Dosage Transmission Disequilibrium Test (dTDT) for Linkage and Association Detection

PubMed Central

Zhang, Zhehao; Wang, Jen-Chyong; Howells, William; Lin, Peng; Agrawal, Arpana; Edenberg, Howard J.; Tischfield, Jay A.; Schuckit, Marc A.; Bierut, Laura J.; Goate, Alison; Rice, John P.

2013-01-01

Both linkage and association studies have been successfully applied to identify disease susceptibility genes with genetic markers such as microsatellites and Single Nucleotide Polymorphisms (SNPs). As one of the traditional family-based studies, the Transmission/Disequilibrium Test (TDT) measures the over-transmission of an allele in a trio from its heterozygous parents to the affected offspring and can be potentially useful to identify genetic determinants for complex disorders. However, there is reduced information when complete trio information is unavailable. In this study, we developed a novel approach to “infer” the transmission of SNPs by combining both the linkage and association data, which uses microsatellite markers from families informative for linkage together with SNP markers from the offspring who are genotyped for both linkage and a Genome-Wide Association Study (GWAS). We generalized the traditional TDT to process these inferred dosage probabilities, which we name as the dosage-TDT (dTDT). For evaluation purpose, we developed a simulation procedure to assess its operating characteristics. We applied the dTDT to the simulated data and documented the power of the dTDT under a number of different realistic scenarios. Finally, we applied our methods to a family study of alcohol dependence (COGA) and performed individual genotyping on complete families for the top signals. One SNP (rs4903712 on chromosome 14) remained significant after correcting for multiple testing Methods developed in this study can be adapted to other platforms and will have widespread applicability in genomic research when case-control GWAS data are collected in families with existing linkage data. PMID:23691058

Linkage disequilibrium interval mapping of quantitative trait loci.

PubMed

Boitard, Simon; Abdallah, Jihad; de Rochambeau, Hubert; Cierco-Ayrolles, Christine; Mangin, Brigitte

2006-03-16

For many years gene mapping studies have been performed through linkage analyses based on pedigree data. Recently, linkage disequilibrium methods based on unrelated individuals have been advocated as powerful tools to refine estimates of gene location. Many strategies have been proposed to deal with simply inherited disease traits. However, locating quantitative trait loci is statistically more challenging and considerable research is needed to provide robust and computationally efficient methods. Under a three-locus Wright-Fisher model, we derived approximate expressions for the expected haplotype frequencies in a population. We considered haplotypes comprising one trait locus and two flanking markers. Using these theoretical expressions, we built a likelihood-maximization method, called HAPim, for estimating the location of a quantitative trait locus. For each postulated position, the method only requires information from the two flanking markers. Over a wide range of simulation scenarios it was found to be more accurate than a two-marker composite likelihood method. It also performed as well as identity by descent methods, whilst being valuable in a wider range of populations. Our method makes efficient use of marker information, and can be valuable for fine mapping purposes. Its performance is increased if multiallelic markers are available. Several improvements can be developed to account for more complex evolution scenarios or provide robust confidence intervals for the location estimates.

Mapping by admixture linkage disequilibrium in human populations: Limits and guidelines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stephens, J.C.; Briscoe, D.; O`Brien, S.J.

1994-10-01

Certain human hereditary conditions, notably those with low penetrance and those which require an environmental event such as infectious disease exposure, are difficult to localize in pedigree analysis, because of uncertainty in the phenotype of an affected patient`s relatives. An approach to locating these genes in human cohort studies would be to use association analysis, which depends on linkage disequilibrium of flanking polymorphic DNA markers. In theory, a high degree of linkage disequilibrium between genes separated by 10-20 cM will be generated and persist in populations that have a history of recent (3-20 generations ago) admixture between genetically differentiated racialmore » groups, such as has occurred in African Americans and Hispanic populations. We have conducted analytic and computer simulations to quantify the effect of genetic, genomic, and population parameters that affect the amount and ascertainment of linkage disequilibrium in populations with a history of genetic admixture. Our goal is to thoroughly explore the ranges of all relevant parameters or factors (e.g., sample size and degree of genetic differentiation between populations) that may be involved in gene localization studies, in hopes of prescribing guidelines for an efficient mapping strategy. The results provide reasonable limits on sample size (200-300 patients), marker number (200-300 in 20-cM intervals), and allele differentiation (loci with allele frequency difference of {ge}.3 between admixed parent populations) to produce an efficient approach (>95% ascertainment) for locating genes not easily tracked in human pedigrees. 321 refs., 8 figs., 7 tabs.« less

[Analysis of HLA haplotype frequency and linkage disequilibrium in patients with acute lymphoblastic leukemia from Northern Chinese Han].

PubMed

Gao, Su-qing; Cheng, Liang-hong; Lu, Liang; Jing, Shi-zheng; Cheng, Xi; Zhang, Yin-ze; Zou, Hong-yan; Deng, Zhi-hui

2009-02-01

To analyze the difference between the frequencies of HLA-A-B, B-DRB1 and A-B-DRB1 haplotype, as well as their linkage disequilibrium pattern in patients with acute lymphoblastic leukemia(ALL) and healthy controls from Northern Chinese Han. The frequencies of HLA-A-B, B-DRB1, A-B-DR haplotypes and linkage disequilibrium were estimated by Expectation Maximization method based on the genotypes of 643 patients with ALL and 2 0359 unrelated healthy donors, and the statistical significance between the two groups were estimated by chi-square test. Linkage disequilibrium was analyzed with population genetic methods. The most common HLA-A-B, B-DRB1, and A-B-DR haplotypes were A30-B13, A2-B46, A33-B58, B13-DR7, B46-DR9, B52-DR15, B58-DR17, A30-B13-DR7, A33-B58-DR17 and A1-B37-DR10 in both groups. The frequencies of A30-B13, A2-B46, A33-B44, B13-DR7, A30-B13-DR7 and A2-B46-DR9 haplotypes and linkage disequilibrium value were significantly decreased (P<0.05) in the patient group than that in the control group. On the other hand, the frequencies of A2-B52, A31-B61, A24- B8, B60-DR9, B27-DR4, B52-DR14, B44-DR17, B27-DR12 and A11-B27-DR12 haplotypes and linkage disequilibrium value were significantly increased (P<0.05) in the patient group than that in the control group. There are some common and positive linkage disequilibrium haplotypes in both the ALL patients and the healthy donors in Northern Chinese Han. Interestingly, some haplotypes and their linkage disequilibrium patterns had significantly different distributions between the two groups. The study provided basic data for the relationship of ALL and HLA haplotype and for finding the HLA-A, B, DR matching donors.

Inferring outcrossing in the homothallic fungus Sclerotinia sclerotiorum using linkage disequilibrium decay

USDA-ARS?s Scientific Manuscript database

The occurrence and frequency of outcrossing in homothallic fungal species in nature is an unresolved question. Here we report detection of frequent outcrossing in the homothallic fungus Sclerotinia sclerotiorum. In using multilocus linkage disequilibrium (LD) to infer recombination among microsatell...

Significant linkage disequilibrium between the Huntington disease gene and the loci D4S10 and D4S95 in the Dutch population

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skraastad, M.I.; Van de Vosse, E.; Belfroid, R.

1992-10-01

Significant linkage disequilibrium has been found between the Huntington disease (HD) gene and DNA markers located around D4S95 and D4S98. The linkage-disequilibrium studies favor the proximal location of the HD gene, in contrast to the conflicting results of recombination analyses. The authors have analyzed 45 Dutch HD families with 19 DNA markers and have calculated the strength of linkage disequilibrium. Highly significant linkage disequilibrium has been detected with D4S95, consistent with the studies in other populations. In contrast with most other studies, however, the area of linkage disequilibrium extends from D4S10 proximally to D4S95, covering 1,100 kb. These results confirmmore » that the HD gene most likely maps near D4S95. 28 refs., 1 fig., 2 tabs.« less

MICA diversity and linkage disequilibrium with HLA-B alleles in renal-transplant candidates in southern Brazil.

PubMed

Yamakawa, Roger Haruki; Saito, Patrícia Keiko; Gelmini, Geórgia Fernanda; da Silva, José Samuel; Bicalho, Maria da Graça; Borelli, Sueli Donizete

2017-01-01

The major histocompatibility complex (MHC) class I chain-related gene A (MICA) is located centromerically to the human leukocyte antigen (HLA)-B. The short distance between these loci in the MHC indicates the presence of linkage disequilibrium (LD). Similarly to the HLA, the MICA is highly polymorphic, and this polymorphism has not been well documented in different populations. In this study, we estimated the allelic frequencies of MICA and the linkage disequilibrium with HLA-B alleles in 346 renal-transplant candidates in southern Brazil. MICA and HLA were typed using the polymerase chain reaction-sequence-specific primer method (PCR-SSO), combined with the Luminex technology. A total of 19 MICA allele groups were identified. The most frequent allele groups were MICA*008 (21.6%), MICA*002 (17.0%) and MICA*004 (14.8%). The most common haplotypes were MICA*009-B*51 (7.8%), MICA*004-B*44 (6.06%) and MICA*002-B*35 (5.63%). As expected from the proximity of the MICA and HLA-B loci, most haplotypes showed strong LD. Renal patients and healthy subjects in the same region of Brazil showed statistically significant differences in their MICA polymorphisms. The MICA*027 allele group was more frequent in renal patients (Pc = 0.018, OR: 3.421, 95% CI: 1.516-7.722), while the MICA*019 allele group was more frequent in healthy subjects (Pc = 0.001, OR: 0.027, 95% CI: 0.002-0.469). This study provided information on the distribution of MICA polymorphisms and linkage disequilibrium with HLA-B alleles in Brazilian renal-transplant candidates. This information should help to determine the mechanisms of susceptibility to different diseases in patients with chronic kidney disease, and to elucidate the mechanisms involved in allograft rejection associated with MICA polymorphisms in a Brazilian population.

MIDAS: software for analysis and visualisation of interallelic disequilibrium between multiallelic markers

PubMed Central

Gaunt, Tom R; Rodriguez, Santiago; Zapata, Carlos; Day, Ian NM

2006-01-01

Background Various software tools are available for the display of pairwise linkage disequilibrium across multiple single nucleotide polymorphisms. The HapMap project also presents these graphics within their website. However, these approaches are limited in their use of data from multiallelic markers and provide limited information in a graphical form. Results We have developed a software package (MIDAS – Multiallelic Interallelic Disequilibrium Analysis Software) for the estimation and graphical display of interallelic linkage disequilibrium. Linkage disequilibrium is analysed for each allelic combination (of one allele from each of two loci), between all pairwise combinations of any type of multiallelic loci in a contig (or any set) of many loci (including single nucleotide polymorphisms, microsatellites, minisatellites and haplotypes). Data are presented graphically in a novel and informative way, and can also be exported in tabular form for other analyses. This approach facilitates visualisation of patterns of linkage disequilibrium across genomic regions, analysis of the relationships between different alleles of multiallelic markers and inferences about patterns of evolution and selection. Conclusion MIDAS is a linkage disequilibrium analysis program with a comprehensive graphical user interface providing novel views of patterns of linkage disequilibrium between all types of multiallelic and biallelic markers. Availability Available from and PMID:16643648

Linkage disequilibrium at the SCA2 locus

PubMed Central

Didierjean, O.; Cancel, G.; Stevanin, G.; Durr, A.; Burk, K.; Benomar, A.; Lezin, A.; Belal, S.; Abada-Bendid, M.; Klockgether, T.; Brice, A.

1999-01-01

Spinocerebellar ataxia type 2 (SCA2) is caused by the expansion of an unstable CAG repeat encoding a polyglutamine tract. Repeats with 32 to 200 CAGs are associated with the disease, whereas normal chromosomes contain 13 to 33 repeats. We tested 220 families of different geographical origins for the SCA2 mutation. Thirty three were positive (15%). Twenty three families with at least two affected subjects were tested for linkage disequilibium (LD) between the SCA2 mutation and three microsatellite markers, two of which (D12S1332-D12S1333) closely flanked the mutation; the other (D12S1672) was intragenic. Many different haplotypes were observed, indicating the occurrence of several ancestral mutations. However, the same haplotype, not observed in controls, was detected in the German, the Serbian, and some of the French families, suggesting a founder effect or recurrent mutations on an at risk haplotype.


Keywords: linkage disequilibrium; SCA2; trinucleotide repeat expansion; founder effect PMID:10353790

Effects of Demographic History on the Detection of Recombination Hotspots from Linkage Disequilibrium

PubMed Central

Dapper, Amy L; Payseur, Bret A

2018-01-01

Abstract In some species, meiotic recombination is concentrated in small genomic regions. These “recombination hotspots” leave signatures in fine-scale patterns of linkage disequilibrium, raising the prospect that the genomic landscape of hotspots can be characterized from sequence variation. This approach has led to the inference that hotspots evolve rapidly in some species, but are conserved in others. Historic demographic events, such as population bottlenecks, are known to affect patterns of linkage disequilibrium across the genome, violating population genetic assumptions of this approach. Although such events are prevalent, demographic history is generally ignored when making inferences about the evolution of recombination hotspots. To determine the effect of demography on the detection of recombination hotspots, we use the coalescent to simulate haplotypes with a known recombination landscape. We measure the ability of popular linkage disequilibrium-based programs to detect hotspots across a range of demographic histories, including population bottlenecks, hidden population structure, population expansions, and population contractions. We find that demographic events have the potential to greatly reduce the power and increase the false positive rate of hotspot discovery. Neither the power nor the false positive rate of hotspot detection can be predicted without also knowing the demographic history of the sample. Our results suggest that ignoring demographic history likely overestimates the power to detect hotspots and therefore underestimates the degree of hotspot sharing between species. We suggest strategies for incorporating demographic history into population genetic inferences about recombination hotspots. PMID:29045724

Assessing microsatellite linkage disequilibrium in wild, cultivated, and mapping populations of Theobroma cacao L and its impact on association mapping

USDA-ARS?s Scientific Manuscript database

Linkage disequilibrium (LD) is the nonrandom association of alleles and loci within sets of genetic data and when measured over the genomes of a species can provide important indications for how future association analyses should proceed. This information can be advantageous especially for slow-gro...

Effects of Demographic History on the Detection of Recombination Hotspots from Linkage Disequilibrium.

PubMed

Dapper, Amy L; Payseur, Bret A

2018-02-01

In some species, meiotic recombination is concentrated in small genomic regions. These "recombination hotspots" leave signatures in fine-scale patterns of linkage disequilibrium, raising the prospect that the genomic landscape of hotspots can be characterized from sequence variation. This approach has led to the inference that hotspots evolve rapidly in some species, but are conserved in others. Historic demographic events, such as population bottlenecks, are known to affect patterns of linkage disequilibrium across the genome, violating population genetic assumptions of this approach. Although such events are prevalent, demographic history is generally ignored when making inferences about the evolution of recombination hotspots. To determine the effect of demography on the detection of recombination hotspots, we use the coalescent to simulate haplotypes with a known recombination landscape. We measure the ability of popular linkage disequilibrium-based programs to detect hotspots across a range of demographic histories, including population bottlenecks, hidden population structure, population expansions, and population contractions. We find that demographic events have the potential to greatly reduce the power and increase the false positive rate of hotspot discovery. Neither the power nor the false positive rate of hotspot detection can be predicted without also knowing the demographic history of the sample. Our results suggest that ignoring demographic history likely overestimates the power to detect hotspots and therefore underestimates the degree of hotspot sharing between species. We suggest strategies for incorporating demographic history into population genetic inferences about recombination hotspots. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Extended Intermarker Linkage Disequilibrium in the Afrikaners

PubMed Central

Hall, Diana; Wijsman, Ellen M.; Roos, J. Louw; Gogos, Joseph A.; Karayiorgou, Maria

2002-01-01

In this study we conducted an investigation of the background level of linkage disequilibrium (LD) in the Afrikaner population to evaluate the appropriateness of this genetic isolate for mapping complex traits. We analyzed intermarker LD in 62 nuclear families using microsatellite markers covering extended chromosomal regions. The markers were selected to allow the first direct comparison of long-range LD in the Afrikaners to LD in other demographic groups. Using several statistical measures, we find significant evidence for LD in the Afrikaners extending remarkably over a 6-cM range. In contrast, LD decays significantly beyond 3-cM distances in the other founder and outbred populations examined. This study strongly supports the appropriateness of the Afrikaner population for genome-wide scans that exploit LD to map common, multigenic disorders. PMID:12045148

Extended intermarker linkage disequilibrium in the Afrikaners.

PubMed

Hall, Diana; Wijsman, Ellen M; Roos, J Louw; Gogos, Joseph A; Karayiorgou, Maria

2002-06-01

In this study we conducted an investigation of the background level of linkage disequilibrium (LD) in the Afrikaner population to evaluate the appropriateness of this genetic isolate for mapping complex traits. We analyzed intermarker LD in 62 nuclear families using microsatellite markers covering extended chromosomal regions. The markers were selected to allow the first direct comparison of long-range LD in the Afrikaners to LD in other demographic groups. Using several statistical measures, we find significant evidence for LD in the Afrikaners extending remarkably over a 6-cM range. In contrast, LD decays significantly beyond 3-cM distances in the other founder and outbred populations examined. This study strongly supports the appropriateness of the Afrikaner population for genome-wide scans that exploit LD to map common, multigenic disorders.

Revealing misassembled segments in the bovine reference genome by high resolution linkage disequilibrium scan

USDA-ARS?s Scientific Manuscript database

Misassembly signatures, created by shuffling the order of sequences while assembling a genome, can be easily seen by analyzing the unexpected behaviour of the linkage disequilibrium (LD) decay. A heuristic process was proposed to identify those misassembly signatures and presented the ones found in ...

Genome-wide distribution of genetic diversity and linkage disequilibrium in a mass-selected population of maritime pine

PubMed Central

2014-01-01

Background The accessibility of high-throughput genotyping technologies has contributed greatly to the development of genomic resources in non-model organisms. High-density genotyping arrays have only recently been developed for some economically important species such as conifers. The potential for using genomic technologies in association mapping and breeding depends largely on the genome wide patterns of diversity and linkage disequilibrium in current breeding populations. This study aims to deepen our knowledge regarding these issues in maritime pine, the first species used for reforestation in south western Europe. Results Using a new map merging algorithm, we first established a 1,712 cM composite linkage map (comprising 1,838 SNP markers in 12 linkage groups) by bringing together three already available genetic maps. Using rigorous statistical testing based on kernel density estimation and resampling we identified cold and hot spots of recombination. In parallel, 186 unrelated trees of a mass-selected population were genotyped using a 12k-SNP array. A total of 2,600 informative SNPs allowed to describe historical recombination, genetic diversity and genetic structure of this recently domesticated breeding pool that forms the basis of much of the current and future breeding of this species. We observe very low levels of population genetic structure and find no evidence that artificial selection has caused a reduction in genetic diversity. By combining these two pieces of information, we provided the map position of 1,671 SNPs corresponding to 1,192 different loci. This made it possible to analyze the spatial pattern of genetic diversity (H e ) and long distance linkage disequilibrium (LD) along the chromosomes. We found no particular pattern in the empirical variogram of H e across the 12 linkage groups and, as expected for an outcrossing species with large effective population size, we observed an almost complete lack of long distance LD. Conclusions These

Population-Specific Patterns of Linkage Disequilibrium and SNP Variation in Spring and Winter Polyploid Wheat

USDA-ARS?s Scientific Manuscript database

Single nucleotide polymorphisms (SNPs) are ideally suited for the construction of high-resolution genetic maps, studying population evolutionary history and performing genome-wide association mapping experiments. Here we used a genome-wide set of 1536 SNPs to study linkage disequilibrium (LD) and po...

A first insight into population structure and linkage disequilibrium in the US peanut minicore collection

USDA-ARS?s Scientific Manuscript database

Knowledge of genetic diversity, population structure, and degree of linkage disequilibrium (LD) in target association mapping populations is of great importance and is a prerequisite for LD-based mapping. In the present study, 96 genotypes comprising 92 accessions of the US peanut minicore collectio...

Potential linkage disequilibrium between schizophrenia and locus D22S278 on the long arm of chromosome 22

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moises, H.W.; Yang, L.; Havsteen, B.

Locus D22S278 at 22q12 has been implicated in schizophrenia by sib-pair analysis. In order to replicate these results, we performed the transmission test for linkage disequilibrium (TDT) in 113 unrelated schizophrenic patients and their 226 parents. Evidence for potential linkage disequilibrium was obtained between schizophrenia and allele 243 of the marker AFM 182xd12 at the locus D22S278 (P = 0.02). The results of our study suggest a detectable oligogenic gene in a multigene system for schizophrenia closely linked to D22S278 on the long arm of chromosome 22. If confirmed by others, this finding could lead to the identification of amore » schizophrenia susceptibility gene. 12 refs., 1 tab.« less

Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yaouanq, J.; Perichon, M.; Treut, A.L.

1994-02-01

The hemochromatosis gene (HFE) maps to 6p21.3 and is less than 1 cM from the HLA class I gene; however, the precise physical location of the gene has remained elusive and controversial. The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex- and age-related penetrance of the disease. For these considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE. The authors therefore embarked upon a linkage-disequilibrium analysis of HFE and normalmore » chromosomes for the Brittany population. In this report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6.7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively. The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6.7 interval (approximately 250 kb). The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE. These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F. Alternatively, the very tight association of HLA-A3 and allele 1 of the 6.7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6.7 locus within the linkage-disequilibrium zone. Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele. 69 refs., 1 fig., 5

Genomewide Linkage Disequilibrium Mapping of Severe Bipolar Disorder in a Population Isolate

PubMed Central

Ophoff, Roel A.; Escamilla, Michael A.; Service, Susan K.; Spesny, Mitzi; Meshi, Dar B.; Poon, Wingman; Molina, Julio; Fournier, Eduardo; Gallegos, Alvaro; Mathews, Carol; Neylan, Thomas; Batki, Steven L.; Roche, Erin; Ramirez, Margarita; Silva, Sandra; De Mille, Melissa C.; Dong, Penny; Leon, Pedro E.; Reus, Victor I.; Sandkuijl, Lodewijk A.; Freimer, Nelson B.

2002-01-01

Genomewide association studies may offer the best promise for genetic mapping of complex traits. Such studies in outbred populations require very densely spaced single-nucleotide polymorphisms. In recently founded population isolates, however, extensive linkage disequilibrium (LD) may make these studies feasible with currently available sets of short tandem repeat markers, spaced at intervals as large as a few centimorgans. We report the results of a genomewide association study of severe bipolar disorder (BP-I), using patients from the isolated population of the central valley of Costa Rica. We observed LD with BP-I on several chromosomes; the most striking results were in proximal 8p, a region that has previously shown linkage to schizophrenia. This region could be important for severe psychiatric disorders, rather than for a specific phenotype. PMID:12119601

Genomic polymorphism, recombination, and linkage disequilibrium in human major histocompatibility complex-encoded antigen-processing genes.

PubMed Central

van Endert, P M; Lopez, M T; Patel, S D; Monaco, J J; McDevitt, H O

1992-01-01

Recently, two subunits of a large cytosolic protease and two putative peptide transporter proteins were found to be encoded by genes within the class II region of the major histocompatibility complex (MHC). These genes have been suggested to be involved in the processing of antigenic proteins for presentation by MHC class I molecules. Because of the high degree of polymorphism in MHC genes, and previous evidence for both functional and polypeptide sequence polymorphism in the proteins encoded by the antigen-processing genes, we tested DNA from 27 consanguineous human cell lines for genomic polymorphism by restriction fragment length polymorphism (RFLP) analysis. These studies demonstrate a strong linkage disequilibrium between TAP1 and LMP2 RFLPs. Moreover, RFLPs, as well as a polymorphic stop codon in the telomeric TAP2 gene, appear to be in linkage disequilibrium with HLA-DR alleles and RFLPs in the HLA-DO gene. A high rate of recombination, however, seems to occur in the center of the complex, between the TAP1 and TAP2 genes. Images PMID:1360671

Uneven recombination and linkage disequilibrium across a reference SNP map for common bean (Phaseolus vulgaris L.)

USDA-ARS?s Scientific Manuscript database

Linkage disequilibrium (LD) and recombination (R) analyses are the basis for plant breeding. LD and R vary by breeding system, by generation of inbreeding or outcrossing and by region of the chromosome. Common bean (Phaseolus vulgaris L.) is a favored food legume with a small sequenced genome and n=...

The effect of missing data on linkage disequilibrium mapping and haplotype association analysis in the GAW14 simulated datasets

PubMed Central

McCaskie, Pamela A; Carter, Kim W; McCaskie, Simon R; Palmer, Lyle J

2005-01-01

We used our newly developed linkage disequilibrium (LD) plotting software, JLIN, to plot linkage disequilibrium between pairs of single-nucleotide polymorphisms (SNPs) for three chromosomes of the Genetic Analysis Workshop 14 Aipotu simulated population to assess the effect of missing data on LD calculations. Our haplotype analysis program, SIMHAP, was used to assess the effect of missing data on haplotype-phenotype association. Genotype data was removed at random, at levels of 1%, 5%, and 10%, and the LD calculations and haplotype association results for these levels of missingness were compared to those for the complete dataset. It was concluded that ignoring individuals with missing data substantially affects the number of regions of LD detected which, in turn, could affect tagging SNPs chosen to generate haplotypes. PMID:16451612

Linkage disequilibrium network analysis (LDna) gives a global view of chromosomal inversions, local adaptation and geographic structure.

PubMed

Kemppainen, Petri; Knight, Christopher G; Sarma, Devojit K; Hlaing, Thaung; Prakash, Anil; Maung Maung, Yan Naung; Somboon, Pradya; Mahanta, Jagadish; Walton, Catherine

2015-09-01

Recent advances in sequencing allow population-genomic data to be generated for virtually any species. However, approaches to analyse such data lag behind the ability to generate it, particularly in nonmodel species. Linkage disequilibrium (LD, the nonrandom association of alleles from different loci) is a highly sensitive indicator of many evolutionary phenomena including chromosomal inversions, local adaptation and geographical structure. Here, we present linkage disequilibrium network analysis (LDna), which accesses information on LD shared between multiple loci genomewide. In LD networks, vertices represent loci, and connections between vertices represent the LD between them. We analysed such networks in two test cases: a new restriction-site-associated DNA sequence (RAD-seq) data set for Anopheles baimaii, a Southeast Asian malaria vector; and a well-characterized single nucleotide polymorphism (SNP) data set from 21 three-spined stickleback individuals. In each case, we readily identified five distinct LD network clusters (single-outlier clusters, SOCs), each comprising many loci connected by high LD. In A. baimaii, further population-genetic analyses supported the inference that each SOC corresponds to a large inversion, consistent with previous cytological studies. For sticklebacks, we inferred that each SOC was associated with a distinct evolutionary phenomenon: two chromosomal inversions, local adaptation, population-demographic history and geographic structure. LDna is thus a useful exploratory tool, able to give a global overview of LD associated with diverse evolutionary phenomena and identify loci potentially involved. LDna does not require a linkage map or reference genome, so it is applicable to any population-genomic data set, making it especially valuable for nonmodel species. © 2015 The Authors. Molecular Ecology Resources Published by John Wiley & Sons Ltd.

Linkage disequilibrium between STRPs and SNPs across the human genome.

PubMed

Payseur, Bret A; Place, Michael; Weber, James L

2008-05-01

Patterns of linkage disequilibrium (LD) reveal the action of evolutionary processes and provide crucial information for association mapping of disease genes. Although recent studies have described the landscape of LD among single nucleotide polymorphisms (SNPs) from across the human genome, associations involving other classes of molecular variation remain poorly understood. In addition to recombination and population history, mutation rate and process are expected to shape LD. To test this idea, we measured associations between short-tandem-repeat polymorphisms (STRPs), which can mutate rapidly and recurrently, and SNPs in 721 regions across the human genome. We directly compared STRP-SNP LD with SNP-SNP LD from the same genomic regions in the human HapMap populations. The intensity of STRP-SNP LD, measured by the average of D', was reduced, consistent with the action of recurrent mutation. Nevertheless, a higher fraction of STRP-SNP pairs than SNP-SNP pairs showed significant LD, on both short (up to 50 kb) and long (cM) scales. These results reveal the substantial effects of mutational processes on LD at STRPs and provide important measures of the potential of STRPs for association mapping of disease genes.

A general model for likelihood computations of genetic marker data accounting for linkage, linkage disequilibrium, and mutations.

PubMed

Kling, Daniel; Tillmar, Andreas; Egeland, Thore; Mostad, Petter

2015-09-01

Several applications necessitate an unbiased determination of relatedness, be it in linkage or association studies or in a forensic setting. An appropriate model to compute the joint probability of some genetic data for a set of persons given some hypothesis about the pedigree structure is then required. The increasing number of markers available through high-density SNP microarray typing and NGS technologies intensifies the demand, where using a large number of markers may lead to biased results due to strong dependencies between closely located loci, both within pedigrees (linkage) and in the population (allelic association or linkage disequilibrium (LD)). We present a new general model, based on a Markov chain for inheritance patterns and another Markov chain for founder allele patterns, the latter allowing us to account for LD. We also demonstrate a specific implementation for X chromosomal markers that allows for computation of likelihoods based on hypotheses of alleged relationships and genetic marker data. The algorithm can simultaneously account for linkage, LD, and mutations. We demonstrate its feasibility using simulated examples. The algorithm is implemented in the software FamLinkX, providing a user-friendly GUI for Windows systems (FamLinkX, as well as further usage instructions, is freely available at www.famlink.se ). Our software provides the necessary means to solve cases where no previous implementation exists. In addition, the software has the possibility to perform simulations in order to further study the impact of linkage and LD on computed likelihoods for an arbitrary set of markers.

Genetic diversity, linkage disequilibrium, population structure and construction of a core collection of Prunus avium L. landraces and bred cultivars.

PubMed

Campoy, José Antonio; Lerigoleur-Balsemin, Emilie; Christmann, Hélène; Beauvieux, Rémi; Girollet, Nabil; Quero-García, José; Dirlewanger, Elisabeth; Barreneche, Teresa

2016-02-24

Depiction of the genetic diversity, linkage disequilibrium (LD) and population structure is essential for the efficient organization and exploitation of genetic resources. The objectives of this study were to (i) to evaluate the genetic diversity and to detect the patterns of LD, (ii) to estimate the levels of population structure and (iii) to identify a 'core collection' suitable for association genetic studies in sweet cherry. A total of 210 genotypes including modern cultivars and landraces from 16 countries were genotyped using the RosBREED cherry 6 K SNP array v1. Two groups, mainly bred cultivars and landraces, respectively, were first detected using STRUCTURE software and confirmed by Principal Coordinate Analysis (PCoA). Further analyses identified nine subgroups using STRUCTURE and Discriminant Analysis of Principal Components (DAPC). Several sub-groups correspond to different eco-geographic regions of landraces distribution. Linkage disequilibrium was evaluated showing lower values than in peach, the reference Prunus species. A 'core collection' containing 156 accessions was selected using the maximum length sub tree method. The present study constitutes the first population genetics analysis in cultivated sweet cherry using a medium-density SNP (single nucleotide polymorphism) marker array. We provided estimations of linkage disequilibrium, genetic structure and the definition of a first INRA's Sweet Cherry core collection useful for breeding programs, germplasm management and association genetics studies.

Assessing signatures of selection through variation in linkage disequilibrium between taurine and indicine cattle

PubMed Central

2014-01-01

Background Signatures of selection are regions in the genome that have been preferentially increased in frequency and fixed in a population because of their functional importance in specific processes. These regions can be detected because of their lower genetic variability and specific regional linkage disequilibrium (LD) patterns. Methods By comparing the differences in regional LD variation between dairy and beef cattle types, and between indicine and taurine subspecies, we aim at finding signatures of selection for production and adaptation in cattle breeds. The VarLD method was applied to compare the LD variation in the autosomal genome between breeds, including Angus and Brown Swiss, representing taurine breeds, and Nelore and Gir, representing indicine breeds. Genomic regions containing the top 0.01 and 0.1 percentile of signals were characterized using the UMD3.1 Bos taurus genome assembly to identify genes in those regions and compared with previously reported selection signatures and regions with copy number variation. Results For all comparisons, the top 0.01 and 0.1 percentile included 26 and 165 signals and 17 and 125 genes, respectively, including TECRL, BT.23182 or FPPS, CAST, MYOM1, UVRAG and DNAJA1. Conclusions The VarLD method is a powerful tool to identify differences in linkage disequilibrium between cattle populations and putative signatures of selection with potential adaptive and productive importance. PMID:24592996

Ignoring Intermarker Linkage Disequilibrium Induces False-Positive Evidence of Linkage for Consanguineous Pedigrees when Genotype Data Is Missing for Any Pedigree Member

PubMed Central

Li, Bingshan; Leal, Suzanne M.

2008-01-01

Missing genotype data can increase false-positive evidence for linkage when either parametric or nonparametric analysis is carried out ignoring intermarker linkage disequilibrium (LD). Previously it was demonstrated by Huang et al. [1] that no bias occurs in this situation for affected sib-pairs with unrelated parents when either both parents are genotyped or genotype data is available for two additional unaffected siblings when parental genotypes are missing. However, this is not the case for autosomal recessive consanguineous pedigrees, where missing genotype data for any pedigree member within a consanguinity loop can increase false-positive evidence of linkage. False-positive evidence for linkage is further increased when cryptic consanguinity is present. The amount of false-positive evidence for linkage, and which family members aid in its reduction, is highly dependent on which family members are genotyped. When parental genotype data is available, the false-positive evidence for linkage is usually not as strong as when parental genotype data is unavailable. For a pedigree with an affected proband whose first-cousin parents have been genotyped, further reduction in the false-positive evidence of linkage can be obtained by including genotype data from additional affected siblings of the proband or genotype data from the proband's sibling-grandparents. For the situation, when parental genotypes are unavailable, false-positive evidence for linkage can be reduced by including genotype data from either unaffected siblings of the proband or the proband's married-in-grandparents in the analysis. PMID:18073490

Short Communication Mendelian inheritance, linkage, and genotypic disequilibrium in microsatellite loci of Hymenaea stigonocarpa Mart. ex Hayne (Fabaceae-Caesalpinioideae).

PubMed

Moraes, M A; Kubota, T Y K; Silva, E C B; Silva, A M; Cambuim, J; Moraes, M L T; Furlani Junior, E; Sebbenn, A M

2016-07-29

Hymenaea stigonocarpa is a deciduous and monoecious Neotropical tree species pollinated by bats. Due to overexploitation and habitat destruction, the population size has drastically diminished in nature. No previous study has investigated Mendelian inheritance, linkage, and genotypic disequilibrium in the available microsatellite markers in this species. So, our aim was to estimate these parameters using six microsatellite loci in a sample of 470 adults and 219 juveniles from two populations of H. stigonocarpa. In addition, 30 seeds per tree from 35 seed-trees were collected. Each seed was kept record of the seed-trees and fruit origin. Based on the six microsatellite loci, we found that only 10.6% of the cases showed significant deviations from Mendelian segregation and 15.3% showed linkage. We detected no evidence of genotypic disequilibrium between the loci in the adult trees or juveniles. Thus, our results suggest that these loci can be used with great accuracy in future genetic analyses of H. stigonocarpa populations.

Detecting Recombination Hotspots from Patterns of Linkage Disequilibrium.

PubMed

Wall, Jeffrey D; Stevison, Laurie S

2016-08-09

With recent advances in DNA sequencing technologies, it has become increasingly easy to use whole-genome sequencing of unrelated individuals to assay patterns of linkage disequilibrium (LD) across the genome. One type of analysis that is commonly performed is to estimate local recombination rates and identify recombination hotspots from patterns of LD. One method for detecting recombination hotspots, LDhot, has been used in a handful of species to further our understanding of the basic biology of recombination. For the most part, the effectiveness of this method (e.g., power and false positive rate) is unknown. In this study, we run extensive simulations to compare the effectiveness of three different implementations of LDhot. We find large differences in the power and false positive rates of these different approaches, as well as a strong sensitivity to the window size used (with smaller window sizes leading to more accurate estimation of hotspot locations). We also compared our LDhot simulation results with comparable simulation results obtained from a Bayesian maximum-likelihood approach for identifying hotspots. Surprisingly, we found that the latter computationally intensive approach had substantially lower power over the parameter values considered in our simulations. Copyright © 2016 Wall and Stevison.

Using Object Oriented Bayesian Networks to Model Linkage, Linkage Disequilibrium and Mutations between STR Markers

PubMed Central

Kling, Daniel; Egeland, Thore; Mostad, Petter

2012-01-01

In a number of applications there is a need to determine the most likely pedigree for a group of persons based on genetic markers. Adequate models are needed to reach this goal. The markers used to perform the statistical calculations can be linked and there may also be linkage disequilibrium (LD) in the population. The purpose of this paper is to present a graphical Bayesian Network framework to deal with such data. Potential LD is normally ignored and it is important to verify that the resulting calculations are not biased. Even if linkage does not influence results for regular paternity cases, it may have substantial impact on likelihood ratios involving other, more extended pedigrees. Models for LD influence likelihoods for all pedigrees to some degree and an initial estimate of the impact of ignoring LD and/or linkage is desirable, going beyond mere rules of thumb based on marker distance. Furthermore, we show how one can readily include a mutation model in the Bayesian Network; extending other programs or formulas to include such models may require considerable amounts of work and will in many case not be practical. As an example, we consider the two STR markers vWa and D12S391. We estimate probabilities for population haplotypes to account for LD using a method based on data from trios, while an estimate for the degree of linkage is taken from the literature. The results show that accounting for haplotype frequencies is unnecessary in most cases for this specific pair of markers. When doing calculations on regular paternity cases, the markers can be considered statistically independent. In more complex cases of disputed relatedness, for instance cases involving siblings or so-called deficient cases, or when small differences in the LR matter, independence should not be assumed. (The networks are freely available at http://arken.umb.no/~dakl/BayesianNetworks.) PMID:22984448

Use of linkage disequilibrium approaches to map genes for bipolar disorder in the Costa Rican population

DOE Office of Scientific and Technical Information (OSTI.GOV)

Escamilla, M.A.; Reus, V.I.; Smith, L.B.

1996-05-31

Linkage disequilibrium (LD) analysis provides a powerful means for screening the genome to map the location of disease genes, such as those for bipolar disorder (BP). As described in this paper, the population of the Central Valley of Costa Rica, which is descended from a small number of founders, should be suitable for LD mapping; this assertion is supported by reconstruction of extended haplotypes shared by distantly related individuals in this population suffering low-frequency hearing loss (LFHL1), which has previously been mapped by linkage analysis. A sampling strategy is described for applying LD methods to map genes for BP, andmore » clinical and demographic characteristics of an initially collected sample are discussed. This sample will provide a complement to a previously collected set of Costa Rican BP families which is under investigation using standard linkage analysis. 42 refs., 4 figs., 2 tabs.« less

Linkage disequilibrium in HLA cannot be explained by selective recombination.

PubMed

Termijtelen, A; D'Amaro, J; van Rood, J J; Schreuder, G M

1995-11-01

Some combinations of HLA-A, -B and -DR antigens occur more frequently than would be expected from their gene frequencies in the population. This phenomenon, referred to as Linkage Disequilibrium (LD) has been the origin of many speculations. One hypothesis to explain LD is that some haplotypes are protected from recombination. A second hypothesis is that these HLA antigens preferentially recombine after cross-over to create an LD haplotype. We tested these 2 hypotheses: from a pool of over 10,000 families typed in our department, we analyzed 126 families in which HLA-A:B or B:DR recombinant offspring was documented. To overcome a possible bias in our material, we used the non-recombined haplotypes from the same 126 families as a control group. Our results show that the number of cross-overs through LD haplotypes is not significantly lower then would be expected if recombination occurred randomly. Also the number of LD haplotypes created upon recombination was not significantly increased.

Single nucleotide polymorphisms generated by genotyping by sequencing to characterize genome-wide diversity, linkage disequilibrium, and selective sweeps in cultivated watermelon

USDA-ARS?s Scientific Manuscript database

Large datasets containing single nucleotide polymorphisms (SNPs) are used to analyze genome-wide diversity in a robust collection of cultivars from representative accessions, across the world. The extent of linkage disequilibrium (LD) within a population determines the number of markers required fo...

Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets.

PubMed

Saeed, Mohammad

2017-05-01

Systemic lupus erythematosus (SLE) is a complex disorder. Genetic association studies of complex disorders suffer from the following three major issues: phenotypic heterogeneity, false positive (type I error), and false negative (type II error) results. Hence, genes with low to moderate effects are missed in standard analyses, especially after statistical corrections. OASIS is a novel linkage disequilibrium clustering algorithm that can potentially address false positives and negatives in genome-wide association studies (GWAS) of complex disorders such as SLE. OASIS was applied to two SLE dbGAP GWAS datasets (6077 subjects; ∼0.75 million single-nucleotide polymorphisms). OASIS identified three known SLE genes viz. IFIH1, TNIP1, and CD44, not previously reported using these GWAS datasets. In addition, 22 novel loci for SLE were identified and the 5 SLE genes previously reported using these datasets were verified. OASIS methodology was validated using single-variant replication and gene-based analysis with GATES. This led to the verification of 60% of OASIS loci. New SLE genes that OASIS identified and were further verified include TNFAIP6, DNAJB3, TTF1, GRIN2B, MON2, LATS2, SNX6, RBFOX1, NCOA3, and CHAF1B. This study presents the OASIS algorithm, software, and the meta-analyses of two publicly available SLE GWAS datasets along with the novel SLE genes. Hence, OASIS is a novel linkage disequilibrium clustering method that can be universally applied to existing GWAS datasets for the identification of new genes.

