mutant allele frequency is low in Japan. However, there may be population stratification in different places, because of the founder effect by some carriers. Therefore, this new assay will be useful for the prevention and control of SD in toy poodles. PMID:24161966

  19. [Distribution and frequency of HLA alleles and haplotypes in Brazilians with type 1 diabetes mellitus].

    PubMed

    Alves, Crésio; Meyer, Isadora; Vieira, Nara; Toralles, Maria Betânia P; LeMaire, Denise

    2006-06-01

    The genetic predisposition to type 1 diabetes (DM1) is associated with genes of the human leukocyte antigen (HLA) system, specially the HLA-DR and -DQ. In Caucasians, the HLA-DR3 and -DR4 antigens are associated with susceptibility and the -DR2, with protection. In Brazil, a country with a large miscegenation of European Caucasians, Native Amerindians and African Blacks, the genetic basis of DM1 has not been adequately studied. The aim of this paper is to present a critical review of articles indexed in the MEDLINE and LILACS-BIREME data basis about the association of HLA with DM1 in Brazilians. Eight papers, all of them from the Southeast region, were found. Immunogenetic susceptibility to DM1 in Brazilians was associated with HLA-DRB1*03, -DRB*04, -DQB1*0201, -DQB1*0302 alleles, and protection against DM1 was associated with HLA-DQB1*0602, -DQB1*0301 alleles and -DR2 and -DR7 antigens. Since the Brazilian population is not racially homogeneous, it is not possible to extrapolate studies from a single region to the remainder of the country. It is necessary to study populations from different regions to identify new associations or to strengthen associations with the ones already identified. This knowledge will contribute to future prophylactic or therapeutic interventions in the group of Brazilians at risk of developing DM1. PMID:16936983

  20. HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies of 10 918 Koreans from bone marrow donor registry in Korea.

    PubMed

    Park, H; Lee, Y-J; Song, E Y; Park, M H

    2016-10-01

    The human leucocyte antigen (HLA) system is the most polymorphic genetic system in humans, and HLA matching is crucial in organ transplantation, especially in hematopoietic stem cell transplantation. We investigated HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies at allelic level in 10 918 Koreans from bone marrow donor registry in Korea. Intermediate resolution HLA typing was performed using Luminex technology (Wakunaga, Japan), and additional allelic level typing was performed using PCR-single-strand conformation polymorphism method and/or sequence-based typing (Abbott Molecular, USA). Allele and haplotype frequencies were calculated by direct counting and maximum likelihood methods, respectively. A total of 39 HLA-A, 66 HLA-B and 47 HLA-DRB1 alleles were identified. High-frequency alleles found at a frequency of ≥5% were 6 HLA-A (A*02:01, *02:06, *11:01, *24:02, *31:01 and *33:03), 6 HLA-B (B*15:01, *35:01, *44:03, *51:01, 54:01 and *58:01) and 8 HLA-DRB1 (DRB1*01:01, *04:05, *04:06, *07:01, *08:03, *09:01, *13:02 and *15:01) alleles. At each locus, A*02, B*15 and DRB1*14 generic groups were most diverse at allelic level, consisting of 9, 12 and 11 different alleles, respectively. A total of 366, 197 and 21 different HLA-A-B-DRB1 haplotypes were estimated with frequencies of ≥0.05%, ≥0.1% and ≥0.5%, respectively. The five most common haplotypes with frequencies of ≥2.0% were A*33:03-B*44:03-DRB1*13:02 (4.97%), A*33:03-B*58:01-DRB1*13:02, A*33:03-B*44:03-DRB1*07:01, A*24:02-B*07:02-DRB1*01:01 and A*24:02-B*52:01-DRB1*15:02. Among 34 serologic HLA-A-B-DR haplotypes with frequencies of ≥0.5%, 17 haplotypes revealed allele-level diversity and majority of the allelic variation was arising from A2, A26, B61, B62, DR4 and DR14 specificities. Haplotype diversity obtained in this study is the most comprehensive data thus far reported in Koreans, and the information will be useful for unrelated stem cell transplantation as well as for disease

  1. HLA-A, -B, -C, -DRB1 Allele and Haplotype Frequencies Distinguish Eastern European Americans from the General European American Population

    PubMed Central

    Mack, Steven J.; Tu, Bin; Lazaro, Ana; Yang, Ruyan; Lancaster, Alex K.; Cao, Kai; Ng, Jennifer; Hurley, Carolyn Katovich

    2012-01-01

    Sequence based typing was used to identify HLA-A,B,C,DRB1 alleles from 558 consecutively recruited U.S. volunteers with Eastern European ancestry for an unrelated hematopoietic stem cell registry. Four of the 31 HLA-A alleles, 29 -C alleles, 59 -B alleles, and 42 -DRB1 alleles identified (A*0325, B*440204, Cw*0332, and *0732N) are novel. The HLA-A*02010101g allele was observed at a frequency of 0.28. Two-, three- and four-locus haplotypes were estimated using the expectation maximization algorithm. The highest-frequency extended haplotypes (A*010101g-Cw*070101g-B*0801g-DRB1*0301 and A*03010101g-Cw*0702-B*0702-DRB1*1501) were observed at frequencies of 0.04 and 0.03, respectively. Linkage disequilibrium values (D’ij) of the constituent 2-locus haplotypes were highly significant for both extended haplotypes (p-values were less than 8 × 10−10), but were consistently higher for the more frequent haplotype. Balancing selection was inferred to be acting on all four loci, with the strongest evidence of balancing selection observed for the HLA-C locus. Comparisons of the A-C-B haplotype and DRB1 frequencies in this population to those for African, European and western Asian populations revealed high degrees of identity with Czech, Polish, and Slovenian populations and significant differences from the general European American population. PMID:19000140

  2. A prospective evaluation of the transthyretin Ile122 allele frequency in an African-American population.

    PubMed

    Yamashita, Taro; Hamidi Asl, Kamran; Yazaki, Masahide; Benson, Merrill D

    2005-06-01

    Transthyretin Val122Ile is one of greater than 80 mutations in transthyretin (TTR) that are associated with hereditary amyloidosis. Retrospective studies have shown a prevalence of this mutation as high as 3.9% in African-Americans. The present study was undertaken to determine in a prospective fashion the prevalence of the TTR Val122Ile allele in African-Americans in a Midwestern American city. DNA was isolated from cord bloods collected at the time of birth in the County hospital of Indianapolis, Indiana. Samples were identified only as to ethnic origin of the mother. Analysis was performed by PCR amplification of TTR exon 4 followed by SSCP and RFLP. Cord bloods from 1,973 children born at the County hospital were analyzed. Thirty of 1,000 DNA samples from African-American newborns were positive for TTR Val122Ile (3%). Two of 453 DNA samples from Caucasian newborns were positive (0.44%). Zero of 490 DNA samples from newborns of Hispanic mothers and 0 of 30 from newborns with mothers classified as other (including Asian) were positive. This prospective study demonstrates that 3% of newborns of African-American women in an urban population have the TTR Val122Ile mutation which is associated with late-onset cardiomyopathy. The degree of penetrance of this mutation at the clinical level has not yet been determined. PMID:16011990

  3. Determination of the Allelic Frequency in Smith-Lemli-Opitz Syndrome by Analysis of Massively Parallel Sequencing Data Sets

    PubMed Central

    Cross, Joanna L.; Iben, James; Simpson, Claire; Thurm, Audrey; Swedo, Susan; Tierney, Elaine; Bailey-Wilson, Joan; Biesecker, Leslie G.; Porter, Forbes D.; Wassif, Christopher A.

    2014-01-01

    Data from massively parallel sequencing or “Next Generation Sequencing” of the human exome has reached a critical mass in both public and private databases, in that these collections now allow researchers to critically evaluate population genetics in a manner that was not feasible a decade ago. The ability to determine pathogenic allele frequencies by evaluation of the full coding sequences and not merely a single SNP or series of SNPs will lead to more accurate estimations of incidence. For demonstrative purposes we analyzed the causative gene for the disorder Smith-Lemli-Opitz Syndrome (SLOS), the 7-dehydrocholesterol reductase (DHCR7) gene and determined both the carrier frequency for DHCR7 mutations, and predicted an expected incidence of the disorder. Estimations of the incidence of SLOS have ranged widely from 1:10,000 to 1:70,000 while the carrier frequency has been reported as high as 1 in 30. Using four exome data sets with a total of 17,836 chromosomes, we ascertained a carrier frequency of pathogenic DHRC7 mutations of 1.01%, and predict a SLOS disease incidence of 1/39,215 conceptions. This approach highlights yet another valuable aspect of the exome sequencing databases, to inform clinical and health policy decisions related to genetic counseling, prenatal testing and newborn screening. PMID:24813812

  4. Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets.

    PubMed

    Cross, J L; Iben, J; Simpson, C L; Thurm, A; Swedo, S; Tierney, E; Bailey-Wilson, J E; Biesecker, L G; Porter, F D; Wassif, C A

    2015-06-01

    Data from massively parallel sequencing or 'Next Generation Sequencing' of the human exome has reached a critical mass in both public and private databases, in that these collections now allow researchers to critically evaluate population genetics in a manner that was not feasible a decade ago. The ability to determine pathogenic allele frequencies by evaluation of the full coding sequences and not merely a single nucleotide polymorphism (SNP) or series of SNPs will lead to more accurate estimations of incidence. For demonstrative purposes, we analyzed the causative gene for the disorder Smith-Lemli-Opitz Syndrome (SLOS), the 7-dehydrocholesterol reductase (DHCR7) gene and determined both the carrier frequency for DHCR7 mutations, and predicted an expected incidence of the disorder. Estimations of the incidence of SLOS have ranged widely from 1:10,000 to 1:70,000 while the carrier frequency has been reported as high as 1 in 30. Using four exome data sets with a total of 17,836 chromosomes, we ascertained a carrier frequency of pathogenic DHRC7 mutations of 1.01%, and predict a SLOS disease incidence of 1/39,215 conceptions. This approach highlights yet another valuable aspect of the exome sequencing databases, to inform clinical and health policy decisions related to genetic counseling, prenatal testing and newborn screening. PMID:24813812

  5. The Adaptive Change of HLA-DRB1 Allele Frequencies Caused by Natural Selection in a Mongolian Population That Migrated to the South of China

    PubMed Central

    Sun, Hao; Yang, Zhaoqing; Lin, Keqin; Liu, Shuyuan; Huang, Kai; Wang, Xiuyun; Chu, Jiayou; Huang, Xiaoqin

    2015-01-01

    Pathogen-driven balancing selection determines the richness of human leukocyte antigen (HLA) alleles. Changes in the pathogen spectrum may cause corresponding changes in HLA loci. Approximately 700 years ago, a Mongolian population moved from the north of China to the Yunnan region in the south of China. The pathogen spectrum in the south of China differs from that in the north. In this study, changes in the HLA genes in the Yunnan Mongolian population, as well as the underlying mechanism, were investigated. A sequence-based typing method (SBT) was used to genotype HLA-DRB1 in 470 individuals from two Mongolian populations and another five ethnic groups. Meanwhile, 10 autosomal short tandem repeats (STRs) were genotyped to assess the influence of genetic background on HLA-DRB1 frequencies. The frequencies of certain alleles changed significantly in the Mongolian population that migrated to Yunnan. For example, DRB1*12:02:01 increased from 6.1% to 35.4%. STR analysis excluded the possibility of a recent bottleneck and indicated that 50% of the genetic consistency between northern and southern Mongolians; Tajima's D value for HLA-DRB1 exon2 and dN/dS analysis showed that the HLA-DRB1 genes in both Mongolian populations were under balancing selection. However, the sites under natural selection changed. We proposed that the dramatically change of HLA frequencies in southern Mongolian was caused by a combination of inter-population gene flow and natural selection. Certain diseases specific to the south of China, such as malaria, may be the driving force behind the enhanced DRB1*12:02:01 frequency. PMID:26230582

  6. Inbreeding of bottlenecked butterfly populations. Estimation using the likelihood of changes in marker allele frequencies.

    PubMed Central

    Saccheri, I J; Wilson, I J; Nichols, R A; Bruford, M W; Brakefield, P M

    1999-01-01

    Polymorphic enzyme and minisatellite loci were used to estimate the degree of inbreeding in experimentally bottlenecked populations of the butterfly, Bicyclus anynana (Satyridae), three generations after founding events of 2, 6, 20, or 300 individuals, each bottleneck size being replicated at least four times. Heterozygosity fell more than expected, though not significantly so, but this traditional measure of the degree of inbreeding did not make full use of the information from genetic markers. It proved more informative to estimate directly the probability distribution of a measure of inbreeding, sigma2, the variance in the number of descendants left per gene. In all bottlenecked lines, sigma2 was significantly larger than in control lines (300 founders). We demonstrate that this excess inbreeding was brought about both by an increase in the variance of reproductive success of individuals, but also by another process. We argue that in bottlenecked lines linkage disequilibrium generated by the small number of haplotypes passing through the bottleneck resulted in hitchhiking of particular marker alleles with those haplotypes favored by selection. In control lines, linkage disequilibrium was minimal. Our result, indicating more inbreeding than expected from demographic parameters, contrasts with the findings of previous (Drosophila) experiments in which the decline in observed heterozygosity was slower than expected and attributed to associative overdominance. The different outcomes may both be explained as a consequence of linkage disequilibrium under different regimes of inbreeding. The likelihood-based method to estimate inbreeding should be of wide applicability. It was, for example, able to resolve small differences in sigma2 among replicate lines within bottleneck-size treatments, which could be related to the observed variation in reproductive viability. PMID:10049922

  7. An Analysis of HLA-A, -B, and -DRB1 Allele and Haplotype Frequencies of 21,918 Residents Living in Liaoning, China

    PubMed Central

    Li, Xiao-Feng; Zhang, Xu; Chen, Yang; Zhang, Kun-Lian; Liu, Xiang-Jun; Li, Jian-Ping

    2014-01-01

    HLA-A, -B and -DRB1 allele frequencies and their haplotype frequencies in 21,918 Chinese residents living in Liaoning Province, who were registered as volunteer donors of China Marrow Donor Registry, were investigated. They are composed of 93.37% Han Chinese, 5.1% Manchus, 0.57% Mongols, 0.46% Hui persons, 0.29% Koreans and 0.14% Xibe ethnic group. In total eighteen different HLA-A alleles, forty-eight different HLA-B alleles and fourteen different HLA-DRB1 alleles have been identified. Their frequencies are in agreement with the Hardy-Weinberg equilibrium. For Han Chinese in Liaoning, 1,534 different HLA-A-B-DRB1 haplotypes were identified, with a frequency of higher than 0.01%. A*30-B*13-DRB1*07, A*02-B*46-DRB1*09 and A*02-B*13-DRB1*12 are the most frequent haplotypes among Liaoning Han. While Liaoning Han, Liaoning Manchu, Liaoning Mongol, Liaoning Hui and Liaoning Korean share the northern Han characteristic haplotypes, all minority ethnic groups with the exception of Liaoning Manchu have developed their own unique HLA profiles. This dataset characterizes the HLA allele and haplotype frequencies in the Liaoning area and suggests that it is different from those in other parts of China and ethnic groups, which implicates transplant donor searching strategies and studies on population genetics. PMID:24691290

  8. Allele frequency for Cystic fibrosis in Indians vis-a/-vis global populations.

    PubMed

    Bepari, Karnajit Kumar; Malakar, Arup Kumar; Paul, Prosenjit; Halder, Binata; Chakraborty, Supriyo

    2015-01-01

    Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. This gene encodes a protein involved in epithelial anion channel. Cystic fibrosis is the most common life-limiting genetic disorder in Caucasians; it also affects other ethnic groups like the Blacks and the Native Americans. Cystic fibrosis is considered to be rare among individuals from the Indian subcontinent. We analyzed a total of 29 world׳s populations for cystic fibrosis on the basis of gene frequency and heterozygosity. Among 29 countries Switzerland revealed the highest gene frequency and heterozygosity for CF (0.022, 0.043) whereas Japan recorded the lowest values (0.002, 0.004) followed by India (0.004, 0.008). Our analysis suggests that the prevalence of cystic fibrosis is very low in India. PMID:26339151

  9. Allelic frequency determination of the 24-bp chitotriosidase duplication in the Portuguese population by real-time PCR.

    PubMed

    Rodrigues, M R; Sá Miranda, M C; Amaral, O

    2004-01-01

    Chitotriosidase is a human chitinase produced by macrophages. Its enzymatic activity is markedly elevated in serum of patients suffering from lysosomal storage disorders, as well as other diseases in which macrophages are activated. Therefore, it is a useful tool as a secondary marker in the diagnosis of several disorders including Gaucher disease type 1 and Niemann-Pick disease. The determination of chitotriosidase levels as a diagnosis complement in some lysosomal storage disorders and in enzyme replacement therapy follow-up of Gaucher disease patients is of great importance. However, the fact that a mutation caused by a 24-bp duplication in the CHIT1 gene resulting in deficiency of plasma chitotriosidase activity is very frequent makes the establishment of the frequency of this mutation in different population groups necessary. Furthermore, in order to validate the use of chitotriosidase activity as a marker, it is indispensable to screen individuals for this particular mutation. In this work, we present the results of a study where the allelic frequency of the above mentioned CHIT1 gene mutation was determined in the Portuguese population by real-time PCR. The frequency of carriers encountered in this sample of Portuguese individuals was of 37%. PMID:15528158

  10. Helicobacter pylori Genotyping from American Indigenous Groups Shows Novel Amerindian vacA and cagA Alleles and Asian, African and European Admixture

    PubMed Central

    Camorlinga-Ponce, Margarita; Perez-Perez, Guillermo; Gonzalez-Valencia, Gerardo; Mendoza, Irma; Peñaloza-Espinosa, Rosenda; Ramos, Irma; Kersulyte, Dangeruta; Reyes-Leon, Adriana; Romo, Carolina; Granados, Julio; Muñoz, Leopoldo; Berg, Douglas E.; Torres, Javier

    2011-01-01

    It is valuable to extend genotyping studies of Helicobacter pylori to strains from indigenous communities across the world to better define adaption, evolution, and associated diseases. We aimed to genetically characterize both human individuals and their infecting H. pylori from indigenous communities of Mexico, and to compare them with those from other human groups. We studied individuals from three indigenous groups, Tarahumaras from the North, Huichols from the West and Nahuas from the center of Mexico. Volunteers were sampled at their community site, DNA was isolated from white blood cells and mtDNA, Y-chromosome, and STR alleles were studied. H. pylori was cultured from gastric juice, and DNA extracted for genotyping of virulence and housekeeping genes. We found Amerindian mtDNA haplogroups (A, B, C, and D), Y-chromosome DYS19T, and Amerindian STRs alleles frequent in the three groups, confirming Amerindian ancestry in these Mexican groups. Concerning H.pylori cagA phylogenetic analyses, although most isolates were of the Western type, a new Amerindian cluster neither Western nor Asian, was formed by some indigenous Mexican, Colombian, Peruvian and Venezuelan isolates. Similarly, vacA phylogenetic analyses showed the existence of a novel Amerindian type in isolates from Alaska, Mexico and Colombia. With hspA strains from Mexico and other American groups clustered within the three major groups, Asian, African or European. Genotyping of housekeeping genes confirmed that Mexican strains formed a novel Asian-related Amerindian group together with strains from remote Amazon Aborigines. This study shows that Mexican indigenous people with Amerindian markers are colonized with H. pylori showing admixture of Asian, European and African strains in genes known to interact with the gastric mucosa. We present evidence of novel Amerindian cagA and vacA alleles in indigenous groups of North and South America. PMID:22073291

  11. Pool-hmm: a Python program for estimating the allele frequency spectrum and detecting selective sweeps from next generation sequencing of pooled samples

    PubMed Central

    Boitard, Simon; Kofler, Robert; Françoise, Pierre; Robelin, David; Schlötterer, Christian; Futschik, Andreas

    2013-01-01

    Due to its cost effectiveness, next generation sequencing of pools of individuals (Pool-Seq) is becoming a popular strategy for genome-wide estimation of allele frequencies in population samples. As the allele frequency spectrum provides information about past episodes of selection, Pool-seq is also a promising design for genomic scans for selection. However, no software tool has yet been developed for selection scans based on Pool-Seq data. We introduce Pool-hmm, a Python program for the estimation of allele frequencies and the detection of selective sweeps in a Pool-Seq sample. Pool-hmm includes several options that allow a flexible analysis of Pool-Seq data, and can be run in parallel on several processors. Source code and documentation for Pool-hmm is freely available at https://qgsp.jouy.inra.fr/. PMID:23311589

  12. Novel rapid genotyping assays for neuronal ceroid lipofuscinosis in Border Collie dogs and high frequency of the mutant allele in Japan.

    PubMed

    Mizukami, Keijiro; Chang, Hye-Sook; Yabuki, Akira; Kawamichi, Takuji; Kawahara, Natsuko; Hayashi, Daisuke; Hossain, Mohammad A; Rahman, Mohammad M; Uddin, Mohammad M; Yamato, Osamu

    2011-11-01

    Neuronal ceroid lipofuscinosis (NCL) constitutes a group of recessively inherited lysosomal storage diseases that primarily affect neuronal cells. Such diseases share certain clinical and pathologic features in human beings and animals. Neuronal ceroid lipofuscinosis in Border Collie dogs was first detected in Australia in the 1980s, and the pathogenic mutation was shown to be a nonsense mutation (c.619C>T) in exon 4 in canine CLN5 gene. In the present study, novel rapid genotyping assays including polymerase chain reaction (PCR)-restriction fragment length polymorphism, PCR primer-induced restriction analysis, mutagenically separated PCR, and real-time PCR with TaqMan minor groove binder probes, were developed. The utility of microchip electrophoresis was also evaluated. Furthermore, a genotyping survey was carried out in a population of Border Collies in Japan using these assays to determine the current allele frequency in Japan, providing information to control and prevent this disease in the next stage. All assays developed in the current study are available to discriminate these genotypes, and microchip electrophoresis showed a timesaving advantage over agarose gel electrophoresis. Of all assays, real-time PCR was the most suitable for large-scale examination because of its high throughput. The genotyping survey demonstrated that the carrier frequency was 8.1%. This finding suggested that the mutant allele frequency of NCL in Border Collies is high enough in Japan that measures to control and prevent the disease would be warranted. The genotyping assays developed in the present study could contribute to the prevention of NCL in Border Collies. PMID:22362793

  13. Could FIV zoonosis responsible of the breakdown of the pathocenosis which has reduced the European CCR5-Delta32 allele frequencies?

    PubMed Central

    Faure, Eric

    2008-01-01

    Background In Europe, the north-south downhill cline frequency of the chemokine receptor CCR5 allele with a 32-bp deletion (CCR5-Δ32) raises interesting questions for evolutionary biologists. We had suggested first that, in the past, the European colonizers, principally Romans, might have been instrumental of a progressively decrease of the frequencies southwards. Indeed, statistical analyses suggested strong negative correlations between the allele frequency and historical parameters including the colonization dates by Mediterranean civilisations. The gene flows from colonizers to native populations were extremely low but colonizers are responsible of the spread of several diseases suggesting that the dissemination of parasites in naive populations could have induced a breakdown rupture of the fragile pathocenosis changing the balance among diseases. The new equilibrium state has been reached through a negative selection of the null allele. Results Most of the human diseases are zoonoses and cat might have been instrumental in the decrease of the allele frequency, because its diffusion through Europe was a gradual process, due principally to Romans; and that several cat zoonoses could be transmitted to man. The possible implication of a feline lentivirus (FIV) which does not use CCR5 as co-receptor is discussed. This virus can infect primate cells in vitro and induces clinical signs in macaque. Moreover, most of the historical regions with null or low frequency of CCR5-Δ32 allele coincide with historical range of the wild felid species which harbor species-specific FIVs. Conclusion We proposed the hypothesis that the actual European CCR5 allelic frequencies are the result of a negative selection due to a disease spreading. A cat zoonosis, could be the most plausible hypothesis. Future studies could provide if CCR5 can play an antimicrobial role in FIV pathogenesis. Moreover, studies of ancient DNA could provide more evidences regarding the implications of

  14. Frequency of BLAD and CVM alleles in sires and elite heifers of Czech Holstein cattle.

    PubMed

    Cítek, J; Rehout, V; Schröffelová, D; Hradecká, E

    2008-12-01

    In this paper, we analyse the occurrence of BLAD and CVM heterozygous animals in Holstein cattle in the Czech Republic in 1993-2005. The occurrence of BLAD heterozygous sires and heifers (BL) during the period 1993-1998 in Czech Holsteins was 13.9% and 10.7%. Radical measures have been taken to restore the population. Evidently, the measures have been efficient, in 2005 one BLAD heterozygous sire of 101 was found. Continuous testing is necessary, because in commercial herds, the eradication process is not short-term. The found occurrence ofCVM heterozygous sires (CV) decreased from 20% in 2001 to 8% (7 positive of 85) in 2005.This is still quite a high frequency. The occurrence in CV females of 20% remains higher. Therefore, the use of CV sires should be restricted thoroughly. Identification of the molecular basis for inherited diseases, should lead to control measures which would enable the quick recovery of the population. PMID:19113030

  15. DNA-PCR system FGA (FIBRA)--genotype and allele frequencies in a sample of western Germany (Düsseldorf region).

    PubMed

    Huckenbeck, W; Scheil, H G; Kuntze, K

    1999-12-01

    Frequency data for the STR system FGA (HumFibra) were obtained from a Caucasoid German population sample (Düsseldorf area) of 424 unrelated individuals. PCR products were detected by horizontal polyacrylamid gel electrophoresis and a total of 16 alleles was identified by side-by-side comparison with a commercially available sequenced ladder. The observed genotype distribution showed no significant deviation from the Hardy-Weinberg equilibrium. The high information content (pooled German data: rate of heterozygosity = 0.8626; probability of match = 0.0344; mean exclusion chance = 0.7240) render this system a useful tool not only in forensic casework (criminal and paternity cases) but in population genetics too. PMID:10646230

  16. Phenotype and allele frequencies of some serum protein polymorphisms in populations of the Balkans.

    PubMed

    Scheil, H G; Schmidt, H D; Efremovska, L; Mikerezi, I; Huckenbeck, W

    2004-12-01

    Within a study of the genetics of Southeastern European populations seven serum protein polymorphisms (AMY2, BF, C3, CP, GC, HPA, TF) were examined in two samples of Aromuns and one reference sample (Musequiar-Aromuns from Dukasi in Albania, Moskopolian-Aromuns from Krusevo, Republic of Macedonia, and Macedonians from Skopje). The neighbor joining tree as well as the principal component analysis show results which do not correspond well to the geographic and historic background. This indicates that in the present case the serum protein polymorphisms give no clearly defined information about the relationships between the Balkan populations and to the origin of Aromuns. PMID:15648851

  17. Allele frequencies and population data for 11 Y-chromosome STRs in samples from Eastern Slovakia.

    PubMed

    Petrejčíková, Eva; Soták, Miroslav; Bernasovská, Jarmila; Bernasovský, Ivan; Rębała, Krzysztof; Sovičová, Adriana; Boroňová, Iveta; Bôžiková, Alexandra; Gabriková, Dana; Svíčková, Petra; Mačeková, Soňa; Carnogurská, Jana; Lohaj, Roman; Vlček, Dávid

    2011-06-01

    Haplotype data of 11 Y-STR loci (DYS391, DYS389I, DYS439, DYS389II, DYS438, DYS437, DYS19, DYS392, DYS393, DYS390 and DYS385) was obtained from 629 Slovak Caucasian men living in Eastern Slovakia. A total of 474 haplotypes were identified, of which 395 were unique. The haplotype diversity value was 0.9982. Pairwise haplotype distances showed that the Eastern Slovak Caucasian population is not significantly different from the Slavs populations and is separated from the Balkan nations and the German speaking populations. PMID:20837407

  18. Allele Frequencies of Variants in Ultra Conserved Elements Identify Selective Pressure on Transcription Factor Binding

    PubMed Central

    Silla, Toomas; Kepp, Katrin; Tai, E. Shyong; Goh, Liang; Davila, Sonia; Ivkovic, Tina Catela; Calin, George A.; Voorhoeve, P. Mathijs

    2014-01-01

    Ultra-conserved genes or elements (UCGs/UCEs) in the human genome are extreme examples of conservation. We characterized natural variations in 2884 UCEs and UCGs in two distinct populations; Singaporean Chinese (n = 280) and Italian (n = 501) by using a pooled sample, targeted capture, sequencing approach. We identify, with high confidence, in these regions the abundance of rare SNVs (MAF<0.5%) of which 75% is not present in dbSNP137. UCEs association studies for complex human traits can use this information to model expected background variation and thus necessary power for association studies. By combining our data with 1000 Genome Project data, we show in three independent datasets that prevalent UCE variants (MAF>5%) are more often found in relatively less-conserved nucleotides within UCEs, compared to rare variants. Moreover, prevalent variants are less likely to overlap transcription factor binding site. Using SNPfold we found no significant influence of RNA secondary structure on UCE conservation. All together, these results suggest UCEs are not under selective pressure as a stretch of DNA but are under differential evolutionary pressure on the single nucleotide level. PMID:25369454

  19. Frequencies of 32 base pair deletion of the (Delta 32) allele of the CCR5 HIV-1 co-receptor gene in Caucasians: a comparative analysis.

    PubMed

    Lucotte, Gérard

    2002-05-01

    The CCR5 gene encodes for the co-receptor for the major macrophage-tropics strains of human immunodeficiency virus (HIV-1), and a mutant allele of this gene (Delta 32) provide to homozygotes a strong resistance against infection by HIV. The frequency of the Delta 32 allele was investigated in 40 populations of 8842 non-infected subjects coming from Europe, the Middle-East and North Africa. A clear north-south decreasing gradient was evident for Delta 32 frequencies, with a significant correlation coefficient (r=0.83). The main frequency value of Delta 32 for Sweden, Norway, Denmark, Finland and Iceland (0.134) is significantly (chi(2)=63.818, P<0.001) highest than the Delta 32 mean value, indicating that probably the Vikings might have been instrumental in disseminating the Delta 32 allele during the eighth to the tenth centuries during historical times. Possibly variola virus has discriminated the Delta 32 carriers in Europe since the eighth century AD, explaining the high frequency of the Delta 32 allele in Europe today. PMID:12798016

  20. Beyond orchids and dandelions: Testing the 5HTT “risky” allele for evidence of phenotypic capacitance and frequency dependent selection

    PubMed Central

    Conley, Dalton; Rauscher, Emily; Siegal, Mark L.

    2013-01-01

    The persistence of behaviorally deleterious genes in the human population poses an interesting question for population genetics: If certain alleles at these loci are deleterious, why have they survived in the population? We consider evidence for phenotypic capacitance and/or frequency dependent selection for an allele that has been putatively shown to have negative associations with human behaviors (the “short” 5-HTT promoter region allele) yet which has persisted in human and non-human primate populations. Using National Longitudinal Study of Adolescent Health data, we compare sibling and twin variation in depression by 5-HTT genotype (specified in several ways) and investigate sibship-level cross-person gene-gene interactions. In support of the “orchid / dandelion” hypothesis, we find evidence that the short allele increases variation in phenotypes in response to environmental (or genetic) differences (i.e. acts as a perturbation of a phenotypic capacitor). Further, we also find some evidence that the effects of allelic variation at this locus are moderated by the genetic environment of the sibship unit (i.e. may be susceptible to frequency dependent selection). We discuss implications of these findings for genetic models in general, specifically with respect to stable unit treatment value assumption violations (i.e. non-independence of units of analysis). PMID:23701535

  1. A new method for studying population genetics of cyst nematodes based on Pool-Seq and genomewide allele frequency analysis.

    PubMed

    Mimee, Benjamin; Duceppe, Marc-Olivier; Véronneau, Pierre-Yves; Lafond-Lapalme, Joël; Jean, Martine; Belzile, François; Bélair, Guy

    2015-11-01

    Cyst nematodes are important agricultural pests responsible for billions of dollars of losses each year. Plant resistance is the most effective management tool, but it requires a close monitoring of population genetics. Current technologies for pathotyping and genotyping cyst nematodes are time-consuming, expensive and imprecise. In this study, we capitalized on the reproduction mode of cyst nematodes to develop a simple population genetic analysis pipeline based on genotyping-by-sequencing and Pool-Seq. This method yielded thousands of SNPs and allowed us to study the relationships between populations of different origins or pathotypes. Validation of the method on well-characterized populations also demonstrated that it was a powerful and accurate tool for population genetics. The genomewide allele frequencies of 23 populations of golden nematode, from nine countries and representing the five known pathotypes, were compared. A clear separation of the pathotypes and fine genetic relationships between and among global populations were obtained using this method. In addition to being powerful, this tool has proven to be very time- and cost-efficient and could be applied to other cyst nematode species. PMID:25846829

  2. Regional differences of HFE (C282Y, H63D) allele frequencies in the Netherlands A model case illustrating the significance of genographics and prehistorical population migration.

    PubMed

    Cobbaert, C M; Delanghe, J; Boer, J M A; Feskens, E J M

    2012-01-01

    We investigated HFE C282Y and H63D allele frequencies in three Dutch towns in the Netherlands, as well as their association with cardiovascular disease (CVD) mortality. Study subjects were selected from participants of the Monitoring Project on Cardiovascular Disease Risk Factors in the Netherlands carried out in Amsterdam, Doetinchem and Maastricht among > 35000 subjects, 20-59 years of age. Mortality follow-up lasted 9 to 13 years. A random sample of the cohort (n = 1075) provided information on the total study population. The random sample and all CVD deaths (n = 301) were genotyped for the C282Y and H63D mutation. Adjusted hazard ratios (HR) for CVD mortality were calculated per genotype. C282Y allele frequencies differed significantly between the towns investigated (p = 0.017), whereas the allele frequencies of H63D were similar (p = 0.141) across towns. In Maastricht we found a C282Y allele frequency of 0.086 compared to 0.055 in Amsterdam and 0.054 in Doetinchem. C282Y and H63D heterozygosity did not predict fatal CVD in either men or women, whereas homozygosity for the H63D mutation increased fatal CVD in women (adjusted HR = 8.5; 95% CI = 2.3-31.1). The unexpected high C282Y allele frequency in Maastricht is in line with the recent evidence of a Celtic origin of citizens from the former southern Netherlands and with prehistorical population migrations revealed in the context of the international Genographic Project, a landmark study of prehistorical human migrations around the globe. We recommend that when designing national screening programmes and national registries for genetic disorders, potential regional prevalence differences should be taken into account. PMID:23340149

  3. Autotetraploids of Vicia cracca show a higher allelic richness in natural populations and a higher seed set after artificial selfing than diploids

    PubMed Central

    Eliášová, Anežka; Trávníček, Pavel; Mandák, Bohumil; Münzbergová, Zuzana

    2014-01-01

    Background and Aims Despite the great importance of autopolyploidy in the evolution of angiosperms, relatively little attention has been devoted to autopolyploids in natural polyploid systems. Several hypotheses have been proposed to explain why autopolyploids are so common and successful, for example increased genetic diversity and heterozygosity and the transition towards selfing. However, case studies on patterns of genetic diversity and on mating systems in autopolyploids are scarce. In this study allozymes were employed to investigate the origin, population genetic diversity and mating system in the contact zone between diploid and assumed autotetraploid cytotypes of Vicia cracca in Central Europe. Methods Four enzyme systems resolved in six putative loci were investigated in ten diploid, ten tetraploid and five mixed-ploidy populations. Genetic diversity and heterozygosity, partitioning of genetic diversity among populations and cytotypes, spatial genetic structure and fixed heterozygosity were analysed. These studies were supplemented by a pollination experiment and meiotic chromosome observation. Key Results and Conclusions Weak evidence of fixed heterozygosity, a low proportion of unique alleles and genetic variation between cytotypes similar to the variation among populations within cytotypes supported the autopolyploid origin of tetraploids, although no multivalent formation was observed. Tetraploids possessed more alleles than diploids and showed higher observed zygotic heterozygosity than diploids, but the observed gametic heterozygosity was similar to the value observed in diploids and smaller than expected under panmixis. Values of the inbreeding coefficient and differentiation among populations (ρST) suggested that the breeding system in both cytotypes of V. cracca is mixed mating with prevailing outcrossing. The reduction in seed production of tetraploids after selfing was less than that in diploids. An absence of correlation between genetic and

  4. Characterization of a DFG comb showing quadratic scaling of the phase noise with frequency.

    PubMed

    Puppe, Thomas; Sell, Alexander; Kliese, Russell; Hoghooghi, Nazanin; Zach, Armin; Kaenders, Wilhelm

    2016-04-15

    We characterize an Er:fiber laser frequency comb that is passively carrier envelope phase-stabilized via difference frequency generation at a wavelength of 1550 nm. A generic method to measure the comb linewidth at different wavelengths is demonstrated. By transferring the properties of a comb line to a cw external cavity diode laser, the phase noise is subsequently measured by tracking the delayed self-heterodyne beat note. This relatively simple characterization method is suitable for a broad range of optical frequencies. Here, it is used to characterize our difference frequency generation (DFG) comb over nearly an optical octave. With repetition-rate stabilization, a radiofrequency reference oscillator limited linewidth is achieved. A lock to an optical reference shows out-of-loop linewidths of the comb at the hertz level. The phase noise measurements are in excellent agreement with the elastic tape model with a fix point at zero frequency. PMID:27082368

  5. Frequency of streptococcal upper respiratory tract infections and HLA-Cw*06 allele in 70 patients with guttate psoriasis from northern Poland

    PubMed Central

    Szczerkowska-Dobosz, Aneta; Rębała, Krzysztof; Wysocka, Joanna; Roszkiewicz, Jadwiga; Szczerkowska, Zofia; Placek, Waldemar

    2015-01-01

    Introduction The association of guttate psoriasis with a streptococcal throat infection and HLA-Cw*06 allele is well established in different populations. Nevertheless, only few studies on this form of disease have been performed in the Polish population. Aim To analyze the frequencies of streptococcal-induced guttate psoriasis and HLA-Cw*06 allele in 70 patients with guttate psoriasis originating from northern Poland. Material and methods Seventy patients with guttate psoriasis and 24 healthy volunteers were enrolled into the study. Both groups were sex- and age-matched. The evidence of streptococcal infection was based on the positive throat swabs and/or elevated ASO titers. The modified method, including PCR-SSP and PCR-RFLP, was applied to HLA-Cw*06 genotyping. Results HLA-Cw*06 allele was confirmed in 49 (70%) out of 70 patients, which is significantly higher than in the control population (30%) (p = 0.001). Evidence for streptococcal infection was found in 34 (48.5%) subjects with psoriasis. Twenty-seven of them (79%) carried HLA-Cw*06 allele. In 36 individuals in whom no evidence of streptococcal infection was found, 14 (39%) did not carry HLA-Cw*06 allele. Conclusions Our data confirm that HLA-Cw*06 is a major, but not imperative, genetic determinant for guttate psoriasis. PMID:26755910

  6. Aged rats show dominant modulation of lower frequency hippocampal theta rhythm during running.

    PubMed

    Li, Jia-Yi; Kuo, Terry B J; Yang, Cheryl C H

    2016-10-01

    Aging causes considerable decline in both physiological and mental functions, particularly cognitive function. The hippocampal theta rhythm (4-12Hz) is related to both cognition and locomotion. Aging-related findings of the frequency and amplitude of hippocampal theta oscillations are inconsistent and occasionally contradictory. This inconsistency may be due to the effects of the sleep/wake state and different frequency subbands being overlooked. We assumed that aged rats have lower responses of the hippocampal theta rhythm during running, which is mainly due to the dominant modulation of theta frequency subbands related to cognition. By simultaneously recording electroencephalography, physical activity (PA), and the heart rate (HR), this experiment explored the theta oscillations before, during, and after treadmill running at a constant speed in 8-week-old (adult) and 60-week-old (middle-aged) rats. Compared with adult rats, the middle-aged rats exhibited lower theta activity in all frequency ranges before running. Running increased the theta frequency (Frq, 4-12Hz), total activity of the whole theta band (total power, TP), activity of the middle theta frequency (MT, 6.5-9.5Hz), and PA in both age groups. However, the middle-aged rats still showed fewer changes in these parameters during the whole running process. After the waking baseline values were substracted, middle-aged rats showed significantly fewer differences in ΔFrq, ΔTP, and ΔMT but significantly more differences in low-frequency theta activity (4.0-6.5Hz) and HR than the adult rats did. Therefore, the decreasing activity and response of the whole theta band in the middle-aged rats resulted in dominant modulation of the middle to lower frequency (4.0-9.5Hz) theta rhythm. The different alterations in the theta rhythm during treadmill running in the two groups may reflect that learning decline with age. PMID:27496645

  7. A dominant negative allele of p34cdc2 shows altered phosphoamino acid content and sequesters p56cdc13 cyclin.

    PubMed Central

    Fleig, U N; Gould, K L; Nurse, P

    1992-01-01

    The cdc2 gene product, a 34-kDa phosphoprotein with serine/threonine protein kinase activity, has been implicated as the key component in the regulation of the eucaryotic cell cycle. Activation of the cdc2 protein kinase is regulated by its phosphorylation state and by interaction with other proteins. We have mutagenized the fission yeast cdc2 gene to obtain conditionally dominant negative alleles. One of these mutants, named DL2, is characterized in this report. Overexpression of the mutant protein in a wild-type cdc2 background is lethal and leads to arrest in the G2 phase of the cell cycle. The mutant phenotype is the result of a single amino acid change in the GDSEID motif of the protein, a region of identity in all cdc2 homologs, and results in a nonfunctional protein that shows an altered content of phosphothreonine. Multicopy suppressors of the dominant negative phenotype have been isolated, and one of these has been shown to encode the cdc13 cyclin B gene product. Images PMID:1533272

  8. Allele frequency-based and polymorphism-versus-divergence indices of balancing selection in a new filtered set of polymorphic genes in Plasmodium falciparum.

    PubMed

    Ochola, Lynette Isabella; Tetteh, Kevin K A; Stewart, Lindsay B; Riitho, Victor; Marsh, Kevin; Conway, David J

    2010-10-01

    Signatures of balancing selection operating on specific gene loci in endemic pathogens can identify candidate targets of naturally acquired immunity. In malaria parasites, several leading vaccine candidates convincingly show such signatures when subjected to several tests of neutrality, but the discovery of new targets affected by selection to a similar extent has been slow. A small minority of all genes are under such selection, as indicated by a recent study of 26 Plasmodium falciparum merozoite-stage genes that were not previously prioritized as vaccine candidates, of which only one (locus PF10_0348) showed a strong signature. Therefore, to focus discovery efforts on genes that are polymorphic, we scanned all available shotgun genome sequence data from laboratory lines of P. falciparum and chose six loci with more than five single nucleotide polymorphisms per kilobase (including PF10_0348) for in-depth frequency-based analyses in a Kenyan population (allele sample sizes >50 for each locus) and comparison of Hudson-Kreitman-Aguade (HKA) ratios of population diversity (π) to interspecific divergence (K) from the chimpanzee parasite Plasmodium reichenowi. Three of these (the msp3/6-like genes PF10_0348 and PF10_0355 and the surf(4.1) gene PFD1160w) showed exceptionally high positive values of Tajima's D and Fu and Li's F indices and have the highest HKA ratios, indicating that they are under balancing selection and should be prioritized for studies of their protein products as candidate targets of immunity. Combined with earlier results, there is now strong evidence that high HKA ratio (as well as the frequency-independent ratio of Watterson's /K) is predictive of high values of Tajima's D. Thus, the former offers value for use in genome-wide screening when numbers of genome sequences within a species are low or in combination with Tajima's D as a 2D test on large population genomic samples. PMID:20457586

  9. Allele Frequencies of the Single Nucleotide Polymorphisms Related to the Body Burden of Heavy Metals in the Korean Population and Their Ethnic Differences

    PubMed Central

    Eom, Sang-Yong; Lim, Ji-Ae; Kim, Yong-Dae; Choi, Byung-Sun; Hwang, Myung Sil; Park, Jung-Duck; Kim, Heon; Kwon, Ho-Jang

    2016-01-01

    This study was performed to select single nucleotide polymorphisms (SNPs) related to the body burden of heavy metals in Koreans, to provide Korean allele frequencies of selected SNPs, and to assess the difference in allele frequencies with other ethnicities. The candidate-gene approach method and genome-wide association screening were used to select SNPs related to the body burden of heavy metals. Genotyping analysis of the final 192 SNPs selected was performed on 1,483 subjects using the VeraCode Goldengate assay. Allele frequencies differences and genetic differentiations between the Korean population and Chinese (CHB), Japanese (JPT), Caucasian (CEU), and African (YIR) populations were tested by Fisher’s exact test and fixation index (FST), respectively. The Korean population was genetically similar to the CHB and JPT populations (FST < 0.05, for all SNPs in both populations). However, a significant difference in the allele frequencies between the Korean and CEU and YIR populations were observed in 99 SNPs (60.7%) and 120 SNPs (73.6%), respectively. Ten (6.1%) and 26 (16.0%) SNPs had genetic differentiation (FST > 0.05) among the Korean-CEU and Korean-YIR comparisons, respectively. The SNP with the largest FST value between the Korean and African populations was cystathionine-β-synthase rs234709 (FST: KOR-YIR, 0.309; KOR-CEU, 0.064). Our study suggests that interethnic differences exist in SNPs associated with heavy metals of Koreans, and it should be considered in future studies that address ethnic differences in heavy-metal concentrations in the body and genetic susceptibility to the body burden of heavy metals. PMID:27437086

  10. Distribution of allele frequencies at TTN g.231054C > T, RPL27A g.3109537C > T and AKIRIN2 c.*188G > A between Japanese Black and four other cattle breeds with differing historical selection for marbling

    PubMed Central

    2011-01-01

    Background Marbling defined by the amount and distribution of intramuscular fat, so-called Shimofuri, is an economically important trait of beef cattle in Japan. Our previous study detected 3 single nucleotide polymorphisms (SNPs), g.231054C > T, g.3109537C > T and c.*188G > A, respectively, in the 5' flanking region of the titin (TTN), the 5' flanking region of the ribosomal protein L27a (RPL27A) and the 3' untranslated region of the akirin 2 genes (AKIRIN2), which have been considered as positional functional candidates for the genes responsible for marbling, and showed association of these SNPs with marbling in Japanese Black beef cattle. In the present study, we investigated the allele frequency distribution of the 3 SNPs among the 5 cattle breeds, Japanese Black, Japanese Brown, Japanese Shorthorn, Holstein and Brown Swiss breeds. Findings We genotyped the TTN g.231054C > T, RPL27A g.3109537C > T and AKIRIN2 c.*188G > A SNPs by polymerase chain reaction-restriction fragment length polymorphism method, using 101 sires and 1,705 paternal half sib progeny steers from 8 sires for Japanese Black, 86 sires and 27 paternal half sib progeny steers from 3 sires for Japanese Brown, 79 sires and 264 paternal half sib progeny steers from 14 sires for Japanese Shorthorn, 119 unrelated cows for Holstein, and 118 unrelated cows for Brown Swiss breeds. As compared to the frequencies of the g.231054C > T T, g.3109537C > T T and c.*188G > A A alleles, associated with high marbling, in Japanese Black breed that has been subjected to a strong selection for high marbling, those in the breeds, Japanese Shorthorn, Holstein and Brown Swiss breeds, that have not been selected for high marbling were null or lower. The Japanese Brown breed selected slightly for high marbling showed lower frequency than Japanese Black breed in the g.3109537C > T T allele, whereas no differences were detected between the 2 breeds in the frequencies of the g.231054C > T T and c.*188G > A A alleles

  11. Status of allele frequency and diversity of Plasmodium falciparum msp1, msp2 and glurp before implementation of an artemisinin-based combined therapy in Northwestern Colombia.

    PubMed Central

    Arango, Eliana; Carmona-Fonseca, Jaime

    2013-01-01

    Introduction: The status of msp1, msp2 and glurp allele frequency and the diversity of Plasmodium falciparum in Northwestern Colombia before the implementation of an artemisinin-combined therapy have been explored only by a few authors and in a relatively small number of samples from this highly endemic region. Objective: To evaluate the frequency of msp1, msp2, and glurp alleles and the diversity of P. falciparum in two Colombian regions before the use of an artemisinin-combined therapy. Methods: This study was part of a major anti-malarial efficacy trial designed as a random, clinically-controlled study for which 224 subjects were recruited. Region 2 of msp1 and msp2 (central region) were amplified by a nested PCR; glurp (region R2) was amplified by a semi-nested PCR. Results: For msp1, five genotypes were observed, representing the K1, MAD20, and RO33 allelic families. All samples corresponded to a MAD20 150 bp allele. For msp2 (IC family), two alleles were detected and for glurp, eight were observed. A total 33 haplotypes were detected. Conclusions: Analysis of glurpcan be used to successfully genotype parasite populations in the new studies in Colombia aimed at exploring Plasmodium spp population dynamics. In addition, analysis of msp1 and msp2 can also be of value for comparisons with past studies, but not when the objective is to study parasites obtained from the same patient in a reduced period of time; for instance, during treatment efficacy studies. PMID:24892236

  12. Recommendations of the DNA Commission of the International Society for Forensic Genetics (ISFG) on quality control of autosomal Short Tandem Repeat allele frequency databasing (STRidER).

    PubMed

    Bodner, Martin; Bastisch, Ingo; Butler, John M; Fimmers, Rolf; Gill, Peter; Gusmão, Leonor; Morling, Niels; Phillips, Christopher; Prinz, Mechthild; Schneider, Peter M; Parson, Walther

    2016-09-01

    The statistical evaluation of autosomal Short Tandem Repeat (STR) genotypes is based on allele frequencies. These are empirically determined from sets of randomly selected human samples, compiled into STR databases that have been established in the course of population genetic studies. There is currently no agreed procedure of performing quality control of STR allele frequency databases, and the reliability and accuracy of the data are largely based on the responsibility of the individual contributing research groups. It has been demonstrated with databases of haploid markers (EMPOP for mitochondrial mtDNA, and YHRD for Y-chromosomal loci) that centralized quality control and data curation is essential to minimize error. The concepts employed for quality control involve software-aided likelihood-of-genotype, phylogenetic, and population genetic checks that allow the researchers to compare novel data to established datasets and, thus, maintain the high quality required in forensic genetics. Here, we present STRidER (http://strider.online), a publicly available, centrally curated online allele frequency database and quality control platform for autosomal STRs. STRidER expands on the previously established ENFSI DNA WG STRbASE and applies standard concepts established for haploid and autosomal markers as well as novel tools to reduce error and increase the quality of autosomal STR data. The platform constitutes a significant improvement and innovation for the scientific community, offering autosomal STR data quality control and reliable STR genotype estimates. PMID:27352221

  13. Adults with Dyslexia Show Deficits on Spatial Frequency Doubling and Visual Attention Tasks

    ERIC Educational Resources Information Center

    Buchholz, Judy; McKone, Elinor

    2004-01-01

    We examine the visual processing of high-functioning adults with developmental dyslexia (mean Performance IQ=126.5) and current phonological problems. In comparison to an age- and IQ-matched control group, the group with dyslexia showed deficits in two tasks associated with magnocellular/dorsal pathway function. For the "frequency doubling"…

  14. High Susceptibility to Cry1Ac and Low Resistance Allele Frequency Reduce the Risk of Resistance of Helicoverpa armigers to Bt Soybean in Brazil.

    PubMed

    Dourado, Patrick M; Bacalhau, Fabiana B; Amado, Douglas; Carvalho, Renato A; Martinelli, Samuel; Head, Graham P; Omoto, Celso

    2016-01-01

    The Old World bollworm, Helicoverpa armigera (Hübner), was recently introduced into Brazil, where it has caused extensive damage to cotton and soybean crops. MON 87701 × MON 89788 soybean, which expresses the Bt protein Cry1Ac, was recently deployed in Brazil, providing high levels of control against H. armigera. To assess the risk of resistance to the Cry1Ac protein expressed by MON 87701 × MON 89788 soybean in Brazil, we conducted studies to evaluate the baseline susceptibility of H. armigera to Cry1Ac, in planta efficacy including the assessment of the high-dose criterion, and the initial resistance allele frequency based on an F2 screen. The mean Cry1Ac lethal concentration (LC50) ranged from 0.11 to 1.82 μg·mL-1 of diet among all H. armigera field populations collected from crop seasons 2013/14 to 2014/15, which indicated about 16.5-fold variation. MON 87701 × MON 89788 soybean exhibited a high level of efficacy against H. armigera and most likely met the high dose criterion against this target species in leaf tissue dilution bioassays up to 50 times. A total of 212 F2 family lines of H. armigera were established from field collections sampled from seven locations across Brazil and were screened for the presence of MON 87701 × MON 89788 soybean resistance alleles. None of the 212 families survived on MON 87701 × MON 89788 soybean leaf tissue (estimated allele frequency = 0.0011). The responses of H. armigera to Cry1Ac protein, high susceptibility to MON 87701 × MON 89788 soybean, and low frequency of resistance alleles across the main soybean-producing regions support the assumptions of a high-dose/refuge strategy. However, maintenance of reasonable compliance with the refuge recommendation will be essential to delay the evolution of resistance in H. armigera to MON 87701 × MON 89788 soybean in Brazil. PMID:27532632

  15. High Susceptibility to Cry1Ac and Low Resistance Allele Frequency Reduce the Risk of Resistance of Helicoverpa armigers to Bt Soybean in Brazil

    PubMed Central

    Bacalhau, Fabiana B.; Amado, Douglas; Carvalho, Renato A.; Martinelli, Samuel; Head, Graham P.; Omoto, Celso

    2016-01-01

    The Old World bollworm, Helicoverpa armigera (Hübner), was recently introduced into Brazil, where it has caused extensive damage to cotton and soybean crops. MON 87701 × MON 89788 soybean, which expresses the Bt protein Cry1Ac, was recently deployed in Brazil, providing high levels of control against H. armigera. To assess the risk of resistance to the Cry1Ac protein expressed by MON 87701 × MON 89788 soybean in Brazil, we conducted studies to evaluate the baseline susceptibility of H. armigera to Cry1Ac, in planta efficacy including the assessment of the high-dose criterion, and the initial resistance allele frequency based on an F2 screen. The mean Cry1Ac lethal concentration (LC50) ranged from 0.11 to 1.82 μg·mL−1 of diet among all H. armigera field populations collected from crop seasons 2013/14 to 2014/15, which indicated about 16.5-fold variation. MON 87701 × MON 89788 soybean exhibited a high level of efficacy against H. armigera and most likely met the high dose criterion against this target species in leaf tissue dilution bioassays up to 50 times. A total of 212 F2 family lines of H. armigera were established from field collections sampled from seven locations across Brazil and were screened for the presence of MON 87701 × MON 89788 soybean resistance alleles. None of the 212 families survived on MON 87701 × MON 89788 soybean leaf tissue (estimated allele frequency = 0.0011). The responses of H. armigera to Cry1Ac protein, high susceptibility to MON 87701 × MON 89788 soybean, and low frequency of resistance alleles across the main soybean-producing regions support the assumptions of a high-dose/refuge strategy. However, maintenance of reasonable compliance with the refuge recommendation will be essential to delay the evolution of resistance in H. armigera to MON 87701 × MON 89788 soybean in Brazil. PMID:27532632

  16. High Frequency of Pathogenic Rearrangements in SPG11 and Extensive Contribution of Mutational Hotspots and Founder Alleles.