The Power to Detect Linkage Disequilibrium with Quantitative Traits in Selected Samples

PubMed Central

Abecasis, Gonçalo R.; Cookson, William O. C.; Cardon, Lon R.

2001-01-01

Results from power studies for linkage detection have led to many ongoing and planned collections of phenotypically extreme nuclear families. Given the great expense of collecting these families and the imminent availability of a dense diallelic marker map, the families are likely to be used in allelic-association as well as linkage studies. However, optimal selection strategies for linkage may not be equally powerful for association. We examine the power to detect linkage disequilibrium for quantitative traits after phenotypic selection. The results encompass six selection strategies that are in widespread use, including single selection (two designs), affected sib pairs, concordant and discordant pairs, and the extreme-concordant and -discordant design. Selection of sibships on the basis of one extreme proband with high or low trait scores provides as much power as discordant sib pairs but requires the screening and phenotyping of substantially fewer initial families from which to select. Analysis of the role of allele frequencies within each selection design indicates that common trait alleles generally offer the most power, but similarities between the marker- and trait-allele frequencies are much more important than the trait-locus frequency alone. Some of the most widespread selection designs, such as single selection, yield power gains only when both the marker and quantitative trait loci (QTL) are relatively rare in the population. In contrast, discordant pairs and the extreme-proband design provide power for the broadest range of QTL–marker-allele frequency differences. Overall, proband selection from either tail provides the best balance of power, robustness, and simplicity of ascertainment for family-based association analysis. PMID:11349228

Divergence between human populations estimated from linkage disequilibrium.

PubMed

Sved, John A; McRae, Allan F; Visscher, Peter M

2008-12-01

Observed linkage disequilibrium (LD) between genetic markers in different populations descended independently from a common ancestral population can be used to estimate their absolute time of divergence, because the correlation of LD between populations will be reduced each generation by an amount that, approximately, depends only on the recombination rate between markers. Although drift leads to divergence in allele frequencies, it has less effect on divergence in LD values. We derived the relationship between LD and time of divergence and verified it with coalescent simulations. We then used HapMap Phase II data to estimate time of divergence between human populations. Summed over large numbers of pairs of loci, we find a positive correlation of LD between African and non-African populations at levels of up to approximately 0.3 cM. We estimate that the observed correlation of LD is consistent with an effective separation time of approximately 1,000 generations or approximately 25,000 years before present. The most likely explanation for such relatively low separation times is the existence of substantial levels of migration between populations after the initial separation. Theory and results from coalescent simulations confirm that low levels of migration can lead to a downward bias in the estimate of separation time.

LD2SNPing: linkage disequilibrium plotter and RFLP enzyme mining for tag SNPs

PubMed Central

Chang, Hsueh-Wei; Chuang, Li-Yeh; Chang, Yan-Jhu; Cheng, Yu-Huei; Hung, Yu-Chen; Chen, Hsiang-Chi; Yang, Cheng-Hong

2009-01-01

Background Linkage disequilibrium (LD) mapping is commonly used to evaluate markers for genome-wide association studies. Most types of LD software focus strictly on LD analysis and visualization, but lack supporting services for genotyping. Results We developed a freeware called LD2SNPing, which provides a complete package of mining tools for genotyping and LD analysis environments. The software provides SNP ID- and gene-centric online retrievals for SNP information and tag SNP selection from dbSNP/NCBI and HapMap, respectively. Restriction fragment length polymorphism (RFLP) enzyme information for SNP genotype is available to all SNP IDs and tag SNPs. Single and multiple SNP inputs are possible in order to perform LD analysis by online retrieval from HapMap and NCBI. An LD statistics section provides D, D', r2, δQ, ρ, and the P values of the Hardy-Weinberg Equilibrium for each SNP marker, and Chi-square and likelihood-ratio tests for the pair-wise association of two SNPs in LD calculation. Finally, 2D and 3D plots, as well as plain-text output of the results, can be selected. Conclusion LD2SNPing thus provides a novel visualization environment for multiple SNP input, which facilitates SNP association studies. The software, user manual, and tutorial are freely available at . PMID:19500380

Genetic variation, population structure and linkage disequilibrium in Switchgrass with ISSR, SCoT and EST-SSR markers.

PubMed

Zhang, Yu; Yan, Haidong; Jiang, Xiaomei; Wang, Xiaoli; Huang, Linkai; Xu, Bin; Zhang, Xinquan; Zhang, Lexin

2016-01-01

To evaluate genetic variation, population structure, and the extent of linkage disequilibrium (LD), 134 switchgrass ( Panicum virgatum L.) samples were analyzed with 51 markers, including 16 ISSRs, 20 SCoTs, and 15 EST-SSRs. In this study, a high level of genetic variation was observed in the switchgrass samples and they had an average Nei's gene diversity index (H) of 0.311. A total of 793 bands were obtained, of which 708 (89.28 %) were polymorphic. Using a parameter marker index (MI), the efficiency of the three types of markers (ISSR, SCoT, and EST-SSR) in the study were compared and we found that SCoT had a higher marker efficiency than the other two markers. The 134 switchgrass samples could be divided into two sub-populations based on STRUCTURE, UPGMA clustering, and principal coordinate analyses (PCA), and upland and lowland ecotypes could be separated by UPGMA clustering and PCA analyses. Linkage disequilibrium analysis revealed an average r 2 of 0.035 across all 51 markers, indicating a trend of higher LD in sub-population 2 than that in sub-population 1 ( P  < 0.01). The population structure revealed in this study will guide the design of future association studies using these switchgrass samples.

Genetic Structure, Linkage Disequilibrium and Signature of Selection in Sorghum: Lessons from Physically Anchored DArT Markers

PubMed Central

Bouchet, Sophie; Pot, David; Deu, Monique; Rami, Jean-François; Billot, Claire; Perrier, Xavier; Rivallan, Ronan; Gardes, Laëtitia; Xia, Ling; Wenzl, Peter; Kilian, Andrzej; Glaszmann, Jean-Christophe

2012-01-01

Population structure, extent of linkage disequilibrium (LD) as well as signatures of selection were investigated in sorghum using a core sample representative of worldwide diversity. A total of 177 accessions were genotyped with 1122 informative physically anchored DArT markers. The properties of DArTs to describe sorghum genetic structure were compared to those of SSRs and of previously published RFLP markers. Model-based (STRUCTURE software) and Neighbor-Joining diversity analyses led to the identification of 6 groups and confirmed previous evolutionary hypotheses. Results were globally consistent between the different marker systems. However, DArTs appeared more robust in terms of data resolution and bayesian group assignment. Whole genome linkage disequilibrium as measured by mean r2 decreased from 0.18 (between 0 to 10 kb) to 0.03 (between 100 kb to 1 Mb), stabilizing at 0.03 after 1 Mb. Effects on LD estimations of sample size and genetic structure were tested using i. random sampling, ii. the Maximum Length SubTree algorithm (MLST), and iii. structure groups. Optimizing population composition by the MLST reduced the biases in small samples and seemed to be an efficient way of selecting samples to make the best use of LD as a genome mapping approach in structured populations. These results also suggested that more than 100,000 markers may be required to perform genome-wide association studies in collections covering worldwide sorghum diversity. Analysis of DArT markers differentiation between the identified genetic groups pointed out outlier loci potentially linked to genes controlling traits of interest, including disease resistance genes for which evidence of selection had already been reported. In addition, evidence of selection near a homologous locus of FAR1 concurred with sorghum phenotypic diversity for sensitivity to photoperiod. PMID:22428056

Genetic structure, linkage disequilibrium and signature of selection in Sorghum: lessons from physically anchored DArT markers.

PubMed

Bouchet, Sophie; Pot, David; Deu, Monique; Rami, Jean-François; Billot, Claire; Perrier, Xavier; Rivallan, Ronan; Gardes, Laëtitia; Xia, Ling; Wenzl, Peter; Kilian, Andrzej; Glaszmann, Jean-Christophe

2012-01-01

Population structure, extent of linkage disequilibrium (LD) as well as signatures of selection were investigated in sorghum using a core sample representative of worldwide diversity. A total of 177 accessions were genotyped with 1122 informative physically anchored DArT markers. The properties of DArTs to describe sorghum genetic structure were compared to those of SSRs and of previously published RFLP markers. Model-based (STRUCTURE software) and Neighbor-Joining diversity analyses led to the identification of 6 groups and confirmed previous evolutionary hypotheses. Results were globally consistent between the different marker systems. However, DArTs appeared more robust in terms of data resolution and bayesian group assignment. Whole genome linkage disequilibrium as measured by mean r(2) decreased from 0.18 (between 0 to 10 kb) to 0.03 (between 100 kb to 1 Mb), stabilizing at 0.03 after 1 Mb. Effects on LD estimations of sample size and genetic structure were tested using i. random sampling, ii. the Maximum Length SubTree algorithm (MLST), and iii. structure groups. Optimizing population composition by the MLST reduced the biases in small samples and seemed to be an efficient way of selecting samples to make the best use of LD as a genome mapping approach in structured populations. These results also suggested that more than 100,000 markers may be required to perform genome-wide association studies in collections covering worldwide sorghum diversity. Analysis of DArT markers differentiation between the identified genetic groups pointed out outlier loci potentially linked to genes controlling traits of interest, including disease resistance genes for which evidence of selection had already been reported. In addition, evidence of selection near a homologous locus of FAR1 concurred with sorghum phenotypic diversity for sensitivity to photoperiod.

Linkage disequilibrium matches forensic genetic records to disjoint genomic marker sets.

PubMed

Edge, Michael D; Algee-Hewitt, Bridget F B; Pemberton, Trevor J; Li, Jun Z; Rosenberg, Noah A

2017-05-30

Combining genotypes across datasets is central in facilitating advances in genetics. Data aggregation efforts often face the challenge of record matching-the identification of dataset entries that represent the same individual. We show that records can be matched across genotype datasets that have no shared markers based on linkage disequilibrium between loci appearing in different datasets. Using two datasets for the same 872 people-one with 642,563 genome-wide SNPs and the other with 13 short tandem repeats (STRs) used in forensic applications-we find that 90-98% of forensic STR records can be connected to corresponding SNP records and vice versa. Accuracy increases to 99-100% when ∼30 STRs are used. Our method expands the potential of data aggregation, but it also suggests privacy risks intrinsic in maintenance of databases containing even small numbers of markers-including databases of forensic significance.

Mapping the Rust Resistant Loci MXC3 and MER in P. trichocarpa and Assessing the Intermarker Linkage Disequilibrium in MXC3 Region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yin, Tongming; Difazio, Stephen P.; Gunter, Lee E

In an attempt to elucidate the molecular mechanisms of Melampsora rust resistance in Populus trichocarpa, we have mapped two resistance loci, MXC3 and MER, and intensively characterized the flanking genomic sequence for the MXC3 locus and the level of linkage disequilibrium (LD) in natural populations. We used an interspecific backcross pedigree and a genetic map that was highly saturated with AFLP and SSR markers, and assembled shotgun-sequence data in the region containing markers linked to MXC3. The two loci were mapped to different linkage groups. Linkage disequilibrium for MXC3 was confined to two closely linked regions spanning 34 and 16more » kb, respectively. The MXC3 region also contained six disease-resistance candidate genes. The MER and MXC3 loci are clearly distinct, and may have different mechanisms of resistance, as different classes of putative resistance genes were present near each locus. The suppressed recombination previously observed in the MXC3 region was possibly caused by extensive hemizygous rearrangements confined to the original parent tree. The relatively low observed LD may facilitate association studies using candidate genes for rust resistance, but will probably inhibit marker-aided selection.« less

Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes

PubMed Central

Lam, Tze Hau; Tay, Matthew Zirui; Wang, Bei; Xiao, Ziwei; Ren, Ee Chee

2015-01-01

Distinct regions of long-range genetic fixation in the human MHC region, known as conserved extended haplotypes (CEHs), possess unique genomic characteristics and are strongly associated with numerous diseases. While CEHs appear to be homogeneous by SNP analysis, the nature of fine variations within their genomic structure is unknown. Using multiple, MHC-homozygous cell lines, we demonstrate extensive sequence conservation in two common Asian MHC haplotypes: A33-B58-DR3 and A2-B46-DR9. However, characterization of phase-resolved MHC haplotypes revealed unique intra-CEH patterns of variation and uncovered 127 single nucleotide variants (SNVs) which are missing from public databases. We further show that the strong linkage disequilibrium structure within the human MHC that typically confounds precise identification of genetic features can be resolved using intra-CEH variants, as evidenced by rs3129063 and rs448489, which affect expression of ZFP57, a gene important in methylation and epigenetic regulation. This study demonstrates an improved strategy that can be used towards genetic dissection of diseases. PMID:26593880

Detection of linkage disequilibrium between the myotonic dystrophy locus and a new polymorphic DNA marker.

PubMed Central

Harley, H G; Brook, J D; Floyd, J; Rundle, S A; Crow, S; Walsh, K V; Thibault, M C; Harper, P S; Shaw, D J

1991-01-01

We have examined the linkage of two new polymorphic DNA markers (D19S62 and D19S63) and a previously unreported polymorphism with an existing DNA marker (ERCC1) to the myotonic dystrophy (DM) locus. In addition, we have used pulsed-field gel electrophoresis to obtain a fine-structure map of this region. The detection of linkage disequilibrium between DM and one of these markers (D19S63) is the first demonstration of this phenomenon in a heterogeneous DM population. The results suggest that at least 58% of DM patients in the British population, as well as those in a French-Canadian subpopulation, are descended from the same ancestral DM mutation. We discuss the implications of this finding in terms of strategies for cloning the DM gene, for a possible role in modification of risk for prenatal and presymptomatic testing, and we speculate on the origin and number of existing mutations which may result in a DM phenotype. PMID:2063878

Linkage Disequilibrium and Inversion-Typing of the Drosophila melanogaster Genome Reference Panel

PubMed Central

Houle, David; Márquez, Eladio J.

2015-01-01

We calculated the linkage disequilibrium between all pairs of variants in the Drosophila Genome Reference Panel with minor allele count ≥5. We used r2 ≥ 0.5 as the cutoff for a highly correlated SNP. We make available the list of all highly correlated SNPs for use in association studies. Seventy-six percent of variant SNPs are highly correlated with at least one other SNP, and the mean number of highly correlated SNPs per variant over the whole genome is 83.9. Disequilibrium between distant SNPs is also common when minor allele frequency (MAF) is low: 37% of SNPs with MAF < 0.1 are highly correlated with SNPs more than 100 kb distant. Although SNPs within regions with polymorphic inversions are highly correlated with somewhat larger numbers of SNPs, and these correlated SNPs are on average farther away, the probability that a SNP in such regions is highly correlated with at least one other SNP is very similar to SNPs outside inversions. Previous karyotyping of the DGRP lines has been inconsistent, and we used LD and genotype to investigate these discrepancies. When previous studies agreed on inversion karyotype, our analysis was almost perfectly concordant with those assignments. In discordant cases, and for inversion heterozygotes, our results suggest errors in two previous analyses or discordance between genotype and karyotype. Heterozygosities of chromosome arms are, in many cases, surprisingly highly correlated, suggesting strong epsistatic selection during the inbreeding and maintenance of the DGRP lines. PMID:26068573

Linkage disequilibrium compared between five populations of domestic sheep.

PubMed

Meadows, Jennifer R S; Chan, Eva K F; Kijas, James W

2008-09-30

The success of genome-wide scans depends on the strength and magnitude of linkage disequilibrium (LD) present within the populations under investigation. High density SNP arrays are currently in development for the sheep genome, however little is known about the behaviour of LD in this livestock species. This study examined the behaviour of LD within five sheep populations using two LD metrics, D' and x2'. Four economically important Australian sheep flocks, three pure breeds (White Faced Suffolk, Poll Dorset, Merino) and a crossbred population (Merino x Border Leicester), along with an inbred Australian Merino museum flock were analysed. Short range LD (0 - 5 cM) was observed in all five populations, however the persistence with increasing distance and magnitude of LD varied considerably between populations. Average LD (x2') for markers spaced up to 20 cM exceeded the non-syntenic average within the White Faced Suffolk, Poll Dorset and Macarthur Merino. LD decayed faster within the Merino and Merino x Border Leicester, with LD below or consistent with observed background levels. Using marker-marker LD as a guide to the behaviour of marker-QTL LD, estimates of minimum marker spacing were made. For a 95% probability of detecting QTL, a microsatellite marker would be required every 0.1 - 2.5 centimorgans, depending on the population used. Sheep populations were selected which were inbred (Macarthur Merino), highly heterogeneous (Merino) or intermediate between these two extremes. This facilitated analysis and comparison of LD (x2') between populations. The strength and magnitude of LD was found to differ markedly between breeds and aligned closely with both observed levels of genetic diversity and expectations based on breed history. This confirmed that breed specific information is likely to be important for genome wide selection and during the design of successful genome scans where tens of thousands of markers will be required.

Impact of population structure, effective bottleneck time, and allele frequency on linkage disequilibrium maps

PubMed Central

Zhang, Weihua; Collins, Andrew; Gibson, Jane; Tapper, William J.; Hunt, Sarah; Deloukas, Panos; Bentley, David R.; Morton, Newton E.

2004-01-01

Genetic maps in linkage disequilibrium (LD) units play the same role for association mapping as maps in centimorgans provide at much lower resolution for linkage mapping. Association mapping of genes determining disease susceptibility and other phenotypes is based on the theory of LD, here applied to relations with three phenomena. To test the theory, markers at high density along a 10-Mb continuous segment of chromosome 20q were studied in African-American, Asian, and Caucasian samples. Population structure, whether created by pooling samples from divergent populations or by the mating pattern in a mixed population, is accurately bioassayed from genotype frequencies. The effective bottleneck time for Eurasians is substantially less than for migration out of Africa, reflecting later bottlenecks. The classical dependence of allele frequency on mutation age does not hold for the generally shorter time span of inbreeding and LD. Limitation of the classical theory to mutation age justifies the assumption of constant time in a LD map, except for alleles that were rare at the effective bottleneck time or have arisen since. This assumption is derived from the Malecot model and verified in all samples. Tested measures of relative efficiency, support intervals, and localization error determine the operating characteristics of LD maps that are applicable to every sexually reproducing species, with implications for association mapping, high-resolution linkage maps, evolutionary inference, and identification of recombinogenic sequences. PMID:15604137

Impact of population structure, effective bottleneck time, and allele frequency on linkage disequilibrium maps.

PubMed

Zhang, Weihua; Collins, Andrew; Gibson, Jane; Tapper, William J; Hunt, Sarah; Deloukas, Panos; Bentley, David R; Morton, Newton E

2004-12-28

Genetic maps in linkage disequilibrium (LD) units play the same role for association mapping as maps in centimorgans provide at much lower resolution for linkage mapping. Association mapping of genes determining disease susceptibility and other phenotypes is based on the theory of LD, here applied to relations with three phenomena. To test the theory, markers at high density along a 10-Mb continuous segment of chromosome 20q were studied in African-American, Asian, and Caucasian samples. Population structure, whether created by pooling samples from divergent populations or by the mating pattern in a mixed population, is accurately bioassayed from genotype frequencies. The effective bottleneck time for Eurasians is substantially less than for migration out of Africa, reflecting later bottlenecks. The classical dependence of allele frequency on mutation age does not hold for the generally shorter time span of inbreeding and LD. Limitation of the classical theory to mutation age justifies the assumption of constant time in a LD map, except for alleles that were rare at the effective bottleneck time or have arisen since. This assumption is derived from the Malecot model and verified in all samples. Tested measures of relative efficiency, support intervals, and localization error determine the operating characteristics of LD maps that are applicable to every sexually reproducing species, with implications for association mapping, high-resolution linkage maps, evolutionary inference, and identification of recombinogenic sequences.

Estimation of linkage disequilibrium and interspecific gene flow in Ficedula flycatchers by a newly developed 50k single-nucleotide polymorphism array

PubMed Central

Kawakami, Takeshi; Backström, Niclas; Burri, Reto; Husby, Arild; Olason, Pall; Rice, Amber M; Ålund, Murielle; Qvarnström, Anna; Ellegren, Hans

2014-01-01

With the access to draft genome sequence assemblies and whole-genome resequencing data from population samples, molecular ecology studies will be able to take truly genome-wide approaches. This now applies to an avian model system in ecological and evolutionary research: Old World flycatchers of the genus Ficedula, for which we recently obtained a 1.1 Gb collared flycatcher genome assembly and identified 13 million single-nucleotide polymorphism (SNP)s in population resequencing of this species and its sister species, pied flycatcher. Here, we developed a custom 50K Illumina iSelect flycatcher SNP array with markers covering 30 autosomes and the Z chromosome. Using a number of selection criteria for inclusion in the array, both genotyping success rate and polymorphism information content (mean marker heterozygosity = 0.41) were high. We used the array to assess linkage disequilibrium (LD) and hybridization in flycatchers. Linkage disequilibrium declined quickly to the background level at an average distance of 17 kb, but the extent of LD varied markedly within the genome and was more than 10-fold higher in ‘genomic islands’ of differentiation than in the rest of the genome. Genetic ancestry analysis identified 33 F1 hybrids but no later-generation hybrids from sympatric populations of collared flycatchers and pied flycatchers, contradicting earlier reports of backcrosses identified from much fewer number of markers. With an estimated divergence time as recently as <1 Ma, this suggests strong selection against F1 hybrids and unusually rapid evolution of reproductive incompatibility in an avian system. PMID:24784959

Natural Allelic Diversity, Genetic Structure and Linkage Disequilibrium Pattern in Wild Chickpea

PubMed Central

Kujur, Alice; Das, Shouvik; Badoni, Saurabh; Kumar, Vinod; Singh, Mohar; Bansal, Kailash C.; Tyagi, Akhilesh K.; Parida, Swarup K.

2014-01-01

Characterization of natural allelic diversity and understanding the genetic structure and linkage disequilibrium (LD) pattern in wild germplasm accessions by large-scale genotyping of informative microsatellite and single nucleotide polymorphism (SNP) markers is requisite to facilitate chickpea genetic improvement. Large-scale validation and high-throughput genotyping of genome-wide physically mapped 478 genic and genomic microsatellite markers and 380 transcription factor gene-derived SNP markers using gel-based assay, fluorescent dye-labelled automated fragment analyser and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass array have been performed. Outcome revealed their high genotyping success rate (97.5%) and existence of a high level of natural allelic diversity among 94 wild and cultivated Cicer accessions. High intra- and inter-specific polymorphic potential and wider molecular diversity (11–94%) along with a broader genetic base (13–78%) specifically in the functional genic regions of wild accessions was assayed by mapped markers. It suggested their utility in monitoring introgression and transferring target trait-specific genomic (gene) regions from wild to cultivated gene pool for the genetic enhancement. Distinct species/gene pool-wise differentiation, admixed domestication pattern, and differential genome-wide recombination and LD estimates/decay observed in a six structured population of wild and cultivated accessions using mapped markers further signifies their usefulness in chickpea genetics, genomics and breeding. PMID:25222488

Linkage Disequilibrium and Inversion-Typing of the Drosophila melanogaster Genome Reference Panel.

PubMed

Houle, David; Márquez, Eladio J

2015-06-10

We calculated the linkage disequilibrium between all pairs of variants in the Drosophila Genome Reference Panel with minor allele count ≥5. We used r(2) ≥ 0.5 as the cutoff for a highly correlated SNP. We make available the list of all highly correlated SNPs for use in association studies. Seventy-six percent of variant SNPs are highly correlated with at least one other SNP, and the mean number of highly correlated SNPs per variant over the whole genome is 83.9. Disequilibrium between distant SNPs is also common when minor allele frequency (MAF) is low: 37% of SNPs with MAF < 0.1 are highly correlated with SNPs more than 100 kb distant. Although SNPs within regions with polymorphic inversions are highly correlated with somewhat larger numbers of SNPs, and these correlated SNPs are on average farther away, the probability that a SNP in such regions is highly correlated with at least one other SNP is very similar to SNPs outside inversions. Previous karyotyping of the DGRP lines has been inconsistent, and we used LD and genotype to investigate these discrepancies. When previous studies agreed on inversion karyotype, our analysis was almost perfectly concordant with those assignments. In discordant cases, and for inversion heterozygotes, our results suggest errors in two previous analyses or discordance between genotype and karyotype. Heterozygosities of chromosome arms are, in many cases, surprisingly highly correlated, suggesting strong epsistatic selection during the inbreeding and maintenance of the DGRP lines. Copyright © 2015 Houle and Márquez.

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

USDA-ARS?s Scientific Manuscript database

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...

Patterns of Genetic Structure and Linkage Disequilibrium in a Large Collection of Pea Germplasm

PubMed Central

Siol, Mathieu; Jacquin, Françoise; Chabert-Martinello, Marianne; Smýkal, Petr; Le Paslier, Marie-Christine; Aubert, Grégoire; Burstin, Judith

2017-01-01

Pea (Pisum sativum, L.) is a major pulse crop used both for animal and human alimentation. Owing to its association with nitrogen-fixing bacteria, it is also a valuable component for low-input cropping systems. To evaluate the genetic diversity and the scale of linkage disequilibrium (LD) decay in pea, we genotyped a collection of 917 accessions, gathering elite cultivars, landraces, and wild relatives using an array of ∼13,000 single nucleotide polymorphisms (SNP). Genetic diversity is broadly distributed across three groups corresponding to wild/landraces peas, winter types, and spring types. At a finer subdivision level, genetic groups relate to local breeding programs and type usage. LD decreases steeply as genetic distance increases. When considering subsets of the data, LD values can be higher, even if the steep decay remains. We looked for genomic regions exhibiting high level of differentiation between wild/landraces, winter, and spring pea, respectively. Two regions on linkage groups 5 and 6 containing 33 SNPs exhibit stronger differentiation between winter and spring peas than would be expected under neutrality. Interestingly, QTL for resistance to cold acclimation and frost resistance have been identified previously in the same regions. PMID:28611254

Significant evidence for linkage disequilibrium over a 5-cM region among Afrikaners.

PubMed

Gordon, D; Simonic, I; Ott, J

2000-05-15

We explore the extent of deviations from Hardy-Weinberg equilibrium (HWE) at a marker locus and linkage disequilibrium (LD) between pairs of marker loci in the Afrikaner population of South Africa. DNA samples were used for genotyping of 23 loci on six chromosomes. The samples were collected from 91 healthy unrelated Afrikaner adults. Exact tests were used to determine evidence for deviations from HWE at a single marker locus or LD between pairs of marker loci. At the 0.05 level of significance, evidence was found for deviation from HWE at only one of the 23 loci. At the same level of significance, LD was found among 8 of the 34 intrachromosomal pairs of loci. On chromosome 21, there was evidence for LD (P = 0.02) between a pair of loci with a genetic distance of 5.51 cM. On chromosome 2, there was evidence for LD between a pair of loci with a genetic distance of 5.28 cM (P = 0.002) and a pair of loci with a genetic distance of 3.68 cM (P = 0.0004). Detailed analysis of LD for one locus pair indicated that only a few of all alleles participated in the LD and that strong LD was most often positive. Our findings indicate that Afrikaans-speaking Afrikaners represent one of those special populations deemed particularly suitable for disequilibrium mapping. Copyright 2000 Academic Press.

Inferring Admixture Histories of Human Populations Using Linkage Disequilibrium

PubMed Central

Loh, Po-Ru; Lipson, Mark; Patterson, Nick; Moorjani, Priya; Pickrell, Joseph K.; Reich, David; Berger, Bonnie

2013-01-01

Long-range migrations and the resulting admixtures between populations have been important forces shaping human genetic diversity. Most existing methods for detecting and reconstructing historical admixture events are based on allele frequency divergences or patterns of ancestry segments in chromosomes of admixed individuals. An emerging new approach harnesses the exponential decay of admixture-induced linkage disequilibrium (LD) as a function of genetic distance. Here, we comprehensively develop LD-based inference into a versatile tool for investigating admixture. We present a new weighted LD statistic that can be used to infer mixture proportions as well as dates with fewer constraints on reference populations than previous methods. We define an LD-based three-population test for admixture and identify scenarios in which it can detect admixture events that previous formal tests cannot. We further show that we can uncover phylogenetic relationships among populations by comparing weighted LD curves obtained using a suite of references. Finally, we describe several improvements to the computation and fitting of weighted LD curves that greatly increase the robustness and speed of the calculations. We implement all of these advances in a software package, ALDER, which we validate in simulations and apply to test for admixture among all populations from the Human Genome Diversity Project (HGDP), highlighting insights into the admixture history of Central African Pygmies, Sardinians, and Japanese. PMID:23410830

Estimating effective population size from linkage disequilibrium between unlinked loci: theory and application to fruit fly outbreak populations.

PubMed

Sved, John A; Cameron, Emilie C; Gilchrist, A Stuart

2013-01-01

There is a substantial literature on the use of linkage disequilibrium (LD) to estimate effective population size using unlinked loci. The Ne estimates are extremely sensitive to the sampling process, and there is currently no theory to cope with the possible biases. We derive formulae for the analysis of idealised populations mating at random with multi-allelic (microsatellite) loci. The 'Burrows composite index' is introduced in a novel way with a 'composite haplotype table'. We show that in a sample of diploid size S, the mean value of x2 or r2 from the composite haplotype table is biased by a factor of 1-1/(2S-1)2, rather than the usual factor 1+1/(2S-1) for a conventional haplotype table. But analysis of population data using these formulae leads to Ne estimates that are unrealistically low. We provide theory and simulation to show that this bias towards low Ne estimates is due to null alleles, and introduce a randomised permutation correction to compensate for the bias. We also consider the effect of introducing a within-locus disequilibrium factor to r2, and find that this factor leads to a bias in the Ne estimate. However this bias can be overcome using the same randomised permutation correction, to yield an altered r2 with lower variance than the original r2, and one that is also insensitive to null alleles. The resulting formulae are used to provide Ne estimates on 40 samples of the Queensland fruit fly, Bactrocera tryoni, from populations with widely divergent Ne expectations. Linkage relationships are known for most of the microsatellite loci in this species. We find that there is little difference in the estimated Ne values from using known unlinked loci as compared to using all loci, which is important for conservation studies where linkage relationships are unknown.

The linkage disequilibrium pattern of the angiotensin converting enzyme gene in Arabic and Asian population groups.

PubMed

Kharrat, Najla; Abdelmouleh, Wafa; Abdelhedi, Rania; Alfadhli, Suad; Rebai, Ahmed

2012-01-01

DNA variations within the Angiotensin-Converting Enzyme (ACE) gene have been shown to be involved in the aetiology of several common diseases and the therapeutic response. This study reports a comparison of haplotype analysis of five SNPs in the ACE gene region using a sample of 100 healthy subjects derived from five different populations (Tunisian, Iranian, Kuwaiti, Bahraini and Indian). Strong linkage disequilibrium was found among all SNPs studied for all populations. Two SNPs (rs1800764 and rs4340) were identified as key SNPs for all populations. These SNPs will be valuable for future effective association studies of the ACE gene polymorphisms in Arab and Asian populations.

Genetic Structure, Linkage Disequilibrium and Association Mapping of Verticillium Wilt Resistance in Elite Cotton (Gossypium hirsutum L.) Germplasm Population

PubMed Central

Zhao, Yunlei; Wang, Hongmei; Chen, Wei; Li, Yunhai

2014-01-01

Understanding the population structure and linkage disequilibrium in an association panel can effectively avoid spurious associations and improve the accuracy in association mapping. In this study, one hundred and fifty eight elite cotton (Gossypium hirsutum L.) germplasm from all over the world, which were genotyped with 212 whole genome-wide marker loci and phenotyped with an disease nursery and greenhouse screening method, were assayed for population structure, linkage disequilibrium, and association mapping of Verticillium wilt resistance. A total of 480 alleles ranging from 2 to 4 per locus were identified from all collections. Model-based analysis identified two groups (G1 and G2) and seven subgroups (G1a–c, G2a–d), and differentiation analysis showed that subgroup having a single origin or pedigree was apt to differentiate with those having a mixed origin. Only 8.12% linked marker pairs showed significant LD (P<0.001) in this association panel. The LD level for linked markers is significantly higher than that for unlinked markers, suggesting that physical linkage strongly influences LD in this panel, and LD level was elevated when the panel was classified into groups and subgroups. The LD decay analysis for several chromosomes showed that different chromosomes showed a notable change in LD decay distances for the same gene pool. Based on the disease nursery and greenhouse environment, 42 marker loci associated with Verticillium wilt resistance were identified through association mapping, which widely were distributed among 15 chromosomes. Among which 10 marker loci were found to be consistent with previously identified QTLs and 32 were new unreported marker loci, and QTL clusters for Verticillium wilt resistanc on Chr.16 were also proved in our study, which was consistent with the strong linkage in this chromosome. Our results would contribute to association mapping and supply the marker candidates for marker-assisted selection of Verticillium wilt

Estimation of linkage disequilibrium and analysis of genetic diversity in Korean chicken lines.

PubMed

Seo, Dongwon; Lee, Doo Ho; Choi, Nuri; Sudrajad, Pita; Lee, Seung-Hwan; Lee, Jun-Heon

2018-01-01

The development of genetic markers for animal breeding is an effective strategy to reduce the time and cost required to improve economically important traits. To implement genomic selection in the multibreed chicken population of Korea, an understanding of the linkage disequilibrium (LD) status of the target population is essential. In this study, we performed population genetic analyses to investigate LD decay, the effective population size, and breed diversity using 600K high-density single nucleotide polymorphism genotypes of 189 native chickens in 14 lines (including Korean native chicken, imported and adapted purebred and commercial chickens). The results indicated that commercial native chickens have less calculated LD (average, r2 = 0.13-0.26) and purebred native chickens have more calculated LD (average, r2 = 0.24-0.37) across the entire genome. The effective population sizes of the examined lines showed patterns opposite to those of population LD. The phylogeny and admixture analyses showed that commercial and purebred chickens were well distinguished, except for Rhode Island Red (RIR) purebred lines of NC (NIAS_RIR_C) and ND (NIAS_RIR_D). These lines are difficult to distinguish clearly because they originated from the same respective breeds. The results of this study may provide important information for the development of genetic markers that can be used in breeding to improve the economic traits of native chickens.

Estimation of linkage disequilibrium and analysis of genetic diversity in Korean chicken lines

PubMed Central

Seo, Dongwon; Lee, Doo Ho; Choi, Nuri; Sudrajad, Pita; Lee, Seung-Hwan

2018-01-01

The development of genetic markers for animal breeding is an effective strategy to reduce the time and cost required to improve economically important traits. To implement genomic selection in the multibreed chicken population of Korea, an understanding of the linkage disequilibrium (LD) status of the target population is essential. In this study, we performed population genetic analyses to investigate LD decay, the effective population size, and breed diversity using 600K high-density single nucleotide polymorphism genotypes of 189 native chickens in 14 lines (including Korean native chicken, imported and adapted purebred and commercial chickens). The results indicated that commercial native chickens have less calculated LD (average, r2 = 0.13–0.26) and purebred native chickens have more calculated LD (average, r2 = 0.24–0.37) across the entire genome. The effective population sizes of the examined lines showed patterns opposite to those of population LD. The phylogeny and admixture analyses showed that commercial and purebred chickens were well distinguished, except for Rhode Island Red (RIR) purebred lines of NC (NIAS_RIR_C) and ND (NIAS_RIR_D). These lines are difficult to distinguish clearly because they originated from the same respective breeds. The results of this study may provide important information for the development of genetic markers that can be used in breeding to improve the economic traits of native chickens. PMID:29425208

A Consensus Genetic Map for Pinus taeda and Pinus elliottii and Extent of Linkage Disequilibrium in Two Genotype-Phenotype Discovery Populations of Pinus taeda

PubMed Central

Westbrook, Jared W.; Chhatre, Vikram E.; Wu, Le-Shin; Chamala, Srikar; Neves, Leandro Gomide; Muñoz, Patricio; Martínez-García, Pedro J.; Neale, David B.; Kirst, Matias; Mockaitis, Keithanne; Nelson, C. Dana; Peter, Gary F.; Echt, Craig S.

2015-01-01

A consensus genetic map for Pinus taeda (loblolly pine) and Pinus elliottii (slash pine) was constructed by merging three previously published P. taeda maps with a map from a pseudo-backcross between P. elliottii and P. taeda. The consensus map positioned 3856 markers via genotyping of 1251 individuals from four pedigrees. It is the densest linkage map for a conifer to date. Average marker spacing was 0.6 cM and total map length was 2305 cM. Functional predictions of mapped genes were improved by aligning expressed sequence tags used for marker discovery to full-length P. taeda transcripts. Alignments to the P. taeda genome mapped 3305 scaffold sequences onto 12 linkage groups. The consensus genetic map was used to compare the genome-wide linkage disequilibrium in a population of distantly related P. taeda individuals (ADEPT2) used for association genetic studies and a multiple-family pedigree used for genomic selection (CCLONES). The prevalence and extent of LD was greater in CCLONES as compared to ADEPT2; however, extended LD with LGs or between LGs was rare in both populations. The average squared correlations, r2, between SNP alleles less than 1 cM apart were less than 0.05 in both populations and r2 did not decay substantially with genetic distance. The consensus map and analysis of linkage disequilibrium establish a foundation for comparative association mapping and genomic selection in P. taeda and P. elliottii. PMID:26068575

Nucleotide diversity and linkage disequilibrium in wild avocado (Persea americana Mill.).

PubMed

Chen, Haofeng; Morrell, Peter L; de la Cruz, Marlene; Clegg, Michael T

2008-01-01

Resequencing studies provide the ultimate resolution of genetic diversity because they identify all mutations in a gene that are present within the sampled individuals. We report a resequencing study of Persea americana, a subtropical tree species native to Meso- and Central America and the progenitor of cultivated avocado. The sample includes 21 wild accessions from Mexico, Costa Rica, Ecuador, and the Dominican Republic. Estimated levels of nucleotide polymorphism and linkage disequilibrium (LD) are obtained from fully resolved haplotype data from 4 nuclear loci that span 5960 nucleotide sites. Results show that, although avocado is a subtropical tree crop and a predominantly outcrossing plant, the overall level of genetic variation is not exceptionally high (nucleotide diversity at silent sites, pi(sil) = 0.0102) compared with available estimates from temperate plant species. Intralocus LD decays rapidly to half the initial value within about 1 kb. Estimates of recombination rate (based on the sequence data) show that the rate is not exceptionally high when compared with annual plants such as wild barley or maize. Interlocus LD is significant owing to substantial population structure induced by mixing of the 3 botanical races of avocado.

Heritability and Familiality of Temperament and Character Dimensions in Korean Families with Schizophrenic Linkage Disequilibrium.

PubMed

Lee, Byung Dae; Park, Je Min; Lee, Young Min; Moon, Eunsoo; Jeong, Hee Jeong; Chung, Young In; Yi, Young Mi

2016-05-31

Categorical syndromes such as schizophrenia may represent complexes of many continuous psychological structural phenotypes along several dimensions of personality development/degeneration. The present study investigated the heritability and familiality of personality dimensions in Korean families with schizophrenic linkage disequilibrium (LD). We recruited 179 probands (with schizophrenia) as well as, whenever possible, their parents and siblings. We used the Temperament and Character Inventory (TCI) to measure personality and symptomatic dimensions. The heritability of personality dimensions in a total of 472 family members was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR). To measure familiality, we compared the personality dimensions of family members with those of 336 healthy unrelated controls using analysis of variance (ANOVA) analysis. Three of the seven TCI variables were significantly heritable and were included in subsequent analyses. The three groups (control, unaffected first-degree relative, case) were found to significantly differ from one another, with the expected order of average group scores, for all heritable dimensions. Despite several study limitations with respect to family recruitment and phenotyping, our results show that aberrations in several personality dimensions related to genetic-environment coactions or interactions may underlie the complexity of the schizophrenic syndrome.

Detecting introgressive hybridization between free-ranging domestic dogs and wild wolves (Canis lupus) by admixture linkage disequilibrium analysis.

PubMed

Verardi, A; Lucchini, V; Randi, E

2006-09-01

Occasional crossbreeding between free-ranging domestic dogs and wild wolves (Canis lupus) has been detected in some European countries by mitochondrial DNA sequencing and genotyping unlinked microsatellite loci. Maternal and unlinked genomic markers, however, might underestimate the extent of introgressive hybridization, and their impacts on the preservation of wild wolf gene pools. In this study, we genotyped 220 presumed Italian wolves, 85 dogs and 7 known hybrids at 16 microsatellites belonging to four different linkage groups (plus four unlinked microsatellites). Population clustering and individual assignments were performed using a Bayesian procedure implemented in structure 2.1, which models the gametic disequilibrium arising between linked loci during admixtures, aiming to trace hybridization events further back in time and infer the population of origin of chromosomal blocks. Results indicate that (i) linkage disequilibrium was higher in wolves than in dogs; (ii) 11 out of 220 wolves (5.0%) were likely admixed, a proportion that is significantly higher than one admixed genotype in 107 wolves found previously in a study using unlinked markers; (iii) posterior maximum-likelihood estimates of the recombination parameter r revealed that introgression in Italian wolves is not recent, but could have continued for the last 70 (+/- 20) generations, corresponding to approximately 140-210 years. Bayesian clustering showed that, despite some admixture, wolf and dog gene pools remain sharply distinct (the average proportions of membership to wolf and dog clusters were Q(w) = 0.95 and Q(d) = 0.98, respectively), suggesting that hybridization was not frequent, and that introgression in nature is counteracted by behavioural or selective constraints.

Evidence, from family studies, for linkage disequilibrium between TGFA and a gene for nonsyndromic cleft lip with or without cleft palate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feng, Hongshu; Lee, A.; Gasser, D.L.

1994-11-01

The inheritance of alleles of the transforming growth factor alpha (TGFA) locus has been studied in families affected with cleft lip with or without cleft palate (CL/P), by using the transmission/disequilibrium test described by Spielman and colleagues. Only heterozygous parents with an affected child can be included in this test, but within such families a significantly greater frequency of C2 alleles were transmitted to affected children than would be expected by chance. There was no evidence that the total number of C2 alleles transmitted to affected and unaffected children differed significantly from random segregation. These data provide evidence from withinmore » families that a gene for susceptibility to CL/P is in significant linkage disequilibrium with the C2 allele of the TGFA locus. 30 refs., 1 fig., 2 tabs.« less

Accuracy of Genomic Prediction in Switchgrass (Panicum virgatum L.) Improved by Accounting for Linkage Disequilibrium

PubMed Central

Ramstein, Guillaume P.; Evans, Joseph; Kaeppler, Shawn M.; Mitchell, Robert B.; Vogel, Kenneth P.; Buell, C. Robin; Casler, Michael D.

2016-01-01

Switchgrass is a relatively high-yielding and environmentally sustainable biomass crop, but further genetic gains in biomass yield must be achieved to make it an economically viable bioenergy feedstock. Genomic selection (GS) is an attractive technology to generate rapid genetic gains in switchgrass, and meet the goals of a substantial displacement of petroleum use with biofuels in the near future. In this study, we empirically assessed prediction procedures for genomic selection in two different populations, consisting of 137 and 110 half-sib families of switchgrass, tested in two locations in the United States for three agronomic traits: dry matter yield, plant height, and heading date. Marker data were produced for the families’ parents by exome capture sequencing, generating up to 141,030 polymorphic markers with available genomic-location and annotation information. We evaluated prediction procedures that varied not only by learning schemes and prediction models, but also by the way the data were preprocessed to account for redundancy in marker information. More complex genomic prediction procedures were generally not significantly more accurate than the simplest procedure, likely due to limited population sizes. Nevertheless, a highly significant gain in prediction accuracy was achieved by transforming the marker data through a marker correlation matrix. Our results suggest that marker-data transformations and, more generally, the account of linkage disequilibrium among markers, offer valuable opportunities for improving prediction procedures in GS. Some of the achieved prediction accuracies should motivate implementation of GS in switchgrass breeding programs. PMID:26869619

A linkage disequilibrium perspective on the genetic mosaic of speciation in two hybridizing Mediterranean white oaks

PubMed Central

Goicoechea, P G; Herrán, A; Durand, J; Bodénès, C; Plomion, C; Kremer, A

2015-01-01

We analyzed the genetic mosaic of speciation in two hybridizing Mediterranean white oaks from the Iberian Peninsula (Quercus faginea Lamb. and Quercus pyrenaica Willd.). The two species show ecological divergence in flowering phenology, leaf morphology and composition, and in their basic or acidic soil preferences. Ninety expressed sequence tag-simple sequence repeats (EST-SSRs) and eight nuclear SSRs were genotyped in 96 trees from each species. Genotyping was designed in two steps. First, we used 69 markers evenly distributed over the 12 linkage groups (LGs) of the oak linkage map to confirm the species genetic identity of the sampled genotypes, and searched for differentiation outliers. Then, we genotyped 29 additional markers from the chromosome bins containing the outliers and repeated the multilocus scans. We found one or two additional outliers within four saturated bins, thus confirming that outliers are organized into clusters. Linkage disequilibrium (LD) was extensive; even for loosely linked and for independent markers. Consequently, score tests for association between two-marker haplotypes and the ‘species trait' showed a broad genomic divergence, although substantial variation across the genome and within LGs was also observed. We discuss the influence of several confounding effects on neutrality tests and review the evolutionary processes leading to extensive LD. Finally, we examine how LD analyses within regions that contain outlier clusters and quantitative trait loci can help to identify regions of divergence and/or genomic hitchhiking in the light of predictions from ecological speciation theory. PMID:25515016

Extended Linkage Disequilibrium Surrounding the Hemoglobin E Variant Due to Malarial Selection

PubMed Central

Ohashi, Jun ; Naka, Izumi ; Patarapotikul, Jintana ; Hananantachai, Hathairad ; Brittenham, Gary ; Looareesuwan, Sornchai ; Clark, Andrew G. ; Tokunaga, Katsushi 

2004-01-01

The hemoglobin E variant (HbE; β26Glu→Lys) is concentrated in parts of Southeast Asia where malaria is endemic, and HbE carrier status has been shown to confer some protection against Plasmodium falciparum malaria. To examine the effect of natural selection on the pattern of linkage disequilibrium (LD) and to infer the evolutionary history of the HbE variant, we analyzed biallelic markers surrounding the HbE variant in a Thai population. Pairwise LD analysis of HbE and 43 surrounding biallelic markers revealed LD of HbE extending beyond 100 kb, whereas no LD was observed between non-HbE variants and the same markers. The inferred haplotype network suggests a single origin of the HbE variant in the Thai population. Forward-in-time computer simulations under a variety of selection models indicate that the HbE variant arose 1,240–4,440 years ago. These results support the conjecture that the HbE mutation occurred recently, and the allele frequency has increased rapidly. Our study provides another clear demonstration that a high-resolution LD map across the human genome can detect recent variants that have been subjected to positive selection. PMID:15114532

Extended linkage disequilibrium surrounding the hemoglobin E variant due to malarial selection.

PubMed

Ohashi, Jun; Naka, Izumi; Patarapotikul, Jintana; Hananantachai, Hathairad; Brittenham, Gary; Looareesuwan, Sornchai; Clark, Andrew G; Tokunaga, Katsushi

2004-06-01

The hemoglobin E variant (HbE; ( beta )26Glu-->Lys) is concentrated in parts of Southeast Asia where malaria is endemic, and HbE carrier status has been shown to confer some protection against Plasmodium falciparum malaria. To examine the effect of natural selection on the pattern of linkage disequilibrium (LD) and to infer the evolutionary history of the HbE variant, we analyzed biallelic markers surrounding the HbE variant in a Thai population. Pairwise LD analysis of HbE and 43 surrounding biallelic markers revealed LD of HbE extending beyond 100 kb, whereas no LD was observed between non-HbE variants and the same markers. The inferred haplotype network suggests a single origin of the HbE variant in the Thai population. Forward-in-time computer simulations under a variety of selection models indicate that the HbE variant arose 1,240-4,440 years ago. These results support the conjecture that the HbE mutation occurred recently, and the allele frequency has increased rapidly. Our study provides another clear demonstration that a high-resolution LD map across the human genome can detect recent variants that have been subjected to positive selection.

Identification of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map.

PubMed

Hewett, Duncan; Samuelsson, Lena; Polding, Joanne; Enlund, Fredrik; Smart, Devi; Cantone, Kathryn; See, Chee Gee; Chadha, Sapna; Inerot, Annica; Enerback, Charlotta; Montgomery, Doug; Christodolou, Chris; Robinson, Phil; Matthews, Paul; Plumpton, Mary; Wahlstrom, Jan; Swanbeck, Gunnar; Martinsson, Tommy; Roses, Allen; Riley, John; Purvis, Ian

2002-03-01

Psoriasis is a chronic inflammatory disease of the skin with both genetic and environmental risk factors. Here we describe the creation of a single-nucleotide polymorphism (SNP) map spanning 900-1200 kb of chromosome 3q21, which had been previously recognized as containing a psoriasis susceptibility locus, PSORS5. We genotyped 644 individuals, from 195 Swedish psoriatic families, for 19 polymorphisms. Linkage disequilibrium (LD) between marker and disease was assessed using the transmission/disequilibrium test (TDT). In the TDT analysis, alleles of three of these SNPs showed significant association with disease (P<0.05). A 160-kb interval encompassing these three SNPs was sequenced, and a coding sequence consisting of 13 exons was identified. The predicted protein shares 30-40% homology with the family of cation/chloride cotransporters. A five-marker haplotype spanning the 3' half of this gene is associated with psoriasis to a P value of 3.8<10(-5). We have called this gene SLC12A8, coding for a member of the solute carrier family 12 proteins. It belongs to a class of genes that were previously unrecognized as playing a role in psoriasis pathogenesis.

Chromosome-wide linkage disequilibrium as a consequence of meiotic drive

PubMed Central

Dyer, Kelly A.; Charlesworth, Brian; Jaenike, John

2007-01-01

Adaptation by natural selection proceeds most efficiently when alleles compete solely on the basis of their effects on the survival and reproduction of their carriers. A major condition for this is equal Mendelian segregation, but meiotic drive can short-circuit this process. The evolution of drive often involves multiple, interacting genetic components, together with enhancers and suppressors of drive. Chromosomal inversions that suppress crossing over are also frequently associated with drive systems. This study investigates the effects of these processes on patterns of molecular evolution in the fly Drosophila recens, which is polymorphic for a driving X chromosome (XD). Whereas standard wild-type chromosomes exhibit high levels of polymorphism at multiple loci, all of the XD chromosomes effectively carry a single multilocus haplotype that spans at least 130 cM. The XD is associated with a complex set of inversions that completely suppresses recombination between the standard wild-type chromosome and XD in heterozygous females, which maintain nonrandom associations among loci that presumably interact epistatically for the expression of drive. The long-term costs of foregoing recombination may be substantial; in combination with its low equilibrium frequency, this makes the XD chromosome susceptible to the accumulation of deleterious mutations. Consistent with this, XD chromosomes are apparently fixed for a recessive mutation that causes female sterility. Thus, the XD in D. recens appears to be in chromosome-wide linkage disequilibrium and in the early stages of mutational degradation. PMID:17242362

Accounting for linkage disequilibrium in association analysis of diverse populations.

PubMed

Charles, Bashira A; Shriner, Daniel; Rotimi, Charles N

2014-04-01

The National Human Genome Research Institute's catalog of published genome-wide association studies (GWAS) lists over 10,000 genetic variants collectively associated with over 800 human diseases or traits. Most of these GWAS have been conducted in European-ancestry populations. Findings gleaned from these studies have led to identification of disease-associated loci and biologic pathways involved in disease etiology. In multiple instances, these genomic findings have led to the development of novel medical therapies or evidence for prescribing a given drug as the appropriate treatment for a given individual beyond phenotypic appearances or socially defined constructs of race or ethnicity. Such findings have implications for populations throughout the globe and GWAS are increasingly being conducted in more diverse populations. A major challenge for investigators seeking to follow up genomic findings between diverse populations is discordant patterns of linkage disequilibrium (LD). We provide an overview of common measures of LD and opportunities for their use in novel methods designed to address challenges associated with following up GWAS conducted in European-ancestry populations in African-ancestry populations or, more generally, between populations with discordant LD patterns. We detail the strengths and weaknesses associated with different approaches. We also describe application of these strategies in follow-up studies of populations with concordant LD patterns (replication) or discordant LD patterns (transferability) as well as fine-mapping studies. We review application of these methods to a variety of traits and diseases. © 2014 WILEY PERIODICALS, INC.

Localization of an ataxia-telangiectasia gene by linkage disequilibrium in the Costa Rican population

DOE Office of Scientific and Technical Information (OSTI.GOV)

Uhrhammer, N.A.; Lange, E.; Gatti, R.A.

1994-09-01

Linkage disequilibrium (LD) was studied in 27 Costa Rican families with ataxia-telangiectasia. Previous studies indicate that the ATA and ATC gene(s) are on chromosome 11q22.3, between D11S1819 and D11S927. We studied the ordered loci D11-S1816, S1817, S1343, S1819, S384, S535, S1295, S1818, S927, S1300 and S1004 by PCR and Southern blotting. We noted moderate LD at the more distant markers S1816, S1300, and S1004. LD was higher at markers closer to A-T, and also where A-T was associated with rarer alleles. This broad region of disequilibrium did not by itself contribute to further localization of the A-T gene(s). We analyzedmore » 54 affected chromosomal haplotypes. The most common haplotype occurred 34 times, including some that had recombined outside the known A-T region. Other haplotypes occurred seven times, five times, two occurred twice, and the four remaining were unique. The most common haplotype had `broken` at S927 in five different patients, placing A-T proximal to this marker. We looked for recombination events in 15 of the families to further localize A-T. We observed one family with a recombination event placing A-T distal to S1819. A second family appears to either not link to 11q22.3 or to have a double-crossover between the markers S384 and S927; two affected sibs share haplotypes for the entire region studied, and a normal sib shared the same two haplotypes. Since all or part of this A-T haplotype occurs in 32 other, unrelated, Costa Rican patients, we anticipate a double-crossover in the 1600 kb between the informative flanking markers. All other families show segregation patterns consistent with placing A-T at 11q22.3. These results demonstrate that the major A-T gene in the Costa Rican population is located between S1819 and S927 at 11q22.3.« less

Construction of the model for the Genetic Analysis Workshop 14 simulated data: genotype-phenotype relationships, gene interaction, linkage, association, disequilibrium, and ascertainment effects for a complex phenotype.

PubMed

Greenberg, David A; Zhang, Junying; Shmulewitz, Dvora; Strug, Lisa J; Zimmerman, Regina; Singh, Veena; Marathe, Sudhir

2005-12-30

The Genetic Analysis Workshop 14 simulated dataset was designed 1) To test the ability to find genes related to a complex disease (such as alcoholism). Such a disease may be given a variety of definitions by different investigators, have associated endophenotypes that are common in the general population, and is likely to be not one disease but a heterogeneous collection of clinically similar, but genetically distinct, entities. 2) To observe the effect on genetic analysis and gene discovery of a complex set of gene x gene interactions. 3) To allow comparison of microsatellite vs. large-scale single-nucleotide polymorphism (SNP) data. 4) To allow testing of association to identify the disease gene and the effect of moderate marker x marker linkage disequilibrium. 5) To observe the effect of different ascertainment/disease definition schemes on the analysis. Data was distributed in two forms. Data distributed to participants contained about 1,000 SNPs and 400 microsatellite markers. Internet-obtainable data consisted of a finer 10,000 SNP map, which also contained data on controls. While disease characteristics and parameters were constant, four "studies" used varying ascertainment schemes based on differing beliefs about disease characteristics. One of the studies contained multiplex two- and three-generation pedigrees with at least four affected members. The simulated disease was a psychiatric condition with many associated behaviors (endophenotypes), almost all of which were genetic in origin. The underlying disease model contained four major genes and two modifier genes. The four major genes interacted with each other to produce three different phenotypes, which were themselves heterogeneous. The population parameters were calibrated so that the major genes could be discovered by linkage analysis in most datasets. The association evidence was more difficult to calibrate but was designed to find statistically significant association in 50% of datasets. We also

Nucleotide Sequence Diversity and Linkage Disequilibrium of Four Nuclear Loci in Foxtail Millet (Setaria italica).

PubMed

He, Shui-Lian; Yang, Yang; Morrell, Peter L; Yi, Ting-Shuang

2015-01-01

Foxtail millet (Setaria italica (L.) Beauv) is one of the earliest domesticated grains, which has been cultivated in northern China by 8,700 years before present (YBP) and across Eurasia by 4,000 YBP. Owing to a small genome and diploid nature, foxtail millet is a tractable model crop for studying functional genomics of millets and bioenergy grasses. In this study, we examined nucleotide sequence diversity, geographic structure, and levels of linkage disequilibrium at four nuclear loci (ADH1, G3PDH, IGS1 and TPI1) in representative samples of 311 landrace accessions across its cultivated range. Higher levels of nucleotide sequence and haplotype diversity were observed in samples from China relative to other sampled regions. Genetic assignment analysis classified the accessions into seven clusters based on nucleotide sequence polymorphisms. Intralocus LD decayed rapidly to half the initial value within ~1.2 kb or less.

Accuracy of genomic prediction in switchgrass ( Panicum virgatum L.) improved by accounting for linkage disequilibrium

DOE PAGES

Ramstein, Guillaume P.; Evans, Joseph; Kaeppler, Shawn M.; ...

2016-02-11

Switchgrass is a relatively high-yielding and environmentally sustainable biomass crop, but further genetic gains in biomass yield must be achieved to make it an economically viable bioenergy feedstock. Genomic selection (GS) is an attractive technology to generate rapid genetic gains in switchgrass, and meet the goals of a substantial displacement of petroleum use with biofuels in the near future. In this study, we empirically assessed prediction procedures for genomic selection in two different populations, consisting of 137 and 110 half-sib families of switchgrass, tested in two locations in the United States for three agronomic traits: dry matter yield, plant height,more » and heading date. Marker data were produced for the families’ parents by exome capture sequencing, generating up to 141,030 polymorphic markers with available genomic-location and annotation information. We evaluated prediction procedures that varied not only by learning schemes and prediction models, but also by the way the data were preprocessed to account for redundancy in marker information. More complex genomic prediction procedures were generally not significantly more accurate than the simplest procedure, likely due to limited population sizes. Nevertheless, a highly significant gain in prediction accuracy was achieved by transforming the marker data through a marker correlation matrix. Our results suggest that marker-data transformations and, more generally, the account of linkage disequilibrium among markers, offer valuable opportunities for improving prediction procedures in GS. Furthermore, some of the achieved prediction accuracies should motivate implementation of GS in switchgrass breeding programs.« less

Accuracy of genomic prediction in switchgrass ( Panicum virgatum L.) improved by accounting for linkage disequilibrium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ramstein, Guillaume P.; Evans, Joseph; Kaeppler, Shawn M.

Switchgrass is a relatively high-yielding and environmentally sustainable biomass crop, but further genetic gains in biomass yield must be achieved to make it an economically viable bioenergy feedstock. Genomic selection (GS) is an attractive technology to generate rapid genetic gains in switchgrass, and meet the goals of a substantial displacement of petroleum use with biofuels in the near future. In this study, we empirically assessed prediction procedures for genomic selection in two different populations, consisting of 137 and 110 half-sib families of switchgrass, tested in two locations in the United States for three agronomic traits: dry matter yield, plant height,more » and heading date. Marker data were produced for the families’ parents by exome capture sequencing, generating up to 141,030 polymorphic markers with available genomic-location and annotation information. We evaluated prediction procedures that varied not only by learning schemes and prediction models, but also by the way the data were preprocessed to account for redundancy in marker information. More complex genomic prediction procedures were generally not significantly more accurate than the simplest procedure, likely due to limited population sizes. Nevertheless, a highly significant gain in prediction accuracy was achieved by transforming the marker data through a marker correlation matrix. Our results suggest that marker-data transformations and, more generally, the account of linkage disequilibrium among markers, offer valuable opportunities for improving prediction procedures in GS. Furthermore, some of the achieved prediction accuracies should motivate implementation of GS in switchgrass breeding programs.« less

Genome-wide patterns of recombination, linkage disequilibrium and nucleotide diversity from pooled resequencing and single nucleotide polymorphism genotyping unlock the evolutionary history of Eucalyptus grandis.

PubMed

Silva-Junior, Orzenil B; Grattapaglia, Dario

2015-11-01

We used high-density single nucleotide polymorphism (SNP) data and whole-genome pooled resequencing to examine the landscape of population recombination (ρ) and nucleotide diversity (ϴw ), assess the extent of linkage disequilibrium (r(2) ) and build the highest density linkage maps for Eucalyptus. At the genome-wide level, linkage disequilibrium (LD) decayed within c. 4-6 kb, slower than previously reported from candidate gene studies, but showing considerable variation from absence to complete LD up to 50 kb. A sharp decrease in the estimate of ρ was seen when going from short to genome-wide inter-SNP distances, highlighting the dependence of this parameter on the scale of observation adopted. Recombination was correlated with nucleotide diversity, gene density and distance from the centromere, with hotspots of recombination enriched for genes involved in chemical reactions and pathways of the normal metabolic processes. The high nucleotide diversity (ϴw = 0.022) of E. grandis revealed that mutation is more important than recombination in shaping its genomic diversity (ρ/ϴw = 0.645). Chromosome-wide ancestral recombination graphs allowed us to date the split of E. grandis (1.7-4.8 million yr ago) and identify a scenario for the recent demographic history of the species. Our results have considerable practical importance to Genome Wide Association Studies (GWAS), while indicating bright prospects for genomic prediction of complex phenotypes in eucalypt breeding. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

Mapping genes underlying ethnic differences in disease risk by linkage disequilibrium in recently admixed populations.

PubMed Central

McKeigue, P M

1997-01-01

Where recent admixture has occurred between two populations that have different disease rates for genetic reasons, family-based association studies can be used to map the genes underlying these differences, if the ancestry of the alleles at each locus examined can be assigned to one of the two founding populations. This article explores the statistical power and design requirements of this approach. Markers suitable for assigning the ancestry of genomic regions could be defined by grouping alleles at closely spaced microsatellite loci into haplotypes, or generated by representational difference analysis. For a given relative risk between populations, the sample size required to detect a disease locus that accounts for this relative risk by linkage-disequilibrium mapping in an admixed population is not critically dependent on assumptions about genotype penetrances or allele frequencies. Using the transmission-disequilibrium test to search the genome for a locus that accounts for a relative risk of between 2 and 3 in a high-risk population, compared with a low-risk population, generally requires between 150 and 800 case-parent pairs of mixed descent. The optimal strategy is to conduct an initial study using markers spaced at < or = 10 cM with cases from the second and third generations of mixed descent, and then to map the disease loci more accurately in a subsequent study of a population with a longer history of admixture. This approach has greater statistical power than allele-sharing designs and has obvious applications to the genetics of hypertension, non-insulin-dependent diabetes, and obesity. PMID:8981962

Temporal dynamics of linkage disequilibrium in two populations of bighorn sheep

PubMed Central

Miller, Joshua M; Poissant, Jocelyn; Malenfant, René M; Hogg, John T; Coltman, David W

2015-01-01

Linkage disequilibrium (LD) is the nonrandom association of alleles at two markers. Patterns of LD have biological implications as well as practical ones when designing association studies or conservation programs aimed at identifying the genetic basis of fitness differences within and among populations. However, the temporal dynamics of LD in wild populations has received little empirical attention. In this study, we examined the overall extent of LD, the effect of sample size on the accuracy and precision of LD estimates, and the temporal dynamics of LD in two populations of bighorn sheep (Ovis canadensis) with different demographic histories. Using over 200 microsatellite loci, we assessed two metrics of multi-allelic LD, D′, and χ′2. We found that both populations exhibited high levels of LD, although the extent was much shorter in a native population than one that was founded via translocation, experienced a prolonged bottleneck post founding, followed by recent admixture. In addition, we observed significant variation in LD in relation to the sample size used, with small sample sizes leading to depressed estimates of the extent of LD but inflated estimates of background levels of LD. In contrast, there was not much variation in LD among yearly cross-sections within either population once sample size was accounted for. Lack of pronounced interannual variability suggests that researchers may not have to worry about interannual variation when estimating LD in a population and can instead focus on obtaining the largest sample size possible. PMID:26380673

Patterns of linkage disequilibrium and haplotype distribution in disease candidate genes.

PubMed

Long, Ji-Rong; Zhao, Lan-Juan; Liu, Peng-Yuan; Lu, Yan; Dvornyk, Volodymyr; Shen, Hui; Liu, Yong-Jun; Zhang, Yuan-Yuan; Xiong, Dong-Hai; Xiao, Peng; Deng, Hong-Wen

2004-05-24

The adequacy of association studies for complex diseases depends critically on the existence of linkage disequilibrium (LD) between functional alleles and surrounding SNP markers. We examined the patterns of LD and haplotype distribution in eight candidate genes for osteoporosis and/or obesity using 31 SNPs in 1,873 subjects. These eight genes are apolipoprotein E (APOE), type I collagen alpha1 (COL1A1), estrogen receptor-alpha (ER-alpha), leptin receptor (LEPR), parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1), transforming growth factor-beta1 (TGF-beta1), uncoupling protein 3 (UCP3), and vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR). Yin yang haplotypes, two high-frequency haplotypes composed of completely mismatching SNP alleles, were examined. To quantify LD patterns, two common measures of LD, D' and r2, were calculated for the SNPs within the genes. The haplotype distribution varied in the different genes. Yin yang haplotypes were observed only in PTHR1 and UCP3. D' ranged from 0.020 to 1.000 with the average of 0.475, whereas the average r2 was 0.158 (ranging from 0.000 to 0.883). A decay of LD was observed as the intermarker distance increased, however, there was a great difference in LD characteristics of different genes or even in different regions within gene. The differences in haplotype distributions and LD patterns among the genes underscore the importance of characterizing genomic regions of interest prior to association studies.

Patterns of linkage disequilibrium in mitochondrial DNA of 16 ruminant populations.

PubMed

Slate, J; Phua, S H

2003-03-01

Mitochondrial DNA (mtDNA) is a widely employed molecular tool in phylogeography, in the inference of human evolutionary history, in dating the domestication of livestock and in forensic science. In humans and other vertebrates the popularity of mtDNA can be partially attributed to an assumption of strict maternal inheritance, such that there is no recombination between mitochondrial lineages. The recent demonstration that linkage disequilibrium (LD) declines as a function of distance between polymorphic sites in hominid mitochondrial genomes has been interpreted as evidence of recombination between mtDNA haplotypes, and hence nonclonal inheritance. However, critics of mtDNA recombination have suggested that this association is an artefact of an inappropriate measure of LD or of sequencing error, and subsequent studies of other populations have failed to replicate the initial finding. Here we report the analysis of 16 ruminant populations and present evidence that LD significantly declines with distance in five of them. A meta-analysis of the data indicates a nonsignificant trend of LD declining with distance. Most of the earlier criticisms of patterns between LD and distance in hominid mtDNA are not applicable to this data set. Our results suggest that either ruminant mtDNA is not strictly clonal or that compensatory selection has influenced patterns of variation at closely linked sites within the mitochondrial control region. The potential impact of these processes should be considered when using mtDNA as a tool in vertebrate population genetic, phylogenetic and forensic studies.

A tool for selecting SNPs for association studies based on observed linkage disequilibrium patterns.

PubMed

De La Vega, Francisco M; Isaac, Hadar I; Scafe, Charles R

2006-01-01

The design of genetic association studies using single-nucleotide polymorphisms (SNPs) requires the selection of subsets of the variants providing high statistical power at a reasonable cost. SNPs must be selected to maximize the probability that a causative mutation is in linkage disequilibrium (LD) with at least one marker genotyped in the study. The HapMap project performed a genome-wide survey of genetic variation with about a million SNPs typed in four populations, providing a rich resource to inform the design of association studies. A number of strategies have been proposed for the selection of SNPs based on observed LD, including construction of metric LD maps and the selection of haplotype tagging SNPs. Power calculations are important at the study design stage to ensure successful results. Integrating these methods and annotations can be challenging: the algorithms required to implement these methods are complex to deploy, and all the necessary data and annotations are deposited in disparate databases. Here, we present the SNPbrowser Software, a freely available tool to assist in the LD-based selection of markers for association studies. This stand-alone application provides fast query capabilities and swift visualization of SNPs, gene annotations, power, haplotype blocks, and LD map coordinates. Wizards implement several common SNP selection workflows including the selection of optimal subsets of SNPs (e.g. tagging SNPs). Selected SNPs are screened for their conversion potential to either TaqMan SNP Genotyping Assays or the SNPlex Genotyping System, two commercially available genotyping platforms, expediting the set-up of genetic studies with an increased probability of success.

Exploiting excess sharing: a more powerful test of linkage for affected sib pairs than the transmission/disequilibrium test.

PubMed Central

Wicks, J

2000-01-01

The transmission/disequilibrium test (TDT) is a popular, simple, and powerful test of linkage, which can be used to analyze data consisting of transmissions to the affected members of families with any kind pedigree structure, including affected sib pairs (ASPs). Although it is based on the preferential transmission of a particular marker allele across families, it is not a valid test of association for ASPs. Martin et al. devised a similar statistic for ASPs, Tsp, which is also based on preferential transmission of a marker allele but which is a valid test of both linkage and association for ASPs. It is, however, less powerful than the TDT as a test of linkage for ASPs. What I show is that the differences between the TDT and Tsp are due to the fact that, although both statistics are based on preferential transmission of a marker allele, the TDT also exploits excess sharing in identity-by-descent transmissions to ASPs. Furthermore, I show that both of these statistics are members of a family of "TDT-like" statistics for ASPs. The statistics in this family are based on preferential transmission but also, to varying extents, exploit excess sharing. From this family of statistics, we see that, although the TDT exploits excess sharing to some extent, it is possible to do so to a greater extent-and thus produce a more powerful test of linkage, for ASPs, than is provided by the TDT. Power simulations conducted under a number of disease models are used to verify that the most powerful member of this family of TDT-like statistics is more powerful than the TDT for ASPs. PMID:10788332

Exploiting excess sharing: a more powerful test of linkage for affected sib pairs than the transmission/disequilibrium test.

PubMed

Wicks, J

2000-06-01

The transmission/disequilibrium test (TDT) is a popular, simple, and powerful test of linkage, which can be used to analyze data consisting of transmissions to the affected members of families with any kind pedigree structure, including affected sib pairs (ASPs). Although it is based on the preferential transmission of a particular marker allele across families, it is not a valid test of association for ASPs. Martin et al. devised a similar statistic for ASPs, Tsp, which is also based on preferential transmission of a marker allele but which is a valid test of both linkage and association for ASPs. It is, however, less powerful than the TDT as a test of linkage for ASPs. What I show is that the differences between the TDT and Tsp are due to the fact that, although both statistics are based on preferential transmission of a marker allele, the TDT also exploits excess sharing in identity-by-descent transmissions to ASPs. Furthermore, I show that both of these statistics are members of a family of "TDT-like" statistics for ASPs. The statistics in this family are based on preferential transmission but also, to varying extents, exploit excess sharing. From this family of statistics, we see that, although the TDT exploits excess sharing to some extent, it is possible to do so to a greater extent-and thus produce a more powerful test of linkage, for ASPs, than is provided by the TDT. Power simulations conducted under a number of disease models are used to verify that the most powerful member of this family of TDT-like statistics is more powerful than the TDT for ASPs.

Identification of positive selection signatures in pigs by comparing linkage disequilibrium variances.

PubMed

Li, X; Yang, S; Dong, K; Tang, Z; Li, K; Fan, B; Wang, Z; Liu, B

2017-10-01

Selection affects the patterns of linkage disequilibrium (LD) around the site of a beneficial allele with an increase in LD among the hitchhiking alleles. Comparing the differences in regional LD between pig populations could help to identify putative genomic regions with potential adaptations for economic traits. In this study, using Illumina Porcine SNP60K BeadChip genotyping data from 207 Chinese indigenous, 117 South American village and 408 Large White pigs, we estimated the variation of genome-wide LD between populations using the varld program. The top 0.1% standardized VarLD scores were used as a criterion for all comparisons, and compared with LD blocks, a total of four selection signatures on Sus scrofa chromosome (SSC) 7, 9, 13 and 14 were identified in all populations. These signatures overlapped with quantitative trait loci for linoleic acid content, age at puberty, number of muscle fibers per unit area, hip structure and body weight traits in pigs. Among them, one of the signatures (56.5-56.6 Mb on SSC7) in Large White pigs harbored the ADAMTSL3 gene, which is known to affect body length. The findings of this study seem to point toward recent selection in different pig populations. Further investigations are encouraged to confirm the selection signatures detected by varld in the present study. © 2017 Stichting International Foundation for Animal Genetics.

Genome wide linkage disequilibrium and genetic structure in Sicilian dairy sheep breeds.

PubMed

Mastrangelo, Salvatore; Di Gerlando, Rosalia; Tolone, Marco; Tortorici, Lina; Sardina, Maria Teresa; Portolano, Baldassare

2014-10-10

The recent availability of sheep genome-wide SNP panels allows providing background information concerning genome structure in domestic animals. The aim of this work was to investigate the patterns of linkage disequilibrium (LD), the genetic diversity and population structure in Valle del Belice, Comisana, and Pinzirita dairy sheep breeds using the Illumina Ovine SNP50K Genotyping array. Average r (2) between adjacent SNPs across all chromosomes was 0.155 ± 0.204 for Valle del Belice, 0.156 ± 0.208 for Comisana, and 0.128 ± 0.188 for Pinzirita breeds, and some variations in LD value across chromosomes were observed, in particular for Valle del Belice and Comisana breeds. Average values of r (2) estimated for all pairwise combinations of SNPs pooled over all autosomes were 0.058 ± 0.023 for Valle del Belice, 0.056 ± 0.021 for Comisana, and 0.037 ± 0.017 for Pinzirita breeds. The LD declined as a function of distance and average r (2) was lower than the values observed in other sheep breeds. Consistency of results among the several used approaches (Principal component analysis, Bayesian clustering, F ST, Neighbor networks) showed that while Valle del Belice and Pinzirita breeds formed a unique cluster, Comisana breed showed the presence of substructure. In Valle del Belice breed, the high level of genetic differentiation within breed, the heterogeneous cluster in Admixture analysis, but at the same time the highest inbreeding coefficient, suggested that the breed had a wide genetic base with inbred individuals belonging to the same flock. The Sicilian breeds were characterized by low genetic differentiation and high level of admixture. Pinzirita breed displayed the highest genetic diversity (He, Ne) whereas the lowest value was found in Valle del Belice breed. This study has reported for the first time estimates of LD and genetic diversity from a genome-wide perspective in Sicilian dairy sheep breeds. Our results indicate that breeds formed non

Linkage disequilibrium and signatures of positive selection around LINE-1 retrotransposons in the human genome.

PubMed

Kuhn, Alexandre; Ong, Yao Min; Cheng, Ching-Yu; Wong, Tien Yin; Quake, Stephen R; Burkholder, William F

2014-06-03

Insertions of the human-specific subfamily of LINE-1 (L1) retrotransposon are highly polymorphic across individuals and can critically influence the human transcriptome. We hypothesized that L1 insertions could represent genetic variants determining important human phenotypic traits, and performed an integrated analysis of L1 elements and single nucleotide polymorphisms (SNPs) in several human populations. We found that a large fraction of L1s were in high linkage disequilibrium with their surrounding genomic regions and that they were well tagged by SNPs. However, L1 variants were only partially captured by SNPs on standard SNP arrays, so that their potential phenotypic impact would be frequently missed by SNP array-based genome-wide association studies. We next identified potential phenotypic effects of L1s by looking for signatures of natural selection linked to L1 insertions; significant extended haplotype homozygosity was detected around several L1 insertions. This finding suggests that some of these L1 insertions may have been the target of recent positive selection.

Population genomic structure and linkage disequilibrium analysis of South African goat breeds using genome-wide SNP data.

PubMed

Mdladla, K; Dzomba, E F; Huson, H J; Muchadeyi, F C

2016-08-01

The sustainability of goat farming in marginal areas of southern Africa depends on local breeds that are adapted to specific agro-ecological conditions. Unimproved non-descript goats are the main genetic resources used for the development of commercial meat-type breeds of South Africa. Little is known about genetic diversity and the genetics of adaptation of these indigenous goat populations. This study investigated the genetic diversity, population structure and breed relations, linkage disequilibrium, effective population size and persistence of gametic phase in goat populations of South Africa. Three locally developed meat-type breeds of the Boer (n = 33), Savanna (n = 31), Kalahari Red (n = 40), a feral breed of Tankwa (n = 25) and unimproved non-descript village ecotypes (n = 110) from four goat-producing provinces of the Eastern Cape, KwaZulu-Natal, Limpopo and North West were assessed using the Illumina Goat 50K SNP Bead Chip assay. The proportion of SNPs with minor allele frequencies >0.05 ranged from 84.22% in the Tankwa to 97.58% in the Xhosa ecotype, with a mean of 0.32 ± 0.13 across populations. Principal components analysis, admixture and pairwise FST identified Tankwa as a genetically distinct population and supported clustering of the populations according to their historical origins. Genome-wide FST identified 101 markers potentially under positive selection in the Tankwa. Average linkage disequilibrium was highest in the Tankwa (r(2)  = 0.25 ± 0.26) and lowest in the village ecotypes (r(2) range = 0.09 ± 0.12 to 0.11 ± 0.14). We observed an effective population size of <150 for all populations 13 generations ago. The estimated correlations for all breed pairs were lower than 0.80 at marker distances >100 kb with the exception of those in Savanna and Tswana populations. This study highlights the high level of genetic diversity in South African indigenous goats as well as the utility of the genome-wide SNP marker panels in

Multilocus Patterns of Nucleotide Diversity, Population Structure and Linkage Disequilibrium in Boechera stricta, a Wild Relative of Arabidopsis

PubMed Central

Song, Bao-Hua; Windsor, Aaron J.; Schmid, Karl J.; Ramos-Onsins, Sebastian; Schranz, M. Eric; Heidel, Andrew J.; Mitchell-Olds, Thomas

2009-01-01

Information about polymorphism, population structure, and linkage disequilibrium (LD) is crucial for association studies of complex trait variation. However, most genomewide studies have focused on model systems, with very few analyses of undisturbed natural populations. Here, we sequenced 86 mapped nuclear loci for a sample of 46 genotypes of Boechera stricta and two individuals of B. holboellii, both wild relatives of Arabidopsis. Isolation by distance was significant across the species range of B. stricta, and three geographic groups were identified by structure analysis, principal coordinates analysis, and distance-based phylogeny analyses. The allele frequency spectrum indicated a genomewide deviation from an equilibrium neutral model, with silent nucleotide diversity averaging 0.004. LD decayed rapidly, declining to background levels in ∼10 kb or less. For tightly linked SNPs separated by <1 kb, LD was dependent on the reference population. LD was lower in the specieswide sample than within populations, suggesting that low levels of LD found in inbreeding species such as B. stricta, Arabidopsis thaliana, and barley may result from broad geographic sampling that spans heterogeneous genetic groups. Finally, analyses also showed that inbreeding B. stricta and A. thaliana have ∼45% higher recombination per kilobase than outcrossing A. lyrata. PMID:19104077

Genome-wide linkage disequilibrium and past effective population size in three Korean cattle breeds.

PubMed

Sudrajad, P; Seo, D W; Choi, T J; Park, B H; Roh, S H; Jung, W Y; Lee, S S; Lee, J H; Kim, S; Lee, S H

2017-02-01

The routine collection and use of genomic data are useful for effectively managing breeding programs for endangered populations. Linkage disequilibrium (LD) using high-density DNA markers has been widely used to determine population structures and predict the genomic regions that are associated with economic traits in beef cattle. The extent of LD also provides information about historical events, including past effective population size (N e ), and it allows inferences on the genetic diversity of breeds. The objective of this study was to estimate the LD and N e in three Korean cattle breeds that are genetically similar but have different coat colors (Brown, Brindle and Jeju Black Hanwoo). Brindle and Jeju Black are endangered breeds with small populations, whereas Brown Hanwoo is the main breeding population in Korea. DNA samples from these cattle breeds were genotyped using the Illumina BovineSNP50 Bead Chip. We examined 13 cattle breeds, including European taurines, African taurines and indicines, and hybrids to compare their LD values. Brown Hanwoo consistently had the lowest mean LD compared to Jeju Black, Brindle and the other 13 cattle breeds (0.13, 0.19, 0.21 and 0.15-0.22 respectively). The high LD values of Brindle and Jeju Black contributed to small N e values (53 and 60 respectively), which were distinct from that of Brown Hanwoo (531) for 11 generations ago. The differences in LD and N e for each breed reflect the breeding strategy applied. The N e for these endangered cattle breeds remain low; thus, effort is needed to bring them back to a sustainable tract. © 2016 Stichting International Foundation for Animal Genetics.

Measuring and partitioning the high-order linkage disequilibrium by multiple order Markov chains.

PubMed

Kim, Yunjung; Feng, Sheng; Zeng, Zhao-Bang

2008-05-01

A map of the background levels of disequilibrium between nearby markers can be useful for association mapping studies. In order to assess the background levels of linkage disequilibrium (LD), multilocus LD measures are more advantageous than pairwise LD measures because the combined analysis of pairwise LD measures is not adequate to detect simultaneous allele associations among multiple markers. Various multilocus LD measures based on haplotypes have been proposed. However, most of these measures provide a single index of association among multiple markers and does not reveal the complex patterns and different levels of LD structure. In this paper, we employ non-homogeneous, multiple order Markov Chain models as a statistical framework to measure and partition the LD among multiple markers into components due to different orders of marker associations. Using a sliding window of multiple markers on phased haplotype data, we compute corresponding likelihoods for different Markov Chain (MC) orders in each window. The log-likelihood difference between the lowest MC order model (MC0) and the highest MC order model in each window is used as a measure of the total LD or the overall deviation from the gametic equilibrium for the window. Then, we partition the total LD into lower order disequilibria and estimate the effects from two-, three-, and higher order disequilibria. The relationship between different orders of LD and the log-likelihood difference involving two different orders of MC models are explored. By applying our method to the phased haplotype data in the ENCODE regions of the HapMap project, we are able to identify high/low multilocus LD regions. Our results reveal that the most LD in the HapMap data is attributed to the LD between adjacent pairs of markers across the whole region. LD between adjacent pairs of markers appears to be more significant in high multilocus LD regions than in low multilocus LD regions. We also find that as the multilocus total LD

Linkage disequilibrium and population structure in wild and domesticated populations of Phaseolus vulgaris L.