    PubMed

    Günther, Sven; Elert-Dobkowska, Ewelina; Soehn, Anne S; Hinreiner, Sophie; Yoon, Grace; Heller, Raoul; Hellenbroich, Yorck; Hübner, Christian A; Ray, Peter N; Hehr, Ute; Bauer, Peter; Sulek, Anna; Beetz, Christian

    2016-07-01

    Biallelic loss-of-function mutations in SPG11 cause a wide spectrum of recessively inherited, neurodegenerative disorders including hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease. By comprehensive screening of three large cohorts of HSP index patients, we identified 83 alleles with "small" mutations and 13 alleles that carry large genomic rearrangements. Including relevant data from previous studies, we estimate that copy number variants (CNVs) account for ∼19% of pathogenic SPG11 alleles. The breakpoints for all novel and some previously reported CNVs were determined by long-range PCR and sequencing. This revealed several Alu-associated recombination hotspots. We also found evidence for additional mutational mechanisms, including for a two-step event in which an Alu retrotransposition preceded the actual rearrangement. Apparently independent samples with identical breakpoints were analyzed by microsatellite PCRs. The resulting haplotypes suggested the existence of two rearrangement founder alleles. Our findings widen the spectra of mutations and mutational mechanisms in SPG11, underscore the pivotal role played by Alus, and are of high diagnostic relevance for a wide spectrum of clinical phenotypes including the most frequent form of recessive HSP. PMID:27071356

  17. Frequency of HLA-DRB1 and HLA-DQB1 Alleles and Haplotype Association in Syrian Population.

    PubMed

    Jazairi, Batoul; Khansaa, Issam; Ikhtiar, Adnan; Murad, Hossam

    2016-02-01

    The study of Human Leukocyte Antigen (HLA) system is very important in health and diseases. As the HLA loci are the most polymorphic in the human genome, it plays a very important role in the immune responses to self and nonself antigens. In the light of the growing importance of typing the HLA alleles in transplantation, autoimmune diseases, cancer, and many other diseases, we studied 225 unrelated healthy Syrian subjects for their HLA class II genotypes in an attempt to reveal the distribution of the HLA (DRB1-DQB1) alleles in the general Syrian population. Our results revealed that the most common alleles for the DRB1 locus were DRB1*11 (26.4%), DRB1*04 (14%), and DRB1*07 (12%). However, the most frequent alleles for the DQB1 locus were DQB1*03 (40.9%) and DQB1*05 (25.1%). The frequent of two-locus haplotypes carry the most frequent alleles at these loci. The most frequently detected class II ''haplotypes'' are DRB1*11-DQB1*03 (8.9%), DRB1*01-DQB1*05 (3.6%), and DRB1*04-DQB1*03 (2.7%). Compared with other populations, our result, deduced from the analysis of genetic distances and the construction of neighbor-joining (NJ) dendrogram, and principal component analysis (PCA) indicates that Syrians are related to Middle Eastern populations. Our data about the Syrian population will aid researchers in studying the relation of HLA class II with different diseases in a Syrian population and will add to the available international literature associated with these loci. PMID:26853713

  18. Frequency of alleles conferring resistance to Bt maize in French and US corn belt populations of the European corn borer, Ostrinia nubilalis.

    PubMed

    Bourguet, D; Chaufaux, J; Séguin, M; Buisson, C; Hinton, J L; Stodola, T J; Porter, P; Cronholm, G; Buschman, L L; Andow, D A

    2003-05-01

    Farmers, industry, governments and environmental groups agree that it would be useful to manage transgenic crops producing insecticidal proteins to delay the evolution of resistance in target pests. The main strategy proposed for delaying resistance to Bacillus thuringiensis ( Bt) toxins in transgenic crops is the high-dose/refuge strategy. This strategy is based on the unverified assumption that resistance alleles are initially rare (<10(-3)). We used an F(2) screen on >1,200 isofemale lines of Ostrinia nubilalis Hübner (Lepidoptera: Crambidae) collected in France and the US corn belt during 1999-2001. In none of the isofemale lines did we detect alleles conferring resistance to Bt maize producing the Cry1Ab toxin. A Bayesian analysis of the data indicates that the frequency of resistance alleles in France was <9.20 x 10(-4) with 95% probability, and a detection probability of >80%. In the northern US corn belt, the frequency of resistance to Bt maize was <4.23 x 10(-4) with 95% probability, and a detection probability of >90%. Only 95 lines have been screened from the southern US corn belt, so these data are still inconclusive. These results suggest that resistance is probably rare enough in France and the northern US corn belt for the high-dose plus refuge strategy to delay resistance to Bt maize. PMID:12748773

  19. HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in a population of 432 healthy unrelated individuals from Albania.

    PubMed

    Sulcebe, Genc; Shyti, Erkena

    2016-08-01

    This paper reports the HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype polymorphism in a population of 432 healthy individuals from Albania. First-field HLA genotyping was performed by polymerase chain reaction sequence-specific priming and/or oligonucleotide methods. The data were analyzed statistically using gene counting and Arlequin software packages. No deviation from Hardy Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database and they can serve as a reference database for further HLA-based population genetics studies including the Albanian population. PMID:27262454

  20. Allele frequencies and population data for 17 Y-STR loci (The AmpFlSTR® Y-filer™) in Casablanca resident population.

    PubMed

    Laouina, Adil; El Houate, Brahim; Yahia, Hakima; Azeddoug, Houssine; Boulouiz, Redouane; Chbel, Faiza

    2011-01-01

    Allele frequencies and population data for 17 Y-STR loci included in the AmpFlSTR® Y-filer™ PCR amplification kit (Applied Biosystems, Foster City, USA), that permit the simultaneous amplification of all the markers included in the actually used European "extended haplotype", DYS19, DYS189I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385I/II, DYS438, DYS439 and also DYS437, DYS448, DYS456, DYS458, DYS635 and Y GATA H4, were obtained from a sample of 166 healthy unrelated males resident in Casablanca (from Morocco). A total of 166 haplotypes were identified, of which 142 were unique. The overall haplotype diversity for the 17 Y-STR loci reached 0.9974, and a discrimination capacity was 0.855. We report some non-standard situations, including duplications and microvariant alleles. PMID:21126935

  1. Inosine triphosphatase allele frequency and association with ribavirin-induced anaemia in Brazilian patients receiving antiviral therapy for chronic hepatitis C

    PubMed Central

    Delvaux, Nathália; da Costa, Vanessa Duarte; da Costa, Maristella Matos; Villar, Livia Melo; Coelho, Henrique Sérgio Moraes; Esberard, Eliane Bordalo Cathalá; Flores, Priscila Pollo; Brandão-Mello, Carlos Eduardo; Villela-Nogueira, Cristiane Alves; de Almeida, Adilson José; Lampe, Elisabeth

    2015-01-01

    Inosine triphosphatase (ITPA) single nucleotide polymorphisms (SNPs) are strongly associated with protection against ribavirin (RBV)-induced anaemia in European, American and Asian patients; however, there is a paucity of data for Brazilian patients. The aim of this study was to evaluate the ITPA SNP (rs7270101/rs1127354) frequency in healthy and hepatitis C virus (HCV)-infected patients from Brazil and the association with the development of severe anaemia during antiviral therapy. ITPA SNPs were determined in 200 HCV infected patients and 100 healthy individuals by sequencing. Biochemical parameters and haemoglobin (Hb) levels were analysed in 97 patients who underwent antiviral therapy. A combination of AArs7270101+CCrs1127354 (100% ITPase activity) was observed in 236/300 individuals. Anaemia was observed in 87.5% and 86.2% of treated patients with AA (rs7270101) and CC genotypes (rs1127354), respectively. Men with AA (rs7270101) showed a considerable reduction in Hb at week 12 compared to those with AC/CC (p = 0.1475). In women, there was no influence of genotype (p = 0.5295). For rs1127354, men with the CC genotype also showed a sudden reduction in Hb compared to those with AC. Allelic distribution of rs7270101 and rs1127354 shows high rates of the genotypes AA and CC, respectively, suggesting that the study population had a great propensity for developing RBV-induced anaemia. A progressive Hb reduction during treatment was observed; however, this reduction was greater in men at week 12 than in women. PMID:26154744

  2. Frequency of Cry1F Non-Recessive Resistance Alleles in North Carolina Field Populations of Spodoptera frugiperda (Lepidoptera: Noctuidae).

    PubMed

    Li, Guoping; Reisig, Dominic; Miao, Jin; Gould, Fred; Huang, Fangneng; Feng, Hongqiang

    2016-01-01

    Fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), is a target species of transgenic corn (Zea mays L.) that expresses single and pyramided Bacillus thuringiensis (Bt) toxin. In 2014, S. frugiperda were collected from a light trap in North Carolina, and a total of 212 F1/F2 isofemale lines of S. frugiperda were screened for resistance to Bt and non-Bt corn. All of the 212 isolines were susceptible to corn tissue expressing Cry1A.105 + Cry2Ab, Cry1F + Cry1A.105 + Cry2Ab, and Cry1F + Cry1Ab + Vip3Aa20. Growth rate bioassays were performed to isolate non-recessive Bt resistance alleles. Seven individuals out of the 212 isofemale lines carried major non-recessive alleles conferring resistance to Cry1F. A pooled colony was created from the seven individuals. This colony was 151.21 times more resistant to Cry1F than a known-susceptible population and was also resistant to Cry1A.105, but was not resistant to Cry2Ab and Vip3Aa20. The results demonstrate that field populations of S. frugiperda collected from North Carolina are generally susceptible to Cry1F, but that some individuals carry resistant alleles. The data generated in this study can be used as baseline data for resistance monitoring. PMID:27119741

  3. Frequency of Cry1F Non-Recessive Resistance Alleles in North Carolina Field Populations of Spodoptera frugiperda (Lepidoptera: Noctuidae)

    PubMed Central

    Li, Guoping; Reisig, Dominic; Miao, Jin; Gould, Fred; Huang, Fangneng; Feng, Hongqiang

    2016-01-01

    Fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), is a target species of transgenic corn (Zea mays L.) that expresses single and pyramided Bacillus thuringiensis (Bt) toxin. In 2014, S. frugiperda were collected from a light trap in North Carolina, and a total of 212 F1/F2 isofemale lines of S. frugiperda were screened for resistance to Bt and non-Bt corn. All of the 212 isolines were susceptible to corn tissue expressing Cry1A.105 + Cry2Ab, Cry1F + Cry1A.105 + Cry2Ab, and Cry1F + Cry1Ab + Vip3Aa20. Growth rate bioassays were performed to isolate non-recessive Bt resistance alleles. Seven individuals out of the 212 isofemale lines carried major non-recessive alleles conferring resistance to Cry1F. A pooled colony was created from the seven individuals. This colony was 151.21 times more resistant to Cry1F than a known-susceptible population and was also resistant to Cry1A.105, but was not resistant to Cry2Ab and Vip3Aa20. The results demonstrate that field populations of S. frugiperda collected from North Carolina are generally susceptible to Cry1F, but that some individuals carry resistant alleles. The data generated in this study can be used as baseline data for resistance monitoring. PMID:27119741

  4. Ancient DNA analysis reveals high frequency of European lactase persistence allele (T-13910) in medieval central europe.

    PubMed

    Krüttli, Annina; Bouwman, Abigail; Akgül, Gülfirde; Della Casa, Philippe; Rühli, Frank; Warinner, Christina

    2014-01-01

    Ruminant milk and dairy products are important food resources in many European, African, and Middle Eastern societies. These regions are also associated with derived genetic variants for lactase persistence. In mammals, lactase, the enzyme that hydrolyzes the milk sugar lactose, is normally down-regulated after weaning, but at least five human populations around the world have independently evolved mutations regulating the expression of the lactase-phlorizin-hydrolase gene. These mutations result in a dominant lactase persistence phenotype and continued lactase tolerance in adulthood. A single nucleotide polymorphism (SNP) at C/T-13910 is responsible for most lactase persistence in European populations, but when and where the T-13910 polymorphism originated and the evolutionary processes by which it rose to high frequency in Europe have been the subject of strong debate. A history of dairying is presumed to be a prerequisite, but archaeological evidence is lacking. In this study, DNA was extracted from the dentine of 36 individuals excavated at a medieval cemetery in Dalheim, Germany. Eighteen individuals were successfully genotyped for the C/T-13910 SNP by molecular cloning and sequencing, of which 13 (72%) exhibited a European lactase persistence genotype: 44% CT, 28% TT. Previous ancient DNA-based studies found that lactase persistence genotypes fall below detection levels in most regions of Neolithic Europe. Our research shows that by AD 1200, lactase persistence frequency had risen to over 70% in this community in western Central Europe. Given that lactase persistence genotype frequency in present-day Germany and Austria is estimated at 71-80%, our results suggest that genetic lactase persistence likely reached modern levels before the historic population declines associated with the Black Death, thus excluding plague-associated evolutionary forces in the rise of lactase persistence in this region. This new evidence sheds light on the dynamic evolutionary

  5. Ancient DNA Analysis Reveals High Frequency of European Lactase Persistence Allele (T-13910) in Medieval Central Europe

    PubMed Central

    Akgül, Gülfirde; Della Casa, Philippe; Rühli, Frank; Warinner, Christina

    2014-01-01

    Ruminant milk and dairy products are important food resources in many European, African, and Middle Eastern societies. These regions are also associated with derived genetic variants for lactase persistence. In mammals, lactase, the enzyme that hydrolyzes the milk sugar lactose, is normally down-regulated after weaning, but at least five human populations around the world have independently evolved mutations regulating the expression of the lactase-phlorizin-hydrolase gene. These mutations result in a dominant lactase persistence phenotype and continued lactase tolerance in adulthood. A single nucleotide polymorphism (SNP) at C/T-13910 is responsible for most lactase persistence in European populations, but when and where the T-13910 polymorphism originated and the evolutionary processes by which it rose to high frequency in Europe have been the subject of strong debate. A history of dairying is presumed to be a prerequisite, but archaeological evidence is lacking. In this study, DNA was extracted from the dentine of 36 individuals excavated at a medieval cemetery in Dalheim, Germany. Eighteen individuals were successfully genotyped for the C/T-13910 SNP by molecular cloning and sequencing, of which 13 (72%) exhibited a European lactase persistence genotype: 44% CT, 28% TT. Previous ancient DNA-based studies found that lactase persistence genotypes fall below detection levels in most regions of Neolithic Europe. Our research shows that by AD 1200, lactase persistence frequency had risen to over 70% in this community in western Central Europe. Given that lactase persistence genotype frequency in present-day Germany and Austria is estimated at 71–80%, our results suggest that genetic lactase persistence likely reached modern levels before the historic population declines associated with the Black Death, thus excluding plague-associated evolutionary forces in the rise of lactase persistence in this region. This new evidence sheds light on the dynamic evolutionary

  6. Stochastic modelling of shifts in allele frequencies reveals a strongly polygynous mating system in the re-introduced Asiatic wild ass.

    PubMed

    Renan, Sharon; Greenbaum, Gili; Shahar, Naama; Templeton, Alan R; Bouskila, Amos; Bar-David, Shirli

    2015-04-01

    Small populations are prone to loss of genetic variation and hence to a reduction in their evolutionary potential. Therefore, studying the mating system of small populations and its potential effects on genetic drift and genetic diversity is of high importance for their viability assessments. The traditional method for studying genetic mating systems is paternity analysis. Yet, as small populations are often rare and elusive, the genetic data required for paternity analysis are frequently unavailable. The endangered Asiatic wild ass (Equus hemionus), like all equids, displays a behaviourally polygynous mating system; however, the level of polygyny has never been measured genetically in wild equids. Combining noninvasive genetic data with stochastic modelling of shifts in allele frequencies, we developed an alternative approach to paternity analysis for studying the genetic mating system of the re-introduced Asiatic wild ass in the Negev Desert, Israel. We compared the shifts in allele frequencies (as a measure of genetic drift) that have occurred in the wild ass population since re-introduction onset to simulated scenarios under different proportions of mating males. We revealed a strongly polygynous mating system in which less than 25% of all males participate in the mating process each generation. This strongly polygynous mating system and its potential effect on the re-introduced population's genetic diversity could have significant consequences for the long-term persistence of the population in the Negev. The stochastic modelling approach and the use of allele-frequency shifts can be further applied to systems that are affected by genetic drift and for which genetic data are limited. PMID:25728575

  7. HLA-Cw Allele Frequency in Definite Meniere’s Disease Compared to Probable Meniere’s Disease and Healthy Controls in an Iranian Sample

    PubMed Central

    Dabiri, Sasan; Ghadimi, Fatemeh; Firouzifar, Mohammadreza; Yazdani, Nasrin; Mohammad-Amoli, Mahsa; Vakili, Varasteh; Mahvi, Zahra

    2016-01-01

    Introduction Several lines of evidence support the contribution of autoimmune mechanisms in the pathogenesis of Meniere’s disease. The aim of this study was determining the association between HLA-Cw Alleles in patients with definite Meniere’s disease and patients with probable Meniere’s disease and a control group. Materials and Methods: HLA-Cw genotyping was performed in 23 patients with definite Meniere’s disease, 24 with probable Meniere’s disease, and 91 healthy normal subjects, using sequence specific primers polymerase chain reaction technique. The statistical analysis was performed using stata 8 software. Results: There was a significant association between HLA-Cw*04 and HLA-Cw*16 in both definite and probable Meniere’s disease compared to normal healthy controls. We observed a significant difference in HLA-Cw*12 frequencies between patients with definite Meniere’s disease compared to patients with probable Meniere’s disease (P=0.04). The frequency of HLA-Cw*18 is significantly higher in healthy controls (P=0.002). Conclusion: Our findings support the rule of HLA-Cw Alleles in both definite and probable Meniere’s disease. In addition, differences in HLA-Cw*12 frequency in definite and probable Meniere’s disease in our study’s population might indicate distinct immune and inflammatory mechanisms involved in each condition. PMID:27602337

  8. Five-year tracking of Plasmodium falciparum allele frequencies in a holoendemic area with indistinct seasonal transitions

    PubMed Central

    Akala, Hoseah M; Achieng, Angela O; Eyase, Fredrick L; Juma, Dennis W; Ingasia, Luiser; Cheruiyot, Agnes C; Okello, Charles; Omariba, Duke; Owiti, Eunice A; Muriuki, Catherine; Yeda, Redemptah; Andagalu, Ben; Johnson, Jacob D; Kamau, Edwin

    2014-01-01

    Background The renewed malaria eradication efforts require an understanding of the seasonal patterns of frequency of polymorphic variants in order to focus limited funds productively. Although cross-sectional studies in holoendemic areas spanning a single year could be useful in describing parasite genotype status at a given point, such information is inadequate in describing temporal trends in genotype polymorphisms. For Plasmodium falciparum isolates from Kisumu District Hospital, Plasmodium falciparum chloroquine-resistance transporter gene (Pfcrt-K76T) and P. falciparum multidrug resistance gene 1 (PfMDR1-N86Y), were analyzed for polymorphisms and parasitemia changes in the 53 months from March 2008 to August 2012. Observations were compared with prevailing climatic factors, including humidity, rainfall, and temperature. Methods Parasitemia (the percentage of infected red blood cells per total red blood cells) was established by microscopy for P. falciparum malaria-positive samples. P. falciparum DNA was extracted from whole blood using a Qiagen DNA Blood Mini Kit. Single nucleotide polymorphism identification at positions Pfcrt-K76T and PfMDR1-N86Y was performed using real-time polymerase chain reaction and/or sequencing. Data on climatic variables were obtained from http://www.tutiempo.net/en/. Results A total of 895 field isolates from 2008 (n=169), 2009 (n=161), 2010 (n=216), 2011 (n=223), and 2012 (n=126) showed large variations in monthly frequency of PfMDR1-N86Y and Pfcrt-K76T as the mutant genotypes decreased from 68.4%±15% and 38.1%±13% to 29.8%±18% and 13.3%±9%, respectively. The mean percentage of parasitemia was 2.61%±1.01% (coefficient of variation 115.86%; n=895). There was no correlation between genotype or parasitemia and climatic factors. Conclusion This study shows variability in the frequency of Pfcrt-K76T and PfMDR1-N86Y polymorphisms during the study period, bringing into focus the role of cross-sectional studies in describing temporal

  9. Quantitative Sequencing for the Determination of Kdr-type Resistance Allele (V419L, L925I, I936F) Frequencies in Common Bed Bug (Hemiptera: Cimicidae) Populations Collected from Israel.

    PubMed

    Palenchar, Daniel J; Gellatly, Kyle J; Yoon, Kyong Sup; Mumcuoglu, Kosta Y; Shalom, Uri; Clark, J Marshall

    2015-09-01

    Human bed bug infestations have dramatically increased worldwide since the mid-1990s. A similar phenomenon was also observed in Israel since 2005, when infestations were reported from all over the country. Two single nucleotide polymorphisms (V419L and L925I) in the bed bug voltage-sensitive sodium channel confer kdr-type resistance to pyrethroids. Using quantitative sequencing (QS), the resistance allele frequencies of Israeli bed bug populations from across the country were determined. Genomic DNA was extracted from samples of 12 populations of bed bugs collected from Israel and DNA fragments containing the V419L or L925I and I936F mutations sites were PCR amplified. The PCR products were analyzed by QS and the nucleotide signal ratios calculated and used to predict the resistance allele frequencies of the unknown populations. Results of the genetic analysis show that resistant nucleotide signals are highly correlated to resistance allele frequencies for both mutations. Ten of the 12 tested populations had 100% of the L925I mutation and 0% of the V419L mutation. One population was heterogeneous for the L925I mutation and had 0% of the V419L mutation and another population was heterogeneous for the V419L mutation and had 100% of the L925I mutation. I936F occurred only at low levels. These results indicate that bed bugs in Israel are genetically resistant to pyrethroids. Thus, pyrethroids should only be used for bed bug management with caution using effective application and careful monitoring procedures. Additionally, new and novel-acting insecticides and nonchemical means of controlling bed bugs should be explored. PMID:26336243

  10. Temporal changes in allele frequencies in a small marble trout Salmo marmoratus population threatened by extreme flood events.

    PubMed

    Pujolar, J M; Vincenzi, S; Zane, L; Crivelli, A J

    2016-03-01

    The effect of extreme floods on the genetic composition of marble trout Salmo marmoratus living in Lipovscek, a tributary of the Soca River in Slovenia, which has been affected by multiple destructive flood events for centuries was investigated. By monitoring genetic variability during the period 2004-2011, apparent signatures of genetic erosion including a decline in observed and expected heterozygosities and allelic richness were observed. Contemporary effective population size was estimated between 11 and 55 individuals, which is congruent with census data. The data suggest asymmetric gene flow between the two sections of the river. The existence of substantial downstream migration (15-19%) was confirmed by paternity analysis. A small (1-3%) upstream migration was also suggested, which was confirmed by tagging data. Overall, low genetic diversity has not prevented the survival of the Lipovscek population, which might be a common feature of salmonid freshwater populations. PMID:26832308

  11. Global patterns of variation in allele and haplotype frequencies and linkage disequilibrium across the CYP2E1 gene

    PubMed Central

    Lee, Mi-Young; Mukherjee, Namita; Pakstis, Andrew J.; Khaliq, Shagufta; Mohyuddin, Aisha; Mehdi, S. Qasim; Speed, William C.; Kidd, Judith R.; Kidd, Kenneth K.

    2009-01-01

    Cytochrome P450 2E1, gene symbol CYP2E1, is one of a family of enzymes with a central role in activating and detoxifying xenobiotics and endogenous compounds. Genetic variation at this gene has been reported in different human populations, and some association studies have reported increased risk for cancers and other diseases. To the best of our knowledge, multi-SNP haplotypes and linkage disequilibrium (LD) have not been systematically studied for CYP2E1 in multiple populations. Haplotypes can greatly increase the power both to identify patterns of genetic variation relevant for gene expression as well as to detect disease-related susceptibility mutations. We present frequency and LD data and analyses for 11 polymorphisms and their haplotypes that we have studied on over 2,600 individuals from 50 human population samples representing the major geographical regions of the world. The diverse patterns of haplotype variation found in the different populations we have studied show that ethnicity may be an important variable helping to explain inconsistencies that have been reported by association studies. More studies clearly are needed of the variants we have studied, especially those in the 5′ region, such as the VNTR, as well as studies of additional polymorphisms known for this gene to establish evidence relating any systematic differences in gene expression that exist to the haplotypes at this gene. PMID:18663376

  12. Sequencing of Sylvilagus VDJ genes reveals a new VHa allelic lineage and shows that ancient VH lineages were retained differently in leporids.

    PubMed

    Pinheiro, Ana; Melo-Ferreira, José; Abrantes, Joana; Martinelli, Nicola; Lavazza, Antonio; Alves, Paulo C; Gortázar, Christian; Esteves, Pedro J

    2014-12-01

    Antigen recognition by immunoglobulins depends upon initial rearrangements of heavy chain V, D, and J genes. In leporids, a unique system exists for the VH genes usage that exhibit highly divergent lineages: the VHa allotypes, the Lepus sL lineage and the VHn genes. For the European rabbit (Oryctolagus cuniculus), four VHa lineages have been described, the a1, a2, a3 and a4. For hares (Lepus sp.), one VHa lineage was described, the a2L, as well as a more ancient sL lineage. Both genera use the VHn genes in a low frequency of their VDJ rearrangements. To address the hypothesis that the VH specificities could be associated with different environments, we sequenced VDJ genes from a third leporid genus, Sylvilagus. We found a fifth and equally divergent VHa lineage, the a5, and an ancient lineage, the sS, related to the hares' sL, but failed to obtain VHn genes. These results show that the studied leporids employ different VH lineages in the generation of the antibody repertoire, suggesting that the leporid VH genes are subject to strong selective pressure likely imposed by specific pathogens. PMID:25267061

  13. High frequency of allelic imbalance at chromosome region 16q22-23 in human breast cancer: correlation with high PgR and low S phase.

    PubMed

    Skirnisdottir, S; Eiriksdottir, G; Baldursson, T; Barkardottir, R B; Egilsson, V; Ingvarrson, S

    1995-04-21

    The loss of genetic material from a specific chromosome region in tumors suggests that presence of tumor-suppressor genes. Loss of heterozygosity (LOH) or allelic imbalance (AI) on the long arm of chromosome 16 is a known event in sporadic breast cancer. To locate the commonly deleted regions, and therefore (a) candidate tumor-suppressor gene(s), a deletion map of chromosome 16 was made, using 10 microsatellite markers on 150 sporadic breast tumors. The 3 smallest regions of overlap (SRO) were detected on the long arm of chromosome 16. Allelic imbalance was observed with at least one marker in 67% of the tumors. One marker, D16S421, at the 16q22-23 region, showed the highest allelic imbalance, 58%. Tumors with and without AI on 16q were tested for correlation with clinico-pathological features of the tumors such as estrogen- and progesterone-receptor content (ER and PgR), age at diagnosis, tumor size, node status, histological type, S-phase fraction, AI on chromosome 3p, and ploidy. A correlation was found between AI on 16q and high PgR content, also low S-phase fraction (99% confidence limits). A comparison of tumors with and without AI at the D16S421 marker locus revealed a slight correlation with high PgR content. The survival data showed no difference between patients with AI on 16q and those with a normal allele pattern on the long arm of chromosome 16. PMID:7615353

  14. HLA-A, B and DRB1 allele and haplotype frequencies in volunteer bone marrow donors from the north of Parana State

    PubMed Central

    Bardi, Marlene Silva; Jarduli, Luciana Ribeiro; Jorge, Adylson Justino; Camargo, Rossana Batista Oliveira Godoy; Carneiro, Fernando Pagotto; Gelinski, Jair Roberto; Silva, Roseclei Assunção Feliciano; Lavado, Edson Lopes

    2012-01-01

    Background Knowledge of allele and haplotype frequencies of the human leukocyte antigen (HLA) system is important in the search for unrelated bone marrow donors. The Brazilian population is very heterogeneous and the HLA system is highly informative of populations because of the high level of polymorphisms. Aim The aim of this study was to characterize the immunogenetic profile of ethnic groups (Caucasians, Afro-Brazilians and Asians) in the north of Parana State. Methods A study was carried out of 3978 voluntary bone marrow donors registered in the Brazilian National Bone Marrow Donor Registry and typed for the HLA-A, B and DRB1 (low resolution) loci. The alleles were characterized by the polymerase chain reaction sequence-specific oligonucleotides method using the LabType SSO kit (One Lambda, CA, USA). The ARLEQUIN v.3.11 computer program was used to calculate allele and haplotype frequencies Results The most common alleles found in Caucasians were HLA-A*02, 24, 01; HLA-B*35, 44, 51; DRB1*11, 13, 07; for Afro-Brazilians they were HLA-A*02, 03, 30; HLA-B*35, 15, 44; DRB1*13, 11, 03; and for Asians they were: HLA-A*24, 02, 26; HLA-B*40, 51, 52; DRB1*04, 15, 09. The most common haplotype combinations were: HLA-A*01, B*08, DRB1*03 and HLA-A*29, B*44, DRB1*07 for Caucasians; HLA-A*29, B*44, DRB1*07 and HLA-A*01, B*08 and DRB1*03 for Afro-Brazilians; and HLA-A*24, B*52, DRB1*15 and HLA-A*24, B*40 and DRB1*09 for Asians. Conclusion There is a need to target and expand bone marrow donor campaigns in the north of Parana State. The data of this study may be used as a reference by the Instituto Nacional de Cancer/Brazilian National Bone Marrow Donor Registry to evaluate the immunogenetic profile of populations in specific regions and in the selection of bone marrow donors PMID:23049380

  15. Huvariome: a web server resource of whole genome next-generation sequencing allelic frequencies to aid in pathological candidate gene selection

    PubMed Central

    2012-01-01

    Background Next generation sequencing provides clinical research scientists with direct read out of innumerable variants, including personal, pathological and common benign variants. The aim of resequencing studies is to determine the candidate pathogenic variants from individual genomes, or from family-based or tumor/normal genome comparisons. Whilst the use of appropriate controls within the experimental design will minimize the number of false positive variations selected, this number can be reduced further with the use of high quality whole genome reference data to minimize false positives variants prior to candidate gene selection. In addition the use of platform related sequencing error models can help in the recovery of ambiguous genotypes from lower coverage data. Description We have developed a whole genome database of human genetic variations, Huvariome, determined by whole genome deep sequencing data with high coverage and low error rates. The database was designed to be sequencing technology independent but is currently populated with 165 individual whole genomes consisting of small pedigrees and matched tumor/normal samples sequenced with the Complete Genomics sequencing platform. Common variants have been determined for a Benelux population cohort and represented as genotypes alongside the results of two sets of control data (73 of the 165 genomes), Huvariome Core which comprises 31 healthy individuals from the Benelux region, and Diversity Panel consisting of 46 healthy individuals representing 10 different populations and 21 samples in three Pedigrees. Users can query the database by gene or position via a web interface and the results are displayed as the frequency of the variations as detected in the datasets. We demonstrate that Huvariome can provide accurate reference allele frequencies to disambiguate sequencing inconsistencies produced in resequencing experiments. Huvariome has been used to support the selection of candidate cardiomyopathy

  16. Life satisfaction in the new country: a multilevel longitudinal analysis of effects of culture and 5-HTT allele frequency distribution in country of origin.

    PubMed

    Kashima, Emiko S; Kent, Stephen; Kashima, Yoshihisa

    2015-01-01

    Life satisfaction of migrants to Australia from 17 countries, assessed at 4-5 months, 16-17 months and 3½ years after arrival, was analyzed with a longitudinal, multilevel analysis. The results indicated that migrants were more satisfied, if the national average life satisfaction was higher in their country of origin, after adjustment for individual-level income, age, and sex and a linear temporal trend. Simultaneously, the migrants were also happier if people in their country of origin had a higher frequency of 5-HTT long allele, a genotype known to be associated with resilience under life stresses. These two relationships were independent, suggesting that both culture and gene matter in international transitions. PMID:24532702

  17. Life satisfaction in the new country: a multilevel longitudinal analysis of effects of culture and 5-HTT allele frequency distribution in country of origin

    PubMed Central

    Kent, Stephen; Kashima, Yoshihisa

    2015-01-01

    Life satisfaction of migrants to Australia from 17 countries, assessed at 4–5 months, 16–17 months and 3½ years after arrival, was analyzed with a longitudinal, multilevel analysis. The results indicated that migrants were more satisfied, if the national average life satisfaction was higher in their country of origin, after adjustment for individual-level income, age, and sex and a linear temporal trend. Simultaneously, the migrants were also happier if people in their country of origin had a higher frequency of 5-HTT long allele, a genotype known to be associated with resilience under life stresses. These two relationships were independent, suggesting that both culture and gene matter in international transitions. PMID:24532702

  18. High-Resolution Analyses of Human Leukocyte Antigens Allele and Haplotype Frequencies Based on 169,995 Volunteers from the China Bone Marrow Donor Registry Program

    PubMed Central

    Zhou, Xiao-Yang; Zhu, Fa-Ming; Li, Jian-Ping; Mao, Wei; Zhang, De-Mei; Liu, Meng-Li; Hei, Ai-Lian; Dai, Da-Peng; Jiang, Ping; Shan, Xiao-Yan; Zhang, Bo-Wei; Zhu, Chuan-Fu; Shen, Jie; Deng, Zhi-Hui; Wang, Zheng-Lei; Yu, Wei-Jian; Chen, Qiang; Qiao, Yan-Hui; Zhu, Xiang-Ming; Lv, Rong; Li, Guo-Ying; Li, Guo-Liang; Li, Heng-Cong; Zhang, Xu; Pei, Bin; Jiao, Li-Xin; Shen, Gang; Liu, Ying; Feng, Zhi-Hui; Su, Yu-Ping; Xu, Zhao-Xia; Di, Wen-Ying; Jiang, Yao-Qin; Fu, Hong-Lei; Liu, Xiang-Jun; Liu, Xiang; Zhou, Mei-Zhen; Du, Dan; Liu, Qi; Han, Ying; Zhang, Zhi-Xin; Cai, Jian-Ping

    2015-01-01

    Allogeneic hematopoietic stem cell transplantation is a widely used and effective therapy for hematopoietic malignant diseases and numerous other disorders. High-resolution human leukocyte antigen (HLA) haplotype frequency distributions not only facilitate individual donor searches but also determine the probability with which a particular patient can find HLA-matched donors in a registry. The frequencies of the HLA-A, -B, -C, -DRB1, and -DQB1 alleles and haplotypes were estimated among 169,995 Chinese volunteers using the sequencing-based typing (SBT) method. Totals of 191 HLA-A, 244 HLA-B, 146 HLA-C, 143 HLA-DRB1 and 47 HLA-DQB1 alleles were observed, which accounted for 6.98%, 7.06%, 6.46%, 9.11% and 7.91%, respectively, of the alleles in each locus in the world (IMGT 3.16 Release, Apr. 2014). Among the 100 most common haplotypes from the 169,995 individuals, nine distinct haplotypes displayed significant regionally specific distributions. Among these, three were predominant in the South China region (i.e., the 20th, 31st, and 81sthaplotypes), another three were predominant in the Southwest China region (i.e., the 68th, 79th, and 95th haplotypes), one was predominant in the South and Southwest China regions (the 18th haplotype), one was relatively common in the Northeast and North China regions (the 94th haplotype), and one was common in the Northeast, North and Northwest China (the 40th haplotype). In conclusion, this is the first to analyze high-resolution HLA diversities across the entire country of China, based on a detailed and complete data set that covered 31 provinces, autonomous regions, and municipalities. Specifically, we also evaluated the HLA matching probabilities within and between geographic regions and analyzed the regional differences in the HLA diversities in China. We believe that the data presented in this study might be useful for unrelated HLA-matched donor searches, donor registry planning, population genetic studies, and anthropogenesis

  19. Eleutherodactylus frogs show frequency but no temporal partitioning: implications for the acoustic niche hypothesis

    PubMed Central

    2014-01-01

    Individuals in acoustic communities compete for the use of the sound resource for communication, a problem that can be studied as niche competition. The acoustic niche hypothesis presents a way to study the partitioning of the resource, but the studies have to take into account the three dimensions of this niche: time, acoustic frequency, and space. I used an Automated Digital Recording System to determine the partitioning of time and acoustic frequency of eight frogs of the genus Eleutherodactylus from Puerto Rico. The calling activity was measured using a calling index. The community exhibited no temporal partitioning since most species called at the same time, between sunset and midnight. The species partitioned the acoustic frequency of their signals, which, in addition to the microhabitat partitioning, can provide some insight into how these species deal with the problem. This data also suggest that monitoring projects with this group should take place only before midnight to avoid false negatives. PMID:25101228

  20. Prevalence and allele frequency estimation of bovine leukocyte adhesion deficiency (BLAD) in Holstein-Friesian cattle in Japan.

    PubMed

    Nagahata, H; Miura, T; Tagaki, K; Ohtake, M; Noda, H; Yasuda, T; Nioka, K

    1997-04-01

    Blood samples from 796 Holstein dairy cows in 20 herds from 6 districts in Japan from June 1994 to August 1995 were examined to determine whether they were BLAD-free, BLAD carriers, or BLAD-affected by use of DNA-polymerase chain reaction (PCR) analysis. The usage of semen of confirmed BLAD-carriers for artificial insemination in the Hokkaido district and two selected dairy farms was examined to estimate the gene frequency of BLAD carriers of sires. BLAD-carrier prevalence in 20 herds (796 cows, over 2.5 years old) ranged from 0 to 23.5%, and the mean BLAD-carrier prevalence was 8.1%. The BLAD-carrier prevalence in 10 herds (363 cows) in which the occurrence of BLAD was not detected by the DNA-PCR test ranged from 0 to 12.5% with a mean of 5.4%. The BLAD-carrier prevalence in 10 herds (433 cows) in which the occurrence of BLAD was confirmed by DNA-PCR analysis ranged from 2.6 to 23.5% with a mean of 10.8%, and these values were significantly (P < 0.05) higher than those of dairy herds in which the occurrence of BLAD was not detected. The age distribution in BLAD carriers in these cows ranged from 2.5 to 11 years. The mean gene frequencies of BLAD among 796 cows from 20 herds and 433 cows from 10 herds in which the occurrence of BLAD was detected were 0.041 and 0.054, respectively. The proportional usage of semen of BLAD carriers for artificial insemination in the Hokkaido district in 1992 was 12.6%, and its gene frequency was 0.058. On two selected farms in which higher BLAD-carrier rates were detected, the prevalences were 35.5% and 25.8%, and their gene frequencies were 0.177 and 0.129, respectively. The occurrence of BLAD-affected in Holstein dairy cattle was estimated to be 0.16-0.31% at birth in Japan without genetic control. PMID:9152929

  1. Big data integration shows Australian bush-fire frequency is increasing significantly.

    PubMed

    Dutta, Ritaban; Das, Aruneema; Aryal, Jagannath

    2016-02-01

    Increasing Australian bush-fire frequencies over the last decade has indicated a major climatic change in coming future. Understanding such climatic change for Australian bush-fire is limited and there is an urgent need of scientific research, which is capable enough to contribute to Australian society. Frequency of bush-fire carries information on spatial, temporal and climatic aspects of bush-fire events and provides contextual information to model various climate data for accurately predicting future bush-fire hot spots. In this study, we develop an ensemble method based on a two-layered machine learning model to establish relationship between fire incidence and climatic data. In a 336 week data trial, we demonstrate that the model provides highly accurate bush-fire incidence hot-spot estimation (91% global accuracy) from the weekly climatic surfaces. Our analysis also indicates that Australian weekly bush-fire frequencies increased by 40% over the last 5 years, particularly during summer months, implicating a serious climatic shift. PMID:26998312

  2. Chronic alcohol self-administration in monkeys shows long-term quantity/frequency categorical stability

    PubMed Central

    Baker, Erich J.; Farro, Jonathan; Gonzales, Steven; Helms, Christa; Grant, Kathleen A.

    2014-01-01

    Background The current criteria for alcohol use disorders (AUD) do not include consumption (quantity/frequency) measures of alcohol intake, in part due to the difficulty of these measures in humans. Animal models of ethanol self-administration have been fundamental in advancing our understanding of the neurobiological basis of (AUD) and can address quantity/frequency measures with accurate measurements over prolonged periods of time. The non-human primate (NHP) model of voluntary oral alcohol self-administration has documented both binge drinking and drinking to dependence and can be used to test the stability of consumption measures over time. Methods and Results Here, an extensive set of alcohol intakes (g/kg/day) was analyzed from a large multi-cohort population of Rhesus (Macaca mulatta) monkeys (n=31). Daily ethanol intake was uniformly distributed over chronic (12 months) access for all animals. Underlying this distribution of intakes were subpopulations of monkeys that exhibited distinctive clustering of drinking patterns, allowing us to categorically define very heavy drinking (VHD), heavy drinking (HD), binge drinking (BD), and low drinking (LD). These categories were stable across the 12-month assessed by the protocol, but exhibited fluctuations when examined at shorter intervals. Conclusions The establishment of persistent drinking categories based on quantity/frequency suggests that consumption variables can be used to track long-term changes in behavioral, molecular or physiochemical mechanisms related to our understanding of diagnosis, prevention, intervention and treatment efficacies. PMID:25421519

  3. Big data integration shows Australian bush-fire frequency is increasing significantly

    PubMed Central

    Dutta, Ritaban; Das, Aruneema; Aryal, Jagannath

    2016-01-01

    Increasing Australian bush-fire frequencies over the last decade has indicated a major climatic change in coming future. Understanding such climatic change for Australian bush-fire is limited and there is an urgent need of scientific research, which is capable enough to contribute to Australian society. Frequency of bush-fire carries information on spatial, temporal and climatic aspects of bush-fire events and provides contextual information to model various climate data for accurately predicting future bush-fire hot spots. In this study, we develop an ensemble method based on a two-layered machine learning model to establish relationship between fire incidence and climatic data. In a 336 week data trial, we demonstrate that the model provides highly accurate bush-fire incidence hot-spot estimation (91% global accuracy) from the weekly climatic surfaces. Our analysis also indicates that Australian weekly bush-fire frequencies increased by 40% over the last 5 years, particularly during summer months, implicating a serious climatic shift. PMID:26998312

  4. alpha1-antitrypsin (PI) alleles as markers of Westeuropean influence in the Baltic Sea region.

    PubMed

    Beckman, L; Sikström, C; Mikelsaar, A; Krumina, A; Kucinskas, V; Beckman, G

    1999-01-01

    The distribution of alpha1-antitrypsin (PI) alleles was studied in an attempt to elucidate migrations and admixture between populations in the Baltic Sea region. The frequency of the PI Z allele, a typically Northwesteuropean marker gene, showed a highly significant regional variation in the Baltic Sea region. The highest frequency (4.5%) was found in the western part of Latvia (Courland). The PI S allele, another marker of Westeuropean influence, also showed an increased frequency in the Courland population. These results indicate that among the populations east of the Baltic Sea the Curonian population has the most pronounced Westeuropean influence. Archaeological data have shown that from the 7th century and for several hundreds of years Courland received immigrations from mainland Sweden and the island of Gotland. We speculate that the increased frequencies of the PI Z alleles and S alleles in Courland may have been caused by these migrations. PMID:9858859

  5. Identification of the third/extra allele for forensic application in cases with TPOX tri-allelic pattern.

    PubMed

    Picanço, Juliane Bentes; Raimann, Paulo Eduardo; da Motta, Carlos Henrique Ares Silveira; Rodenbusch, Rodrigo; Gusmão, Leonor; Alho, Clarice Sampaio

    2015-05-01

    Genotyping of polymorphic short tandem repeats (STRs) loci is widely used in forensic DNA analysis. STR loci eventually present tri-allelic pattern as a genotyping irregularity and, in that situation, the doubt about the tri-allele locus frequency calculation can reduce the analysis strength. In the TPOX human STR locus, tri-allelic genotypes have been reported with a widely varied frequency among human populations. We investigate whether there is a single extra allele (the third allele) in the TPOX tri-allelic pattern, what it is, and where it is, aiming to understand its genomic anatomy and to propose the knowledge of this TPOX extra allele from genetic profile, thus preserving the two standard TPOX alleles in forensic analyses. We looked for TPOX tri-allelic subjects in 75,113 Brazilian families. Considering only the parental generation (mother+father) we had 150,226 unrelated subjects evaluated. From this total, we found 88 unrelated subjects with tri-allelic pattern in the TPOX locus (0.06%; 88/150,226). Seventy three of these 88 subjects (73/88; 83%) had the Clayton's original Type 2 tri-allelic pattern (three peaks of even intensity). The remaining 17% (15/88) show a new Type 2 derived category with heterozygote peak imbalance (one double dose peak plus one regular sized peak). In this paper we present detailed data from 66 trios (mother+father+child) with true biological relationships. In 39 of these families (39/66; 59%) the extra TPOX allele was transmitted either from the mother or from the father to the child. Evidences indicated the allele 10 as the extra TPOX allele, and it is on the X chromosome. The present data, which support the previous Lane hypothesis, improve the knowledge about tri-allelic pattern of TPOX CODIS' locus allowing the use of TPOX profile in forensic analyses even when with tri-allelic pattern. This evaluation is now available for different forensic applications. PMID:25549886

  6. Frequency of alleles conferring resistance to the Bacillus thuringiensis toxins Cry1Ac and Cry2Ab in Australian populations of Helicoverpa punctigera (Lepidoptera: Noctuidae) from 2002 to 2006.

    PubMed

    Downes, S; Parker, T L; Mahon, R J

    2009-04-01

    Helicoverpa punctigera and Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) are important pests of field and horticultural crops in Australia. The former is endemic to the continent, whereas the latter is also distributed in Africa and Asia. Although H. armigera rapidly developed resistance to virtually every group of insecticide used against it, there is only one report of resistance to an insecticide in H. punctigera. In 1996 the Australian cotton industry adopted Ingard, which expresses the Bacillus thuringiensis (Bt) toxin gene cry1Ac. In 2004/2005, Bollgard II (which expresses Cry1Ac and Cry2Ab) replaced Ingard and has subsequently been grown on 80% of the area planted to cotton, Gossypium hirsutum L. From 2002/2003 to 2006/2007, F2 screens were used to detect resistance to Cry1Ac or Cry2Ab. We detected no alleles conferring resistance to Cry1Ac; the frequency was < 0.0005 (n = 2,180 alleles), with a 95% credibility interval between 0 and 0.0014. However, during the same period, we detected alleles that confer resistance to Cry2Ab at a frequency of 0.0018 (n = 2,192 alleles), with a 95% credibility interval between 0.0005 and 0.0040. For both toxins, the experiment-wise detection probability was 94%, i.e., if there actually was a resistance allele in any tested lines, we would have detected it 94% of the time. The first isolation of Cry2Ab resistance in H. punctigera was before the widespread deployment of Bollgard II. This finding supports our published notion for H. armigera that alleles conferring resistance to Cry2Ab may be present at detectable frequencies in populations before selection by transgenic crops. PMID:19449655

  7. Analysis of the distribution of HLA-A alleles in populations from five continents.

    PubMed

    Middleton, D; Williams, F; Meenagh, A; Daar, A S; Gorodezky, C; Hammond, M; Nascimento, E; Briceno, I; Perez, M P

    2000-10-01

    The variation and frequency of HLA-A genotypes were established by PCR-SSOP typing in diverse geographically distributed populations: Brazilian, Colombian Kogui, Cuban, Mexican, Omani, Singapore Chinese, and South African Zulu. HLA-A allelic families with only one allele were identified for HLA-A*01, -A*23, -A*25, -A*31, -A*32, -A*36, -A*43, -A*69, -A*80; and with two alleles for HLA-A*03, -A*11, -A*26, -A*29, -A*33, -A*34, and -A*66. Greater variation was detected for HLA-A*02, -A*24, and -A*68 allele families. Colombian Kogui and Mexican Seris showed the least diversity with respect to HLA-A alleles, albeit with small numbers tested, with only four and five HLA-A alleles identified, respectively. It would appear by their presence in all populations studied, either rural or indigenous, that certain alleles are very important in pathogen peptide presentation. PMID:11082518

  8. Type 2 diabetes risk alleles demonstrate extreme directional differentiation among human populations, compared to other diseases.

    PubMed

    Chen, Rong; Corona, Erik; Sikora, Martin; Dudley, Joel T; Morgan, Alex A; Moreno-Estrada, Andres; Nilsen, Geoffrey B; Ruau, David; Lincoln, Stephen E; Bustamante, Carlos D; Butte, Atul J

    2012-01-01

    Many disease-susceptible SNPs exhibit significant disparity in ancestral and derived allele frequencies across worldwide populations. While previous studies have examined population differentiation of alleles at specific SNPs, global ethnic patterns of ensembles of disease risk alleles across human diseases are unexamined. To examine these patterns, we manually curated ethnic disease association data from 5,065 papers on human genetic studies representing 1,495 diseases, recording the precise risk alleles and their measured population frequencies and estimated effect sizes. We systematically compared the population frequencies of cross-ethnic risk alleles for each disease across 1,397 individuals from 11 HapMap populations, 1,064 individuals from 53 HGDP populations, and 49 individuals with whole-genome sequences from 10 populations. Type 2 diabetes (T2D) demonstrated extreme directional differentiation of risk allele frequencies across human populations, compared with null distributions of European-frequency matched control genomic alleles and risk alleles for other diseases. Most T2D risk alleles share a consistent pattern of decreasing frequencies along human migration into East Asia. Furthermore, we show that these patterns contribute to disparities in predicted genetic risk across 1,397 HapMap individuals, T2D genetic risk being consistently higher for individuals in the African populations and lower in the Asian populations, irrespective of the ethnicity considered in the initial discovery of risk alleles. We observed a similar pattern in the distribution of T2D Genetic Risk Scores, which are associated with an increased risk of developing diabetes in the Diabetes Prevention Program cohort, for the same individuals. This disparity may be attributable to the promotion of energy storage and usage appropriate to environments and inconsistent energy intake. Our results indicate that the differential frequencies of T2D risk alleles may contribute to the observed

  9. Type 2 Diabetes Risk Alleles Demonstrate Extreme Directional Differentiation among Human Populations, Compared to Other Diseases

    PubMed Central

    Chen, Rong; Corona, Erik; Sikora, Martin; Dudley, Joel T.; Morgan, Alex A.; Moreno-Estrada, Andres; Nilsen, Geoffrey B.; Ruau, David; Lincoln, Stephen E.; Bustamante, Carlos D.; Butte, Atul J.

    2012-01-01

    Many disease-susceptible SNPs exhibit significant disparity in ancestral and derived allele frequencies across worldwide populations. While previous studies have examined population differentiation of alleles at specific SNPs, global ethnic patterns of ensembles of disease risk alleles across human diseases are unexamined. To examine these patterns, we manually curated ethnic disease association data from 5,065 papers on human genetic studies representing 1,495 diseases, recording the precise risk alleles and their measured population frequencies and estimated effect sizes. We systematically compared the population frequencies of cross-ethnic risk alleles for each disease across 1,397 individuals from 11 HapMap populations, 1,064 individuals from 53 HGDP populations, and 49 individuals with whole-genome sequences from 10 populations. Type 2 diabetes (T2D) demonstrated extreme directional differentiation of risk allele frequencies across human populations, compared with null distributions of European-frequency matched control genomic alleles and risk alleles for other diseases. Most T2D risk alleles share a consistent pattern of decreasing frequencies along human migration into East Asia. Furthermore, we show that these patterns contribute to disparities in predicted genetic risk across 1,397 HapMap individuals, T2D genetic risk being consistently higher for individuals in the African populations and lower in the Asian populations, irrespective of the ethnicity considered in the initial discovery of risk alleles. We observed a similar pattern in the distribution of T2D Genetic Risk Scores, which are associated with an increased risk of developing diabetes in the Diabetes Prevention Program cohort, for the same individuals. This disparity may be attributable to the promotion of energy storage and usage appropriate to environments and inconsistent energy intake. Our results indicate that the differential frequencies of T2D risk alleles may contribute to the observed

  10. Areas V1 and V2 show microsaccade-related 3-4-Hz covariation in gamma power and frequency.

    PubMed

    Lowet, E; Roberts, M J; Bosman, C A; Fries, P; De Weerd, P

    2016-05-01

    Neuronal gamma-band synchronization (25-80 Hz) in visual cortex appears sustained and stable during prolonged visual stimulation when investigated with conventional averages across trials. However, recent studies in macaque visual cortex have used single-trial analyses to show that both power and frequency of gamma oscillations exhibit substantial moment-by-moment variation. This has raised the question of whether these apparently random variations might limit the functional role of gamma-band synchronization for neural processing. Here, we studied the moment-by-moment variation in gamma oscillation power and frequency, as well as inter-areal gamma synchronization, by simultaneously recording local field potentials in V1 and V2 of two macaque monkeys. We additionally analyzed electrocorticographic V1 data from a third monkey. Our analyses confirm that gamma-band synchronization is not stationary and sustained but undergoes moment-by-moment variations in power and frequency. However, those variations are neither random and nor a possible obstacle to neural communication. Instead, the gamma power and frequency variations are highly structured, shared between areas and shaped by a microsaccade-related 3-4-Hz theta rhythm. Our findings provide experimental support for the suggestion that cross-frequency coupling might structure and facilitate the information flow between brain regions. PMID:26547390

  11. Automated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles

    PubMed Central

    Gadala-Maria, Daniel; Yaari, Gur; Uduman, Mohamed; Kleinstein, Steven H.

    2015-01-01

    Individual variation in germline and expressed B-cell immunoglobulin (Ig) repertoires has been associated with aging, disease susceptibility, and differential response to infection and vaccination. Repertoire properties can now be studied at large-scale through next-generation sequencing of rearranged Ig genes. Accurate analysis of these repertoire-sequencing (Rep-Seq) data requires identifying the germline variable (V), diversity (D), and joining (J) gene segments used by each Ig sequence. Current V(D)J assignment methods work by aligning sequences to a database of known germline V(D)J segment alleles. However, existing databases are likely to be incomplete and novel polymorphisms are hard to differentiate from the frequent occurrence of somatic hypermutations in Ig sequences. Here we develop a Tool for Ig Genotype Elucidation via Rep-Seq (TIgGER). TIgGER analyzes mutation patterns in Rep-Seq data to identify novel V segment alleles, and also constructs a personalized germline database containing the specific set of alleles carried by a subject. This information is then used to improve the initial V segment assignments from existing tools, like IMGT/HighV-QUEST. The application of TIgGER to Rep-Seq data from seven subjects identified 11 novel V segment alleles, including at least one in every subject examined. These novel alleles constituted 13% of the total number of unique alleles in these subjects, and impacted 3% of V(D)J segment assignments. These results reinforce the highly polymorphic nature of human Ig V genes, and suggest that many novel alleles remain to be discovered. The integration of TIgGER into Rep-Seq processing pipelines will increase the accuracy of V segment assignments, thus improving B-cell repertoire analyses. PMID:25675496

  12. Fixation probability with multiple alleles and projected average allelic effect on selection.

    PubMed

    Lessard, Sabin; Lahaie, Philippe

    2009-06-01

    The first-order effect of selection on the probability of fixation of an allele, with respect to an intensity of selection s>0 in a diploid population of fixed finite size N, undergoing discrete, non-overlapping generations, is shown to be given by the sum of the average effects of that allele on the coefficient of selection in the current generation and all future generations, given the population state in the current generation. This projected average allelic effect is a weighted sum of average allelic effects in allozygous and autozygous offspring in the initial generation, with weights given in terms of expected coalescence times, under neutrality, for the lineages of two or three gametes chosen at random in the same generation. This is shown in the framework of multiple alleles at one locus, with genotypic values determining either viability or fertility differences, and with either multinomial or exchangeable reproduction schemes. In the limit of weak selection in a large population such that Ns tends to zero, the initial average allelic effects in allozygous offspring and autozygous offspring have the same weight on the fixation probability only in the domain of application of the Kingman coalescent. With frequency-dependent selection in a linear-game-theoretic context with two phenotypes determined by additive gene action, the first-order effect on the fixation probability is a combination of two effects of frequency-independent selection, one in a haploid population, the other in a diploid population. In the domain of application of the Kingman coalescent as the population size goes to infinity and Ns to zero, the first effect is three times more important than the second effect. This explains the one-third law of evolutionary dynamics in this domain, and shows how this law can be extended beyond this domain. PMID:19249322

  13. Linkage disequilibrium levels in Bos indicus and Bos taurus cattle using medium and high density SNP chip data and different minor allele frequency distributions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Linkage disequilibrium (LD), the observed correlation between alleles at different loci in the genome, is a determinant parameter in many applications of molecular genetics. With the wider use of genomic technologies in animal breeding and animal genetics, it is worthwhile revising and improving the...

  14. Effects of cigarette smoking on human in vivo somatic mutation: Longitudinal sampling of smokers demonstrates a decrease in glycophorin A (GPA) allele-loss variant cell frequencies following cessation

    SciTech Connect

    Bigbee, W.L.; Langlois, R.G. ); Grant, S.G.; Jensen, R.H. ); Mooney, L.M.; Perera, F.P. )

    1993-01-01

    The human in vivo glycophorin A (GPA) assay uses immunolabeling and flow cytometry to quantitate somatic variation in erythrocytes expressing GPA allele loss and allele-loss and duplication phenotypes in peripheral blood samples. The frequency of these variant erythrocytes (V[sub f]) presumably reflects the level of somatic mutation at this locus in the nucleated hematopoietic precursor cells of the bone marrow. We have previously shown that the GPA assay is a cumulative, integrating biodosimeter of accidental, medical, and occupational exposure to chemical mutagens and ionizing radiation. Surveys of otherwise unexposed populations point to an increased GPA allele loss V[sub f] in cigarette smokers compared to nonsmokers consistent with the induction of somatic mutation by mutagenic components of tobacco smoke. To further test this association, blood samples from active heavy smokers who entered a multi-endpoint Smokender study were obtained at enrollment and at 10 wks and 6 and 12 mo following smoking cessation. Results from the first 109 individuals reveal a decrease in the mean GPA allele loss V[sub f] ranging from 9.0 [+-] 1.0 [times] 10[sup [minus]6] (n = 109) for the active smoking samples, to 9.1 [+-] 1.8 [times] 10[sup [minus]6] (n = 46), 6.0 [+-] 0.7 [times] 10[sup [minus]6] (n = 15), and 5.8 [+-] 1.6 [times] 10[sup [minus]6] (n = 8) for the three postcessation samples, respectively. No change in the GPA allele loss and duplication V[sub f] was observed, thus confining the spectrum of mutational events induced by exposure to cigarette smoke. The observed decrease in the level of somatic mutation in smokers following cessation suggests limited persistence and/or repair of tobacco-smoke-induced genetic alterations consistent with epidemiologic findings of decreased cancer risk in smokers following cessation.