PubMed Central

Rossi, Monica; Bitocchi, Elena; Bellucci, Elisa; Nanni, Laura; Rau, Domenico; Attene, Giovanna; Papa, Roberto

2009-01-01

Together with the knowledge of the population structure, a critical aspect for the planning of association and/or population genomics studies is the level of linkage disequilibrium (LD) that characterizes the species and the population used for such an analysis. We have analyzed the population structure and LD in wild and domesticated populations of Phaseolus vulgaris L. using amplified fragment length polymorphism markers, most of which were genetically mapped in two recombinant inbred populations. Our results reflect the previous knowledge of the occurrence of two major wild gene pools of P. vulgaris, from which two independent domestication events originated, one in the Andes and one in Mesoamerica. The high level of LD in the whole sample was mostly due to the gene pool structure, with a much higher LD in domesticated compared to wild populations. In relation to association studies, our results also suggest that whole-genome-scan approaches are feasible in the common bean. Interestingly, an excess of inter-chromosomal LD was found in the domesticated populations, which suggests an important role for epistatic selection during domestication. Moreover, our results indicate the occurrence of a strong bottleneck in the Andean wild population before domestication, suggesting a Mesoamerican origin of P. vulgaris. Finally, our data support the occurrence of a single domestication event in Mesoamerica, and the same scenario in the Andes. PMID:25567895

A Comprehensive Linkage Map of the Dog Genome

PubMed Central

Wong, Aaron K.; Ruhe, Alison L.; Dumont, Beth L.; Robertson, Kathryn R.; Guerrero, Giovanna; Shull, Sheila M.; Ziegle, Janet S.; Millon, Lee V.; Broman, Karl W.; Payseur, Bret A.; Neff, Mark W.

2010-01-01

We have leveraged the reference sequence of a boxer to construct the first complete linkage map for the domestic dog. The new map improves access to the dog's unique biology, from human disease counterparts to fascinating evolutionary adaptations. The map was constructed with ∼3000 microsatellite markers developed from the reference sequence. Familial resources afforded 450 mostly phase-known meioses for map assembly. The genotype data supported a framework map with ∼1500 loci. An additional ∼1500 markers served as map validators, contributing modestly to estimates of recombination rate but supporting the framework content. Data from ∼22,000 SNPs informing on a subset of meioses supported map integrity. The sex-averaged map extended 21 M and revealed marked region- and sex-specific differences in recombination rate. The map will enable empiric coverage estimates and multipoint linkage analysis. Knowledge of the variation in recombination rate will also inform on genomewide patterns of linkage disequilibrium (LD), and thus benefit association, selective sweep, and phylogenetic mapping approaches. The computational and wet-bench strategies can be applied to the reference genome of any nonmodel organism to assemble a de novo linkage map. PMID:19966068

X-chromosome as a marker for population history: linkage disequilibrium and haplotype study in Eurasian populations

PubMed Central

Laan, Maris; Wiebe, Victor; Khusnutdinova, Elza; Remm, Maido; Pääbo, Svante

2005-01-01

Linkage disequilibrium structure is still unpredictable because the interplay of regional recombination rate and demographic history is poorly understood. We have compared the distribution of LD across two genomic regions differing in crossing-over activity – Xq13 (0.166 cM/Mb) and Xp22 (1.3 cM/Mb) – in 15 Eurasian populations. Demographic events predicted to increase the LD level – genetic drift, bottleneck and admixture – had a very strong impact on extent and patterns of regional LD across Xq13 compared to Xp22. The haplotype distribution of the DXS1225-DXS8082 microsatellites from Xq13 exhibiting strong association in all populations was remarkably influenced by population history. European populations shared one common haplotype with a frequency of 25-40%. The Volga-Ural populations studied, living at the geographic borderline of Europe, showed elevated LD as well as harboring a significant fraction of haplotypes originating from East Asia, thus reflecting their past migrations and admixture. In the young Kuusamo isolate from Finland, a bottleneck has led to allelic associations between loci and shifted the haplotype distribution, but has much less affected single microsatellite allele frequencies compared to the main Finnish population. The data show that the footprint of a demographic event is longer preserved in haplotype distribution within a region of low crossing-over rate, than in the information content of a single marker, or between actively recombining markers. As the knowledge of LD patterns is often chosen to assist association mapping of common disease, our conclusions emphasise the importance of understanding the history, structure and variation of a study population. PMID:15657606

Linkage disequilibrium between polymorphisms of ABCB1 and ABCC2 to predict the treatment outcome of Malaysians with complex partial seizures on treatment with carbamazepine mono-therapy at the Kuala Lumpur Hospital.

PubMed

Subenthiran, Soobitha; Abdullah, Noor Rain; Joseph, Joyce Pauline; Muniandy, Prem Kumar; Mok, Boon Teck; Kee, Chee Cheong; Ismail, Zakiah; Mohamed, Zahurin

2013-01-01

Carbamazepine (CBZ) is used as the first line of treatment of Complex Partial Seizures (CPS) in the Epilepsy Clinic, Neurology Department of Kuala Lumpur Hospital (KLH). More than 30% of the patients remain drug resistant to CBZ mono-therapy. CBZ is transported by the P-glycoprotein (P-gp). The P-gp encoded by the ABCB1 and ABCC2 genes are expressed in drug resistant patients with epilepsy. A few studies have shown significant association between CBZ resistant epilepsy and Linkage Disequilibrium (LD) with adjacent polymorphisms of these genes. Our study is aimed at determining the correlation between patients' response to CBZ mono-therapy to Single Nucleotide Polymorphisms G2677T and C3435T of the ABCB1 gene as well as G1249A and -24C>T of the ABCC2 gene. 314 patients with CPS were recruited from the Neurology Department of the KLH based on stringent inclusion and exclusion criteria, of whom 152 were responders and the other 162 were non-responders. DNA was extracted from their blood samples and Taqman technology for allelic discrimination was performed. Results were described as genotype frequencies. The SHEsis analysis platform was used to calculate linkage disequilibrium index and infer haplotype frequencies. Haploview was used to do permutation test to obtain a corrected p-value. Resistance to treatment with CBZ mono-therapy was significantly associated with the 2677TT and the 3435TT genotypes while it was not significantly associated with the G1249A and -24C>T polymorphisms. The GCGC haplotype combination of the 2677G>T, 3435C>T, 1249G>A and -24C>T respectively was found to be extremely significant (p = 1.10e-20) with good drug response to CBZ mono-therapy. Linkage disequilibrium between the 2677G>T, 3435C>T, 1249G>A and -24C>T SNPs may be used as a reliable screening marker to determine the treatment outcome of CBZ mono-therapy with CPS irrespective of race or gender.

Identification of a Linkage Disequilibrium Block in Chromosome 1q Associated With BMD in Premenopausal White Women

PubMed Central

Ichikawa, Shoji; Koller, Daniel L; Curry, Leah R; Lai, Dongbing; Xuei, Xiaoling; Pugh, Elizabeth W; Tsai, Ya-Yu; Doheny, Kimberly F; Edenberg, Howard J; Hui, Siu L; Foroud, Tatiana; Peacock, Munro; Econs, Michael J

2008-01-01

Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporotic fractures is peak BMD obtained during young adulthood. We previously reported linkage of chromosome 1q (LOD = 4.3) with variation in spinal areal BMD in healthy premenopausal white women. In this study, we used a two-stage genotyping approach to identify genes in the linked region that contributed to the variation of femoral neck and lumbar spine areal BMD. In the first stage, 654 SNPs across the linked region were genotyped in a sample of 1309 premenopausal white women. The most significant evidence of association for lumbar spine (p = 1.3 × 10−6) was found with rs1127091 in the GATAD2B gene. In the second stage, 52 SNPs around this candidate gene were genotyped in an expanded sample of 1692 white women. Significant evidence of association with spinal BMD (p < 10−5), and to a lesser extent with femoral neck BMD, was observed with eight SNPs within a single 230-kb linkage disequilibrium (LD) block. The most significant SNP (p = 3.4 × 10−7) accounted for >2.5% of the variation in spinal BMD in these women. The 230-kb LD block contains 11 genes, but because of the extensive LD, the specific gene(s) contributing to the variation in BMD could not be determined. In conclusion, the significant association between spinal BMD and SNPs in the 230-kb LD block in chromosome 1q indicates that genetic factor(s) in this block plays an important role in peak spinal BMD in healthy premenopausal white women. PMID:18505370

Uneven recombination rate and linkage disequilibrium across a reference SNP map for common bean (Phaseolus vulgaris L.)

PubMed Central

Farmer, Andrew D.; Huang, Wei; Ambachew, Daniel; Penmetsa, R. Varma; Carrasquilla-Garcia, Noelia; Assefa, Teshale; Cannon, Steven B.

2018-01-01

Recombination (R) rate and linkage disequilibrium (LD) analyses are the basis for plant breeding. These vary by breeding system, by generation of inbreeding or outcrossing and by region in the chromosome. Common bean (Phaseolus vulgaris L.) is a favored food legume with a small sequenced genome (514 Mb) and n = 11 chromosomes. The goal of this study was to describe R and LD in the common bean genome using a 768-marker array of single nucleotide polymorphisms (SNP) based on Trans-legume Orthologous Group (TOG) genes along with an advanced-generation Recombinant Inbred Line reference mapping population (BAT93 x Jalo EEP558) and an internationally available diversity panel. A whole genome genetic map was created that covered all eleven linkage groups (LG). The LGs were linked to the physical map by sequence data of the TOGs compared to each chromosome sequence of common bean. The genetic map length in total was smaller than for previous maps reflecting the precision of allele calling and mapping with SNP technology as well as the use of gene-based markers. A total of 91.4% of TOG markers had singleton hits with annotated Pv genes and all mapped outside of regions of resistance gene clusters. LD levels were found to be stronger within the Mesoamerican genepool and decay more rapidly within the Andean genepool. The recombination rate across the genome was 2.13 cM / Mb but R was found to be highly repressed around centromeres and frequent outside peri-centromeric regions. These results have important implications for association and genetic mapping or crop improvement in common bean. PMID:29522524

Population structure and linkage disequilibrium in Lupinus albus L. germplasm and its implication for association mapping.

PubMed

Iqbal, Muhammad Javed; Mamidi, Sujan; Ahsan, Rubina; Kianian, Shahryar F; Coyne, Clarice J; Hamama, Anwar A; Narina, Satya S; Bhardwaj, Harbans L

2012-08-01

White lupin (Lupinus albus L.) has been around since 300 B.C. and is recognized for its ability to grow on poor soils and application as green manure in addition to seed harvest. The seed has very high levels of protein (33-47 %) and oil (6-13 %). It also has many secondary metabolites that are potentially of nutraceutical value to animals and humans. Despite such a great potential, lupins role in modern agriculture began only in the twentieth century. Although a large collection of Lupinus germplasm accessions is available worldwide, rarely have they been genetically characterized. Additionally, scarce genomic resources in terms of recombinant populations and genome information have been generated for L. albus. With the advancement in association mapping methods, the natural populations have the potential to replace the recombinant populations in gene mapping and marker-trait associations. Therefore, we studied the genetic similarity, population structure and marker-trait association in a USDA germplasm collection for their current and future application in this crop improvement. A total of 122 PI (Plant Inventory) lines were screened with 18 AFLP primer pairs that generated 2,277 fragments. A subset of 892 polymorphic markers with MAF >0.05 (minor allele frequency) were used for association mapping. The cluster analysis failed to group accessions on the basis of their passport information, and a weak structure and low linkage disequilibrium (LD) were observed indicating the usefulness of the collection for association mapping. Moreover, we were also able to identify two markers (a p value of 1.53 × 10(-4) and 2.3 × 10(-4)) that explained 22.69 and 20.5 % of seed weight variation determined using R (LR) (2) . The implications of lack of geographic clustering, population structure, low LD and the ability of AFLP to map seed weight trait using association mapping and the usefulness of the PI collections in breeding programs are discussed.

Evaluation of Linkage Disequilibrium Pattern and Association Study on Seed Oil Content in Brassica napus Using ddRAD Sequencing.

PubMed

Wu, Zhikun; Wang, Bo; Chen, Xun; Wu, Jiangsheng; King, Graham J; Xiao, Yingjie; Liu, Kede

2016-01-01

High-density genetic markers are the prerequisite for understanding linkage disequilibrium (LD) and genome-wide association studies (GWASs) of complex traits in crops. To evaluate the LD pattern in oilseed rape, we sequenced a previous association panel containing 189 B. napus inbred lines using double-digested restriction-site associated DNA (ddRAD) and genotyped 19,327 RAD tags. A total of 15,921 RAD tags were assigned to a published genetic linkage map and the majority (71.1%) of these tags was uniquely mapped to the draft reference genome "Darmor-bzh." The distance of LD decay was 1,214 kb across the genome at the background level (r2 = 0.26), with the distances of LD decay being 405 kb and 2,111 kb in the A and C subgenomes, respectively. A total of 361 haplotype blocks with length > 100 kb were identified in the entire genome. The association panel could be classified into two groups, P1 and P2, which are essentially consistent with the geographical origins of varieties. A large number of group-specific haplotypes were identified, reflecting that varieties in the P1 and P2 groups experienced distinct selection in breeding programs to adapt their different growth habitats. GWAS repeatedly detected two loci significantly associated with oil content of seeds based on the developed SNPs, suggesting that the high-density SNPs were useful for understanding the genetic determinants of complex traits in GWAS.

Linkage disequilibrium between polymorphisms at the 5{prime} untranslated region and intron 5 (Dde I) of the antithrombin III (ATIII) gene in the Chinese

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tay, J.S.H.; Liu, Y.; Low, P.S.

A length polymorphism at the 5{prime} untranslated region of exon 1 and an RFLP (Dde I) in intron 5 (nt 160) of the ATIII gene were amplified by polymerase chain reaction with primers of published sequences. DNA fragments were size-fractionated by agarose gel electrophoresis (3% NuSieve and 1% Seakem GTG) and photographed over a UV transilluminator. A strong linkage disequilibrium was observed between these two polymorphisms of the ATIII gene in the Chinese ({chi}{sup 2} = 63.7; {triangle} 0.42, P < 0.001). The estimated frequencies of the three haplotypes were found to be 0.37 for SD+, 0.40 for LD+ andmore » 0.23 for LD-.« less

Refined mapping of a gene responsible for Fukuyama-type congenital muscular dystrophy: Evidence for strong linkage disequilibrium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Toda, Tatsushi; Ikegawa, Shiro; Okui, Keiko

1994-11-01

Fukuyama-type congenital muscular dystrophy (FCMD), the second most common form of childhood muscular dystrophy in Japan, is an autosomal recessive severe muscular dystrophy associated with an anomaly of the brain. After our initial mapping of the FCMD locus to chromosome 9q31-33, we further defined the locus within a region of {approximately}5 cM between loci D9S127 and CA246, by homozygosity mapping in patients born to consanguineous marriages and by recombination analyses in other families. We also found evidence for strong linkage disequilibrium between FCMD and a polymorphic microsatellite marker, mfd220, which showed no recombination and a lod score of (Z) 17.49.more » A {open_quotes}111-bp{close_quotes} allele for the mfd220 was observed in 22 (34%) of 64 FCMD chromosomes, but it was present in only 1 of 120 normal chromosomes. This allelic association with FCMD was highly significant ({chi}{sup 2} = 50.7; P < .0001). Hence, we suspect that the FCMD gene could lie within a few hundred kilobases of the mfd220 locus. 32 refs., 2 figs., 2 tabs.« less

Genetic diversity and linkage disequilibrium in the chemokine receptor CCR2-CCR5 region among individuals and populations

PubMed Central

Lawhorn, Collene; Yuferov, Vadim; Randesi, Matthew; Ho, Ann; Morgello, Susan; Kreek, Mary Jeanne; Levran, Orna

2013-01-01

Background Chemokine receptors CCR2 and CCR5 play a key role in immune and inflammatory responses and have been associated with several diseases, including AIDS. In order to comprehend health disparities it is important to understand the nature of genetic variation in specific genes of interest in different populations. Current studies of the CCR2 and CCR5 receptor genes are primarily focused on the CCR5-Δ32, and CCR2-V64I SNPs. Methods Sanger sequencing was used to sequence the regions containing 16 SNPs in the adjacent CCR2 and CCR5 genes (including CCR5-Δ32, and CCR2-V64I) in 249 subjects of African, European and Hispanic ancestry. Linkage disequilibrium (LD) and haplotypes were determined using Haploview. Results The data revealed large differences in allele frequencies of several SNPs and LD patterns among the ethnic groups, including SNPs that were restricted to Africans or Europeans. Seven known CCR5 haplotypes and six novel CCR2 haplotypes were identified. A rare case of an HIV+ subject with the CCR5-Δ32/Δ32 was identified. Conclusions These data demonstrate a LD between CCR2 and CCR5 at several loci and provide new information about CCR2 that contributes to our understanding of its population-specific genetic variability. The data indicate that in addition to CCR5-Δ32 and CCR2-V64I, other SNPs and haplotypes may be important genetic determinants of disease and should be investigated. PMID:24011637

Increased level of linkage disequilibrium in rural compared with urban communities: a factor to consider in association-study design.

PubMed

Vitart, Veronique; Carothers, Andrew D; Hayward, Caroline; Teague, Peter; Hastie, Nicholas D; Campbell, Harry; Wright, Alan F

2005-05-01

Few studies have investigated genetic differentiation within nonisolate European populations, despite the initiation of large national sample collections such as U.K. Biobank. Here, we used short tandem repeat markers to explore fine-scale genetic structure and to examine the extent of linkage disequilibrium (LD) within national subpopulations. We studied 955 unrelated individuals of local ancestry from nine Scottish rural regions and the urban center of Edinburgh, as well as 96 unrelated individuals from the general U.K. population. Despite little overall differentiation on the basis of allele frequencies, there were clear differences among subpopulations in the extent of pairwise LD, measured between a subset of X-linked markers, that reflected presumed differences in the depths of the underlying genealogies within these subpopulations. Therefore, there are strategic advantages in studying rural subpopulations, in terms of increased power and reduced cost, that are lost by sampling across regions or within urban populations. Similar rural-urban contrasts are likely to exist in many other populations with stable rural subpopulations, which could influence the design of genetic association studies and national biobank data collections.

Chromosome-wide linkage disequilibrium caused by an inversion polymorphism in the white-throated sparrow (Zonotrichia albicollis).

PubMed

Huynh, L Y; Maney, D L; Thomas, J W

2011-04-01

Chromosomal inversions have been of long-standing interest to geneticists because they are capable of suppressing recombination and facilitating the formation of adaptive gene complexes. An exceptional inversion polymorphism (ZAL2(m)) in the white-throated sparrow (Zonotrichia albicollis) is linked to variation in plumage, social behavior and mate choice, and is maintained in the population by negative assortative mating. The ZAL2(m) polymorphism is a complex inversion spanning > 100 Mb and has been proposed to be a strong suppressor of recombination, as well as a potential model for studying neo-sex chromosome evolution. To quantify and evaluate these features of the ZAL2(m) polymorphism, we generated sequence from 8 ZAL2(m) and 16 ZAL2 chromosomes at 58 loci inside and 4 loci outside the inversion. Inside the inversion we found that recombination was completely suppressed between ZAL2 and ZAL2(m), resulting in uniformly high levels of genetic differentiation (F(ST)=0.94), the formation of two distinct haplotype groups representing the alternate chromosome arrangements and extensive linkage disequilibrium spanning ~104 Mb within the inversion, whereas gene flow was not suppressed outside the inversion. Finally, although ZAL2(m) homozygotes are exceedingly rare in the population, occurring at a frequency of < 1%, we detected evidence of historical recombination between ZAL2(m) chromosomes inside the inversion, refuting its potential status as a non-recombining autosome.

Multilocus Patterns of Nucleotide Diversity, Linkage Disequilibrium and Demographic History of Norway Spruce [Picea abies (L.) Karst

PubMed Central

Heuertz, Myriam; De Paoli, Emanuele; Källman, Thomas; Larsson, Hanna; Jurman, Irena; Morgante, Michele; Lascoux, Martin; Gyllenstrand, Niclas

2006-01-01

DNA polymorphism at 22 loci was studied in an average of 47 Norway spruce [Picea abies (L.) Karst.] haplotypes sampled in seven populations representative of the natural range. The overall nucleotide variation was limited, being lower than that observed in most plant species so far studied. Linkage disequilibrium was also restricted and did not extend beyond a few hundred base pairs. All populations, with the exception of the Romanian population, could be divided into two main domains, a Baltico–Nordic and an Alpine one. Mean Tajima's D and Fay and Wu's H across loci were both negative, indicating the presence of an excess of both rare and high-frequency-derived variants compared to the expected frequency spectrum in a standard neutral model. Multilocus neutrality tests based on D and H led to the rejection of the standard neutral model and exponential growth in the whole population as well as in the two main domains. On the other hand, in all three cases the data are compatible with a severe bottleneck occurring some hundreds of thousands of years ago. Hence, demographic departures from equilibrium expectations and population structure will have to be accounted for when detecting selection at candidate genes and in association mapping studies, respectively. PMID:17057229

Linkage disequilibrium with HLA-DRB1-DQB1 haplotypes explains the association of TNF-308G>A variant with type 1 diabetes in a Brazilian cohort.

PubMed

Patente, Thiago A; Monteiro, Maria B; Vieira, Suzana M; Rossi da Silva, Maria E; Nery, Márcia; Queiroz, Márcia; Azevedo, Mirela J; Canani, Luis H; Parisi, Maria C; Pavin, Elizabeth J; Mainardi, Débora; Javor, Juraj; Velho, Gilberto; Coimbra, Cássio N; Corrêa-Giannella, Maria Lúcia

2015-08-15

A functional variant in the promoter region of the gene encoding tumor necrosis factor (TNF; rs1800629, -308G>A) showed to confer susceptibility to T1D. However, TNF rs1800629 was found, in several populations, to be in linkage disequilibrium with HLA susceptibility haplotypes to T1D. We evaluated the association of TNF rs1800629 with T1D in a cohort of Brazilian subjects, and assessed the impact of HLA susceptibility haplotypes in this association. 659 subjects with T1D and 539 control subjects were genotyped for TNF-308G>A variant. HLA-DRB1 and HLA-DQB1 genes were genotyped in a subset of 313 subjects with T1D and 139 control subjects. Associations with T1D were observed for the A-allele of rs1800629 (OR 1.69, 95% CI 1.33-2.15, p<0.0001, in a codominant model) and for 3 HLA haplotypes: DRB1*03:01-DQB1*02:01 (OR 5.37, 95% CI 3.23-8.59, p<0.0001), DRB1*04:01-DQB1*03:02 (OR 2.95, 95% CI 1.21-7.21, p=0.01) and DRB1*04:02-DQB1*03:02 (OR 2.14, 95% CI 1.02-4.50, p=0.04). Linkage disequilibrium was observed between TNF rs1800629 and HLA-DRB1 and HLA-DQB1 alleles. In a stepwise regression analysis HLA haplotypes, but not TNF rs1800629, remained independently associated with T1D. Our results do not support an independent effect of allelic variations of TNF in the genetic susceptibility to T1D. Copyright © 2015 Elsevier B.V. All rights reserved.

Linkage disequilibrium at the APA insecticidal seed protein locus of common bean (Phaseolus vulgaris L.).

PubMed

Blair, Matthew W; Prieto, Sergio; Díaz, Lucy M; Buendía, Héctor F; Cardona, César

2010-04-29

An interesting seed protein family with a role in preventing insect herbivory is the multi-gene, APA family encoding the alpha-amylase inhibitor, phytohemagglutinin and arcelin proteins of common bean (Phaseolus vulgaris). Variability for this gene family exists and has been exploited to breed for insect resistance. For example, the arcelin locus has been successfully transferred from wild to cultivated common bean genotypes to provide resistance against the bruchid species Zabrotes subfasciatus although the process has been hampered by a lack of genetic tools for and understanding about the locus. In this study, we analyzed linkage disequilibrium (LD) between microsatellite markers at the APA locus and bruchid resistance in a germplasm survey of 105 resistant and susceptible genotypes and compared this with LD in other parts of the genome. Microsatellite allele diversity was found to vary with each of the eight APA-linked markers analyzed, and two markers within the APA locus were found to be diagnostic for bruchid resistance or susceptibility and for the different arcelin alleles inherited from the wild accessions. Arc1 was found to provide higher levels of resistance than Arc5 and the markers in the APA locus were highly associated with resistance showing that introgression of this gene-family from wild beans provides resistance in cultivated beans. LD around the APA locus was found to be intermediate compared to other regions of the genome and the highest LD was found within the APA locus itself for example between the markers PV-atct001 and PV-ag004. We found the APA locus to be an important genetic determinant of bruchid resistance and also found that LD existed mostly within the APA locus but not beyond it. Moderate LD was also found for some other regions of the genome perhaps related to domestication genes. The LD pattern may reflect the introgression of arcelin from the wild into the cultivated background through breeding. LD and association studies for

Linkage Disequilibrium Mapping in Domestic Dog Breeds Narrows the Progressive Rod-Cone Degeneration (prcd) Interval and Identifies Ancestral Disease Transmitting Chromosome

PubMed Central

Goldstein, Orly; Zangerl, Barbara; Pearce-Kelling, Sue; Sidjanin, Duska J.; Kijas, James W.; Felix, Jeanette; Acland, Gregory M; Aguirre, Gustavo D.

2014-01-01

Canine progressive rod-cone degeneration (prcd) is a retinal disease previously mapped to a broad, gene-rich centromeric region of canine chromosome 9. As allelic disorders are present in multiple breeds, we used linkage disequilibrium (LD) to narrow the ∼6.4 Mb interval candidate region. Multiple dog breeds, each representing genetically isolated populations, were typed for SNPs and other polymorphisms identified from BACs. The candidate region was initially localized to a 1.5 Mb zero recombination interval between growth factor receptor-bound protein 2 (GRB2) and SEC14-like 1 (SEC14L). A fine-scale haplotype of the region was developed which reduced the LD interval to 106 Kb, and identified a conserved haplotype of 98 polymorphisms present in all prcd-affected chromosomes from 14 different dog breeds. The findings strongly suggest that a common ancestor transmitted the prcd disease allele to many of the modern dog breeds, and demonstrate the power of LD approach in the canine model. PMID:16859891

CYP21A2 polymorphisms in patients with autoimmune Addison's disease, and linkage disequilibrium to HLA risk alleles.

PubMed

Brønstad, Ingeborg; Skinningsrud, Beate; Bratland, Eirik; Løvås, Kristian; Undlien, Dag; Sverre Husebye, Eystein; Wolff, Anette Susanne Bøe

2014-12-01

Steroid 21-hydroxylase, encoded by CYP21A2, is the major autoantigen in autoimmune Addison's disease (AAD). CYP21A2 is located in the region of the HLA complex on chromosome 6p21.3, which harbours several risk alleles for AAD. The objective was to investigate whether CYP21A2 gene variants confer risk of AAD independently of other risk alleles in the HLA loci. DNA samples from 381 Norwegian patients with AAD and 340 healthy controls (HC) previously genotyped for the HLA-A, -B, -DRB1, and -DQB1 and MICA loci were used for genotyping of CYP21A2. Genotyping of CYP21A2 was carried out by direct sequencing. Linkage of CYP21A2 to the HLA loci was assessed using UNPHASED version 3.0.10 and PHASE version 2.1. Heterozygotes of the single-nucleotide polymorphisms (SNPs) rs397515394, rs6467, rs6474, rs76565726 and rs6473 were detected significantly more frequently in AAD patients compared with HC (P<0.005), but all SNPs were in a linkage disequilibrium (LD) with high-risk HLA-DRB1 haplotypes. rs6472C protected against AAD (odds ratio=0.15, 95% CI (0.08-0.30), P=3.8×10(-10)). This SNP was not in an LD with HLA loci (P=0.02), but did not increase protection when considering the effect of HLA-DRB1 alleles. Mutations causing congenital adrenal hyperplasia were found in heterozygosity in <1.5% of the cases in both groups. Genetic variants of CYP21A2 associated to AAD are in LD with the main AAD risk locus HLA-DRB1, and CYP21A2 does not constitute an independent susceptibility locus. © 2014 European Society of Endocrinology.

Genetics of recurrent early-onset major depression (GenRED): significant linkage on chromosome 15q25-q26 after fine mapping with single nucleotide polymorphism markers.

PubMed

Levinson, Douglas F; Evgrafov, Oleg V; Knowles, James A; Potash, James B; Weissman, Myrna M; Scheftner, William A; Depaulo, J Raymond; Crowe, Raymond R; Murphy-Eberenz, Kathleen; Marta, Diana H; McInnis, Melvin G; Adams, Philip; Gladis, Madeline; Miller, Erin B; Thomas, Jo; Holmans, Peter

2007-02-01

The authors studied a dense map of single nucleotide polymorphism (SNP) DNA markers on chromosome 15q25-q26 to maximize the informativeness of genetic linkage analyses in a region where they previously reported suggestive evidence for linkage of recurrent early-onset major depressive disorder. In 631 European-ancestry families with multiple cases of recurrent early-onset major depressive disorder, 88 SNPs were genotyped, and multipoint allele-sharing linkage analyses were carried out. Marker-marker linkage disequilibrium was minimized, and a simulation study with founder haplotypes from these families suggested that linkage scores were not inflated by linkage disequilibrium. The dense SNP map increased the information content of the analysis from around 0.7 to over 0.9. The maximum evidence for linkage was the Z likelihood ratio score statistic of Kong and Cox (Z(LR))=4.69 at 109.8 cM. The exact p value was below the genomewide significance threshold. By contrast, in the genome scan with microsatellite markers at 9 cM spacing, the maximum Z(LR) for European-ancestry families was 3.43 (106.53 cM). It was estimated that the linked locus or loci in this region might account for a 20% or less populationwide increase in risk to siblings of cases. This region has produced modestly positive evidence for linkage to depression and related traits in other studies. These results suggest that DNA sequence variations in one or more genes in the 15q25-q26 region can increase susceptibility to major depression and that efforts are warranted to identify these genes.

Whole genome sequences are required to fully resolve the linkage disequilibrium structure of human populations.

PubMed

Pengelly, Reuben J; Tapper, William; Gibson, Jane; Knut, Marcin; Tearle, Rick; Collins, Andrew; Ennis, Sarah

2015-09-03

An understanding of linkage disequilibrium (LD) structures in the human genome underpins much of medical genetics and provides a basis for disease gene mapping and investigating biological mechanisms such as recombination and selection. Whole genome sequencing (WGS) provides the opportunity to determine LD structures at maximal resolution. We compare LD maps constructed from WGS data with LD maps produced from the array-based HapMap dataset, for representative European and African populations. WGS provides up to 5.7-fold greater SNP density than array-based data and achieves much greater resolution of LD structure, allowing for identification of up to 2.8-fold more regions of intense recombination. The absence of ascertainment bias in variant genotyping improves the population representativeness of the WGS maps, and highlights the extent of uncaptured variation using array genotyping methodologies. The complete capture of LD patterns using WGS allows for higher genome-wide association study (GWAS) power compared to array-based GWAS, with WGS also allowing for the analysis of rare variation. The impact of marker ascertainment issues in arrays has been greatest for Sub-Saharan African populations where larger sample sizes and substantially higher marker densities are required to fully resolve the LD structure. WGS provides the best possible resource for LD mapping due to the maximal marker density and lack of ascertainment bias. WGS LD maps provide a rich resource for medical and population genetics studies. The increasing availability of WGS data for large populations will allow for improved research utilising LD, such as GWAS and recombination biology studies.

Linkage disequilibrium analysis in young populations: Pseudo-vitamin D-deficiency rickets and the founder effect in French Canadians

DOE Office of Scientific and Technical Information (OSTI.GOV)

Labuda, M.; Glorieux, F.H.; Labuda, D.

1996-09-01

Pseudo-vitamin D-deficiency rickets (PDDR) was mapped close to D12S90 and between proximal D12S312 and distal (D12S305, D12S104) microsatellites that were subsequently found on a single YAC clone. Analysis of a complex haplotype in linkage disequilibrium (LD) with the disease discriminated among distinct founder effects in French Canadian populations in Acadia and in Charlevoix-Saguenay-Lac-Saint-Jean (Ch-SLSJ), as well as an earlier one in precolonial Europe. A simple demographic model suggested the historical age of the founder effect in Ch-SLSJ to be {approximately}12 generations. The corresponding LD data are consistent with this figure when they are analyzed within the framework of Luria-Delbruck model,more » which takes into account the population growth. Population sampling due to a limited number of first settlers and the rapid demographic expansion appear to have played a major role in the founding of PDDR in Ch-SLSJ and, presumably, other genetic disorders endemic to French Canada. Similarly, the founder effect in Ashkenazim, coinciding with their early settlement in medieval Poland and subsequent expansion eastward, could explain the origin of frequent genetic diseases in this population. 48 refs., 5 figs., 2 tabs.« less

The Genetic Diversity and Structure of Linkage Disequilibrium of the MTHFR Gene in Populations of Northern Eurasia.

PubMed

Trifonova, E A; Eremina, E R; Urnov, F D; Stepanov, V A

2012-01-01

The structure of the haplotypes and linkage disequilibrium (LD) of the methylenetetrahydrofolate reductase gene (MTHFR) in 9 population groups from Northern Eurasia and populations of the international HapMap project was investigated in the present study. The data suggest that the architecture of LD in the human genome is largely determined by the evolutionary history of populations; however, the results of phylogenetic and haplotype analyses seems to suggest that in fact there may be a common "old" mechanism for the formation of certain patterns of LD. Variability in the structure of LD and the level of diversity of MTHFRhaplotypes cause a certain set of tagSNPs with an established prognostic significance for each population. In our opinion, the results obtained in the present study are of considerable interest for understanding multiple genetic phenomena: namely, the association of interpopulation differences in the patterns of LD with structures possessing a genetic susceptibility to complex diseases, and the functional significance of the pleiotropicMTHFR gene effect. Summarizing the results of this study, a conclusion can be made that the genetic variability analysis with emphasis on the structure of LD in human populations is a powerful tool that can make a significant contribution to such areas of biomedical science as human evolutionary biology, functional genomics, genetics of complex diseases, and pharmacogenomics.

The extent of linkage disequilibrium in beef cattle breeds using high-density SNP genotypes.

PubMed

Porto-Neto, Laercio R; Kijas, James W; Reverter, Antonio

2014-03-24

The extent of linkage disequilibrium (LD) between molecular markers impacts genome-wide association studies and implementation of genomic selection. The availability of high-density single nucleotide polymorphism (SNP) genotyping platforms makes it possible to investigate LD at an unprecedented resolution. In this work, we characterised LD decay in breeds of beef cattle of taurine, indicine and composite origins and explored its variation across autosomes and the X chromosome. In each breed, LD decayed rapidly and r2 was less than 0.2 for marker pairs separated by 50 kb. The LD decay curves clustered into three groups of similar LD decay that distinguished the three main cattle types. At short distances between markers (<10 kb), taurine breeds showed higher LD (r2=0.45) than their indicine (r2=0.25) and composite (r2=0.32) counterparts. This higher LD in taurine breeds was attributed to a smaller effective population size and a stronger bottleneck during breed formation. Using all SNPs on only the X chromosome, the three cattle types could still be distinguished. However for taurine breeds, the LD decay on the X chromosome was much faster and the background level much lower than for indicine breeds and composite populations. When using only SNPs that were polymorphic in all breeds, the analysis of the X chromosome mimicked that of the autosomes. The pattern of LD mirrored some aspects of the history of breed populations and showed a sharp decay with increasing physical distance between markers. We conclude that the availability of the HD chip can be used to detect association signals that remained hidden when using lower density genotyping platforms, since LD dropped below 0.2 at distances of 50 kb.

Extent of Linkage Disequilibrium in the Domestic Cat, Felis silvestris catus, and Its Breeds

PubMed Central

Alhaddad, Hasan; Khan, Razib; Grahn, Robert A.; Gandolfi, Barbara; Mullikin, James C.; Cole, Shelley A.; Gruffydd-Jones, Timothy J.; Häggström, Jens; Lohi, Hannes; Longeri, Maria; Lyons, Leslie A.

2013-01-01

Domestic cats have a unique breeding history and can be used as models for human hereditary and infectious diseases. In the current era of genome-wide association studies, insights regarding linkage disequilibrium (LD) are essential for efficient association studies. The objective of this study is to investigate the extent of LD in the domestic cat, Felis silvestris catus, particularly within its breeds. A custom illumina GoldenGate Assay consisting of 1536 single nucleotide polymorphisms (SNPs) equally divided over ten 1 Mb chromosomal regions was developed, and genotyped across 18 globally recognized cat breeds and two distinct random bred populations. The pair-wise LD descriptive measure (r 2) was calculated between the SNPs in each region and within each population independently. LD decay was estimated by determining the non-linear least-squares of all pair-wise estimates as a function of distance using established models. The point of 50% decay of r2 was used to compare the extent of LD between breeds. The longest extent of LD was observed in the Burmese breed, where the distance at which r2 ≈ 0.25 was ∼380 kb, comparable to several horse and dog breeds. The shortest extent of LD was found in the Siberian breed, with an r2 ≈ 0.25 at approximately 17 kb, comparable to random bred cats and human populations. A comprehensive haplotype analysis was also conducted. The haplotype structure of each region within each breed mirrored the LD estimates. The LD of cat breeds largely reflects the breeds’ population history and breeding strategies. Understanding LD in diverse populations will contribute to an efficient use of the newly developed SNP array for the cat in the design of genome-wide association studies, as well as to the interpretation of results for the fine mapping of disease and phenotypic traits. PMID:23308248

Extent of linkage disequilibrium in the domestic cat, Felis silvestris catus, and its breeds.

PubMed

Alhaddad, Hasan; Khan, Razib; Grahn, Robert A; Gandolfi, Barbara; Mullikin, James C; Cole, Shelley A; Gruffydd-Jones, Timothy J; Häggström, Jens; Lohi, Hannes; Longeri, Maria; Lyons, Leslie A

2013-01-01

Domestic cats have a unique breeding history and can be used as models for human hereditary and infectious diseases. In the current era of genome-wide association studies, insights regarding linkage disequilibrium (LD) are essential for efficient association studies. The objective of this study is to investigate the extent of LD in the domestic cat, Felis silvestris catus, particularly within its breeds. A custom illumina GoldenGate Assay consisting of 1536 single nucleotide polymorphisms (SNPs) equally divided over ten 1 Mb chromosomal regions was developed, and genotyped across 18 globally recognized cat breeds and two distinct random bred populations. The pair-wise LD descriptive measure (r(2)) was calculated between the SNPs in each region and within each population independently. LD decay was estimated by determining the non-linear least-squares of all pair-wise estimates as a function of distance using established models. The point of 50% decay of r(2) was used to compare the extent of LD between breeds. The longest extent of LD was observed in the Burmese breed, where the distance at which r(2) ≈ 0.25 was ∼380 kb, comparable to several horse and dog breeds. The shortest extent of LD was found in the Siberian breed, with an r(2) ≈ 0.25 at approximately 17 kb, comparable to random bred cats and human populations. A comprehensive haplotype analysis was also conducted. The haplotype structure of each region within each breed mirrored the LD estimates. The LD of cat breeds largely reflects the breeds' population history and breeding strategies. Understanding LD in diverse populations will contribute to an efficient use of the newly developed SNP array for the cat in the design of genome-wide association studies, as well as to the interpretation of results for the fine mapping of disease and phenotypic traits.

Nucleotide variability and linkage disequilibrium patterns in the porcine MUC4 gene

PubMed Central

2012-01-01

Background MUC4 is a type of membrane anchored glycoprotein and serves as the major constituent of mucus that covers epithelial surfaces of many tissues such as trachea, colon and cervix. MUC4 plays important roles in the lubrication and protection of the surface epithelium, cell proliferation and differentiation, immune response, cell adhesion and cancer development. To gain insights into the evolution of the porcine MUC4 gene, we surveyed the nucleotide variability and linkage disequilibrium (LD) within this gene in Chinese indigenous breeds and Western commercial breeds. Results A total of 53 SNPs covering the MUC4 gene were genotyped on 5 wild boars and 307 domestic pigs representing 11 Chinese breeds and 3 Western breeds. The nucleotide variability, haplotype phylogeny and LD extent of MUC4 were analyzed in these breeds. Both Chinese and Western breeds had considerable nucleotide diversity at the MUC4 locus. Western pig breeds like Duroc and Large White have comparable nucleotide diversity as many of Chinese breeds, thus artificial selection for lean pork production have not reduced the genetic variability of MUC4 in Western commercial breeds. Haplotype phylogeny analyses indicated that MUC4 had evolved divergently in Chinese and Western pigs. The dendrogram of genetic differentiation between breeds generally reflected demographic history and geographical distribution of these breeds. LD patterns were unexpectedly similar between Chinese and Western breeds, in which LD usually extended less than 20 kb. This is different from the presumed high LD extent (more than 100 kb) in Western commercial breeds. The significant positive Tajima’D, and Fu and Li’s D statistics in a few Chinese and Western breeds implied that MUC4 might undergo balancing selection in domestic breeds. Nevertheless, we cautioned that the significant statistics could be upward biased by SNP ascertainment process. Conclusions Chinese and Western breeds have similar nucleotide diversity

Nucleotide variability and linkage disequilibrium patterns in the porcine MUC4 gene.

PubMed

Yang, Ming; Yang, Bin; Yan, Xueming; Ouyang, Jing; Zeng, Weihong; Ai, Huashui; Ren, Jun; Huang, Lusheng

2012-07-13

MUC4 is a type of membrane anchored glycoprotein and serves as the major constituent of mucus that covers epithelial surfaces of many tissues such as trachea, colon and cervix. MUC4 plays important roles in the lubrication and protection of the surface epithelium, cell proliferation and differentiation, immune response, cell adhesion and cancer development. To gain insights into the evolution of the porcine MUC4 gene, we surveyed the nucleotide variability and linkage disequilibrium (LD) within this gene in Chinese indigenous breeds and Western commercial breeds. A total of 53 SNPs covering the MUC4 gene were genotyped on 5 wild boars and 307 domestic pigs representing 11 Chinese breeds and 3 Western breeds. The nucleotide variability, haplotype phylogeny and LD extent of MUC4 were analyzed in these breeds. Both Chinese and Western breeds had considerable nucleotide diversity at the MUC4 locus. Western pig breeds like Duroc and Large White have comparable nucleotide diversity as many of Chinese breeds, thus artificial selection for lean pork production have not reduced the genetic variability of MUC4 in Western commercial breeds. Haplotype phylogeny analyses indicated that MUC4 had evolved divergently in Chinese and Western pigs. The dendrogram of genetic differentiation between breeds generally reflected demographic history and geographical distribution of these breeds. LD patterns were unexpectedly similar between Chinese and Western breeds, in which LD usually extended less than 20 kb. This is different from the presumed high LD extent (more than 100 kb) in Western commercial breeds. The significant positive Tajima'D, and Fu and Li's D statistics in a few Chinese and Western breeds implied that MUC4 might undergo balancing selection in domestic breeds. Nevertheless, we cautioned that the significant statistics could be upward biased by SNP ascertainment process. Chinese and Western breeds have similar nucleotide diversity but evolve divergently in the MUC4

The linkage disequilibrium maps of three human chromosomes across four populations reflect their demographic history and a common underlying recombination pattern

PubMed Central

De La Vega, Francisco M.; Isaac, Hadar; Collins, Andrew; Scafe, Charles R.; Halldórsson, Bjarni V.; Su, Xiaoping; Lippert, Ross A.; Wang, Yu; Laig-Webster, Marion; Koehler, Ryan T.; Ziegle, Janet S.; Wogan, Lewis T.; Stevens, Junko F.; Leinen, Kyle M.; Olson, Sheri J.; Guegler, Karl J.; You, Xiaoqing; Xu, Lily H.; Hemken, Heinz G.; Kalush, Francis; Itakura, Mitsuo; Zheng, Yi; de Thé, Guy; O'Brien, Stephen J.; Clark, Andrew G.; Istrail, Sorin; Hunkapiller, Michael W.; Spier, Eugene G.; Gilbert, Dennis A.

2005-01-01

The extent and patterns of linkage disequilibrium (LD) determine the feasibility of association studies to map genes that underlie complex traits. Here we present a comparison of the patterns of LD across four major human populations (African-American, Caucasian, Chinese, and Japanese) with a high-resolution single-nucleotide polymorphism (SNP) map covering almost the entire length of chromosomes 6, 21, and 22. We constructed metric LD maps formulated such that the units measure the extent of useful LD for association mapping. LD reaches almost twice as far in chromosome 6 as in chromosomes 21 or 22, in agreement with their differences in recombination rates. By all measures used, out-of-Africa populations showed over a third more LD than African-Americans, highlighting the role of the population's demography in shaping the patterns of LD. Despite those differences, the long-range contour of the LD maps is remarkably similar across the four populations, presumably reflecting common localization of recombination hot spots. Our results have practical implications for the rational design and selection of SNPs for disease association studies. PMID:15781572

Homozygosity and linkage-disequilibrium mapping of the syndrome of congenital hypoparathyroidism, growth and mental retardation, and dysmorphism to a 1-cM interval on chromosome 1q42-43.

PubMed

Parvari, R; Hershkovitz, E; Kanis, A; Gorodischer, R; Shalitin, S; Sheffield, V C; Carmi, R

1998-07-01

The syndrome of hypoparathyroidism associated with growth retardation, developmental delay, and dysmorphism (HRD) is a newly described, autosomal recessive, congenital disorder with severe, often fatal consequences. Since the syndrome is very rare, with all parents of affected individuals being consanguineous, it is presumed to be caused by homozygous inheritance of a single recessive mutation from a common ancestor. To localize the HRD gene, we performed a genomewide screen using DNA pooling and homozygosity mapping for apparently unlinked kindreds. Analysis of a panel of 359 highly polymorphic markers revealed linkage to D1S235. The maximum LOD score obtained was 4.11 at a recombination fraction of 0. Analysis of three additional markers-GGAA6F06, D1S2678, and D1S179-in a 2-cM interval around D1S235 resulted in LOD scores >3. Analysis of additional chromosome 1 markers revealed evidence of genetic linkage disequilibrium and place the HRD locus within an approximately 1-cM interval defined by D1S1540 and D1S2678 on chromosome 1q42-43.

Extent of Linkage Disequilibrium and Effective Population Size in Four South African Sanga Cattle Breeds.

PubMed

Makina, Sithembile O; Taylor, Jeremy F; van Marle-Köster, Este; Muchadeyi, Farai C; Makgahlela, Mahlako L; MacNeil, Michael D; Maiwashe, Azwihangwisi

2015-01-01

Knowledge on the extent of linkage disequilibrium (LD) in livestock populations is essential to determine the minimum distance between markers required for effective coverage when conducting genome-wide association studies (GWAS). This study evaluated the extent of LD, persistence of allelic phase and effective population size (Ne) for four Sanga cattle breeds in South Africa including the Afrikaner (n = 44), Nguni (n = 54), Drakensberger (n = 47), and Bonsmara breeds (n = 46), using Angus (n = 31) and Holstein (n = 29) as reference populations. We found that moderate LD extends up to inter-marker distances of 40-60 kb in Angus (0.21) and Holstein (0.21) and up to 100 kb in Afrikaner (0.20). This suggests that genomic selection and association studies performed within these breeds using an average inter-marker r (2)≥ 0.20 would require about 30,000-50,000 SNPs. However, r (2)≥ 0.20 extended only up to 10-20 kb in the Nguni and Drakensberger and 20-40 kb in the Bonsmara indicating that 75,000 to 150,000 SNPs would be necessary for GWAS in these breeds. Correlation between alleles at contiguous loci indicated that phase was not strongly preserved between breeds. This suggests the need for breed-specific reference populations in which a much greater density of markers should be scored to identify breed specific haplotypes which may then be imputed into multi-breed commercial populations. Analysis of effective population size based on the extent of LD, revealed Ne = 95 (Nguni), Ne = 87 (Drakensberger), Ne = 77 (Bonsmara), and Ne = 41 (Afrikaner). Results of this study form the basis for implementation of genomic selection programs in the Sanga breeds of South Africa.

Extent of Linkage Disequilibrium and Effective Population Size in Four South African Sanga Cattle Breeds

PubMed Central

Makina, Sithembile O.; Taylor, Jeremy F.; van Marle-Köster, Este; Muchadeyi, Farai C.; Makgahlela, Mahlako L.; MacNeil, Michael D.; Maiwashe, Azwihangwisi

2015-01-01

Knowledge on the extent of linkage disequilibrium (LD) in livestock populations is essential to determine the minimum distance between markers required for effective coverage when conducting genome-wide association studies (GWAS). This study evaluated the extent of LD, persistence of allelic phase and effective population size (Ne) for four Sanga cattle breeds in South Africa including the Afrikaner (n = 44), Nguni (n = 54), Drakensberger (n = 47), and Bonsmara breeds (n = 46), using Angus (n = 31) and Holstein (n = 29) as reference populations. We found that moderate LD extends up to inter-marker distances of 40–60 kb in Angus (0.21) and Holstein (0.21) and up to 100 kb in Afrikaner (0.20). This suggests that genomic selection and association studies performed within these breeds using an average inter-marker r2≥ 0.20 would require about 30,000–50,000 SNPs. However, r2≥ 0.20 extended only up to 10–20 kb in the Nguni and Drakensberger and 20–40 kb in the Bonsmara indicating that 75,000 to 150,000 SNPs would be necessary for GWAS in these breeds. Correlation between alleles at contiguous loci indicated that phase was not strongly preserved between breeds. This suggests the need for breed-specific reference populations in which a much greater density of markers should be scored to identify breed specific haplotypes which may then be imputed into multi-breed commercial populations. Analysis of effective population size based on the extent of LD, revealed Ne = 95 (Nguni), Ne = 87 (Drakensberger), Ne = 77 (Bonsmara), and Ne = 41 (Afrikaner). Results of this study form the basis for implementation of genomic selection programs in the Sanga breeds of South Africa. PMID:26648975

The heterogeneous levels of linkage disequilibrium in white spruce genes and comparative analysis with other conifers.

PubMed

Pavy, N; Namroud, M-C; Gagnon, F; Isabel, N; Bousquet, J

2012-03-01

In plants, knowledge about linkage disequilibrium (LD) is relevant for the design of efficient single-nucleotide polymorphism arrays in relation to their use in population and association genomics studies. Previous studies of conifer genes have shown LD to decay rapidly within gene limits, but exceptions have been reported. To evaluate the extent of heterogeneity of LD among conifer genes and its potential causes, we examined LD in 105 genes of white spruce (Picea glauca) by sequencing a panel of 48 haploid megagametophytes from natural populations and further compared it with LD in other conifer species. The average pairwise r(2) value was 0.19 (s.d.=0.19), and LD dropped quickly with a half-decay being reached at a distance of 65 nucleotides between sites. However, LD was significantly heterogeneous among genes. A first group of 29 genes had stronger LD (mean r(2)=0.28), and a second group of 38 genes had weaker LD (mean r(2)=0.12). While a strong relationship was found with the recombination rate, there was no obvious relationship between LD and functional classification. The level of nucleotide diversity, which was highly heterogeneous across genes, was also not significantly correlated with LD. A search for selection signatures highlighted significant deviations from the standard neutral model, which could be mostly attributed to recent demographic changes. Little evidence was seen for hitchhiking and clear relationships with LD. When compared among conifer species, on average, levels of LD were similar in genes from white spruce, Norway spruce and Scots pine, whereas loblolly pine and Douglas fir genes exhibited a significantly higher LD.

Combined linkage and association mapping of flowering time in Sunflower (Helianthus annuus L.).

PubMed

Cadic, Elena; Coque, Marie; Vear, Felicity; Grezes-Besset, Bruno; Pauquet, Jerôme; Piquemal, Joël; Lippi, Yannick; Blanchard, Philippe; Romestant, Michel; Pouilly, Nicolas; Rengel, David; Gouzy, Jerôme; Langlade, Nicolas; Mangin, Brigitte; Vincourt, Patrick

2013-05-01

Association mapping and linkage mapping were used to identify quantitative trait loci (QTL) and/or causative mutations involved in the control of flowering time in cultivated sunflower Helianthus annuus. A panel of 384 inbred lines was phenotyped through testcrosses with two tester inbred lines across 15 location × year combinations. A recombinant inbred line (RIL) population comprising 273 lines was phenotyped both per se and through testcrosses with one or two testers in 16 location × year combinations. In the association mapping approach, kinship estimation using 5,923 single nucleotide polymorphisms was found to be the best covariate to correct for effects of panel structure. Linkage disequilibrium decay ranged from 0.08 to 0.26 cM for a threshold of 0.20, after correcting for structure effects, depending on the linkage group (LG) and the ancestry of inbred lines. A possible hitchhiking effect is hypothesized for LG10 and LG08. A total of 11 regions across 10 LGs were found to be associated with flowering time, and QTLs were mapped on 11 LGs in the RIL population. Whereas eight regions were demonstrated to be common between the two approaches, the linkage disequilibrium approach did not detect a documented QTL that was confirmed using the linkage mapping approach.

Linkage disequilibrium, SNP frequency change due to selection, and association mapping in popcorn chromosome regions containing QTLs for quality traits

PubMed Central

Paes, Geísa Pinheiro; Viana, José Marcelo Soriano; Silva, Fabyano Fonseca e; Mundim, Gabriel Borges

2016-01-01

Abstract The objectives of this study were to assess linkage disequilibrium (LD) and selection-induced changes in single nucleotide polymorphism (SNP) frequency, and to perform association mapping in popcorn chromosome regions containing quantitative trait loci (QTLs) for quality traits. Seven tropical and two temperate popcorn populations were genotyped for 96 SNPs chosen in chromosome regions containing QTLs for quality traits. The populations were phenotyped for expansion volume, 100-kernel weight, kernel sphericity, and kernel density. The LD statistics were the difference between the observed and expected haplotype frequencies (D), the proportion of D relative to the expected maximum value in the population, and the square of the correlation between the values of alleles at two loci. Association mapping was based on least squares and Bayesian approaches. In the tropical populations, D-values greater than 0.10 were observed for SNPs separated by 100-150 Mb, while most of the D-values in the temperate populations were less than 0.05. Selection for expansion volume indirectly led to increase in LD values, population differentiation, and significant changes in SNP frequency. Some associations were observed for expansion volume and the other quality traits. The candidate genes are involved with starch, storage protein, lipid, and cell wall polysaccharides synthesis. PMID:27007903

Linkage disequilibrium, SNP frequency change due to selection, and association mapping in popcorn chromosome regions containing QTLs for quality traits.

PubMed

Paes, Geísa Pinheiro; Viana, José Marcelo Soriano; Silva, Fabyano Fonseca E; Mundim, Gabriel Borges

2016-03-01

The objectives of this study were to assess linkage disequilibrium (LD) and selection-induced changes in single nucleotide polymorphism (SNP) frequency, and to perform association mapping in popcorn chromosome regions containing quantitative trait loci (QTLs) for quality traits. Seven tropical and two temperate popcorn populations were genotyped for 96 SNPs chosen in chromosome regions containing QTLs for quality traits. The populations were phenotyped for expansion volume, 100-kernel weight, kernel sphericity, and kernel density. The LD statistics were the difference between the observed and expected haplotype frequencies (D), the proportion of D relative to the expected maximum value in the population, and the square of the correlation between the values of alleles at two loci. Association mapping was based on least squares and Bayesian approaches. In the tropical populations, D-values greater than 0.10 were observed for SNPs separated by 100-150 Mb, while most of the D-values in the temperate populations were less than 0.05. Selection for expansion volume indirectly led to increase in LD values, population differentiation, and significant changes in SNP frequency. Some associations were observed for expansion volume and the other quality traits. The candidate genes are involved with starch, storage protein, lipid, and cell wall polysaccharides synthesis.

Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks.

PubMed

Zhao, Huiying; Nyholt, Dale R; Yang, Yuanhao; Wang, Jihua; Yang, Yuedong

2017-06-14

Genome-wide association studies (GWAS) have successfully identified single variants associated with diseases. To increase the power of GWAS, gene-based and pathway-based tests are commonly employed to detect more risk factors. However, the gene- and pathway-based association tests may be biased towards genes or pathways containing a large number of single-nucleotide polymorphisms (SNPs) with small P-values caused by high linkage disequilibrium (LD) correlations. To address such bias, numerous pathway-based methods have been developed. Here we propose a novel method, DGAT-path, to divide all SNPs assigned to genes in each pathway into LD blocks, and to sum the chi-square statistics of LD blocks for assessing the significance of the pathway by permutation tests. The method was proven robust with the type I error rate >1.6 times lower than other methods. Meanwhile, the method displays a higher power and is not biased by the pathway size. The applications to the GWAS summary statistics for schizophrenia and breast cancer indicate that the detected top pathways contain more genes close to associated SNPs than other methods. As a result, the method identified 17 and 12 significant pathways containing 20 and 21 novel associated genes, respectively for two diseases. The method is available online by http://sparks-lab.org/server/DGAT-path .

Homozygosity and linkage-disequilibrium mapping of the syndrome of congenital hypoparathyroidism, growth and mental retardation, and dysmorphism to a 1-cM interval on chromosome 1q42-43.

PubMed Central

Parvari, R; Hershkovitz, E; Kanis, A; Gorodischer, R; Shalitin, S; Sheffield, V C; Carmi, R

1998-01-01

The syndrome of hypoparathyroidism associated with growth retardation, developmental delay, and dysmorphism (HRD) is a newly described, autosomal recessive, congenital disorder with severe, often fatal consequences. Since the syndrome is very rare, with all parents of affected individuals being consanguineous, it is presumed to be caused by homozygous inheritance of a single recessive mutation from a common ancestor. To localize the HRD gene, we performed a genomewide screen using DNA pooling and homozygosity mapping for apparently unlinked kindreds. Analysis of a panel of 359 highly polymorphic markers revealed linkage to D1S235. The maximum LOD score obtained was 4.11 at a recombination fraction of 0. Analysis of three additional markers-GGAA6F06, D1S2678, and D1S179-in a 2-cM interval around D1S235 resulted in LOD scores >3. Analysis of additional chromosome 1 markers revealed evidence of genetic linkage disequilibrium and place the HRD locus within an approximately 1-cM interval defined by D1S1540 and D1S2678 on chromosome 1q42-43. PMID:9634513

Genetic Diversity and Linkage Disequilibrium in Chinese Bread Wheat (Triticum aestivum L.) Revealed by SSR Markers

PubMed Central

Hao, Chenyang; Wang, Lanfen; Ge, Hongmei; Dong, Yuchen; Zhang, Xueyong

2011-01-01

Two hundred and fifty bread wheat lines, mainly Chinese mini core accessions, were assayed for polymorphism and linkage disequilibrium (LD) based on 512 whole-genome microsatellite loci representing a mean marker density of 5.1 cM. A total of 6,724 alleles ranging from 1 to 49 per locus were identified in all collections. The mean PIC value was 0.650, ranging from 0 to 0.965. Population structure and principal coordinate analysis revealed that landraces and modern varieties were two relatively independent genetic sub-groups. Landraces had a higher allelic diversity than modern varieties with respect to both genomes and chromosomes in terms of total number of alleles and allelic richness. 3,833 (57.0%) and 2,788 (41.5%) rare alleles with frequencies of <5% were found in the landrace and modern variety gene pools, respectively, indicating greater numbers of rare variants, or likely new alleles, in landraces. Analysis of molecular variance (AMOVA) showed that A genome had the largest genetic differentiation and D genome the lowest. In contrast to genetic diversity, modern varieties displayed a wider average LD decay across the whole genome for locus pairs with r2>0.05 (P<0.001) than the landraces. Mean LD decay distance for the landraces at the whole genome level was <5 cM, while a higher LD decay distance of 5–10 cM in modern varieties. LD decay distances were also somewhat different for each of the 21 chromosomes, being higher for most of the chromosomes in modern varieties (<5∼25 cM) compared to landraces (<5∼15 cM), presumably indicating the influences of domestication and breeding. This study facilitates predicting the marker density required to effectively associate genotypes with traits in Chinese wheat genetic resources. PMID:21365016

Genome-Wide Divergence and Linkage Disequilibrium Analyses for Capsicum baccatum Revealed by Genome-Anchored Single Nucleotide Polymorphisms

PubMed Central

Nimmakayala, Padma; Abburi, Venkata L.; Saminathan, Thangasamy; Almeida, Aldo; Davenport, Brittany; Davidson, Joshua; Reddy, C. V. Chandra Mohan; Hankins, Gerald; Ebert, Andreas; Choi, Doil; Stommel, John; Reddy, Umesh K.

2016-01-01

Principal component analysis (PCA) with 36,621 polymorphic genome-anchored single nucleotide polymorphisms (SNPs) identified collectively for Capsicum annuum and Capsicum baccatum was used to characterize population structure and species domestication of these two important incompatible cultivated pepper species. Estimated mean nucleotide diversity (π) and Tajima's D across various chromosomes revealed biased distribution toward negative values on all chromosomes (except for chromosome 4) in cultivated C. baccatum, indicating a population bottleneck during domestication of C. baccatum. In contrast, C. annuum chromosomes showed positive π and Tajima's D on all chromosomes except chromosome 8, which may be because of domestication at multiple sites contributing to wider genetic diversity. For C. baccatum, 13,129 SNPs were available, with minor allele frequency (MAF) ≥0.05; PCA of the SNPs revealed 283 C. baccatum accessions grouped into 3 distinct clusters, for strong population structure. The fixation index (FST) between domesticated C. annuum and C. baccatum was 0.78, which indicates genome-wide divergence. We conducted extensive linkage disequilibrium (LD) analysis of C. baccatum var. pendulum cultivars on all adjacent SNP pairs within a chromosome to identify regions of high and low LD interspersed with a genome-wide average LD block size of 99.1 kb. We characterized 1742 haplotypes containing 4420 SNPs (range 9–2 SNPs per haplotype). Genome-wide association study (GWAS) of peduncle length, a trait that differentiates wild and domesticated C. baccatum types, revealed 36 significantly associated genome-wide SNPs. Population structure, identity by state (IBS) and LD patterns across the genome will be of potential use for future GWAS of economically important traits in C. baccatum peppers. PMID:27857720

Genome-Wide Divergence and Linkage Disequilibrium Analyses for Capsicum baccatum Revealed by Genome-Anchored Single Nucleotide Polymorphisms.

PubMed

Nimmakayala, Padma; Abburi, Venkata L; Saminathan, Thangasamy; Almeida, Aldo; Davenport, Brittany; Davidson, Joshua; Reddy, C V Chandra Mohan; Hankins, Gerald; Ebert, Andreas; Choi, Doil; Stommel, John; Reddy, Umesh K

2016-01-01

Principal component analysis (PCA) with 36,621 polymorphic genome-anchored single nucleotide polymorphisms (SNPs) identified collectively for Capsicum annuum and Capsicum baccatum was used to characterize population structure and species domestication of these two important incompatible cultivated pepper species. Estimated mean nucleotide diversity (π) and Tajima's D across various chromosomes revealed biased distribution toward negative values on all chromosomes (except for chromosome 4) in cultivated C. baccatum , indicating a population bottleneck during domestication of C. baccatum . In contrast, C. annuum chromosomes showed positive π and Tajima's D on all chromosomes except chromosome 8, which may be because of domestication at multiple sites contributing to wider genetic diversity. For C. baccatum , 13,129 SNPs were available, with minor allele frequency (MAF) ≥0.05; PCA of the SNPs revealed 283 C. baccatum accessions grouped into 3 distinct clusters, for strong population structure. The fixation index ( F ST ) between domesticated C. annuum and C. baccatum was 0.78, which indicates genome-wide divergence. We conducted extensive linkage disequilibrium (LD) analysis of C. baccatum var. pendulum cultivars on all adjacent SNP pairs within a chromosome to identify regions of high and low LD interspersed with a genome-wide average LD block size of 99.1 kb. We characterized 1742 haplotypes containing 4420 SNPs (range 9-2 SNPs per haplotype). Genome-wide association study (GWAS) of peduncle length, a trait that differentiates wild and domesticated C. baccatum types, revealed 36 significantly associated genome-wide SNPs. Population structure, identity by state (IBS) and LD patterns across the genome will be of potential use for future GWAS of economically important traits in C. baccatum peppers.

Genome-wide linkage disequilibrium and genetic diversity in five populations of Australian domestic sheep.

PubMed

Al-Mamun, Hawlader Abdullah; Clark, Samuel A; Kwan, Paul; Gondro, Cedric

2015-11-24

Knowledge of the genetic structure and overall diversity of livestock species is important to maximise the potential of genome-wide association studies and genomic prediction. Commonly used measures such as linkage disequilibrium (LD), effective population size (N e ), heterozygosity, fixation index (F ST) and runs of homozygosity (ROH) are widely used and help to improve our knowledge about genetic diversity in animal populations. The development of high-density single nucleotide polymorphism (SNP) arrays and the subsequent genotyping of large numbers of animals have greatly increased the accuracy of these population-based estimates. In this study, we used the Illumina OvineSNP50 BeadChip array to estimate and compare LD (measured by r (2) and D'), N e , heterozygosity, F ST and ROH in five Australian sheep populations: three pure breeds, i.e., Merino (MER), Border Leicester (BL), Poll Dorset (PD) and two crossbred populations i.e. F1 crosses of Merino and Border Leicester (MxB) and MxB crossed to Poll Dorset (MxBxP). Compared to other livestock species, the sheep populations that were analysed in this study had low levels of LD and high levels of genetic diversity. The rate of LD decay was greater in Merino than in the other pure breeds. Over short distances (<10 kb), the levels of LD were higher in BL and PD than in MER. Similarly, BL and PD had comparatively smaller N e than MER. Observed heterozygosity in the pure breeds ranged from 0.3 in BL to 0.38 in MER. Genetic distances between breeds were modest compared to other livestock species (highest F ST = 0.063) but the genetic diversity within breeds was high. Based on ROH, two chromosomal regions showed evidence of strong recent selection. This study shows that there is a large range of genome diversity in Australian sheep breeds, especially in Merino sheep. The observed range of diversity will influence the design of genome-wide association studies and the results that can be obtained from them. This

New generation pharmacogenomic tools: a SNP linkage disequilibrium Map, validated SNP assay resource, and high-throughput instrumentation system for large-scale genetic studies.

PubMed

De La Vega, Francisco M; Dailey, David; Ziegle, Janet; Williams, Julie; Madden, Dawn; Gilbert, Dennis A

2002-06-01

Since public and private efforts announced the first draft of the human genome last year, researchers have reported great numbers of single nucleotide polymorphisms (SNPs). We believe that the availability of well-mapped, quality SNP markers constitutes the gateway to a revolution in genetics and personalized medicine that will lead to better diagnosis and treatment of common complex disorders. A new generation of tools and public SNP resources for pharmacogenomic and genetic studies--specifically for candidate-gene, candidate-region, and whole-genome association studies--will form part of the new scientific landscape. This will only be possible through the greater accessibility of SNP resources and superior high-throughput instrumentation-assay systems that enable affordable, highly productive large-scale genetic studies. We are contributing to this effort by developing a high-quality linkage disequilibrium SNP marker map and an accompanying set of ready-to-use, validated SNP assays across every gene in the human genome. This effort incorporates both the public sequence and SNP data sources, and Celera Genomics' human genome assembly and enormous resource ofphysically mapped SNPs (approximately 4,000,000 unique records). This article discusses our approach and methodology for designing the map, choosing quality SNPs, designing and validating these assays, and obtaining population frequency ofthe polymorphisms. We also discuss an advanced, high-performance SNP assay chemisty--a new generation of the TaqMan probe-based, 5' nuclease assay-and high-throughput instrumentation-software system for large-scale genotyping. We provide the new SNP map and validation information, validated SNP assays and reagents, and instrumentation systems as a novel resource for genetic discoveries.

Testing association and linkage using affected-sib-parent study designs.

PubMed

Millstein, Joshua; Siegmund, Kimberly D; Conti, David V; Gauderman, W James

2005-11-01

We have developed a method for jointly testing linkage and association using data from affected sib pairs and their parents. We specify a conditional logistic regression model with two covariates, one that quantifies association (either direct association or indirect association via linkage disequilibrium), and a second that quantifies linkage. The latter covariate is computed based on expected identity-by-descend (ibd) sharing of marker alleles between siblings. In addition to a joint test of linkage and association, our general framework can be used to obtain a linkage test comparable to the mean test (Blackwelder and Elston [1985] Genet. Epidemiol. 2:85-97), and an association test comparable to the Family-Based Association Test (FBAT; Rabinowitz and Laird [2000] Hum. Hered. 50:211-223). We present simulation results demonstrating that our joint test can be more powerful than some standard tests of linkage or association. For example, with a relative risk of 2.7 per variant allele at a disease locus, the estimated power to detect a nearby marker with a modest level of LD was 58.1% by the mean test (linkage only), 69.8% by FBAT, and 82.5% by our joint test of linkage and association. Our model can also be used to obtain tests of linkage conditional on association and association conditional on linkage, which can be helpful in fine mapping. Copyright 2005 Wiley-Liss, Inc.

Linkage Disequilibrium and Haplotype Diversity in the Genes of the Renin–Angiotensin System: Findings From the Family Blood Pressure Program

PubMed Central

Zhu, Xiaofeng; Yan, Denise; Cooper, Richard S.; Luke, Amy; Ikeda, Morna A.; Chang, Yen-Pei C.; Weder, Alan; Chakravarti, Aravinda

2003-01-01

Association studies of candidate genes with complex traits have generally used one or a few single nucleotide polymorphisms (SNPs), although variation in the extent of linkage disequilibrium (LD) within genes markedly influences the sensitivity and precision of association studies. The extent of LD and the underlying haplotype structure for most candidate genes are still unavailable. We sampled 193 blacks (African-Americans) and 160 whites (European-Americans) and estimated the intragenic LD and the haplotype structure in four genes of the renin–angiotensin system. We genotyped 25 SNPs, with all but one of the pairs spaced between 1 and 20 kb, thus providing resolution at small scale. The pattern of LD within a gene was very heterogeneous. Using a robust method to define haplotype blocks, blocks of limited haplotype diversity were identified at each locus; between these blocks, LD was lost owing to the history of recombination events. As anticipated, there was less LD among blacks, the number of haplotypes was substantially larger, and shorter haplotype segments were found, compared with whites. These findings have implications for candidate-gene association studies and indicate that variation between populations of European and African origin in haplotype diversity is characteristic of most genes. [The sequence data described in this paper are available in GenBank under the following accession nos: AGT, MIM 106150; Renin, MIM 179820; ACE, MIM 106180; Angiotensin receptor I, MIM 106165. Supplementary material is available online at http://www.genome.org.] PMID:12566395

Tests for linkage and association in nuclear families.

PubMed Central

Martin, E R; Kaplan, N L; Weir, B S

1997-01-01

The transmission/disequilibrium test (TDT) originally was introduced to test for linkage between a genetic marker and a disease-susceptibility locus, in the presence of association. Recently, the TDT has been used to test for association in the presence of linkage. The motivation for this is that linkage analysis typically identifies large candidate regions, and further refinement is necessary before a search for the disease gene is begun, on the molecular level. Evidence of association and linkage may indicate which markers in the region are closest to a disease locus. As a test of linkage, transmissions from heterozygous parents to all of their affected children can be included in the TDT; however, the TDT is a valid chi2 test of association only if transmissions to unrelated affected children are used in the analysis. If the sample contains independent nuclear families with multiple affected children, then one procedure that has been used to test for association is to select randomly a single affected child from each sibship and to apply the TDT to those data. As an alternative, we propose two statistics that use data from all of the affected children. The statistics give valid chi2 tests of the null hypothesis of no association or no linkage and generally are more powerful than the TDT with a single, randomly chosen, affected child from each family. PMID:9311750

Recombination patterns reveal information about centromere location on linkage maps.

PubMed

Limborg, Morten T; McKinney, Garrett J; Seeb, Lisa W; Seeb, James E

2016-05-01

Linkage mapping is often used to identify genes associated with phenotypic traits and for aiding genome assemblies. Still, many emerging maps do not locate centromeres - an essential component of the genomic landscape. Here, we demonstrate that for genomes with strong chiasma interference, approximate centromere placement is possible by phasing the same data used to generate linkage maps. Assuming one obligate crossover per chromosome arm, information about centromere location can be revealed by tracking the accumulated recombination frequency along linkage groups, similar to half-tetrad analyses. We validate the method on a linkage map for sockeye salmon (Oncorhynchus nerka) with known centromeric regions. Further tests suggest that the method will work well in other salmonids and other eukaryotes. However, the method performed weakly when applied to a male linkage map (rainbow trout; O. mykiss) characterized by low and unevenly distributed recombination - a general feature of male meiosis in many species. Further, a high frequency of double crossovers along chromosome arms in barley reduced resolution for locating centromeric regions on most linkage groups. Despite these limitations, our method should work well for high-density maps in species with strong recombination interference and will enrich many existing and future mapping resources. © 2015 The Authors. Molecular Ecology Resources published by John Wiley & Sons Ltd.

Linkage disequilibrium and association analysis of stripe rust resistance in wild emmer wheat (Triticum turgidum ssp. dicoccoides) population in Israel.

PubMed

Sela, Hanan; Ezrati, Smadar; Ben-Yehuda, Pnina; Manisterski, Jacob; Akhunov, Eduard; Dvorak, Jan; Breiman, Adina; Korol, Abraham

2014-11-01

Rapid LD decay in wild emmer population from Israel allows high-resolution association mapping. Known and putative new stripe rust resistance genes were found. Genome-wide association mapping (GWAM) is becoming an important tool for the discovery and mapping of loci underlying trait variation in crops, but in the wild relatives of crops the use of GWAM has been limited. Critical factors for the use of GWAM are the levels of linkage disequilibrium (LD) and genetic diversity in mapped populations, particularly in those of self-pollinating species. Here, we report LD estimation in a population of 128 accessions of self-pollinating wild emmer, Triticum turgidum ssp. dicoccoides, the progenitor of cultivated wheat, collected in Israel. LD decayed fast along wild emmer chromosomes and reached the background level within 1 cM. We employed GWAM for the discovery and mapping of genes for resistance to three isolates of Puccinia striiformis, the causative agent of wheat stripe rust. The wild emmer population was genotyped with the wheat iSelect assay including 8643 gene-associated SNP markers (wheat 9K Infinium) of which 2,278 were polymorphic. The significance of association between stripe rust resistance and each of the polymorphic SNP was tested using mixed linear model implemented in EMMA software. The model produced satisfactory results and uncovered four significant associations on chromosome arms 1BS, 1BL and 3AL. The locus on 1BS was located in a region known to contain stripe rust resistance genes. These results show that GWAM is an effective strategy for gene discovery and mapping in wild emmer that will accelerate the utilization of this genetic resource in wheat breeding.

Significant Linkage for Tourette Syndrome in a Large French Canadian Family

PubMed Central

Mérette, Chantal; Brassard, Andrée; Potvin, Anne; Bouvier, Hélène; Rousseau, François; Émond, Claudia; Bissonnette, Luc; Roy, Marc-André; Maziade, Michel; Ott, Jurg; Caron, Chantal

2000-01-01

Family and twin studies provide strong evidence that genetic factors are involved in the transmission of Gilles de la Tourette syndrome (TS) and related psychiatric disorders. To detect the underlying susceptibility gene(s) for TS, we performed linkage analysis in one large French Canadian family (127 members) from the Charlevoix region, in which 20 family members were definitely affected by TS and 20 others showed related tic disorders. Using model-based linkage analysis, we observed a LOD score of 3.24 on chromosome 11 (11q23). This result was obtained in a multipoint approach involving marker D11S1377, the marker for which significant linkage disequilibrium with TS recently has been detected in an Afrikaner population. Altogether, 25 markers were studied, and, for level of significance, we derived a criterion that took into account the multiple testing arising from the use of three phenotype definitions and three modes of inheritance, a procedure that yielded a LOD score of 3.18. Hence, even after adjustment for multiple testing, the present study shows statistically significant evidence for genetic linkage with TS. PMID:10986045

[Transmission disequilibrium test for nonsyndromic cleft lip and palate and segment homeobox gene-1 gene].

PubMed

Wu, Ping-An; Li, Yun-Liang; Wu, Han-Jiang; Wang, Kai; Fan, Guo-Zheng

2007-09-01

To investigate the relationship between muscle segment homeobox gene-1 (MSX1) and the genetic susceptibility of nonsyndromic cleft lip and palate (NSCLP) in Hunan Hans. One microsatellite DNA marker CA repeat in MSX1 intron region was used as genetic marker. The genotypes of 387 members in 129 NSCLP nuclear family trios were analyzed by polymerase chain reaction (PCR) and denaturing polyacrylamide gel electrophoresis. Then transmission disequilibrium test (TDT) and Logistic regression analysis were used to conduct association analysis. TDT analysis confirmed that CA4 allele in CL/P and CPO groups preferentially transmitted to the affected offspring (P = 0.018, P = 0.041). Logistic regression analysis indicated that the recessive model of inheritance was supported, and CA4 itself or CA4 acting as a marker for a disease allele or haplotype was inherited in a recessive fashion (P = 0.009). MSX1 gene is associated with NSCLP, and MSX1 gene may be directly involved either in the etiology of NSCLP or in linkage disequilibrium with disease-predisposing sites.

Evidence for linkage disequilibrium in chromosome 13-linked Duchenne-like muscular dystrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Othmane, K.B.; Speer, M.C.; Stauffer, J.

1995-09-01

Duchenne-like muscular dystrophy (DLMD) is an autosomal recessive Limb Girdle muscular dystrophy (LGMD2C) characterized by late age of onset, proximal muscle weakness leading to disability, high creatine kinase values, normal intelligence and normal dystrophin in muscle biopsy. We have shown previously that three DLMD families from Tunisia are linked to chromosome 13q12. To further localize the LGMD2C gene, we have investigated seven additional families (119 individuals). Both genotyping and two-point linkage analysis were performed as described elsewhere. 7 refs., 1 fig., 1 tab.

Convective dynamics and chemical disequilibrium in the atmospheres of substellar objects

NASA Astrophysics Data System (ADS)

Bordwell, Baylee; Brown, Benjamin P.; Oishi, Jeffrey S.

2017-11-01

The thousands of substellar objects now known provide a unique opportunity to test our understanding of atmospheric dynamics across a range of environments. The chemical timescales of certain species transition from being much shorter than the dynamical timescales to being much longer than them at a point in the atmosphere known as the quench point. This transition leads to a state of dynamical disequilibrium, the effects of which can be used to probe the atmospheric dynamics of these objects. Unfortunately, due to computational constraints, models that inform the interpretation of these observations are run at dynamical parameters which are far from realistic values. In this study, we explore the behavior of a disequilibrium chemical process with increasingly realistic planetary conditions, to quantify the effects of the approximations used in current models. We simulate convection in 2-D, plane-parallel, polytropically-stratified atmospheres, into which we add reactive passive tracers that explore disequilibrium behavior. We find that as we increase the Rayleigh number, and thus achieve more realistic planetary conditions, the behavior of these tracers does not conform to the classical predictions of disequilibrium chemistry.

Whole-genome patterns of linkage disequilibrium across flycatcher populations clarify the causes and consequences of fine-scale recombination rate variation in birds.

PubMed

Kawakami, Takeshi; Mugal, Carina F; Suh, Alexander; Nater, Alexander; Burri, Reto; Smeds, Linnéa; Ellegren, Hans

2017-08-01

Recombination rate is heterogeneous across the genome of various species and so are genetic diversity and differentiation as a consequence of linked selection. However, we still lack a clear picture of the underlying mechanisms for regulating recombination. Here we estimated fine-scale population recombination rate based on the patterns of linkage disequilibrium across the genomes of multiple populations of two closely related flycatcher species (Ficedula albicollis and F. hypoleuca). This revealed an overall conservation of the recombination landscape between these species at the scale of 200 kb, but we also identified differences in the local rate of recombination despite their recent divergence (<1 million years). Genetic diversity and differentiation were associated with recombination rate in a lineage-specific manner, indicating differences in the extent of linked selection between species. We detected 400-3,085 recombination hotspots per population. Location of hotspots was conserved between species, but the intensity of hotspot activity varied between species. Recombination hotspots were primarily associated with CpG islands (CGIs), regardless of whether CGIs were at promoter regions or away from genes. Recombination hotspots were also associated with specific transposable elements (TEs), but this association appears indirect due to shared preferences of the transposition machinery and the recombination machinery for accessible open chromatin regions. Our results suggest that CGIs are a major determinant of the localization of recombination hotspots, and we propose that both the distribution of TEs and fine-scale variation in recombination rate may be associated with the evolution of the epigenetic landscape. © 2017 The Authors. Molecular Ecology Published by John Wiley & Sons Ltd.

The transmission/disequilibrium test and parental-genotype reconstruction: the reconstruction-combined transmission/ disequilibrium test.

PubMed Central

Knapp, M

1999-01-01

Spielman and Ewens recently proposed a method for testing a marker for linkage with a disease, which combines data from families with and without information on parental genotypes. For some families without parental-genotype information, it may be possible to reconstruct missing parental genotypes from the genotypes of their offspring. The treatment of such a reconstructed family as if parental genotypes have been typed, however, can introduce bias. In the present study, a new method is presented that employs parental-genotype reconstruction and corrects for the biases resulting from reconstruction. The results of an application of this method to a real data set and of a simulation study suggest that this approach may increase the power to detect linkage. PMID:10053021

Marker selection for the transmission/disequilibrium test, in recently admixed populations.