  15. Tetra-allelic SNPs: Informative forensic markers compiled from public whole-genome sequence data.

    PubMed

    Phillips, C; Amigo, J; Carracedo, Á; Lareu, M V

    2015-11-01

    Multiple-allele single nucleotide polymorphisms (SNPs) are potentially useful for forensic DNA analysis as they can provide more discrimination power than normal binary SNPs. In addition, the presence in a profile of more than two alleles per marker provides a clearer indication of mixed DNA than assessments of imbalanced signals in the peak pairs of binary SNPs. Using the 1000 Genomes Phase III human variant data release of 2014 as the starting point, this study collated 961 tetra-allelic SNPs that pass minimum sequence quality thresholds and where four separate nucleotide substitution alleles were detected. Although most of these loci had three of the four alleles in combined frequencies of 2% or less, 160 had high heterozygosities with 50 exceeding those of 'ideal' 0.5:0.5 binary SNPs. From this set of most polymorphic tetra-allelic SNPs, we identified markers most informative for forensic purposes and explored these loci in detail. Subsets of the most polymorphic tetra-allelic SNPs will make useful additions to current panels of forensic identification SNPs and ancestry-informative SNPs. The 24 most discriminatory tetra-allelic SNPs were estimated to detect more than two alleles in at least one marker per profile in 99.9% of mixtures of African contributors. In European contributor mixtures 99.4% of profiles would show multiple allele patterns, but this drops to 92.6% of East Asian contributor mixtures due to reduced levels of polymorphism for the 24 SNPs in this population group. PMID:26209763

  16. Anthelmintic resistance in Swedish sheep flocks based on a comparison of the results from the faecal egg count reduction test and resistant allele frequencies of the beta-tubulin gene.

    PubMed

    Höglund, Johan; Gustafsson, Katarina; Ljungström, Britt-Louise; Engström, Annie; Donnan, Alison; Skuce, Philip

    2009-04-01

    A faecal egg count reduction test (FECRT) survey was conducted during the grazing season 2006 and 2007 to provide an updated indication of the prevalence of anthelmintic resistance in sheep flocks in Sweden. A total of 1330 faecal samples from 90 flocks on 45 farms, with a minimum of 20 ewes each, was collected by local sheep veterinarians. Per treatment group, approximately 15 lambs were dewormed either with oral suspensions of ivermectin (Ivomec vet.) or albendazole (Valbazen vet.). The efficacy on each farm was investigated either in 2006 or 2007 by faecal egg counts collected on the day of treatment and in a new sample from the same animals 7-10 days later. Third-stage larvae (L3) were initially identified morphologically from pooled cultures. These were then used as the source of genomic DNA template for two molecular tests. The first was a PCR-based test for specific identification of Haemonchus contortus, and the second was a Pyrosequencing assay for the analysis of benzimidazole (BZ) resistance targeting the P200 mutation in the parasite's beta-tubulin gene. Larval cultures indicated that Teladorsagia and Trichostrongylus were the predominant genera, but Haemonchus was diagnosed in 37% of the flocks. The PCR results revealed an almost 100% agreement with those farms that had previously been shown to have Haemonchus present, even when the % prevalence was low (approximately 3%). Only two (4%) of the surveyed farms showed evidence of BZ-resistant worm populations, with H. contortus being the species implicated according to post-treatment larval culture results. The Pyrosequencing assay detected BZ resistant allele frequencies of >40% in the Haemonchus-positive farms and 100% resistant alleles in the clinically most resistant farms. These preliminary results suggest that the FECRT is less sensitive than the molecular test at detecting BZ resistance. However, both tests need to be interpreted carefully, bearing in mind the relative proportions of species

  17. Increasing long term response by selecting for favorable minor alleles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term response of genomic selection can be improved by considering allele frequencies of selected markers or quantitative trait loci (QTLs). A previous formula to weight allele frequency of favorable minor alleles was tested, and 2 new formulas were developed. The previous formula used nonlinear...

  18. Neurons in the inferior colliculus of the rat show stimulus-specific adaptation for frequency, but not for intensity

    PubMed Central

    Duque, Daniel; Wang, Xin; Nieto-Diego, Javier; Krumbholz, Katrin; Malmierca, Manuel S.

    2016-01-01

    Electrophysiological and psychophysical responses to a low-intensity probe sound tend to be suppressed by a preceding high-intensity adaptor sound. Nevertheless, rare low-intensity deviant sounds presented among frequent high-intensity standard sounds in an intensity oddball paradigm can elicit an electroencephalographic mismatch negativity (MMN) response. This has been taken to suggest that the MMN is a correlate of true change or “deviance” detection. A key question is where in the ascending auditory pathway true deviance sensitivity first emerges. Here, we addressed this question by measuring low-intensity deviant responses from single units in the inferior colliculus (IC) of anesthetized rats. If the IC exhibits true deviance sensitivity to intensity, IC neurons should show enhanced responses to low-intensity deviant sounds presented among high-intensity standards. Contrary to this prediction, deviant responses were only enhanced when the standards and deviants differed in frequency. The results could be explained with a model assuming that IC neurons integrate over multiple frequency-tuned channels and that adaptation occurs within each channel independently. We used an adaptation paradigm with multiple repeated adaptors to measure the tuning widths of these adaption channels in relation to the neurons’ overall tuning widths. PMID:27066835

  19. Experimental demonstration of a displacement noise free interferometry scheme for gravitational wave detectors showing displacement noise reduction at low frequencies

    SciTech Connect

    Perreca, Antonio; Chelkowski, Simon; Freise, Andreas; Hild, Stefan

    2010-03-15

    This paper reports an experimental demonstration of partial displacement noise free laser interferometry in the gravitational wave detection band. The used detuned Fabry-Perot cavity allows the isolation of the mimicked gravitational wave signal from the displacement noise on the cavities input mirror. By properly combining the reflected and transmitted signals from the cavity a reduction of the displacement noise was achieved. Our results represent the first experimental demonstration of this recently proposed displacement noise free laser interferometry scheme. Overall, we show that the rejection ratio of the displacement noise to the gravitational wave signal was improved in the frequency range of 10 Hz to 10 kHz with a typical factor of {approx}60.

  20. A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5

    PubMed Central

    Sigurdsson, Snaevar; Nordmark, Gunnel; Garnier, Sophie; Grundberg, Elin; Kwan, Tony; Nilsson, Olof; Eloranta, Maija-Leena; Gunnarsson, Iva; Svenungsson, Elisabet; Sturfelt, Gunnar; Bengtsson, Anders A.; Jönsen, Andreas; Truedsson, Lennart; Rantapää-Dahlqvist, Solbritt; Eriksson, Catharina; Alm, Gunnar; Göring, Harald H.H.; Pastinen, Tomi; Syvänen, Ann-Christine; Rönnblom, Lars

    2008-01-01

    Systemic lupus erythematosus (SLE) is the prototype autoimmune disease where genes regulated by type I interferon (IFN) are over-expressed and contribute to the disease pathogenesis. Because signal transducer and activator of transcription 4 (STAT4) plays a key role in the type I IFN receptor signaling, we performed a candidate gene study of a comprehensive set of single nucleotide polymorphism (SNPs) in STAT4 in Swedish patients with SLE. We found that 10 out of 53 analyzed SNPs in STAT4 were associated with SLE, with the strongest signal of association (P = 7.1 × 10−8) for two perfectly linked SNPs rs10181656 and rs7582694. The risk alleles of these 10 SNPs form a common risk haplotype for SLE (P = 1.7 × 10−5). According to conditional logistic regression analysis the SNP rs10181656 or rs7582694 accounts for all of the observed association signal. By quantitative analysis of the allelic expression of STAT4 we found that the risk allele of STAT4 was over-expressed in primary human cells of mesenchymal origin, but not in B-cells, and that the risk allele of STAT4 was over-expressed (P = 8.4 × 10−5) in cells carrying the risk haplotype for SLE compared with cells with a non-risk haplotype. The risk allele of the SNP rs7582694 in STAT4 correlated to production of anti-dsDNA (double-stranded DNA) antibodies and displayed a multiplicatively increased, 1.82-fold risk of SLE with two independent risk alleles of the IRF5 (interferon regulatory factor 5) gene. PMID:18579578

  1. 47 CFR 101.705 - Special showing for renewal of common carrier station facilities using frequency diversity.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... station facilities using frequency diversity. 101.705 Section 101.705 Telecommunication FEDERAL... facilities using frequency diversity. Any application for renewal of license, for a term commencing January 1, 1975, or after, involving facilities utilizing frequency diversity must contain a statement...

  2. 47 CFR 101.705 - Special showing for renewal of common carrier station facilities using frequency diversity.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... station facilities using frequency diversity. 101.705 Section 101.705 Telecommunication FEDERAL... facilities using frequency diversity. Any application for renewal of license, for a term commencing January 1, 1975, or after, involving facilities utilizing frequency diversity must contain a statement...

  3. 47 CFR 101.705 - Special showing for renewal of common carrier station facilities using frequency diversity.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... station facilities using frequency diversity. 101.705 Section 101.705 Telecommunication FEDERAL... facilities using frequency diversity. Any application for renewal of license, for a term commencing January 1, 1975, or after, involving facilities utilizing frequency diversity must contain a statement...

  4. High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.

    PubMed

    Apellániz-Ruiz, M; Inglada-Pérez, L; Naranjo, M E G; Sánchez, L; Mancikova, V; Currás-Freixes, M; de Cubas, A A; Comino-Méndez, I; Triki, S; Rebai, A; Rasool, M; Moya, G; Grazina, M; Opocher, G; Cascón, A; Taboada-Echalar, P; Ingelman-Sundberg, M; Carracedo, A; Robledo, M; Llerena, A; Rodríguez-Antona, C

    2015-06-01

    Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation. CYP3A4*20 was determined in more than 4000 individuals representing different populations, and haplotype analysis was performed using CYP3A polymorphisms and microsatellite markers. CYP3A4*20 allele was present in 1.2% of the Spanish population (up to 3.8% in specific regions), and all CYP3A4*20 carriers had a common haplotype. This is compatible with a Spanish founder effect and classifies CYP3A4 as a polymorphic enzyme. This constitutes the first description of a CYP3A4 loss-of-function variant with high frequency in a population. CYP3A4*20 results together with the key role of CYP3A4 in drug metabolism support screening for rare CYP3A4 functional alleles among subjects with adverse drug events in certain populations. PMID:25348618

  5. μ-Calpain, calpastatin, and growth hormone receptor genetic effects on preweaning performance, carcass quality traits, and residual variance of tenderness in Angus cattle selected to increase minor haplotype and allele frequencies.

    PubMed

    Tait, R G; Shackelford, S D; Wheeler, T L; King, D A; Casas, E; Thallman, R M; Smith, T P L; Bennett, G L

    2014-02-01

    Genetic marker effects and interactions are estimated with poor precision when minor marker allele frequencies are low. An Angus population was subjected to marker assisted selection for multiple years to increase divergent haplotype and minor marker allele frequencies to 1) estimate effect size and mode of inheritance for previously reported SNP on targeted beef carcass quality traits; 2) estimate effects of previously reported SNP on nontarget performance traits; and 3) evaluate tenderness SNP specific residual variance models compared to a single residual variance model for tenderness. Divergent haplotypes within µ-calpain (CAPN1), and SNP within calpastatin (CAST) and growth hormone receptor (GHR) were successfully selected to increase their frequencies. Traits evaluated were birth BW, weaning BW, final BW, fat thickness, LM area, USDA marbling score, yield grade, slice shear force (SSF), and visible and near infrared predicted slice shear force. Both CAPN1 and CAST exhibited additive (P < 0.001) modes of inheritance for SSF and neither exhibited dominance (P ≥ 0.19). Furthermore, the interaction between CAPN1 and CAST for SSF was not significant (P = 0.55). Estimated additive effects of CAPN1 (1.049 kg) and CAST (1.257 kg) on SSF were large in this study. Animals homozygous for tender alleles at both CAPN1 and CAST would have 4.61 kg lower SSF (38.6% of the mean) than animals homozygous tough for both markers. There was also an effect of CAST on yield grade (P < 0.02). The tender CAST allele was associated with more red meat yield and less trimmable fat. There were no significant effects (P ≥ 0.23) for GHR on any of the traits evaluated in this study. Furthermore, CAST specific residual variance models were found to fit significantly better (P < 0.001) than single residual variance models for SSF, with the tougher genotypes having larger residual variance. Thus, the risk of a tough steak from the undesired CAST genotype is increased through both an

  6. Data on IL-6 c.-174 G>C genotype and allele frequencies in patients with coronary heart disease in dependence of cardiovascular outcome.

    PubMed

    Reichert, Stefan; Schlitt, Axel; Benten, Ann-Christin; Hofmann, Britt; Schaller, Hans-Günter; Schulz, Susanne

    2016-09-01

    In this data article we present data on the distribution of alleles and genotypes of the interleukin (IL)-6 c.-174 G>C polymorphism (rs 1800795) in patients with coronary heart disease (CHD) in dependence of the incidence of new cardiovascular events (combined endpoint: myocardial infarction, stroke/TIA, cardiac death, death according to stroke) within three years follow-up. Moreover, we investigated putative associations between individual expression of IL-6 genotypes and IL-6 serum level. This investigation is a subanalysis of the article entitled "The Interleukin 6 c.-174 CC genotype is a predictor for new cardiovascular events in patients with coronary heart disease within three years follow-up" (ClinicalTrials.gov identifier: NCT01045070) (Reichert et al., 2016) [1]. PMID:27570807

  7. Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe.

    PubMed

    Ścieżyńska, Aneta; Oziębło, Dominika; Ambroziak, Anna M; Korwin, Magdalena; Szulborski, Kamil; Krawczyński, Maciej; Stawiński, Piotr; Szaflik, Jerzy; Szaflik, Jacek P; Płoski, Rafał; Ołdak, Monika

    2016-04-01

    Variation in the ABCA4 locus has emerged as the most prevalent cause of monogenic retinal diseases. The study aimed to discover causative ABCA4 mutations in a large but not previously investigated cohort with ABCA4-related diseases originating from Central Europe and to refine the genetic relevance of all identified variants based on population evidence. Comprehensive clinical studies were performed to identify patients with Stargardt disease (STGD, n = 76) and cone-rod dystrophy (CRD, n = 16). Next-generation sequencing targeting ABCA4 was applied for a widespread screening of the gene. The results were analyzed in the context of exome data from a corresponding population (n = 594) and other large genomic databases. Our data disprove the pathogenic status of p.V552I and provide more evidence against a causal role of four further ABCA4 variants as drivers of the phenotype under a recessive paradigm. The study identifies 12 novel potentially pathogenic mutations (four of them recurrent) and a novel complex allele p.[(R152*; V2050L)]. In one third (31/92) of our cohort we detected the p.[(L541P; A1038V)] complex allele, which represents an unusually high level of genetic homogeneity for ABCA4-related diseases. Causative ABCA4 mutations account for 79% of STGD and 31% of CRD cases. A combination of p.[(L541P; A1038V)] and/or a truncating ABCA4 mutation always resulted in an early disease onset. Identification of ABCA4 retinopathies provides a specific molecular diagnosis and justifies a prompt introduction of simple precautions that may slow disease progression. The comprehensive, population-specific study expands our knowledge on the genetic landscape of retinal diseases. PMID:26593885

  8. Allele surfing promotes microbial adaptation from standing variation.

    PubMed

    Gralka, Matti; Stiewe, Fabian; Farrell, Fred; Möbius, Wolfram; Waclaw, Bartlomiej; Hallatschek, Oskar

    2016-08-01

    The coupling of ecology and evolution during range expansions enables mutations to establish at expanding range margins and reach high frequencies. This phenomenon, called allele surfing, is thought to have caused revolutions in the gene pool of many species, most evidently in microbial communities. It has remained unclear, however, under which conditions allele surfing promotes or hinders adaptation. Here, using microbial experiments and simulations, we show that, starting with standing adaptive variation, range expansions generate a larger increase in mean fitness than spatially uniform population expansions. The adaptation gain results from 'soft' selective sweeps emerging from surfing beneficial mutations. The rate of these surfing events is shown to sensitively depend on the strength of genetic drift, which varies among strains and environmental conditions. More generally, allele surfing promotes the rate of adaptation per biomass produced, which could help developing biofilms and other resource-limited populations to cope with environmental challenges. PMID:27307400

  9. SLC40A1 Q248H allele frequencies and Q248H-associated risk of non-HFE iron overload in persons of sub-Saharan African descent.

    PubMed

    Barton, James C; Acton, Ronald T; Lee, Pauline L; West, Carol

    2007-01-01

    The ferroportin polymorphism SLC40A1 Q248H (exon 6, cDNA 744G-->T; Gln248His) occurs in persons of sub-Saharan African descent with and without iron overload, and is associated with elevated serum ferritin concentrations (SF). However, the risk of iron overload associated with Q248H has not been defined. We tabulated previously reported Q248H allele frequency estimates in African-Americans and Native Africans, and computed the risk of iron overload associated with Q248H in subjects who lacked HFE C282Y. The aggregate Q248H allele frequency in 1038 African-Americans in two cohorts from Alabama and one cohort each from Washington, DC and California was 0.0525 (95% CI: 0.0451, 0.0652); there was no significant difference in frequencies across these cohorts. The aggregate frequency in 259 Natives from southeast Africa in two cohorts was 0.0946 (95% CI: 0.0694, 0.1198); the difference between the frequencies of these cohorts was not significant. The aggregate Q248H frequencies in African-Americans and Native Africans differed significantly (0.0525 vs. 0.0946, respectively; p=0.0021). There were reports of 24 unrelated African-Americans and 15 unrelated Native Africans without HFE C282Y who had iron overload. In African-Americans, the odds ratio (OR) of Q248H-associated risk of iron overload using 610 C282Y-negative control subjects unselected for SF was 1.57 (95% CI: 0.52, 4.72; p=0.29). In Native Africans, the OR using 208 control subjects unselected for SF was 1.05 (95% CI: 0.28, 3.90; p=0.58). We conclude that the frequency of SLC40A1 Q248H is significantly lower in African-Americans than in Native Africans. Although OR estimates of iron overload in African-Americans and Native Africans with Q248H were greater than unity, the increased OR were not statistically significant. PMID:17490902

  10. The role of culture-gene coevolution in morality judgment: examining the interplay between tightness-looseness and allelic variation of the serotonin transporter gene.

    PubMed

    Mrazek, Alissa J; Chiao, Joan Y; Blizinsky, Katherine D; Lun, Janetta; Gelfand, Michele J

    2013-01-01

    This research provides novel insights into the evolutionary basis of cultural norm development and maintenance. We yield evidence for a unique culture-gene coevolutionary model between ecological threat, allelic frequency of the serotonin transporter polymorphism (5-HTTLPR), cultural tightness-looseness-the strength of norms and tolerance for deviance from norms-and moral justifiability. As hypothesized, the results across 21 nations show that: (a) propensity for ecological threat correlates with short (S) allele frequency in the 5-HTTLPR, (b) allelic frequency in the 5-HTTLPR and vulnerability to ecological threat both correlate with cultural tightness-looseness, (c) susceptibility to ecological threat predicts tightness-looseness via the mediation of S allele carriers, and (d) frequency of S allele carriers predicts justifiability of morally relevant behavior via tightness-looseness. This research highlights the importance of studying the interplay between environmental, genetic, and cultural factors underlying contemporary differences in social behavior and presents an empirical framework for future research. PMID:24404439

  11. Null allele, allelic dropouts or rare sex detection in clonal organisms: simulations and application to real data sets of pathogenic microbes

    PubMed Central

    2014-01-01

    Background Pathogens and their vectors are organisms whose ecology is often only accessible through population genetics tools based on spatio-temporal variability of molecular markers. However, molecular tools may present technical difficulties due to the masking of some alleles (allelic dropouts and/or null alleles), which tends to bias the estimation of heterozygosity and thus the inferences concerning the breeding system of the organism under study. This is especially critical in clonal organisms in which deviation from panmixia, as measured by Wright’s FIS, can, in principle, be used to infer both the extent of clonality and structure in a given population. In particular, null alleles and allelic dropouts are locus specific and likely produce high variance of Wright’s FIS across loci, as rare sex is expected to do. In this paper we propose a tool enabling to discriminate between consequences of these technical problems and those of rare sex. Methods We have performed various simulations of clonal and partially clonal populations. We introduce allelic dropouts and null alleles in clonal data sets and compare the results with those that exhibit increasing rates of sexual recombination. We use the narrow relationship that links Wright’s FIS to genetic diversity in purely clonal populations as assessment criterion, since this relationship disappears faster with sexual recombination than with amplification problems of certain alleles. Results We show that the relevance of our criterion for detecting poorly amplified alleles depends partly on the population structure, the level of homoplasy and/or mutation rate. However, the interpretation of data becomes difficult when the number of poorly amplified alleles is above 50%. The application of this method to reinterpret published data sets of pathogenic clonal microbes (yeast and trypanosomes) confirms its usefulness and allows refining previous estimates concerning important pathogenic agents. Conclusion Our

  12. How Old Is the Most Recent Ancestor of Two Copies of an Allele?

    PubMed Central

    Patterson, Nick J.

    2005-01-01

    An important clue to the evolutionary history of an allele is the structure of the neighboring region of the genome, which we term the genomic background of the allele. Consider two copies of the allele. How similar we expect their genomic background to be is strongly influenced by the age of their most recent common ancestor (MRCA). We apply diffusion theory, first used by Motoo Kimura as a tool for predicting the changes in allele frequencies over time and developed by him in many articles in this journal, to prove a variety of new results on the age of the MRCA under the simplest demographic assumptions. In particular, we show that the expected age of the MRCA of two copies of an allele with population frequency f is just 2Nf generations, where N is the effective population size. Our results are a first step in running exact coalescent simulations, where we also simulate the history of the population frequency of an allele. PMID:15520271

  13. Characterization of the treefrog null allele, 1991

    SciTech Connect

    Guttman, S.I.

    1992-04-01

    Spring peeper (Hyla crucifer) tadpoles collected from the waste storage area during the Biological and Ecological Site Characterization of the Feed Materials Production Center (FEMP) in 1986 and 1987 appeared to be unique. A null (inactive) allele was found at the glucose phosphate isomerase enzyme locus in significant frequencies (approximately 20%) each year; this allele did not appear to occur in the offsite sample collected approximately 15km from the FEMP. Null alleles at this locus have not been reported in other amphibian populations; when they have been found in other organisms they have invariably been lethal in the homozygous condition.

  14. Characterization of the treefrog null allele

    SciTech Connect

    Guttman, S.I. . Dept. of Zoology)

    1990-12-01

    As part of the authors intensive year-long baseline ecological study, they characterized the degree of genetic polymorphism and heterozygosity in selected Feed Materials Production Center (FMPC) populations using electrophoretic techniques. These data are being used as an indicator of stress by comparing populations on and off the FMPC site. The current study was initiated to determine whether this GPI null allele is lethal, when homozygous, in spring peepers. Also, a sampling protocol was implemented to determine whether a linear effect occurs relative to the frequency of the null allele offsite and to determine the origination site of the null allele. 18 refs., 2 figs., 4 tabs.

  15. 47 CFR 101.705 - Special showing for renewal of common carrier station facilities using frequency diversity.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES FIXED MICROWAVE SERVICES Common Carrier Fixed Point-to-Point Microwave Service § 101.705 Special showing for renewal of common carrier...

  16. 47 CFR 101.705 - Special showing for renewal of common carrier station facilities using frequency diversity.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES FIXED MICROWAVE SERVICES Common Carrier Fixed Point-to-Point Microwave Service § 101.705 Special showing for renewal of common carrier...

  17. Increase in NRAS mutant allele percentage during metastatic melanoma progression.

    PubMed

    Funck-Brentano, Elisa; Hélias-Rodzewicz, Zofia; Longvert, Christine; Mokhtari, Karima; Saiag, Philippe; Emile, Jean-François

    2016-06-01

    One-fifth of cutaneous melanomas have dominant gain-of-function mutations of the NRAS oncogene. We report the first two cases of increasing NRAS mutant allele frequency in melanoma metastases and show that the chromosomal mechanism of this homozygosity is an increased polysomy of chromosome 1. We observed an increase in NRAS mutant allele percentage (NRAS-MA%) in the metastatic melanoma progression from 2 patients with melanomas harbouring a NRAS mutation (p.Q61K in case 1 and p.Q61R in case 2). In case 1, we observed a NRAS-MA% increase from 18% within the first metastatic node to 81%, 92% and 85% respectively in the three subsequent metastases: lymph node, brain and subcutaneous metastases biopsied 1, 6 and 17 months, respectively, after the initial lymph node biopsy. In case 2, we observed an increase in NRAS-MA% from 40% within the primary melanoma to 63% within the metastatic lymph node. FISH analysis showed the same results in both cases: a frequent polysomy of chromosome 1 in metastasis samples with NRAS mutant allele percentage >60%, while most cells were disomic in the samples with well-balanced heterozygous mutations. The percentage of NRAS mutant allele may increase during metastatic progression and may be associated with chromosomal instability. Further studies are needed to evaluate the prognostic impact of the NRAS homozygous status and/or polyploidy in metastatic cutaneous melanomas. PMID:26990546

  18. Higher frequency of social learning in China than in the West shows cultural variation in the dynamics of cultural evolution.

    PubMed

    Mesoudi, Alex; Chang, Lei; Murray, Keelin; Lu, Hui Jing

    2015-01-01

    Cultural evolutionary models have identified a range of conditions under which social learning (copying others) is predicted to be adaptive relative to asocial learning (learning on one's own), particularly in humans where socially learned information can accumulate over successive generations. However, cultural evolution and behavioural economics experiments have consistently shown apparently maladaptive under-utilization of social information in Western populations. Here we provide experimental evidence of cultural variation in people's use of social learning, potentially explaining this mismatch. People in mainland China showed significantly more social learning than British people in an artefact-design task designed to assess the adaptiveness of social information use. People in Hong Kong, and Chinese immigrants in the UK, resembled British people in their social information use, suggesting a recent shift in these groups from social to asocial learning due to exposure to Western culture. Finally, Chinese mainland participants responded less than other participants to increased environmental change within the task. Our results suggest that learning strategies in humans are culturally variable and not genetically fixed, necessitating the study of the 'social learning of social learning strategies' whereby the dynamics of cultural evolution are responsive to social processes, such as migration, education and globalization. PMID:25392473

  19. Higher frequency of social learning in China than in the West shows cultural variation in the dynamics of cultural evolution

    PubMed Central

    Mesoudi, Alex; Chang, Lei; Murray, Keelin; Lu, Hui Jing

    2015-01-01

    Cultural evolutionary models have identified a range of conditions under which social learning (copying others) is predicted to be adaptive relative to asocial learning (learning on one's own), particularly in humans where socially learned information can accumulate over successive generations. However, cultural evolution and behavioural economics experiments have consistently shown apparently maladaptive under-utilization of social information in Western populations. Here we provide experimental evidence of cultural variation in people's use of social learning, potentially explaining this mismatch. People in mainland China showed significantly more social learning than British people in an artefact-design task designed to assess the adaptiveness of social information use. People in Hong Kong, and Chinese immigrants in the UK, resembled British people in their social information use, suggesting a recent shift in these groups from social to asocial learning due to exposure to Western culture. Finally, Chinese mainland participants responded less than other participants to increased environmental change within the task. Our results suggest that learning strategies in humans are culturally variable and not genetically fixed, necessitating the study of the ‘social learning of social learning strategies' whereby the dynamics of cultural evolution are responsive to social processes, such as migration, education and globalization. PMID:25392473

  20. Natural selection for the Duffy-null allele in the recently admixed people of Madagascar.

    PubMed

    Hodgson, Jason A; Pickrell, Joseph K; Pearson, Laurel N; Quillen, Ellen E; Prista, António; Rocha, Jorge; Soodyall, Himla; Shriver, Mark D; Perry, George H

    2014-08-22

    While gene flow between distantly related populations is increasingly recognized as a potentially important source of adaptive genetic variation for humans, fully characterized examples are rare. In addition, the role that natural selection for resistance to vivax malaria may have played in the extreme distribution of the protective Duffy-null allele, which is nearly completely fixed in mainland sub-Saharan Africa and absent elsewhere, is controversial. We address both these issues by investigating the evolution of the Duffy-null allele in the Malagasy, a recently admixed population with major ancestry components from both East Asia and mainland sub-Saharan Africa. We used genome-wide genetic data and extensive computer simulations to show that the high frequency of the Duffy-null allele in Madagascar can only be explained in the absence of positive natural selection under extreme demographic scenarios involving high genetic drift. However, the observed genomic single nucleotide polymorphism diversity in the Malagasy is incompatible with such extreme demographic scenarios, indicating that positive selection for the Duffy-null allele best explains the high frequency of the allele in Madagascar. We estimate the selection coefficient to be 0.066. Because vivax malaria is endemic to Madagascar, this result supports the hypothesis that malaria resistance drove fixation of the Duffy-null allele in mainland sub-Saharan Africa. PMID:24990677

  1. Natural selection for the Duffy-null allele in the recently admixed people of Madagascar

    PubMed Central

    Hodgson, Jason A.; Pickrell, Joseph K.; Pearson, Laurel N.; Quillen, Ellen E.; Prista, António; Rocha, Jorge; Soodyall, Himla; Shriver, Mark D.; Perry, George H.

    2014-01-01

    While gene flow between distantly related populations is increasingly recognized as a potentially important source of adaptive genetic variation for humans, fully characterized examples are rare. In addition, the role that natural selection for resistance to vivax malaria may have played in the extreme distribution of the protective Duffy-null allele, which is nearly completely fixed in mainland sub-Saharan Africa and absent elsewhere, is controversial. We address both these issues by investigating the evolution of the Duffy-null allele in the Malagasy, a recently admixed population with major ancestry components from both East Asia and mainland sub-Saharan Africa. We used genome-wide genetic data and extensive computer simulations to show that the high frequency of the Duffy-null allele in Madagascar can only be explained in the absence of positive natural selection under extreme demographic scenarios involving high genetic drift. However, the observed genomic single nucleotide polymorphism diversity in the Malagasy is incompatible with such extreme demographic scenarios, indicating that positive selection for the Duffy-null allele best explains the high frequency of the allele in Madagascar. We estimate the selection coefficient to be 0.066. Because vivax malaria is endemic to Madagascar, this result supports the hypothesis that malaria resistance drove fixation of the Duffy-null allele in mainland sub-Saharan Africa. PMID:24990677

  2. Allelic Associations between 100 DNA Markers and High versus Low IQ.

    ERIC Educational Resources Information Center

    Plomin, Robert; And Others

    1995-01-01

    For DNA markers in or near genes of neurological relevance, allelic frequencies were compared for groups of high- and low-IQ children (total sample of 86). This study adds 40 markers to the 60 already studied. Only one showed a significant association with IQ in original and replication samples. (SLD)

  3. Co-selection and replacement of resistance alleles to Lysinibacillus sphaericus in a Culex quinquefasciatus colony.

    PubMed

    Chalegre, Karlos Diogo de Melo; Tavares, Daniella A; Romão, Tatiany P; de Menezes, Heverly Suzany G; Nascimento, Nathaly A; de Oliveira, Cláudia Maria F; de-Melo-Neto, Osvaldo P; Silva-Filha, Maria Helena N L

    2015-09-01

    The Cqm1 α-glucosidase, expressed within the midgut of Culex quinquefasciatus mosquito larvae, is the receptor for the Binary toxin (Bin) from the entomopathogen Lysinibacillus sphaericus. Mutations of the Cqm1 α-glucosidase gene cause high resistance levels to this bacterium in both field and laboratory populations, and a previously described allele, cqm1REC, was found to be associated with a laboratory-resistant colony (R2362). This study described the identification of a novel resistance allele, cqm1REC-2, that was co-selected with cqm1REC within the R2362 colony. The two alleles display distinct mutations but both generate premature stop codons that prevent the expression of midgut-bound Cqm1 proteins. Using a PCR-based assay to monitor the frequency of each allele during long-term maintenance of the resistant colony, cqm1REC was found to predominate early on but later was replaced by cqm1REC-2 as the most abundant resistance allele. Homozygous larvae for each allele were then generated that displayed similar high-resistance phenotypes with equivalent low levels of transcript and lack of protein expression for both cqm1REC and cqm1REC-2. In progeny from a cross of homozygous individuals for each allele at a 1 : 1 ratio, analyzed for ten subsequent generations, cqm1REC showed a higher frequency than cqm1REC-2. The replacement of cqm1REC by cqm1REC -2 observed in the R2362 colony, kept for 210 generations, indicates changes in fitness related to traits that are unknown but linked to these two alleles, and constitutes a unique example of evolution of resistance within a controlled laboratory environment. PMID:26131741

  4. Prolonged P300 latency in children with the D[sub 2] dopamine receptor A1 allele

    SciTech Connect

    Noble, E.P.; Berman, S.M.; Ozkaragoz, T.Z.; Ritchie, T. )

    1994-04-01

    Previous studies have indicated the presence of a hereditary component in the generation of the P300, or P3, a late positive component of the event-related potential. Moreover, the dopaminergic system has been implicated in the P3. In the present study, 98 healthy Caucasian boys, mean age of 12.5 years and of above-average intelligence, were studied. The sample was composed of 32 sons of active alcoholic (SAA) fathers, 36 sons of recovering alcoholic (SRA) fathers, and 30 sons of social drinker (SSD) fathers, with none of them having yet begun to consume alcohol or other drugs. TaqI A D[sub 2] dopamine receptor alleles (A1 and A2) were determined. A significant difference in the frequency of the A1 allele was found among these three groups of boys, with the SAA group having the highest A1 allele frequency (.313), followed by the SRA (.139) and the SSD (.133) groups. The relationship of the A1 and A2 alleles to P3 amplitude and latency was also determined. The results showed no significant difference in P3 amplitude between boys with the A1 and A2 allele. However, P3 latency was significantly longer in the total sample of boys with the A1 allele compared with those carrying the A2 allele. These findings suggest that polymorphism of the D[sub 2] dopamine receptor gene is an important determinant of P3 latency. 84 refs., 2 figs., 3 tabs.

  5. Increasing long-term response by selecting for favorable minor alleles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term response of genomic selection can be improved by considering allele frequencies of selected markers or quantitative trait loci (QTLs). A previous formula to weight allele frequency of favorable minor alleles was tested, and 2 new formulas were developed. The previous formula used nonlinear...

  6. Allele-specific disparity in breast cancer

    PubMed Central

    2011-01-01

    Background In a cancer cell the number of copies of a locus may vary due to amplification and deletion and these variations are denoted as copy number alterations (CNAs). We focus on the disparity of CNAs in tumour samples, which were compared to those in blood in order to identify the directional loss of heterozygosity. Methods We propose a numerical algorithm and apply it to data from the Illumina 109K-SNP array on 112 samples from breast cancer patients. B-allele frequency (BAF) and log R ratio (LRR) of Illumina were used to estimate Euclidian distances. For each locus, we compared genotypes in blood and tumour for subset of samples being heterozygous in blood. We identified loci showing preferential disparity from heterozygous toward either the A/B-allele homozygous (allelic disparity). The chi-squared and Cochran-Armitage trend tests were used to examine whether there is an association between high levels of disparity in single nucleotide polymorphisms (SNPs) and molecular, clinical and tumour-related parameters. To identify pathways and network functions over-represented within the resulting gene sets, we used Ingenuity Pathway Analysis (IPA). Results To identify loci with a high level of disparity, we selected SNPs 1) with a substantial degree of disparity and 2) with substantial frequency (at least 50% of the samples heterozygous for the respective locus). We report the overall difference in disparity in high-grade tumours compared to low-grade tumours (p-value < 0.001) and significant associations between disparity in multiple single loci and clinical parameters. The most significantly associated network functions within the genes represented in the loci of disparity were identified, including lipid metabolism, small-molecule biochemistry, and nervous system development and function. No evidence for over-representation of directional disparity in a list of stem cell genes was obtained, however genes appeared to be more often altered by deletion than by

  7. Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism

    PubMed Central

    Sachse, Christoph; Bhambra, Upinder; Smith, Gillian; Lightfoot, Tracy J; Barrett, Jennifer H; Scollay, Jenna; Garner, R Colin; Boobis, Alan R; Wolf, C Roland; Gooderham, Nigel J

    2003-01-01

    Aim Several single nucleotide polymorphisms (SNPs) of the cytochrome P450 enzyme 1A2 gene (CYP1A2) have been reported. Here, frequencies, linkage disequilibrium and phenotypic consequences of six SNPs are described. Methods From genomic DNA, 114 British Caucasians (49 colorectal cancer cases and 65 controls) were genotyped for the CYP1A2 polymorphisms −3858G→A (allele CYP1A2*1C), −2464T→delT (CYP1A2*1D), −740T→G (CYP1A2*1E and *1G), −164A→C (CYP1A2*1F), 63C→G (CYP1A2*2), and 1545T→C (alleles CYP1A2*1B, *1G, *1H and *3), using polymerase chain reaction–restriction fragment length polymorphism assays. All patients and controls were phenotyped for CYP1A2 by h.p.l.c. analysis of urinary caffeine metabolites. Results In 114 samples, the most frequent CYP1A2 SNPs were 1545T→C (38.2% of tested chromosomes), −164A→C (CYP1A2*1F, 33.3%) and −2464T→delT (CYP1A2*1D, 4.82%). The SNPs were in linkage disequilibrium: the most frequent constellations were found to be −3858G/−2464T/−740T/−164A/63C/1545T (61.8%), −3858G/−2464T/−740T/−164C/63C/1545C (33.3%), and −3858G/−2464delT/−740T/−164A/63C/1545C (3.51%), with no significant frequency differences between cases and controls. In the phenotype analysis, lower caffeine metabolic ratios were detected in cases than in controls. This was significant in smokers (n = 14, P = 0.020), and in a subgroup of 15 matched case-control pairs (P = 0.007), but it was not significant in nonsmokers (n = 100, P = 0.39). There was no detectable association between CYP1A2 genotype and caffeine phenotype. Conclusions (i) CYP1A2 polymorphisms are in linkage disequilibrium. Therefore, only −164A→C (CYP1A2*1F) and −2464T→delT (CYP1A2*1D) need to be analysed in the routine assessment of CYP1A2 genotype; (ii) in vivo CYP1A2 activity is lower in colorectal cancer patients than in controls, and (iii) CYP1A2 genotype had no effect on phenotype (based on the caffeine metabolite ratio). However, this

  8. Distribution of HLA-DRB1 and HLA-DQB1 alleles in Lak population of Iran.

    PubMed

    Varzi, Ali Mohammad; Shahsavar, Farhad; Tarrahi, Mohammad Javad

    2016-07-01

    Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and encode the highly polymorphic molecules critically involved in immune responses. Anthropological studies based on highly polymorphic HLA genes provide useful information for bone marrow donor registry, forensic medicine, disease association studies, as well as designing peptide vaccines against tumors, and infectious or autoimmune diseases. The aim of this study was to determine the HLA-DRB1 and HLA-DQB1 allele frequencies in 100 unrelated Lak individuals from Lorestan province of Iran. Finally, we compared the results with those previously described in four other Iranian populations. Commercial HLA-Type kits were used for determination of the HLA-DRB1 and HLA-DQB1 allele frequencies. Differences between populations in the distribution of HLA-DRB1 and HLA-DQB1 alleles were estimated by χ2 test with Yate's correction and Fisher's exact test. The most frequent HLA-DRB1 alleles were (*)1103=4 (23%), (*)1502 (9.5%), (*)0701 (9%), (*)0301 (8.5%), (*)1101 (7.5%) and (*)1501 (6%) while HLA-DQB1(*)0301 (40%), (*)0201 (15%), (*)0502 (10.5%), (*)0303 (10%), (*)0602=3 (9.5%), and (*)0501 (7.5%) were the most frequent alleles in Lak population. HLA-DRB1(*)0409, (*)0804, (*)1102, (*)1112, (*)1405, and HLA-DQB1(*)0503, (*)0604 were the least observed frequencies in Lak population. Our results based on HLA-DRB1 and HLA-DQB1 allele frequencies showed that the Lak population possesses the previously reported general features of the Lur and Kurd populations but still with unique, decreased or increased frequencies of several alleles. In other words, the Lak population is close to Lurs Khorramabadi and Kurd but far from Lurs Kohkiloyeh/Boyerahmad and Bakhtiari. PMID:27189628

  9. The Dominant Ms Allele in Onion Shows Reduced Penetrance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The most commonly used source of cytoplasmic male sterility in onion is controlled by the interaction of the cytoplasm [male-sterile (S) or normal (N) male-fertile] and one nuclear male-fertility-restoration locus (Ms). Scoring of genotypes at Ms is generally done by testcrossing male-fertile to mal...

  10. Population Dynamics of Sex-Determining Alleles in Honey Bees and Self-Incompatibility Alleles in Plants

    PubMed Central

    Yokoyama, Shozo; Nei, Masatoshi

    1979-01-01

    Mathematical theories of the population dynamics of sex-determining alleles in honey bees are developed. It is shown that in an infinitely large population the equilibrium frequency of a sex allele is 1/n, where n is the number of alleles in the population, and the asymptotic rate of approach to this equilibrium is 2/(3n) per generation. Formulae for the distribution of allele frequencies and the effective and actual numbers of alleles that can be maintained in a finite population are derived by taking into account the population size and mutation rate. It is shown that the allele frequencies in a finite population may deviate considerably from 1/n. Using these results, available data on the number of sex alleles in honey bee populations are discussed. It is also shown that the number of self-incompatibility alleles in plants can be studied in a much simpler way by the method used in this paper. A brief discussion about general overdominant selection is presented. PMID:17248901

  11. Allelic genealogies in sporophytic self-incompatibility systems in plants.

    PubMed Central

    Schierup, M H; Vekemans, X; Christiansen, F B

    1998-01-01

    Expectations for the time scale and structure of allelic genealogies in finite populations are formed under three models of sporophytic self-incompatibility. The models differ in the dominance interactions among the alleles that determine the self-incompatibility phenotype: In the SSIcod model, alleles act codominantly in both pollen and style, in the SSIdom model, alleles form a dominance hierarchy, and in SSIdomcod, alleles are codominant in the style and show a dominance hierarchy in the pollen. Coalescence times of alleles rarely differ more than threefold from those under gametophytic self-incompatibility, and transspecific polymorphism is therefore expected to be equally common. The previously reported directional turnover process of alleles in the SSIdomcod model results in coalescence times lower and substitution rates higher than those in the other models. The SSIdom model assumes strong asymmetries in allelic action, and the most recessive extant allele is likely to be the most recent common ancestor. Despite these asymmetries, the expected shape of the allele genealogies does not deviate markedly from the shape of a neutral gene genealogy. The application of the results to sequence surveys of alleles, including interspecific comparisons, is discussed. PMID:9799270

  12. Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: implication for the development of an universal CD8+ T-cell epitope-based vaccine.

    PubMed

    Samandary, Sarah; Kridane-Miledi, Hédia; Sandoval, Jacqueline S; Choudhury, Zareen; Langa-Vives, Francina; Spencer, Doran; Chentoufi, Aziz A; Lemonnier, François A; BenMohamed, Lbachir

    2014-08-01

    A significant portion of the world's population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) over a half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA-A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A(∗)24, HLA-B(∗)27, HLA-B(∗)53 and HLA-B(∗)58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B(∗)44 allele. The finding will aid in developing a T-cell epitope-based universal herpes vaccine and immunotherapy. PMID:24798939

  13. Associations of HLA-A, HLA-B and HLA-C Alleles Frequency with Prevalence of Herpes Simplex Virus Infections and Diseases Across Global Populations: Implication for the Development of an Universal CD8+ T-Cell Epitope-Based Vaccine

    PubMed Central

    Samandary, Sarah; Kridane-Miledi, Hédia; Sandoval, Jacqueline S.; Choudhury, Zareen; Langa-Vives, Francina; Spencer, Doran; Chentoufi, Aziz A.; Lemonnier, François A.; BenMohamed, Lbachir

    2014-01-01

    A significant portion of the world’s population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) Over half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA-A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A*24, HLA-B*27, HLA-B*53 and HLA-B*58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B*44 allele. The finding will aid in developing a T-cell epitope-based universal herpes vaccine and immunotherapy. PMID:24798939

  14. HLA-B alleles of the Cayapa of Ecuador: New B39 and B15 alleles

    SciTech Connect

    Garber, T.L.; Butler, L.M.; Watkins, D.I.

    1995-05-01

    Recent data suggest that HLA-B locus alleles can evolve quickly in native South American populations. To investigate further this phenomenon of new HLA-B variants among Amerindians, we studied samples from another South American tribe, the Cayapa from Ecuador. We selected individuals for HLA-B molecular typing based upon their HLA class II typing results. Three new variants of HLA-B39 and one new variant of HLA-B15 were found in the Cayapa: HLA-B*3905, HLA-B*3906, HLA-B*3907, and HLA-B*1522. A total of thirteen new HLA-B alleles have now been found in the four South American tribes studied. Each of these four tribes studied, including the Cayapa, had novel alleles that were not found in any of the other tribes, suggesting that many of these new HLA-B alleles may have evolved since the Paleo-Indians originally populated South America. Each of these 13 new alleles contained predicted amino acid replacements that were located in the peptide binding site. These amino acid replacements may affect the sequence motif of the bound peptides, suggesting that these new alleles have been maintained by selection. New allelic variants have been found for all common HLA-B locus antigenic groups present in South American tribes with the exception of B48. In spite of its high frequency in South American tribes, no evidence for variants of B48 has been found in all the Amerindians studied, suggesting that B48 may have unique characteristics among the B locus alleles. 70 refs., 2 figs., 2 tabs.

  15. The Association Between HLA Class II Alleles and the Occurrence of Factor VIII Inhibitor in Thai Patients with Hemophilia A

    PubMed Central

    Nathalang, Oytip; Sriwanitchrak, Pramote; Sasanakul, Werasak; Chuansumrit, Ampaiwan

    2012-01-01

    Objective: This study aimed to investigate the association between HLA class II alleles and the occurrence of FVIIIinhibitor in Thai hemophilia A patients. Material and Methods: The distribution of HLA-DRB1 alleles and DQB1 alleles in 57 Thai hemophilia A patientsand 36 blood donors as controls was determined using the PCR sequence-specific primer (PCR-SSP) method, and theassociation between the occurrence of factor VIII (FVIII) inhibitor and the presence of certain HLA class II alleles wasinvestigated. Results: The frequency of HLA-DRB1*15 was higher in the hemophilia A patients with and without FVIII inhibitor,whereas that of DRB1*14, DRB1*07, and DQB1*02 was lower in the hemophilia A patients with FVIII inhibitor, ascompared to controls. Interestingly, only the frequency of DRB1*15 was significantly higher in the patients with inhibitorthan in the controls (P = 0.021). Moreover, the frequency of DRB1*15 in the patients with inhibitor was higher than inthose without inhibitor (P = 0.198). Conclusion: The study’s findings show that the DRB1*15 allele might have contributed to the occurrence of inhibitorin the Thai hemophilia A patients; however, additional research using larger samples and high-resolution DRB1 typingis warranted. PMID:24744621

  16. HLA-DQA1/B1 alleles as putative susceptibility markers in congenital toxoplasmosis.

    PubMed

    Shimokawa, Paulo Tadashi; Targa, Lília Spaleta; Yamamoto, Lidia; Rodrigues, Jonatas Cristian; Kanunfre, Kelly Aparecida; Okay, Thelma Suely

    2016-05-18

    Host and parasite genotypes are among the factors associated with congenital toxoplasmosis pathogenesis. As HLA class II molecules play a key role in the immune system regulation, the aim of this study was to investigate whether HLA-DQA1/B1 alleles are associated with susceptibility or protection to congenital toxoplasmosis. One hundred and twenty-two fetuses with and 103 without toxoplasmosis were studied. The two study groups were comparable according to a number of socio-demographic and genetic variables. HLA alleles were typed by PCR-SSP. In the HLA-DQA1 region, the allele frequencies showed that *01:03 and *03:02 alleles could confer susceptibility (OR= 3.06, p = 0.0002 and OR= 9.60, p= 0.0001, respectively) as they were more frequent among infected fetuses. Regarding the HLA-DQB1 region, the *05:04 allele could confer susceptibility (OR = 6.95, p < 0.0001). Of the 122 infected fetuses, 10 presented susceptibility haplotypes contrasting with only one in the non-infected group. This difference was not statistically significant after correction for multiple comparison (OR = 9.37, p=0.011). In the casuistic, there were two severely damaged fetuses with high parasite loads determined in amniotic fluid samples and HLA-DQA1 susceptibility alleles. In the present study, a discriminatory potential of HLA-DQA1/B1 alleles to identify susceptibility to congenital toxoplasmosis and the most severe cases has been shown. PMID:26856406

  17. Female sticklebacks count alleles in a strategy of sexual selection explaining MHC polymorphism.

    PubMed

    Reusch, T B; Häberli, M A; Aeschlimann, P B; Milinski, M

    2001-11-15

    The origin and maintenance of polymorphism in major histocompatibility complex (MHC) genes in natural populations is still unresolved. Sexual selection, frequency-dependent selection by parasites and pathogens, and heterozygote advantage have been suggested to explain the maintenance of high allele diversity at MHC genes. Here we argue that there are two (non-exclusive) strategies for MHC-related sexual selection, representing solutions to two different problems: inbreeding avoidance and parasite resistance. In species prone to inadvertent inbreeding, partners should prefer dissimilar MHC genotypes to similar ones. But if the goal is to maximize the resistance of offspring towards potential infections, the choosing sex should prefer mates with a higher diversity of MHC alleles. This latter strategy should apply when there are several MHC loci, as is the case in most vertebrates. We tested the relative importance of an 'allele counting' strategy compared to a disassortative mating strategy using wild-caught three-spined sticklebacks (Gasterosteus aculeatus) from an interconnected system of lakes. Here we show that gravid female fish preferred the odour of males with a large number of MHC class-IIB alleles to that of males with fewer alleles. Females did not prefer male genotypes dissimilar to their own. PMID:11713527

  18. Allelic Variation in a Willow Warbler Genomic Region Is Associated with Climate Clines

    PubMed Central

    Larson, Keith W.; Liedvogel, Miriam; Addison, BriAnne; Kleven, Oddmund; Laskemoen, Terje; Lifjeld, Jan T.; Lundberg, Max; Åkesson, Susanne; Bensch, Staffan

    2014-01-01

    Local adaptation is an important process contributing to population differentiation which can occur in continuous or isolated populations connected by various amounts of gene flow. The willow warbler (Phylloscopus trochilus) is one of the most common songbirds in Fennoscandia. It has a continuous breeding distribution where it is found in all forested habitats from sea level to the tree line and therefore constitutes an ideal species for the study of locally adapted genes associated with environmental gradients. Previous studies in this species identified a genetic marker (AFLP-WW1) that showed a steep north-south cline in central Sweden with one allele associated with coastal lowland habitats and the other with mountainous habitats. It was further demonstrated that this marker is embedded in a highly differentiated chromosome region that spans several megabases. In the present study, we sampled 2,355 individuals at 128 sites across all of Fennoscandia to study the geographic and climatic variables associated with the allele frequency distributions of WW1. Our results demonstrate that 1) allele frequency patterns significantly differ between mountain and lowland populations, 2) these allele differences coincide with extreme temperature conditions and the short growing season in the mountains, and milder conditions in coastal areas, and 3) the northern-allele or “altitude variant” of WW1 occurs in willow warblers that occupy mountainous habitat regardless of subspecies. Finally these results suggest that climate may exert selection on the genomic region associated with these alleles and would allow us to develop testable predictions for the distribution of the genetic marker based on climate change scenarios. PMID:24788148

  19. Negative Selection on BRCA1 Susceptibility Alleles Sheds Light on the Population Genetics of Late-Onset Diseases and Aging Theory

    PubMed Central

    Pavard, Samuel; Metcalf, C. Jessica E.

    2007-01-01

    The magnitude of negative selection on alleles involved in age-specific mortality decreases with age. This is the foundation of the evolutionary theory of senescence. Because of this decrease in negative selection with age, and because of the absence of reproduction after menopause, alleles involved in women's late-onset diseases are generally considered evolutionarily neutral. Recently, genetic and epidemiological data on alleles involved in late onset-diseases have become available. It is therefore timely to estimate selection on these alleles. Here, we estimate selection on BRCA1 alleles leading to susceptibility to late-onset breast and ovarian cancer. For this, we integrate estimates of the risk of developing a cancer for BRCA1-carriers into population genetics frameworks, and calculate selection coefficients on BRCA1 alleles for different demographic scenarios varying across the extent of human demography. We then explore the magnitude of negative selection on alleles leading to a diverse range of risk patterns, to capture a variety of late-onset diseases. We show that BRCA1 alleles may have been under significant negative selection during human history. Although the mean age of onset of the disease is long after menopause, variance in age of onset means that there are always enough cases occurring before the end of reproductive life to compromise the selective value of women carrying a susceptibility allele in BRCA1. This seems to be the case for an extended range of risk of onset functions varying both in mean and variance. This finding may explain the distribution of BRCA1 alleles' frequency, and also why alleles for many late-onset diseases, like certain familial forms of cancer, coronary artery diseases and Alzheimer dementia, are typically recent and rare. Finally, we discuss why the two most popular evolutionary theories of aging, mutation accumulation and antagonistic pleiotropy, may underestimate the effect of selection on survival at old ages. PMID

  20. PCSK9 polymorphism in a Tunisian cohort: identification of a new allele, L8, and association of allele L10 with reduced coronary heart disease risk.

    PubMed

    Slimani, Afef; Hrira, Mohamed Yahia; Najah, Mohamed; Jomaa, Walid; Maatouk, Faouzi; Hamda, Khaldoun Ben; Abifadel, Marianne; Rabès, Jean-Pierre; Boileau, Catherine; Rouis, Mustapha; Slimane, Mohamed Naceur; Varret, Mathilde

    2015-02-01

    The c.61_63dupCTG (L10) allele of rs72555377 polymorphism in PCSK9 has been reported to be associated with low-density lipoprotein-cholesterol (LDL-C) levels and with a decreased risk of coronary artery disease (CAD). We investigated the effect of two known alleles for rs72555377, L10 and L11, on the risk of CAD in a Tunisian cohort (218 patients diagnosed by angiography and 125 control subjects). Two subgroups of patients were defined by their level of stenosis: ≥50% for CAD and <50% for no-CAD. The genotypes were obtained by the size measurement of fluorescent-labeled PCR products. We identified a novel allele for the rs72555377 polymorphism: an in-frame deletion, c.61_63delCTG (L8). The frequency of the L10 allele was significantly higher in the no-CAD subgroup than in the CAD subgroup (0.210 vs 0.114, p = 0.045), and than in the subgroup of CAD patients presenting a stenosis ≥50% in two or three major coronary arteries (0.210 vs 0.125, p = 0.028). Multiple regression analysis showed that the L10 allele was significantly associated with a reduced risk of CAD (p = 0.049, OR = 0.51[0.26-1.00]), and with its reduced severity (p = 0.045, OR = 0.44[0.20-0.98]). The L10 allele is associated with a reduced risk and severity of CAD, seemingly independently of its LDL-lowering effect, suggesting a direct effect of PCSK9 on atherogenesis. PMID:25239117

  1. Inferring the age of a fixed beneficial allele.

    PubMed

    Ormond, Louise; Foll, Matthieu; Ewing, Gregory B; Pfeifer, Susanne P; Jensen, Jeffrey D

    2016-01-01

    Estimating the age and strength of beneficial alleles is central to understanding how adaptation proceeds in response to changing environmental conditions. Several haplotype-based estimators exist for inferring the age of segregating beneficial mutations. Here, we develop an approximate Bayesian-based approach that rather estimates these parameters for fixed beneficial mutations in single populations. We integrate a range of existing diversity, site frequency spectrum, haplotype- and linkage disequilibrium-based summary statistics. We show that for strong selective sweeps on de novo mutations the method can estimate allele age and selection strength even in nonequilibrium demographic scenarios. We extend our approach to models of selection on standing variation, and co-infer the frequency at which selection began to act upon the mutation. Finally, we apply our method to estimate the age and selection strength of a previously identified mutation underpinning cryptic colour adaptation in a wild deer mouse population, and compare our findings with previously published estimates as well as with geological data pertaining to the presumed shift in selective pressure. PMID:26576754

  2. Evidence of the phenotypic expression of a lethal recessive allele under inbreeding in a wild population of conservation concern.

    PubMed

    Trask, Amanda E; Bignal, Eric M; McCracken, Davy I; Monaghan, Pat; Piertney, Stuart B; Reid, Jane M

    2016-07-01

    Deleterious recessive alleles that are masked in outbred populations are predicted to be expressed in small, inbred populations, reducing both individual fitness and population viability. However, there are few definitive examples of phenotypic expression of lethal recessive alleles under inbreeding conditions in wild populations. Studies that demonstrate the action of such alleles, and infer their distribution and dynamics, are required to understand their potential impact on population viability and inform management responses. The Scottish population of red-billed choughs (Pyrrhocorax pyrrhocorax), which currently totals <60 breeding pairs and is of major conservation concern, has recently been affected by lethal blindness in nestlings. We used family data to show that the pattern of occurrence of blindness within and across affected families that produced blind nestlings was exactly 0·25, matching that expected given a single-locus autosomal lethal recessive allele. Furthermore, the observed distribution of blind nestlings within affected families did not differ from that expected given Mendelian inheritance of such an allele. Relatedness estimates showed that individuals from affected families were not more closely related to each other than they were to individuals from unaffected families that did not produce blind nestlings. Blind individuals tended to be less heterozygous than non-blind individuals, as expected if blindness was caused by the expression of a recessive allele under inbreeding. However, there was no difference in the variance in heterozygosity estimates, suggesting that some blind individuals were relatively outbred. These results suggest carriers of the blindness allele may be widely distributed across contemporary families rather than restricted to a single family lineage, implying that the allele has persisted across multiple generations. Blindness occurred at low frequency (affecting 1·6% of observed nestlings since 1981). However

  3. Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots.

    PubMed

    Baker, Christopher L; Petkova, Pavlina; Walker, Michael; Flachs, Petr; Mihola, Ondrej; Trachtulec, Zdenek; Petkov, Petko M; Paigen, Kenneth

    2015-09-01

    Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9+/- heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape. PMID:26368021

  4. Further data on the microsatellite locus D12S67 in worldwide populations: an unusual distribution of D12S67 alleles in Native Americans.

    PubMed

    Mitchell, R J; Federle, L; Sofro, A S; Papiha, S S; Briceno, I; Bernal, J E

    2000-08-01

    We report the frequencies of alleles at the microsatellite locus D12S67 in 2 widely separated ethnic groups of the world: 2 populations from Sulawesi, an island in the Indonesian archipelago, and 5 Native American tribes of Colombia, South America. The allele frequencies in the Minihasans and Torajans of Sulawesi are similar to each other (but the modal class allele is different) and in general agreement with those reported in mainland Asian groups, but different from both Europeans and Chinese Han of Taiwan. The 5 Native American tribes (Arsario, Kogui, Ijka, Wayuu, and Coreguaje) display different allele frequencies from those seen in Sulawesi populations, in other groups from Europe and mainland Asia, and in Chinese Han of Taiwan. Native Americans exhibit a bimodal distribution of alleles, unlike other groups, with significant differences among the tribes. The Arsario and Kogui have no admixture with Europeans or Africans and are the most distinctive, while the Wayuu have the most admixture and show most similarity to other groups. The data suggest that nonadmixed Native Americans may be quite distinctive with respect to this marker. The most common allele varies across the 5 tribes, from 249 base pairs to 261 base pairs. All samples exhibit Hardy-Weinberg genotype proportions; heterozygosities are lowest in the 2 nonadmixed Native American tribes. Examination of all the available data indicates that some east Asian and southeast Asian groups are characterized by a high frequency of smaller sized D12S67 alleles, while other populations have a greater proportion of the larger sized alleles. The cumulative, though still highly restricted, population data on locus D12S67 demonstrate that it may be of considerable value in anthropological genetic studies of ethnic groups. Data are required on Native Americans outside Colombia before this marker can be used in admixture studies of this group. PMID:11048795

  5. The effect of deleterious alleles on adaptation in asexual populations.

    PubMed Central

    Johnson, Toby; Barton, Nick H

    2002-01-01

    We calculate the fixation probability of a beneficial allele that arises as the result of a unique mutation in an asexual population that is subject to recurrent deleterious mutation at rate U. Our analysis is an extension of previous works, which make a biologically restrictive assumption that selection against deleterious alleles is stronger than that on the beneficial allele of interest. We show that when selection against deleterious alleles is weak, beneficial alleles that confer a selective advantage that is small relative to U have greatly reduced probabilities of fixation. We discuss the consequences of this effect for the distribution of effects of alleles fixed during adaptation. We show that a selective sweep will increase the fixation probabilities of other beneficial mutations arising during some short interval afterward. We use the calculated fixation probabilities to estimate the expected rate of fitness improvement in an asexual population when beneficial alleles arise continually at some low rate proportional to U. We estimate the rate of mutation that is optimal in the sense that it maximizes this rate of fitness improvement. Again, this analysis relaxes the assumption made previously that selection against deleterious alleles is stronger than on beneficial alleles. PMID:12242249

  6. Genetic instability of the lozenge locus in Drosophila melanogaster: Characterization of the lz{sup 75V} allele

    SciTech Connect

    Voloshina, M.A.; Golubovskii, M.D.

    1995-12-01

    Genetic properties of lz{sup 75V}, an unstable allele of the lozenge locus, are described. The lz{sup 75V} allele appeared in progeny of a male from a Far East natural population of Drosophila melanogaster. Mutation of this allele produces a broad spectrum of mutant derivatives with phenotypes varying from normal to extreme. The arising alleles can be stable or unstable. Some lz{sup 75V} derivatives continuously preserve their spontaneous mutability in laboratory conditions, whereas other alleles of the same family show progressive stabilization at the intralocus or intrachromosome level. Instability of the lz{sup 75V}-bearing X chromosome is locus-specific: only the lozenge gene mutates with high frequency, while visible mutations at other loci rarely occur. As shown previously, the lz{sup 75V} allele appears to be caused by a P-element insertion. The appearance of spontaneous instability is discussed with regard to the general problem of transposition regulation in mobile elements. Different systems of hybrid dysgenesis, and, in particular, P elements are assumed to play an important role in induction of unstable mutations in nature. 24 refs., 5 tabs.

  7. The ataxia telangiectasia mutated and cyclin D3 proteins cooperate to help enforce TCRβ and IgH allelic exclusion.

    PubMed

    Steinel, Natalie C; Fisher, Megan R; Yang-Iott, Katherine S; Bassing, Craig H

    2014-09-15

    Coordination of V rearrangements between loci on homologous chromosomes is critical for Ig and TCR allelic exclusion. The Ataxia Telangietasia mutated (ATM) protein kinase promotes DNA repair and activates checkpoints to suppress aberrant Ig and TCR rearrangements. In response to RAG cleavage of Igκ loci, ATM inhibits RAG expression and suppresses further Vκ-to-Jκ rearrangements to enforce Igκ allelic exclusion. Because V recombination between alleles is more strictly regulated for TCRβ and IgH loci, we evaluated the ability of ATM to restrict biallelic expression and V-to-DJ recombination of TCRβ and IgH genes. We detected greater frequencies of lymphocytes with biallelic expression or aberrant V-to-DJ rearrangement of TCRβ or IgH loci in mice lacking ATM. A preassembled DJβ complex that decreases the number of TCRβ rearrangements needed for a productive TCRβ gene further increased frequencies of ATM-deficient cells with biallelic TCRβ expression. IgH and TCRβ proteins drive proliferation of prolymphocytes through cyclin D3 (Ccnd3), which also inhibits VH transcription. We show that inactivation of Ccnd3 leads to increased frequencies of lymphocytes with biallelic expression of IgH or TCRβ genes. We also show that Ccnd3 inactivation cooperates with ATM deficiency to increase the frequencies of cells with biallelic TCRβ or IgH expression while decreasing the frequency of ATM-deficient lymphocytes with aberrant V-to-DJ recombination. Our data demonstrate that core components of the DNA damage response and cell cycle machinery cooperate to help enforce IgH and TCRβ allelic exclusion and indicate that control of V-to-DJ rearrangements between alleles is important to maintain genomic stability. PMID:25127855

  8. Major histocompatibility complex class II DAB alleles associated with intestinal parasite load in the vulnerable Chinese egret (Egretta eulophotes).

    PubMed

    Lei, Wei; Zhou, Xiaoping; Fang, Wenzhen; Lin, Qingxian; Chen, Xiaolin

    2016-07-01

    The maintenance of major histocompatibility complex (MHC) polymorphism has been hypothesized to result from many mechanisms such as rare-allele advantage, heterozygote advantage, and allele counting. In the study reported herein, 224 vulnerable Chinese egrets (Egretta eulophotes) were used to examine these hypotheses as empirical results derived from bird studies are rare. Parasite survey showed that 147 (65.63%) individuals were infected with 1-3 helminths, and 82.31% of these infected individuals carried Ascaridia sp. Using asymmetric polymerase chain reaction technique, 10 DAB1, twelve DAB2, and three DAB3 exon 2 alleles were identified at each single locus. A significant association of the rare allele Egeu-DAB2*05 (allele frequency: 0.022) with helminth resistance was found for all helminths, as well as for the most abundant morphotype Ascaridia sp. in the separate analyses. Egeu-DAB2*05 occurred frequently in uninfected individuals, and individuals carrying Egeu-DAB2*05 had significantly lower helminth morphotypes per individual (HMI) (the number of HMI) and the fecal egg count values. Further, the parasite infection measurements were consistently lower in individuals with an intermediate number of different alleles in the duplicated DAB loci. Significantly, heterozygosity within each DAB locus was not correlated with any parasite infection measurements. These results indicate that the diversity in MHC Egeu-DAB gene is associated with intestinal parasite load and maintained by pathogen-driven selection that probably operate through both the rare-allele advantage and the allele counting strategy, and suggest that Egeu-DAB2*05 might be a valuable indicator of better resistance to helminth diseases in the vulnerable Chinese egret. PMID:27386085

  9. Dominance of Deleterious Alleles Controls the Response to a Population Bottleneck

    PubMed Central

    Balick, Daniel J.; Do, Ron; Cassa, Christopher A.; Reich, David; Sunyaev, Shamil R.

    2015-01-01

    Population bottlenecks followed by re-expansions have been common throughout history of many populations. The response of alleles under selection to such demographic perturbations has been a subject of great interest in population genetics. On the basis of theoretical analysis and computer simulations, we suggest that this response qualitatively depends on dominance. The number of dominant or additive deleterious alleles per haploid genome is expected to be slightly increased following the bottleneck and re-expansion. In contrast, the number of completely or partially recessive alleles should be sharply reduced. Changes of population size expose differences between recessive and additive selection, potentially providing insight into the prevalence of dominance in natural populations. Specifically, we use a simple statistic, BR≡∑xipop1/∑xjpop2, where x i represents the derived allele frequency, to compare the number of mutations in different populations, and detail its functional dependence on the strength of selection and the intensity of the population bottleneck. We also provide empirical evidence showing that gene sets associated with autosomal recessive disease in humans may have a B R indicative of recessive selection. Together, these theoretical predictions and empirical observations show that complex demographic history may facilitate rather than impede inference of parameters of natural selection. PMID:26317225

  10. Dominance of Deleterious Alleles Controls the Response to a Population Bottleneck.

    PubMed

    Balick, Daniel J; Do, Ron; Cassa, Christopher A; Reich, David; Sunyaev, Shamil R

    2015-08-01

    Population bottlenecks followed by re-expansions have been common throughout history of many populations. The response of alleles under selection to such demographic perturbations has been a subject of great interest in population genetics. On the basis of theoretical analysis and computer simulations, we suggest that this response qualitatively depends on dominance. The number of dominant or additive deleterious alleles per haploid genome is expected to be slightly increased following the bottleneck and re-expansion. In contrast, the number of completely or partially recessive alleles should be sharply reduced. Changes of population size expose differences between recessive and additive selection, potentially providing insight into the prevalence of dominance in natural populations. Specifically, we use a simple statistic, [Formula: see text], where xi represents the derived allele frequency, to compare the number of mutations in different populations, and detail its functional dependence on the strength of selection and the intensity of the population bottleneck. We also provide empirical evidence showing that gene sets associated with autosomal recessive disease in humans may have a BR indicative of recessive selection. Together, these theoretical predictions and empirical observations show that complex demographic history may facilitate rather than impede inference of parameters of natural selection. PMID:26317225

  11. Population genetics of the vitamin D binding protein (GC) subtypes in the Asian-Pacific area: description of new alleles at the GC locus.

    PubMed

    Kamboh, M I; Ranford, P R; Kirk, R L

    1984-01-01

    Isoelectric focussing (IEF) in thin layer polyacrylamide gels pH range 4-6.5 has been used to analyse the GC phenotypes of 4233 individuals from 28 different population groups in the Asian, Pacific, and Australian area. Because this technique reveals subtypes of the common GC*1 allele, there is almost a two-fold increase in the mean heterozygosity at the GC locus using IEF compared with conventional electrophoresis. The highest frequency (above 50%) of the GC*1S allele was encountered in Indian populations, reflecting genetic affinities with Europeans. By comparison, east and south east Asians are unique offing maximum values of the GC*1F allele (50%). With the exception of a few Pacific populations which show similar frequencies to east Asians, all other groups in the Pacific area, including Australia, have values of GC*1F similar to GC*1S ranging from 27% to 40%. The GC*2 frequency in most populations varies from 20% to 30%. However, some Polynesian groups have values up to 40% and Australian Aborigines less than 10%. Among other alleles, GC*1A1 is found to be widely distributed among Australian Aborigines and Melanesians and occurs sporadically in Polynesians, Micronesians, and in the Lesser Sunda Islands. Four new alleles, GC*1C24, GC*1C35 Aborigine, GC*1A21, and GC*1A22 are described. The gene frequency data at the GC locus has been used to calculate Nei genetic distances between the populations studied. PMID:6541632

  12. Apolipoprotein E alleles in women with severe pre-eclampsia.

    PubMed Central

    Nagy, B; Rigó, J; Fintor, L; Karádi, I; Tóth, T

    1998-01-01

    This study investigated the frequency of apolipoprotein E (apoE) alleles among women with severe pre-eclampsia. The presence of the three most common apoE alleles (epsilon 2, epsilon 3, epsilon 4) was determined by polymerase chain reaction-restriction fragment length polymorphism in three groups of white women: non-pregnant healthy (n = 101), pregnant healthy (n = 52), and pregnant with a diagnosis of severe pre-eclampsia (n = 54). The frequency of apo epsilon 2 was highest among women with severe pre-eclampsia (16.6%) followed by non-pregnant women (12.9%), and those experiencing a healthy pregnancy (10.6%). The higher frequency of the apo epsilon 2 allele detected among women with severe pre-eclampsia suggests that apoE may play a role in the development of pre-eclampsia. PMID:9659248

  13. Different Alleles of a Gene Encoding Leucoanthocyanidin Reductase (PaLAR3) Influence Resistance against the Fungus Heterobasidion parviporum in Picea abies.

    PubMed

    Nemesio-Gorriz, Miguel; Hammerbacher, Almuth; Ihrmark, Katarina; Källman, Thomas; Olson, Åke; Lascoux, Martin; Stenlid, Jan; Gershenzon, Jonathan; Elfstrand, Malin

    2016-08-01

    Despite the fact that fungal diseases are a growing menace for conifers in modern silviculture, only a very limited number of molecular markers for pathogen resistance have been validated in conifer species. A previous genetic study indicated that the resistance of Norway spruce (Picea abies) to Heterobasidion annosum s.l., a pathogenic basidiomycete species complex, is linked to a quantitative trait loci that associates with differences in fungal growth in sapwood (FGS) that includes a gene, PaLAR3, which encodes a leucoanthocyanidin reductase. In this study, gene sequences showed the presence of two PaLAR3 allelic lineages in P. abies. Higher resistance was associated with the novel allele, which was found in low frequency in the four P. abies populations that we studied. Norway spruce plants carrying at least one copy of the novel allele showed a significant reduction in FGS after inoculation with Heterobasidion parviporum compared to their half-siblings carrying no copies, indicating dominance of this allele. The amount of (+) catechin, the enzymatic product of PaLAR3, was significantly higher in bark of trees homozygous for the novel allele. Although we observed that the in vitro activities of the enzymes encoded by the two alleles were similar, we could show that allele-specific transcript levels were significantly higher for the novel allele, indicating that regulation of gene expression is responsible for the observed effects in resistance, possibly caused by differences in cis-acting elements that we observe in the promoter region of the two alleles. PMID:27317690

  14. What Is a Recessive Allele?

    ERIC Educational Resources Information Center

    American Biology Teacher, 1991

    1991-01-01

    Presents four misconceptions students have concerning the concepts of recessive and dominant alleles. Discusses the spectrum of dominant-recessive relationships, different levels of analysis between phenotype and genotype, possible causes of dominance, and an example involving wrinkled peas. (MDH)

  15. A pilot study showing associations between frequency of CD4(+) memory cell subsets at diagnosis and duration of partial remission in type 1 diabetes.

    PubMed

    Moya, Rosita; Robertson, Hannah Kathryn; Payne, Dawson; Narsale, Aditi; Koziol, Jim; Davies, Joanna Davida

    2016-05-01

    In some patients with type 1 diabetes the dose of insulin required to achieve euglycemia is substantially reduced soon after diagnosis. This partial remission is associated with β-cell function and good glucose control. The purpose of this study was to assess whether frequencies of CD4(+) T cell subsets in children newly diagnosed with type 1 diabetes are associated with length of partial remission. We found that the frequency of CD4(+) memory cells, activated Treg cells and CD25(+) cells that express a high density of the IL-7 receptor, CD127 (CD127(hi)) are strongly associated with length of partial remission. Prediction of length of remission via Cox regression is significantly enhanced when CD25(+) CD127(hi) cell frequency is combined with either Insulin Dependent Adjusted A1c (IDAA1c), or glycosylated hemoglobin (HbA1c), or C-peptide levels at diagnosis. CD25(+) CD127(hi) cells do not express Foxp3, LAG-3 and CD49b, indicating that they are neither Treg nor Tr1 cells. PMID:27114212

  16. Evolution of HLA class II molecules: Allelic and amino acid site variability across populations.

    PubMed Central

    Salamon, H; Klitz, W; Easteal, S; Gao, X; Erlich, H A; Fernandez-Viña, M; Trachtenberg, E A; McWeeney, S K; Nelson, M P; Thomson, G

    1999-01-01

    Analysis of the highly polymorphic beta1 domains of the HLA class II molecules encoded by the DRB1, DQB1, and DPB1 loci reveals contrasting levels of diversity at the allele and amino acid site levels. Statistics of allele frequency distributions, based on Watterson's homozygosity statistic F, reveal distinct evolutionary patterns for these loci in ethnically diverse samples (26 populations for DQB1 and DRB1 and 14 for DPB1). When examined over all populations, the DQB1 locus allelic variation exhibits striking balanced polymorphism (P < 10(-4)), DRB1 shows some evidence of balancing selection (P < 0.06), and while there is overall very little evidence for selection of DPB1 allele frequencies, there is a trend in the direction of balancing selection (P < 0.08). In contrast, at the amino acid level all three loci show strong evidence of balancing selection at some sites. Averaged over polymorphic amino acid sites, DQB1 and DPB1 show similar deviation from neutrality expectations, and both exhibit more balanced polymorphic amino acid sites than DRB1. Across ethnic groups, polymorphisms at many codons show evidence for balancing selection, yet data consistent with directional selection were observed at other codons. Both antigen-binding pocket- and non-pocket-forming amino acid sites show overall deviation from neutrality for all three loci. Only in the case of DRB1 was there a significant difference between pocket- and non-pocket-forming amino acid sites. Our findings indicate that balancing selection at the MHC occurs at the level of polymorphic amino acid residues, and that in many cases this selection is consistent across populations. PMID:10224269

  17. Genetic Heterogeneity within Electrophoretic "Alleles" of Xanthine Dehydrogenase in DROSOPHILA PSEUDOOBSCURA

    PubMed Central

    Singh, R. S.; Lewontin, R. C.; Felton, A. A.

    1976-01-01

    An experimental plan for an exhaustive determination of genic variation at structural gene loci is presented. In the initial steps of this program, 146 isochromosomal lines from 12 geographic populations of D. pseudoobscura were examined for allelic variation of xanthine dehydrogenase by the serial use of 4 different electrophoretic conditions and a heat stability test. The 5 criteria revealed a total of 37 allelic classes out of the 146 genomes examined where only 6 had been previously revealed by the usual method of gel electrophoresis. This immense increase in genic variation also showed previously unsuspected population differences between the main part of the species distribution and the isolated population of Bogotá, Colombia, in conformity with the known partial reproductive isolation of the Bogotá population. The average heterozygosity at the Xdh locus is at least 72% in natural populations. This result, together with the very large number of alleles segregating and the pattern of allelic frequencies, has implications for theories of genetic polymorphism which are discussed. PMID:1001881

  18. Distribution of CGG repeats and FRAXAC1/DXS548 alleles in South American populations.

    PubMed

    Mingroni-Netto, Regina Célia; Angeli, Claudia B; Auricchio, Maria Teresa B M; Leal-Mesquita, Emygdia R; Ribeiro-dos-Santos, Andrea K C; Ferrari, Iris; Hutz, Mara H; Salzano, Francisco M; Hill, Kim; Hurtado, A Magdalena; Vianna-Morgante, Angela M

    2002-08-15

    In order to assess the molecular variability related to fragile X (FMR1 locus), we investigated the distribution of CGG repeats and DXS548/FRAXAC1 haplotypes in normal South American populations of different ethnic backgrounds. Special attention was given to Amerindian Wai-Wai (Northern Brazil) and Ache (Paraguay), as well as to Brazilian isolated communities of African ancestry, the remnants of quilombos. Comparison of samples from quilombos, Amerindians, and the ethnically mixed, but mainly European-derived population of São Paulo revealed that the 30-copy allele of the fragile X gene is the most frequent in all groups. A second peak at 20 repeats was present in the population of São Paulo only, confirming this as a European peculiarity. The distribution of DXS548 and FRAXAC1 alleles led to a high expected heterozygosity in African Brazilians, followed by that observed in the population of São Paulo. Amerindians showed the lowest diversity in CGG repeats and DXS548/FRAXAC1 haplotypes. Some rare alleles, for example, the 148-bp (FRAXAC1) or 200-bp (DXS548) variants, which seem to be almost absent in Europe, occurred in higher frequencies among African Brazilians. This suggests a general trend for higher genetic diversity among Africans; these rarer alleles could be African in origin and would have been lost or possibly were not present in the groups that gave rise to the Europeans. PMID:12210320

  19. Association between AgI-CA alleles and severity of autosomal recessive proximal spina lmuscular atrophy

    SciTech Connect

    DiDonato, C.J.; Carpten, J.D.; Fuerst, P.; Ingraham, S.E.; Mendell, J.R.; Burghes, A.H.M.; Morgan, K.; Prescott, G.; Simard, L.R.; McPherson, J.D.

    1994-12-01

    The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has been mapped to an 850-kb interval on 5q11.2-q13.3, between the centromeric D5S823 and telomeric D5S557 markers. We report a new complex marker, Ag1-CA, that lies in this interval, whose primers produce one, two, or rarely three amplification-fragment-length variants (AFLVs) per allele. Class I chromosomes are those which amplify a single AFLV allele, and class II chromosomes are those which amplify an allele with two or three AFLVs. Ag1-CA shows highly significant allelic association with type I SMA in both the French Canadian (Hopital Sainte-Justine (HSJ)) and American (Ohio State University (OSU)) populations (P < .0001). Significant association between the Ag1-CA genotype and disease severity was also observed. Type I patients were predominantly homozygous for class I chromosomes (P = .0003 OSU; P = 0.0012 HSJ), whereas the majority of type II patients were heterozygous for class I and II chromosomes (P = .0014 OSU; P = .001 HSJ). There was no significant difference in Ag1-CA genotype frequencies between type III patients (P = .5 OSU; P = .25 HSJ) and the paired normal chromosomes from both carrier parents. Our results indicate that Ag1-CA is the most closely linked marker to SMA and defines the critical candidate-gene region. Finally, we have proposed a model that should be taken into consideration when screening candidates SMA genes.

  20. Do Heliconius butterfly species exchange mimicry alleles?

    PubMed Central

    Smith, Joel; Kronforst, Marcus R.

    2013-01-01

    Hybridization has the potential to transfer beneficial alleles across species boundaries, and there are a growing number of examples in which this has apparently occurred. Recent studies suggest that Heliconius butterflies have transferred wing pattern mimicry alleles between species via hybridization, but ancestral polymorphism could also produce a signature of shared ancestry around mimicry genes. To distinguish between these alternative hypotheses, we measured DNA sequence divergence around putatively introgressed mimicry loci and compared this with the rest of the genome. Our results reveal that putatively introgressed regions show strongly reduced sequence divergence between co-mimetic species, suggesting that their divergence times are younger than the rest of the genome. This is consistent with introgression and not ancestral variation. We further show that this signature of introgression occurs at sites throughout the genome, not just around mimicry genes. PMID:23864282

  1. Allelic Spectra of Risk SNPs Are Different for Environment/Lifestyle Dependent versus Independent Diseases

    PubMed Central

    Amos, Christopher I.

    2015-01-01

    Genome-wide association studies (GWAS) have generated sufficient data to assess the role of selection in shaping allelic diversity of disease-associated SNPs. Negative selection against disease risk variants is expected to reduce their frequencies making them overrepresented in the group of minor (<50%) alleles. Indeed, we found that the overall proportion of risk alleles was higher among alleles with frequency <50% (minor alleles) compared to that in the group of major alleles. We hypothesized that negative selection may have different effects on environment (or lifestyle)-dependent versus environment (or lifestyle)-independent diseases. We used an environment/lifestyle index (ELI) to assess influence of environmental/lifestyle factors on disease etiology. ELI was defined as the number of publications mentioning “environment” or “lifestyle” AND disease per 1,000 disease-mentioning publications. We found that the frequency distributions of the risk alleles for the diseases with strong environmental/lifestyle components follow the distribution expected under a selectively neutral model, while frequency distributions of the risk alleles for the diseases with weak environmental/lifestyle influences is shifted to the lower values indicating effects of negative selection. We hypothesized that previously selectively neutral variants become risk alleles when environment changes. The hypothesis of ancestrally neutral, currently disadvantageous risk-associated alleles predicts that the distribution of risk alleles for the environment/lifestyle dependent diseases will follow a neutral model since natural selection has not had enough time to influence allele frequencies. The results of our analysis suggest that prediction of SNP functionality based on the level of evolutionary conservation may not be useful for SNPs associated with environment/lifestyle dependent diseases. PMID:26201053

  2. No association between an allele at the D sub 2 dopamine receptor gene (DRD2) and alcoholism

    SciTech Connect

    Gelernter, J.; Krystal, J.; Kennedy, J.L. West Haven Dept. of Veterans Affairs Medical Center, CT ); O'Malley, S.; Risch, N.; Merikangas, K.; Kidd, K.K. ); Kranzler, H.R. )

    1991-10-02

    The author attempted to replicate a positive allelic association between the A1 allele of DRD2 (the D{sub 2} dopamine receptor locus) and alcoholism that has been reported. They compared allele frequencies at the previously described Taq I restriction fragment length polymorphism system of DRD2 in alcoholics and random population controls.

  3. Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles.

    PubMed

    Laffita-Mesa, José Miguel; Velázquez-Pérez, Luis C; Santos Falcón, Nieves; Cruz-Mariño, Tania; González Zaldívar, Yanetza; Vázquez Mojena, Yaimee; Almaguer-Gotay, Dennis; Almaguer Mederos, Luis Enrique; Rodríguez Labrada, Roberto

    2012-01-01

    The role of short, large or intermediate normal alleles (ANs) of the ataxin-2 gene in generating expanded alleles (EAs) causing spinocerebellar ataxia type 2 (SCA2) is poorly understood. It has been postulated that SCA2 prevalence is related to the frequency of large ANs. SCA2 shows the highest worldwide prevalence in Cuban population, which is therefore a unique source for studying the relationship between the frequency of large and intermediate alleles and the frequency of SCA2 mutation. Through genetic polymorphism analyses in a comprehensive sample (~3000 chromosomes), we show that the frequency of large ANs in the ataxin-2 gene is the highest worldwide, although short ANs are also frequent. This highly polymorphic population displayed also high variability in the CAG sequence, featured by loss of the anchor CAA interruption(s). In addition, large ANs showed germinal and somatic instability. Our study also includes related genotypic, genealogical and haplotypic data and provides substantial evidence with regard to the role of large and intermediate alleles in the generation of pathological EAs. PMID:21934711

  4. Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles

    PubMed Central

    Laffita-Mesa, José Miguel; Velázquez-Pérez, Luis C; Santos Falcón, Nieves; Cruz-Mariño, Tania; González Zaldívar, Yanetza; Vázquez Mojena, Yaimee; Almaguer-Gotay, Dennis; Almaguer Mederos, Luis Enrique; Rodríguez Labrada, Roberto

    2012-01-01

    The role of short, large or intermediate normal alleles (ANs) of the ataxin-2 gene in generating expanded alleles (EAs) causing spinocerebellar ataxia type 2 (SCA2) is poorly understood. It has been postulated that SCA2 prevalence is related to the frequency of large ANs. SCA2 shows the highest worldwide prevalence in Cuban population, which is therefore a unique source for studying the relationship between the frequency of large and intermediate alleles and the frequency of SCA2 mutation. Through genetic polymorphism analyses in a comprehensive sample (∼3000 chromosomes), we show that the frequency of large ANs in the ataxin-2 gene is the highest worldwide, although short ANs are also frequent. This highly polymorphic population displayed also high variability in the CAG sequence, featured by loss of the anchor CAA interruption(s). In addition, large ANs showed germinal and somatic instability. Our study also includes related genotypic, genealogical and haplotypic data and provides substantial evidence with regard to the role of large and intermediate alleles in the generation of pathological EAs. PMID:21934711

  5. Delimiting Allelic Imbalance of TYMS by Allele-Specific Analysis

    PubMed Central

    Balboa-Beltrán, Emilia; Cruz, Raquel; Carracedo, Angel; Barros, Francisco

    2015-01-01

    Abstract Allelic imbalance of thymidylate synthase (TYMS) is attributed to polymorphisms in the 5′- and 3′-untranslated region (UTR). These polymorphisms have been related to the risk of suffering different cancers, for example leukemia, breast or gastric cancer, and response to different drugs, among which are methotrexate glutamates, stavudine, and specifically 5-fluorouracil (5-FU), as TYMS is its direct target. A vast literature has been published in relation to 5-FU, even suggesting the sole use of these polymorphisms to effectively manage 5-FU dosage. Estimates of the extent to which these polymorphisms influence in TYMS expression have in the past been based on functional analysis by luciferase assays and quantification of TYMS mRNA, but both these studies, as the association studies with cancer risk or with toxicity or response to 5-FU, are very contradictory. Regarding functional assays, the artificial genetic environment created in luciferase assay and the problems derived from quantitative polymerase chain reactions (qPCRs), for example the use of a reference gene, may have distorted the results. To avoid these sources of interference, we have analyzed the allelic imbalance of TYMS by allelic-specific analysis in peripheral blood mononuclear cells (PBMCs) from patients. Allelic imbalance in PBMCs, taken from 40 patients with suspected myeloproliferative haematological diseases, was determined by fluorescent fragment analysis (for the 3′-UTR polymorphism), Sanger sequencing and allelic-specific qPCR in multiplex (for the 5′-UTR polymorphisms). For neither the 3′- nor the 5′-UTR polymorphisms did the observed allelic imbalance exceed 1.5 fold. None of the TYMS polymorphisms is statistically associated with allelic imbalance. The results acquired allow us to deny the previously established assertion of an influence of 2 to 4 fold of the rs45445694 and rs2853542 polymorphisms in the expression of TYMS and narrow its allelic imbalance to 1.5 fold

  6. Distribution of the lactase persistence-associated variant alleles -13910* T and -13915* G among the people of Oman and Yemen.

    PubMed

    Al-Abri, Abdul Rahim; Al-Rawas, Omar; Al-Yahyaee, Saeed; Al-Habori, Molham; Al-Zubairi, Adel Sharaf; Bayoumi, Riad

    2012-06-01

    The high prevalence of lactase persistence (LP) among the people of Saudi Arabia is associated with the -13915(*)G variant allele upstream of the lactase gene (LCT). We, therefore, examined the frequency of the commonly known LP associated SNPs among randomly collected samples from Omani and Yemeni adult populations and obtained further data on the distribution of the two most common LP-associated variants, -13910(*)T and -13915T(*)G, in the Arabian Peninsula. The DNA fragment containing all the reported LP- associated SNPs was amplified and genotyped. The frequency of the -13915(*)G allele was highest among Dhofari Arabs of southern Oman (0.72) followed by Yemeni Arabs (0.54) and Arabs of northern Oman (0.14). It was not detected in Omanis of Asian origin. The frequency of the -13910(*)T allele was extremely low in Arabs of northern and southern Oman (0.00-0.01) and Yemenis (0.002). However, it had a frequency of 0.160 among Omanis of Asian origin. Results show that the highest frequency of the LCT -13915(*)G variant allele appears to be in the south of the Arabian Peninsula with clinal decrease within the Peninsula and further out in surrounding countries. PMID:23256641

  7. Identification of 48 full-length MHC-DAB functional alleles in miiuy croaker and evidence for positive selection.

    PubMed

    Liu, Jiang; Sun, Yueyan; Xu, Tianjun

    2016-07-01

    Major histocompatibility complex (MHC) molecules play a vital role in the immune response and are a highly polymorphic gene superfamily in vertebrates. As the molecular marker associated with polymorphism and disease susceptibility/resistance, the polymorphism of MHC genes has been investigated in many tetrapods and teleosts. Most studies were focused on the polymorphism of the second exon, which encodes the peptide-binding region (PBR) in the α1- or β1-domain, but few studies have examined the full-length coding region. To comprehensive investigate the polymorphism of MHC gene, we identified 48 full-length miiuy croaker (Miichthys miiuy) MHC class IIB (Mimi-DAB) functional alleles from 26 miiuy croaker individuals. All of the alleles encode 34 amino acid sequences, and a high level of polymorphism was detected in Mimi-DAB alleles. The rate of non-synonymous substitutions (dN) occurred at a significantly higher frequency than that of synonymous substitutions (dS) in the PBR, and this result suggests that balancing selection maintains polymorphisms at the Mimi-DAB locus. Phylogenetic analysis based on the full-length and exon 2 sequences of Mimi-DAB alleles both showed that the Mimi-DAB alleles were clustered into two major groups. A total of 19 positive selected sites were identified on the Mimi-DAB alleles after testing for positive selection, and 14 sites were predicted to be associated with antigen-binding sites, which suggests that most of selected sites are significant for disease resistance. The polymorphism of Mimi-DAB alleles provides an important resource for analyzing the association between the polymorphism of MHC gene and disease susceptibility/resistance, and for researching the molecular selective breeding of miiuy croaker with enhanced disease resistance. PMID:27164216

  8. Responders to Wide-Pulse, High-Frequency Neuromuscular Electrical Stimulation Show Reduced Metabolic Demand: A 31P-MRS Study in Humans

    PubMed Central

    Wegrzyk, Jennifer; Fouré, Alexandre; Le Fur, Yann; Maffiuletti, Nicola A.; Vilmen, Christophe; Guye, Maxime; Mattei, Jean-Pierre; Place, Nicolas; Bendahan, David; Gondin, Julien

    2015-01-01

    Conventional (CONV) neuromuscular electrical stimulation (NMES) (i.e., short pulse duration, low frequencies) induces a higher energetic response as compared to voluntary contractions (VOL). In contrast, wide-pulse, high-frequency (WPHF) NMES might elicit–at least in some subjects (i.e., responders)–a different motor unit recruitment compared to CONV that resembles the physiological muscle activation pattern of VOL. We therefore hypothesized that for these responder subjects, the metabolic demand of WPHF would be lower than CONV and comparable to VOL. 18 healthy subjects performed isometric plantar flexions at 10% of their maximal voluntary contraction force for CONV (25 Hz, 0.05 ms), WPHF (100 Hz, 1 ms) and VOL protocols. For each protocol, force time integral (FTI) was quantified and subjects were classified as responders and non-responders to WPHF based on k-means clustering analysis. Furthermore, a fatigue index based on FTI loss at the end of each protocol compared with the beginning of the protocol was calculated. Phosphocreatine depletion (ΔPCr) was assessed using 31P magnetic resonance spectroscopy. Responders developed four times higher FTI’s during WPHF (99 ± 37 ×103 N.s) than non-responders (26 ± 12 ×103 N.s). For both responders and non-responders, CONV was metabolically more demanding than VOL when ΔPCr was expressed relative to the FTI. Only for the responder group, the ∆PCr/FTI ratio of WPHF (0.74 ± 0.19 M/N.s) was significantly lower compared to CONV (1.48 ± 0.46 M/N.s) but similar to VOL (0.65 ± 0.21 M/N.s). Moreover, the fatigue index was not different between WPHF (-16%) and CONV (-25%) for the responders. WPHF could therefore be considered as the less demanding NMES modality–at least in this subgroup of subjects–by possibly exhibiting a muscle activation pattern similar to VOL contractions. PMID:26619330

  9. A robust statistical method to detect null alleles in microsatellite and SNP datasets in both panmictic and inbred populations.

    PubMed

    Girard, Philippe

    2011-01-01

    Null alleles are common technical artifacts in genetic-based analysis. Powerful methods enabling their detection in either panmictic or inbred populations have been proposed. However, none of these methods appears unbiased in both types of mating systems, necessitating a priori knowledge of the inbreeding level of the population under study. To counter this problem, I propose to use the software FDist2 to detect the atypical fixation indices that characterize markers with null alleles. The rational behind this approach and the parameter settings are explained. The power of the method for various sample sizes, degrees of inbreeding and null allele frequencies is evaluated using simulated microsatellite and SNP datasets and then compared to two other null allele detection methods. The results clearly show the robustness of the method proposed here as well as its greater accuracy in both panmictic and inbred populations for both types of marker. By allowing a proper detection of null alleles for a wide range of mating systems and markers, this new method is particularly appealing for numerous genetic studies using co-dominant loci. PMID:21381434

  10. Characterization of 40 full-length MHC class IIA functional alleles in miiuy croaker: Polymorphism and positive selection.

    PubMed

    Xu, Tianjun; Liu, Jiang; Sun, Yueyan; Zhu, Zhihuang; Liu, Tianxing

    2016-02-01

    The major histocompatibility complex is a highly polymorphic gene superfamily in vertebrates that plays an important role in adaptive immune response. In the present study, we identified 40 full-length miiuy croaker MHC class IIA (Mimi-DAA) functional alleles from 26 miiuy croaker individuals and found that the alleles encode 30 amino acid sequences. A high level of polymorphism in Mimi-DAA was detected in miiuy croaker. The rate of non-synonymous substitutions (d(N)) occurred at a significantly higher frequency than that of synonymous substitutions (d(S)) in the peptide-binding region (PBR) and non-PBR. This result suggests that balancing selection maintains polymorphisms at the Mimi-DAA locus. Phylogenetic analysis based on the full-length sequences showed that the Mimi-DAA alleles clustered into three groups. However, the phylogenetic tree constructed using the exon 2 sequences indicated that the Mimi-DAA alleles clustered into two groups. A total of 22 positively selected sites were identified on the Mimi-DAA alleles after testing for positive selection, and five sites were predicted to be associated with the binding of peptide antigen, suggesting that a few selected residues may play a significant role in immune function. PMID:26598111

  11. Immunoglobulin light chain allelic inclusion in systemic lupus erythematosus.

    PubMed

    Fraser, Louise D; Zhao, Yuan; Lutalo, Pamela M K; D'Cruz, David P; Cason, John; Silva, Joselli S; Dunn-Walters, Deborah K; Nayar, Saba; Cope, Andrew P; Spencer, Jo

    2015-08-01

    The principles of allelic exclusion state that each B cell expresses a single light and heavy chain pair. Here, we show that B cells with both kappa and lambda light chains (Igκ and Igλ) are enriched in some patients with the systemic autoimmune disease systemic lupus erythematosus (SLE), but not in the systemic autoimmune disease control granulomatosis with polyangiitis. Detection of dual Igκ and Igλ expression by flow cytometry could not be abolished by acid washing or by DNAse treatment to remove any bound polyclonal antibody or complexes, and was retained after two days in culture. Both surface and intracytoplasmic dual light chain expression was evident by flow cytometry and confocal microscopy. We observed reduced frequency of rearrangements of the kappa-deleting element (KDE) in SLE and an inverse correlation between the frequency of KDE rearrangement and the frequency of dual light chain expressing B cells. We propose that dual expression of Igκ and Igλ by a single B cell may occur in some patients with SLE when this may be a consequence of reduced activity of the KDE. PMID:26036683

  12. Allelic variation at a single gene increases food value in a drought-tolerant staple cereal.

    PubMed

    Gilding, Edward K; Frère, Celine H; Cruickshank, Alan; Rada, Anna K; Prentis, Peter J; Mudge, Agnieszka M; Mace, Emma S; Jordan, David R; Godwin, Ian D

    2013-01-01

    The production of adequate agricultural outputs to support the growing human population places great demands on agriculture, especially in light of ever-greater restrictions on input resources. Sorghum is a drought-adapted cereal capable of reliable production where other cereals fail, and thus represents a good candidate to address food security as agricultural inputs of water and arable land grow scarce. A long-standing issue with sorghum grain is that it has an inherently lower digestibility. Here we show that a low-frequency allele type in the starch metabolic gene, pullulanase, is associated with increased digestibility, regardless of genotypic background. We also provide evidence that the beneficial allele type is not associated with deleterious pleiotropic effects in the modern field environment. We argue that increasing the digestibility of an adapted crop is a viable way forward towards addressing food security while maximizing water and land-use efficiency. PMID:23403584

  13. Association of apolipoprotein E allele {epsilon}4 with late-onset sporadic Alzheimer`s disease

    SciTech Connect

    Lucotte, G.; David, F.; Berriche, S.

    1994-09-15

    Apolipoprotein E, type {epsilon}4 allele (ApoE {epsilon}4), is associated with late-onset sporadic Alzheimer`s disease (AD) in French patients. The association is highly significant (0.45 AD versus 0.12 controls for {epsilon}4 allele frequencies). These data support the involvement of ApoE {epsilon}4 allele as a very important risk factor for the clinical expression of AD. 22 refs., 1 fig., 3 tabs.

  14. Distribution of CYP2D6 alleles and phenotypes in the Brazilian population.

    PubMed

    Friedrich, Deise C; Genro, Júlia P; Sortica, Vinicius A; Suarez-Kurtz, Guilherme; de Moraes, Maria Elizabete; Pena, Sergio D J; dos Santos, Andrea K Ribeiro; Romano-Silva, Marco A; Hutz, Mara H

    2014-01-01

    The CYP2D6 enzyme is one of the most important members of the cytochrome P450 superfamily. This enzyme metabolizes approximately 25% of currently prescribed medications. The CYP2D6 gene presents a high allele heterogeneity that determines great inter-individual variation. The aim of this study was to evaluate the variability of CYP2D6 alleles, genotypes and predicted phenotypes in Brazilians. Eleven single nucleotide polymorphisms and CYP2D6 duplications/multiplications were genotyped by TaqMan assays in 1020 individuals from North, Northeast, South, and Southeast Brazil. Eighteen CYP2D6 alleles were identified in the Brazilian population. The CYP2D6*1 and CYP2D6*2 alleles were the most frequent and widely distributed in different geographical regions of Brazil. The highest number of CYPD6 alleles observed was six and the frequency of individuals with more than two copies ranged from 6.3% (in Southern Brazil) to 10.2% (Northern Brazil). The analysis of molecular variance showed that CYP2D6 is homogeneously distributed across different Brazilian regions and most of the differences can be attributed to inter-individual differences. The most frequent predicted metabolic status was EM (83.5%). Overall 2.5% and 3.7% of Brazilians were PMs and UMs respectively. Genomic ancestry proportions differ only in the prevalence of intermediate metabolizers. The IM predicted phenotype is associated with a higher proportion of African ancestry and a lower proportion of European ancestry in Brazilians. PM and UM classes did not vary among regions and/or ancestry proportions therefore unique CYP2D6 testing guidelines for Brazilians are possible and could potentially avoid ineffective or adverse events outcomes due to drug prescriptions. PMID:25329392

  15. Distribution of CYP2D6 Alleles and Phenotypes in the Brazilian Population

    PubMed Central

    Sortica, Vinicius A.; Suarez-Kurtz, Guilherme; de Moraes, Maria Elizabete; Pena, Sergio D. J.; dos Santos, Ândrea K. Ribeiro; Romano-Silva, Marco A.; Hutz, Mara H.

    2014-01-01

    Abstract The CYP2D6 enzyme is one of the most important members of the cytochrome P450 superfamily. This enzyme metabolizes approximately 25% of currently prescribed medications. The CYP2D6 gene presents a high allele heterogeneity that determines great inter-individual variation. The aim of this study was to evaluate the variability of CYP2D6 alleles, genotypes and predicted phenotypes in Brazilians. Eleven single nucleotide polymorphisms and CYP2D6 duplications/multiplications were genotyped by TaqMan assays in 1020 individuals from North, Northeast, South, and Southeast Brazil. Eighteen CYP2D6 alleles were identified in the Brazilian population. The CYP2D6*1 and CYP2D6*2 alleles were the most frequent and widely distributed in different geographical regions of Brazil. The highest number of CYPD6 alleles observed was six and the frequency of individuals with more than two copies ranged from 6.3% (in Southern Brazil) to 10.2% (Northern Brazil). The analysis of molecular variance showed that CYP2D6 is homogeneously distributed across different Brazilian regions and most of the differences can be attributed to inter-individual differences. The most frequent predicted metabolic status was EM (83.5%). Overall 2.5% and 3.7% of Brazilians were PMs and UMs respectively. Genomic ancestry proportions differ only in the prevalence of intermediate metabolizers. The IM predicted phenotype is associated with a higher proportion of African ancestry and a lower proportion of European ancestry in Brazilians. PM and UM classes did not vary among regions and/or ancestry proportions therefore unique CYP2D6 testing guidelines for Brazilians are possible and could potentially avoid ineffective or adverse events outcomes due to drug prescriptions. PMID:25329392

  16. Characterization of 12 silent alleles of the human butyrylcholinesterase (BCHE) gene.

    PubMed Central

    Primo-Parmo, S. L.; Bartels, C. F.; Wiersema, B.; van der Spek, A. F.; Innis, J. W.; La Du, B. N.

    1996-01-01

    The silent phenotype of human butyrylcholinesterase (BChE), present in most human populations in frequencies of approximately 1/100,000, is characterized by the complete absence of BChE activity or by activity <10% of the average levels of the usual phenotype. Heterogeneity in this phenotype has been well established at the phenotypic level, but only a few silent BCHE alleles have been characterized at the DNA level. Twelve silent alleles of the human butyrylcholinesterase gene (BCHE) have been identified in 17 apparently unrelated patients who were selected by their increased sensitivity to the muscle relaxant succinylcholine. All of these alleles are characterized by single nucleotide substitutions or deletions leading to distinct changes in the structure of the BChE enzyme molecule. Nine of the nucleotide substitutions result in the replacement of single amino acid residues. Three of these variants, BCHE*33C, BCHE*198G, and BCHE*201T, produce normal amounts of immunoreactive but enzymatically inactive BChE protein in the plasma. The other six amino acid substitutions, encoded by BCHE*37S, BCHE*125F, BCHE*170E, BCHE*471R, and BCHE*518L, seem to cause reduced expression of BChE protein, and their role in determining the silent phenotype was confirmed by expression in cell culture. The other four silent alleles, BCHE*271STOP, BCHE*500STOP, BCHE*FS6, and BCHE*I2E3-8G, encode BChES truncated at their C-terminus because of premature stop codons caused by nucleotide substitutions, a frame shift, or altered splicing. The large number of different silent BCHE alleles found within a relatively small number of patients shows that the heterogeneity of the silent BChE phenotype is high. The characterization of silent BChE variants will be useful in the study of the structure/function relationship for this and other closely related enzymes. Images Figure 2 PMID:8554068

  17. Distortion of maternal-fetal angiotensin II type 1 receptor allele transmission in pre-eclampsia.

    PubMed Central

    Morgan, L; Crawshaw, S; Baker, P N; Brookfield, J F; Broughton Pipkin, F; Kalsheker, N

    1998-01-01

    OBJECTIVE: To investigate the fetal angiotensin II type 1 receptor genotype in pre-eclampsia. DESIGN: Case-control study. POPULATION: Forty-one maternal-fetal pairs from pre-eclamptic pregnancies and 80 maternal-fetal pairs from normotensive pregnancies. METHODS: Maternal and fetal DNA was genotyped at three diallelic polymorphisms, at nucleotides 573, 1062, and 1166, in the coding exon of the angiotensin II type 1 receptor gene, and at a dinucleotide repeat polymorphism in its 3' flanking region. RESULTS: Allele and genotype frequencies at the four polymorphic regions investigated did not differ between pre-eclamptic and normotensive groups, in either fetal or maternal samples. Mothers heterozygous for the dinucleotide repeat allele designated A4 transmitted this allele to the fetus in 15 of 18 informative pre-eclamptic pregnancies and in eight of 26 normotensive pregnancies. This was greater than the expected probability in pre-eclamptic pregnancies (p=0.04) and less than expected in normotensive pregnancies (p<0.005). The 573T variant, which is in partial linkage disequilibrium with the A4 allele, showed a similar distortion of maternal-fetal transmission. CONCLUSION: Angiotensin II type 1 receptor gene expression in the fetus may contribute to the aetiology of pre-eclampsia. It is unclear whether susceptibility is conferred by the fetal genotype acting alone, or by allele sharing by mother and fetus. Possible mechanisms for the effect of the angiotensin II type 1 receptor gene are suggested by the association of the 573T variant with low levels of surface receptor expression on platelets. If receptor expression is similarly genetically determined in the placenta, responsiveness to angiotensin II may be affected, with the potential to influence placentation or placental prostaglandin secretion. PMID:9719367

  18. Parallel Adaptation: One or Many Waves of Advance of an Advantageous Allele?

    PubMed Central

    Ralph, Peter; Coop, Graham

    2010-01-01

    Models for detecting the effect of adaptation on population genomic diversity are often predicated on a single newly arisen mutation sweeping rapidly to fixation. However, a population can also adapt to a new environment by multiple mutations of similar phenotypic effect that arise in parallel, at the same locus or different loci. These mutations can each quickly reach intermediate frequency, preventing any single one from rapidly sweeping to fixation globally, leading to a “soft” sweep in the population. Here we study various models of parallel mutation in a continuous, geographically spread population adapting to a global selection pressure. The slow geographic spread of a selected allele due to limited dispersal can allow other selected alleles to arise and start to spread elsewhere in the species range. When these different selected alleles meet, their spread can slow dramatically and so initially form a geographic patchwork, a random tessellation, which could be mistaken for a signal of local adaptation. This spatial tessellation will dissipate over time due to mixing by migration, leaving a set of partial sweeps within the global population. We show that the spatial tessellation initially formed by mutational types is closely connected to Poisson process models of crystallization, which we extend. We find that the probability of parallel mutation and the spatial scale on which parallel mutation occurs are captured by a single compound parameter, a characteristic length, which reflects the expected distance a spreading allele travels before it encounters a different spreading allele. This characteristic length depends on the mutation rate, the dispersal parameter, the effective local density of individuals, and to a much lesser extent the strength of selection. While our knowledge of these parameters is poor, we argue that even in widely dispersing species, such parallel geographic sweeps may be surprisingly common. Thus, we predict that as more data

  19. Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations

    PubMed Central

    Li, Mingkun; Schröder, Roland; Ni, Shengyu; Madea, Burkhard; Stoneking, Mark

    2015-01-01

    Heteroplasmy in human mtDNA may play a role in cancer, other diseases, and aging, but patterns of heteroplasmy variation across different tissues have not been thoroughly investigated. Here, we analyzed complete mtDNA genome sequences at ∼3,500× average coverage from each of 12 tissues obtained at autopsy from each of 152 individuals. We identified 4,577 heteroplasmies (with an alternative allele frequency of at least 0.5%) at 393 positions across the mtDNA genome. Surprisingly, different nucleotide positions (nps) exhibit high frequencies of heteroplasmy in different tissues, and, moreover, heteroplasmy is strongly dependent on the specific consensus allele at an np. All of these tissue-related and allele-related heteroplasmies show a significant age-related accumulation, suggesting positive selection for specific alleles at specific positions in specific tissues. We also find a highly significant excess of liver-specific heteroplasmies involving nonsynonymous changes, most of which are predicted to have an impact on protein function. This apparent positive selection for reduced mitochondrial function in the liver may reflect selection to decrease damaging byproducts of liver mitochondrial metabolism (i.e., “survival of the slowest”). Overall, our results provide compelling evidence for positive selection acting on some somatic mtDNA mutations. PMID:25675502

  20. Common alleles contribute to schizophrenia in CNV carriers

    PubMed Central

    Tansey, K E; Rees, E; Linden, D E; Ripke, S; Chambert, K D; Moran, J L; McCarroll, S A; Holmans, P; Kirov, G; Walters, J; Owen, M J; O'Donovan, M C

    2016-01-01

    The genetic architecture of schizophrenia is complex, involving risk alleles ranging from common alleles of weak effect to rare alleles of large effect, the best exemplar of the latter being large copy number variants (CNVs). It is currently unknown whether pathophysiology in those with defined rare mutations overlaps with that in other individuals with the disorder who do not share the same rare mutation. Under an extreme heterogeneity model, carriers of specific high-penetrance mutations form distinct subgroups. In contrast, under a polygenic threshold model, high-penetrance rare allele carriers possess many risk factors, of which the rare allele is the only one, albeit an important, factor. Under the latter model, cases with rare mutations can be expected to share some common risk alleles, and therefore pathophysiological mechanisms, with cases without the same mutation. Here we show that, compared with controls, individuals with schizophrenia who have known pathogenic CNVs carry an excess burden of common risk alleles (P=2.25 × 10−17) defined from a genome-wide association study largely based on individuals without known CNVs. Our finding is not consistent with an extreme heterogeneity model for CNV carriers, but does offer support for the polygenic threshold model of schizophrenia. That this is so provides support for the notion that studies aiming to model the effects of rare variation may uncover pathophysiological mechanisms of relevance to those with the disorder more widely. PMID:26390827

  1. Common alleles contribute to schizophrenia in CNV carriers.

    PubMed

    Tansey, K E; Rees, E; Linden, D E; Ripke, S; Chambert, K D; Moran, J L; McCarroll, S A; Holmans, P; Kirov, G; Walters, J; Owen, M J; O'Donovan, M C

    2016-08-01

    The genetic architecture of schizophrenia is complex, involving risk alleles ranging from common alleles of weak effect to rare alleles of large effect, the best exemplar of the latter being large copy number variants (CNVs). It is currently unknown whether pathophysiology in those with defined rare mutations overlaps with that in other individuals with the disorder who do not share the same rare mutation. Under an extreme heterogeneity model, carriers of specific high-penetrance mutations form distinct subgroups. In contrast, under a polygenic threshold model, high-penetrance rare allele carriers possess many risk factors, of which the rare allele is the only one, albeit an important, factor. Under the latter model, cases with rare mutations can be expected to share some common risk alleles, and therefore pathophysiological mechanisms, with cases without the same mutation. Here we show that, compared with controls, individuals with schizophrenia who have known pathogenic CNVs carry an excess burden of common risk alleles (P=2.25 × 10(-17)) defined from a genome-wide association study largely based on individuals without known CNVs. Our finding is not consistent with an extreme heterogeneity model for CNV carriers, but does offer support for the polygenic threshold model of schizophrenia. That this is so provides support for the notion that studies aiming to model the effects of rare variation may uncover pathophysiological mechanisms of relevance to those with the disorder more widely. PMID:26390827

  2. Rats showing low and high sensitization of frequency-modulated 50-kHz vocalization response to amphetamine differ in amphetamine-induced brain Fos expression.