PubMed Central

Kaplan, N L; Martin, E R; Morris, R W; Weir, B S

1998-01-01

Recent admixture between genetically differentiated populations can result in high levels of association between alleles at loci that are <=10 cM apart. The transmission/disequilibrium test (TDT) proposed by Spielman et al. (1993) can be a powerful test of linkage between disease and marker loci in the presence of association and therefore could be a useful test of linkage in admixed populations. The degree of association between alleles at two loci depends on the differences in allele frequencies, at the two loci, in the founding populations; therefore, the choice of marker is important. For a multiallelic marker, one strategy that may improve the power of the TDT is to group marker alleles within a locus, on the basis of information about the founding populations and the admixed population, thereby collapsing the marker into one with fewer alleles. We have examined the consequences of collapsing a microsatellite into a two-allele marker, when two founding populations are assumed for the admixed population, and have found that if there is random mating in the admixed population, then typically there is a collapsing for which the power of the TDT is greater than that for the original microsatellite marker. A method is presented for finding the optimal collapsing that has minimal dependence on the disease and that uses estimates either of marker allele frequencies in the two founding populations or of marker allele frequencies in the current, admixed population and in one of the founding populations. Furthermore, this optimal collapsing is not always the collapsing with the largest difference in allele frequencies in the founding populations. To demonstrate this strategy, we considered a recent data set, published previously, that provides frequency estimates for 30 microsatellites in 13 populations. PMID:9497257

High Prevalence of Posterior Polymorphous Corneal Dystrophy in the Czech Republic; Linkage Disequilibrium Mapping and Dating an Ancestral Mutation

PubMed Central

Filipec, Martin; Jirsova, Katerina; Reinstein Merjava, Stanislava; Deloukas, Panos; Webb, Tom R.; Bhattacharya, Shomi S.; Ebenezer, Neil D.; Morris, Alex G.; Hardcastle, Alison J.

2012-01-01

Posterior polymorphous corneal dystrophy (PPCD) is a rare autosomal dominant genetically heterogeneous disorder. Nineteen Czech PPCD pedigrees with 113 affected family members were identified, and 17 of these kindreds were genotyped for markers on chromosome 20p12.1- 20q12. Comparison of haplotypes in 81 affected members, 20 unaffected first degree relatives and 13 spouses, as well as 55 unrelated controls, supported the hypothesis of a shared ancestor in 12 families originating from one geographic location. In 38 affected individuals from nine of these pedigrees, a common haplotype was observed between D20S48 and D20S107 spanning approximately 23 Mb, demonstrating segregation of disease with the PPCD1 locus. This haplotype was not detected in 110 ethnically matched control chromosomes. Within the common founder haplotype, a core mini-haplotype was detected for D20S605, D20S182 and M189K2 in all 67 affected members from families 1–12, however alleles representing the core mini-haplotype were also detected in population matched controls. The most likely location of the responsible gene within the disease interval, and estimated mutational age, were inferred by linkage disequilibrium mapping (DMLE+2.3). The appearance of a disease-causing mutation was dated between 64–133 generations. The inferred ancestral locus carrying a PPCD1 disease-causing variant within the disease interval spans 60 Kb on 20p11.23, which contains a single known protein coding gene, ZNF133. However, direct sequence analysis of coding and untranslated exons did not reveal a potential pathogenic mutation. Microdeletion or duplication was also excluded by comparative genomic hybridization using a dense chromosome 20 specific array. Geographical origin, haplotype and statistical analysis suggest that in 14 unrelated families an as yet undiscovered mutation on 20p11.23 was inherited from a common ancestor. Prevalence of PPCD in the Czech Republic appears to be the highest worldwide and our data

Extent of genome-wide linkage disequilibrium in Australian Holstein-Friesian cattle based on a high-density SNP panel.

PubMed

Khatkar, Mehar S; Nicholas, Frank W; Collins, Andrew R; Zenger, Kyall R; Cavanagh, Julie A L; Barris, Wes; Schnabel, Robert D; Taylor, Jeremy F; Raadsma, Herman W

2008-04-24

The extent of linkage disequilibrium (LD) within a population determines the number of markers that will be required for successful association mapping and marker-assisted selection. Most studies on LD in cattle reported to date are based on microsatellite markers or small numbers of single nucleotide polymorphisms (SNPs) covering one or only a few chromosomes. This is the first comprehensive study on the extent of LD in cattle by analyzing data on 1,546 Holstein-Friesian bulls genotyped for 15,036 SNP markers covering all regions of all autosomes. Furthermore, most studies in cattle have used relatively small sample sizes and, consequently, may have had biased estimates of measures commonly used to describe LD. We examine minimum sample sizes required to estimate LD without bias and loss in accuracy. Finally, relatively little information is available on comparative LD structures including other mammalian species such as human and mouse, and we compare LD structure in cattle with public-domain data from both human and mouse. We computed three LD estimates, D', Dvol and r2, for 1,566,890 syntenic SNP pairs and a sample of 365,400 non-syntenic pairs. Mean D' is 0.189 among syntenic SNPs, and 0.105 among non-syntenic SNPs; mean r2 is 0.024 among syntenic SNPs and 0.0032 among non-syntenic SNPs. All three measures of LD for syntenic pairs decline with distance; the decline is much steeper for r2 than for D' and Dvol. The value of D' and Dvol are quite similar. Significant LD in cattle extends to 40 kb (when estimated as r2) and 8.2 Mb (when estimated as D'). The mean values for LD at large physical distances are close to those for non-syntenic SNPs. Minor allelic frequency threshold affects the distribution and extent of LD. For unbiased and accurate estimates of LD across marker intervals spanning < 1 kb to > 50 Mb, minimum sample sizes of 400 (for D') and 75 (for r2) are required. The bias due to small samples sizes increases with inter-marker interval. LD in cattle

Linkage disequilibria at the D[sub 2] dopamine receptor locus (DRD2) in alcoholics and controls

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suarez, B.K.; Parsian, A.; Hampe, C.L.

1994-01-01

Because of its central role in the neuromodulation of appetitive behaviors, the D[sub 2] dopamine receptor gene (DRD2) has received considerable scrutiny as a possible candidate that may affect susceptibility to addictive behaviors--especially alcoholism. Association studies that compare the frequencies of anonymous restriction fragment length polymorphisms (RFLPs) in alcoholics and controls have yielded equivocal results, suggesting that any role played by this receptor will account for only part of the variation. Since these RFLPs are not located in coding regions, the hypothesis has been advanced that the association seen in some studies results from linkage disequilibrium between these markers andmore » one or more functional DRD2 alleles that affect susceptibility. To test this hypothesis, the authors have assayed four DRD2 RFLPs that span coding regions as well as a 3[prime] flanking RFLP in an expanded sample of 88 unrelated Caucasian alcoholics and 89 unrelated race-matched controls. No significant difference for any RFLP frequency between these samples was observed, although for one marker (phD2-244), the alcoholic sample showed a significant departure from the Hardy-Weinberg equilibrium. The pattern of pairwise composite disequilibrium coefficients is broadly similar in the two samples, although when the five-marker haplotype frequencies are compared, a significant difference is revealed. This difference appears to be due to greater linkage disequilibrium of the control sample. These results do not support the involvement of the DRD2 region in the etiology of alcoholism. 64 refs., 2 figs., 6 tabs.« less

State-Level Immunization Information Systems: Potential for Childhood Immunization Data Linkages.

PubMed

Fuller, Jill E; Walter, Emmanuel B; Dole, Nancy; O'Hara, Richard; Herring, Amy H; Durkin, Maureen S; Specker, Bonny; Wey, Betty

2017-01-01

Objectives Sources of immunization data include state registries or immunization information systems (IIS), medical records, and surveys. Little is known about the quality of these data sources or the feasibility of using IIS data for research. We assessed the feasibility of collecting immunization information for a national children's health study by accessing existing IIS data and comparing the completeness of these data against medical record abstractions (MRA) and parent report. Staff time needed to obtain IIS and MRA data was assessed. Methods We administered a questionnaire to state-level IIS representatives to ascertain availability and completeness of their data for research and gather information about data formats. We evaluated quality of data from IIS, medical records, and reports from parents of 119 National Children's Study participants at three locations. Results IIS data were comparable to MRA data and both were more complete than parental report. Agreement between IIS and MRA data was greater than between parental report and MRA, suggesting IIS and MRA are better sources than parental report. Obtaining IIS data took less staff time than chart review, making IIS data linkage for research a preferred choice. Conclusions IIS survey results indicate data can be obtained by researchers using data linkages. IIS are an accessible and feasible child immunization information source and these registries reduce reliance on parental report or medical record abstraction. Researchers seeking to link IIS data with large multi-site studies should consider acquiring IIS data, but may need strategies to overcome barriers to data completeness and linkage.

Disequilibrium in planetary atmospheres and the search for habitability

NASA Astrophysics Data System (ADS)

Simoncini, E.

It has long been observed that Earth's atmosphere is uniquely far from its thermochemical equilibrium state in terms of its chemical composition. Studying this state of disequilibrium is important for its potential role in the detection of life on other suitable planets \\citep{Lovelock_1965,Kleidon_2010,Simoncini_2015}. We developed a methodology to calculate the extent of atmospheric chemical disequilibrium\\citep{Simoncini_2015,Kondepudi_1996}. This tool allows us to understand, on a thermodynamic basis, how life affected - and still affects - geochemical processes on Earth, and if other planetary atmospheres are habitable or have a disequilibrium similar to the Earth's one. A new computational framework called KROME has been applied to atmospheric models in order to give a correct computation of reactions´ kinetics \\citep{Grassi_2015}. In this work we present a first computation of the extent of disequilibrium for the present Earth atmosphere, considering the specific contribution of the different atmospheric processes, such as thermochemical reactions, eddy diffusion, photochemistry, deposition, and the effect of the biosphere. We then assess the effect of life on atmospheric disequilibrium of the Earth and provide a useful discussion about how the study of atmospheric disequilibrium can help in finding habitable (exo)planets. We finally compare the chemical disequilibrium of Earth and Mars atmospheres, for present and early conditions.

Linked Records of Children with Traumatic Brain Injury. Probabilistic Linkage without Use of Protected Health Information.

PubMed

Bennett, T D; Dean, J M; Keenan, H T; McGlincy, M H; Thomas, A M; Cook, L J

2015-01-01

Record linkage may create powerful datasets with which investigators can conduct comparative effectiveness studies evaluating the impact of tests or interventions on health. All linkages of health care data files to date have used protected health information (PHI) in their linkage variables. A technique to link datasets without using PHI would be advantageous both to preserve privacy and to increase the number of potential linkages. We applied probabilistic linkage to records of injured children in the National Trauma Data Bank (NTDB, N = 156,357) and the Pediatric Health Information Systems (PHIS, N = 104,049) databases from 2007 to 2010. 49 match variables without PHI were used, many of them administrative variables and indicators for procedures recorded as International Classification of Diseases, 9th revision, Clinical Modification codes. We validated the accuracy of the linkage using identified data from a single center that submits to both databases. We accurately linked the PHIS and NTDB records for 69% of children with any injury, and 88% of those with severe traumatic brain injury eligible for a study of intervention effectiveness (positive predictive value of 98%, specificity of 99.99%). Accurate linkage was associated with longer lengths of stay, more severe injuries, and multiple injuries. In populations with substantial illness or injury severity, accurate record linkage may be possible in the absence of PHI. This methodology may enable linkages and, in turn, comparative effectiveness studies that would be unlikely or impossible otherwise.

Linkage disequilibrium between the CYP2C19*2,*17 and CYP2C9*1 alleles and impact of VKORC1, CYP2C9, CYP2C19 gene polymorphisms and gene-gene interactions on warfarin therapy.

PubMed

Khalighi, Koroush; Cheng, Gang; Mirabbasi, Seyedabbas; Khalighi, Bahar; Wu, Yin; Fan, Wuqiang

2017-01-01

Warfarin therapy is complicated by its large inter-individual and intra-individual variability. Both genetic and non-genetic factors can affect warfarin therapy. This study aims to investigate the allele distribution of VKORC1, CYP2C9 and CYP2C19, contribution of different allele variants and possible gene-gene interaction on warfarin therapy. Four hundreds and ninety-two patients were enrolled and single nucleotide polymorphisms for vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 CYP2C9 and cytochrome P450 CYP2C19 were genotyped. CYP2C9*1 allele is in complete linkage disequilibrium with CYP2C19*2 and CYP2C19*17 (D' = 1) in our study population. Patient with VKORC1-1639 G > A, CYP2C9*2 and CYP2C9*3 genetic variants need significant lower warfarin dose than patient with wild type allele of VKORC1 1639 G or CYP2C9*1. There is no significant differences between CYP2C19 allele variants for warfarin stable dose and INR > 5 event. Because of the complete linkage disequilibrium between CYP2C19*2,*17 and CYP2C9*1, patient with CYP2C19 *2/*2, *2/*17 and *17/*17 genotypes tend to have higher warfarin dose than patient with CYP2C19*1/*1 genotype. Stepwise regression analysis showed that VKORC1, CYP2C9, body mass index (BMI), age and gender were included as a factor significantly contributing to warfarin dose, whereas CYP2C19 did not contribute to warfarin dose. No statistically significant interaction between CYP2C9 and VKORC1 on warfarin dose and INR > 5 event was detected in univariate general linear model analysis. Our study suggests that polymorphic variants of VKORC1 and CYP2C9 affect warfarin dose independently, whereas CYP2C19 did not contribute to warfarin therapy.

Exploiting genotyping by sequencing to characterize the genomic structure of the American cranberry through high-density linkage mapping.

PubMed

Covarrubias-Pazaran, Giovanny; Diaz-Garcia, Luis; Schlautman, Brandon; Deutsch, Joseph; Salazar, Walter; Hernandez-Ochoa, Miguel; Grygleski, Edward; Steffan, Shawn; Iorizzo, Massimo; Polashock, James; Vorsa, Nicholi; Zalapa, Juan

2016-06-13

The application of genotyping by sequencing (GBS) approaches, combined with data imputation methodologies, is narrowing the genetic knowledge gap between major and understudied, minor crops. GBS is an excellent tool to characterize the genomic structure of recently domesticated (~200 years) and understudied species, such as cranberry (Vaccinium macrocarpon Ait.), by generating large numbers of markers for genomic studies such as genetic mapping. We identified 10842 potentially mappable single nucleotide polymorphisms (SNPs) in a cranberry pseudo-testcross population wherein 5477 SNPs and 211 short sequence repeats (SSRs) were used to construct a high density linkage map in cranberry of which a total of 4849 markers were mapped. Recombination frequency, linkage disequilibrium (LD), and segregation distortion at the genomic level in the parental and integrated linkage maps were characterized for first time in cranberry. SSR markers, used as the backbone in the map, revealed high collinearity with previously published linkage maps. The 4849 point map consisted of twelve linkage groups spanning 1112 cM, which anchored 2381 nuclear scaffolds accounting for ~13 Mb of the estimated 470 Mb cranberry genome. Bin mapping identified 592 and 672 unique bins in the parentals and a total of 1676 unique marker positions in the integrated map. Synteny analyses comparing the order of anchored cranberry scaffolds to their homologous positions in kiwifruit, grape, and coffee genomes provided initial evidence of homology between cranberry and closely related species. GBS data was used to rapidly saturate the cranberry genome with markers in a pseudo-testcross population. Collinearity between the present saturated genetic map and previous cranberry SSR maps suggests that the SNP locations represent accurate marker order and chromosome structure of the cranberry genome. SNPs greatly improved current marker genome coverage, which allowed for genome-wide structure investigations such

On Detecting Biospheres from Chemical Thermodynamic Disequilibrium in Planetary Atmospheres.

PubMed

Krissansen-Totton, Joshua; Bergsman, David S; Catling, David C

2016-01-01

Atmospheric chemical disequilibrium has been proposed as a method for detecting extraterrestrial biospheres from exoplanet observations. Chemical disequilibrium is potentially a generalized biosignature since it makes no assumptions about particular biogenic gases or metabolisms. Here, we present the first rigorous calculations of the thermodynamic chemical disequilibrium in Solar System atmospheres, in which we quantify the available Gibbs energy: the Gibbs free energy of an observed atmosphere minus that of atmospheric gases reacted to equilibrium. The purely gas phase disequilibrium in Earth's atmosphere is mostly attributable to O2 and CH4. The available Gibbs energy is not unusual compared to other Solar System atmospheres and smaller than that of Mars. However, Earth's fluid envelope contains an ocean, allowing gases to react with water and requiring a multiphase calculation with aqueous species. The disequilibrium in Earth's atmosphere-ocean system (in joules per mole of atmosphere) ranges from ∼20 to 2 × 10(6) times larger than the disequilibria of other atmospheres in the Solar System, where Mars is second to Earth. Only on Earth is the chemical disequilibrium energy comparable to the thermal energy per mole of atmosphere (excluding comparison to Titan with lakes, where quantification is precluded because the mean lake composition is unknown). Earth's disequilibrium is biogenic, mainly caused by the coexistence of N2, O2, and liquid water instead of more stable nitrate. In comparison, the O2-CH4 disequilibrium is minor, although kinetics requires a large CH4 flux into the atmosphere. We identify abiotic processes that cause disequilibrium in the other atmospheres. Our metric requires minimal assumptions and could potentially be calculated from observations of exoplanet atmospheres. However, further work is needed to establish whether thermodynamic disequilibrium is a practical exoplanet biosignature, requiring an assessment of false positives, noisy

Linkage of A-to-I RNA Editing in Metazoans and the Impact on Genome Evolution

PubMed Central

Duan, Yuange; Dou, Shengqian; Zhang, Hong; Wu, Changcheng; Wu, Mingming

2018-01-01

Abstract The adenosine-to-inosine (A-to-I) RNA editomes have been systematically characterized in various metazoan species, and many editing sites were found in clusters. However, it remains unclear whether the clustered editing sites tend to be linked in the same RNA molecules or not. By adopting a method originally designed to detect linkage disequilibrium of DNA mutations, we examined the editomes of ten metazoan species and detected extensive linkage of editing in Drosophila and cephalopods. The prevalent linkages of editing in these two clades, many of which are conserved between closely related species and might be associated with the adaptive proteomic recoding, are maintained by natural selection at the cost of genome evolution. Nevertheless, in worms and humans, we only detected modest proportions of linked editing events, the majority of which were not conserved. Furthermore, the linkage of editing in coding regions of worms and humans might be overall deleterious, which drives the evolution of DNA sites to escape promiscuous editing. Altogether, our results suggest that the linkage landscape of A-to-I editing has evolved during metazoan evolution. This present study also suggests that linkage of editing should be considered in elucidating the functional consequences of RNA editing. PMID:29048557

Nucleon-Alpha Particle Disequilibrium and Short-Lived r-Process Radioactivities

NASA Technical Reports Server (NTRS)

Meyer, B. S.; Clayton, D. D.; Chellapilla, S.; The, L.-S.

2002-01-01

r-Process yields can be extremely sensitive to expansion parameters when a persistent disequilibrium between free nucleons and alpha particles is present. This may provide a natural scenario for understanding the variation of heavy and light r-process isotopes in different r-process events. Additional information is contained in the original extended abstract.

Linkages: Effective Keys to Success.

ERIC Educational Resources Information Center

Tindall, Lloyd W.

1986-01-01

Discusses various elements of linkages: informal agreements; formal written agreements; making agreements work; the non-financial agreement; how linkages work at the elementary, secondary, and postsecondary levels in Wisconsin; mandated linkages; and the importance of linkages in the vocational education and training arena. (CT)

Exploiting Genome Structure in Association Analysis

PubMed Central

Kim, Seyoung

2014-01-01

Abstract A genome-wide association study involves examining a large number of single-nucleotide polymorphisms (SNPs) to identify SNPs that are significantly associated with the given phenotype, while trying to reduce the false positive rate. Although haplotype-based association methods have been proposed to accommodate correlation information across nearby SNPs that are in linkage disequilibrium, none of these methods directly incorporated the structural information such as recombination events along chromosome. In this paper, we propose a new approach called stochastic block lasso for association mapping that exploits prior knowledge on linkage disequilibrium structure in the genome such as recombination rates and distances between adjacent SNPs in order to increase the power of detecting true associations while reducing false positives. Following a typical linear regression framework with the genotypes as inputs and the phenotype as output, our proposed method employs a sparsity-enforcing Laplacian prior for the regression coefficients, augmented by a first-order Markov process along the sequence of SNPs that incorporates the prior information on the linkage disequilibrium structure. The Markov-chain prior models the structural dependencies between a pair of adjacent SNPs, and allows us to look for association SNPs in a coupled manner, combining strength from multiple nearby SNPs. Our results on HapMap-simulated datasets and mouse datasets show that there is a significant advantage in incorporating the prior knowledge on linkage disequilibrium structure for marker identification under whole-genome association. PMID:21548809

Linkage of A-to-I RNA Editing in Metazoans and the Impact on Genome Evolution.

PubMed

Duan, Yuange; Dou, Shengqian; Zhang, Hong; Wu, Changcheng; Wu, Mingming; Lu, Jian

2018-01-01

The adenosine-to-inosine (A-to-I) RNA editomes have been systematically characterized in various metazoan species, and many editing sites were found in clusters. However, it remains unclear whether the clustered editing sites tend to be linked in the same RNA molecules or not. By adopting a method originally designed to detect linkage disequilibrium of DNA mutations, we examined the editomes of ten metazoan species and detected extensive linkage of editing in Drosophila and cephalopods. The prevalent linkages of editing in these two clades, many of which are conserved between closely related species and might be associated with the adaptive proteomic recoding, are maintained by natural selection at the cost of genome evolution. Nevertheless, in worms and humans, we only detected modest proportions of linked editing events, the majority of which were not conserved. Furthermore, the linkage of editing in coding regions of worms and humans might be overall deleterious, which drives the evolution of DNA sites to escape promiscuous editing. Altogether, our results suggest that the linkage landscape of A-to-I editing has evolved during metazoan evolution. This present study also suggests that linkage of editing should be considered in elucidating the functional consequences of RNA editing. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Improving record linkage performance in the presence of missing linkage data.

PubMed

Ong, Toan C; Mannino, Michael V; Schilling, Lisa M; Kahn, Michael G

2014-12-01

Existing record linkage methods do not handle missing linking field values in an efficient and effective manner. The objective of this study is to investigate three novel methods for improving the accuracy and efficiency of record linkage when record linkage fields have missing values. By extending the Fellegi-Sunter scoring implementations available in the open-source Fine-grained Record Linkage (FRIL) software system we developed three novel methods to solve the missing data problem in record linkage, which we refer to as: Weight Redistribution, Distance Imputation, and Linkage Expansion. Weight Redistribution removes fields with missing data from the set of quasi-identifiers and redistributes the weight from the missing attribute based on relative proportions across the remaining available linkage fields. Distance Imputation imputes the distance between the missing data fields rather than imputing the missing data value. Linkage Expansion adds previously considered non-linkage fields to the linkage field set to compensate for the missing information in a linkage field. We tested the linkage methods using simulated data sets with varying field value corruption rates. The methods developed had sensitivity ranging from .895 to .992 and positive predictive values (PPV) ranging from .865 to 1 in data sets with low corruption rates. Increased corruption rates lead to decreased sensitivity for all methods. These new record linkage algorithms show promise in terms of accuracy and efficiency and may be valuable for combining large data sets at the patient level to support biomedical and clinical research. Copyright © 2014 Elsevier Inc. All rights reserved.

speed-ne: Software to simulate and estimate genetic effective population size (Ne ) from linkage disequilibrium observed in single samples.

PubMed

Hamilton, Matthew B; Tartakovsky, Maria; Battocletti, Amy

2018-05-01

The genetic effective population size, N e , can be estimated from the average gametic disequilibrium (r2^) between pairs of loci, but such estimates require evaluation of assumptions and currently have few methods to estimate confidence intervals. speed-ne is a suite of matlab computer code functions to estimate Ne^ from r2^ with a graphical user interface and a rich set of outputs that aid in understanding data patterns and comparing multiple estimators. speed-ne includes functions to either generate or input simulated genotype data to facilitate comparative studies of Ne^ estimators under various population genetic scenarios. speed-ne was validated with data simulated under both time-forward and time-backward coalescent models of genetic drift. Three classes of estimators were compared with simulated data to examine several general questions: what are the impacts of microsatellite null alleles on Ne^, how should missing data be treated, and does disequilibrium contributed by reduced recombination among some loci in a sample impact Ne^. Estimators differed greatly in precision in the scenarios examined, and a widely employed Ne^ estimator exhibited the largest variances among replicate data sets. speed-ne implements several jackknife approaches to estimate confidence intervals, and simulated data showed that jackknifing over loci and jackknifing over individuals provided ~95% confidence interval coverage for some estimators and should be useful for empirical studies. speed-ne provides an open-source extensible tool for estimation of Ne^ from empirical genotype data and to conduct simulations of both microsatellite and single nucleotide polymorphism (SNP) data types to develop expectations and to compare Ne^ estimators. © 2018 John Wiley & Sons Ltd.

Using SNP markers to dissect linkage disequilibrium at a major quantitative trait locus for resistance to the potato cyst nematode Globodera pallida on potato chromosome V.

PubMed

Achenbach, Ute; Paulo, Joao; Ilarionova, Evgenyia; Lübeck, Jens; Strahwald, Josef; Tacke, Eckhard; Hofferbert, Hans-Reinhard; Gebhardt, Christiane

2009-02-01

The damage caused by the parasitic root cyst nematode Globodera pallida is a major yield-limiting factor in potato cultivation . Breeding for resistance is facilitated by the PCR-based marker 'HC', which is diagnostic for an allele conferring high resistance against G. pallida pathotype Pa2/3 that has been introgressed from the wild potato species Solanum vernei into the Solanum tuberosum tetraploid breeding pool. The major quantitative trait locus (QTL) controlling this nematode resistance maps on potato chromosome V in a hot spot for resistance to various pathogens including nematodes and the oomycete Phytophthora infestans. An unstructured sample of 79 tetraploid, highly heterozygous varieties and breeding clones was selected based on presence (41 genotypes) or absence (38 genotypes) of the HC marker. Testing the clones for resistance to G. pallida confirmed the diagnostic power of the HC marker. The 79 individuals were genotyped for 100 single nucleotide polymorphisms (SNPs) at 10 loci distributed over 38 cM on chromosome V. Forty-five SNPs at six loci spanning 2 cM in the interval between markers GP21-GP179 were associated with resistance to G. pallida. Based on linkage disequilibrium (LD) between SNP markers, six LD groups comprising between 2 and 18 SNPs were identified. The LD groups indicated the existence of multiple alleles at a single resistance locus or at several, physically linked resistance loci. LD group C comprising 18 SNPs corresponded to the 'HC' marker. LD group E included 16 SNPs and showed an association peak, which positioned one nematode resistance locus physically close to the R1 gene family.

Extent of linkage disequilibrium, consistency of gametic phase, and imputation accuracy within and across Canadian dairy breeds.

PubMed

Larmer, S G; Sargolzaei, M; Schenkel, F S

2014-05-01

Genomic selection requires a large reference population to accurately estimate single nucleotide polymorphism (SNP) effects. In some Canadian dairy breeds, the available reference populations are not large enough for accurate estimation of SNP effects for traits of interest. If marker phase is highly consistent across multiple breeds, it is theoretically possible to increase the accuracy of genomic prediction for one or all breeds by pooling several breeds into a common reference population. This study investigated the extent of linkage disequilibrium (LD) in 5 major dairy breeds using a 50,000 (50K) SNP panel and 3 of the same breeds using the 777,000 (777K) SNP panel. Correlation of pair-wise SNP phase was also investigated on both panels. The level of LD was measured using the squared correlation of alleles at 2 loci (r(2)), and the consistency of SNP gametic phases was correlated using the signed square root of these values. Because of the high cost of the 777K panel, the accuracy of imputation from lower density marker panels [6,000 (6K) or 50K] was examined both within breed and using a multi-breed reference population in Holstein, Ayrshire, and Guernsey. Imputation was carried out using FImpute V2.2 and Beagle 3.3.2 software. Imputation accuracies were then calculated as both the proportion of correct SNP filled in (concordance rate) and allelic R(2). Computation time was also explored to determine the efficiency of the different algorithms for imputation. Analysis showed that LD values >0.2 were found in all breeds at distances at or shorter than the average adjacent pair-wise distance between SNP on the 50K panel. Correlations of r-values, however, did not reach high levels (<0.9) at these distances. High correlation values of SNP phase between breeds were observed (>0.94) when the average pair-wise distances using the 777K SNP panel were examined. High concordance rate (0.968-0.995) and allelic R(2) (0.946-0.991) were found for all breeds when imputation

A Targeted Capture Linkage Map Anchors the Genome of the Schistosomiasis Vector Snail, Biomphalaria glabrata.

PubMed

Tennessen, Jacob A; Bollmann, Stephanie R; Blouin, Michael S

2017-07-05

The aquatic planorbid snail Biomphalaria glabrata is one of the most intensively-studied mollusks due to its role in the transmission of schistosomiasis. Its 916 Mb genome has recently been sequenced and annotated, but it remains poorly assembled. Here, we used targeted capture markers to map over 10,000 B. glabrata scaffolds in a linkage cross of 94 F1 offspring, generating 24 linkage groups (LGs). We added additional scaffolds to these LGs based on linkage disequilibrium (LD) analysis of targeted capture and whole-genome sequences of 96 unrelated snails. Our final linkage map consists of 18,613 scaffolds comprising 515 Mb, representing 56% of the genome and 75% of genic and nonrepetitive regions. There are 18 large (> 10 Mb) LGs, likely representing the expected 18 haploid chromosomes, and > 50% of the genome has been assigned to LGs of at least 17 Mb. Comparisons with other gastropod genomes reveal patterns of synteny and chromosomal rearrangements. Linkage relationships of key immune-relevant genes may help clarify snail-schistosome interactions. By focusing on linkage among genic and nonrepetitive regions, we have generated a useful resource for associating snail phenotypes with causal genes, even in the absence of a complete genome assembly. A similar approach could potentially improve numerous poorly-assembled genomes in other taxa. This map will facilitate future work on this host of a serious human parasite. Copyright © 2017 Tennessen et al.

Disequilibrium biosignatures over Earth history and implications for detecting exoplanet life.

PubMed

Krissansen-Totton, Joshua; Olson, Stephanie; Catling, David C

2018-01-01

Chemical disequilibrium in planetary atmospheres has been proposed as a generalized method for detecting life on exoplanets through remote spectroscopy. Among solar system planets with substantial atmospheres, the modern Earth has the largest thermodynamic chemical disequilibrium due to the presence of life. However, how this disequilibrium changed over time and, in particular, the biogenic disequilibria maintained in the anoxic Archean or less oxic Proterozoic eons are unknown. We calculate the atmosphere-ocean disequilibrium in the Precambrian using conservative proxy- and model-based estimates of early atmospheric and oceanic compositions. We omit crustal solids because subsurface composition is not detectable on exoplanets, unlike above-surface volatiles. We find that (i) disequilibrium increased through time in step with the rise of oxygen; (ii) both the Proterozoic and Phanerozoic may have had remotely detectable biogenic disequilibria due to the coexistence of O 2 , N 2 , and liquid water; and (iii) the Archean had a biogenic disequilibrium caused by the coexistence of N 2 , CH 4 , CO 2 , and liquid water, which, for an exoplanet twin, may be remotely detectable. On the basis of this disequilibrium, we argue that the simultaneous detection of abundant CH 4 and CO 2 in a habitable exoplanet's atmosphere is a potential biosignature. Specifically, we show that methane mixing ratios greater than 10 -3 are potentially biogenic, whereas those exceeding 10 -2 are likely biogenic due to the difficulty in maintaining large abiotic methane fluxes to support high methane levels in anoxic atmospheres. Biogenicity would be strengthened by the absence of abundant CO, which should not coexist in a biological scenario.

Privacy preserving interactive record linkage (PPIRL).

PubMed

Kum, Hye-Chung; Krishnamurthy, Ashok; Machanavajjhala, Ashwin; Reiter, Michael K; Ahalt, Stanley

2014-01-01

Record linkage to integrate uncoordinated databases is critical in biomedical research using Big Data. Balancing privacy protection against the need for high quality record linkage requires a human-machine hybrid system to safely manage uncertainty in the ever changing streams of chaotic Big Data. In the computer science literature, private record linkage is the most published area. It investigates how to apply a known linkage function safely when linking two tables. However, in practice, the linkage function is rarely known. Thus, there are many data linkage centers whose main role is to be the trusted third party to determine the linkage function manually and link data for research via a master population list for a designated region. Recently, a more flexible computerized third-party linkage platform, Secure Decoupled Linkage (SDLink), has been proposed based on: (1) decoupling data via encryption, (2) obfuscation via chaffing (adding fake data) and universe manipulation; and (3) minimum information disclosure via recoding. We synthesize this literature to formalize a new framework for privacy preserving interactive record linkage (PPIRL) with tractable privacy and utility properties and then analyze the literature using this framework. Human-based third-party linkage centers for privacy preserving record linkage are the accepted norm internationally. We find that a computer-based third-party platform that can precisely control the information disclosed at the micro level and allow frequent human interaction during the linkage process, is an effective human-machine hybrid system that significantly improves on the linkage center model both in terms of privacy and utility.

Privacy preserving interactive record linkage (PPIRL)

PubMed Central

Kum, Hye-Chung; Krishnamurthy, Ashok; Machanavajjhala, Ashwin; Reiter, Michael K; Ahalt, Stanley

2014-01-01

Objective Record linkage to integrate uncoordinated databases is critical in biomedical research using Big Data. Balancing privacy protection against the need for high quality record linkage requires a human–machine hybrid system to safely manage uncertainty in the ever changing streams of chaotic Big Data. Methods In the computer science literature, private record linkage is the most published area. It investigates how to apply a known linkage function safely when linking two tables. However, in practice, the linkage function is rarely known. Thus, there are many data linkage centers whose main role is to be the trusted third party to determine the linkage function manually and link data for research via a master population list for a designated region. Recently, a more flexible computerized third-party linkage platform, Secure Decoupled Linkage (SDLink), has been proposed based on: (1) decoupling data via encryption, (2) obfuscation via chaffing (adding fake data) and universe manipulation; and (3) minimum information disclosure via recoding. Results We synthesize this literature to formalize a new framework for privacy preserving interactive record linkage (PPIRL) with tractable privacy and utility properties and then analyze the literature using this framework. Conclusions Human-based third-party linkage centers for privacy preserving record linkage are the accepted norm internationally. We find that a computer-based third-party platform that can precisely control the information disclosed at the micro level and allow frequent human interaction during the linkage process, is an effective human–machine hybrid system that significantly improves on the linkage center model both in terms of privacy and utility. PMID:24201028

Inferring Short-Range Linkage Information from Sequencing Chromatograms

PubMed Central

Beggel, Bastian; Neumann-Fraune, Maria; Kaiser, Rolf; Verheyen, Jens; Lengauer, Thomas

2013-01-01

Direct Sanger sequencing of viral genome populations yields multiple ambiguous sequence positions. It is not straightforward to derive linkage information from sequencing chromatograms, which in turn hampers the correct interpretation of the sequence data. We present a method for determining the variants existing in a viral quasispecies in the case of two nearby ambiguous sequence positions by exploiting the effect of sequence context-dependent incorporation of dideoxynucleotides. The computational model was trained on data from sequencing chromatograms of clonal variants and was evaluated on two test sets of in vitro mixtures. The approach achieved high accuracies in identifying the mixture components of 97.4% on a test set in which the positions to be analyzed are only one base apart from each other, and of 84.5% on a test set in which the ambiguous positions are separated by three bases. In silico experiments suggest two major limitations of our approach in terms of accuracy. First, due to a basic limitation of Sanger sequencing, it is not possible to reliably detect minor variants with a relative frequency of no more than 10%. Second, the model cannot distinguish between mixtures of two or four clonal variants, if one of two sets of linear constraints is fulfilled. Furthermore, the approach requires repetitive sequencing of all variants that might be present in the mixture to be analyzed. Nevertheless, the effectiveness of our method on the two in vitro test sets shows that short-range linkage information of two ambiguous sequence positions can be inferred from Sanger sequencing chromatograms without any further assumptions on the mixture composition. Additionally, our model provides new insights into the established and widely used Sanger sequencing technology. The source code of our method is made available at http://bioinf.mpi-inf.mpg.de/publications/beggel/linkageinformation.zip. PMID:24376502

Exploiting semantic linkages among multiple sources for semantic information retrieval

NASA Astrophysics Data System (ADS)

Li, JianQiang; Yang, Ji-Jiang; Liu, Chunchen; Zhao, Yu; Liu, Bo; Shi, Yuliang

2014-07-01

The vision of the Semantic Web is to build a global Web of machine-readable data to be consumed by intelligent applications. As the first step to make this vision come true, the initiative of linked open data has fostered many novel applications aimed at improving data accessibility in the public Web. Comparably, the enterprise environment is so different from the public Web that most potentially usable business information originates in an unstructured form (typically in free text), which poses a challenge for the adoption of semantic technologies in the enterprise environment. Considering that the business information in a company is highly specific and centred around a set of commonly used concepts, this paper describes a pilot study to migrate the concept of linked data into the development of a domain-specific application, i.e. the vehicle repair support system. The set of commonly used concepts, including the part name of a car and the phenomenon term on the car repairing, are employed to build the linkage between data and documents distributed among different sources, leading to the fusion of documents and data across source boundaries. Then, we describe the approaches of semantic information retrieval to consume these linkages for value creation for companies. The experiments on two real-world data sets show that the proposed approaches outperform the best baseline 6.3-10.8% and 6.4-11.1% in terms of top five and top 10 precisions, respectively. We believe that our pilot study can serve as an important reference for the development of similar semantic applications in an enterprise environment.

Disequilibrium condensation environments in space - A frontier in thermodynamics

NASA Technical Reports Server (NTRS)

De, B. R.

1979-01-01

The thermal-disequilibrium aspect of the problem of dust-particle formation from a gas phase in an open space environment is discussed in an effort to draw attention to the space condensation environment as an interesting arena for application and extension of the ideas and formalisms of nonequilibrium thermodynamics. It is shown that quasi-steady states with a disequilibrium between the gas-phase kinetic temperature and the condensed-phase internal temperature appear to be the norm of condensation environments in space. Consideration of the case of condensation onto a bulk condensed phase indicates that these quasi-steady states may constitute Prigogine dissipative structures. It is suggested that a proper study of the process of condensation in a space environment should include any effects arising from thermal disequilibrium.

Disequilibrium biosignatures over Earth history and implications for detecting exoplanet life

PubMed Central

Krissansen-Totton, Joshua; Olson, Stephanie; Catling, David C.

2018-01-01

Chemical disequilibrium in planetary atmospheres has been proposed as a generalized method for detecting life on exoplanets through remote spectroscopy. Among solar system planets with substantial atmospheres, the modern Earth has the largest thermodynamic chemical disequilibrium due to the presence of life. However, how this disequilibrium changed over time and, in particular, the biogenic disequilibria maintained in the anoxic Archean or less oxic Proterozoic eons are unknown. We calculate the atmosphere-ocean disequilibrium in the Precambrian using conservative proxy- and model-based estimates of early atmospheric and oceanic compositions. We omit crustal solids because subsurface composition is not detectable on exoplanets, unlike above-surface volatiles. We find that (i) disequilibrium increased through time in step with the rise of oxygen; (ii) both the Proterozoic and Phanerozoic may have had remotely detectable biogenic disequilibria due to the coexistence of O2, N2, and liquid water; and (iii) the Archean had a biogenic disequilibrium caused by the coexistence of N2, CH4, CO2, and liquid water, which, for an exoplanet twin, may be remotely detectable. On the basis of this disequilibrium, we argue that the simultaneous detection of abundant CH4 and CO2 in a habitable exoplanet’s atmosphere is a potential biosignature. Specifically, we show that methane mixing ratios greater than 10−3 are potentially biogenic, whereas those exceeding 10−2 are likely biogenic due to the difficulty in maintaining large abiotic methane fluxes to support high methane levels in anoxic atmospheres. Biogenicity would be strengthened by the absence of abundant CO, which should not coexist in a biological scenario. PMID:29387792

Disequilibrium, complexity, the Schottky effect, and q-entropies, in paramagnetism

NASA Astrophysics Data System (ADS)

Pennini, F.; Plastino, A.

2017-12-01

We investigate connections between statistical quantifiers and paramagnetism. More concretely, we apply the notions of (i) disequilibrium and (ii) statistical complexity, to a paramagnetic system of non-coupled dipoles. Interesting insights are thereby obtained. In particular, we encounter a kind of criticality, not associated to the temperature but to the disequilibrium.

THE ROLE OF TEMPERATURE DISEQUILIBRIUM IN MONITORING LOW VOLATILITY CONTAMINANT MIGRATION

EPA Science Inventory

Temperature disequilibrium is a common phenomenon within and among envirornnental media at local regional continental and global scales. The significance of temperature disequilibrium on low vapor pressure environmental contaminant migration has only rarely been addressed in the ...

Strong linkage disequilibrium of a HbE variant with the (AT)9(T)5 repeat in the BP1 binding site upstream of the beta-globin gene in the Thai population.

PubMed

Ohashi, Jun; Naka, Izumi; Patarapotikul, Jintana; Hananantachai, Hathairad; Brittenham, Gary; Looareesuwan, Sornchai; Clark, Andrew G; Tokunaga, Katsushi

2005-01-01

A binding site for the repressor protein BP1, which contains a tandem (AT)x(T)y repeat, is located approximately 530 bp 5' to the human beta-globin gene (HBB). There is accumulating evidence that BP1 binds to the (AT)9(T)5 allele more strongly than to other alleles, thereby reducing the expression of HBB. In this study, we investigated polymorphisms in the (AT)x(T)y repeat in 57 individuals living in Thailand, including three homozygotes for the hemoglobin E variant (HbE; beta26Glu-->Lys), 22 heterozygotes, and 32 normal homozygotes. We found that (AT)9(T)5 and (AT)7(T)7 alleles were predominant in the studied population and that the HbE variant is in strong linkage disequilibrium with the (AT)9(T)5 allele, which can explain why the betaE chain is inefficiently synthesized compared to the normal betaA chain. Moreover, the mildness of the HbE disease compared to other hemoglobinopathies in Thai may be due, in part, to the presence of the (AT)9(T)5 repeat on the HbE chromosome. In addition, a novel (AC)n polymorphism adjacent to the (AT)x(T)y repeat (i.e., (AC)3(AT)7(T)5) was found through the variation screening in this study.

Privacy-preserving record linkage on large real world datasets.

PubMed

Randall, Sean M; Ferrante, Anna M; Boyd, James H; Bauer, Jacqueline K; Semmens, James B

2014-08-01

Record linkage typically involves the use of dedicated linkage units who are supplied with personally identifying information to determine individuals from within and across datasets. The personally identifying information supplied to linkage units is separated from clinical information prior to release by data custodians. While this substantially reduces the risk of disclosure of sensitive information, some residual risks still exist and remain a concern for some custodians. In this paper we trial a method of record linkage which reduces privacy risk still further on large real world administrative data. The method uses encrypted personal identifying information (bloom filters) in a probability-based linkage framework. The privacy preserving linkage method was tested on ten years of New South Wales (NSW) and Western Australian (WA) hospital admissions data, comprising in total over 26 million records. No difference in linkage quality was found when the results were compared to traditional probabilistic methods using full unencrypted personal identifiers. This presents as a possible means of reducing privacy risks related to record linkage in population level research studies. It is hoped that through adaptations of this method or similar privacy preserving methods, risks related to information disclosure can be reduced so that the benefits of linked research taking place can be fully realised. Copyright © 2013 Elsevier Inc. All rights reserved.

Construction of Ultradense Linkage Maps with Lep-MAP2: Stickleback F2 Recombinant Crosses as an Example

PubMed Central

Rastas, Pasi; Calboli, Federico C. F.; Guo, Baocheng; Shikano, Takahito; Merilä, Juha

2016-01-01

High-density linkage maps are important tools for genome biology and evolutionary genetics by quantifying the extent of recombination, linkage disequilibrium, and chromosomal rearrangements across chromosomes, sexes, and populations. They provide one of the best ways to validate and refine de novo genome assemblies, with the power to identify errors in assemblies increasing with marker density. However, assembly of high-density linkage maps is still challenging due to software limitations. We describe Lep-MAP2, a software for ultradense genome-wide linkage map construction. Lep-MAP2 can handle various family structures and can account for achiasmatic meiosis to gain linkage map accuracy. Simulations show that Lep-MAP2 outperforms other available mapping software both in computational efficiency and accuracy. When applied to two large F2-generation recombinant crosses between two nine-spined stickleback (Pungitius pungitius) populations, it produced two high-density (∼6 markers/cM) linkage maps containing 18,691 and 20,054 single nucleotide polymorphisms. The two maps showed a high degree of synteny, but female maps were 1.5–2 times longer than male maps in all linkage groups, suggesting genome-wide recombination suppression in males. Comparison with the genome sequence of the three-spined stickleback (Gasterosteus aculeatus) revealed a high degree of interspecific synteny with a low frequency (<5%) of interchromosomal rearrangements. However, a fairly large (ca. 10 Mb) translocation from autosome to sex chromosome was detected in both maps. These results illustrate the utility and novel features of Lep-MAP2 in assembling high-density linkage maps, and their usefulness in revealing evolutionarily interesting properties of genomes, such as strong genome-wide sex bias in recombination rates. PMID:26668116

Empirical characteristics of family-based linkage to a complex trait: the ADIPOQ region and adiponectin levels.

PubMed

Hellwege, Jacklyn N; Palmer, Nicholette D; Mark Brown, W; Brown, Mark W; Ziegler, Julie T; Sandy An, S; An, Sandy S; Guo, Xiuqing; Ida Chen, Y-D; Chen, Ida Y-D; Taylor, Kent; Hawkins, Gregory A; Ng, Maggie C Y; Speliotes, Elizabeth K; Lorenzo, Carlos; Norris, Jill M; Rotter, Jerome I; Wagenknecht, Lynne E; Langefeld, Carl D; Bowden, Donald W

2015-02-01

We previously identified a low-frequency (1.1 %) coding variant (G45R; rs200573126) in the adiponectin gene (ADIPOQ) which was the basis for a multipoint microsatellite linkage signal (LOD = 8.2) for plasma adiponectin levels in Hispanic families. We have empirically evaluated the ability of data from targeted common variants, exome chip genotyping, and genome-wide association study data to detect linkage and association to adiponectin protein levels at this locus. Simple two-point linkage and association analyses were performed in 88 Hispanic families (1,150 individuals) using 10,958 SNPs on chromosome 3. Approaches were compared for their ability to map the functional variant, G45R, which was strongly linked (two-point LOD = 20.98) and powerfully associated (p value = 8.1 × 10(-50)). Over 450 SNPs within a broad 61 Mb interval around rs200573126 showed nominal evidence of linkage (LOD > 3) but only four other SNPs in this region were associated with p values < 1.0 × 10(-4). When G45R was accounted for, the maximum LOD score across the interval dropped to 4.39 and the best p value was 1.1 × 10(-5). Linked and/or associated variants ranged in frequency (0.0018-0.50) and type (coding, non-coding) and had little detectable linkage disequilibrium with rs200573126 (r (2) < 0.20). In addition, the two-point linkage approach empirically outperformed multipoint microsatellite and multipoint SNP analysis. In the absence of data for rs200573126, family-based linkage analysis using a moderately dense SNP dataset, including both common and low-frequency variants, resulted in stronger evidence for an adiponectin locus than association data alone. Thus, linkage analysis can be a useful tool to facilitate identification of high-impact genetic variants.

Identifying Candidate Chemical-Disease Linkages ...

EPA Pesticide Factsheets

Presentation at meeting on Environmental and Epigenetic Determinants of IBD in New York, NY on identifying candidate chemical-disease linkages by using AOPs to identify molecular initiating events and using relevant high throughput assays to screen for candidate chemicals. This hazard information is combined with exposure models to inform risk assessment. Presentation at meeting on Environmental and Epigenetic Determinants of IBD in New York, NY on identifying candidate chemical-disease linkages by using AOPs to identify molecular initiating events and using relevant high throughput assays to screen for candidate chemicals. This hazard information is combined with exposure models to inform risk assessment.

Nonsyndromic cleft lip with or without cleft palate: Evidence of linkage to BCL3 in 17 multigenerational families

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stein, J.; Hecht, T.; Stal, S.

1995-08-01

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common craniofacial developmental defect. Recent segregation analyses have suggested that major genes play a role in the etiology of CL/P. Linkage to 22 candidate genes was tested in 11 multigenerational families with CL/P, and 21 of these candidates were excluded. APOC2, 19q13.1, which is linked to the proto-oncogene BCL3, gave suggestive evidence for linkage to CL/P. The study was expanded to include a total of 39 multigenerational CL/P families. Linkage was tested in all families, using anonymous marker, D19S178, and intragenic markers in BCL3 and APOC2. Linkage was testedmore » under two models, autosomal dominant with reduced penetrance and affecteds-only model. Both models showed evidence of heterogeneity, with 43% of families linked at zero recombination to BCL3 when marker data from BCL3 and APOC2 were included. A maximum multipoint LOD score of 7.00 at BCL3 was found among the 17 families that had posterior probabilities {ge}50% in favor of linkage. The transmission disequilibrium test provided additional evidence for linkage with the 3 allele of BCL3 more often transmitted to affected children. These results suggest that BCL3, or a nearby gene, plays a role in the etiology of CL/P in some families. 39 refs., 8 figs., 4 tabs.« less

Umbrella project for Bangladesh: strengthening NGO capacity and linkages to improve reproductive health service and information. RAS/98/P55.

PubMed

1999-06-01

In Bangladesh, the UN Population Fund is working to strengthen nongovernmental organization (NGO) capacity and linkages to improve reproductive health services and information. Specifically, the aim is to strengthen the technical and human resource capacity of participating NGOs and the functional linkages between national NGOs and relevant government agencies to help harmonize and standardize the delivery of reproductive health information and services. This umbrella project collaborates with RHI-participating NGOs in a policy paper on adolescent reproductive health, and will maintain contact with the regional dimension project to collaborate its activities. Programs implemented by partner NGOs are being reviewed and monitored, and linkages among national NGOs and government agencies are being developed. The main activities of the project are enumerated.

Genetic mapping of the gene for Usher syndrome: linkage analysis in a large Samaritan kindred.

PubMed

Bonné-Tamir, B; Korostishevsky, M; Kalinsky, H; Seroussi, E; Beker, R; Weiss, S; Godel, V

1994-03-01

Usher syndrome is a group of autosomal recessive disorders associated with congenital sensorineural deafness and progressive visual loss due to retinitis pigmentosa. Sixteen members of the small inbred Samaritan isolate with autosomal recessive deafness were studied in 10 related sibships. DNA samples from 59 individuals including parents and affected and nonaffected sibs were typed for markers on chromosomes 1q and 11q for which linkage has recently been established for Usher syndrome types II and I. Statistically significant linkage was observed with four markers on 11q (D11S533, D11S527, OMP, and INT2) with a maximum six-point location score of 11.61 at the D11S533 locus. Analysis of haplotypes supports the notion that the mutation arose only once in an ancestral chromosome carrying a specific haplotype. The availability of markers closely linked to the disease locus allows indirect genotype analysis and identifies all carriers of the gene within the community. Furthermore, the detection of complete linkage disequilibrium between the D11S533 marker and the Usher gene suggests that these loci are either identical or adjacent and narrows the critical region to which physical mapping efforts are currently directed.

Creative Activities in Music--A Genome-Wide Linkage Analysis.

PubMed

Oikkonen, Jaana; Kuusi, Tuire; Peltonen, Petri; Raijas, Pirre; Ukkola-Vuoti, Liisa; Karma, Kai; Onkamo, Päivi; Järvelä, Irma

2016-01-01

Creative activities in music represent a complex cognitive function of the human brain, whose biological basis is largely unknown. In order to elucidate the biological background of creative activities in music we performed genome-wide linkage and linkage disequilibrium (LD) scans in musically experienced individuals characterised for self-reported composing, arranging and non-music related creativity. The participants consisted of 474 individuals from 79 families, and 103 sporadic individuals. We found promising evidence for linkage at 16p12.1-q12.1 for arranging (LOD 2.75, 120 cases), 4q22.1 for composing (LOD 2.15, 103 cases) and Xp11.23 for non-music related creativity (LOD 2.50, 259 cases). Surprisingly, statistically significant evidence for linkage was found for the opposite phenotype of creative activity in music (neither composing nor arranging; NCNA) at 18q21 (LOD 3.09, 149 cases), which contains cadherin genes like CDH7 and CDH19. The locus at 4q22.1 overlaps the previously identified region of musical aptitude, music perception and performance giving further support for this region as a candidate region for broad range of music-related traits. The other regions at 18q21 and 16p12.1-q12.1 are also adjacent to the previously identified loci with musical aptitude. Pathway analysis of the genes suggestively associated with composing suggested an overrepresentation of the cerebellar long-term depression pathway (LTD), which is a cellular model for synaptic plasticity. The LTD also includes cadherins and AMPA receptors, whose component GSG1L was linked to arranging. These results suggest that molecular pathways linked to memory and learning via LTD affect music-related creative behaviour. Musical creativity is a complex phenotype where a common background with musicality and intelligence has been proposed. Here, we implicate genetic regions affecting music-related creative behaviour, which also include genes with neuropsychiatric associations. We also propose

Information-Theoretic Metrics for Visualizing Gene-Environment Interactions

PubMed Central

Chanda, Pritam ; Zhang, Aidong ; Brazeau, Daniel ; Sucheston, Lara ; Freudenheim, Jo L. ; Ambrosone, Christine ; Ramanathan, Murali 

2007-01-01

The purpose of our work was to develop heuristics for visualizing and interpreting gene-environment interactions (GEIs) and to assess the dependence of candidate visualization metrics on biological and study-design factors. Two information-theoretic metrics, the k-way interaction information (KWII) and the total correlation information (TCI), were investigated. The effectiveness of the KWII and TCI to detect GEIs in a diverse range of simulated data sets and a Crohn disease data set was assessed. The sensitivity of the KWII and TCI spectra to biological and study-design variables was determined. Head-to-head comparisons with the relevance-chain, multifactor dimensionality reduction, and the pedigree disequilibrium test (PDT) methods were obtained. The KWII and TCI spectra, which are graphical summaries of the KWII and TCI for each subset of environmental and genotype variables, were found to detect each known GEI in the simulated data sets. The patterns in the KWII and TCI spectra were informative for factors such as case-control misassignment, locus heterogeneity, allele frequencies, and linkage disequilibrium. The KWII and TCI spectra were found to have excellent sensitivity for identifying the key disease-associated genetic variations in the Crohn disease data set. In head-to-head comparisons with the relevance-chain, multifactor dimensionality reduction, and PDT methods, the results from visual interpretation of the KWII and TCI spectra performed satisfactorily. The KWII and TCI are promising metrics for visualizing GEIs. They are capable of detecting interactions among numerous single-nucleotide polymorphisms and environmental variables for a diverse range of GEI models. PMID:17924337

A linkage and family-based association analysis of a potential neurocognitive endophenotype of bipolar disorder.

PubMed

Savitz, Jonathan; van der Merwe, Lize; Solms, Mark; Ramesar, Rajkumar

2007-01-01

The identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance characterized by genetic and phenotypic heterogeneity, genetic epistasis, and gene-environment interactions. In this paper two strategies were used to ameliorate these confounding factors. A unique South African sample including 190 individuals of the relatively, reproductively isolated Afrikaner population was assessed with a battery of neuropsychological tests in an attempt to identify a BPD-associated quantitative trait or endophenotype. BPD individuals performed significantly worse than their unaffected relatives on visual and verbal memory tasks, a finding congruent with the literature. Afocused linkage and family-based association study was carried out using this memory-related endophenotype. In the largest 77-strong Afrikaner pedigree significant evidence for linkage was detected on chromosome 22q11, a region previously implicated in BPD. The quantitative transmission disequilibrium tests-based association analysis suggested that functional variants of the DRD4 and MAO-A genes modulate memory-related cognition. We speculate that polymorphisms at these loci may predispose to a subtype of BPD characterized by memory-related deficits.

Linkage disequilibrium, persistence of phase, and effective population size in Spanish local beef cattle breeds assessed through a high-density single nucleotide polymorphism chip.

PubMed

Cañas-Álvarez, J J; Mouresan, E F; Varona, L; Díaz, C; Molina, A; Baro, J A; Altarriba, J; Carabaño, M J; Casellas, J; Piedrafita, J

2016-07-01

Linkage disequilibrium (LD) and persistence of phase are fundamental approaches for exploring the genetic basis of economically important traits in cattle, including the identification of QTL for genomic selection and the estimation of effective population size () to determine the size of the training populations. In this study, we have used the Illumina BovineHD chip in 168 trios of 7 Spanish beef cattle breeds to obtain an overview of the magnitude of LD and the persistence of LD phase through the physical distance between markers. Also, we estimated the time of divergence based on the persistence of the LD phase and calculated past from LD estimates using different alternatives to define the recombination rate. Estimates of average (as a measure of LD) for adjacent markers were close to 0.52 in the 7 breeds and decreased with the distance between markers, although in long distances, some LD still remained (0.07 and 0.05 for markers 200 kb and 1 Mb apart, respectively). A panel with a lower boundary of 38,000 SNP would be necessary to launch a successful within-breed genomic selection program. Persistence of phase, measured as the pairwise correlations between estimates of in 2 breeds at short distances (10 kb), was in the 0.89 to 0.94 range and decreased from 0.33 to 0.52 to a range of 0.01 to 0.08 when marker distance increased from 200 kb to 1 Mb, respectively. The magnitude of the persistence of phase between the Spanish beef breeds was similar to those found in dairy breeds. For across-breed genomic selection, the size of the SNP panels must be in the range of 50,000 to 83,000 SNP. Estimates of past showed values ranging from 26 to 31 for 1 generation ago in all breeds. The divergence among breeds occurred between 129 and 207 generations ago. The results of this study are relevant for the future implementation of within- and across-breed genomic selection programs in the Spanish beef cattle populations. Our results suggest that a reduced subset of the SNP

Creative Activities in Music – A Genome-Wide Linkage Analysis

PubMed Central

Oikkonen, Jaana; Kuusi, Tuire; Peltonen, Petri; Raijas, Pirre; Ukkola-Vuoti, Liisa; Karma, Kai; Onkamo, Päivi; Järvelä, Irma

2016-01-01

Creative activities in music represent a complex cognitive function of the human brain, whose biological basis is largely unknown. In order to elucidate the biological background of creative activities in music we performed genome-wide linkage and linkage disequilibrium (LD) scans in musically experienced individuals characterised for self-reported composing, arranging and non-music related creativity. The participants consisted of 474 individuals from 79 families, and 103 sporadic individuals. We found promising evidence for linkage at 16p12.1-q12.1 for arranging (LOD 2.75, 120 cases), 4q22.1 for composing (LOD 2.15, 103 cases) and Xp11.23 for non-music related creativity (LOD 2.50, 259 cases). Surprisingly, statistically significant evidence for linkage was found for the opposite phenotype of creative activity in music (neither composing nor arranging; NCNA) at 18q21 (LOD 3.09, 149 cases), which contains cadherin genes like CDH7 and CDH19. The locus at 4q22.1 overlaps the previously identified region of musical aptitude, music perception and performance giving further support for this region as a candidate region for broad range of music-related traits. The other regions at 18q21 and 16p12.1-q12.1 are also adjacent to the previously identified loci with musical aptitude. Pathway analysis of the genes suggestively associated with composing suggested an overrepresentation of the cerebellar long-term depression pathway (LTD), which is a cellular model for synaptic plasticity. The LTD also includes cadherins and AMPA receptors, whose component GSG1L was linked to arranging. These results suggest that molecular pathways linked to memory and learning via LTD affect music-related creative behaviour. Musical creativity is a complex phenotype where a common background with musicality and intelligence has been proposed. Here, we implicate genetic regions affecting music-related creative behaviour, which also include genes with neuropsychiatric associations. We also propose

Evidence of linkage disequilibrium between schizophrenia and the SCA1 CAG repeat on chromosome 6p23

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, S.; Sun, Cui-E; Diehl, S.R.

Schizophrenia and the closely related phenotype schizoaffective disorder are severe mental illnesses that affect >1.0% of the population. The major role that genetic factors contribute to disease susceptibility is very well established. Schizophrenia appears to be a highly complex and heterogeneous disorder, however, and gene-mapping efforts also face challenges in assigning diagnoses and in delineating the disease`s phenotypic boundary. Several recently reported studies indicate that a schizophrenia-susceptibility gene may reside on the distal short arm of chromosome 6. Wang et al. reported a strong suggestion of linkage to chromosome 6pter-p22, using a resource based on 186 Irish families that wasmore » developed by K. S, Kendler, D. Walsh and colleagues, and one of us (S.R.D.), as described elsewhere. In that study, locus D6S260 gave the highest pairwise LOD score, 3.5, allowing for locus heterogeneity. Analysis with D6S260 and the distal locus F13A1 yielded a multipoint LOD score of 3.9, which maximized by allowing for locus heterogeneity and assuming that 50% of families are linked to this region. Nonparametric affected-pedigree-member analyses also supported this finding. Several other groups have recently reported additional evidence suggesting linkage to this region, both in an expanded collection of Irish families and in families from a variety of other geographic locations. However, none of these studies succeed in narrowing the location of the putative disease gene beyond the {approximately}30-cM region first identified by Wang et al. 44 refs., 1 fig., 1 tab.« less

Chemical evolution of the Earth: Equilibrium or disequilibrium process?

NASA Technical Reports Server (NTRS)

Sato, M.

1985-01-01

To explain the apparent chemical incompatibility of the Earth's core and mantle or the disequilibrium process, various core forming mechanisms have been proposed, i.e., rapid disequilibrium sinking of molten iron, an oxidized core or protocore materials, and meteorite contamination of the upper mantle after separation from the core. Adopting concepts used in steady state thermodynamics, a method is devised for evaluating how elements should distribute stable in the Earth's interior for the present gradients of temperature, pressure, and gravitational acceleration. Thermochemical modeling gives useful insights into the nature of chemical evolution of the Earth without overly speculative assumptions. Further work must be done to reconcile siderophile elements, rare gases, and possible light elements in the outer core.

A systematic retrieval analysis of secondary eclipse spectra. III. Diagnosing chemical disequilibrium in planetary atmospheres

DOE Office of Scientific and Technical Information (OSTI.GOV)

Line, Michael R.; Yung, Yuk L., E-mail: mrl@gps.caltech.edu

2013-12-10

Chemical disequilibrium has recently become a relevant topic in the study of the atmospheres of transiting extrasolar planets, brown dwarfs, and directly imaged exoplanets. We present a new way of assessing whether or not a Jovian-like atmosphere is in chemical disequilibrium from observations of detectable or inferred gases such as H{sub 2}O, CH{sub 4}, CO, and H{sub 2}. Our hypothesis, based on previous kinetic modeling studies, is that cooler atmospheres will show stronger signs of disequilibrium than hotter atmospheres. We verify this with chemistry-transport models and show that planets with temperatures less than ∼1200 K are likely to show themore » strongest signs of disequilibrium due to the vertical quenching of CO, and that our new approach is able to capture this process. We also find that in certain instances a planetary composition may appear in equilibrium when it actually is not due to the degeneracy in the shape of the vertical mixing ratio profiles. We determine the state of disequilibrium in eight exoplanets using the results from secondary eclipse temperature and abundance retrievals. We find that all of the planets in our sample are consistent with thermochemical equilibrium to within 3σ. Future observations are needed to further constrain the abundances in order to definitively identify disequilibrium in exoplanet atmospheres.« less

Detection of gene-environment interactions in the presence of linkage disequilibrium and noise by using genetic risk scores with internal weights from elastic net regression.

PubMed

Hüls, Anke; Ickstadt, Katja; Schikowski, Tamara; Krämer, Ursula

2017-06-12

SNPs estimated by a multivariate elastic net regression were shown to be a powerful tool to detect gene-environment interactions in scenarios of high Linkage disequilibrium and noise.

Role of syn-eruptive plagioclase disequilibrium crystallization in basaltic magma ascent dynamics.

PubMed

La Spina, G; Burton, M; De' Michieli Vitturi, M; Arzilli, F

2016-12-12

Timescales of magma ascent in conduit models are typically assumed to be much longer than crystallization and gas exsolution for basaltic eruptions. However, it is now recognized that basaltic magmas may rise fast enough for disequilibrium processes to play a key role on the ascent dynamics. The quantification of the characteristic times for crystallization and exsolution processes are fundamental to our understanding of such disequilibria and ascent dynamics. Here we use observations from Mount Etna's 2001 eruption and a magma ascent model to constrain timescales for crystallization and exsolution processes. Our results show that plagioclase reaches equilibrium in 1-2 h, whereas ascent times were <1 h. Using these new constraints on disequilibrium plagioclase crystallization we also reproduce observed crystal abundances for different basaltic eruptions. The strong relation between magma ascent rate and disequilibrium crystallization and exsolution plays a key role in controlling eruption dynamics in basaltic volcanism.

Privacy-preserving record linkage using Bloom filters.

PubMed

Schnell, Rainer; Bachteler, Tobias; Reiher, Jörg

2009-08-25

Combining multiple databases with disjunctive or additional information on the same person is occurring increasingly throughout research. If unique identification numbers for these individuals are not available, probabilistic record linkage is used for the identification of matching record pairs. In many applications, identifiers have to be encrypted due to privacy concerns. A new protocol for privacy-preserving record linkage with encrypted identifiers allowing for errors in identifiers has been developed. The protocol is based on Bloom filters on q-grams of identifiers. Tests on simulated and actual databases yield linkage results comparable to non-encrypted identifiers and superior to results from phonetic encodings. We proposed a protocol for privacy-preserving record linkage with encrypted identifiers allowing for errors in identifiers. Since the protocol can be easily enhanced and has a low computational burden, the protocol might be useful for many applications requiring privacy-preserving record linkage.

Y-chromosome specific alleles and haplotypes in European and Asian populations: linkage disequilibrium and geographic diversity.

PubMed

Mitchell, R J; Earl, L; Fricke, B

1997-10-01

Variation on the Y chromosome may permit our understanding the evolution of the human paternal lineage and male gene flow. This study reports upon the distribution and non random association of alleles at four Y-chromosome specific loci in four populations, three Caucasoid (Italian, Greek and Slav) and one Asian. The markers include insertion/deletion (p12f), point mutation (92R7 and pY alpha I), and repeat sequence (p21A1) polymorphisms. Our data confirm that the p12f/TaqI 8 kb allele is a Caucasoid marker and that Asians are monomorphic at three of the loci (p12f, 92R7, and pY alpha I). The alleles at 92R7 and pY alpha I were found to be in complete disequilibrium in Europeans. Y-haplotype diversity was highly significant between Asians and all three European groups (P < 0.001), but the Greeks and Italians were also significantly different with respect to some alleles and haplotypes (P < 0.02). We find strong evidence that the p12f/TaqI 8 kb allele may have arisen only once, as a deletion event, and, additionally, that the present-day frequency distribution of Y chromosomes carrying the p12f/8 kb allele suggests that it may have been spread by colonising sea-faring peoples from the Near East, possibly the Phoenicians, rather than by expansion of Neolithic farmers into continental Europe. The p12f deletion is the key marker of a unique Y chromosome, found only in Caucasians to date, labelled 'Mediterranean' and this further increases the level of Y-chromosome diversity seen among Caucasoids when compared to the other major population groups.

Role of syn-eruptive plagioclase disequilibrium crystallization in basaltic magma ascent dynamics

PubMed Central

La Spina, G.; Burton, M.; de' Michieli Vitturi, M.; Arzilli, F.

2016-01-01

Timescales of magma ascent in conduit models are typically assumed to be much longer than crystallization and gas exsolution for basaltic eruptions. However, it is now recognized that basaltic magmas may rise fast enough for disequilibrium processes to play a key role on the ascent dynamics. The quantification of the characteristic times for crystallization and exsolution processes are fundamental to our understanding of such disequilibria and ascent dynamics. Here we use observations from Mount Etna's 2001 eruption and a magma ascent model to constrain timescales for crystallization and exsolution processes. Our results show that plagioclase reaches equilibrium in 1–2 h, whereas ascent times were <1 h. Using these new constraints on disequilibrium plagioclase crystallization we also reproduce observed crystal abundances for different basaltic eruptions. The strong relation between magma ascent rate and disequilibrium crystallization and exsolution plays a key role in controlling eruption dynamics in basaltic volcanism. PMID:27941750

No association detected between a D{sub 3} receptor gene-expressed variant and schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rothschild, L.G.; Badner, J.; Cravchik, A.

1996-04-09

A missense polymorphism (glycine to serine) in the first exon of the dopamine D{sub 3} (DRD3) gene was examined in a sib-pairs schizophrenia collection by the transmission test for linkage disequilibrium (TDT). No association due to linkage disequilibrium was detected using TDT. Additionally, no evidence for excess homozygosity was found. 26 refs., 3 tabs.

The evolutionary history of Drosophila buzzatii. XXXII. Linkage disequilibrium between allozymes and chromosome inversions in two colonizing populations.

PubMed

Betrán, E; Quezada-Díaz, J E; Ruiz, A; Santos, M; Fontdevila, A

1995-02-01

Chromosome polymorphism in Drosophila buzzatii is under selection but the genes responsible for the effect of the inversions of fitness are unknown. On the other hand, there is evidence for selection on several allozyme loci but the presence of paracentric inversions on the second chromosome, where most of the polymorphic loci are located, complicates the interpretation. Studies of the associations between allozymes and inversions are thus necessary to help understand the effect of selection at both the chromosomal and allozymic level. Until now this kind of information has only been available in D. buzzatii for two loci, Est-1 and Est-2, in Australian populations. Here we describe the genetic constitution of two Old World populations, Carboneras and Colera. Emphasis has been placed on the analysis of the linkage disequilibria between the second chromosome arrangements and three allozyme loci, Est-2, Pept-2 and Aldox, located on this chromosome. In addition, the recombination frequencies between the loci, and between the loci and the inversion breakpoints, have been estimated and a genetic map of the three loci has been produced. The two populations differ in allele and arrangement frequencies, as well as in the pattern of one-locus disequilibria. Est-2 and Aldox are associated with the second chromosome arrangements in both populations. On the other hand, Pept-2 is associated with the inversions in Colera but not in Carboneras. The gametic associations among the three loci are discussed taking into account the position of these loci on the chromosome map and the lack of recombination in the heterokaryotypes.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tahvanainen, E.; Karila, E.; Kolehmainen, J.

We recently assigned a gene for autosomal recessive cornea plana congenita (CNA2; MIM No. 217300) by linkage analysis to the approximately 3-cM interval between markers D12S82 and D12S327. Here, we extended these studies by exploiting the haplotype and linkage disequilibrium information that can be derived from the genetically isolated Finnish population and its subpopulations. By testing 32 independent families with 10 polymorphic markers in the CNA2 interval, strong allelic association between CNA2 and a set of markers with a peak at marker D12S351 was detected. Based on linkage disequilibrium analysis, the critical region for CNA2 could be narrowed to onlymore » 0.04-0.3 cM from marker D12S351, thus defining a critical interval 0.08-0.60 cM in length. These results provide a basis for highly focused positional cloning of CNA2. 18 refs., 5 figs., 1 tab.« less

Probabilistic record linkage

PubMed Central

Sayers, Adrian; Ben-Shlomo, Yoav; Blom, Ashley W; Steele, Fiona

2016-01-01

Abstract Studies involving the use of probabilistic record linkage are becoming increasingly common. However, the methods underpinning probabilistic record linkage are not widely taught or understood, and therefore these studies can appear to be a ‘black box’ research tool. In this article, we aim to describe the process of probabilistic record linkage through a simple exemplar. We first introduce the concept of deterministic linkage and contrast this with probabilistic linkage. We illustrate each step of the process using a simple exemplar and describe the data structure required to perform a probabilistic linkage. We describe the process of calculating and interpreting matched weights and how to convert matched weights into posterior probabilities of a match using Bayes theorem. We conclude this article with a brief discussion of some of the computational demands of record linkage, how you might assess the quality of your linkage algorithm, and how epidemiologists can maximize the value of their record-linked research using robust record linkage methods. PMID:26686842

A Genetic Linkage Map for Cattle

PubMed Central

Bishop, M. D.; Kappes, S. M.; Keele, J. W.; Stone, R. T.; Sunden, SLF.; Hawkins, G. A.; Toldo, S. S.; Fries, R.; Grosz, M. D.; Yoo, J.; Beattie, C. W.

1994-01-01

We report the most extensive physically anchored linkage map for cattle produced to date. Three-hundred thirteen genetic markers ordered in 30 linkage groups, anchored to 24 autosomal chromosomes (n = 29), the X and Y chromosomes, four unanchored syntenic groups and two unassigned linkage groups spanning 2464 cM of the bovine genome are summarized. The map also assigns 19 type I loci to specific chromosomes and/or syntenic groups and four cosmid clones containing informative microsatellites to chromosomes 13, 25 and 29 anchoring syntenic groups U11, U7 and U8, respectively. This map provides the skeletal framework prerequisite to development of a comprehensive genetic map for cattle and analysis of economic trait loci (ETL). PMID:7908653

An Autosomal Genetic Linkage Map of the Sheep Genome

PubMed Central

Crawford, A. M.; Dodds, K. G.; Ede, A. J.; Pierson, C. A.; Montgomery, G. W.; Garmonsway, H. G.; Beattie, A. E.; Davies, K.; Maddox, J. F.; Kappes, S. W.; Stone, R. T.; Nguyen, T. C.; Penty, J. M.; Lord, E. A.; Broom, J. E.; Buitkamp, J.; Schwaiger, W.; Epplen, J. T.; Matthew, P.; Matthews, M. E.; Hulme, D. J.; Beh, K. J.; McGraw, R. A.; Beattie, C. W.

1995-01-01

We report the first extensive ovine genetic linkage map covering 2070 cM of the sheep genome. The map was generated from the linkage analysis of 246 polymorphic markers, in nine three-generation fullsib pedigrees, which make up the AgResearch International Mapping Flock. We have exploited many markers from cattle so that valuable comparisons between these two ruminant linkage maps can be made. The markers, used in the segregation analyses, comprised 86 anonymous microsatellite markers derived from the sheep genome, 126 anonymous microsatellites from cattle, one from deer, and 33 polymorphic markers of various types associated with known genes. The maximum number of informative meioses within the mapping flock was 222. The average number of informative meioses per marker was 140 (range 18-209). Linkage groups have been assigned to all 26 sheep autosomes. PMID:7498748

The Impact of Accelerating Faster than Exponential Population Growth on Genetic Variation

PubMed Central

Reppell, Mark; Boehnke, Michael; Zöllner, Sebastian

2014-01-01

Current human sequencing projects observe an abundance of extremely rare genetic variation, suggesting recent acceleration of population growth. To better understand the impact of such accelerating growth on the quantity and nature of genetic variation, we present a new class of models capable of incorporating faster than exponential growth in a coalescent framework. Our work shows that such accelerated growth affects only the population size in the recent past and thus large samples are required to detect the models’ effects on patterns of variation. When we compare models with fixed initial growth rate, models with accelerating growth achieve very large current population sizes and large samples from these populations contain more variation than samples from populations with constant growth. This increase is driven almost entirely by an increase in singleton variation. Moreover, linkage disequilibrium decays faster in populations with accelerating growth. When we instead condition on current population size, models with accelerating growth result in less overall variation and slower linkage disequilibrium decay compared to models with exponential growth. We also find that pairwise linkage disequilibrium of very rare variants contains information about growth rates in the recent past. Finally, we demonstrate that models of accelerating growth may substantially change estimates of present-day effective population sizes and growth times. PMID:24381333

The impact of accelerating faster than exponential population growth on genetic variation.

PubMed

Reppell, Mark; Boehnke, Michael; Zöllner, Sebastian

2014-03-01

Current human sequencing projects observe an abundance of extremely rare genetic variation, suggesting recent acceleration of population growth. To better understand the impact of such accelerating growth on the quantity and nature of genetic variation, we present a new class of models capable of incorporating faster than exponential growth in a coalescent framework. Our work shows that such accelerated growth affects only the population size in the recent past and thus large samples are required to detect the models' effects on patterns of variation. When we compare models with fixed initial growth rate, models with accelerating growth achieve very large current population sizes and large samples from these populations contain more variation than samples from populations with constant growth. This increase is driven almost entirely by an increase in singleton variation. Moreover, linkage disequilibrium decays faster in populations with accelerating growth. When we instead condition on current population size, models with accelerating growth result in less overall variation and slower linkage disequilibrium decay compared to models with exponential growth. We also find that pairwise linkage disequilibrium of very rare variants contains information about growth rates in the recent past. Finally, we demonstrate that models of accelerating growth may substantially change estimates of present-day effective population sizes and growth times.

Privacy-preserving record linkage using Bloom filters

PubMed Central

2009-01-01

Background Combining multiple databases with disjunctive or additional information on the same person is occurring increasingly throughout research. If unique identification numbers for these individuals are not available, probabilistic record linkage is used for the identification of matching record pairs. In many applications, identifiers have to be encrypted due to privacy concerns. Methods A new protocol for privacy-preserving record linkage with encrypted identifiers allowing for errors in identifiers has been developed. The protocol is based on Bloom filters on q-grams of identifiers. Results Tests on simulated and actual databases yield linkage results comparable to non-encrypted identifiers and superior to results from phonetic encodings. Conclusion We proposed a protocol for privacy-preserving record linkage with encrypted identifiers allowing for errors in identifiers. Since the protocol can be easily enhanced and has a low computational burden, the protocol might be useful for many applications requiring privacy-preserving record linkage. PMID:19706187

Age-Dependent Association between Pulmonary Tuberculosis and Common TOX Variants in the 8q12–13 Linkage Region

PubMed Central

Grant, Audrey V.; El Baghdadi, Jamila; Sabri, Ayoub; El Azbaoui, Safa; Alaoui-Tahiri, Kebir; Abderrahmani Rhorfi, Ismail; Gharbaoui, Yasser; Abid, Ahmed; Benkirane, Majid; Raharimanga, Vaomalala; Richard, Vincent; Orlova, Marianna; Boland, Anne; Migaud, Mélanie; Okada, Satoshi; Nolan, Daniel K.; Bustamante, Jacinta; Barreiro, Luis B.; Schurr, Erwin; Boisson-Dupuis, Stephanie; Rasolofo, Voahangy; Casanova, Jean-Laurent; Abel, Laurent

2013-01-01

Only a small fraction of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis (TB) in their lifetime. Genetic epidemiological evidence suggests a genetic determinism of pulmonary TB (PTB), but the molecular basis of genetic predisposition to PTB remains largely unknown. We used a positional-cloning approach to carry out ultrafine linkage-disequilibrium mapping of a previously identified susceptibility locus in chromosomal region 8q12–13 by genotyping 3,216 SNPs in a family-based Moroccan sample including 286 offspring with PTB. We observed 44 PTB-associated SNPs (p < 0.01), which were genotyped in an independent set of 317 cases and 650 controls from Morocco. A single signal, consisting of two correlated SNPs close to TOX, rs1568952 and rs2726600 (combined p = 1.1 × 10−5 and 9.2 × 10−5, respectively), was replicated. Stronger evidence of association was found in individuals who developed PTB before the age of 25 years (combined p for rs1568952 = 4.4 × 10−8; odds ratio of PTB for AA versus AG/GG = 3.09 [1.99–4.78]). The association with rs2726600 (p = 0.04) was subsequently replicated in PTB-affected subjects under 25 years in a study of 243 nuclear families from Madagascar. Stronger evidence of replication in Madagascar was obtained for additional SNPs in strong linkage disequilibrium with the two initial SNPs (p = 0.003 for rs2726597), further confirming the signal. We thus identified around rs1568952 and rs2726600 a cluster of SNPs strongly associated with early-onset PTB in Morocco and Madagascar. SNP rs2726600 is located in a transcription-factor binding site in the 3′ region of TOX, and further functional explorations will focus on CD4 T lymphocytes. PMID:23415668

Ultra-high density intra-specific genetic linkage maps accelerate identification of functionally relevant molecular tags governing important agronomic traits in chickpea

PubMed Central

Kujur, Alice; Upadhyaya, Hari D.; Shree, Tanima; Bajaj, Deepak; Das, Shouvik; Saxena, Maneesha S.; Badoni, Saurabh; Kumar, Vinod; Tripathi, Shailesh; Gowda, C. L. L.; Sharma, Shivali; Singh, Sube; Tyagi, Akhilesh K.; Parida, Swarup K.

2015-01-01

We discovered 26785 and 16573 high-quality SNPs differentiating two parental genotypes of a RIL mapping population using reference desi and kabuli genome-based GBS assay. Of these, 3625 and 2177 SNPs have been integrated into eight desi and kabuli chromosomes, respectively in order to construct ultra-high density (0.20–0.37 cM) intra-specific chickpea genetic linkage maps. One of these constructed high-resolution genetic map has potential to identify 33 major genomic regions harbouring 35 robust QTLs (PVE: 17.9–39.7%) associated with three agronomic traits, which were mapped within <1 cM mean marker intervals on desi chromosomes. The extended LD (linkage disequilibrium) decay (~15 cM) in chromosomes of genetic maps have encouraged us to use a rapid integrated approach (comparative QTL mapping, QTL-region specific haplotype/LD-based trait association analysis, expression profiling and gene haplotype-based association mapping) rather than a traditional QTL map-based cloning method to narrow-down one major seed weight (SW) robust QTL region. It delineated favourable natural allelic variants and superior haplotype-containing one seed-specific candidate embryo defective gene regulating SW in chickpea. The ultra-high-resolution genetic maps, QTLs/genes and alleles/haplotypes-related genomic information generated and integrated strategy for rapid QTL/gene identification developed have potential to expedite genomics-assisted breeding applications in crop plants, including chickpea for their genetic enhancement. PMID:25942004

An autosomal genetic linkage map of the sheep genome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crawford, A.M.; Ede, A.J.; Pierson, C.A.