    PubMed

    Kaniuga, Ewelina; Taracha, Ewa; Stępień, Tomasz; Wierzba-Bobrowicz, Teresa; Płaźnik, Adam; Chrapusta, Stanisław J

    2016-10-01

    Individuals predisposed to addiction constitute a minority of drug users, in both humans and animal models of the disorder, but there are no established characteristics that would allow identifying them beforehand. Our studies demonstrate that sensitization of rat 50-kHz ultrasonic vocalization (USV) response to amphetamine shows marked inter-individual diversity but substantial intra-individual stability. Low sensitization of the response shows relevance to the acquisition of self-administration of this drug and hence might be of predictive value regarding the risk of addiction. We compared amphetamine-induced Fos expression in 16 brain regions considered important for the development of addiction between rats preselected for low and high sensitization of the response and next given nine daily amphetamine doses followed by a 2-week withdrawal and final amphetamine challenge. Ventral tegmental area and nucleus accumbens shell Fos-positive nuclei counts correlated positively with 50-kHz USV response to the challenge in high-sensitized rats. Compared to those in amphetamine-untreated controls, Fos-positive nuclei counts were significantly and markedly (2-6 times) higher in 12 regions in high-sensitized rats, whereas in low-sensitized rats they were significantly higher in the cingulate cortex and dorsomedial striatum only. The difference in the counts between the latter two subsets reached statistical significance in dorsomedial and dorsolateral striatum and three out of four cortical regions studied. The fact that the diversification was most distinct in dorsal striatum that plays a critical role in the transition from controlled to compulsive drug intake suggests that the USV-based categorization may be related to divergent vulnerability of rats to AMPH addiction. PMID:27507424

  3. Variant mapping of the Apo(B) AT rich minisatellite. Dependence on nucleotide sequence of the copy number variations. Instability of the non-canonical alleles.

    PubMed Central

    Desmarais, E; Vigneron, S; Buresi, C; Cambien, F; Cambou, J P; Roizes, G

    1993-01-01

    Because of its variations in length, the AT rich Hyper-Variable Region (HVR) of the 3' end of the Apolipoprotein B gene is used as a polymorphic maker in genetic studies. It contains a SspI site in its repeated motif and we used this feature to precisely analyse the internal structure of the different alleles found at this locus in a Caucasian population. We performed total digestion on 194 alleles as well as Minisatellite Variant Repeat mapping (MVR mapping: partial digestion) on 54. The results show that the level of length variability (in copy number) of the 5' end of this locus is at least two times higher than that of the 3' end. This could be correlated with the difference in nucleotide sequence between the two parts of the HVR and suggests the dependence on the primary structure of the mechanism that produces length variability. A molecular model is proposed to explain this result. Moreover, the sharp analysis of the minisatellite structure by the distribution of SspI sites reveals differences between long and short alleles, indicating that in most cases, no recombination occurs between alleles of different sizes. Finally the rare alleles exhibit a non-canonical structure. These important points could explain the bimodal distribution of the frequencies of the alleles in the population. Images PMID:8502559

  4. "The Show"

    ERIC Educational Resources Information Center

    Gehring, John

    2004-01-01

    For the past 16 years, the blue-collar city of Huntington, West Virginia, has rolled out the red carpet to welcome young wrestlers and their families as old friends. They have come to town chasing the same dream for a spot in what many of them call "The Show". For three days, under the lights of an arena packed with 5,000 fans, the state's best…

  5. Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain

    PubMed Central

    Richards, Alexander L; Jones, Lesley; Moskvina, Valentina; Kirov, George; Gejman, Pablo V; Levinson, Douglas F; Sanders, Alan R; Purcell, Shaun; Visscher, Peter M; Craddock, Nick; Owen, Michael J; Holmans, Peter; O’Donovan, Michael C

    2016-01-01

    It is widely thought that alleles that influence susceptibility to common diseases, including schizophrenia, will frequently do so through effects on gene expression. Since only a small proportion of the genetic variance for schizophrenia has been attributed to specific loci, this remains an unproven hypothesis. The International Schizophrenia Consortium (ISC) recently reported a substantial polygenic contribution to that disorder, and that schizophrenia risk alleles are enriched among SNPs selected for marginal evidence for association (p<0.5) from genome wide association studies (GWAS). It follows that if schizophrenia susceptibility alleles are enriched for those that affect gene expression, those marginally associated SNPs which are also eQTLs should carry more true association signals compared with SNPs which are not. To test this, we identified marginally associated (p<0.5) SNPs from two of the largest available schizophrenia GWAS datasets. We assigned eQTL status to those SNPs based upon an eQTL dataset derived from adult human brain. Using the polygenic score method of analysis reported by the ISC, we observed and replicated the observation that higher probability cis-eQTLs predicted schizophrenia better than those with a lower probability for being a cis-eQTL. Our data support the hypothesis that alleles conferring risk of schizophrenia are enriched among those that affect gene expression. Moreover, our data show that notwithstanding the likely developmental origin of schizophrenia, studies of adult brain tissue can in principle allow relevant susceptibility eQTLs to be identified. PMID:21339752

  6. Apolipoprotein E alleles in Alzheimer`s and Parkinson`s patients

    SciTech Connect

    Poduslo, S.E.; Schwankhaus, J.D.

    1994-09-01

    A number of investigators have found an association between the apolipoprotein E4 allele and Alzheimer`s disease. The E4 allele appears at a higher frequency in late onset familial Alzheimer`s patients. In our studies we obtained blood samples from early and late onset familial and sporadic Alzheimer`s patients and spouses, as well as from Parkinson`s patients. The patients were diagnosed as probable Alzheimer`s patients after a neurological examination, extensive blood work, and a CAT scan. The diagnosis was made according to the NINCDS-ADRDA criteria. The apolipoprotein E4 polymorphism was detected after PCR amplification of genomic DNA, restriction enzyme digestion with Hhal, and polyacrylamide gel electrophoresis. Ethidium bromide-stained bands at 91 bp were designated as allele 3, at 83 bp as allele 2, and at 72 bp as allele 4. Of the 84 probable Alzheimer`s patients (all of whom were Caucasian), 47 were heterozygous and 13 were homozygous for the E4 allele. There were 26 early onset patients; 13 were heterozygous and 7 homozygous for the E4 allele. The frequencies for the E4 allele for late onset familial patients was 0.45 and for sporadic patients was 0.37. We analyzed 77 spouses with an average age of 71.9 {plus_minus} 7.4 years as controls, and 15 were heterozygous for the E4 allele for an E4 frequency of 0.097. Of the 53 Parkinson`s patients, 11 had the E4 allele for a frequency of 0.113. Thus our findings support the association of the ApoE4 allele with Alzheimer`s disease.

  7. Geostatistical analysis of allele presence patterns among American black bears in eastern North Carolina

    USGS Publications Warehouse

    Thompson, L.M.; Van Manen, F.T.; King, T.L.

    2005-01-01

    Highways are one of the leading causes of wildlife habitat fragmentation and may particularly affect wide-ranging species, such as American black bears (Ursus americanus). We initiated a research project in 2000 to determine potential effects of a 4-lane highway on black bear ecology in Washington County, North Carolina. The research design included a treatment area (highway construction) and a control area and a pre- and post-construction phase. We used data from the pre-construction phase to determine whether we could detect scale dependency or directionality among allele occurrence patterns using geostatistics. Detection of such patterns could provide a powerful tool to measure the effects of landscape fragmentation on gene flow. We sampled DNA from roots of black bear hair at 70 hair-sampling sites on each study area for 7 weeks during fall of 2000. We used microsatellite analysis based on 10 loci to determine unique multi-locus genotypes. We examined all alleles sampled at ???25 sites on each study area and mapped their presence or absence at each hair-sample site. We calculated semivariograms, which measure the strength of statistical correlation as a function of distance, and adjusted them for anisotropy to determine the maximum direction of spatial continuity. We then calculated the mean direction of spatial continuity for all examined alleles. The mean direction of allele frequency variation was 118.3?? (SE = 8.5) on the treatment area and 172.3?? (SE = 6.0) on the control area. Rayleigh's tests showed that these directions differed from random distributions (P = 0.028 and P < 0.001, respectively), indicating consistent directional patterns for the alleles we examined in each area. Despite the small spatial scale of our study (approximately 11,000 ha for each study area), we observed distinct and consistent patterns of allele occurrence, suggesting different directions of gene flow between the study areas. These directions seemed to coincide with the

  8. Pollution-tolerant allele in fingernail clams (Musculium transversum).

    PubMed

    Sloss, B L; Romano, M A; Anderson, R V

    1998-08-01

    For nearly 50 years, the fingernail clam (Musculium transversum) was believed to be virtually eliminated from the Illinois River. In 1991, workers began finding substantial populations of M. transversum in the Illinois River including several beds in and around the highly polluted Chicago Sanitary District. In order to determine if populations of M. transversum from polluted sites exhibited any genetic response to the high levels of toxins and to examine the genetic structure of several populations of M. transversum for any changes due to the population crash, starch-gel electrophoresis was performed on M. transversum from three Illinois River localities and four Mississippi River basin locations. The sampled populations produced an inbreeding coefficient (FIS) of 0.929, indicating that the populations were highly inbred. The results of a suspected founder effect due to a bottleneck was suggested by an FST = 0.442. The isozyme Glucose-6-phosphate isomerase-2 (Gpi-2) produced allelic frequency patterns that were consistent with expected patterns of a pollution-tolerant allele. Polluted sites exhibited elevated frequencies of Gpi-2(100) whereas nonpolluted sites exhibited elevated frequencies of Gpi-2(74). This frequency pattern suggested that natural selection was occurring in populations under severe toxic pressures, leading to an increase in the frequency of the allele Gpi-2(100). Therefore, Gpi-2(100) is a possible pollution-tolerant mutation in M. transversum. PMID:9680522

  9. Rare HLA Drive Additional HIV Evolution Compared to More Frequent Alleles

    PubMed Central

    Lockhart, David W.; Listgarten, Jennifer; Maley, Stephen N.; Kadie, Carl; Learn, Gerald H.; Nickle, David C.; Heckerman, David E.; Deng, Wenjie; Brander, Christian; Ndung'u, Thumbi; Coovadia, Hoosen; Goulder, Philip J.R.; Korber, Bette T.; Walker, Bruce D.; Mullins, James I.

    2009-01-01

    Abstract HIV-1 can evolve HLA-specific escape variants in response to HLA-mediated cellular immunity. HLA alleles that are common in the host population may increase the frequency of such escape variants at the population level. When loss of viral fitness is caused by immune escape variation, these variants may revert upon infection of a new host who does not have the corresponding HLA allele. Furthermore, additional escape variants may appear in response to the nonconcordant HLA alleles. Because individuals with rare HLA alleles are less likely to be infected by a partner with concordant HLA alleles, viral populations infecting hosts with rare HLA alleles may undergo a greater amount of evolution than those infecting hosts with common alleles due to the loss of preexisting escape variants followed by new immune escape. This hypothesis was evaluated using maximum likelihood phylogenetic trees of each gene from 272 full-length HIV-1 sequences. Recent viral evolution, as measured by the external branch length, was found to be inversely associated with HLA frequency in nef (p < 0.02), env (p < 0.03), and pol (p ≤ 0.05), suggesting that rare HLA alleles provide a disproportionate force driving viral evolution compared to common alleles, likely due to the loss of preexisting escape variants during early stages postinfection. PMID:19327049

  10. DRD4 dopamine receptor allelic diversity in various primate species

    SciTech Connect

    Adamson, M.; Higley, D.; O`Brien, S.

    1994-09-01

    The DRD4 dopamine receptor is uniquely characterized by a 48 bp repeating segment within the coding region, located in exon III. Different DRD4 alleles are produced by the presence of additional 48 bp repeats, each of which adds 16 amino acids to the length of the 3rd intracytoplasmic loop of the receptor. The DRD4 receptor is therefore an intriguing candidate gene for behaviors which are influenced by dopamine function. In several human populations, DRD4 alleles with 2-8 and 10 repeats have previously been identified, and the 4 and 7 repeat alleles are the most abundant. We have determined DRD4 genotypes in the following nonhuman primate species: chimpanzee N=2, pygmy chimpanzee N=2, gorilla N=4, siamang N=2, Gelada baboon N=1, gibbon N=1, orangutan (Bornean and Sumatran) N=62, spider monkey N=4, owl monkey N=1, Colobus monkey N=1, Patas monkey N=1, ruffed lemur N=1, rhesus macaque N=8, and vervet monkey N=28. The degree of DRD4 polymorphism and which DRD4 alleles were present both showed considerable variation across primate species. In contrast to the human, rhesus macaque monkeys were monomorphic. The 4 and 7 repeat allels, highly abundant in the human, may not be present in certain other primates. For example, the four spider monkeys we studied showed the 7, 8 and 9 repeat length alleles and the only gibbon we analyzed was homozygous for the 9 repeat allele (thus far not observed in the human). Genotyping of other primate species and sequencing of the individual DRD4 repeat alleles in different species may help us determine the ancestral DRD4 repeat length and identify connections between DRD4 genotype and phenotype.

  11. Estimating allelic diversity generated by excision of different transposon types.

    PubMed

    Nordborg, M; Walbot, V

    1995-05-01

    Methods are presented for calculating the number and type of different DNA sequences generated by base excision and insertion events at a given site in a known DNA sequence. We calculate, for example, that excision of the Mu1 transposon from the bz1::Mu1 allele of maize should generate more than 500,000 unique alleles given the extent of base deletion (up to 34 bases removed) and base insertion (0-5 bases) observed thus far in sequenced excision alleles. Analysis of this universe of potential alleles can, for example, be used to predict the frequency of creation of stop codons or repair-generated duplications. In general, knowledge of the distribution of alleles can be used to evaluate models of both excision and repair by determining whether particular events occur more frequently than expected. Such quantitative analysis complements the qualitative description provided by the DNA sequence of individual events. Similar methods can be used to evaluate the outcome of other cases of DNA breakage and repair such as programmed V(D)J recombination in immunoglobin genes. PMID:24172918

  12. Sex differences in the JAK2V617F allele burden in chronic myeloproliferative disorders

    PubMed Central

    Stein, Brady L.; Williams, Donna M.; Wang, Nae-Yuh; Rogers, Ophelia; Isaacs, Mary Ann; Pemmaraju, Naveen; Spivak, Jerry L.; Moliterno, Alison R.

    2010-01-01

    Background The JAK2V617F allele burden is a variable measure, determined by the frequency of mitotic recombination events and the expansion of JAK2V617F clones. Since variability in the JAK2V617F allele burden is partly responsible for the distinct phenotypes seen in the myeloproliferative disorders, the objective of this study was to identify modifiers of the allele burden. Design and Methods Blood samples were obtained between May 2005 and January 2009 from 272 patients with essential thrombocytosis, polycythemia vera, and myelofibrosis. The JAK2V617F allele burden was measured by an allele-specific quantitative polymerase chain reaction using DNA from purified neutrophils. Repeated measures, on average 2 years apart, were available for 104 patients. Results Sex, age at diagnosis, and disease duration all independently influenced the JAK2V617F allele burden. When considering all patients with myeloproliferative disorders, women had significantly lower allele burdens than men (P=0.04). In those patients with repeated measures, the increase in allele burden per year between the first and second evaluations was significantly less in females than in males. Among those who experienced disease evolution, females were 4.5 times more likely to have evolution from essential thrombocytosis to polycythemia vera, but 0.23 times as likely to have evolution from essential thrombocytosis to myelofibrosis. Conclusions Sex is an independent factor accounting for variability in the JAK2V617F allele burden. We speculate that lower allele burdens in females reflect a lower frequency of mitotic recombination events in females than in males, and should be considered when evaluating the relationship of allele burden to disease phenotype and also in evaluating responses to JAK2V617F-inhibitors. Because sex may influence genotype and/or clonal expansion, underpinning the variability in JAK2V617F allele burden, it will be important to explore factors that determine susceptibility to

  13. Invasive Allele Spread under Preemptive Competition

    NASA Astrophysics Data System (ADS)

    Yasi, J. A.; Korniss, G.; Caraco, T.

    We study a discrete spatial model for invasive allele spread in which two alleles compete preemptively, initially only the "residents" (weaker competitors) being present. We find that the spread of the advantageous mutation is well described by homogeneous nucleation; in particular, in large systems the time-dependent global density of the resident allele is well approximated by Avrami's law.

  14. Significance of the Amyloidogenic Transthyretin Val 122 Ile allele in African-Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies

    PubMed Central

    Buxbaum, Joel; Alexander, Alice; Koziol, James; Tagoe, Clement; Fox, Ervin; Kitzman, Dalane

    2010-01-01

    Many African-Americans carry an amyloidogenic transthyretin mutation (TTR V122I), with a high risk for cardiac TTR amyloid deposition after age 65. We wished to determine the allele frequency and its clinical penetrance in community-dwelling African-Americans. Study subjects 5000 consenting African-Americans, ages 41 to 93, in two community studies of cardiovascular risk (CHS and ARIC). Methods genotyping of banked DNA for TTR V122I allele status; review of cardiovascular and demographic parameters in CHS and ARIC databases with statistical comparisons of the frequency of congestive heart failure, survival and occurrence of features of cardiac amyloidosis, in carriers of the amyloidogenic allele and controls. Results 119 (3.23%) of 3712 ARIC and 17 (2.12%) of 805 CHS African-Americans carried TTR V122I. After age 65 (CHS) the frequency of congestive heart failure (38% vs 15%, RR 2.62, p = 0.04) and mortality (76% vs 53 %, RR 1.46, p =0.08) were higher in V122I allele carriers than in age, gender and ethnically matched controls. In ARIC (all subjects younger than 65) there were no differences between carriers and non-carriers in mortality, frequency of congestive heart failure or findings consistent with cardiac amyloidosis. Conclusions Heterozygosity for the amyloidogenic TTR V122I mutation is relatively common in community dwelling African-Americans. Before 65 the allele has no discernible impact on cardiac function or mortality. After age 70carriers show a higher frequency of congestive failure and greater mortality with more echocardiographic evidence suggestive of cardiac amyloidosis, findings consistent with age dependent clinical penetrance of this autosomal dominant gene. PMID:20435197

  15. Sexual selection by female immunity against paternal antigens can fix loss of function alleles.

    PubMed

    Ghaderi, Darius; Springer, Stevan A; Ma, Fang; Cohen, Miriam; Secrest, Patrick; Taylor, Rachel E; Varki, Ajit; Gagneux, Pascal

    2011-10-25

    Humans lack the common mammalian cell surface molecule N-glycolylneuraminic acid (Neu5Gc) due to a CMAH gene inactivation, which occurred approximately three million years ago. Modern humans produce antibodies specific for Neu5Gc. We hypothesized that anti-Neu5Gc antibodies could enter the female reproductive tract and target Neu5Gc-positive sperm or fetal tissues, reducing reproductive compatibility. Indeed, female mice with a human-like Cmah(-/-) mutation and immunized to express anti-Neu5Gc antibodies show lower fertility with Neu5Gc-positive males, due to prezygotic incompatibilities. Human anti-Neu5Gc antibodies are also capable of targeting paternally derived antigens and mediate cytotoxicity against Neu5Gc-bearing chimpanzee sperm in vitro. Models of populations polymorphic for such antigens show that reproductive incompatibility by female immunity can drive loss-of-function alleles to fixation from moderate initial frequencies. Initially, the loss of a cell-surface antigen can occur due to drift in isolated populations or when natural selection favors the loss of a receptor exploited by pathogens, subsequently the same loss-of-function allele can come under sexual selection because it avoids being targeted by the female immune system. Thus, we provide evidence of a link between sexual selection and immune function: Antigenicity in females can select against foreign paternal antigens on sperm and rapidly fix loss-of-function alleles. Similar circumstances existed when the CMAH null allele was polymorphic in ancestral hominins, just before the divergence of Homo from australopithecines. PMID:21987817

  16. Sexual selection by female immunity against paternal antigens can fix loss of function alleles

    PubMed Central

    Ghaderi, Darius; Springer, Stevan A.; Ma, Fang; Cohen, Miriam; Secrest, Patrick; Taylor, Rachel E.; Varki, Ajit; Gagneux, Pascal

    2011-01-01

    Humans lack the common mammalian cell surface molecule N-glycolylneuraminic acid (Neu5Gc) due to a CMAH gene inactivation, which occurred approximately three million years ago. Modern humans produce antibodies specific for Neu5Gc. We hypothesized that anti-Neu5Gc antibodies could enter the female reproductive tract and target Neu5Gc-positive sperm or fetal tissues, reducing reproductive compatibility. Indeed, female mice with a human-like Cmah(−/−) mutation and immunized to express anti-Neu5Gc antibodies show lower fertility with Neu5Gc-positive males, due to prezygotic incompatibilities. Human anti-Neu5Gc antibodies are also capable of targeting paternally derived antigens and mediate cytotoxicity against Neu5Gc-bearing chimpanzee sperm in vitro. Models of populations polymorphic for such antigens show that reproductive incompatibility by female immunity can drive loss-of-function alleles to fixation from moderate initial frequencies. Initially, the loss of a cell-surface antigen can occur due to drift in isolated populations or when natural selection favors the loss of a receptor exploited by pathogens, subsequently the same loss-of-function allele can come under sexual selection because it avoids being targeted by the female immune system. Thus, we provide evidence of a link between sexual selection and immune function: Antigenicity in females can select against foreign paternal antigens on sperm and rapidly fix loss-of-function alleles. Similar circumstances existed when the CMAH null allele was polymorphic in ancestral hominins, just before the divergence of Homo from australopithecines. PMID:21987817

  17. HLA-DRB1 alleles in four Amerindian populations from Argentina and Paraguay

    PubMed Central

    2009-01-01

    The major histocompatibility complex (MHC) is one of the biological systems of major polymorphisms. The study of HLA class II variability has allowed the identification of several alleles that are characteristic to Amerindian populations, and it is an excellent tool to define the relations and biological affinities among them. In this work, we analyzed the allelic distribution of the HLA-DRB1 class II locus in four Amerindian populations: Mapuche (n = 34) and Tehuelche (n = 23) from the Patagonian region of Argentina, and Wichi SV (n = 24) and Lengua (n = 17) from the Argentinean and Paraguayan Chaco regions, respectively. In all of these groups, relatively high frequencies of Amerindian HLA-DRB1 alleles were observed (DRB1*0403, DRB1*0407, DRB1*0411, DRB1*0417, DRB1*0802, DRB1*0901, DRB1*1402, DRB1*1406 and DRB1*1602). However, we also detected the presence of non-Amerindian variants in Mapuche (35%) and Tehuelche (22%). We compared our data with those obtained in six indigenous groups of the Argentinean Chaco region and in a sample from Buenos Aires City. The genetic distance dendrogram showed a clear-cut division between the Patagonian and Chaco populations, which formed two different clusters. In spite of their linguistic differences, it can be inferred that the biological affinities observed are in concordance with the geographic distributions and interethnic relations established among the groups studied. PMID:21637670

  18. HLA-DRB1 alleles in four Amerindian populations from Argentina and Paraguay.

    PubMed

    Parolín, Maria L; Carnese, Francisco R

    2009-04-01

    The major histocompatibility complex (MHC) is one of the biological systems of major polymorphisms. The study of HLA class II variability has allowed the identification of several alleles that are characteristic to Amerindian populations, and it is an excellent tool to define the relations and biological affinities among them. In this work, we analyzed the allelic distribution of the HLA-DRB1 class II locus in four Amerindian populations: Mapuche (n = 34) and Tehuelche (n = 23) from the Patagonian region of Argentina, and Wichi SV (n = 24) and Lengua (n = 17) from the Argentinean and Paraguayan Chaco regions, respectively. In all of these groups, relatively high frequencies of Amerindian HLA-DRB1 alleles were observed (DRB1*0403, DRB1*0407, DRB1*0411, DRB1*0417, DRB1*0802, DRB1*0901, DRB1*1402, DRB1*1406 and DRB1*1602). However, we also detected the presence of non-Amerindian variants in Mapuche (35%) and Tehuelche (22%). We compared our data with those obtained in six indigenous groups of the Argentinean Chaco region and in a sample from Buenos Aires City. The genetic distance dendrogram showed a clear-cut division between the Patagonian and Chaco populations, which formed two different clusters. In spite of their linguistic differences, it can be inferred that the biological affinities observed are in concordance with the geographic distributions and interethnic relations established among the groups studied. PMID:21637670

  19. Distribution of HLA alleles in Portugal and Cabo Verde. Relationships with the slave trade route.

    PubMed

    Spínola, H; Brehm, A; Williams, F; Jesus, J; Middleton, D

    2002-07-01

    HLA-A, -B, and -DR frequencies were analysed in populations from Portugal and the Madeira and Cabo Verde Archipelagos, aiming to characterize their genetic composition. Portuguese settlers colonized both Archipelagos in the 15th and 16th centuries. Madeira received many sub-Saharan slaves to work in the sugar plantations, and Cabo Verde served as a pivotal market in the Atlantic slave trade and was populated by individuals coming from the Senegambia region of the West African coast. The population of Madeira shows the highest genetic diversity and the presence of alleles and haplotypes usually linked to sub-Saharan populations, the haplotypes accounting for 3.5% of the total. Cabo Verde presents typical markers acknowledged to be of European or Ibero-Mediterranean origin, thus revealing the admixture of European settlers with Sub-Saharan slaves. Altogether the number of European haplotypes reaches 15% of the total. The Portuguese population shows a perceivable and significant heterogeneity both in allele and haplotype frequencies, unveiling a differential input of peoples from different origins. A PCA of the populations studied, plus other relevant ones, clearly shows gene heterogeneity in mainland Portugal as well as the differences and relationships between these populations and Madeira and Cabo Verde. PMID:12418969

  20. Ventricular Tachycardia and Early Fibrillation in Patients With Brugada Syndrome and Ischemic Cardiomyopathy Show Predictable Frequency-Phase Properties on the Precordial ECG Consistent With the Respective Arrhythmogenic Substrate

    PubMed Central

    Calvo, David; Atienza, Felipe; Saiz, Javier; Martínez, Laura; Ávila, Pablo; Rubín, José; Herreros, Benito; Arenal, Ángel; García-Fernández, Javier; Ferrer, Ana; Sebastián, Rafael; Martínez-Camblor, Pablo; Jalife, José

    2015-01-01

    Background— Ventricular fibrillation (VF) has been proposed to be maintained by localized high-frequency sources. We tested whether spectral-phase analysis of the precordial ECG enabled identification of periodic activation patterns generated by such sources. Methods and Results— Precordial ECGs were recorded from 15 ischemic cardiomyopathy and 15 Brugada syndrome (type 1 ECG) patients during induced VF and analyzed in the frequency-phase domain. Despite temporal variability, induced VF episodes lasting 19.6±7.9 s displayed distinctly high power at a common frequency (shared frequency, 5.7±1.1 Hz) in all leads about half of the time. In patients with Brugada syndrome, phase analysis of shared frequency showed a V1–V6 sequence as would be expected from patients displaying a type 1 ECG pattern (P<0.001). Hilbert-based phases confirmed that the most stable sequence over the whole VF duration was V1–V6. Analysis of shared frequency in ischemic cardiomyopathy patients with anteroseptal (n=4), apical (n=3), and inferolateral (n=4) myocardial infarction displayed a sequence starting at V1–V2, V3–V4, and V5–V6, respectively, consistent with an activation origin at the scar location (P=0.005). Sequences correlated with the Hilbert-based phase analysis (P<0.001). Posterior infarction (n=4) displayed no specific sequence. On paired comparison, phase sequences during monomorphic ventricular tachycardia correlated moderately with VF (P<0.001). Moreover, there was a dominant frequency gradient from precordial leads facing the scar region to the contralateral leads (5.8±0.8 versus 5.4±1.1 Hz; P=0.004). Conclusions— Noninvasive analysis of ventricular tachycardia and early VF in patients with Brugada syndrome and ischemic cardiomyopathy shows a predictable sequence in the frequency-phase domain, consistent with anatomic location of the arrhythmogenic substrate. PMID:26253505

  1. Vitamin D Responsive Elements within the HLA-DRB1 Promoter Region in Sardinian Multiple Sclerosis Associated Alleles

    PubMed Central

    Murru, Maria Rita; Corongiu, Daniela; Tranquilli, Stefania; Fadda, Elisabetta; Murru, Raffaele; Schirru, Lucia; Secci, Maria Antonietta; Costa, Gianna; Asunis, Isadora; Cuccu, Stefania; Fenu, Giuseppe; Lorefice, Lorena; Carboni, Nicola; Mura, Gioia; Rosatelli, Maria Cristina; Marrosu, Maria Giovanna

    2012-01-01

    Vitamin D response elements (VDREs) have been found in the promoter region of the MS-associated allele HLA-DRB1*15∶01, suggesting that with low vitamin D availability VDREs are incapable of inducing *15∶01 expression allowing in early life autoreactive T-cells to escape central thymic deletion. The Italian island of Sardinia exhibits a very high frequency of MS and high solar radiation exposure. We test the contribution of VDREs analysing the promoter region of the MS-associated DRB1 *04∶05, *03∶01, *13∶01 and *15∶01 and non-MS-associated *16∶01, *01, *11, *07∶01 alleles in a cohort of Sardinians (44 MS patients and 112 healthy subjects). Sequencing of the DRB1 promoter region revealed a homozygous canonical VDRE in all *15∶01, *16∶01, *11 and in 45/73 *03∶01 and in heterozygous state in 28/73 *03∶01 and all *01 alleles. A new mutated homozygous VDRE was found in all *13∶03, *04∶05 and *07∶01 alleles. Functionality of mutated and canonical VDREs was assessed for its potential to modulate levels of DRB1 gene expression using an in vitro transactivation assay after stimulation with active vitamin D metabolite. Vitamin D failed to increase promoter activity of the *04∶05 and *03∶01 alleles carrying the new mutated VDRE, while the *16∶01 and *03∶01 alleles carrying the canonical VDRE sequence showed significantly increased transcriptional activity. The ability of VDR to bind the mutant VDRE in the DRB1 promoter was evaluated by EMSA. Efficient binding of VDR to the VDRE sequence found in the *16∶01 and in the *15∶01 allele reduced electrophoretic mobility when either an anti-VDR or an anti-RXR monoclonal antibody was added. Conversely, the Sardinian mutated VDRE sample showed very low affinity for the RXR/VDR heterodimer. These data seem to exclude a role of VDREs in the promoter region of the DRB1 gene in susceptibility to MS carried by DRB1* alleles in Sardinian patients. PMID:22848563

  2. Analysis of the inter-alpha-trypsin inhibitor polymorphism in west Africa: description of a new allele, ITI*7.

    PubMed

    Caeiro, J L; Liste, I; Vogt, U; Ribeiro, J C

    1994-01-01

    Inter-alpha-trypsin inhibitor (ITI) phenotypes were classified in the West African population of Cabo Verde by polyacrylamide gel isoelectric focusing, followed by immunofixation and silver staining. Gene frequencies of the alleles ITI*1, ITI*2, ITI*3, and ITI*4 were calculated to be 0.532, 0.153, 0.307 and 0.002, respectively. A new rare allele, ITI*7, was found, providing evidence for further genetic variability of the ITI protein. The ITI*7 allele frequency has been determined to 0.006. The assumption that allele ITI*3 may be used to characterize populations of African origin is supported by our data. PMID:7532128

  3. Protective effect of the AT137RQ and ARQK176 PrP alleles against classical scrapie in Sarda breed sheep

    PubMed Central

    Vaccari, Gabriele; Scavia, Gaia; Sala, Marcello; Cosseddu, Gianmario; Chiappini, Barbara; Conte, Michela; Esposito, Elena; Lorenzetti, Raniero; Perfetti, Gabriella; Marconi, Paola; Scholl, Francesco; Barbaro, Katia; Bella, Antonino; Nonno, Romolo; Agrimi, Umberto

    2009-01-01

    The susceptibility of sheep to scrapie is under the control of the host’s prion protein (PrP) gene and is also influenced by the strain of the agent. PrP polymorphisms at codons 136 (A/V), 154 (R/H) and 171 (Q/R/H) are the main determinants of susceptibility/resistance of sheep to classical scrapie. They are combined in four main variants of the wild-type ARQ allele: VRQ, AHQ, ARH and ARR. Breeding programmes have been undertaken on this basis in the European Union and the USA to increase the frequency of the resistant ARR allele in sheep populations. Herein, we report the results of a multi-flock study showing the protective effect of polymorphisms other than those at codons 136, 154 and 171 in Sarda breed sheep. All ARQ/ARQ affected sheep (n = 154) and 378 negative ARQ/ARQ controls from four scrapie outbreaks were submitted to sequencing of the PrP gene. The distribution of variations other than those at the standard three codons, between scrapie cases and negative controls, was statistically different in all flocks. In particular, the AT137RQ and ARQK176 alleles showed a clear protective effect. This is the first study demonstrating a protective influence of alleles other than ARR under field conditions. If further investigations in other sheep breeds and with other scrapie sources confirm these findings, the availability of various protective alleles in breeding programmes of sheep for scrapie resistance could be useful in breeds with a low frequency of the ARR allele and would allow maintaining a wider variability of the PrP gene. PMID:19171116

  4. Persistence of the common Hartnup disease D173N allele in populations of European origin.

    PubMed

    Azmanov, Dimitar N; Rodgers, Helen; Auray-Blais, Christiane; Giguère, Robert; Bailey, Charles; Bröer, Stefan; Rasko, John E J; Cavanaugh, Juleen A

    2007-11-01

    Hartnup disorder is an aminoaciduria that results from mutations in the recently described gene SLC6A19 on chromosome 5p15.33. The disease is inherited in a simple recessive manner and ten different mutations have been described to date. One mutation, the D173N allele, is present in 42% of Hartnup chromosomes from apparently unrelated families from both Australia and North America. We report an investigation of the origins of the D173N allele using a unique combination of variants including SNPs, microsatellites, and a VNTR across 211 Kb spanning the SLC6A19 locus. All individuals who carry the mutant allele share an identical core haplotype suggesting a single common ancestor, indicating that the elevated frequency of the D173N allele is not a result of recurrent mutation. Analyses of these data indicate that the allele is more than 1000 years old. We compare the reasons for survival of this allele with other major alleles in some other common autosomal recessive diseases occurring in European Caucasians. We postulate that survival of this allele may be a consequence of failure of the allele to completely inactivate the transport of neutral amino acids. PMID:17555458

  5. [A KEL*02mod allele responsible for an apparent maternity exclusion].

    PubMed

    Monfort, M; Peyrard, T; Arnaud, L; Helias, V; Maggipinto, G; Gérard, C

    2013-12-01

    The patient's rare KEL:1,-2 phenotype was highlighted in course of a routine preoperative erythrocyte typing. Unexpectedly, her two daughters presented a KEL:-1,2 phenotype what appeared first as an apparent maternity exclusion. Flow cytometry, genotyping and adsorption-elution analyses were then performed for those three patients. KEL genotyping showed that the patient's genotype was KEL*01/KEL*02 whereas that of her daughters was KEL*02/KEL*02. By using polyclonal anti-KEL2 reagent, weak amount of KEL2 was identified on the patient's erythrocytes, a result which was confirmed by both flow cytometry and adsorption-elution assays, suggesting that patient's phenotype was in fact KEL:1,2w. These results are in favour of a weak expressed KEL*02 allele (KEL*2mod) transmission coding for a KEL2 antigen detected in some technical conditions only. Those results allowed to explain the apparent maternity exclusion based on initial KEL phenotype. This study also seems to confirm the presence of a compensatory mechanism of the KELmod allele deficient expression in heterozygote patients. A KEL phenotype retrospective study of 80,000 subjects showed a local KEL:1,-2 frequency four times lower than that described in literature. Moreover, a significant number of those individuals would in reality be KEL:1,2w, what still would decrease the real frequency of the KEL:1,2 subjects. PMID:23727116

  6. Allelic variation in the squirrel monkey x-linked color vision gene: biogeographical and behavioral correlates.

    PubMed

    Cropp, Susan; Boinski, Sue; Li, Wen-Hsiung

    2002-06-01

    Most Neotropical primate species possess a polymorphic X-linked and a monomorphic autosomal color vision gene. Consequently, populations are composed of both dichromatics and trichromatics. Most theories on the maintenance of this genetic system revolve around possible advantages for foraging ecology. To examine the issue from a different angle, we compared the numbers and relative frequencies of alleles at the X-linked locus among three species of Saimiri representing a wide range of geographical and behavioral variation in the genus. Exons 3, 4, and 5 of the X-linked opsin gene were sequenced for a large number of X chromosomes for all three species. Several synonymous mutations were detected in exons 4 and 5 for the originally reported alleles but only a single nonsynonymous change was detected. Two alleles were found that appeared to be the result of recombination events. The low occurrence of recombinant alleles and absence of mutations in the amino acids critical for spectral tuning indicates that stabilizing selection acts to maintain the combinations of critical sites specific to each allele. Allele frequencies were approximately the same for all Saimiri species, with a slight but significant difference between S. boliviensis and S. oerstedii. No apparent correlation exists between allele frequencies and behavioral or biogeographical differences between species, casting doubt on the speculation that the spectral sensitivities of the alleles have been maintained because they are specifically well-tuned to Saimiri visual ecology. Rather, the spectral tuning peaks might have been maintained because they are as widely spaced as possible within the limited range of middlewave to longwave spectra useful to all primates. This arrangement creates a balance between maximizing the distance between spectral tuning peaks (allowing the color opponency of the visual system to distinguish between peaks) and maximizing the number of alleles within a limited range (yielding

  7. How the Number of Alleles Influences Gene Expression

    NASA Astrophysics Data System (ADS)

    Hat, Beata; Paszek, Pawel; Kimmel, Marek; Piechor, Kazimierz; Lipniacki, Tomasz

    2007-07-01

    The higher organisms, eukaryotes, are diploid and most of their genes have two homological copies (alleles). However, the number of alleles in a cell is not constant. In the S phase of the cell cycle all the genome is duplicated and then in the G2 phase and mitosis, which together last for several hours, most of the genes have four copies instead of two. Cancer development is, in many cases, associated with a change in allele number. Several genetic diseases are caused by haploinsufficiency: Lack of one of the alleles or its improper functioning. In the paper we consider the stochastic expression of a gene having a variable number of copies. We applied our previously developed method in which the reaction channels are split into slow (connected with change of gene state) and fast (connected with mRNA/protein synthesis/decay), the later being approximated by deterministic reaction rate equations. As a result we represent gene expression as a piecewise deterministic time-continuous Markov process, which is further related with a system of partial differential hyperbolic equations for probability density functions (pdfs) of protein distribution. The stationary pdfs are calculated analytically for haploidal gene or numerically for diploidal and tetraploidal ones. We distinguished nine classes of simultaneous activation of haploid, diploid and tetraploid genes. This allows for analysis of potential consequences of gene duplication or allele loss. We show that when gene activity is autoregulated by a positive feedback, the change in number of gene alleles may have dramatic consequences for its regulation and may not be compensated by the change of efficiency of mRNA synthesis per allele.

  8. Sporophytic self-incompatibility in Senecio squalidus (Asteraceae): S allele dominance interactions and modifiers of cross-compatibility and selfing rates

    PubMed Central

    Brennan, A C; Tabah, D A; Harris, S A; Hiscock, S J

    2011-01-01

    Understanding genetic mechanisms of self-incompatibility (SI) and how they evolve is central to understanding the mating behaviour of most outbreeding angiosperms. Sporophytic SI (SSI) is controlled by a single multi-allelic locus, S, which is expressed in the diploid (sporophyte) plant to determine the SI phenotype of its haploid (gametophyte) pollen. This allows complex patterns of independent S allele dominance interactions in male (pollen) and female (pistil) reproductive tissues. Senecio squalidus is a useful model for studying the genetic regulation and evolution of SSI because of its population history as an alien invasive species in the UK. S. squalidus maintains a small number of S alleles (7–11) with a high frequency of dominance interactions. Some S. squalidus individuals also show partial selfing and/or greater levels of cross-compatibility than expected under SSI. We previously speculated that these might be adaptations to invasiveness. Here we describe a detailed characterization of the regulation of SSI in S. squalidus. Controlled crosses were used to determine the S allele dominance hierarchy of six S alleles and effects of modifiers on cross-compatibility and partial selfing. Complex dominance interactions among S alleles were found with at least three levels of dominance and tissue-specific codominance. Evidence for S gene modifiers that increase selfing and/or cross-compatibility was also found. These empirical findings are discussed in the context of theoretical predictions for maintenance of S allele dominance interactions, and the role of modifier loci in the evolution of SI. PMID:20372180

  9. Sporophytic self-incompatibility in Senecio squalidus (Asteraceae): S allele dominance interactions and modifiers of cross-compatibility and selfing rates.

    PubMed

    Brennan, A C; Tabah, D A; Harris, S A; Hiscock, S J

    2011-01-01

    Understanding genetic mechanisms of self-incompatibility (SI) and how they evolve is central to understanding the mating behaviour of most outbreeding angiosperms. Sporophytic SI (SSI) is controlled by a single multi-allelic locus, S, which is expressed in the diploid (sporophyte) plant to determine the SI phenotype of its haploid (gametophyte) pollen. This allows complex patterns of independent S allele dominance interactions in male (pollen) and female (pistil) reproductive tissues. Senecio squalidus is a useful model for studying the genetic regulation and evolution of SSI because of its population history as an alien invasive species in the UK. S. squalidus maintains a small number of S alleles (7-11) with a high frequency of dominance interactions. Some S. squalidus individuals also show partial selfing and/or greater levels of cross-compatibility than expected under SSI. We previously speculated that these might be adaptations to invasiveness. Here we describe a detailed characterization of the regulation of SSI in S. squalidus. Controlled crosses were used to determine the S allele dominance hierarchy of six S alleles and effects of modifiers on cross-compatibility and partial selfing. Complex dominance interactions among S alleles were found with at least three levels of dominance and tissue-specific codominance. Evidence for S gene modifiers that increase selfing and/or cross-compatibility was also found. These empirical findings are discussed in the context of theoretical predictions for maintenance of S allele dominance interactions, and the role of modifier loci in the evolution of SI. PMID:20372180

  10. Allelic and genotypic associations of DRD2 TaqI A polymorphism with heroin dependence in Spanish subjects: a case control study

    PubMed Central

    Perez de los Cobos, Jose; Baiget, Montserrat; Trujols, Joan; Sinol, Nuria; Volpini, Victor; Banuls, Enrique; Calafell, Francesc; Luquero, Elena; del Rio, Elisabeth; Alvarez, Enric

    2007-01-01

    Background Conflicting associations with heroin dependence have been found involving the A1 allele of dopamine D2 receptor gene (DRD2) TaqI A polymorphism. Methods We compared two samples of unrelated Spanish individuals, all of European origin: 281 methadone-maintained heroin-dependent patients (207 males and 74 females) who frequently used non-opioid substances, and 145 control subjects (98 males and 47 females). Results The A1-A1 genotype was detected in 7.1% of patients and 1.4% of controls (P = 0.011, odds ratio = 5.48, 95% CI 1.26–23.78). Although the A1 allele was not associated with heroin dependence in the entire sample, the frequency of A1 allele was higher in male patients than in male controls (24.4% vs. 16.3%, P = 0.024, odds ratio = 1.65, 95% CI 1.07–2.57). A logistic regression analysis showed an interaction between DRD2 alleles and gender (odds ratio = 1.77, 95% CI 1.15–2.70). Conclusion Our results indicate that, in Spanish individuals, genotypes of the DRD2 TaqI A polymorphism contribute to variations in the risk of heroin dependence, while single alleles contribute only in males. PMID:17543096

  11. Crohn's Disease Risk Alleles on the NOD2 Locus Have Been Maintained by Natural Selection on Standing Variation

    PubMed Central

    Nakagome, Shigeki; Mano, Shuhei; Kozlowski, Lukasz; Bujnicki, Janusz M.; Shibata, Hiroki; Fukumaki, Yasuaki; Kidd, Judith R.; Kidd, Kenneth K.; Kawamura, Shoji; Oota, Hiroki

    2012-01-01

    Risk alleles for complex diseases are widely spread throughout human populations. However, little is known about the geographic distribution and frequencies of risk alleles, which may contribute to differences in disease susceptibility and prevalence among populations. Here, we focus on Crohn's disease (CD) as a model for the evolutionary study of complex disease alleles. Recent genome-wide association studies and classical linkage analyses have identified more than 70 susceptible genomic regions for CD in Europeans, but only a few have been confirmed in non-European populations. Our analysis of eight European-specific susceptibility genes using HapMap data shows that at the NOD2 locus the CD-risk alleles are linked with a haplotype specific to CEU at a frequency that is significantly higher compared with the entire genome. We subsequently examined nine global populations and found that the CD-risk alleles spread through hitchhiking with a high-frequency haplotype (H1) exclusive to Europeans. To examine the neutrality of NOD2, we performed phylogenetic network analyses, coalescent simulation, protein structural prediction, characterization of mutation patterns, and estimations of population growth and time to most recent common ancestor (TMRCA). We found that while H1 was significantly prevalent in European populations, the H1 TMRCA predated human migration out of Africa. H1 is likely to have undergone negative selection because 1) the root of H1 genealogy is defined by a preexisting amino acid substitution that causes serious conformational changes to the NOD2 protein, 2) the haplotype has almost become extinct in Africa, and 3) the haplotype has not been affected by the recent European expansion reflected in the other haplotypes. Nevertheless, H1 has survived in European populations, suggesting that the haplotype is advantageous to this group. We propose that several CD-risk alleles, which destabilize and disrupt the NOD2 protein, have been maintained by natural

  12. Estimating the age of alleles by use of intraallelic variability

    SciTech Connect

    Slatkin, M.; Rannala, B.

    1997-02-01

    A method is presented for estimating the age of an allele by use of its frequency and the extent of variation among different copies. The method uses the joint distribution of the number of copies in a population sample and the coalescence times of the intraallelic gene genealogy conditioned on the number of copies. The linear birth-death process is used to approximate the dynamics of a rare allele in a finite population. A maximum-likelihood estimate of the age of the allele is obtained by Monte Carlo integration over the coalescence times. The method is applied to two alleles at the cystic fibrosis (CFTR) locus, {Delta}F508 and G542X, for which intraallelic variability at three intronic microsatellite loci has been examined. Our results indicate that G542X is somewhat older than {Delta}F508. Although absolute estimates depend on the mutation rates at the microsatellite loci, our results support the hypothesis that {Delta}F508 arose <500 generations ({approx}10,000 years) ago. 32 refs., 4 figs.

  13. Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome.

    PubMed

    Alcántara-Ortigoza, M A; García-de Teresa, B; González-Del Angel, A; Berumen, J; Guardado-Estrada, M; Fernández-Hernández, L; Navarrete-Martínez, J I; Maza-Morales, M; Rius-Domínguez, R

    2016-05-01

    Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions. PMID:26762690

  14. Effective marker alleles associated with type 2 resistance to Fusarium head blight infection in fields

    PubMed Central

    Li, Tao; Luo, Meng; Zhang, Dadong; Wu, Di; Li, Lei; Bai, Guihua

    2016-01-01

    Molecular markers associated with known quantitative trait loci (QTLs) for type 2 resistance to Fusarium head blight (FHB) in bi-parental mapping population usually have more than two alleles in breeding populations. Therefore, understanding the association of each allele with FHB response is particularly important to marker-assisted enhancement of FHB resistance. In this paper, we evaluated FHB severities of 192 wheat accessions including landraces and commercial varieties in three field growing seasons, and genotyped this panel with 364 genome-wide informative molecular markers. Among them, 11 markers showed reproducible marker-trait association (p < 0.05) in at least two experiments using a mixed model. More than two alleles were identified per significant marker locus. These alleles were classified into favorable, unfavorable and neutral alleles according to the normalized genotypic values. The distributions of effective alleles at these loci in each wheat accession were characterized. Mean FHB severities increased with decreased number of favorable alleles at the reproducible loci. Chinese wheat landraces and Japanese accessions have more favorable alleles at the majority of the reproducible marker loci. FHB resistance levels of varieties can be greatly improved by introduction of these favorable alleles and removal of unfavorable alleles simultaneously at these QTL-linked marker loci. PMID:27436944

  15. The functional importance of sequence versus expression variability of MHC alleles in parasite resistance.

    PubMed

    Axtner, Jan; Sommer, Simone

    2012-12-01

    Understanding selection processes driving the pronounced allelic polymorphism of the major histocompatibility complex (MHC) genes and its functional associations to parasite load have been the focus of many recent wildlife studies. Two main selection scenarios are currently debated which explain the susceptibility or resistance to parasite infections either by the effects of (1) specific MHC alleles which are selected frequency-dependent in space and time or (2) a heterozygote or divergent allele advantage. So far, most studies have focused only on structural variance in co-evolutionary processes although this might not be the only trait subject to natural selection. In the present study, we analysed structural variance stretching from exon1 through exon3 of MHC class II DRB genes as well as genotypic expression variance in relation to the gastrointestinal helminth prevalence and infection intensity in wild yellow-necked mice (Apodemus flavicollis). We found support for the functional importance of specific alleles both on the sequence and expression level. By resampling a previously investigated study population we identified specific MHC alleles affected by temporal shifts in parasite pressure and recorded associated changes in allele frequencies. The allele Apfl-DRB*23 was associated with resistance to infections by the oxyurid nematode Syphacia stroma and at the same time with susceptibility to cestode infection intensity. In line with our expectation, MHC mRNA transcript levels tended to be higher in cestode-infected animals carrying the allele Apfl-DRB*23. However, no support for a heterozygote or divergent allele advantage on the sequence or expression level was detected. The individual amino acid distance of genotypes did not explain individual differences in parasite loads and the genetic distance had no effect on MHC genotype expression. For ongoing studies on the functional importance of expression variance in parasite resistance, allele

  16. Allele-specific DNA methylation reinforces PEAR1 enhancer activity.

    PubMed

    Izzi, Benedetta; Pistoni, Mariaelena; Cludts, Katrien; Akkor, Pinar; Lambrechts, Diether; Verfaillie, Catherine; Verhamme, Peter; Freson, Kathleen; Hoylaerts, Marc F

    2016-08-18

    Genetic variation in the PEAR1 locus is linked to platelet reactivity and cardiovascular disease. The major G allele of rs12041331, an intronic cytosine guanine dinucleotide-single-nucleotide polymorphism (CpG-SNP), is associated with higher PEAR1 expression in platelets and endothelial cells than the minor A allele. The molecular mechanism underlying this difference remains elusive. We have characterized the histone modification profiles of the intronic region surrounding rs12041331 and identified H3K4Me1 enhancer-specific enrichment for the region that covers the CpG-SNP. Interestingly, methylation studies revealed that the CpG site is fully methylated in leukocytes of GG carriers. Nuclear protein extracts from megakaryocytes, endothelial cells, vs control HEK-293 cells show a 3-fold higher affinity for the methylated G allele compared with nonmethylated G or A alleles in a gel electrophoretic mobility shift assay. To understand the positive relationship between methylation and gene expression, we studied DNA methylation at 4 different loci of PEAR1 during in vitro megakaryopoiesis. During differentiation, the CpG-SNP remained fully methylated, while we observed rapid methylation increases at the CpG-island overlapping the first 5'-untranslated region exon, paralleling the increased PEAR1 expression. In the same region, A-allele carriers of rs12041331 showed significantly lower DNA methylation at CGI1 compared with GG homozygote. This CpG-island contains binding sites for the methylation-sensitive transcription factor CTCF, whose binding is known to play a role in enhancer activation and/or repression. In conclusion, we report the molecular characterization of the first platelet function-related CpG-SNP, a genetic predisposition that reinforces PEAR1 enhancer activity through allele-specific DNA methylation. PMID:27313330

  17. Sporadic inclusion body myositis: HLA-DRB1 allele interactions influence disease risk and clinical phenotype.

    PubMed

    Mastaglia, Frank L; Needham, Merrilee; Scott, Adrian; James, Ian; Zilko, Paul; Day, Timothy; Kiers, Lynette; Corbett, Alastair; Witt, Campbell S; Allcock, Richard; Laing, Nigel; Garlepp, Michael; Christiansen, Frank T

    2009-11-01

    Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestral haplotype (HLA-A1, B8, DRB1*03) but little is known about the effects of allelic interactions at the DRB1 locus or disease-modifying effects of HLA alleles. HLA-A, B and DRB1 genotyping was performed in 80 Australian sIBM cases and the frequencies of different alleles and allele combinations were compared with those in a group of 190 healthy controls. Genotype-phenotype correlations were also investigated. Amongst carriers of the HLA-DRB1*03 allele, DRB1*03/*01 heterozygotes were over-represented in the sIBM group (p<0.003) while. DRB1*03/*04 heterozygotes were under-represented (p<0.008). The mean age-at-onset (AAO) was 6.5 years earlier in DRB1*03/*01 heterozygotes who also had more severe quadriceps muscle weakness than the rest of the cohort. The findings indicate that interactions between the HLA-DRB1*03 allele and other alleles at the DRB1 locus can influence disease susceptibility and the clinical phenotype in sIBM. PMID:19720533

  18. The Sex Determination Gene Shows No Founder Effect in the Giant Honey Bee, Apis dorsata

    PubMed Central

    Yan, Wei Yu; Wu, Xiao Bo; Zeng, Zhi Jiang; Huang, Zachary Y.

    2012-01-01

    Background All honey bee species (Apis spp) share the same sex determination mechanism using the complementary sex determination (csd) gene. Only individuals heterogeneous at the csd allele develop into females, and the homozygous develop into diploid males, which do not survive. The honeybees are therefore under selection pressure to generate new csd alleles. Previous studies have shown that the csd gene is under balancing selection. We hypothesize that due to the long separation from the mainland of Hainan Island, China, that the giant honey bees (Apis dorsata) should show a founder effect for the csd gene, with many different alleles clustered together, and these would be absent on the mainland. Methodology/Principal Findings We sampled A. dorsata workers from both Hainan and Guangxi Provinces and then cloned and sequenced region 3 of the csd gene and constructed phylogenetic trees. We failed to find any clustering of the csd alleles according to their geographical origin, i.e. the Hainan and Guangxi samples did not form separate clades. Further analysis by including previously published csd sequences also failed to show any clade-forming in both the Philippines and Malaysia. Conclusions/Significance Results from this study and those from previous studies did not support the expectations of a founder effect. We conclude that because of the extremely high mating frequency of A. dorsata queens, a founder effect does not apply in this species. PMID:22511940

  19. Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles | Office of Cancer Genomics

    Cancer.gov

    Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic.

  20. Identification of alleles of carotenoid pathway genes important for zeaxanthin accumulation in potato tubers

    PubMed Central

    Uitdewilligen, Jan G. A. M. L.; Kloosterman, Bjorn A.; Hutten, Ronald C. B.; Visser, Richard G. F.; van Eck, Herman J.

    2010-01-01

    We have investigated the genetics and molecular biology of orange flesh colour in potato (Solanum tuberosum L.). To this end the natural diversity in three genes of the carotenoid pathway was assessed by SNP analyses. Association analysis was performed between SNP haplotypes and flesh colour phenotypes in diploid and tetraploid potato genotypes. We observed that among eleven beta-carotene hydroxylase 2 (Chy2) alleles only one dominant allele has a major effect, changing white into yellow flesh colour. In contrast, none of the lycopene epsilon cyclase (Lcye) alleles seemed to have a large effect on flesh colour. Analysis of zeaxanthin epoxidase (Zep) alleles showed that all (diploid) genotypes with orange tuber flesh were homozygous for one specific Zep allele. This Zep allele showed a reduced level of expression. The complete genomic sequence of the recessive Zep allele, including the promoter, was determined, and compared with the sequence of other Zep alleles. The most striking difference was the presence of a non-LTR retrotransposon sequence in intron 1 of the recessive Zep allele, which was absent in all other Zep alleles investigated. We hypothesise that the presence of this large sequence in intron 1 caused the lower expression level, resulting in reduced Zep activity and accumulation of zeaxanthin. Only genotypes combining presence of the dominant Chy2 allele with homozygosity for the recessive Zep allele produced orange-fleshed tubers that accumulated large amounts of zeaxanthin. Electronic supplementary material The online version of this article (doi:10.1007/s11103-010-9647-y) contains supplementary material, which is available to authorized users. PMID:20490894

  1. Y-chromosome Short Tandem Repeat DYS458.2 Non-consensus Alleles Occur Independently in Both Binary Haplogroups J1-M267 and R1b3-M405

    PubMed Central

    Myres, Natalie M.; Ekins, Jayne E.; Lin, Alice A.; Cavalli-Sforza, L. Luca; Woodward, Scott R.; Underhill, Peter A.

    2007-01-01

    Aim To determine the human Y-chromosome haplogroup backgrounds of non-consensus DYS458.2 short tandem repeat alleles and evaluate their phylogenetic substructure and frequency in representative samples from the Middle East, Europe, and Pakistan. Methods Molecular characterization of lineages was achieved using a combination of Y-chromosome haplogroup defining binary polymorphisms and up to 37 short tandem repeat loci, including DYS388 to construct haplotypes. DNA sequencing of the DYS458 locus and median-joining network analyses were used to evaluate Y-chromosome lineages displaying the DYS458.2 motif. Results We showed that the DYS458.2 allelic innovation arose independently on at least two distinctive binary haplogroup backgrounds and possibly a third as well. The partial allele length pattern was fixed in all haplogroup J1 chromosomes examined, including its known rare sub-haplogroups. Within the alternative R1b3 associated M405 defined sub-haplogroup, both DYS458.0 and DYS458.2 allele classes occurred. A single chromosome also allocated to the R1b3-M269*(xM405) classification. The physical position of the partial insertion/deletion occurrence within the normal tetramer tract differed distinctly in each haplogroup context. Conclusions While unusual DYS458.2 alleles are informative, additional information for other linked polymorphic loci is required when using such non-conforming alleles to infer haplogroup background and common ancestry. PMID:17696299

  2. Tomato Fruits Show Wide Phenomic Diversity but Fruit Developmental Genes Show Low Genomic Diversity

    PubMed Central

    Mohan, Vijee; Gupta, Soni; Thomas, Sherinmol; Mickey, Hanjabam; Charakana, Chaitanya; Chauhan, Vineeta Singh; Sharma, Kapil; Kumar, Rakesh; Tyagi, Kamal; Sarma, Supriya; Gupta, Suresh Kumar; Kilambi, Himabindu Vasuki; Nongmaithem, Sapana; Kumari, Alka; Gupta, Prateek; Sreelakshmi, Yellamaraju; Sharma, Rameshwar

    2016-01-01

    Domestication of tomato has resulted in large diversity in fruit phenotypes. An intensive phenotyping of 127 tomato accessions from 20 countries revealed extensive morphological diversity in fruit traits. The diversity in fruit traits clustered the accessions into nine classes and identified certain promising lines having desirable traits pertaining to total soluble salts (TSS), carotenoids, ripening index, weight and shape. Factor analysis of the morphometric data from Tomato Analyzer showed that the fruit shape is a complex trait shared by several factors. The 100% variance between round and flat fruit shapes was explained by one discriminant function having a canonical correlation of 0.874 by stepwise discriminant analysis. A set of 10 genes (ACS2, COP1, CYC-B, RIN, MSH2, NAC-NOR, PHOT1, PHYA, PHYB and PSY1) involved in various plant developmental processes were screened for SNP polymorphism by EcoTILLING. The genetic diversity in these genes revealed a total of 36 non-synonymous and 18 synonymous changes leading to the identification of 28 haplotypes. The average frequency of polymorphism across the genes was 0.038/Kb. Significant negative Tajima’D statistic in two of the genes, ACS2 and PHOT1 indicated the presence of rare alleles in low frequency. Our study indicates that while there is low polymorphic diversity in the genes regulating plant development, the population shows wider phenotype diversity. Nonetheless, morphological and genetic diversity of the present collection can be further exploited as potential resources in future. PMID:27077652

  3. The CFTR Met 470 Allele Is Associated with Lower Birth Rates in Fertile Men from a Population Isolate

    PubMed Central

    Kosova, Gülüm; Pickrell, Joseph K.; Kelley, Joanna L.; McArdle, Patrick F.; Shuldiner, Alan R.; Abney, Mark; Ober, Carole

    2010-01-01

    Although little is known about the role of the cystic fibrosis transmembrane regulator (CFTR) gene in reproductive physiology, numerous variants in this gene have been implicated in etiology of male infertility due to congenital bilateral absence of the vas deferens (CBAVD). Here, we studied the fertility effects of three CBAVD–associated CFTR polymorphisms, the (TG)m and polyT repeat polymorphisms in intron 8 and Met470Val in exon 10, in healthy men of European descent. Homozygosity for the Met470 allele was associated with lower birth rates, defined as the number of births per year of marriage (P = 0.0029). The Met470Val locus explained 4.36% of the phenotypic variance in birth rate, and men homozygous for the Met470 allele had 0.56 fewer children on average compared to Val470 carrier men. The derived Val470 allele occurs at high frequencies in non-African populations (allele frequency  = 0.51 in HapMap CEU), whereas it is very rare in African population (Fst  = 0.43 between HapMap CEU and YRI). In addition, haplotypes bearing Val470 show a lack of genetic diversity and are thus longer than haplotypes bearing Met470 (measured by an integrated haplotype score [iHS] of −1.93 in HapMap CEU). The fraction of SNPs in the HapMap Phase2 data set with more extreme Fst and iHS measures is 0.003, consistent with a selective sweep outside of Africa. The fertility advantage conferred by Val470 relative to Met470 may provide a selective mechanism for these population genetic observations. PMID:20532200

  4. Association of HLA class II alleles with hepatitis C virus clearance and persistence in thalassemia patients from Iran.

    PubMed

    Samimi-Rad, Katayoun; Sadeghi, Farzin; Amirzargar, Aliakbar; Eshraghian, Mohamad Reza; Alavian, Seyed-Moayed; Rahimnia, Ramin

    2015-09-01

    There is no published data on association of HLA class II alleles with clearance or persistence after acute hepatitis C virus (HCV) infection in patients from Iran. HLA DRB1, DQA1, and DQB1 alleles were determined using polymerase chain reaction amplification with sequence specific primers (PCR-SSP) on a total of 117 thalassemia patients (63 with chronic infection, and 54 with viral clearance) and 120 healthy controls. HLA-DRB1*0301 and DQA1*0501 alleles were found significantly present in patients with HCV clearance compared to those with chronic infection (P = 0.03 and P = 0.0007, respectively). By contrast, DRB1*0701, DQA1*0201, and DQB1*0602 alleles occurred significantly in those with chronic infection compared to those with viral clearance (P = 0.004, P = 0.007, and P = 0.02, respectively). As compared to the controls, DRB1*0301, DRB1*11, DQA1*0501, and DQB1*0301 alleles showed a significant decrease in chronic patients (P = 0.002, P = 0.001, P = 0.0001, and P = 0.0004, respectively). Furthermore, the haplotype frequencies of DRB1*0301, DQA1*0501, DQB1*0201, and DRB1*1101, DQA1*0501, DQB1*0301 were found significantly higher (P = 0.004 and P = 0.04, respectively) in patients with HCV clearance than those with chronic infection. By contrast, the haplotype DRB1*0701, DQA1*0201, DQB1*0201 occurred more frequently (P = 0.02) in those with chronic infection compared with those with viral clearance. These findings suggest that particular HLA alleles and related haplotypes may have an influence on the outcome of HCV infection among the Iranian patients. Some of the HLA alleles found in the Iranian patients are different from those reported elsewhere, suggesting that the immunogenetic makeup for HCV clearance or persistence may vary based on the ethnicity. PMID:25970464

  5. Assessment of biodiversity in Chilean cattle using the distribution of major histocompatibility complex class II BoLA-DRB3 allele.

    PubMed

    Takeshima, S-N; Miyasaka, T; Matsumoto, Y; Xue, G; Diaz, V de la Barra; Rogberg-Muñoz, A; Giovambattista, G; Ortiz, M; Oltra, J; Kanemaki, M; Onuma, M; Aida, Y

    2015-01-01

    Bovine leukocyte antigens (BoLAs) are used extensively as markers for bovine disease and immunological traits. In this study, we estimated BoLA-DRB3 allele frequencies using 888 cattle from 10 groups, including seven cattle breeds and three crossbreeds: 99 Red Angus, 100 Black Angus, 81 Chilean Wagyu, 49 Hereford, 95 Hereford × Angus, 71 Hereford × Jersey, 20 Hereford × Overo Colorado, 113 Holstein, 136 Overo Colorado, and 124 Overo Negro cattle. Forty-six BoLA-DRB3 alleles were identified, and each group had between 12 and 29 different BoLA-DRB3 alleles. Overo Negro had the highest number of alleles (29); this breed is considered in Chile to be an 'Old type' European Holstein Friesian descendant. By contrast, we detected 21 alleles in Holstein cattle, which are considered to be a 'Present type' Holstein Friesian cattle. Chilean cattle groups and four Japanese breeds were compared by neighbor-joining trees and a principal component analysis (PCA). The phylogenetic tree showed that Red Angus and Black Angus cattle were in the same clade, crossbreeds were closely related to their parent breeds, and Holstein cattle from Chile were closely related to Holstein cattle in Japan. Overall, the tree provided a thorough description of breed history. It also showed that the Overo Negro breed was closely related to the Holstein breed, consistent with historical data indicating that Overo Negro is an 'Old type' Holstein Friesian cattle. This allelic information will be important for investigating the relationship between major histocompatibility complex (MHC) and disease. PMID:25430590

  6. Inferring Selection Intensity and Allele Age from Multilocus Haplotype Structure

    PubMed Central

    Chen, Hua; Slatkin, Montgomery

    2013-01-01

    It is a challenging task to infer selection intensity and allele age from population genetic data. Here we present a method that can efficiently estimate selection intensity and allele age from the multilocus haplotype structure in the vicinity of a segregating mutant under positive selection. We use a structured-coalescent approach to model the effect of directional selection on the gene genealogies of neutral markers linked to the selected mutant. The frequency trajectory of the selected allele follows the Wright-Fisher model. Given the position of the selected mutant, we propose a simplified multilocus haplotype model that can efficiently model the dynamics of the ancestral haplotypes under the joint influence of selection and recombination. This model approximates the ancestral genealogies of the sample, which reduces the number of states from an exponential function of the number of single-nucleotide polymorphism loci to a quadratic function. That allows parameter inference from data covering DNA regions as large as several hundred kilo-bases. Importance sampling algorithms are adopted to evaluate the probability of a sample by exploring the space of both allele frequency trajectories of the selected mutation and gene genealogies of the linked sites. We demonstrate by simulation that the method can accurately estimate selection intensity for moderate and strong positive selection. We apply the method to a data set of the G6PD gene in an African population and obtain an estimate of 0.0456 (95% confidence interval 0.0144−0.0769) for the selection intensity. The proposed method is novel in jointly modeling the multilocus haplotype pattern caused by recombination and mutation, allowing the analysis of haplotype data in recombining regions. Moreover, the method is applicable to data from populations under exponential growth and a variety of other demographic histories. PMID:23797107

  7. Molecular detection and identification of intimin alleles in pathogenic Escherichia coli by multiplex PCR.

    PubMed

    Reid, S D; Betting, D J; Whittam, T S

    1999-08-01

    A multiplex PCR was designed to detect the eae gene and simultaneously identify specific alleles in pathogenic Escherichia coli. The method was tested on 87 strains representing the diarrheagenic E. coli clones. The results show that the PCR assay accurately detects eae and resolves alleles encoding the alpha, beta, and gamma intimin variants. PMID:10405431

  8. Molecular Detection and Identification of Intimin Alleles in Pathogenic Escherichia coli by Multiplex PCR

    PubMed Central

    Reid, Sean D.; Betting, David J.; Whittam, Thomas S.

    1999-01-01

    A multiplex PCR was designed to detect the eae gene and simultaneously identify specific alleles in pathogenic Escherichia coli. The method was tested on 87 strains representing the diarrheagenic E. coli clones. The results show that the PCR assay accurately detects eae and resolves alleles encoding the α, β, and γ intimin variants. PMID:10405431

  9. Conditional Allele Mouse Planner (CAMP): software to facilitate the planning and design of breeding strategies involving mice with conditional alleles.

    PubMed

    Hoffert, Jason D; Pisitkun, Trairak; Miller, R Lance

    2012-06-01

    Transgenic and conditional knockout mouse models play an important role in biomedical research and their use has grown exponentially in the last 5-10 years. Generating conditional knockouts often requires breeding multiple alleles onto the background of a single mouse or group of mice. Breeding these mice depends on parental genotype, litter size, transmission frequency, and the number of breeding rounds. Therefore, a well planned breeding strategy is critical for keeping costs to a minimum. However, designing a viable breeding strategy can be challenging. With so many different variables this would be an ideal task for a computer program. To facilitate this process, we created a Java-based program called Conditional Allele Mouse Planner (CAMP). CAMP is designed to provide an estimate of the number of breeders, amount of time, and costs associated with generating mice of a particular genotype. We provide a description of CAMP, how to use it, and offer it freely as an application. PMID:21870117

  10. Cytochrome P450 2C8*2 allele in Botswana: Human genetic diversity and public health implications.

    PubMed

    Motshoge, Thato; Tawe, Leabaneng; Muthoga, Charles Waithaka; Allotey, Joel; Romano, Rita; Quaye, Isaac; Paganotti, Giacomo Maria

    2016-05-01

    Human cytochrome P450 2C8 is a highly polymorphic gene and shows variation according to ethnicity. The CYP2C8*2 is a slow drug metabolism allele and shows 10-24% frequency in Black populations. The objective of this study was to assess the prevalence of CYP2C8*2 allele in Botswana among the San (or Bushmen) and the Bantu ethnic groups. For that purpose we recruited 544 children of the two ethnicities in three districts of Botswana from primary schools, collected blood samples, extracted DNA and genotyped them through PCR-based restriction fragment length polymorphism analysis. The results demonstrated that in the San the prevalence of the CYP2C8*2 allele is significantly higher than among the Bantu-related ethnic groups (17.5% and 8.5% for San and Bantu, respectively; P=0.00002). These findings support the evidence of a different genetic background of the San with respect to Bantu-related populations, and highlight a possible higher risk of longer drug clearance or poor level of activation of pro-drugs among the San group. PMID:26836270

  11. Preferential segregation of two allelic mutations for small leaf character in groundnut.

    PubMed

    Patil, S H; Mouli, C

    1984-02-01

    Two radiation induced small leaf mutants were isolated in a Spanish Improved variety of groundnut. Both had more than a 50% reduced leaflet size which was associated with an increased number of imparipinnate leaves in one mutant and light yellow flower colour in the other. Genetic studies demonstrated that both mutants were allelic and controlled by recessive factors. Phenotypic and genotypic segregation ratios indicated a lower frequency of mutants. This was attributed to preferential segregation in favour of normal leaf size. Marker genes controlling krinkle leaf, virescent and chlorina characters showed independent assortment in crosses with the small leaf mutants. Absence of assortment of associated mutant characters viz., small leaf and light yellow flower colour, generally indicated pleiotropic effects. However, monohybrid segregation for flower colour in the cross between the two small leaf mutants showed that the two characters were independently induced and hence attributed to close linkage and not pleiotropy. PMID:24258654

  12. Facultative cheating supports the coexistence of diverse quorum-sensing alleles

    PubMed Central

    Pollak, Shaul; Omer-Bendori, Shira; Even-Tov, Eran; Lipsman, Valeria; Bareia, Tasneem; Ben-Zion, Ishay; Eldar, Avigdor

    2016-01-01

    Bacterial quorum sensing enables bacteria to cooperate in a density-dependent manner via the group-wide secretion and detection of specific autoinducer molecules. Many bacterial species show high intraspecific diversity of autoinducer–receptor alleles, called pherotypes. The autoinducer produced by one pherotype activates its coencoded receptor, but not the receptor of another pherotype. It is unclear what selection forces drive the maintenance of pherotype diversity. Here, we use the ComQXPA system of Bacillus subtilis as a model system, to show that pherotype diversity can be maintained by facultative cheating—a minority pherotype exploits the majority, but resumes cooperation when its frequency increases. We find that the maintenance of multiple pherotypes by facultative cheating can persist under kin-selection conditions that select against “obligate cheaters” quorum-sensing response null mutants. Our results therefore support a role for facultative cheating and kin selection in the evolution of quorum-sensing diversity. PMID:26787913

  13. Tissue-specific patterns of allelically-skewed DNA methylation

    PubMed Central

    Marzi, Sarah J.; Meaburn, Emma L.; Dempster, Emma L.; Lunnon, Katie; Paya-Cano, Jose L.; Smith, Rebecca G.; Volta, Manuela; Troakes, Claire; Schalkwyk, Leonard C.; Mill, Jonathan

    2016-01-01

    ABSTRACT While DNA methylation is usually thought to be symmetrical across both alleles, there are some notable exceptions. Genomic imprinting and X chromosome inactivation are two well-studied sources of allele-specific methylation (ASM), but recent research has indicated a more complex pattern in which genotypic variation can be associated with allelically-skewed DNA methylation in cis. Given the known heterogeneity of DNA methylation across tissues and cell types we explored inter- and intra-individual variation in ASM across several regions of the human brain and whole blood from multiple individuals. Consistent with previous studies, we find widespread ASM with > 4% of the ∼220,000 loci interrogated showing evidence of allelically-skewed DNA methylation. We identify ASM flanking known imprinted regions, and show that ASM sites are enriched in DNase I hypersensitivity sites and often located in an extended genomic context of intermediate DNA methylation. We also detect examples of genotype-driven ASM, some of which are tissue-specific. These findings contribute to our understanding of the nature of differential DNA methylation across tissues and have important implications for genetic studies of complex disease. As a resource to the community, ASM patterns across each of the tissues studied are available in a searchable online database: http://epigenetics.essex.ac.uk/ASMBrainBlood. PMID:26786711

  14. Genomic structure of the human plasma prekallikrein gene, identification of allelic variants, and analysis in end-stage renal disease.

    PubMed

    Yu, H; Anderson, P J; Freedman, B I; Rich, S S; Bowden, D W

    2000-10-15

    polymorphism in the coding sequence was a C699A shift that caused an amino acid change, H183Q. This allele was observed in 8 cases from 6 ESRD families but was not found in any control DNAs. Individually or combined, the allelic variants observed are not statistically associated with ESRD, though in several cases (e.g., H183Q) the small number of people in the population carrying these alleles limits our ability to statistically test for significant association with ESRD. Two new CA/GT repeat polymorphic markers, designated KLK3f and KLK3g, that have heterozygosities of 0.65 and 0.84, respectively, were identified within introns M and N. Analysis using the relative predispositional effect technique indicated that the frequencies of alleles 4 and 8 of KLK3f and allele 8 of KLK3g were significantly different between controls and ESRD cases. They accounted for 0.226, 0.096, and 0.313, respectively, in the probands of 166 ESRD families compared to 0.172, 0.066, and 0.244 in 139 healthy race-matched controls (allele P and total P < 0.05 for all three alleles). Therefore, although polymorphisms in the coding and 5'-proximal promoter of KLKB1 show no statistically significant association with ESRD in African Americans, there is still evidence for association of this part of chromosome 4 with ESRD. This observation suggests that other sequences within or near KLKB1, or another gene nearby, may contribute to ESRD susceptibility. PMID:11031105

  15. Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer

    PubMed Central

    Halabi, Najeeb M.; Martinez, Alejandra; Al-Farsi, Halema; Mery, Eliane; Puydenus, Laurence; Pujol, Pascal; Khalak, Hanif G.; McLurcan, Cameron; Ferron, Gwenael; Querleu, Denis; Al-Azwani, Iman; Al-Dous, Eman; Mohamoud, Yasmin A.; Malek, Joel A.; Rafii, Arash

    2016-01-01

    Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies. PMID:26735499

  16. Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer.

    PubMed

    Halabi, Najeeb M; Martinez, Alejandra; Al-Farsi, Halema; Mery, Eliane; Puydenus, Laurence; Pujol, Pascal; Khalak, Hanif G; McLurcan, Cameron; Ferron, Gwenael; Querleu, Denis; Al-Azwani, Iman; Al-Dous, Eman; Mohamoud, Yasmin A; Malek, Joel A; Rafii, Arash

    2016-01-01

    Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies. PMID:26735499

  17. Further evidence for allelic heterogeneity in Hartnup disorder.

    PubMed

    Azmanov, Dimitar N; Kowalczuk, Sonja; Rodgers, Helen; Auray-Blais, Christiane; Giguère, Robert; Rasko, John E J; Bröer, Stefan; Cavanaugh, Juleen A

    2008-10-01

    Hartnup disorder is an autosomal recessive impairment of amino acid transport in kidney and intestine. Mutations in SLC6A19 have been shown to cosegregate with the disease in the predicted recessive manner; however, in two previous studies (Seow et al., Nat Genet 2004;36:1003-1007; Kleta et al., Nat Genet 2004;36:999-1002), not all causative alleles were identified in all affected individuals, raising the possibility that other genes may contribute to Hartnup disorder. We have now investigated six newly acquired families of Australian and Canadian (Province of Quebec) origin and resequenced the entire coding region of SLC6A19 in families with only a single disease allele identified. We also studied one American family in whom no mutations had been identified in a previous study (Kleta et al., Nat Genet 2004;36:999-1002). We have identified seven novel mutations in SLC6A19 that show functional obliteration of the protein in vitro, explaining Hartnup disorder in all reported families so far. We demonstrate that Hartnup disorder is allelically heterogeneous with two mutated SLC6A19 alleles, whether identical or not, necessary for manifestation of the characteristic aminoaciduria in affected individuals. This study resolves the previous hypothesis that other genes contribute to the Hartnup phenotype. PMID:18484095

  18. FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States

    PubMed Central

    2012-01-01

    Background Population screening for FMR1 mutations has been a topic of considerable discussion since the FMR1 gene was identified in 1991. Advances in understanding the molecular basis of fragile X syndrome (FXS) and in genetic testing methods have led to new, less expensive methodology to use for large screening endeavors. A core criterion for newborn screening is an accurate understanding of the public health burden of a disease, considering both disease severity and prevalence rate. This article addresses this need by reporting prevalence rates observed in a pilot newborn screening study for FXS in the US. Methods Blood spot screening of 14,207 newborns (7,312 males and 6,895 females) was conducted in three birthing hospitals across the United States beginning in November 2008, using a PCR-based approach. Results The prevalence of gray zone alleles was 1:66 females and 1:112 males, while the prevalence of a premutation was 1:209 females and 1:430 males. Differences in prevalence rates were observed among the various ethnic groups; specifically higher frequency for gray zone alleles in males was observed in the White group compared to the Hispanic and African-American groups. One full mutation male was identified (>200 CGG repeats). Conclusions The presented pilot study shows that newborn screening in fragile X is technically feasible and provides overall prevalence of the premutation and gray zone alleles in the USA, suggesting that the prevalence of the premutation, particularly in males, is higher than has been previously reported. PMID:23259642

  19. Tracing pastoralist migrations to southern Africa with lactase persistence alleles.

    PubMed

    Macholdt, Enrico; Lede, Vera; Barbieri, Chiara; Mpoloka, Sununguko W; Chen, Hua; Slatkin, Montgomery; Pakendorf, Brigitte; Stoneking, Mark

    2014-04-14

    Although southern African Khoisan populations are often assumed to have remained largely isolated during prehistory, there is growing evidence for a migration of pastoralists from eastern Africa some 2,000 years ago, prior to the arrival of Bantu-speaking populations in southern Africa. Eastern Africa harbors distinctive lactase persistence (LP) alleles, and therefore LP alleles in southern African populations may be derived from this eastern African pastoralist migration. We sequenced the lactase enhancer region in 457 individuals from 18 Khoisan and seven Bantu-speaking groups from Botswana, Namibia, and Zambia and additionally genotyped four short tandem repeat (STR) loci that flank the lactase enhancer region. We found nine single-nucleotide polymorphisms, of which the most frequent is -14010(∗)C, which was previously found to be associated with LP in Kenya and Tanzania and to exhibit a strong signal of positive selection. This allele occurs in significantly higher frequency in pastoralist groups and in Khoe-speaking groups in our study, supporting the hypothesis of a migration of eastern African pastoralists that was primarily associated with Khoe speakers. Moreover, we find a signal of ongoing positive selection in all three pastoralist groups in our study, as well as (surprisingly) in two foraging groups. PMID:24704073

  20. The CYP4502D6 *4 and *6 alleles are the molecular genetic markers for drug response: implications in colchicine non-responder FMF patients.

    PubMed

    Yalcıntepe, Sinem; Ozdemır, Ozturk; Sılan, Coskun; Ozen, Filiz; Uludag, Ahmet; Candan, Ferhan; Sılan, Fatma

    2016-06-01

    The cytochrome P450 2D6 (CYP2D6) is a cytochrome P450 enzyme involved in the oxidative biotransformation of the xenobiotics, carcinogens and various clinically important drugs. Patients are evaluated in three sub-groups of extensive (EM), intermediate (IM) and poor metabolizer (PM) phenotypes due to their drug-metabolising ability for the target CYP2D6 gene. Colchicine non-responsive FMF patients were prospectively genotyped for the major CYP2D6 alleles in the current study. Major CYP2D6 alleles of *1, *3, *4, *5, and *6 were genotyped for 30 responsive and 60 non-responsive FMF patients by multiplex PCR-based reverse-hybridization StripAssay and real-time PCR methods. DNA banks isolated from blood-EDTA were retrospectively used in the current patients and results were compared statistically. Increased CYP2D6 *4 and *6 allele frequencies were highly detected in the colchicine non-responsive FMF patients when compared to the responsive group. Results showed the frequencies of major CYP2D6 *1(wild), *3(2637A > delA), *4(G1934A), *5(total gene deletion) and *6(1707T del) alleles in 0.550, 0.042, 0.158, 0.025 and 0.225 for non-responder and 0.880 and 0.120 (CYP2D6*1 and *4) for the responder groups, respectively. Despite small sample size, this study suggests that there is an association between CYP2D6*4 and CYP2D6*6 alleles and drug intoxicants in colchicine non-responder FMF patients. PMID:25645282

  1. Association between Anti-Ganglionic Nicotinic Acetylcholine Receptor (gAChR) Antibodies and HLA-DRB1 Alleles in the Japanese Population

    PubMed Central

    Maeda, Yasuhiro; Migita, Kiyoshi; Higuchi, Osamu; Mukaino, Akihiro; Furukawa, Hiroshi; Komori, Atsumasa; Nakamura, Minoru; Hashimoto, Satoru; Nagaoka, Shinya; Abiru, Seigo; Yatsuhashi, Hiroshi; Matsuo, Hidenori; Kawakami, Atsushi; Yasunami, Michio; Nakane, Shunya

    2016-01-01

    Background/Aims Anti-ganglionic nicotinic acetylcholine receptor (gAChR) antibodies are observed in autoimmune diseases, as well as in patients with autoimmune autonomic ganglionopathy. However, the genetic background of anti-gAChR antibodies is unclear. Here, we investigated HLA alleles in autoimmune hepatitis (AIH) patients with or without anti-gAChR antibodies. Methodology/Principal Findings Genomic DNA from 260 patients with type-1 autoimmune hepatitis (AIH) were genotyped for HLA-A, B, DRB1, and DQB1 loci. Anti-gAChR antibodies in the sera form AIH patients were measured using the luciferase immunoprecipitation system, and examined allelic association in patients with or without anti-gAChR antibodies. Methodology/ Methods We detected anti-α3 or -β4 gAChR antibodies in 11.5% (30/260) of patients with AIH. Among AIH patients there was no significant association between HLA-A, B DQB1 alleles and the positivity for anti-gAChR antibodies. Whereas the HLA-DRB1*0403 allele showed a significantly increased frequency in AIH patients with anti-gAChR antibodies compared with those without anti-gAChR antibodies. Conclusions/Significance The frequency of the HLA-DRB1*0403 allele differed among Japanese patients with AIH according to the presence or absence of anti-gAChR antibodies. Our findings suggest that particular HLA class II molecules might control the development of anti-gAChR antibodies in the autoimmune response to gAChR. PMID:26807576

  2. Pyrosequencing for Accurate Imprinted Allele Expression Analysis

    PubMed Central

    Yang, Bing; Damaschke, Nathan; Yao, Tianyu; McCormick, Johnathon; Wagner, Jennifer; Jarrard, David

    2016-01-01

    Genomic imprinting is an epigenetic mechanism that restricts gene expression to one inherited allele. Improper maintenance of imprinting has been implicated in a number of human diseases and developmental syndromes. Assays are needed that can quantify the contribution of each paternal allele to a gene expression profile. We have developed a rapid, sensitive quantitative assay for the measurement of individual allelic ratios termed Pyrosequencing for Imprinted Expression (PIE). Advantages of PIE over other approaches include shorter experimental time, decreased labor, avoiding the need for restriction endonuclease enzymes at polymorphic sites, and prevent heteroduplex formation which is problematic in quantitative PCR-based methods. We demonstrate the improved sensitivity of PIE including the ability to detect differences in allelic expression down to 1%. The assay is capable of measuring genomic heterozygosity as well as imprinting in a single run. PIE is applied to determine the status of Insulin-like Growth Factor-2 (IGF2) imprinting in human and mouse tissues. PMID:25581900

  3. Is the European spatial distribution of the HIV-1-resistant CCR5-Delta32 allele formed by a breakdown of the pathocenosis due to the historical Roman expansion?

    PubMed

    Faure, Eric; Royer-Carenzi, Manuela

    2008-12-01

    We studied the possible effects of the expansion of ancient Mediterranean civilizations during the five centuries before and after Christ on the European distribution of the mutant allele for the chemokine receptor gene CCR5 which has a 32-bp deletion (CCR5-Delta32). There is a strong evidence for the unitary origin of the CCR5-Delta32 mutation, this it is found principally in Europe and Western Asia, with generally a north-south downhill cline frequency. Homozygous carriers of this mutation show a resistance to HIV-1 infection and a slower progression towards AIDS. However, HIV has clearly emerged too recently to have been the selective force on CCR5. Our analyses showed strong negative correlations in Europe between the allele frequency and two historical parameters, i.e. the first colonization dates by the great ancient Mediterranean civilizations, and the distances from the Northern frontiers of the Roman Empire in its greatest expansion. Moreover, other studies have shown that the deletion frequencies in both German Bronze Age and Swedish Neolithic populations were similar to those found in the corresponding modern populations, and this deletion has been found in ancient DNA of around 7000 years ago, suggesting that in the past, the deletion frequency could have been relatively high in European populations. In addition, in West Nile virus pathogenesis, CCR5 plays an antimicrobial role showing that host genetic factors are highly pathogen-specific. Our results added to all these previous data suggest that the actual European allele frequency distribution might not be due to genes spreading, but to a negative selection resulting in the spread of pathogens principally during Roman expansion. Indeed, as gene flows from colonizers to European native populations were extremely low, the mutational changes might be associated with vulnerability to imported infections. To date, the nature of the parasites remains unknown; however, zoonoses could be incriminated. PMID

  4. Allelic imbalance within the E-cadherin gene is an infrequent event in prostate carcinogenesis.

    PubMed

    Murant, S J; Rolley, N; Phillips, S M; Stower, M; Maitland, N J

    2000-01-01

    By exploiting two single nucleotide polymorphisms (SNPs) located within the E-cadherin gene, at 16q22, we have determined the frequency of allelic imbalance at this proposed tumor suppressor locus in a series of human prostatic carcinoma DNA samples. Whereas results with seven highly polymorphic microsatellite markers flanking the E-cadherin locus confirmed the existence of three separate loci on chromosome 16, at which allelic imbalance increased with increasing loss of tumor cell differentiation, no allelic imbalance within the E-cadherin gene was detected either by single-strand conformational polymorphism analysis or by direct sequencing. We conclude that the loss of E-cadherin function observed in prostate cancer is not a result of allelic deletion. Genes Chromosomes Cancer 27:104-109, 2000. PMID:10564592

  5. Reintroduction of a Homocysteine Level-Associated Allele into East Asians by Neanderthal Introgression.

    PubMed

    Hu, Ya; Ding, Qiliang; He, Yungang; Xu, Shuhua; Jin, Li

    2015-12-01

    In this study, we present an analysis of Neanderthal introgression at the dipeptidase 1 gene, DPEP1. A Neanderthal origin for the putative introgressive haplotypes was demonstrated using an established three-step approach. This introgression was under positive natural selection, reached a frequency of >50%, and introduced a homocysteine level- and pigmentation-associated allele (rs460879-T) into East Asians. However, the same allele was also found in non-East Asians, but not from Neanderthal introgression. It is likely that rs460879-T was lost in East Asians and was reintroduced subsequently through Neanderthal introgression. Our findings suggest that Neanderthal introgression could reintroduce an important previously existing allele into populations where the allele had been lost. This study sheds new light on understanding the contribution of Neanderthal introgression to the adaptation of non-Africans. PMID:26392408

  6. No Association Between CEL-HYB Hybrid Allele and Chronic Pancreatitis in Asian Populations.

    PubMed

    Zou, Wen-Bin; Boulling, Arnaud; Masamune, Atsushi; Issarapu, Prachand; Masson, Emmanuelle; Wu, Hao; Sun, Xiao-Tian; Hu, Liang-Hao; Zhou, Dai-Zhan; He, Lin; Fichou, Yann; Nakano, Eriko; Hamada, Shin; Kakuta, Yoichi; Kume, Kiyoshi; Isayama, Hiroyuki; Paliwal, Sumit; Mani, K Radha; Bhaskar, Seema; Cooper, David N; Férec, Claude; Shimosegawa, Tooru; Chandak, Giriraj R; Chen, Jian-Min; Li, Zhao-Shen; Liao, Zhuan

    2016-06-01

    A hybrid allele between the carboxyl ester lipase gene (CEL) and its pseudogene, CELP (called CEL-HYB), generated by nonallelic homologous recombination between CEL intron 10 and CELP intron 10', was found to increase susceptibility to chronic pancreatitis in a case-control study of patients of European ancestry. We attempted to replicate this finding in 3 independent cohorts from China, Japan, and India, but failed to detect the CEL-HYB allele in any of these populations. The CEL-HYB allele might therefore be an ethnic-specific risk factor for chronic pancreatitis. An alternative hybrid allele (CEL-HYB2) was identified in all 3 Asian populations (1.7% combined carrier frequency), but was not associated with chronic pancreatitis. PMID:26946345

  7. The polymorphic hMSH5 C85T allele augments radiotherapy-induced spermatogenic impairment.

    PubMed

    Zhu, Y; Gao, G; Xia, L; Li, X; Wu, X; Her, C; Xu, K

    2016-09-01

    The hMSH5 C85T polymorphism (encoding hMSH5 P29S) is associated with male infertility and radiation-induced apoptotic response. To date, however, the potential association of hMSH5 C85T polymorphism with DNA damage accumulation in spermatozoa of cancer patients treated with radiotherapy is largely unknown. We investigated hMSH5 C85T allele and genotype frequencies, routine semen analysis and sperm DNA Fragmentation Index (DFI) in 113 testicular germ cell tumor (TGCT) patients before and after radiotherapy. The hMSH5 C85T allele is not associated with the occurrence of TGCT. However, in comparison with the CC genotype, TGCT patients with the CT + TT genotypes showed significantly altered sperm counts, sperm morphology and DFI after radiotherapy. Finally, the results of the DSB repair assay demonstrated that hMSH5 P29S could enhance radiotherapy-induced DNA damage by unleashing error-prone non-homologous end joining. Together, our studies indicate that the hMSH5 C85T variation could have an impact on the severity of radiotherapy-provoked long-term side effects through compromising the repair of radiation-induced DNA lesions. PMID:27370712

  8. KIR2DL2/2DL3-E35 alleles are functionally stronger than -Q35 alleles

    NASA Astrophysics Data System (ADS)

    Bari, Rafijul; Thapa, Rajoo; Bao, Ju; Li, Ying; Zheng, Jie; Leung, Wing

    2016-03-01

    KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E35) are functionally stronger than those with glutamine at the same position (Q35). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E35 could kill more target cells lacking their ligands than NK cells with the weaker -Q35 alleles, indicating better licensing of KIR2DL2/L3+ NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation.

  9. KIR2DL2/2DL3-E35 alleles are functionally stronger than -Q35 alleles

    PubMed Central

    Bari, Rafijul; Thapa, Rajoo; Bao, Ju; Li, Ying; Zheng, Jie; Leung, Wing

    2016-01-01

    KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E35) are functionally stronger than those with glutamine at the same position (Q35). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E35 could kill more target cells lacking their ligands than NK cells with the weaker -Q35 alleles, indicating better licensing of KIR2DL2/L3+ NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation. PMID:27030405

  10. Distribution of repeat unit differences between alleles at tandem repeat microsatellite loci

    SciTech Connect

    Jin, L. |; Zhong, Y.; Chakraborty, R.

    1994-09-01

    PCR-based assays of tandemly repeated microsatellite loci detect genetic variation from which alleles may be scored by their repeat unit lengths. Comparison of allele sizes from such data yields a probability distribution (P{sub k}) of repeat unit differences (k) between alleles segregating in a population. We show that this distribution (P{sub k}; k = 0, 1,2,...) provides insight regarding the mechanism of production of new alleles at such loci and the demographic history of populations, far better than that obtained from other summary measures (e.g., heterozygosity, number of alleles, and the range of allele sizes). The distributions of P{sub k} under multi-step stepwise models of mutation are analytically derived, which show that when a population is at equilibrium under the mutation-drift balance, the distribution of repeat unit differences between alleles is positively skewed with a mode larger than zero. However, when the heterozygosity at a locus is low (say, less than 40%), P{sub k} is a monotonically decreasing function of k. Applications of this theory to data on repeat unit sizes at over 1,240 microsatellite loci from the Caucasians, categorized by the average heterozygosity of loci, indicate that at most microsatellite loci new alleles are produced by stepwise mutations, and this is consistent with the replication slippage mechanism of mutations. The repeat size changes of mutants are probably within one or two units of alleles from which the mutants arise. Distributions of P{sub k} at microsatellite loci located within genes show evidence of allele size constraints. No significant evidence of recent expansion of population sizes in the Caucasians is detected by the distribution of P{sub k}.

  11. Genotyping of 28 blood group alleles in blood donors from Mali: Prediction of rare phenotypes.

    PubMed

    Ba, Alhassane; Bagayoko, Seydou; Chiaroni, Jacques; Baiily, Pascal; Silvy, Monique

    2016-04-01

    We determined the frequencies of clinically relevant blood group alleles in 300 blood donors from Mali. Multiplex test based on xMAP technology was used to investigate six blood group systems (RH, KEL, MNS, FY, JK, DO, HPA) and complementary analysis were conducted for MNS and RH systems. Polymorphisms that affect the specificity of molecular tests leading to discrepant genotype results are discussed. Antigen expressions were predicted showing that 50% of donors expressed at least one traditional low prevalence antigen, and 11.6% lacked the ability to express at least one high prevalence antigen compatible with Dob-, HPA1a-, S-s-U-, Jsb-, RH:-31 and/or RH:-34 phenotypes. PMID:26616029

  12. Allele Workbench: transcriptome pipeline and interactive graphics for allele-specific expression.

    PubMed

    Soderlund, Carol A; Nelson, William M; Goff, Stephen A

    2014-01-01

    Sequencing the transcriptome can answer various questions such as determining the transcripts expressed in a given species for a specific tissue or condition, evaluating differential expression, discovering variants, and evaluating allele-specific expression. Differential expression evaluates the expression differences between different strains, tissues, and conditions. Allele-specific expression evaluates expression differences between parental alleles. Both differential expression and allele-specific expression have been studied for heterosis (hybrid vigor), where the hybrid has improved performance over the parents for one or more traits. The Allele Workbench software was developed for a heterosis study that evaluated allele-specific expression for a mouse F1 hybrid using libraries from multiple tissues with biological replicates. This software has been made into a distributable package, which includes a pipeline, a Java interface to build the database, and a Java interface for query and display of the results. The required input is a reference genome, annotation file, and one or more RNA-Seq libraries with optional replicates. It evaluates allelic imbalance at the SNP and transcript level and flags transcripts with significant opposite directional allele-specific expression. The Java interface allows the user to view data from libraries, replicates, genes, transcripts, exons, and variants, including queries on allele imbalance for selected libraries. To determine the impact of allele-specific SNPs on protein folding, variants are annotated with their effect (e.g., missense), and the parental protein sequences may be exported for protein folding analysis. The Allele Workbench processing results in transcript files and read counts that can be used as input to the previously published Transcriptome Computational Workbench, which has a new algorithm for determining a trimmed set of gene ontology terms. The software with demo files is available from https://code.google.com/p/allele

  13. Allele Workbench: Transcriptome Pipeline and Interactive Graphics for Allele-Specific Expression

    PubMed Central

    Soderlund, Carol A.; Nelson, William M.; Goff, Stephen A.

    2014-01-01

    Sequencing the transcriptome can answer various questions such as determining the transcripts expressed in a given species for a specific tissue or condition, evaluating differential expression, discovering variants, and evaluating allele-specific expression. Differential expression evaluates the expression differences between different strains, tissues, and conditions. Allele-specific expression evaluates expression differences between parental alleles. Both differential expression and allele-specific expression have been studied for heterosis (hybrid vigor), where the hybrid has improved performance over the parents for one or more traits. The Allele Workbench software was developed for a heterosis study that evaluated allele-specific expression for a mouse F1 hybrid using libraries from multiple tissues with biological replicates. This software has been made into a distributable package, which includes a pipeline, a Java interface to build the database, and a Java interface for query and display of the results. The required input is a reference genome, annotation file, and one or more RNA-Seq libraries with optional replicates. It evaluates allelic imbalance at the SNP and transcript level and flags transcripts with significant opposite directional allele-specific expression. The Java interface allows the user to view data from libraries, replicates, genes, transcripts, exons, and variants, including queries on allele imbalance for selected libraries. To determine the impact of allele-specific SNPs on protein folding, variants are annotated with their effect (e.g., missense), and the parental protein sequences may be exported for protein folding analysis. The Allele Workbench processing results in transcript files and read counts that can be used as input to the previously published Transcriptome Computational Workbench, which has a new algorithm for determining a trimmed set of gene ontology terms. The software with demo files is available from https://code.google.com/p/allele

  14. Effects of allelic variations in starch synthesis-related genes on grain quality traits of Korean nonglutinous rice varieties under different temperature conditions

    PubMed Central

    Mo, Young-Jun; Jeung, Ji-Ung; Shin, Woon-Chul; Kim, Ki-Young; Ye, Changrong; Redoña, Edilberto D.; Kim, Bo-Kyeong

    2014-01-01

    Influences of allelic variations in starch synthesis-related genes (SSRGs) on rice grain quality were examined. A total of 187 nonglutinous Korean rice varieties, consisting of 170 Japonica and 17 Tongil-type varieties, were grown in the field and in two greenhouse conditions. The percentages of head rice and chalky grains, amylose content, alkali digestion value, and rapid visco-analysis characteristics were evaluated in the three different environments. Among the 10 previously reported SSRG markers used in this study, seven were polymorphic, and four of those showed subspecies-specific allele distributions. Six out of the seven polymorphic SSRG markers were significantly associated with at least one grain quality trait (R2 > 0.1) across the three different environments. However, the association level and significance were markedly lower when the analysis was repeated using only the 170 Japonica varieties. Similarly, the significant associations between SSRG allelic variations and changes in grain quality traits under increased temperature were largely attributable to the biased allele frequency between the two subpopulations. Our results suggest that within Korean Japonica varieties, these 10 major SSRG loci have been highly fixed during breeding history and variations in grain quality traits might be influenced by other genetic factors. PMID:24987303

  15. Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations.

    PubMed

    Pompei, Fiorenza; Ciminelli, Bianca Maria; Bombieri, Cristina; Ciccacci, Cinzia; Koudova, Monika; Giorgi, Silvia; Belpinati, Francesca; Begnini, Angela; Cerny, Milos; Des Georges, Marie; Claustres, Mireille; Ferec, Claude; Macek, Milan; Modiano, Guido; Pignatti, Pier Franco

    2006-01-01

    An average of about 1700 CFTR (cystic fibrosis transmembrane conductance regulator) alleles from normal individuals from different European populations were extensively screened for DNA sequence variation. A total of 80 variants were observed: 61 coding SNSs (results already published), 13 noncoding SNSs, three STRs, two short deletions, and one nucleotide insertion. Eight DNA variants were classified as non-CF causing due to their high frequency of occurrence. Through this survey the CFTR has become the most exhaustively studied gene for its coding sequence variability and, though to a lesser extent, for its noncoding sequence variability as well. Interestingly, most variation was associated with the M470 allele, while the V470 allele showed an 'extended haplotype homozygosity' (EHH). These findings make us suggest a role for selection acting either on the M470V itself or through an hitchhiking mechanism involving a second site. The possible ancient origin of the V allele in an 'out of Africa' time frame is discussed. PMID:16251901

  16. Analysis of FMR1 (CGG)n alleles and FRAXA microsatellite haplotypes in the population of Greenland: implications for the population of the New World from Asia.

    PubMed

    Larsen, L A; Armstrong, J S; Grønskov, K; Hjalgrim, H; Brøndum-Nielsen, K; Hasholt, L; Nørgaard-Pedersen, B; Vuust, J

    1999-01-01

    The fragile X syndrome is caused by the expansion of a polymorphic (CGG)n tract in the promoter region of the FMR1 gene. Apparently the incidence of fragile X syndrome is rare in the population of Greenland. In order to examine population-related factors involved in stability of the (CGG)n sequence, DNA samples obtained randomly from the Greenlandic population were analysed for size and AGG interspersion pattern of the FMR1 (CGG)n region and associated DXS548-FRAXAC1 haplotypes. In addition a large Greenland family with unstable transmission in the premutation range was analysed. The (CGG)n allele sizes in the Greenland population showed a narrow distribution similar to that reported for Asian populations. DNA sequencing of alleles with 36 CGG repeats revealed an AGG(CGG)6 insertion previously reported exclusively in Asian populations and a high frequency of alleles with a (CGG)10AGG(CGG)9AGG(CGG)9 or (CGG)9AGG(CGG)9AGG(CGG)6AGG(CGG)9 sequence pattern was found. Thus the data confirm the Asian origin of the Greenlandic (Eskimo) population and indicates that some (CGG)n alleles have remained stable for 15-30,000 years, since the population of the New World arrived from Asia via the Bering Strait. PMID:10573009

  17. Complex and multi-allelic copy number variation in human disease

    PubMed Central

    McCarroll, Steven A.

    2015-01-01

    Hundreds of copy number variants are complex and multi-allelic, in that they have many structural alleles and have rearranged multiple times in the ancestors who contributed chromosomes to current humans. Not only are the relationships of these multi-allelic CNVs (mCNVs) to phenotypes generally unknown, but many mCNVs have not yet been described at the basic levels—alleles, allele frequencies, structural features—that support genetic investigation. To date, most reported disease associations to these variants have been ascertained through candidate gene studies. However, only a few associations have reached the level of acceptance defined by durable replications in many cohorts. This likely stems from longstanding challenges in making precise molecular measurements of the alleles individuals have at these loci. However, approaches for mCNV analysis are improving quickly, and some of the unique characteristics of mCNVs may assist future association studies. Their various structural alleles are likely to have different magnitudes of effect, creating a natural allelic series of growing phenotypic impact and giving investigators a set of natural predictions and testable hypotheses about the extent to which each allele of an mCNV predisposes to a phenotype. Also, mCNVs’ low-to-modest correlation to individual single-nucleotide polymorphisms (SNPs) may make it easier to distinguish between mCNVs and nearby SNPs as the drivers of an association signal, and perhaps, make it possible to preliminarily screen candidate loci, or the entire genome, for the many mCNV–disease relationships that remain to be discovered. PMID:26163405

  18. A Computer Simulation Study of Vntr Population Genetics: Constrained Recombination Rules Out the Infinite Alleles Model

    PubMed Central

    Harding, R. M.; Boyce, A. J.; Martinson, J. J.; Flint, J.; Clegg, J. B.

    1993-01-01

    Extensive allelic diversity in variable numbers of tandem repeats (VNTRs) has been discovered in the human genome. For population genetic studies of VNTRs, such as forensic applications, it is important to know whether a neutral mutation-drift balance of VNTR polymorphism can be represented by the infinite alleles model. The assumption of the infinite alleles model that each new mutant is unique is very likely to be violated by unequal sister chromatid exchange (USCE), the primary process believed to generate VNTR mutants. We show that increasing both mutation rates and misalignment constraint for intrachromosomal recombination in a computer simulation model reduces simulated VNTR diversity below the expectations of the infinite alleles model. Maximal constraint, represented as slippage of single repeats, reduces simulated VNTR diversity to levels expected from the stepwise mutation model. Although misalignment rule is the more important variable, mutation rate also has an effect. At moderate rates of USCE, simulated VNTR diversity fluctuates around infinite alleles expectation. However, if rates of USCE are high, as for hypervariable VNTRs, simulated VNTR diversity is consistently lower than predicted by the infinite alleles model. This has been observed for many VNTRs and accounted for by technical problems in distinguishing alleles of neighboring size classes. We use sampling theory to confirm the intrinsically poor fit to the infinite alleles model of both simulated VNTR diversity and observed VNTR polymorphisms sampled from two Papua New Guinean populations. PMID:8293988

  19. The associations of HLA-A, -B, DRB1 alleles and haplotypes in Turkish lymphoma patients.

    PubMed

    Uçar, Fahri; Sönmez, Mehmet; Ermantaş, Nilay; Özbaş, Hasan Mücahit; Cansız, Abide; Balcı, Mustafa; Yılmazz, Mustafa

    2016-07-25

    A significant association between lymphomas and HLA alleles has been shown in previous studies. However, the frequency of HLA alleles and haplotypes has not been studied in Turkish lymphoma patients. We studied HLA-A, -B, -DRB1 alleles and haplotypes in 80 adult lymphomas and 360 unrelated normal subjects by PCR-SSOP method using Luminex technology. The allele frequencies of HLA-A*29, B*07, and DRB1*11 were higher in patients with Hodgkin's lymphoma (HL) compared with the controls [OR; 5.65 (95%CI; 2.16-14.81), P=0.001], [OR; 3.00 (95%CI; 1.50-5.99), P=0.003)], and [OR; 1.80 (95%CI; 1.08-3.01), P=0.002); respectively]. In patients with non-Hodgkin's lymphoma (NHL) HLA-B*51 and DRB1*04 allele frequencies were higher than controls [OR; 2.25 (95%CI; 1.27-4.00), P=0.007] and [OR; 2.14 (95%CI; 1.20-3.78), P=0.01]. The most frequently observed haplotypes were A*02 B*35 DRB1*11 (7.50% vs. 1.89%) in HL patients, A*02 B*51 DRB1*11 (5.00% vs. 1.96%) in NHL patients, and A*02 B*35 DRB1*13 (2.19%) in the controls. We detected four haplotypes specific to NHL, five haplotypes to HL patients. Seven haplotypes were unique to controls. Our findings suggest that in HL patients, HLA-A*29, B*07, and DRB1*11 alleles, and in NHL patients, HLA-B*51 and DRB1*04 alleles might be presumptive predisposing factors. PMID:27063556

  20. MHC class II alleles and haplotypes in patients with pemphigus vulgaris from India.

    PubMed

    Delgado, J C; Yunis, D E; Bozón, M V; Salazar, M; Deulofeut, R; Turbay, D; Mehra, N K; Pasricha, J S; Raval, R S; Patel, H; Shah, B K; Bhol, K; Alper, C A; Ahmed, A R; Yunis, E J

    1996-12-01

    Pemphigus vulgaris (PV) is a blistering disease of the skin and mucous membranes characterized by an autoantibody response against a keratinocyte adhesion molecule, desmoglein 3, causing acantholysis and blister formation. We compared high resolution MHC class II alleles and haplotype frequencies (HLA-DRB, DQA1 and DQB1) in 37 patients with PV to 89 haplotypes of normal relatives from New Delhi and Ahmedabad. We found that PV patients had significantly increased frequencies of DRB1*1404 (P < 0.0001), DQA1*0101 (P = 0.001), and DQB1*0503 (P < 0.0001). These associations were due to the increased frequencies of the haplotype HLA-DRB1*1404, DRB3*0202, DQA1*0101, DQB1*0503 in patients compared to control haplotypes (p < 0.0001). Also, patients from Ahmedabad had a significant increase in HLA-DQB1*0302 (p = 0.03). An identical amino acid sequence (Leu-Leu-Glu-Arg-Arg-Arg-Ala-Glu), in positions 67-74 of the beta domain of DRB alleles is restricted to some DR14 alleles. Therefore, there are three possible explanations for class II allele involvement in autoantibody in PV patients with class II haplotypes marked by HLA-DR14. First, the class II alleles could be markers for an unidentified susceptibility gene in linkage disequilibrium with them. Second, the primary association could be with DQB1*0503 and the association with HLA-DR14 alleles would be the result of linkage disequilibrium. Third, the HLA-DRB1 locus susceptibility could involve a specific amino acid sequence in the third hypervariable region shared by several HLA-DR14 alleles. PMID:9008309

  1. Mining the LIPG allelic spectrum reveals the contribution of rare and common regulatory variants to HDL cholesterol.

    PubMed

    Khetarpal, Sumeet A; Edmondson, Andrew C; Raghavan, Avanthi; Neeli, Hemanth; Jin, Weijun; Badellino, Karen O; Demissie, Serkalem; Manning, Alisa K; DerOhannessian, Stephanie L; Wolfe, Megan L; Cupples, L Adrienne; Li, Mingyao; Kathiresan, Sekar; Rader, Daniel J

    2011-12-01

    Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5' UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5' UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci. PMID:22174694

  2. Mining the LIPG Allelic Spectrum Reveals the Contribution of Rare and Common Regulatory Variants to HDL Cholesterol

    PubMed Central

    Raghavan, Avanthi; Neeli, Hemanth; Jin, Weijun; Badellino, Karen O.; Demissie, Serkalem; Manning, Alisa K.; DerOhannessian, Stephanie L.; Wolfe, Megan L.; Cupples, L. Adrienne; Li, Mingyao; Kathiresan, Sekar; Rader, Daniel J.

    2011-01-01

    Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5′ UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5′ UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci. PMID:22174694

  3. Transvection in the Drosophila Ultrabithorax Gene: A Cbx(1) Mutant Allele Induces Ectopic Expression of a Normal Allele in Trans

    PubMed Central

    Castelli-Gair, J. E.; Micol, J. L.; Garcia-Bellido, A.

    1990-01-01

    In wild-type Drosophila melanogaster larvae, the Ultrabithorax (Ubx) gene is expressed in the haltere imaginal discs but not in the majority of cells of the wing imaginal discs. Ectopic expression of the Ubx gene in wing discs can be elicited by the presence of Contrabithorax (Cbx) gain-of-function alleles of the Ubx gene or by loss-of-function mutations in Polycomb (Pc) or in other trans-regulatory genes which behave as repressors of Ubx gene activity. Several Ubx loss-of-function alleles cause the absence of detectable Ubx proteins (UBX) or the presence of truncated UBX lacking the homeodomain. We have compared adult wing phenotypes with larval wing disc UBX patterns in genotypes involving double mutant chromosomes carrying in cis one of those Ubx mutations and the Cbx(1) mutation. We show that such double mutant genes are (1) active in the same cells in which the single mutant Cbx(1) is expressed, although they are unable to yield functional proteins, and (2) able to induce ectopic expression of a normal homologous Ubx allele in a part of the cells in which the single mutant Cbx(1) is active. That induction is conditional upon pairing of the homologous chromosomes (the phenomenon known as transvection), and it is not mediated by UBX. Depletion of Pc gene products by Pc(3) mutation strongly enhances the induction phenomenon, as shown by (1) the increase of the number of wing disc cells in which induction of the homologous allele is detectable, and (2) the induction of not only a paired normal allele but also an unpaired one. PMID:2121595

  4. Triploidy with cyclopia and identical HLA alleles in the parents.

    PubMed Central

    Lambert, J C; Philip, P; Charpentier, G; Ferrari, M; Donzeau, M; Ayraud, N

    1984-01-01

    A 22-week pregnancy was terminated after discovery of serious echographic abnormalities. Fetal examination showed cyclopia, sacral meningocele, and syndactyly. The karyotype was 69,XXX. The parents had identical HLA alleles A1, A2, and Bw21. The mechanism of the triploidy was determined by chromosome marker analysis to be digyny. The association of triploidy with holoprosencephaly and the parents' identical immunological status are discussed. Images PMID:6607355

  5. Linguistic tone is related to the population frequency of the adaptive haplogroups of two brain size genes, ASPM and Microcephalin

    PubMed Central

    Dediu, Dan; Ladd, D. Robert

    2007-01-01

    The correlations between interpopulation genetic and linguistic diversities are mostly noncausal (spurious), being due to historical processes and geographical factors that shape them in similar ways. Studies of such correlations usually consider allele frequencies and linguistic groupings (dialects, languages, linguistic families or phyla), sometimes controlling for geographic, topographic, or ecological factors. Here, we consider the relation between allele frequencies and linguistic typological features. Specifically, we focus on the derived haplogroups of the brain growth and development-related genes ASPM and Microcephalin, which show signs of natural selection and a marked geographic structure, and on linguistic tone, the use of voice pitch to convey lexical or grammatical distinctions. We hypothesize that there is a relationship between the population frequency of these two alleles and the presence of linguistic tone and test this hypothesis relative to a large database (983 alleles and 26 linguistic features in 49 populations), showing that it is not due to the usual explanatory factors represented by geography and history. The relationship between genetic and linguistic diversity in this case may be causal: certain alleles can bias language acquisition or processing and thereby influence the trajectory of language change through iterated cultural transmission. PMID:17537923

  6. Human Leukocyte Antigen Alleles and Cytomegalovirus Infection After Renal Transplantation

    PubMed Central

    Futohi, Farzaneh; Saber, Azadeh; Nemati, Eglim; Einollahi, Behzad; Rostami, Zohre

    2015-01-01

    Background: Several studies have been conducted on the relationship between a number of human leukocyte antigen (HLA) alleles and cytomegalovirus infection (CMV), in kidney transplant recipients, after transplantation. However, only a limited number of HLAs have been investigated, so far, and the results have been contradictory. Objectives: This study aimed to investigate the relationship between 59 HLA alleles and the CMV infection, in transplant recipients, after kidney transplantation. Patients and Methods: This retrospective cohort study was conducted on 200 patients, receiving a kidney transplant, in Baqiyatallah Hospital, in Tehran, during 2013. Throughout a one-year follow-up of kidney transplant recipients, in case of detecting the CMV antigen in patients’ blood, at any time, they were placed in the group of patients with CMV infection, whereas, if no CMV-specific antigen was developed, over a year, patients were placed in the group of patients without CMV infection, after transplantation. This study investigated the relationship between CMV infection in kidney transplant recipients and 59 HLA alleles, including 14 HLA-A, 28 HLA-B, and 17 HLA-DRB1 cases. Results: Of all participants, 104 patients (52%) were diagnosed with CMV infection. There was no significant difference between the two groups, with and without CMV infection, in terms of patient’s characteristics. The CMV infection, in patients receiving a transplanted organ from deceased donor, was significantly more prevalent than in those receiving kidney transplant from living donor (63% vs. 39%, respectively, P = 0.001). Recipients with HLA-B44 were more infected with CMV compared with patients without this allele (80% vs. 50%, respectively, P = 0.024); on the contrary, kidney recipients with HLA-DRB1-1 were less infected with CMV than patients without this allele (31% vs. 55%, respectively, P = 0.020). There was no significant relationship between CMV infection and other HLA alleles. Results of

  7. An ancient transpecific polymorphism shows extreme divergence in a multitrait cline in an intertidal snail (Nucella lapillus (L.)).

    PubMed

    Kirby, R R

    2000-12-01

    Clines in intraspecific genetic variation are frequently associated with an environmental transition. Here, divergence among nucleotide sequences of two nuclear loci, cytosolic and mitochondrial malate dehydrogenase (cMDH and mMDH, respectively), is described, in a multitrait cline over a distance of ca. 3 km where shell phenotype, allozyme, mitochondrial DNA haplotype, and centric fusion (Robertsonian translocations) frequencies covary with temperature and humidity and change abruptly in a continuous population of the dog-whelk (Nucella lapillus), a common intertidal snail of the north temperate Atlantic. Protein electrophoresis has already shown two alleles of mMDH varying from fixation of one allele to near fixation of the other, whereas cMDH appears to be monomorphic. The results of this study show a striking disparity in nucleotide sequence divergence among alleles at the two loci, with extreme molecular differentiation in one of them. Four alleles of cMDH were found to have nucleotide and amino acid sequence divergences of 0.4% and 0.3%, respectively. In contrast, the two mMDH cDNA alleles differed by 23% and 20% at the nucleotide and amino acid levels, respectively. Analysis of a 91-bp partial nucleotide sequence of mMDH from Nucella freycineti, the closest relative of N. lapillus, revealed two similar alleles and indicated that the divergence in mMDH in N. lapillus represents an ancient transpecific polymorphism in these Nucella. Together with earlier studies on variation in N. lapillus, it is argued that the polymorphism in mMDH and the clines in N. lapillus represent the presence of two persistent coadapted gene complexes, multitrait coevolving genetic solutions to environmental variation, which may presently enable this snail to exploit a diverse environment successfully. PMID:11110897

  8. Three allele combinations associated with Multiple Sclerosis

    PubMed Central

    Favorova, Olga O; Favorov, Alexander V; Boiko, Alexey N; Andreewski, Timofey V; Sudomoina, Marina A; Alekseenkov, Alexey D; Kulakova, Olga G; Gusev, Eugenyi I; Parmigiani, Giovanni; Ochs, Michael F

    2006-01-01

    Background Multiple sclerosis (MS) is an immune-mediated disease of polygenic etiology. Dissection of its genetic background is a complex problem, because of the combinatorial possibilities of gene-gene interactions. As genotyping methods improve throughput, approaches that can explore multigene interactions appropriately should lead to improved understanding of MS. Methods 286 unrelated patients with definite MS and 362 unrelated healthy controls of Russian descent were genotyped at polymorphic loci (including SNPs, repeat polymorphisms, and an insertion/deletion) of the DRB1, TNF, LT, TGFβ1, CCR5 and CTLA4 genes and TNFa and TNFb microsatellites. Each allele carriership in patients and controls was compared by Fisher's exact test, and disease-associated combinations of alleles in the data set were sought using a Bayesian Markov chain Monte Carlo-based method recently developed by our group. Results We identified two previously unknown MS-associated tri-allelic combinations: -509TGFβ1*C, DRB1*18(3), CTLA4*G and -238TNF*B1,-308TNF*A2, CTLA4*G, which perfectly separate MS cases from controls, at least in the present sample. The previously described DRB1*15(2) allele, the microsatellite TNFa9 allele and the biallelic combination CCR5Δ32, DRB1*04 were also reidentified as MS-associated. Conclusion These results represent an independent validation of MS association with DRB1*15(2) and TNFa9 in Russians and are the first to find the interplay of three loci in conferring susceptibility to MS. They demonstrate the efficacy of our approach for the identification of complex-disease-associated combinations of alleles. PMID:16872485

  9. Semiparametric Allelic Tests for Mapping Multiple Phenotypes: Binomial Regression and Mahalanobis Distance.

    PubMed

    Majumdar, Arunabha; Witte, John S; Ghosh, Saurabh

    2015-12-01

    Binary phenotypes commonly arise due to multiple underlying quantitative precursors and genetic variants may impact multiple traits in a pleiotropic manner. Hence, simultaneously analyzing such correlated traits may be more powerful than analyzing individual traits. Various genotype-level methods, e.g., MultiPhen (O'Reilly et al. []), have been developed to identify genetic factors underlying a multivariate phenotype. For univariate phenotypes, the usefulness and applicability of allele-level tests have been investigated. The test of allele frequency difference among cases and controls is commonly used for mapping case-control association. However, allelic methods for multivariate association mapping have not been studied much. In this article, we explore two allelic tests of multivariate association: one using a Binomial regression model based on inverted regression of genotype on phenotype (Binomial regression-based Association of Multivariate Phenotypes [BAMP]), and the other employing the Mahalanobis distance between two sample means of the multivariate phenotype vector for two alleles at a single-nucleotide polymorphism (Distance-based Association of Multivariate Phenotypes [DAMP]). These methods can incorporate both discrete and continuous phenotypes. Some theoretical properties for BAMP are studied. Using simulations, the power of the methods for detecting multivariate association is compared with the genotype-level test MultiPhen's. The allelic tests yield marginally higher power than MultiPhen for multivariate phenotypes. For one/two binary traits under recessive mode of inheritance, allelic tests are found to be substantially more powerful. All three tests are applied to two different real data and the results offer some support for the simulation study. We propose a hybrid approach for testing multivariate association that implements MultiPhen when Hardy-Weinberg Equilibrium (HWE) is violated and BAMP otherwise, because the allelic approaches assume HWE

  10. Semi-parametric Allelic Tests For Mapping Multiple Phenotypes: Binomial Regression And Mahalanobis Distance

    PubMed Central

    Majumdar, Arunabha; Witte, John S.; Ghosh, Saurabh

    2016-01-01

    Binary phenotypes commonly arise due to multiple underlying quantitative precursors. Genetic variants may impact multiple traits in a pleiotropic manner. Hence, simultaneously analyzing such correlated traits may be more powerful than analyzing individual traits. Various genotype-level methods, e.g. MultiPhen [O'Reilly et al., 2012], have been developed to identify genetic factors underlying a multivariate phenotype. For univariate phenotypes, the usefulness and applicability of allele-level tests have been investigated. The test of allele frequency difference among cases and controls is commonly used for mapping case-control association. However, allelic methods for multivariate association mapping have not been studied much. We explore two allelic tests of multivariate association: one using a Binomial regression model based on inverted regression of genotype on phenotype (BAMP), and the other employing the Mahalanobis distance between two sample means of the multivariate phenotype vector for two alleles at a SNP (DAMP). These methods can incorporate both discrete and continuous phenotypes. Some theoretical properties for BAMP are studied. Using simulations, the power of the methods for detecting multivariate association are compared with the genotype-level test MultiPhen. The allelic tests yield marginally higher power than MultiPhen for multivariate phenotypes. For one/two binary traits under recessive mode of inheritance, allelic tests are found substantially more powerful. All three tests are applied to two real data and the results offer some support for the simulation study. Since the allelic approaches assume Hardy-Weinberg Equilibrium (HWE), we propose a hybrid approach for testing multivariate association that implements MultiPhen when HWE is violated and BAMP otherwise. PMID:26493781

  11. Allelic associations of two polymorphic microsatellites in intron 40 of the human von Willebrand factor gene

    SciTech Connect

    Pena, S.D.J.; De Souza, K.T. ); De Andrade, M.; Chakraborty, R. )

    1994-01-18

    At intron 40 of the von Willebrand factor (vWF) gene, two GATA-repeat polymorphic sites exist that are physically separated by 212 bp. At the first site (vWF1 locus), seven segregating repeat alleles were observed in a Brazilian Caucasian population, and at the second (vWF2 locus) there were eight alleles, detected through PCR amplifications of this DNA region. Haplotype analysis of individuals revealed 36 different haplotypes in a sample of 338 chromosomes examined. Allele frequencies between generations and gender at each locus were not significantly different, and the genotype frequencies were consistent with their Hardy-Weinberg expectations. Linkage disequilibrium between loci is highly significant with positive allele size association; that is, large alleles at the loci tend to occur together, and so do the same alleles. Variability at each locus appeared to have arisen in a stepwise fashion, suggesting replication slippage as a possible mechanism of production of new alleles. However, the authors observed an increased number of haplotypes, in contrast with the predictions of a stepwise production of variation in the entire region, suggesting some form of cooperative changes between loci that could be due to either gene conversion, or a common control mechanism of production of new variation at these repeat polymorphism sites. The high degree of polymorphism (gene diversity values of 72% and 78% at vWF1 and vWF2, respectively, and of 93% at the haplotype level) makes these markers informative for paternity testing, genetic counseling, and individual-identification purposes.

  12. Healthy Preterm Newborns Show an Increased Frequency of CD4(+) CD25(high) CD127(low) FOXP3(+) Regulatory T Cells with a Naive Phenotype and High Expression of Gut-Homing Receptors.

    PubMed

    Rennó, C; Nadaf, M I V; Zago, C A; Carneiro-Sampaio, M; Palmeira, P

    2016-06-01

    Treg cells are crucial to prevent immune dysregulation, but little is known about the frequency of these cells in neonates, particularly in very/moderate and late preterm newborns studied as separate groups. The CD4(+) CD25(hi) CD127(lo) FOXP3(+) Treg population was phenotypically characterized to assess maturation markers and gut-homing integrins by flow cytometry in the cord blood of healthy preterm newborns born at 30-33(6/7) gestation weeks (Group 1), at 34-36(6/7) gestation weeks (Group 2) and term newborns born at 37-41 gestation weeks (Group 3), compared to healthy adults. An inverse correlation of the Treg percentage and gestational age was found, with significantly higher frequencies in Group 1 compared to Groups 2 and 3 and in Group 2 compared to Group 3, and significantly higher Treg frequencies and numbers in the neonates compared to the adults. All of the newborns exhibited increased Treg frequencies with a naive phenotype compared to adults. Cytotoxic T-lymphocyte-associated protein 4 CTLA-4 expression in the naive Treg was decreased in both preterm groups compared with those from term newborns and adults, and in the memory Treg from Group 1 compared with the other groups. The frequencies of Treg expressing α4β7 and α4β1 integrins were higher in both preterm groups, but significantly different only in Group 1, when compared with those from the term newborns and the adults. In conclusion, although a high frequency of Treg is present in newborns, an immature phenotype with a higher expression of CD45RA and α4β7/α4β1 and a lower expression of CTLA-4 is found, particularly in the very preterm group. PMID:27007547

  13. Genetic factors required to maintain repression of a paramutagenic maize pl1 allele.

    PubMed Central

    Hollick, J B; Chandler, V L

    2001-01-01

    A genetic screen identified two novel gene functions required to maintain mitotically and meiotically heritable gene silencing associated with paramutation of the maize purple plant 1 (pl1) locus. Paramutation at pl1 leads to heritable alterations of pl1 gene regulation; the Pl-Rhoades (Pl-Rh) allele, which typically confers strong pigmentation to juvenile and adult plant structures, changes to a lower expression state termed Pl'-mahogany (Pl'). Paramutation spontaneously occurs at low frequencies in Pl-Rh homozygotes but always occurs when Pl-Rh is heterozygous with Pl'. We identified four mutations that caused increased Pl' pigment levels. Allelism tests revealed that three mutations identified two new maize loci, required to maintain repression 1 (rmr1) and rmr2 and that the other mutation represents a new allele of the previously described mediator of paramutation 1 (mop1) locus. RNA levels from Pl' are elevated in rmr mutants and genetic tests demonstrate that Pl' can heritably change back to Pl-Rh in rmr mutant individuals at variable frequencies. Pigment levels controlled by two pl1 alleles that do not participate in paramutation are unaffected in rmr mutants. These results suggest that RMR functions are intimately involved in maintaining the repressed expression state of paramutant Pl' alleles. Despite strong effects on Pl' repression, rmr mutant plants have no gross developmental abnormalities even after several generations of inbreeding, implying that RMR1 and RMR2 functions are not generally required for developmental homeostasis. PMID:11139517

  14. Uncommon HLA alleles identified by hemizygous ultra-high Sanger sequencing: haplotype associations and reconsideration of their assignment in the Common and Well-Documented catalogue.

    PubMed

    Voorter, Christina E M; Groeneweg, Mathijs; Groeneveld, Lisette; Tilanus, Marcel G J

    2016-02-01

    Although the number of HLA alleles still increases, many of them have been reported being uncommon. This is partly due to lack of full length gene sequencing, especially for those alleles belonging to an allele ambiguity in which the first discovered allele has been assigned as the most frequent one. As members of the working group on Common and Well Documented (CWD) alleles and since we implemented full length group-specific sequencing as standard method routinely, we have investigated the presence of presumably rare alleles in our collection of HLA typing data. We identified 50 alleles, that were not previously encountered as Common or Well Documented. Sixteen of them should be added to the CWD catalogue, since we encountered them in 5 or more unrelated individuals. Another 11 could be added, based upon our results and the data present in the IMGT database and the rare allele section of the allele frequencies database. Furthermore, tight associations were observed between several different alleles even at the level of synonymous and non-coding sequences. In addition, in several cases the uncommon allele was found to be more frequent than its common counterpart. PMID:26610902

  15. HLA-B allele dropout in PCR sequence-specific oligonucleotide probe typing due to intronic polymorphism in the novel B*58:01:01:02 allele.

    PubMed

    He, Y; Wang, W; Han, Z; He, J; Chen, N; Dong, L; Tao, S; Zhang, W; He, J; Zhu, F; Lv, H

    2016-06-01

    Currently, Luminex technology based on the PCR sequence-specific oligonucleotide (SSO) probe method has been widely used for HLA genotyping in the immunogenetics laboratories. Here, we reported a case with HLA-B allele dropout by Luminex technology. The initial HLA-B result of the Luminex method with a commercial agent kit was inconclusive, and then, the result of PCR-SBT technology indicated the dropout as a HLA-B*58 allele. Subsequently, the full-length sequence of HLA-B allele was determined by TOPO-TA cloning, and a novel allele B*58:01:01:02 was identified in the individual. Compared with HLA-B*58:01:01:01, the novel allele showed some nucleotides difference at 509 C>T, 521 T>G and CCC insertion in position 503 of intron 2. According to the full-length sequence, the new mutations of intron 2 were contributed to HLA-B locus allele dropout in the sample. Our results indicated multiplatform should be used to improve the HLA typing accuracy when a conclusive HLA genotype cannot be determined. PMID:27016176

  16. Significant Association of HLA-B Alleles and Genotypes in Thai Children with Autism Spectrum Disorders: A Case-Control Study

    PubMed Central

    Puangpetch, Apichaya; Suwannarat, Pongwut; Chamnanphol, Montri; Koomdee, Napatrupron; Ngamsamut, Nattawat; Limsila, Penkhae; Sukasem, Chonlaphat

    2015-01-01

    Autism is a severe neurodevelopmental disorder. Many susceptible causative genes have been identified. Most of the previous reports showed the relationship between the Human Leukocyte Antigen (HLA) gene and etiology of autism. In order to identify HLA-B alleles associated with autism in Thai population, we compared the frequency of HLA-B allele in 364 autistic subjects with 952 normal subjects by using a two-stage sequence-specific oligonucleotide probe system (PCR-SSOP) method based on flow-cytometry technology. HLA-B⁎13:02 (P = 0.019, OR = 2.229), HLA-B⁎38:02 (P = 0.049, OR = 1.628), HLA-B⁎44:03 (P = 0.016, OR = 1.645), and HLA-B⁎56:01 (P = 1.78 × 10−4, OR = 4.927) alleles were significantly increased in autistic subjects compared with normal subjects. Moreover, we found that the HLA-B⁎18:02 (P = 0.016, OR = 0.375) and HLA-B⁎46:12 (P = 0.008, OR = 0.147) alleles were negatively associated with autism when compared to normal controls. Both alleles might have a protective role in disease development. In addition, four HLA-B genotypes of autistic patients had statistically significant relationship with control groups, consisting of HLA-B⁎3905/⁎5801 (P = 0.032, OR = 24.697), HLA-B⁎2704/⁎5801 (P = 0.022, OR = 6.872), HLA-B⁎3501/⁎4403 (P = 0.021, OR = 30.269), and HLA-B⁎1801/⁎4402 (P = 0.017, OR = 13.757). This is the first report on HLA-B associated with Thai autism and may serve as a marker for genetic susceptibility to autism in Thai population. PMID:26819491

  17. Melting Curve Analysis after T Allele Enrichment (MelcaTle) as a Highly Sensitive and Reliable Method for Detecting the JAK2V617F Mutation

    PubMed Central

    Morishita, Soji; Takahashi, Kochi; Araki, Marito; Hironaka, Yumi; Sunami, Yoshitaka; Edahiro, Yoko; Tsutsui, Miyuki; Ohsaka, Akimichi; Tsuneda, Satoshi; Komatsu, Norio

    2015-01-01

    Detection of the JAK2V617F mutation is essential for diagnosing patients with classical myeloproliferative neoplasms (MPNs). However, detection of the low-frequency JAK2V617F mutation is a challenging task due to the necessity of discriminating between true-positive and false-positive results. Here, we have developed a highly sensitive and accurate assay for the detection of JAK2V617F and named it melting curve analysis after T allele enrichment (MelcaTle). MelcaTle comprises three steps: 1) two cycles of JAK2V617F allele enrichment by PCR amplification followed by BsaXI digestion, 2) selective amplification of the JAK2V617F allele in the presence of a bridged nucleic acid (BNA) probe, and 3) a melting curve assay using a BODIPY-FL-labeled oligonucleotide. Using this assay, we successfully detected nearly a single copy of the JAK2V617F allele, without false-positive signals, using 10 ng of genomic DNA standard. Furthermore, MelcaTle showed no positive signals in 90 assays screening healthy individuals for JAK2V617F. When applying MelcaTle to 27 patients who were initially classified as JAK2V617F-positive on the basis of allele-specific PCR analysis and were thus suspected as having MPNs, we found that two of the patients were actually JAK2V617F-negative. A more careful clinical data analysis revealed that these two patients had developed transient erythrocytosis of unknown etiology but not polycythemia vera, a subtype of MPNs. These findings indicate that the newly developed MelcaTle assay should markedly improve the diagnosis of JAK2V617F-positive MPNs. PMID:25794279

  18. Functional screening of willow alleles in Arabidopsis combined with QTL mapping in willow (Salix) identifies SxMAX4 as a coppicing response gene

    PubMed Central

    Salmon, Jemma; Ward, Sally P; Hanley, Steven J; Leyser, Ottoline; Karp, Angela

    2014-01-01

    Willows (Salix spp.) are important biomass crops due to their ability to grow rapidly with low fertilizer inputs and ease of cultivation in short-rotation coppice cycles. They are relatively undomesticated and highly diverse, but functional testing to identify useful allelic variation is time-consuming in trees and transformation is not yet possible in willow. Arabidopsis is heralded as a model plant from which knowledge can be transferred to advance the improvement of less tractable species. Here, knowledge and methodologies from Arabidopsis were successfully used to identify a gene influencing stem number in coppiced willows, a complex trait of key biological and industrial relevance. The strigolactone-related More AXillary growth (MAX) genes were considered candidates due to their role in shoot branching. We previously demonstrated that willow and Arabidopsis show similar response to strigolactone and that transformation rescue of Arabidopsis max mutants with willow genes could be used to detect allelic differences. Here, this approach was used to screen 45 SxMAX1, SxMAX2, SxMAX3 and SxMAX4 alleles cloned from 15 parents of 11 mapping populations varying in shoot-branching traits. Single-nucleotide polymorphism (SNP) frequencies were locus dependent, ranging from 29.2 to 74.3 polymorphic sites per kb. SxMAX alleles were 98%–99% conserved at the amino acid level, but different protein products varying in their ability to rescue Arabidopsis max mutants were identified. One poor rescuing allele, SxMAX4D, segregated in a willow mapping population where its presence was associated with increased shoot resprouting after coppicing and colocated with a QTL for this trait. PMID:24393130

  19. Impact of protective IL-2 allelic variants on CD4+ Foxp3+ regulatory T cell function in situ and resistance to autoimmune diabetes in NOD mice.

    PubMed

    Sgouroudis, Evridiki; Albanese, Alexandre; Piccirillo, Ciriaco A

    2008-11-01

    Type I diabetes (T1D) susceptibility is inherited through multiple insulin-dependent diabetes (Idd) genes. NOD.B6 Idd3 congenic mice, introgressed with an Idd3 allele from T1D-resistant C57BL/6 mice (Idd3(B6)), show a marked resistance to T1D compared with control NOD mice. The protective function of the Idd3 locus is confined to the Il2 gene, whose expression is critical for naturally occurring CD4(+)Foxp3(+) regulatory T (nT(reg)) cell development and function. In this study, we asked whether Idd3(B6) protective alleles in the NOD mouse model confer T1D resistance by promoting the cellular frequency, function, or homeostasis of nT(reg) cells in vivo. We show that resistance to T1D in NOD.B6 Idd3 congenic mice correlates with increased levels of IL-2 mRNA and protein production in Ag-activated diabetogenic CD4(+) T cells. We also observe that protective IL2 allelic variants (Idd3(B6) resistance allele) also favor the expansion and suppressive functions of CD4(+)Foxp3(+) nT(reg) cells in vitro, as well as restrain the proliferation, IL-17 production, and pathogenicity of diabetogenic CD4(+) T cells in vivo more efficiently than control do nT(reg) cells. Lastly, the resistance to T1D in Idd3 congenic mice does not correlate with an augmented systemic frequency of CD4(+)Foxp3(+) nT(reg) cells but more so with the ability of protective IL2 allelic variants to promote the expansion of CD4(+)Foxp3(+) nT(reg) cells directly in the target organ undergoing autoimmune attack. Thus, protective, IL2 allelic variants impinge the development of organ-specific autoimmunity by bolstering the IL-2 producing capacity of self-reactive CD4(+) T cells and, in turn, favor the function and homeostasis of CD4(+)Foxp3(+) nT(reg) cells in vivo. PMID:18941219

  20. Allelic association of the D2 dopamine receptor gene with cocaine dependence.

    PubMed

    Noble, E P; Blum, K; Khalsa, M E; Ritchie, T; Montgomery, A; Wood, R C; Fitch, R J; Ozkaragoz, T; Sheridan, P J; Anglin, M D

    1993-10-01

    The objective of the present study was to examine allelic prevalence of the D2 dopamine receptor (DRD2) gene in male cocaine-dependent (CD) Caucasian (non-Hispanic) subjects and to determine the relationship of DRD2 alleles to family history and selected behavioral measures. The prevalence of the A1 allele in CD subjects (n = 53) was 50.9%. It was significantly higher than either the 16.0% prevalence (P < 10(-4)) in non-substance abusing controls (n = 100) or the 30.9% prevalence (P < 10(-2)) in population controls (n = 265) wherein substance abusers were not excluded. Similarly, a significantly higher prevalence (P < 10(-2)) of the B1 allele was found in CD subjects (n = 52) compared with non-substance abusing controls (n = 53); 38.5% vs. 13.2%. Logistic regression analysis of CD subjects identified potent routes of cocaine use and the interaction of early deviant behaviors and parental alcoholism as significant risk factors associated with the A1 allele. The cumulative number of these three risk factors in CD subjects was positively and significantly (P < 10(-3)) related to A1 allelic prevalence. The data showing a strong association of the minor alleles (A1 and B1) of the DRD2 with cocaine dependence suggest that a gene, located on the q22-q23 region of chromosome 11, confers susceptibility to this drug disorder. PMID:8261891

  1. Dynamic variation in allele-specific gene expression of Paraoxonase-1 in murine and human tissues

    PubMed Central

    Parker-Katiraee, Layla; Bousiaki, Eleni; Monk, David; Moore, Gudrun E.; Nakabayashi, Kazuhiko; Scherer, Stephen W.

    2008-01-01

    Differential allelic expression has been shown to be common in mice, humans and maize, and variability in the expression of polymorphic alleles has been associated with human disease. Here, we describe the differential expression pattern of Paraoxonase-1, a gene involved in lipid metabolism and implicated in the formation of atherosclerotic lesions. We measured the expression of the murine Paraoxonase-1 gene (Pon1) in livers at different stages of embryonic development using F1 hybrid crosses and quantified the transcriptional level of both parental alleles. Using human foetal tissues, we analysed the expression of the human orthologue (PON1) and found monoallelic or preferential allelic expression in 6/7 and 4/4 samples from liver and pancreas, respectively. We observed that Pon1 does not show a parent-of-origin preference in its allelic expression, but has dramatic variations in allele-specific expression occurring throughout development. This study has important repercussions in the analysis of haplotypes at disease loci, since it implies that the expression of polymorphic alleles can be unequal and dynamic. PMID:18678600

  2. Are ‘Endurance’ Alleles ‘Survival’ Alleles? Insights from the ACTN3 R577X Polymorphism

    PubMed Central

    Fiuza-Luces, Carmen; Ruiz, Jonatan R.; Rodríguez-Romo, Gabriel; Santiago, Catalina; Gómez-Gallego, Félix; Yvert, Thomas; Cano-Nieto, Amalia; Garatachea, Nuria

    2011-01-01

    Exercise phenotypes have played a key role for ensuring survival over human evolution. We speculated that some genetic variants that influence exercise phenotypes could be associated with exceptional survival (i.e. reaching ≥100years of age). Owing to its effects on muscle structure/function, a potential candidate is the Arg(R)577Ter(X) polymorphism (rs1815739) in ACTN3, the structural gene encoding the skeletal muscle protein α-actinin-3. We compared the ACTN3 R577X genotype/allele frequencies between the following groups of ethnically-matched (Spanish) individuals: centenarians (cases, n = 64; 57 female; age range: 100–108 years), young healthy controls (n = 283, 67 females, 216 males; 21±2 years), and humans who are at the two end-points of exercise capacity phenotypes, i.e. muscle endurance (50 male professional road cyclists) and muscle power (63 male jumpers/sprinters). Although there were no differences in genotype/allele frequencies between centenarians (RR:28.8%; RX:47.5%; XX:23.7%), and controls (RR:31.8%; RX:49.8%; XX:18.4%) or endurance athletes (RR:28.0%; RX:46%; XX:26.0%), we observed a significantly higher frequency of the X allele (P = 0.019) and XX genotype (P = 0.011) in centenarians compared with power athletes (RR:47.6%; RX:36.5%;XX:15.9%). Notably, the frequency of the null XX (α-actinin-3 deficient) genotype in centenarians was the highest ever reported in non-athletic Caucasian populations. In conclusion, despite there were no significant differences with the younger, control population, overall the ACTN3 genotype of centenarians resembles that of world-class elite endurance athletes and differs from that of elite power athletes. Our preliminary data would suggest a certain ‘survival’ advantage brought about by α-actinin-3 deficiency and the ‘endurance’/oxidative muscle phenotype that is commonly associated with this condition. PMID:21407828

  3. Tetrasomic Segregation for Multiple Alleles in Alfalfa

    PubMed Central

    Quiros, Carlos F.

    1982-01-01

    Evidence of tetrasomic inheritance in alfalfa, Medicago sativa L. and M. falcata L., for multiple codominant alleles at three isozymic loci is reported in this study. The locus Prx-1 governing anodal peroxidase and the loci Lap-1 and Lap-2 governing anodal leucine-aminopeptidase were studied by starch gel electrophoresis in seedling root tissue or seeds. The progenies from several di-, tri- or tetra-allelic plants belong to the species M. sativa and M. falcata and their hybrids were studied for the segregation of the three genes. In all cases, tetrasomic inheritance of chromosomal-type segregation was observed. In another progeny resulting from the crossing of two plants involving four different alleles at locus Lap-2, tetrasomic segregation with the possible occurrence of double reduction was observed. This study presents direct evidence of autotetraploidy and the existence of tetra-allelic loci in alfalfa. It also supports the concept that the species M. sativa and M. falcata are genetically close enough to be considered biotypes of a common species. PMID:17246077

  4. Allele-specific tumor spectrum in pten knockin mice.

    PubMed

    Wang, Hui; Karikomi, Matt; Naidu, Shan; Rajmohan, Ravi; Caserta, Enrico; Chen, Hui-Zi; Rawahneh, Maysoon; Moffitt, Julie; Stephens, Julie A; Fernandez, Soledad A; Weinstein, Michael; Wang, Danxin; Sadee, Wolfgang; La Perle, Krista; Stromberg, Paul; Rosol, Thomas J; Eng, Charis; Ostrowski, Michael C; Leone, Gustavo

    2010-03-16

    Germline mutations in the tumor suppressor gene PTEN (phosphatase and tensin homology deleted on chromosome 10) cause Cowden and Bannayan-Riley-Ruvalcaba (BRR) syndromes, two dominantly inherited disorders characterized by mental retardation, multiple hamartomas, and variable cancer risk. Here, we modeled three sentinel mutant alleles of PTEN identified in patients with Cowden syndrome and show that the nonsense Pten(4-5) and missense Pten(C124R) and Pten(G129E) alleles lacking lipid phosphatase activity cause similar developmental abnormalities but distinct tumor spectra with varying severity and age of onset. Allele-specific differences may be accounted for by loss of function for Pten(4-5), hypomorphic function for Pten(C124R), and gain of function for Pten(G129E). These data demonstrate that the variable tumor phenotypes observed in patients with Cowden and BRR syndromes can be attributed to specific mutations in PTEN that alter protein function through distinct mechanisms. PMID:20194734

  5. Frequency of Multiple Blood Meals Taken in a Single Gonotrophic Cycle by Anopheles arabiensis Mosquitoes in Macha, Zambia

    PubMed Central

    Norris, Laura C.; Fornadel, Christen M.; Hung, Wei-Chien; Pineda, Fernando J.; Norris, Douglas E.

    2010-01-01

    Anopheles arabiensis is a major vector of Plasmodium falciparum in southern Zambia. This study aimed to determine the rate of multiple human blood meals taken by An. arabiensis to more accurately estimate entomologic inoculation rates (EIRs). Mosquitoes were collected in four village areas over two seasons. DNA from human blood meals was extracted and amplified at four microsatellite loci. Using the three-allele method, which counts ≥ 3 alleles at any microsatellite locus as a multiple blood meal, we determined that the overall frequency of multiple blood meals was 18.9%, which was higher than rates reported for An. gambiae in Kenya and An. funestus in Tanzania. Computer simulations showed that the three-allele method underestimates the true multiple blood meal proportion by 3–5%. Although P. falciparum infection status was not shown to influence the frequency of multiple blood feeding, the high multiple feeding rate found in this study increased predicted malaria risk by increasing EIR. PMID:20595474

  6. Apolipoprotein E ε4 Allele was Associated With Nonlesional Mesial Temporal Lobe Epilepsy in Han Chinese Population

    PubMed Central

    Li, Zhimei; Ding, Chengyun; Gong, Xiping; Wang, Xiaofei; Cui, Tao

    2016-01-01

    Abstract Apolipoprotein E (APOE) gene has been implicated as one of the genes susceptible to temporal lobe epilepsy (TLE), but the association is inconsistent. We carried out a study to investigate the association of APOEε4 allele with a subtype of TLE-nonlesional mesial temporal lobe epilepsy (NLMTLE) in Han Chinese people. The study consisted of total 308 NLMTLE patients and 302 controls in Han Chinese. The APOE polymorphisms were genotyped using polymerase chain reaction (PCR) DNA sequencing. We compared the frequency of APOEε4 allele and carrying status between NLMTLE patients and control subjects to test for the association of APOEε4 allele with NLMTLE clinical status. Carrying status of APOEε4 allele was significantly associated with the risk of NLMTLE. No effect of APOEε4 allele was found on the age of onset, duration of epilepsy, or frequency of seizure. Moreover, there was no association between APOEε4 allele and hippocampal sclerosis (HS) or febrile convulsion (FC) history. Our study provided an evidence that APOEε4 allele was a possible risk factor for NLMTLE, and further study with a larger sample is needed to warrant this finding. PMID:26945380

  7. Allelic background of LEPRE1 mutations that cause recessive forms of osteogenesis imperfecta in different populations

    PubMed Central

    Pepin, Melanie G; Schwarze, Ulrike; Singh, Virendra; Romana, Marc; Jones-LeCointe, Altheia; Byers, Peter H

    2013-01-01

    Biallelic mutations in LEPRE1 result in recessively inherited forms of osteogenesis imperfecta (OI) that are often lethal in the perinatal period. A mutation (c.1080+1G>T, IVS5+1G>T) in African Americans has a carrier frequency of about 1/240. The mutant allele originated in West Africa in tribes of Ghana and Nigeria where the carrier frequencies are 2% and 5%. By examining 200 samples from an African-derived population in Tobago and reviewing hospital neonatal death records, we determined that the carrier frequency of c.1080+1G>T was about one in 200 and did not contribute to the neonatal deaths recorded over a 3-year period of time in Trinidad. In the course of sequence analysis, we found surprisingly high LEPRE1 allelic diversity in the Tobago DNA samples in which there were 11 alleles distinguished by a single basepair variant in or near exon 5. All the alleles found in the Tobago population that were within the sequence analysis region were found in the African American population in the Exome Variant Project. This diversity appeared to reflect the geographic origin of the original population in Tobago. In 44 individuals with biallelic LEPRE1 mutations identified by clinical diagnostic testing, we found the sequence alterations occurred on seven of the 11 variant alleles. All but one of the mutations identified resulted in mRNA or protein instability for the majority of the transcripts from the altered allele. These findings suggest that the milder end of the clinical spectrum could be due to as yet unidentified missense mutations in LEPRE1. PMID:24498616

  8. Susceptible and protective associations of HLA DRB1*/DQB1* alleles and haplotypes with ischaemic stroke.

    PubMed

    Murali, V; Rathika, C; Ramgopal, S; Padma Malini, R; Arun Kumar, M J; Neethi Arasu, V; Jeyaram Illiayaraja, K; Balakrishnan, K

    2016-06-01

    Stroke has emerged as the second commonest cause of mortality worldwide and is a major public health problem. For the first time, we present here the association of human leucocyte antigen (HLA)-DRB1*/DQB1* alleles and haplotypes with ischaemic stroke in South Indian patients. Ischaemic stroke (IS) cases and controls were genotyped for HLA-DRB1*/DQB1* alleles by polymerase chain reaction sequence-specific primers (PCR-SSP) method. The frequencies of HLA class II alleles such as DRB1*04, DRB1*07, DRB1*11, DRB1*12, DRB1*13, DQB1*02 and DQB1*07 were high in IS patients than in the age- and gender-matched controls, suggesting that the individuals with these alleles are susceptible to ischaemic stroke in South India. The frequencies of alleles such as DRB1*03, DRB1*10, DRB1*14, DQB1*04 and DQB1*05 were less in IS cases than in the controls, suggesting a protective association. Haplotypes DRB1*04-DQB1*0301, DRB1*07-DQB1*02, DRB1*07-DQB1*0301, DRB1*11-DQB1*0301 and DRB1*13-DQB1*06 were found to be high in IS patients conferring susceptibility. The frequency of haplotype DRB1*10-DQB1*05 was high in controls conferring protection. IS-LVD and gender-stratified analysis too confirmed these susceptible and protective associations. Thus, HLA-DRB1*/DQB1* alleles and haplotypes strongly predispose South Indian population to ischaemic stroke. Further studies in different populations with large sample size or the meta-analysis are needed to explain the exact mechanism of associations of HLA gene(s) with IS. PMID:27105925

  9. Isoelectric focusing of superoxide dismutase: report of the unique SOD A*2 allele in a US white population.

    PubMed

    DeCroo, S; Kamboh, M I; Leppert, M; Ferrell, R E

    1988-01-01

    An isoelectric focusing procedure in an ultranarrow pH range (5.0-5.5) polyacrylamide gel is described for the determination of superoxide dismutase (SOD) phenotypes. The occurrence of the rare SOD A*2 allele in the Caucasian population of Utah is also reported at a polymorphic frequency (0.011). The presence of the SOD A 2 unique allele in the Mormons of Utah is compatible with their historical affinity with Scandinavians. PMID:3350528

  10. No evidence for allelic association between bipolar disorder and monoamine oxidase A gene polymorphisms

    SciTech Connect

    Craddock, N.; Daniels, J.; Roberts, E.

    1995-08-14

    We have tested the hypothesis that DNA markers in the MAOA gene show allelic association with bipolar affective disorder. Eighty-four unrelated Caucasian patients with DSM III-R bipolar disorder and 84 Caucasian controls were typed for three markers in MAOA: a dinucleotide repeat in intron 2, a VNTR in intron 1, and an Fnu4HI RFLP in exon 8. No evidence for allelic association was observed between any of the markers and bipolar disorder. 9 refs., 1 tab.

  11. Extensive Allelic Diversity of MHC Class I in Wild Mallard Ducks.

    PubMed

    Fleming-Canepa, Ximena; Jensen, Shawna M; Mesa, Christine M; Diaz-Satizabal, Laura; Roth, Alexa J; Parks-Dely, Julie A; Moon, Debra A; Wong, Janet P; Evseev, Danyel; Gossen, Desolie A; Tetrault, David G; Magor, Katharine E

    2016-08-01

    MHC class I is critically involved in defense against viruses, and diversity from polygeny and polymorphism contributes to the breadth of the immune response and health of the population. In this article, we examine MHC class I diversity in wild mallard ducks, the natural host and reservoir of influenza A viruses. We previously showed domestic ducks predominantly use UAA, one of five MHC class I genes, but whether biased expression is also true for wild mallards is unknown. Using RT-PCR from blood, we examined expressed MHC class I alleles from 38 wild mallards (Anas platyrhynchos) and identified 61 unique alleles, typically 1 or 2 expressed alleles in each individual. To determine whether expressed alleles correspond to UAA adjacent to TAP2 as in domestic ducks, we cloned and sequenced genomic UAA-TAP2 fragments from all mallards, which matched transcripts recovered and allowed us to assign most alleles as UAA Allelic differences are primarily located in α1 and α2 domains in the residues known to interact with peptide in mammalian MHC class I, suggesting the diversity is functional. Most UAA alleles have unique residues in the cleft predicting distinct specificity; however, six alleles have an unusual conserved cleft with two cysteine residues. Residues that influence peptide-loading properties and tapasin involvement in chicken are fixed in duck alleles and suggest tapasin independence. Biased expression of one MHC class I gene may make viral escape within an individual easy, but high diversity in the population places continual pressure on the virus in the reservoir species. PMID:27342841

  12. Switching of a Mating-Type a Mutant Allele in Budding Yeast SACCHAROMYCES CEREVISIAE

    PubMed Central

    Klar, Amar J. S.; Fogel, Seymour; Radin, David N.

    1979-01-01

    Aimed at investigating the recovery of a specific mutant allele of the mating type locus (MAT) by switching a defective MAT allele, these experiments provide information bearing on several models proposed for MAT interconversion in bakers yeast, Saccharomyces cerevisiae. Hybrids between heterothallic (ho) cells carrying a mutant MATa allele, designated mata-2, and MATα ho strains show a high capacity for mating with MATa strains. The MATα/mata-2 diploids do not sporulate. However, zygotic clones obtained by mating MATα homothallic (HO) cells with mata-2 ho cells are unable to mate and can sporulate. Tetrad analysis of such clones revealed two diploid (MATα/MATa):two haploid segregants. Therefore, MAT switches occur in MATα/mata-2 HO/ho cells to produce MATα/MATa cells capable of sporulation. In heterothallic strains, the mata-2 allele can be switched to a functional MATα and subsequently to a functional MATa. Among 32 MATα to MATa switches tested, where the MATα was previously derived from the mata-2 mutant, only one mata-2 like isolate was observed. However, the recovered allele, unlike the parental allele, conplements the matα ste1–5 mutant, suggesting that these alleles are not identical and that the recovered allele presumably arose as a mutation of the MATα locus. No mata-2 was recovered by HO-mediated switching of MATα (previously obtained from mata-2 by HO) in 217 switches analyzed. We conclude that in homothallic and heterothallic strains, the mata-2 allele can be readily switched to a functional MATα and subsequently to a functional MATa locus. Overall, the results are in accord with the cassette model (Hicks, Strathern and Herskowitz 1977b) proposed to explain MAT interconversions. PMID:395020

  13. A₁A₂BO and Rh gene frequencies among six populations of Jammu and Kashmir, India.

    PubMed

    Fareed, Mohd; Hussain, Ruqaiya; Shah, Ahsana; Afzal, Mohammad

    2014-04-01

    A study was undertaken to record gene frequencies of ABO blood groups, their subtypes and Rh antigen for six different endogamous groups including a tribal population. The ABO phenotypic frequency varies among six different populations showing significant difference (p<0.0005). Gujjar and Bakarwal (a tribal population) shows highest (42.29%) of B blood phenotypes. A1 is the highest among Syeds (39.31%), O blood group frequency highest among Mughals (43.23%) and A1B and A2B are rare phenotypes showing very low frequency among all populations. The pattern of allele frequencies (p<0.025) is in order of I(O)>I(B)>I(A1)>I(A2), except Syeds (I(O)>I(A1)>I(B)>I(A2)). The rhesus protein (Rh) phenotypic frequency (p<0.01) shows significant increase in Rh(D) positive (87.86% in Syed to 96.03% in Khan) among all populations. The Rh allele (p<0.05) and genotype (p<0.02) frequencies shows a significant difference. Heterozygosity for Rh protein is less than homozygosity among six populations. The result from this study provides information on the genetic variation in blood antigens and rhesus protein among human populations inhabiting Jammu and Kashmir. PMID:24485956

  14. Mitochondrial DNA genetic diversity and LCT-13910 and deltaF508 CFTR alleles typing in the medieval sample from Poland.

    PubMed

    Płoszaj, T; Jerszyńska, B; Jędrychowska-Dańska, K; Lewandowska, M; Kubiak, D; Grzywnowicz, K; Masłowska, A; Witas, H W

    2015-06-01

    We attempted to confirm the resemblance of a local medieval population and to reconstruct their contribution to the formation of the modern Polish population at the DNA level. The HVR I mtDNA sequence and two nuclear alleles, LCT-13910C/T SNP and deltaF508 CFTR, were chosen as markers since the distribution of selected nuclear alleles varies among ethnic groups. A total of 47 specimens were selected from a medieval cemetery in Cedynia (located in the western Polish lowland). Regarding the HVR I profile, the analyzed population differed from the present-day population (P = 0.045, F(st) = 0.0103), in contrast to lactase persistence (LP) based on the LCT-13910T allele, thus indicating the lack of notable frequency changes of this allele during the last millennium (P = 0.141). The sequence of the HVR I mtDNA fragment allowed to identify six major haplogroups including H, U5, T, K, and HV0 within the medieval population of Cedynia which are common in today's central Europe. An analysis of haplogroup frequency and its comparison with modern European populations shows that the studied medieval population is more closely related to Finno-Ugric populations than to the present Polish population. Identification of less common haplogroups, i.e., Z and U2, both atypical of the modern Polish population and of Asian origin, provides evidence for some kind of connections between the studied and foreign populations. Furthermore, a comparison of the available aDNA sequences from medieval Europe suggests that populations differed from one another and a number of data from other locations are required to find out more about the features of the medieval gene pool profile. PMID:25896719

  15. Synchronous waves of failed soft sweeps in the laboratory: remarkably rampant clonal interference of alleles at a single locus.

    PubMed

    Lee, Ming-Chun; Marx, Christopher J

    2013-03-01

    It has increasingly been recognized that adapting populations of microbes contain not one, but many lineages continually arising and competing at once. This process, termed "clonal interference," alters the rate and dynamics of adaptation and biases winning mutations toward those with the largest selective effect. Here we uncovered a dramatic example of clonal interference between multiple similar mutations occurring at the same locus within replicate populations of Methylobacterium extorquens AM1. Because these mutational events involved the transposition of an insertion sequence into a narrow window of a single gene, they were both readily detectable at low frequencies and could be distinguished due to differences in insertion sites. This allowed us to detect up to 17 beneficial alleles of this type coexisting in a single population. Despite conferring a large selective benefit, the majority of these alleles rose and then fell in frequency due to other lineages emerging that were more fit. By comparing allele-frequency dynamics to the trajectories of fitness gains by these populations, we estimated the fitness values of the genotypes that contained these mutations. Collectively across all populations, these alleles arose upon backgrounds with a wide range of fitness values. Within any single population, however, multiple alleles tended to rise and fall synchronously during a single wave of multiple genotypes with nearly identical fitness values. These results suggest that alleles of large benefit arose repeatedly in failed "soft sweeps" during narrow windows of adaptation due to the combined effects of epistasis and clonal interference. PMID:23307898

  16. Geographical patterns of turnover and nestedness-resultant components of allelic diversity among populations.

    PubMed

    Diniz-Filho, Jose Alexandre Felizola; Collevatti, Rosane Garcia; Soares, Thannya Nascimento; Telles, Mariana Pires de Campos

    2012-06-01

    The analysis of geographical patterns in population divergence has always been a powerful way to infer microevolutionary processes involved in population differentiation, and several approaches have been used to investigate such patterns. Most frequently, multivariate spatial patterns of population differentiation are analyzed by computing pairwise genetic distances or F(ST) (or related statistics, such as ϕ(ST) from AMOVA), which are then correlated with geographical distances or landscape features. However, when calculating distances, especially based on presence-absence of alleles in local populations, there would be a confounding effect of allelic richness differences in the population differentiation. Moreover, the relative magnitude of these components and their spatial patterns can help identifying microevolutionary processes driving population differentiation. Here we show how recent methodological advances in ecological community analyses that allows partitioning dissimilarity into turnover (turnover) and richness differences, or nestedness-resultant dissimilarity, can be applied to allelic variation data, using an endemic Cerrado tree (Dipteryx alata) as a case study. Individuals from 15 local populations were genotyped for eight microsatellite loci, and pairwise dissimilarities were computed based on presence-absence of alleles. The turnover of alleles among populations represented 69 % of variation in dissimilarity, but only the richness difference component shows a clear spatial structure, appearing as a westward decrease of allelic richness. We show that decoupling richness difference and turnover components of allelic variation reveals more clearly how similarity among populations reflects geographical patterns in allelic diversity that can be interpreted in respect to historical range expansion in the species. PMID:22886007

  17. Human leukocyte antigen-G allele polymorphisms have evolved following three different evolutionary lineages based on intron sequences.

    PubMed

    Cervera, Isabel; Herraiz, Miguel Angel; Peñaloza, Jorge; Barbolla, Maria Luz; Jurado, Maria Luisa; Macedo, Jacqueline; Vidart, José Antonio; Martinez-Laso, Jorge

    2010-11-01

    Human leukocyte antigen (HLA)-G alleles follow a different pattern of polymorphism generation from those of the HLA classical I alleles. These polymorphisms have been defined as a result of random permitted point mutations in exons. However, this polymorphism maintenance could have an evolutionary specific pathways based on noncoding regions as introns, 14-bp deletion/insertion (exon 8), or promoter regions. Therefore a systematic sequencing study of HLA-G alleles was done obtaining the complete genomic sequence of 16 different HLA-G alleles: nine alleles were intron and exon confirmatory sequences, four were exon confirmatory and new intron described sequences, and three were new alleles. A 14-bp deletion/insertion polymorphism was also sequenced in these alleles. These sequences, together with those previously published, were compared, and phylogenetic and molecular evolutionary analyses were performed. Results showed the presence of three major specific evolutionary patterns, tentatively named lineages, and the other four as minor lineages (only one allele). The relative age of the major lineages could also be established based on the number of lineage-specific positions and the number of alleles of each lineage. Two main mechanisms are clearly defined in the generation of the lineages (introns), gene conversion, and/or convergent evolution following specific patterns. PMID:20650296

  18. Several different lactase persistence associated alleles and high diversity of the lactase gene in the admixed Brazilian population.

    PubMed

    Friedrich, Deise C; Santos, Sidney E B; Ribeiro-dos-Santos, Ândrea K C; Hutz, Mara H

    2012-01-01

    Adult-type hypolactasia is a common phenotype caused by the lactase enzyme deficiency. The -13910 C>T polymorphism, located 14 Kb upstream of the lactase gene (LCT) in the MCM6 gene was associated with lactase persistence (LP) in Europeans. This polymorphism is rare in Africa but several other variants associated with lactase persistence were observed in Africans. The aims of this study were to identify polymorphisms in the MCM6 region associated with the lactase persistence phenotype and to determine the distribution of LCT gene haplotypes in 981 individuals from North, Northeast and South Brazil. These polymorphisms were genotyped by PCR based methods and sequencing. The -13779*C,-13910*T, -13937*A, -14010*C, -14011*T LP alleles previously described in the MCM6 gene region that acts as an enhancer for the LCT gene were identified in Brazilians. The most common LP allele was -13910*T. Its frequency was highly correlated with European ancestry in the Brazilian populations investigated. The -13910*T was higher (0.295) in southern Brazilians of European ancestry and lower (0.175) in the Northern admixed population. LCT haplotypes were derived from the 10 LCT SNPs genotyped. Overall twenty six haplotypes previously described were identified in the four Brazilian populations studied. The Multidimensional Scaling analysis showed that Belém, in the north, was closer to Amerindians. Northeastern and southern Afro-descendants were more related with Bantu-speaking South Africans whereas the Southern population with European ancestry grouped with Southern and Northern Europeans. This study shows a high variability considering the number of LCT haplotypes observed. Due to the highly admixed nature of the Brazilian populations, the diagnosis of hypolactasia in Brazil, based only in the investigation of the -13910*T allele is an oversimplification. PMID:23029545

  19. Alloreactive T Cells to Identify Risk HLA Alleles for Retransplantation After Acute Accelerated Steroid-Resistant Rejection.

    PubMed

    Leyking, S; Wolf, M; Mihm, J; Schaefer, M; Bohle, R M; Fliser, D; Sester, M; Sester, U

    2015-10-01

    The risk of rejection by cellular alloreactivity to the transplant donor is not routinely assessed. Here we analyzed alloreactive T cells in kidney transplant recipients and report how their detection may have helped to prevent rejection of a second kidney graft in a patient with a history of acute accelerated steroid-resistant nonhumoral rejection. Alloreactive CD4 and CD8 T cells were quantified using a flow-cytometric mixed lymphocyte reaction assay based on interferon-γ induction. A group of 16 nonrejecting transplant recipients did not show any alloreactive T-cell immunity to their respective donors, whereas alloreactivity to third-party controls was detectable. In the patient with rejection, HLA-specific antibodies were not detectable before and shortly after rejection, but after transplantation the patient showed exceptionally high frequencies of alloreactive T cells against 2 of 11 HLA-typed controls (0.604% and 0.791% alloreactive CD4 T cells and 0.792% and 0.978% alloreactive CD8 T cells) who shared HLA alleles (HLA-A*24, -B*44, -C*02, -DQB1*5) with the kidney donor. These HLA alleles were subsequently excluded for allocation of a second graft. No alloreactive T cells were observed toward the second kidney donor, and this transplantation was performed successfully. Thus, shared HLA alleles between the donor and third-party controls may suggest that alloreactive T cells had contributed to rejection of the first graft. The rejecting patient highlights that determination of cellular alloreactivity before transplantation may be applied to identify unacceptable mismatches and to reduce the risk for acute cellular rejection episodes. PMID:26518945

  20. Evidence for a genetic association between alleles of monoamine oxidase A gene and bipolar affective disorder

    SciTech Connect

    Lim, L.C.C.; Sham, P.; Castle, D.

    1995-08-14

    We present evidence of a genetic association between bipolar disorder and alleles at 3 monoamine oxidase A (MAOA) markers, but not with alleles of a monoamine oxidase B (MAOB) polymorphism. The 3 MAOA markers, including one associated with low MAOA activity, show strong allelic association with each other but surprisingly not with MAOB. Our results are significantly only for females, though the number of males in our sample is too small to draw any definite conclusions. Our data is consistent with recent reports of reduced MAOA activity in patients with abnormal behavioral phenotypes. The strength of the association is weak, but significant, which suggests that alleles at the MAOA locus contribute to susceptibility to bipolar disorder rather than being a major determinant. 58 refs., 1 fig., 3 tabs.

  1. Statistics of Natural Populations. II. Estimating an Allele Probability in Families Descended from Cryptic Mothers

    PubMed Central

    Arnold, Jonathan; Morrison, Melvin L.

    1985-01-01

    In population studies, adults are frequently difficult or inconvenient to identify for genotype, but a family profile of genotypes can be obtained from an unidentified female crossed with a single unidentified male. The problem is to estimate an allele frequency in the cryptic parental gene pool from the observed family profiles. For example, a worker may wish to estimate inversion frequencies in Drosophila; inversion karyotypes are cryptic in adults but visible in salivary gland squashes from larvae. A simple mixture model, which assumes the Hardy-Weinberg law, Mendelian laws and a single randomly chosen mate per female, provides the vehicle for studying three competing estimators of an allele frequency. A simple, heuristically appealing estimator called the Dobzhansky estimator is compared with the maximum likelihood estimator and a close relative called the grouped profiles estimator. The Dobzhansky estimator is computationally simple, consistent and highly efficient and is recommended in practice over its competitors. PMID:17246258

  2. Confirmation of association between the e4 allele of apolipoprotein E and Alzheimer's disease.

    PubMed Central

    Liddell, M; Williams, J; Bayer, A; Kaiser, F; Owen, M

    1994-01-01

    The Apo E genotype of 86 patients with Alzheimer's disease (AD) and 77 age matched controls was determined by digestion of Apo E PCR products with the restriction enzyme CfoI. The frequency of the e4 allele was significantly increased in the patient group (0.33) as compared with controls (0.12). This effect was seen in patients with a family history and in sporadic cases. The odds ratio in homozygotes for the e4 allele was 11.24 (95% confidence interval 2.45-51.50). There was no relationship between age of onset and Apo E genotype. There was no linkage disequilibrium between the apolipoprotein E locus and a TaqI polymorphism at the Apo CII locus, and no allelic association between Apo CII and AD. Images PMID:8014966

  3. Allelic association at the D14S43 locus in early onset Alzheimer`s disease

    SciTech Connect

    Brice, A.; Tardieu, S.; Campion, D.; Martinez, M.

    1995-04-24

    The D14S43 marker is closely linked to the major gene for early onset autosomal dominant Alzheimer`s disease on chromosome 14. Allelic frequencies at the D14S43 locus were compared in 113 familial and isolated cases of early onset Alzheimer`s disease (<60 years of age at onset) (EOAD) and 109 unaffected individuals of the same geographic origin. Allele 7 was significantly (P = 0.033) more frequent in type 1 EOAD patients (13.2%), defined by the presence of at least another first degree relative with EOAD, than in controls (4.1%). Since an autosomal dominant gene is probably responsible for type 1 patients, allelic association may reflect linkage disequilibrium at the D14S43 locus. This would mean that some patients share a common ancestral mutation. However, since multiple tests were carried out, this result must be interpreted with caution, and needs confirmation in an independent sample. 16 refs., 2 tabs.

  4. Lichen planopilaris is associated with HLA DRB1*11 and DQB1*03 alleles.

    PubMed

    Pavlovsky, Lev; Israeli, Moshe; Sagy, Eti; Berg, Amy L; David, Michael; Shemer, Avner; Klein, Tirza; Hodak, Emmilia

    2015-02-01

    There are no studies of the possible association of the human leukocyte antigen (HLA) system with lichen planopilaris (LPP). To determine whether the HLA system is associated with LPP, 40 consecutive Jewish Israeli patients with LPP (study group) and 252 volunteers (controls) were typed for DRB1*and DQB1* loci by molecular methods. Compared with controls, the study group had a significantly higher frequency of the DRB1*11 allele (62% vs. 21%, corrected p-value (pc) = 0.001) owing to increased frequencies of DRB1*11: 01 and DRB1*11: 04. The DQB1*03 allele was also expressed at a significantly higher frequency in the study group (70% vs. 33%, pc = 0.0005); specifically, the frequency of DQB1*03: 01 was increased. The majority (82.5%) of the patients were of non-Ashkenazi origin. We conclude that LPP appears to be over-represented in non-Ashkenazi Jewish patients and is associated with an increased frequency of HLA DRB1*11 and DQB1*03 alleles. These findings suggest that immunogenetic factors play a role in LPP. PMID:24806356

  5. The Burden of JAK2V617F Mutated Allele in Turkish Patients With Myeloproliferative Neoplasms

    PubMed Central

    Yonal-Hindilerden, Ipek; Daglar-Aday, Aynur; Akadam-Teker, Basak; Yilmaz, Ceylan; Nalcaci, Meliha; Yavuz, Akif Selim; Sargin, Deniz

    2015-01-01

    Background Studies regarding the impact of JAK2V617F allele burden on phenotypic properties and clinical course in Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) have reported variable results. We aimed to analyze the association of mutated JAK2V617F allele burden with laboratory characteristics and clinical phenotype in Turkish patients (107 essential thrombocythemia (ET) and 77 primary myelofibrosis (PMF)). Methods Peripheral blood samples of 184 patients with Ph-negative MPNs were analyzed for JAK2V617F allele status and burden. JAK2 MutaScreen assay (Ipsogen, Luminy Biotech, Marseille, France) was used to detect the JAK2V617F status and quantitative JAK2V617F allele burdens in genomic DNA using TaqMan allelic discrimination. Results Frequency of JAK2V617F-positive patients with high mutation load (allele burden > 50%) was higher in PMF compared to ET (23.4% and 4.7%, respectively; P = 0.001). We found significant association between ET patients with high JAK2V617F allele burden and lower hemoglobin (Hgb) and hematocrit (Hct), higher LDH levels and more prevalent massive splenomegaly (P = 0.001, P = 0.001, P = 0.012 and P = 0.015, respectively). ET patients with high mutation load displayed higher prevalence of bleeding compared to low mutation load and wild-type mutational status (P = 0.003). Rate of DVT was significantly higher in ET patients with mutant allele burden in upper half compared to lower half and wild-type (P = 0.029). We observed significant association between PMF patients with high JAK2V617F allele burden and higher Hgb, Hct levels and leukocyte counts (P = 0.003, P = 0.021 and P = 0.001, respectively). Conclusions Our study demonstrated JAK2V617F allele burden correlates with clinical features in ET and PMF. We conclude quantification of JAK2V617F mutation contributes to the workup of Ph-negative MPNs. PMID:25584101

  6. Restrictive flamenco alleles are maintained in Drosophila melanogaster population cages, despite the absence of their endogenous gypsy retroviral targets.

    PubMed

    Pélisson, Alain; Payen-Groschêne, Geneviève; Terzian, Christophe; Bucheton, Alain

    2007-02-01

    The flamenco (flam) locus, located at 20A1-3 in the centromeric heterochromatin of the Drosophila melanogaster X chromosome, is a major regulator of the gypsy/mdg4 endogenous retrovirus. In restrictive strains, functional flam alleles maintain gypsy proviruses in a repressed state. By contrast, in permissive strains, proviral amplification results from infection of the female germ line and subsequent insertions into the chromosomes of the progeny. A restrictive/permissive polymorphism prevails in natural and laboratory populations. This polymorphism was assumed to be maintained by the interplay of opposite selective forces; on one hand, the increase of genetic load caused by proviral insertions would favor restrictive flam alleles because they make flies resistant to these gypsy replicative transpositions and, on the other, a hypothetical resistance cost would select against such alleles in the absence of the retrovirus. However, the population cage data presented in this paper do not fit with this simple resistance cost hypothesis because restrictive alleles were not eliminated in the absence of functional gypsy proviruses; on the contrary, using 2 independent flam allelic pairs, the restrictive frequency rose to about 90% in every experimental population, whatever the pair of alleles and the allelic proportions in the initial inoculum. These data suggest that the flam polymorphism is maintained by some strong balancing selection, which would act either on flam itself, independently of the deleterious effect of gypsy, or on a hypothetical flanking gene, in linkage disequilibrium with flam. Alternatively, restrictive flam alleles might also be resistant to some other retroelements that would be still present in the cage populations, causing a positive selection for these alleles. Whatever selective forces that maintain high levels of restrictive alleles independently of gypsy, this unknown mechanism can set up an interesting kind of antiviral innate immunity, at

  7. Analysis of FBN1 allele expression by dermal fibroblasts from Marfan syndrome patients

    SciTech Connect

    Putman, E.A.; Cao, S.N.; Milewicz, D.M.

    1994-09-01

    Screening for mutations in the FBN1 cDNA from Marfan patient cell strains has detected mutations in only 10-15% of patients. In an attempt to explain this poor detection rate, we examined FBN1 allele expression and fibrillin synthesis by 26 cell strains from Marfan patients. DNA from the patients and 10 controls was assessed for the presence of a polymorphic Rsa I restriction site in the 3{prime} untranslated region of the FBN1 gene. Twelve of 26 patient and 5 of 10 control DNAs were heterozygous. Fibroblast RNA from the heterozygous cell strains was reverse-transcribed and subsequently PCR amplified using a [{sup 32}P]-labelled primer, digested with Rsa I and analyzed. Although 3 samples showed no transcript from one allele by ethidium bromide staining, a Betagen scanner detected low levels (10-15%) of that allele. In addition, there was unequal expression of the two alleles in three other patients; for example, only 30% expression from one allele. The remaining patients and the controls had equal expression of each allele. Fibrillin protein synthesis by fibroblasts from these heterozygous patients was also examined. After a 30 minute pulse with [{sup 35}S]-cysteine, cell lysates were collected and proteins analyzed by SDS-PAGE. The amount of fibrillin produced relative to a reference protein was determined using a Betagen scanner. Fibrillin protein synthesis was reduced in 2 of the 3 patients with very low RNA production from one of the FBN1 alleles. All other Marfan and control cell strains showed normal amounts of fibrillin synthesized. The low expression levels from one allele may contribute to, but not fully account for, the low detection rate of FBN1 mutations. Interestingly, protein synthesis levels were not affected in 4 of 6 cell strains demonstrating low levels of RNA expression.

  8. Association of the apolipoprotein E {epsilon}4 allele with clinical subtypes of autopsy-confirmed Alzheimer`s Disease

    SciTech Connect

    Zubenko, G.S.; Stiffler, S.; Kopp, U.

    1994-09-15

    Consistent with previous reports, we observed a significant association of the APOE {epsilon}4 allele with Alzheimer`s Disease (AD) in a series of 91 autopsy-confirmed cases. The {epsilon}4 allele frequency was higher in cases with a family history of AD-like dementia (0.54 {+-} 0.07), although the {epsilon}4 allele frequency in the AD cases with a negative family history (0.38 {+-} 0.05) remained significantly greater than that for the non-AD control group (0.13 {+-} 0.03). A similar increase in {epsilon}4 allele frequency (0.54 {+-} 0.07) was observed in the AD cases with amyloid angiopathy, compared to those who did not have amyloid angiopathy (0.35 {+-} 0.04). Contrary to previous reports, no effect of the dosage of the {epsilon}4 allele was found on the age of onset of dementia among the AD cases and, contrary to reports suggesting an association of {epsilon}4 and atherosclerosis, the {epsilon}4 allele frequency was similar in cases with or without concurrent brain infarcts. Modest but consistent correlations were observed between the dosage of {epsilon}4 alleles and the cortical density of senile plaques, but not neurofibrillary tangles. The last finding suggests that the pathogenic events mediated by the {epsilon}4 allele may be more directly involved in the formation of senile plaques, the identifying lesions in AD, than neurofibrillary tangles. A robust association of both the presence of an {epsilon}4 allele and a family history of AD-like dementia with concurrent amyloid angiopathy occurred within our sample of AD cases. This association arose from an interaction of the {epsilon}4 allele with a separate familial factor for which a family history of dementia served as a surrogate. These results suggest that amyloid angiopathy may be a common or central feature of a form of familial AD that is associated with the transmission of the APOE {epsilon}4 allele. 22 refs., 2 figs., 5 tabs.

  9. Allele-specific expression assays using Solexa

    PubMed Central

    Main, Bradley J; Bickel, Ryan D; McIntyre, Lauren M; Graze, Rita M; Calabrese, Peter P; Nuzhdin, Sergey V

    2009-01-01

    Background Allele-specific expression (ASE) assays can be used to identify cis, trans, and cis-by-trans regulatory variation. Understanding the source of expression variation has important implications for disease susceptibility, phenotypic diversity, and adaptation. While ASE is commonly measured via relative fluorescence at a SNP, next generation sequencing provides an opportunity to measure ASE in an accurate and high-throughput manner using read counts. Results We introduce a Solexa-based method to perform large numbers of ASE assays using only a single lane of a Solexa flowcell. In brief, transcripts of interest, which contain a known SNP, are PCR enriched and barcoded to enable multiplexing. Then high-throughput sequencing is used to estimate allele-specific expression using sequencing counts. To validate this method, we measured the allelic bias in a dilution series and found high correlations between measured and expected values (r>0.9, p < 0.001). We applied this method to a set of 5 genes in a Drosophila simulans parental mix, F1 and introgression and found that for these genes the majority of expression divergence can be explained by cis-regulatory variation. Conclusion We present a new method with the capacity to measure ASE for large numbers of assays using as little as one lane of a Solexa flowcell. This will be a valuable technique for molecular and population genetic studies, as well as for verification of genome-wide data sets. PMID:19740431

  10. Allelic variation contributes to bacterial host specificity

    SciTech Connect

    Yue, Min; Han, Xiangan; Masi, Leon De; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Schmieder, Robert; Kaushik, Radhey S.; Fraser, George P.; Zhao, Shaohua; McDermott, Patrick F.; Weill, François-Xavier; Mainil, Jacques G.; Arze, Cesar; Fricke, W. Florian; Edwards, Robert A.; Brisson, Dustin; Zhang, Nancy R.; Rankin, Shelley C.; Schifferli, Dieter M.

    2015-10-30

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. In conclusion, together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts.

  11. Allelic variation contributes to bacterial host specificity

    DOE PAGESBeta

    Yue, Min; Han, Xiangan; Masi, Leon De; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Schmieder, Robert; Kaushik, Radhey S.; Fraser, George P.; et al

    2015-10-30

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population andmore » functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. In conclusion, together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts.« less

  12. Allelic variation contributes to bacterial host specificity

    PubMed Central

    Yue, Min; Han, Xiangan; Masi, Leon De; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Schmieder, Robert; Kaushik, Radhey S.; Fraser, George P.; Zhao, Shaohua; McDermott, Patrick F.; Weill, François-Xavier; Mainil, Jacques G.; Arze, Cesar; Fricke, W. Florian; Edwards, Robert A.; Brisson, Dustin; Zhang, Nancy R.; Rankin, Shelley C.; Schifferli, Dieter M.

    2015-01-01

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. Together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts. PMID:26515720

  13. Reconstructing the prior probabilities of allelic phylogenies.

    PubMed Central

    Golding, G Brian

    2002-01-01

    In general when a phylogeny is reconstructed from DNA or protein sequence data, it makes use only of the probabilities of obtaining some phylogeny given a collection of data. It is also possible to determine the prior probabilities of different phylogenies. This information can be of use in analyzing the biological causes for the observed divergence of sampled taxa. Unusually "rare" topologies for a given data set may be indicative of different biological forces acting. A recursive algorithm is presented that calculates the prior probabilities of a phylogeny for different allelic samples and for different phylogenies. This method is a straightforward extension of Ewens' sample distribution. The probability of obtaining each possible sample according to Ewens' distribution is further subdivided into each of the possible phylogenetic topologies. These probabilities depend not only on the identity of the alleles and on 4N(mu) (four times the effective population size times the neutral mutation rate) but also on the phylogenetic relationships among the alleles. Illustrations of the algorithm are given to demonstrate how different phylogenies are favored under different conditions. PMID:12072482

  14. Allelic variation contributes to bacterial host specificity.

    PubMed

    Yue, Min; Han, Xiangan; De Masi, Leon; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Schmieder, Robert; Kaushik, Radhey S; Fraser, George P; Zhao, Shaohua; McDermott, Patrick F; Weill, François-Xavier; Mainil, Jacques G; Arze, Cesar; Fricke, W Florian; Edwards, Robert A; Brisson, Dustin; Zhang, Nancy R; Rankin, Shelley C; Schifferli, Dieter M

    2015-01-01

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. Together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts. PMID:26515720

  15. Cytomegalovirus Infection in Ireland: Seroprevalence, HLA Class I Alleles, and Implications.

    PubMed

    Hassan, Jaythoon; O'Neill, Derek; Honari, Bahman; De Gascun, Cillian; Connell, Jeff; Keogan, Mary; Hickey, David

    2016-02-01

    Cytomegalovirus (CMV) infections occur worldwide and primary infection usually occurs in early childhood and is often asymptomatic whereas primary infection in adults may result in symptomatic illness. CMV establishes a chronic latent infection with intermittent periods of reactivation. Primary infection or reactivation associate with increased mortality and morbidity in those who are immunocompromised. Transplacental transmission may result in significant birth defects or long-term sensorineural hearing loss.We performed a study to determine the CMV seroprevalence and the association between HLA Class I alleles and frequency of CMV infection in Ireland. The presence of CMV IgG, a marker of previous CMV infection, was determined for a cohort of 1849 HLA typed solid organ transplant donors between 1990 and 2013. The presence of CMV IgG was correlated with HLA type.The CMV seroprevalence in solid organ transplant donors was 33.4% (range 22-48% per annum) over the time period 1990 to 2013. Multivariate logistic regression analysis showed that both age and HLA alleles were associated with CMV seropositivity. A significant and positive relationship between age and CMV seropositivity was observed (OR = 1.013, P < 0.001, CI [1.007, 1.019]). Chi-square analysis revealed that the female gender was independently associated with CMV seropositivity (P < 0.01). Seroprevalence in women of reproductive age (20-39 years) was significantly higher than men of the same age (37% vs 26%, P < 0.01). The frequencies of HLA-A1, HLA-A2, and HLA-A3 in our cohort were 40.8%, 48.8%, and 25.9%, respectively. Logistic regression analysis showed that the presence of HLA-A1 but not HLA-A2 or HLA-A3 was independently associated with CMV seronegativity (P < 0.01). Interestingly, individuals who co-expressed HLA-A2 and HLA-A3 alleles were significantly more likely to be CMV seropositive (P < 0.02). The frequencies of HLA-B5, HLA-B7, and HLA-B8 in our cohort were 6.1%, 31

  16. Predicting Carriers of Ongoing Selective Sweeps without Knowledge of the Favored Allele

    PubMed Central

    Zakov, Shay; Rosenberg, Noah A.; Bafna, Vineet

    2015-01-01

    Methods for detecting the genomic signatures of natural selection have been heavily studied, and they have been successful in identifying many selective sweeps. For most of these sweeps, the favored allele remains unknown, making it difficult to distinguish carriers of the sweep from non-carriers. In an ongoing selective sweep, carriers of the favored allele are likely to contain a future most recent common ancestor. Therefore, identifying them may prove useful in predicting the evolutionary trajectory—for example, in contexts involving drug-resistant pathogen strains or cancer subclones. The main contribution of this paper is the development and analysis of a new statistic, the Haplotype Allele Frequency (HAF) score. The HAF score, assigned to individual haplotypes in a sample, naturally captures many of the properties shared by haplotypes carrying a favored allele. We provide a theoretical framework for computing expected HAF scores under different evolutionary scenarios, and we validate the theoretical predictions with simulations. As an application of HAF score computations, we develop an algorithm (PreCIOSS: Predicting Carriers of Ongoing Selective Sweeps) to identify carriers of the favored allele in selective sweeps, and we demonstrate its power on simulations of both hard and soft sweeps, as well as on data from well-known sweeps in human populations. PMID:26402243

  17. Diploid male dynamics under different numbers of sexual alleles and male dispersal abilities.

    PubMed

    Faria, Luiz R R; Soares, Elaine Della Giustina; Carmo, Eduardo do; Oliveira, Paulo Murilo Castro de

    2016-09-01

    Insects in the order Hymenoptera (bees, wasps and ants) present an haplodiploid system of sexual determination in which fertilized eggs become females and unfertilized eggs males. Under single locus complementary sex-determination (sl-CSD) system, the sex of a specimen depends on the alleles at a single locus: when diploid, an individual will be a female if heterozygous and male if homozygous. Significant diploid male (DM) production may drive a population to an extinction scenario called "diploid male vortex". We aimed at studying the dynamics of populations of a sl-CSD organism under several combinations of two parameters: male flight abilities and number of sexual alleles. In these simulations, we evaluated the frequency of DM and a genetic diversity measure over 10,000 generations. The number of sexual alleles varied from 10 to 100 and, at each generation, a male offspring might fly to another random site within a varying radius R. Two main results emerge from our simulations: (i) the number of DM depends more on male flight radius than on the number of alleles; (ii) in large geographic regions, the effect of males flight radius on the allelic diversity turns out much less pronounced than in small regions. In other words, small regions where inbreeding normally appears recover genetic diversity due to large flight radii. These results may be particularly relevant when considering the population dynamics of species with increasingly limited dispersal ability (e.g., forest-dependent species of euglossine bees in fragmented landscapes). PMID:27067711

  18. Paternal-specific S-allele transmission in sweet cherry (Prunus avium L.): the potential for sexual selection.

    PubMed

    Hedhly, A; Wünsch, A; Kartal, Ö; Herrero, M; Hormaza, J I

    2016-03-01

    Homomorphic self-incompatibility is a well-studied example of a physiological process that is thought to increase population diversity and reduce the expression of inbreeding depression. Whereas theoretical models predict the presence of a large number of S-haplotypes with equal frequencies at equilibrium, unequal allele frequencies have been repeatedly reported and attributed to sampling effects, population structure, demographic perturbation, sheltered deleterious mutations or selection pressure on linked genes. However, it is unclear to what extent unequal segregations are the results of gametophytic or sexual selection. Although these two forces are difficult to disentangle, testing S-alleles in the offspring of controlled crosses provides an opportunity to separate these two phenomena. In this work, segregation and transmission of S-alleles have been characterized in progenies of mixed donors and fully compatible pollinations under field conditions in Prunus avium. Seed set patterns and pollen performance have also been characterized. The results reveal paternal-specific distorted transmission of S-alleles in most of the crosses. Interestingly, S-allele segregation within any given paternal or maternal S-locus was random. Observations on pollen germination, pollen tube growth rate, pollen tube cohort size, seed set dynamics and transmission patterns strongly suggest post-pollination, prezygotic sexual selection, with male-male competition as the most likely mechanism. According to these results, post-pollination sexual selection takes precedence over frequency-dependent selection in explaining unequal S-haplotype frequencies. PMID:26559165

  19. Slight instability of a FMR-1 allele over three generations in a family from the general population

    SciTech Connect

    Abramowicz, M.J.; Parma, J.; Cochaux, P.

    1996-08-09

    We report on a family segregating a FMR-1 allele within the {open_quotes}grey zone{close_quotes} of triplet repeat length (n = 51). The allele showed a 1-unit increment when transmitted through a female meiosis and a 1-unit increment when transmitted through a male of the next generation. At the following generation, a pregnant woman had amniocentesis performed. The latter showed she transmitted the allele unchanged (n = 53) to her male fetus. This family was not ascertained through an affected subject, and there was no family history of mental retardation. Thus our observation reflects the natural history of an unstable allele in the general population. Systematic analysis of such alleles may help refine our understanding of the grey zone of triplet repeat length. 5 refs., 1 fig.

  20. HLA-B alleles and complotypes in Mexican patients with seronegative spondyloarthropathies.

    PubMed Central

    Vargas-Alarcón, G; Garcia, A; Bahena, S; Melin-Aldana, H; Andrade, F; Ibañez-de-Kasep, G; Alcocer-Varela, J; Alarcón-Segovia, D; Granados, J

    1994-01-01

    OBJECTIVES--To analyse major histocompatibility complex (MHC) haplotypes in Mexican mestizo patients with seronegative spondyloarthropathies (SSpA) and normal controls, to discover if there are other antigens, besides B27, in the HLA region that might show association with the disease. METHODS--The study included 100 Mexican mestizo patients with SSpA and 200 of their first degree relatives. These groups were compared with 85 ethnically matched controls. The class I and class III MHC antigens were obtained by standard methods. The significance of differences between patients and controls was tested by chi 2 analysis; linkage disequilibrium among the different alleles in each haplotype was estimated by computing delta values. RESULTS--We found a significantly increased frequency of the HLA-B27 antigen (pcorr. = 1 x 10(-5), odds ratio (OR) = 33.4, 95% confidence interval (CI) = 9.3-142.0). In the group of 45 SSpA patients negative for the B27 antigen, independent increased frequencies of HLA-B49 antigen (pcorr. = 0.03, OR = 6.5, 95% CI = 1.5-32.8)) and the FC31 complotype (pcorr. = 0.04, OR = 3.7, 95% CI = 1.2-11.1) were found. Significant delta values were obtained for the [B27;SC30] haplotype (p = 0.0005) but not for haplotypes marked by the FC31 complotype. HLA-B antigens on the homologous chromosome in B27 positive patients were mainly HLA-B51 (18%) and HLA-B60 (16%); however, the observed genotypes B27/B51 and B27/B60 were not significantly different than expected from the allele frequencies alone. CONCLUSIONS--These data suggest that in Mexicans additional genes within the MHC region besides the HLA-B27 antigen, might be related to the genetic susceptibility for developing SSpA. Relevant antigens included the HLA-B49 and the FC31 complotype. PMID:7826137

  1. HLA alleles and haplotypes among the Lakota Sioux: report of the ASHI minority workshops, part III.

    PubMed

    Leffell, Mary S; Fallin, M Daniele; Hildebrand, William H; Cavett, Joshua W; Iglehart, Brian A; Zachary, Andrea A

    2004-01-01

    Human leukocyte antigen (HLA) class I and II alleles were defined for 302 Lakota Sioux American Indians as part of the American Society for Histocompatibility and Immunogenetics coordinated studies on minority populations. The study group was comprised of adult volunteers from the Cheyenne River and Ogala Sioux tribes residing, respectively, on the Cheyenne River and Pine Ridge Reservations in South Dakota. Of the participants, 263 (87%) claimed full American Indian ancestry through both maternal and paternal grandparents. The study group included 25 nuclear families that were informative for genotyping. HLA phenotypes from 202 adults with no other known first-degree relative included in the study were used for calculation of allele and haplotype frequencies by maximum likelihood estimation. HLA-A, -B, and -Cw alleles were found to be in Hardy Weinberg equilibrium. Deviation from equilibrium was observed for DRB1 alleles (p=0.01), but could be attributed to the sample size and the occurrence of some genotypes with low expected frequencies. Polymorphism among the Sioux was limited with four to seven alleles comprising >80% of those observed at each locus. Several alleles were found at high frequency (0.05-0.30) among the Sioux that are also prevalent in other Native Americans and Alaska Natives, including: A*2402, *3101, and *0206; B*3501,*3901, *5101, and *2705; Cw*0702, *0404, and *03041; DRB1*0407, *0404, *1402, and *16021; and DQB1*0301, *0302, and *0402. DRB1*0811, which has been only previously described in Navajo and Tlingit Indians, was found to occur at a frequency of 0.119 among the Sioux. Two new alleles were defined among the Sioux: Cw*0204 and DRB1*040703, which were found in two and four individuals, respectively. In the haplotype analyses, significant linkage disequilibrium (p<0.00001) was seen in all pairwise comparisons of loci and numerous two and three locus haplotypes were found to have strong, positive linkage disequilibrium values. The two most

  2. Mutant maize variety containing the glt1-1 allele

    DOEpatents

    Nelson, O.E.; Pan, D.

    1994-07-19

    A maize plant has in its genome a non-mutable form of a mutant allele designated vitX-8132. The allele is located at a locus designated as glt which conditions kernels having an altered starch characteristic. Maize plants including such a mutant allele produce a starch that does not increase in viscosity on cooling, after heating. 2 figs.

  3. Mutant maize variety containing the glt1-1 allele

    DOEpatents

    Nelson, Oliver E.; Pan, David

    1994-01-01

    A maize plant has in its genome a non-mutable form of a mutant allele designated vitX-8132. The allele is located at a locus designated as glt which conditions kernels having an altered starch characteristic. Maize plants including such a mutant allele produce a starch that does not increase in viscosity on cooling, after heating.

  4. A novel HLA-B*14 allele - B*14:53 - genetics and serology.

    PubMed

    Street, J; Davies, E; Darke, C

    2016-08-01

    HLA-B*14:53 was found in a UK European normal blood donor prior to registration on the Welsh Bone Marrow Donor Registry. It differs from B*14:13 by one base (103G>T) in exon 2 resulting in a substitution of alanine (A) in B*14:13 to serine (S) in B*14:53. Unique among current HLA-B*14 alleles, B*14:53 and B*14:13 share a motif of 59 bases between positions 361 and 419 in exon 3. This motif is present in numerous HLA-B alleles the commonest overall being B*08:01, suggesting that both B*14:53 and B*14:13 arose from intralocus gene conversion events with B*08:01. Thus, B*14:53 probably arose from B*14:01:01 (which has TCC at codon 11 (S), while B*14:13 arose from B*14:02:01:01 which has GCC at codon 11 (A). Additionally, the two likely B*14:53-bearing and B*14:13-bearing haplotypes are typical of B*14:01:01-bearing and B*14:02:01:01-bearing haplotypes, respectively. Serological testing, using 49 antisera with HLA-B64, or B64, B65 reactivity, showed that the B*14:53 specificity did not react as a B64 (B*14:01) specificity and may appear as a short/weak HLA-B14. This implies that residues additional to S at position 11 are involved in HLA-B64 serological identity; for example, the motif 11S 97W 116F is possessed by B*14:01 and many other B*14 products (and B*39:79 plus some HLA-C products) but not B65 (B*14:02) or the B*14:53 specificity. B*14:53 was found in a random HLA sequence-based typed population of 32 530 normal subjects indicating a low precision allele frequency of 0.000015 in subjects resident in Wales. PMID:27312672

  5. Carriage of One or Two FMR1 Premutation Alleles Seems to Have No Effect on Illness Severity in a FXTAS Female with an Autozygous FMR1 Premutation Allele.

    PubMed

    Rodriguez-Revenga, Laia; Pagonabarraga, Javier; Gómez-Anson, Beatriz; López-Mourelo, Olga; Izquierdo, Silvia; Alvarez-Mora, Maria Isabel; Granell, Esther; Madrigal, Irene; Milà, Montserrat

    2016-10-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that occurs in FMR1 premutation carriers. The prevalence of FMR1 premutation carriers in the general population is relatively high, and although rare, a premutation in both X chromosomes may occur in females inheriting a premutation allele from each of both parent carriers. Here, we report the first female with an autozygous (homozygous by descendent) FMR1 premutation allele, who fulfills neurological and radiological FXTAS findings/criteria. Molecular characterization included CGG repeat length, AGG interruption pattern, FMR1 messenger RNA (mRNA), fragile X mental retardation protein (FMRP) level quantification, and single-nucleotide polymorphism (SNP) microarray. Neuroradiological assessment of 3-T magnetic resonance imaging and neurological and cognitive/neuropsychological evaluations were performed. Neurological and neuroradiological examination of the female with the same FMR1 allele in the premutation range (77 CGGs) demonstrated FXTAS features. Further familial evaluation showed a similar neuropsychiatric profile, with impairments in cognitive flexibility and visuospatial function, mainly. A unique family with an autozygous FMR1 premutation female is presented. Neurological/cognitive and neuroradiological examinations revealed FXTAS-specific findings in the female with the autozygous FMR1 premutation allele. The consistent molecular and cognitive/psychiatric phenotype in family members suggests that carrying one or two FMR1 premutation alleles has no effect on illness severity. PMID:27315125

  6. Population Bottlenecks and Nonequilibrium Models in Population Genetics. I. Allele Numbers When Populations Evolve from Zero Variability

    PubMed Central

    Maruyama, Takeo; Fuerst, Paul A.

    1984-01-01

    A simple numerical method was developed for the mean number and average age of alleles in a population that was initiated with no genetic variation following a sudden population expansion. The methods are used to examine the question of whether allele numbers are elevated compared with values seen in equilibrium populations having equivalent gene diversity. Excess allele numbers in expanding populations were found to be the rule. This was true whether the population began with zero variation or with low levels of variation in either of two initial distributions (initially an equilibrium allele frequency distribution or initially with loci occurring in only two classes of variation). Although the increase of alleles may persist for only a short time, when compared with the time which is required for approach to final equilibrium, the increase may be long when measured in absolute generation numbers. The pattern of increase in very rare alleles (those present only once in a sample) and the persistence of the original allele were also investigated. PMID:6500263

  7. PCR Strategies for Complete Allele Calling in Multigene Families Using High-Throughput Sequencing Approaches.

    PubMed

    Marmesat, Elena; Soriano, Laura; Mazzoni, Camila J; Sommer, Simone; Godoy, José A

    2016-01-01

    The characterization of multigene families with high copy number variation is often approached through PCR amplification with highly degenerate primers to account for all expected variants flanking the region of interest. Such an approach often introduces PCR biases that result in an unbalanced representation of targets in high-throughput sequencing libraries that eventually results in incomplete detection of the targeted alleles. Here we confirm this result and propose two different amplification strategies to alleviate this problem. The first strategy (called pooled-PCRs) targets different subsets of alleles in multiple independent PCRs using different moderately degenerate primer pairs, whereas the second approach (called pooled-primers) uses a custom-made pool of non-degenerate primers in a single PCR. We compare their performance to the common use of a single PCR with highly degenerate primers using the MHC class I of the Iberian lynx as a model. We found both novel approaches to work similarly well and better than the conventional approach. They significantly scored more alleles per individual (11.33 ± 1.38 and 11.72 ± 0.89 vs 7.94 ± 1.95), yielded more complete allelic profiles (96.28 ± 8.46 and 99.50 ± 2.12 vs 63.76 ± 15.43), and revealed more alleles at a population level (13 vs 12). Finally, we could link each allele's amplification efficiency with the primer-mismatches in its flanking sequences and show that ultra-deep coverage offered by high-throughput technologies does not fully compensate for such biases, especially as real alleles may reach lower coverage than artefacts. Adopting either of the proposed amplification methods provides the opportunity to attain more complete allelic profiles at lower coverages, improving confidence over the downstream analyses and subsequent applications. PMID:27294261

  8. Dose effect of allele {epsilon}4 of apolipoprotein E on risk and age at onset of Pick disease

    SciTech Connect

    Farrer, L.A.; Abraham, C.; Volicer, L.

    1994-09-01

    Pick disease (PD) is a rare progressive dementing illness characterized by severe atrophy of the frontal and temporal lobes. Brains of PD patients lack neurofibrillary tangles which are characteristic findings of Alzheimer disease (AD), but display neuronal swelling and argyrophilic inclusions (i.e., Pick bodies) which contain phosphorylated neurofilaments, tau and complex lipids. Clinically, PD is often difficult to distinguish from AD. The fact that PD is often familial and the evidence suggesting that the {epsilon}4 allele of apoE is a risk factor for AD and multi-infarct dementia prompted us to study apoE isoforms in PD. ApoE genotypes were evaluated in an autopsy series of cases (19 AD, 15 PD, and 7 {open_quotes}controls{close_quotes} with other or no pathology). All subjects were unrelated except for 2 brothers who both had PD. Age at onset in the PD patients ranged from 41 to 59 years. The frequency of {epsilon}4 is significantly higher among AD subjects (47.4%) than in Pick cases (23.3%; P=0.4) or controls (7.1%; P=.008), but the 16% difference between PD and control subjects was not significant, perhaps due to small sample sizes. Linear regression analysis showed that the number of {epsilon}4 alleles was inversely related to age at onset of PD (P=.04) and accounted for 27% of the variation in age at onset. These results suggest that {epsilon}4 may be a susceptibility factor for dementia and not specifically AD. Preliminary experiments using an antibody against apoE suggest that Pick bodies may be immunoreactive with this antibody and that apoE binds to abnormal filaments. The association of the {epsilon}4 allele with dementias other than AD and the apoE staining results support a model postulating an interaction between the {epsilon}4 isoform and tau.

  9. Allele-specific expression of mutated in colorectal cancer (MCC) gene and alternative susceptibility to colorectal cancer in schizophrenia

    PubMed Central

    Wang, Yang; Cao, Yanfei; Huang, Xiaoye; Yu, Tao; Wei, Zhiyun; McGrath, John; Xu, Fei; Bi, Yan; Li, Xingwang; Yang, Fengping; Li, Weidong; Zou, Xia; Peng, Zhihai; Xiao, Yanzeng; Zhang, Yan; He, Lin; He, Guang

    2016-01-01

    Evidence has indicated that the incidence of colorectal cancer (CRC) among schizophrenia is lower than normal. To explore this potential protective effect, we employed an innovative strategy combining association study with allele-specific expression (ASE) analysis in MCC gene. We first genotyped four polymorphisms within MCC in 312 CRC patients, 270 schizophrenia patients and 270 controls. Using the MassArray technique, we performed ASE measurements in a second sample series consisting of 50 sporadic CRC patients, 50 schizophrenia patients and 52 controls. Rs2227947 showed significant differences between schizophrenia cases and controls, and haplotype analysis reported some significant discrepancies among these three subject groups. ASE values of rs2227948 and rs2227947 presented consistently differences between CRC (or schizophrenia) patients and controls. Of the three groups, highest frequencies of ASE in MCC were concordantly found in CRC group, whereas lowest frequencies of ASE were observed in schizophrenia group. Similar trends were confirmed in both haplotype frequencies and ASE frequencies (i.e. CRC > control > schizophrenia). We provide a first indication that MCC might confer alterative genetic susceptibility to CRC in individuals with schizophrenia promising to shed more light on the relationship between schizophrenia and cancer progression. PMID:27226254

  10. Allele-specific expression of mutated in colorectal cancer (MCC) gene and alternative susceptibility to colorectal cancer in schizophrenia.

    PubMed

    Wang, Yang; Cao, Yanfei; Huang, Xiaoye; Yu, Tao; Wei, Zhiyun; McGrath, John; Xu, Fei; Bi, Yan; Li, Xingwang; Yang, Fengping; Li, Weidong; Zou, Xia; Peng, Zhihai; Xiao, Yanzeng; Zhang, Yan; He, Lin; He, Guang

    2016-01-01

    Evidence has indicated that the incidence of colorectal cancer (CRC) among schizophrenia is lower than normal. To explore this potential protective effect, we employed an innovative strategy combining association study with allele-specific expression (ASE) analysis in MCC gene. We first genotyped four polymorphisms within MCC in 312 CRC patients, 270 schizophrenia patients and 270 controls. Using the MassArray technique, we performed ASE measurements in a second sample series consisting of 50 sporadic CRC patients, 50 schizophrenia patients and 52 controls. Rs2227947 showed significant differences between schizophrenia cases and controls, and haplotype analysis reported some significant discrepancies among these three subject groups. ASE values of rs2227948 and rs2227947 presented consistently differences between CRC (or schizophrenia) patients and controls. Of the three groups, highest frequencies of ASE in MCC were concordantly found in CRC group, whereas lowest frequencies of ASE were observed in schizophrenia group. Similar trends were confirmed in both haplotype frequencies and ASE frequencies (i.e. CRC > control > schizophrenia). We provide a first indication that MCC might confer alterative genetic susceptibility to CRC in individuals with schizophrenia promising to shed more light on the relationship between schizophrenia and cancer progression. PMID:27226254

  11. Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes

    PubMed Central

    Cochran, Rory L.; Cidado, Justin; Kim, Minsoo; Zabransky, Daniel J.; Croessmann, Sarah; Chu, David; Wong, Hong Yuen; Beaver, Julia A.; Cravero, Karen; Erlanger, Bracha; Parsons, Heather; Heaphy, Christopher M.; Meeker, Alan K.; Lauring, Josh; Park, Ben Ho

    2015-01-01

    Clinical genetic testing of BRCA1 and BRCA2 is commonly performed to identify specific individuals at risk for breast and ovarian cancers who may benefit from prophylactic therapeutic interventions. Unfortunately, it is evident that deleterious BRCA1 alleles demonstrate variable penetrance and that many BRCA1 variants of unknown significance (VUS) exist. In order to further refine hereditary risks that may be associated with specific BRCA1 alleles, we performed gene targeting to establish an isogenic panel of immortalized human breast epithelial cells harboring eight clinically relevant BRCA1 alleles. Interestingly, BRCA1 mutations and VUS had distinct, quantifiable phenotypes relative to isogenic parental BRCA1 wild type cells and controls. Heterozygous cells with known deleterious BRCA1 mutations (185delAG, C61G and R71G) demonstrated consistent phenotypes in radiation sensitivity and genomic instability assays, but showed variability in other assays. Heterozygous BRCA1 VUS cells also demonstrated assay variability, with some VUS demonstrating phenotypes more consistent with deleterious alleles. Taken together, our data suggest that BRCA1 deleterious mutations and VUS can differ in their range of tested phenotypes, suggesting they might impart varying degrees of risk. These results demonstrate that functional isogenic modeling of BRCA1 alleles could aid in classifying BRCA1 mutations and VUS, and determining BRCA allele cancer risk. PMID:26246475

  12. Identification of the new HLA-DRB1{sup *}0812 allele detected by sequencing based typing

    SciTech Connect

    Versluis, L.F.; Zwan, A.W. van der; Tilanus, M.G.J.; Savelkoul, P.H.M.; Berg-Loonen, E.M. van den

    1996-12-31

    HLA-DRB typing by polymerase chain reaction-sequence specific priming (PCR-SSP) and sequencing based typing (SBT) was studied within the framework of the Antigen and Haplotype Society 11 and the Sequencing Based Typing Component of the Twelfth International HLA workshop. Sequencing was performed as described by McGinnis and co-workers in 1995 on coded samples, including most DR2 subtypes, resulting in high resolution HLA-DR typing. Sequences were compared with a database containing 107 DRB1, four DRB3, and five DRB5 alleles in a similar way as described for HLA-DPB. One sample showed a new DR8 sequence, indicating the presence of a new allele. This individual (4390) is of Indonesian origin. The specific amplification of the DR8 allele and subsequent sequencing resulted in a sequence which did not match the database and new polymorphism was identified. The complementary strand was sequenced and confirmed the presence of a new DRB1 allele. Cloning and subsequent sequencing of the polymerase chain reaction fragment resulted in confirmation of the direct sequence data. Later this variant was officially named DRB1{sup *}0812. The complete nucleotide sequence of exon 2 of this new allele is shown. This allele differs from DRB1{sup *}0810 by one nucleotide at codon 85, resulting in an alanine (GTT), whereas DRB1{sup *}0810 carries a valine (GCT). 5 refs., 1 fig.

  13. Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes.

    PubMed

    Cochran, Rory L; Cidado, Justin; Kim, Minsoo; Zabransky, Daniel J; Croessmann, Sarah; Chu, David; Wong, Hong Yuen; Beaver, Julia A; Cravero, Karen; Erlanger, Bracha; Parsons, Heather; Heaphy, Christopher M; Meeker, Alan K; Lauring, Josh; Park, Ben Ho

    2015-09-22

    Clinical genetic testing of BRCA1 and BRCA2 is commonly performed to identify specific individuals at risk for breast and ovarian cancers who may benefit from prophylactic therapeutic interventions. Unfortunately, it is evident that deleterious BRCA1 alleles demonstrate variable penetrance and that many BRCA1 variants of unknown significance (VUS) exist. In order to further refine hereditary risks that may be associated with specific BRCA1 alleles, we performed gene targeting to establish an isogenic panel of immortalized human breast epithelial cells harboring eight clinically relevant BRCA1 alleles. Interestingly, BRCA1 mutations and VUS had distinct, quantifiable phenotypes relative to isogenic parental BRCA1 wild type cells and controls. Heterozygous cells with known deleterious BRCA1 mutations (185delAG, C61G and R71G) demonstrated consistent phenotypes in radiation sensitivity and genomic instability assays, but showed variability in other assays. Heterozygous BRCA1 VUS cells also demonstrated assay variability, with some VUS demonstrating phenotypes more consistent with deleterious alleles. Taken together, our data suggest that BRCA1 deleterious mutations and VUS can differ in their range of tested phenotypes, suggesting they might impart varying degrees of risk. These results demonstrate that functional isogenic modeling of BRCA1 alleles could aid in classifying BRCA1 mutations and VUS, and determining BRCA allele cancer risk. PMID:26246475

  14. Imprinting control regions (ICRs) are marked by mono-allelic bivalent chromatin when transcriptionally inactive

    PubMed Central

    Maupetit-Méhouas, Stéphanie; Montibus, Bertille; Nury, David; Tayama, Chiharu; Wassef, Michel; Kota, Satya K.; Fogli, Anne; Cerqueira Campos, Fabiana; Hata, Kenichiro; Feil, Robert; Margueron, Raphael; Nakabayashi, Kazuhiko; Court, Franck; Arnaud, Philippe

    2016-01-01

    Parental allele-specific expression of imprinted genes is mediated by imprinting control regions (ICRs) that are constitutively marked by DNA methylation imprints on the maternal or paternal allele. Mono-allelic DNA methylation is strictly required for the process of imprinting and has to be faithfully maintained during the entire life-span. While the regulation of DNA methylation itself is well understood, the mechanisms whereby the opposite allele remains unmethylated are unclear. Here, we show that in the mouse, at maternally methylated ICRs, the paternal allele, which is constitutively associated with H3K4me2/3, is marked by default by H3K27me3 when these ICRs are transcriptionally inactive, leading to the formation of a bivalent chromatin signature. Our data suggest that at ICRs, chromatin bivalency has a protective role by ensuring that DNA on the paternal allele remains unmethylated and protected against spurious and unscheduled gene expression. Moreover, they provide the proof of concept that, beside pluripotent cells, chromatin bivalency is the default state of transcriptionally inactive CpG island promoters, regardless of the developmental stage, thereby contributing to protect cell identity. PMID:26400168

  15. Rapid Microarray-Based Identification of Different mecA Alleles in Staphylococci

    PubMed Central

    Müller, Elke; Schwarz, Stefan; Hotzel, Helmut; Ehricht, Ralf

    2012-01-01

    To screen isolates and to identify mecA alleles, published mecA sequences were analyzed, and a microarray for the rapid discrimination of mecA alleles was designed. A GenBank analysis yielded 135 full-length gene sequences annotated as mecA. These sequences clustered into 32 different alleles corresponding to 28 unique amino acid sequences and to 15 distinct hybridization patterns on this microarray. A collection of 78 clinical and veterinary isolates of Staphylococcus spp. was characterized using this assay. Nine of the 15 expected patterns, as well as one as-yet-unknown pattern, were identified. These patterns were detected in various epidemic methicillin-resistant Staphylococcus aureus strains, in S. pseudintermedius, and in coagulase-negative species such as S. epidermidis, S. fleurettii, or S. haemolyticus. There was no correlation between the different mecA hybridization patterns and the SCCmec type. Determination of MICs showed that mecA alleles corresponding to only four of these nine patterns were associated with β-lactam resistance. The mecA alleles that did not confer β-lactam resistance were largely restricted to coagulase-negative staphylococci of animal origin, such as S. sciuri and S. vitulinus. Because of the diversity of sequences and the different impact on β-lactam susceptibility, the existence of different mecA alleles needs to be taken into account when designing diagnostic assays for the detection of mecA. PMID:22890767

  16. Relationship between HLA-DRB1 allele polymorphisms and familial aggregations of hepatocellular carcinoma

    PubMed Central

    Ma, S.; Wu, J.; Wu, J.; Wei, Y.; Zhang, L.; Ning, Q.; Hu, D.

    2016-01-01

    Objective We explored the relationship between HLA-DRB1 allele polymorphisms and familial aggregation of hepatocellular carcinoma (fhcc). Methods Polymerase chain reaction sequence-specific primers were used to determine HLA-DRB1 genotypes for 130 members of families with 2 or more liver cancer patients and for 130 members of families without any diagnosed cancers. The genotype profiles were then compared to explore the relationship between HLA-DRB1 gene polymorphism and fhcc. Result Of 11 selected alleles, the frequencies of DRB1*11 and DRB1*12 were significantly lower in the fhcc group than in no-cancer group (p < 0.05; odds ratio: 0.286; 95% confidence interval: 0.091 to 0.901; and odds ratio: 0.493; 95% confidence interval: 0.292 to 0.893). Differences in the frequencies of the other 9 alleles were not statistically significant in the two groups (p > 0.05). Conclusions Our research suggests that if genetic factors play a role in fhcc, the deficiency in the DRB1*11 and DRB1*12 alleles might be the risk factor at work in Guangxi Zhuang Autonomous Region, P.R.C. PMID:26966407

  17. Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility.

    PubMed

    Li, M; Luo, X-J; Rietschel, M; Lewis, C M; Mattheisen, M; Müller-Myhsok, B; Jamain, S; Leboyer, M; Landén, M; Thompson, P M; Cichon, S; Nöthen, M M; Schulze, T G; Sullivan, P F; Bergen, S E; Donohoe, G; Morris, D W; Hargreaves, A; Gill, M; Corvin, A; Hultman, C; Toga, A W; Shi, L; Lin, Q; Shi, H; Gan, L; Meyer-Lindenberg, A; Czamara, D; Henry, C; Etain, B; Bis, J C; Ikram, M A; Fornage, M; Debette, S; Launer, L J; Seshadri, S; Erk, S; Walter, H; Heinz, A; Bellivier, F; Stein, J L; Medland, S E; Arias Vasquez, A; Hibar, D P; Franke, B; Martin, N G; Wright, M J; Su, B

    2014-04-01

    Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among

  18. Isolation and Genetic Characterization of Mother-of-Snow-White, a Maternal Effect Allele Affecting Laterality and Lateralized Behaviors in Zebrafish

    PubMed Central

    Domenichini, Alice; Dadda, Marco; Facchin, Lucilla; Bisazza, Angelo; Argenton, Francesco

    2011-01-01

    In the present work we report evidence compatible with a maternal effect allele affecting left-right development and functional lateralization in vertebrates. Our study demonstrates that the increased frequency of reversed brain asymmetries in a zebrafish line isolated through a behavioral assay is due to selection of mother-of-snow-white (msw), a maternal effect allele involved in early stages of left-right development in zebrafish. msw homozygous females could be identified by screening of their progeny for the position of the parapineal organ because in about 50% of their offspring we found an altered, either bilateral or right-sided, expression of lefty1 and spaw. Deeper investigations at earlier stages of development revealed that msw is involved in the specification and differentiation of precursors of the Kupffer's vesicle, a structure homologous to the mammalian node. To test the hypothesis that msw, by controlling Kupffer's vesicle morphogenesis, controls lateralized behaviors related to diencephalic asymmetries, we analyzed left- and right-parapineal offspring in a “viewing test”. As a result, left- and right-parapineal individuals showed opposite and complementary eye preference when scrutinizing a model predator, and a different degree of lateralization when scrutinizing a virtual companion. As maternal effect genes are expected to evolve more rapidly when compared to zygotic ones, our results highlight the driving force of maternal effect alleles in the evolution of vertebrates behaviors. PMID:22022484

  19. Forensic Spanish allele and haplotype database for a 17 X-STR panel.

    PubMed

    Prieto-Fernández, Endika; Núñez, Carolina; Baeta, Miriam; Jiménez-Moreno, Susana; Martínez-Jarreta, Begoña; de Pancorbo, Marian M

    2016-09-01

    The currently developed 17 X-STR panel (DXS8378, DXS9898, DXS7133, GATA31E08, GATA172D05, DXS6801, DXS7423, DXS6809, DXS6799, DXS7132, DXS9902, DXS6800, DXS6789, DXS10075, DXS10079, DXS6807, and DXS6803) offers a highly discriminative tool for forensic identification and kinship testing. With the aim of providing a global Spanish population X-STR database, we present haplotype and allele frequencies and parameters of forensic interest for the 17 X-STR panel obtained from 593 unrelated individuals from Alicante, Aragon, the Basque Country, Andalusia, Galicia, Madrid, and Barcelona that represent the most populated regions of the Spanish Peninsular territory. The seven populations were compared to test possible population genetic substructures. The lack of significant differences among the studied Spanish populations supports the use of the allele and haplotype frequency database presented herein as a global Spanish population sample useful for statistical evaluation in forensic casework. After conducting the LD plots derived from HapMap and pairwise linkage disequilibrium tests, DXS7132, DXS10075, and DXS10079 markers were included in a cluster and haplotype frequencies were calculated. The improvement in the forensic parameters for the Spanish population using 17 X-STRs in comparison to the previous 10 X-STR allele frequencies database is also shown. PMID:27388427

  20. Comparison of somatic reversions between the ivory allele and transposon-caused mutant alleles at the white locus of Drosophila melanogaster after larval treatment with X rays and ethyl methanesulfonate

    SciTech Connect

    Ryo, H.; Yoo, M.A.; Fujikawa, K.; Kondo, S.

    1985-07-01

    Somatic reversion of strains with the ivory (wi) allele, a mutation associated with a tandem duplication of a DNA sequence at the white locus, increased with the age of larvae at the time of X-irradiation as expected from the increase in the number of target cells. In contrast, two independently isolated strains with unstable w+ loci associated with insertion of transposable elements showed higher reversion frequencies after treatment with X rays or ethyl methanesulfonate (EMS) at early larval stages than at late stages. Nevertheless, both the wi strain and the two unstable w+ strains reverted at nearly equal rates after treatment with X rays or EMS at early larval stages. Possible similarity in hot spot structure for the high reversibility of the two types of mutations is discussed in relation to production of presumed mutator-type cofactors specific to the transposon-caused mutations at early larval stages.

  1. At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns.

    PubMed

    Mitchell, G A; Brody, L C; Sipila, I; Looney, J E; Wong, C; Engelhardt, J F; Patel, A S; Steel, G; Obie, C; Kaiser-Kupfer, M

    1989-01-01

    Gyrate atrophy of the choroid and retina (GA) is an inherited chorioretinal degeneration caused by deficiency of ornithine delta-aminotransferase (OAT; L-ornithine: 2-oxo-acid aminotransferase; EC 2.6.1.13). GA is one of the "Finnish genetic diseases," a group of several rare monogenic disorders that occur with increased frequency in the Finnish population. Using a combination of RNase A protection, genomic cloning, and polymerase chain reaction amplification of genomic DNA, we found one of two missense mutant OAT alleles to be present in each of 16 Finnish GA pedigrees. The first mutation R180T, in which arginine-180 is replaced by threonine, was present in homozygous form in patients from two pedigrees. The second mutation L402P, in which leucine-402 is replaced by proline, was present in homozygous form in patients from 14 pedigrees. Neither mutation was present in 19 Finnish controls. L402P was not present in 18 non-Finnish GA patients but R180T was found in an American GA patient. We constructed full-length mutant cDNAs by amplifying patient cDNA with the polymerase chain reaction and cloning a restriction fragment containing the mutation into an otherwise normal human OAT cDNA. These mutant cDNAs were then expressed in CHO-K1 cells, which lack endogenous OAT. Both R180T and L402P inactivate OAT. These results show molecular heterogeneity in GA alleles even in the Finnish population. PMID:2492100

  2. HLA DRB1/DQB1 alleles and DRB1-DQB1 haplotypes and the risk of rheumatoid arthritis in Tunisians: a population-based case-control study.

    PubMed

    Lagha, A; Messadi, A; Boussaidi, S; Kochbati, S; Tazeghdenti, A; Ghazouani, E; Almawi, W Y; Yacoubi-Loueslati, B

    2016-09-01

    Rheumatoid arthritis (RA) is an inflammatory disease, which affects synovial joints, and is influenced by environmental and genetic factors, in particular the human leucocyte antigen (HLA) system. In our study, we investigated the association of HLA class II DRB1 and DQB1 alleles and DRB1-DQB1 haplotypes with RA susceptibility in Tunisian subjects. Therefore, HLA class II low-resolution genotyping was done in 110 RA patients and 116 controls, with a HLA-DRB1*04 high-resolution typing. Our results showed a strong association between HLA-DRB1*04/DRB1*04:05 alleles and RA presence, which persisted after correcting for multiple comparisons (Pc < 10-3, Pc = 0.020, respectively), in contrast to the protective effect of HLA-DRB1*04:03 allele (Pc = 15.2 × 10-4). However, increased frequency of DQB1*05 (Pc = 0.020) and decreased frequency of DRB1*04:03 subtype (Pc = 0.032) were seen in RF+ patients than controls. Moreover, when RA patients were compared to controls, DRB1*04-DQB1*03 haplotype was associated with RA susceptibility in Tunisians (Pc = 16.8 × 10-5), independently of RF status. Conversely, DRB1*01 allele and DRB1*01-DQB1*05 haplotype was highly present in RF+ vs RF- groups (Pc < 10-3, Pc = 5.6 × 10-3, respectively) and seems to be linked to seropositivity. Investigation of HLA class II alleles and haplotypes association with RA susceptibility with secondary Sjögren's syndrome (sSS) showed a predisposing effect of DRB1*04 (Pc < 10-3) and DRB1*04-DQB1*03 haplotype when RA with sSS/without sSS groups were compared to healthy controls. Our results confirms the association of HLA-DRB1*04, specifically HLA-DRB1*04:05 subtype, and DRB1*04-DQB1*03 haplotype with RA susceptibility in Tunisians, independently of seropositivity or the sSS presence. PMID:27580864

  3. Allele-Specific Deletions in Mouse Tumors Identify Fbxw7 as Germline Modifier of Tumor Susceptibility

    PubMed Central

    Perez-Losada, Jesus; Wu, Di; DelRosario, Reyno; Balmain, Allan; Mao, Jian-Hua

    2012-01-01

    Genome-wide association studies (GWAS) have been successful in finding associations between specific genetic variants and cancer susceptibility in human populations. These studies have identified a range of highly statistically significant associations between single nucleotide polymorphisms (SNPs) and susceptibility to development of a range of human tumors. However, the effect of each SNP in isolation is very small, and all of the SNPs combined only account for a relatively minor proportion of the total genetic risk (5–10%). There is therefore a major requirement for alternative routes to the discovery of genetic risk factors for cancer. We have previously shown using mouse models that chromosomal regions harboring susceptibility genes identified by linkage analysis frequently exhibit allele-specific genetic alterations in tumors. We demonstrate here that the Fbxw7 gene, a commonly mutated gene in a wide range of mouse and human cancers, shows allele-specific deletions in mouse lymphomas and skin tumors. Lymphomas from three different F1 hybrids show 100% allele-specificity in the patterns of allelic loss. Parental alleles from 129/Sv or Spretus/Gla mice are lost in tumors from F1 hybrids with C57BL/6 animals, due to the presence of a specific non-synonymous coding sequence polymorphism at the N-terminal portion of the gene. A specific genetic test of association between this SNP and lymphoma susceptibility in interspecific backcross mice showed a significant linkage (p = 0.001), but only in animals with a functional p53 gene. These