1995-06-01

We report the first extensive ovine genetic linkage map covering 2070 cM of the sheep genome. The map was generated from the linkage analysis of 246 polymorphic markers, in nine three-generation full-sib pedigrees, which make up the AgResearch International Mapping Flock. We have exploited many markers from cattle so that valuable comparisons between these two ruminant linkage maps can be made. The markers, used in the segregation analyses, comprised 86 anonymous microsatellite markers derived from the sheep genome, 126 anonymous microsatellites from cattle, one from deer, and 33 polymorphic markers of various types associated with known genes. The maximum numbermore » of informative meioses within the mapping flock was 22. The average number of informative meioses per marker was 140 (range 18-209). Linkage groups have been assigned to all 26 sheep autosomes. 102 refs., 8 figs., 5 tabs.« less

Modeling haplotype block variation using Markov chains.

PubMed

Greenspan, G; Geiger, D

2006-04-01

Models of background variation in genomic regions form the basis of linkage disequilibrium mapping methods. In this work we analyze a background model that groups SNPs into haplotype blocks and represents the dependencies between blocks by a Markov chain. We develop an error measure to compare the performance of this model against the common model that assumes that blocks are independent. By examining data from the International Haplotype Mapping project, we show how the Markov model over haplotype blocks is most accurate when representing blocks in strong linkage disequilibrium. This contrasts with the independent model, which is rendered less accurate by linkage disequilibrium. We provide a theoretical explanation for this surprising property of the Markov model and relate its behavior to allele diversity.

Modeling Haplotype Block Variation Using Markov Chains

PubMed Central

Greenspan, G.; Geiger, D.

2006-01-01

Models of background variation in genomic regions form the basis of linkage disequilibrium mapping methods. In this work we analyze a background model that groups SNPs into haplotype blocks and represents the dependencies between blocks by a Markov chain. We develop an error measure to compare the performance of this model against the common model that assumes that blocks are independent. By examining data from the International Haplotype Mapping project, we show how the Markov model over haplotype blocks is most accurate when representing blocks in strong linkage disequilibrium. This contrasts with the independent model, which is rendered less accurate by linkage disequilibrium. We provide a theoretical explanation for this surprising property of the Markov model and relate its behavior to allele diversity. PMID:16361244

Evidence of linkage and association on chromosome 20 for late-onset Alzheimer disease.

PubMed

Goddard, Katrina A B; Olson, Jane M; Payami, Haydeh; van der Voet, Monique; Kuivaniemi, Helena; Tromp, Gerard

2004-06-01

Recently, we reported evidence of linkage on chromosome 20 for Alzheimer disease (AD) using a novel statistical approach to incorporate covariates (e.g., age, ApoE genotype) into the analysis. These results suggest that very elderly subjects (>85 years), and individuals who carry an epsilon2 allele at the ApoE locus are more likely to be linked to this candidate region. The region on chromosome 20 includes a strong candidate gene, cystatin C (CST3), which has previously been associated with AD in case-control studies. We investigated these findings further by genotyping additional markers to narrow the candidate region, and to identify evidence of linkage disequilibrium as additional support for a susceptibility locus on chromosome 20. We selected 43 elderly sibships (89 subjects) from the NIMH AD Genetics Initiative based on current age older than 84 years, and identified 129 unrelated control subjects who were older than 84 years from the Oregon Brain Aging Study to conduct linkage and association studies in this region. Fourteen additional markers were evaluated, including 4 markers located within or near CST3. We narrowed the candidate region on chromosome 20 to an 11.8-cM region between markers D20S174 and D20S471, which includes the CST3 candidate gene. In addition, we observed evidence of association for markers located near the CST3 candidate gene, with P values between 0.002 and 0.08 for two-locus haplotypes. These results support the presence of a susceptibility locus for AD in the vicinity of CST3 for very elderly subjects with AD.

Estimating glacier response times and disequilibrium in a changing climate

NASA Astrophysics Data System (ADS)

Christian, J. E.; Koutnik, M.; Roe, G.

2017-12-01

Glaciers respond to climate variations according to a characteristic timescale that, for most mountain glaciers, is on the order of 10—100 years. An important consequence of this multi-decadal memory is that a glacier's transient response to a climate trend exhibits a persistent lag behind the equilibrium response. In the context of anthropogenic warming, this means that most glaciers are currently well out of equilibrium, and that a substantial amount of retreat is committed even without further warming. The degree of disequilibrium depends fundamentally on the glacier response timescale, making it an important parameter to constrain. A common and robust metric for the response timescale is τ=H/bt, where H and bt are characteristic values for ice thickness and the terminus mass-balance rate, respectively. However, sparse observations, climate variability, and glacier disequilibrium make it difficult to define these characteristic values. We compare several sources of uncertainty that will affect estimates of the response timescale and thus the degree of disequilibrium. Ice thickness is poorly constrained for many glaciers, which bears directly on estimates of the response timescale. However, errors may also arise from estimating thickness and mass-balance rates in a variable climate. We assess how noisy mass balance and observed terminus fluctuations introduce sampling errors into estimates of the glacier's response timescale and the expected equilibrium response to a climate change. Additionally, the instantaneous value of τ evolves during sustained warming as the glacier thins and retreats. Perhaps counterintuitively, τ can increase if retreat into higher elevations exceeds thinning. This has implications for estimating the timescale based on currently observed geometry and mass balance. We use shallow-ice and 3-stage linear models to explore these effects with synthetic glacier geometries and climate forcings. In this way, we can diagnose the geometric and

Composite Bloom Filters for Secure Record Linkage.

PubMed

Durham, Elizabeth Ashley; Kantarcioglu, Murat; Xue, Yuan; Toth, Csaba; Kuzu, Mehmet; Malin, Bradley

2014-12-01

The process of record linkage seeks to integrate instances that correspond to the same entity. Record linkage has traditionally been performed through the comparison of identifying field values ( e.g., Surname ), however, when databases are maintained by disparate organizations, the disclosure of such information can breach the privacy of the corresponding individuals. Various private record linkage (PRL) methods have been developed to obscure such identifiers, but they vary widely in their ability to balance competing goals of accuracy, efficiency and security. The tokenization and hashing of field values into Bloom filters (BF) enables greater linkage accuracy and efficiency than other PRL methods, but the encodings may be compromised through frequency-based cryptanalysis. Our objective is to adapt a BF encoding technique to mitigate such attacks with minimal sacrifices in accuracy and efficiency. To accomplish these goals, we introduce a statistically-informed method to generate BF encodings that integrate bits from multiple fields, the frequencies of which are provably associated with a minimum number of fields. Our method enables a user-specified tradeoff between security and accuracy. We compare our encoding method with other techniques using a public dataset of voter registration records and demonstrate that the increases in security come with only minor losses to accuracy.

Composite Bloom Filters for Secure Record Linkage

PubMed Central

Durham, Elizabeth Ashley; Kantarcioglu, Murat; Xue, Yuan; Toth, Csaba; Kuzu, Mehmet; Malin, Bradley

2014-01-01

The process of record linkage seeks to integrate instances that correspond to the same entity. Record linkage has traditionally been performed through the comparison of identifying field values (e.g., Surname), however, when databases are maintained by disparate organizations, the disclosure of such information can breach the privacy of the corresponding individuals. Various private record linkage (PRL) methods have been developed to obscure such identifiers, but they vary widely in their ability to balance competing goals of accuracy, efficiency and security. The tokenization and hashing of field values into Bloom filters (BF) enables greater linkage accuracy and efficiency than other PRL methods, but the encodings may be compromised through frequency-based cryptanalysis. Our objective is to adapt a BF encoding technique to mitigate such attacks with minimal sacrifices in accuracy and efficiency. To accomplish these goals, we introduce a statistically-informed method to generate BF encodings that integrate bits from multiple fields, the frequencies of which are provably associated with a minimum number of fields. Our method enables a user-specified tradeoff between security and accuracy. We compare our encoding method with other techniques using a public dataset of voter registration records and demonstrate that the increases in security come with only minor losses to accuracy. PMID:25530689

Detecting structure of haplotypes and local ancestry

USDA-ARS?s Scientific Manuscript database

We present a two-layer hidden Markov model to detect the structure of haplotypes for unrelated individuals. This allows us to model two scales of linkage disequilibrium (one within a group of haplotypes and one between groups), thereby taking advantage of rich haplotype information to infer local an...

DNA Commission of the International Society for Forensic Genetics (ISFG): Guidelines on the use of X-STRs in kinship analysis.

PubMed

Tillmar, Andreas O; Kling, Daniel; Butler, John M; Parson, Walther; Prinz, Mechthild; Schneider, Peter M; Egeland, Thore; Gusmão, Leonor

2017-07-01

Forensic genetic laboratories perform an increasing amount of genetic analyses of the X chromosome, in particular to solve complex cases of kinship analysis. For some biological relationships X-chromosomal markers can be more informative than autosomal markers, and there are a large number of markers, methods and databases that have been described for forensic use. Due to their particular mode of inheritance, and their physical location on a single chromosome, some specific considerations are required when estimating the weight of evidence for X-chromosomal marker DNA data. The DNA Commission of the International Society for Forensic Genetics (ISFG) hereby presents guidelines and recommendations for the use of X-chromosomal markers in kinship analysis with a special focus on the biostatistical evaluation. Linkage and linkage disequilibrium (association of alleles) are of special importance for such evaluations and these concepts and the implications for likelihood calculations are described in more detail. Furthermore it is important to use appropriate computer software that accounts for linkage and linkage disequilibrium among loci, as well as for mutations. Even though some software exist, there is still a need for further improvement of dedicated software. Copyright © 2017 Elsevier B.V. All rights reserved.

Preselection statistics and Random Forest classification identify population informative single nucleotide polymorphisms in cosmopolitan and autochthonous cattle breeds.

PubMed

Bertolini, F; Galimberti, G; Schiavo, G; Mastrangelo, S; Di Gerlando, R; Strillacci, M G; Bagnato, A; Portolano, B; Fontanesi, L

2018-01-01

Commercial single nucleotide polymorphism (SNP) arrays have been recently developed for several species and can be used to identify informative markers to differentiate breeds or populations for several downstream applications. To identify the most discriminating genetic markers among thousands of genotyped SNPs, a few statistical approaches have been proposed. In this work, we compared several methods of SNPs preselection (Delta, F st and principal component analyses (PCA)) in addition to Random Forest classifications to analyse SNP data from six dairy cattle breeds, including cosmopolitan (Holstein, Brown and Simmental) and autochthonous Italian breeds raised in two different regions and subjected to limited or no breeding programmes (Cinisara, Modicana, raised only in Sicily and Reggiana, raised only in Emilia Romagna). From these classifications, two panels of 96 and 48 SNPs that contain the most discriminant SNPs were created for each preselection method. These panels were evaluated in terms of the ability to discriminate as a whole and breed-by-breed, as well as linkage disequilibrium within each panel. The obtained results showed that for the 48-SNP panel, the error rate increased mainly for autochthonous breeds, probably as a consequence of their admixed origin lower selection pressure and by ascertaining bias in the construction of the SNP chip. The 96-SNP panels were generally more able to discriminate all breeds. The panel derived by PCA-chrom (obtained by a preselection chromosome by chromosome) could identify informative SNPs that were particularly useful for the assignment of minor breeds that reached the lowest value of Out Of Bag error even in the Cinisara, whose value was quite high in all other panels. Moreover, this panel contained also the lowest number of SNPs in linkage disequilibrium. Several selected SNPs are located nearby genes affecting breed-specific phenotypic traits (coat colour and stature) or associated with production traits. In

Model-Based Linkage Analysis of a Quantitative Trait.

PubMed

Song, Yeunjoo E; Song, Sunah; Schnell, Audrey H

2017-01-01

Linkage Analysis is a family-based method of analysis to examine whether any typed genetic markers cosegregate with a given trait, in this case a quantitative trait. If linkage exists, this is taken as evidence in support of a genetic basis for the trait. Historically, linkage analysis was performed using a binary disease trait, but has been extended to include quantitative disease measures. Quantitative traits are desirable as they provide more information than binary traits. Linkage analysis can be performed using single-marker methods (one marker at a time) or multipoint (using multiple markers simultaneously). In model-based linkage analysis the genetic model for the trait of interest is specified. There are many software options for performing linkage analysis. Here, we use the program package Statistical Analysis for Genetic Epidemiology (S.A.G.E.). S.A.G.E. was chosen because it also includes programs to perform data cleaning procedures and to generate and test genetic models for a quantitative trait, in addition to performing linkage analysis. We demonstrate in detail the process of running the program LODLINK to perform single-marker analysis, and MLOD to perform multipoint analysis using output from SEGREG, where SEGREG was used to determine the best fitting statistical model for the trait.

Adjusting for founder relatedness in a linkage analysis using prior information.

PubMed

Sheehan, N A; Egeland, T

2008-01-01

In genetic linkage studies, while the pedigrees are generally known, background relatedness between the founding individuals, assumed by definition to be unrelated, can seriously affect the results of the analysis. Likelihood approaches to relationship estimation from genetic marker data can all be expressed in terms of finding the most likely pedigree connecting the individuals of interest. When the true relationship is the main focus, the set of all possible alternative pedigrees can be too large to consider. However, prior information is often available which, when incorporated in a formal and structured way, can restrict this set to a manageable size thus enabling the calculation of a posterior distribution from which inferences can be drawn. Here, the unknown relationships are more of a nuisance factor than of interest in their own right, so the focus is on adjusting the results of the analysis rather than on direct estimation. In this paper, we show how prior information on founder relationships can be exploited in some applications to generate a set of candidate extended pedigrees. We then weight the relevant pedigree-specific likelihoods by their posterior probabilities to adjust the lod score statistics. (c) 2007 S. Karger AG, Basel

Qualifying information on deaths and serious injuries caused by road traffic in five Brazilian capitals using record linkage.

PubMed

Mandacaru, Polyana Maria Pimenta; Andrade, Ana Lucia; Rocha, Marli Souza; Aguiar, Fernanda Pinheiro; Nogueira, Maria Sueli M; Girodo, Anne Marielle; Pedrosa, Ana Amélia Galas; Oliveira, Vera Lídia Alves de; Alves, Marta Maria Malheiros; Paixão, Lúcia Maria Miana M; Malta, Deborah Carvalho; Silva, Marta Maria Alves; Morais Neto, Otaliba Libanio de

2017-09-01

Road traffic crashes (RTC) are an important public health problem, accounting for 1.2 million deaths per year worldwide. In Brazil, approximately 40,000 deaths caused by RTC occur every year, with different trends in the Federal Units. However, these figures may be even greater if health databases are linked to police records. In addition, the linkage procedure would make it possible to qualify information from the health and police databases, improving the quality of the data regarding underlying cause of death, cause of injury in hospital records, and injury severity. This study linked different data sources to measure the numbers of deaths and serious injuries and to estimate the percentage of corrections regarding the underlying cause of death, cause of injury, and the severity injury in victims in matched pairs from record linkage in five representative state capitals of the five macro-regions of Brazil. This cross-sectional, population-based study used data from the Hospital Information System (HIS), Mortality Information System (MIS), and Police Road Traffic database of Belo Horizonte, Campo Grande, Curitiba, Palmas, and Teresina, for the year 2013 for Teresina, and 2012 for the other capitals. RecLink III was used to perform probabilistic record linkage by identifying matched pairs to calculate the global correction percentage of the underlying cause of death, the circumstance that caused the road traffic injury, and the injury severity of the victims in the police database. There was a change in the cause of injury in the HIS, with an overall percentage of correction estimated at 24.4% for Belo Horizonte, 96.9% for Campo Grande, 100.0% for Palmas, and 33.2% for Teresina. The overall percentages of correction of the underlying cause of death in the MIS were 29.9%, 11.9%, 4.2%, and 33.5% for Belo Horizonte, Campo Grande, Curitiba, and Teresina, respectively. The correction of the classification of injury severity in police database were 100.0% for Belo

The role of the GABRA2 polymorphism in multiplex alcohol dependence families with minimal comorbidity: within-family association and linkage analyses.

PubMed

Matthews, Abigail G; Hoffman, Eric K; Zezza, Nicholas; Stiffler, Scott; Hill, Shirley Y

2007-09-01

The genes encoding the gamma-aminobutyric acid(A) (GABA(A)) receptor have been the focus of several recent studies investigating the genetic etiology of alcohol dependence. Analyses of multiplex families found a particular gene, GABRA2, to be highly associated with alcohol dependence, using within-family association tests and other methods. Results were confirmed in three case-control studies. The objective of this study was to investigate the GABRA2 gene in another collection of multiplex families. Analyses were based on phenotypic and genotypic data available for 330 individuals from 65 bigenerational pedigrees with a total of 232 alcohol-dependent subjects. A proband pair of same-sex siblings meeting Diagnostic and Statistical Manual of Mental Disorders, Third Edition, criteria for alcohol dependence was required for entry of a family into the study. One member of the proband pair was identified while in treatment for alcohol dependence. Linkage and association of GABRA2 and alcohol dependence were evaluated using SIBPAL (a nonparametric linkage package) and both the Pedigree Disequilibrium Test and the Family-Based Association Test, respectively. We find no evidence of a relationship between GABRA2 and alcohol dependence. Linkage analyses exhibited no linkage using affected/affected, affected/unaffected, and unaffected/unaffected sib pairs (all p's < .13). There was no evidence of a within-family association (all p's > .39). Comorbidity may explain why our results differ from those in the literature. The presence of primary drug dependence and/or other psychiatric disorders is minimal in our pedigrees, although several of the other previously published multiplex family analyses exhibit a greater degree of comorbidity.

Trans-ethnic follow-up of breast cancer GWAS hits using the preferential linkage disequilibrium approach

PubMed Central

Zhu, Qianqian; Shepherd, Lori; Lunetta, Kathryn L.; Yao, Song; Liu, Qian; Hu, Qiang; Haddad, Stephen A.; Sucheston-Campbell, Lara; Bensen, Jeannette T.; Bandera, Elisa V.; Rosenberg, Lynn; Liu, Song; Haiman, Christopher A.; Olshan, Andrew F.; Palmer, Julie R.; Ambrosone, Christine B.

2016-01-01

Leveraging population-distinct linkage equilibrium (LD) patterns, trans-ethnic follow-up of variants discovered from genome-wide association studies (GWAS) has proved to be useful in facilitating the identification of bona fide causal variants. We previously developed the preferential LD approach, a novel method that successfully identified causal variants driving the GWAS signals within European-descent populations even when the causal variants were only weakly linked with the GWAS-discovered variants. To evaluate the performance of our approach in a trans-ethnic setting, we applied it to follow up breast cancer GWAS hits identified mostly from populations of European ancestry in African Americans (AA). We evaluated 74 breast cancer GWAS variants in 8,315 AA women from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Only 27% of them were associated with breast cancer risk at significance level α=0.05, suggesting race-specificity of the identified breast cancer risk loci. We followed up on those replicated GWAS hits in the AMBER consortium utilizing the preferential LD approach, to search for causal variants or better breast cancer markers from the 1000 Genomes variant catalog. Our approach identified stronger breast cancer markers for 80% of the GWAS hits with at least nominal breast cancer association, and in 81% of these cases, the marker identified was among the top 10 of all 1000 Genomes variants in the corresponding locus. The results support trans-ethnic application of the preferential LD approach in search for candidate causal variants, and may have implications for future genetic research of breast cancer in AA women. PMID:27825120

Record linkage for pharmacoepidemiological studies in cancer patients.

PubMed

Herk-Sukel, Myrthe P P van; Lemmens, Valery E P P; Poll-Franse, Lonneke V van de; Herings, Ron M C; Coebergh, Jan Willem W

2012-01-01

An increasing need has developed for the post-approval surveillance of (new) anti-cancer drugs by means of pharmacoepidemiology and outcomes research in the area of oncology. To create an overview that makes researchers aware of the available database linkages in Northern America and Europe which facilitate pharmacoepidemiology and outcomes research in cancer patients. In addition to our own database, i.e. the Eindhoven Cancer Registry (ECR) linked to the PHARMO Record Linkage System, we considered database linkages between a population-based cancer registry and an administrative healthcare database that at least contains information on drug use and offers a longitudinal perspective on healthcare utilization. Eligible database linkages were limited to those that had been used in multiple published articles in English language included in Pubmed. The HMO Cancer Research Network (CRN) in the US was excluded from this review, as an overview of the linked databases participating in the CRN is already provided elsewhere. Researchers who had worked with the data resources included in our review were contacted for additional information and verification of the data presented in the overview. The following database linkages were included: the Surveillance, Epidemiology, and End-Results-Medicare; cancer registry data linked to Medicaid; Canadian cancer registries linked to population-based drug databases; the Scottish cancer registry linked to the Tayside drug dispensing data; linked databases in the Nordic Countries of Europe: Norway, Sweden, Finland and Denmark; and the ECR-PHARMO linkage in the Netherlands. Descriptives of the included database linkages comprise population size, generalizability of the population, year of first data availability, contents of the cancer registry, contents of the administrative healthcare database, the possibility to select a cancer-free control cohort, and linkage to other healthcare databases. The linked databases offer a longitudinal

Two-trait-locus linkage analysis: A powerful strategy for mapping complex genetic traits

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schork, N.J.; Boehnke, M.; Terwilliger, J.D.

1993-11-01

Nearly all diseases mapped to date follow clear Mendelian, single-locus segregation patterns. In contrast, many common familial diseases such as diabetes, psoriasis, several forms of cancer, and schizophrenia are familial and appear to have a genetic component but do not exhibit simple Mendelian transmission. More complex models are required to explain the genetics of these important diseases. In this paper, the authors explore two-trait-locus, two-marker-locus linkage analysis in which two trait loci are mapped simultaneously to separate genetic markers. The authors compare the utility of this approach to standard one-trait-locus, one-marker-locus linkage analysis with and without allowance for heterogeneity. Themore » authors also compare the utility of the two-trait-locus, two-marker-locus analysis to two-trait-locus, one-marker-locus linkage analysis. For common diseases, pedigrees are often bilineal, with disease genes entering via two or more unrelated pedigree members. Since such pedigrees often are avoided in linkage studies, the authors also investigate the relative information content of unilineal and bilineal pedigrees. For the dominant-or-recessive and threshold models that the authors consider, the authors find that two-trait-locus, two-marker-locus linkage analysis can provide substantially more linkage information, as measured by expected maximum lod score, than standard one-trait-locus, one-marker-locus methods, even allowing for heterogeneity, while, for a dominant-or-dominant generating model, one-locus models that allow for heterogeneity extract essentially as much information as the two-trait-locus methods. For these three models, the authors also find that bilineal pedigrees provide sufficient linkage information to warrant their inclusion in such studies. The authors discuss strategies for assessing the significance of the two linkages assumed in two-trait-locus, two-marker-locus models. 37 refs., 1 fig., 4 tabs.« less

Local thermodynamic equilibrium for globally disequilibrium open systems under stress

NASA Astrophysics Data System (ADS)

Podladchikov, Yury

2016-04-01

Predictive modeling of far and near equilibrium processes is essential for understanding of patterns formation and for quantifying of natural processes that are never in global equilibrium. Methods of both equilibrium and non-equilibrium thermodynamics are needed and have to be combined. For example, predicting temperature evolution due to heat conduction requires simultaneous use of equilibrium relationship between internal energy and temperature via heat capacity (the caloric equation of state) and disequilibrium relationship between heat flux and temperature gradient. Similarly, modeling of rocks deforming under stress, reactions in system open for the porous fluid flow, or kinetic overstepping of the equilibrium reaction boundary necessarily needs both equilibrium and disequilibrium material properties measured under fundamentally different laboratory conditions. Classical irreversible thermodynamics (CIT) is the well-developed discipline providing the working recipes for the combined application of mutually exclusive experimental data such as density and chemical potential at rest under constant pressure and temperature and viscosity of the flow under stress. Several examples will be presented.

Linkage Analysis of a Model Quantitative Trait in Humans: Finger Ridge Count Shows Significant Multivariate Linkage to 5q14.1

PubMed Central

Medland, Sarah E; Loesch, Danuta Z; Mdzewski, Bogdan; Zhu, Gu; Montgomery, Grant W; Martin, Nicholas G

2007-01-01

The finger ridge count (a measure of pattern size) is one of the most heritable complex traits studied in humans and has been considered a model human polygenic trait in quantitative genetic analysis. Here, we report the results of the first genome-wide linkage scan for finger ridge count in a sample of 2,114 offspring from 922 nuclear families. Both univariate linkage to the absolute ridge count (a sum of all the ridge counts on all ten fingers), and multivariate linkage analyses of the counts on individual fingers, were conducted. The multivariate analyses yielded significant linkage to 5q14.1 (Logarithm of odds [LOD] = 3.34, pointwise-empirical p-value = 0.00025) that was predominantly driven by linkage to the ring, index, and middle fingers. The strongest univariate linkage was to 1q42.2 (LOD = 2.04, point-wise p-value = 0.002, genome-wide p-value = 0.29). In summary, the combination of univariate and multivariate results was more informative than simple univariate analyses alone. Patterns of quantitative trait loci factor loadings consistent with developmental fields were observed, and the simple pleiotropic model underlying the absolute ridge count was not sufficient to characterize the interrelationships between the ridge counts of individual fingers. PMID:17907812

Linkages between public and non-government sectors in healthcare: A case study from Uttar Pradesh, India.

PubMed

Srivastava, Aradhana; Bhattacharyya, Sanghita; Gautham, Meenakshi; Schellenberg, Joanna; Avan, Bilal I

2016-12-01

Effective utilisation of collaborative non-governmental organisation (NGO)-public health system linkages in pluralistic health systems of developing countries can substantially improve equity and quality of services. This study explores level and types of linkages between public health sector and NGOs in Uttar Pradesh (UP), an underprivileged state of India, using a social science model for the first time. It also identifies gaps and challenges for effective linkage. Two NGOs were selected as case studies. Data collection included semi-structured in-depth interviews with senior staff and review of records and reporting formats. Formal linkages of NGOs with the public health system related to registration, participation in district level meetings, workforce linkages and sharing information on government-supported programmes. Challenges included limited data sharing, participation in planning and limited monitoring of regulatory compliances. Linkage between public health system and NGOs in UP was moderate, marked by frequent interaction and some reciprocity in information and resource flows, but weak participation in policy and planning. The type of linkage could be described as 'complementarity', entailing information and resource sharing but not joint action. Stronger linkage is required for sustained and systematic collaboration, with joint planning, implementation and evaluation.

Tests of linkage and/or association of the LEPR gene polymorphisms with obesity phenotypes in Caucasian nuclear families.

PubMed

Liu, Yong-Jun; Rocha-Sanchez, Sonia M S; Liu, Peng-Yuan; Long, Ji-Rong; Lu, Yan; Elze, Leo; Recker, Robert R; Deng, Hong-Wen

2004-04-13

Genetic variations in the leptin receptor (LEPR) gene have been conceived to affect body weight in general populations. In this study, using the tests implemented in the statistical package QTDT, we evaluated association and/or linkage of the LEPR gene with obesity phenotypes in a large sample comprising 1,873 subjects from 405 Caucasian nuclear families. Obesity phenotypes tested include body mass index (BMI), fat mass, percentage fat mass (PFM), and lean mass, with the latter three measured by dual-energy X-ray absorptiometry (DXA). Three single nucleotide polymorphisms (SNPs), namely Lys109Arg (A/G), Lys656Asn (G/C), Pro1019Pro (G/A), in the LEPR gene were analyzed. Significant linkage disequilibrium (0.394 < or = |D'| < or = 0.688, P < 0.001) was observed between pairs of the three SNPs. No significant population stratification was found for any SNP/phenotype. In single-locus analyses, evidence of association was observed for Lys656Asn with lean mass (P = 0.002) and fat mass (P = 0.015). The contribution of this polymorphism to the phenotypic variation of lean mass and fat mass was 2.63% and 1.15%, respectively. Subjects carrying allele G at the Lys656Asn site had, on average, 3.16% higher lean mass and 2.71% higher fat mass than those without it. In the analyses for haplotypes defined by the three SNPs, significant associations were detected between haplotype GCA (P = 0.005) and lean mass. In addition, marginally significant evidence of association was observed for this haplotype with fat mass (P = 0.012). No statistically significant linkage was found, largely due to the limited power of the linkage approach to detect small genetic effects in our data sets. Our results suggest that the LEPR gene polymorphisms contribute to variation in obesity phenotypes.

Linking environmental filtering and disequilibrium to biogeography with a community climate framework.

PubMed

Blonder, Benjamin; Nogués-Bravo, David; Borregaard, Michael K; Donoghue, John C; Jørgensen, Peter M; Kraft, Nathan J B; Lessard, Jean-Philippe; Morueta-Holme, Naia; Sandel, Brody; Svenning, Jens-Christian; Violle, Cyrille; Rahbek, Carsten; Enquist, Brian J

2015-04-01

We present a framework to measure the strength of environmental filtering and disequilibrium of the species composition of a local community across time, relative to past, current, and future climates. We demonstrate the framework by measuring the impact of climate change on New World forests, integrating data for climate niches of more than 14000 species, community composition of 471 New World forest plots, and observed climate across the most recent glacial-interglacial interval. We show that a majority of communities have species compositions that are strongly filtered and are more in equilibrium with current climate than random samples from the regional pool. Variation in the level of current community disequilibrium can be predicted from Last Glacial Maximum climate and will increase with near-future climate change.

Statistical manifestation of quantum correlations via disequilibrium

NASA Astrophysics Data System (ADS)

Pennini, F.; Plastino, A.

2017-12-01

The statistical notion of disequilibrium (D) was introduced by López-Ruiz, Mancini, and Calbet (LMC) (1995) [1] more than 20 years ago. D measures the amount of ;correlational structure; of a system. We wish to use D to analyze one of the simplest types of quantum correlations, those present in gaseous systems due to symmetry considerations. To this end we extend the LMC formalism to the grand canonical environment and show that D displays distinctive behaviors for simple gases, that allow for interesting insights into their structural properties.

Some methods for blindfolded record linkage.

PubMed

Churches, Tim; Christen, Peter

2004-06-28

The linkage of records which refer to the same entity in separate data collections is a common requirement in public health and biomedical research. Traditionally, record linkage techniques have required that all the identifying data in which links are sought be revealed to at least one party, often a third party. This necessarily invades personal privacy and requires complete trust in the intentions of that party and their ability to maintain security and confidentiality. Dusserre, Quantin, Bouzelat and colleagues have demonstrated that it is possible to use secure one-way hash transformations to carry out follow-up epidemiological studies without any party having to reveal identifying information about any of the subjects - a technique which we refer to as "blindfolded record linkage". A limitation of their method is that only exact comparisons of values are possible, although phonetic encoding of names and other strings can be used to allow for some types of typographical variation and data errors. A method is described which permits the calculation of a general similarity measure, the n-gram score, without having to reveal the data being compared, albeit at some cost in computation and data communication. This method can be combined with public key cryptography and automatic estimation of linkage model parameters to create an overall system for blindfolded record linkage. The system described offers good protection against misdeeds or security failures by any one party, but remains vulnerable to collusion between or simultaneous compromise of two or more parties involved in the linkage operation. In order to reduce the likelihood of this, the use of last-minute allocation of tasks to substitutable servers is proposed. Proof-of-concept computer programmes written in the Python programming language are provided to illustrate the similarity comparison protocol. Although the protocols described in this paper are not unconditionally secure, they do suggest the

Some methods for blindfolded record linkage

PubMed Central

Churches, Tim; Christen, Peter

2004-01-01

Background The linkage of records which refer to the same entity in separate data collections is a common requirement in public health and biomedical research. Traditionally, record linkage techniques have required that all the identifying data in which links are sought be revealed to at least one party, often a third party. This necessarily invades personal privacy and requires complete trust in the intentions of that party and their ability to maintain security and confidentiality. Dusserre, Quantin, Bouzelat and colleagues have demonstrated that it is possible to use secure one-way hash transformations to carry out follow-up epidemiological studies without any party having to reveal identifying information about any of the subjects – a technique which we refer to as "blindfolded record linkage". A limitation of their method is that only exact comparisons of values are possible, although phonetic encoding of names and other strings can be used to allow for some types of typographical variation and data errors. Methods A method is described which permits the calculation of a general similarity measure, the n-gram score, without having to reveal the data being compared, albeit at some cost in computation and data communication. This method can be combined with public key cryptography and automatic estimation of linkage model parameters to create an overall system for blindfolded record linkage. Results The system described offers good protection against misdeeds or security failures by any one party, but remains vulnerable to collusion between or simultaneous compromise of two or more parties involved in the linkage operation. In order to reduce the likelihood of this, the use of last-minute allocation of tasks to substitutable servers is proposed. Proof-of-concept computer programmes written in the Python programming language are provided to illustrate the similarity comparison protocol. Conclusion Although the protocols described in this paper are not

Evolution of recombination in a constant environment

PubMed Central

Feldman, Marcus W.; Christiansen, Freddy B.; Brooks, Lisa D.

1980-01-01

The theory of evolution at a selectively neutral locus that controls the recombination between two major loci that are under selection is studied. If the major loci are at a stable equilibrium in linkage disequilibrium under selection and recombination, then a mutation at the modifier locus will increase in frequency when rare if and only if it decreases the recombination fraction. If the major loci are in disequilibrium at a balance between selection against deleterious alleles and mutation towards them, then two new phenomena are observed. First, a recombination increasing mutation will succeed if the disequilibrium is negative and the modifier is sufficiently tightly linked to the major loci. Second, depending on the strength of selection, even if the disequilibrium is negative, recombination reduction may occur for looser linkage between the major and modifier loci. PMID:16592864

Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium

PubMed Central

Shete, Sanjay; Lau, Ching C; Houlston, Richard S; Claus, Elizabeth B; Barnholtz-Sloan, Jill; Lai, Rose; Il’yasova, Dora; Schildkraut, Joellen; Sadetzki, Siegal; Johansen, Christoffer; Bernstein, Jonine L; Olson, Sara H; Jenkins, Robert B; Yang, Ping; Vick, Nicholas A; Wrensch, Margaret; Davis, Faith G; McCarthy, Bridget J; Leung, Eastwood Hon-chiu; Davis, Caleb; Cheng, Rita; Hosking, Fay J; Armstrong, Georgina N; Liu, Yanhong; Yu, Robert K; Henriksson, Roger; Consortium, The Gliogene; Melin, Beatrice S; Bondy, Melissa L

2011-01-01

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have demonstrated that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium SNPs, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P=0.0005) at 17q12–21.32 and the Z-score of 4.20 (P=0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P=0.008) and the Z-score of 1.47 (P=0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P=0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma. PMID:22037877

Germany's Persistent Balance-of-Payments Disequilibrium Revisited. German Studies Notes.

ERIC Educational Resources Information Center

Kindleberger, Charles P.

This essay compares Germany's persistent financial disequilibrium with the balance of payments situation in the United States. Delivered at a Symposium on German Economic Growth and Stability, the author concentrates on Germany's balance of payments surplus and presents U.S. figures mainly as a point of comparison. The material on Germany has been…

Role for syn-eruptive plagioclase disequilibrium crystallisation in basaltic magma ascent dynamics

NASA Astrophysics Data System (ADS)

La Spina, Giuseppe; Burton, Mike; de'Michieli Vitturi, Mattia; Arzilli, Fabio

2017-04-01

Magma ascent dynamics in volcanic conduits play a key role in determining the eruptive style of a volcano. The lack of direct observations inside the conduit means that numerical conduit models, constrained with observational data, provide invaluable tools for quantitative insights into complex magma ascent dynamics. The highly nonlinear, interdependent processes involved in magma ascent dynamics require several simplifications when modelling their ascent. For example, timescales of magma ascent in conduit models are typically assumed to be much longer than crystallisation and gas exsolution for basaltic eruptions. However, it is now recognized that basaltic magmas may rise fast enough for disequilibrium processes to play a key role on the ascent dynamics. The quantification of the characteristic times for crystallisation and exsolution processes are fundamental to our understanding of such disequilibria and ascent dynamics. Using observations from Mount Etna's 2001 eruption and a magma ascent model we are able to constrain timescales for crystallisation and exsolution processes. Our results show that plagioclase reaches equilibrium in 1-2 h, whereas ascent times were 1 h. Furthermore, we have related the amount of plagioclase in erupted products with the ascent dynamics of basaltic eruptions. We find that relatively high plagioclase content requires crystallisation in a shallow reservoir, whilst a low plagioclase content reflects a disequilibrium crystallisation occurring during a fast ascent from depth to the surface. Using these new constraints on disequilibrium plagioclase crystallisation we also reproduce observed crystal abundances for different basaltic eruptions: Etna 2002/2003, Stromboli 2007 (effusive eruption) and 1930 (paroxysm) and different Pu'u' O'o eruptions at Kilauea (episodes 49-53). Therefore, our results show that disequilibrium processes play a key role on the ascent dynamics of basaltic magmas and cannot be neglected when describing basaltic

Nance-Horan syndrome: linkage analysis in a family from The Netherlands.

PubMed

Bergen, A A; ten Brink, J; Schuurman, E J; Bleeker-Wagemakers, E M

1994-05-01

Linkage analysis was carried out in a Dutch family with Nance-Horan (NH) syndrome. Close linkage without recombination between NH and the Xp loci DXS207, DXS43, and DXS365 (zmax = 3.23) was observed. Multipoint linkage analysis and the analysis of recombinations in multiple informative meioses suggest the genetic order Xcen-DMD (exon 49)-DXS451-(NH, DXS207, DXS365, DXS43)-(STS, DXF30)-Xpter. These data refine the localization of the NH locus on the distal Xp.

A microsatellite genetic linkage map of black rockfish ( Sebastes schlegeli)

NASA Astrophysics Data System (ADS)

Chu, Guannan; Jiang, Liming; He, Yan; Yu, Haiyang; Wang, Zhigang; Jiang, Haibin; Zhang, Quanqi

2014-12-01

Ovoviviparous black rockfish ( Sebastes schlegeli) is an important marine fish species for aquaculture and fisheries in China. Genetic information of this species is scarce because of the lack of microsatellite markers. In this study, a large number of microsatellite markers of black rockfish were isolated by constructing microsatellite-enriched libraries. Female- and male-specific genetic linkage maps were constructed using 435 microsatellite markers genotyped in a full-sib family of the fish species. The female linkage map contained 140 microsatellite markers, in which 23 linkage groups had a total genetic length of 1334.1 cM and average inter-marker space of 13.3 cM. The male linkage map contained 156 microsatellite markers, in which 25 linkage groups had a total genetic length of 1359.6 cM and average inter-marker distance of 12.4 cM. The genome coverage of the female and male linkage maps was 68.6% and 69.3%, respectively. The female-to-male ratio of the recombination rate was approximately 1.07:1 in adjacent microsatellite markers. This paper presents the first genetic linkage map of microsatellites in black rockfish. The collection of polymorphic markers and sex-specific linkage maps of black rockfish could be useful for further investigations on parental assignment, population genetics, quantitative trait loci mapping, and marker-assisted selection in related breeding programs.

A case study of the Secure Anonymous Information Linkage (SAIL) Gateway: A privacy-protecting remote access system for health-related research and evaluation☆

PubMed Central

Jones, Kerina H.; Ford, David V.; Jones, Chris; Dsilva, Rohan; Thompson, Simon; Brooks, Caroline J.; Heaven, Martin L.; Thayer, Daniel S.; McNerney, Cynthia L.; Lyons, Ronan A.

2014-01-01

With the current expansion of data linkage research, the challenge is to find the balance between preserving the privacy of person-level data whilst making these data accessible for use to their full potential. We describe a privacy-protecting safe haven and secure remote access system, referred to as the Secure Anonymised Information Linkage (SAIL) Gateway. The Gateway provides data users with a familiar Windows interface and their usual toolsets to access approved anonymously-linked datasets for research and evaluation. We outline the principles and operating model of the Gateway, the features provided to users within the secure environment, and how we are approaching the challenges of making data safely accessible to increasing numbers of research users. The Gateway represents a powerful analytical environment and has been designed to be scalable and adaptable to meet the needs of the rapidly growing data linkage community. PMID:24440148

A guide to evaluating linkage quality for the analysis of linked data.

PubMed

Harron, Katie L; Doidge, James C; Knight, Hannah E; Gilbert, Ruth E; Goldstein, Harvey; Cromwell, David A; van der Meulen, Jan H

2017-10-01

Linked datasets are an important resource for epidemiological and clinical studies, but linkage error can lead to biased results. For data security reasons, linkage of personal identifiers is often performed by a third party, making it difficult for researchers to assess the quality of the linked dataset in the context of specific research questions. This is compounded by a lack of guidance on how to determine the potential impact of linkage error. We describe how linkage quality can be evaluated and provide widely applicable guidance for both data providers and researchers. Using an illustrative example of a linked dataset of maternal and baby hospital records, we demonstrate three approaches for evaluating linkage quality: applying the linkage algorithm to a subset of gold standard data to quantify linkage error; comparing characteristics of linked and unlinked data to identify potential sources of bias; and evaluating the sensitivity of results to changes in the linkage procedure. These approaches can inform our understanding of the potential impact of linkage error and provide an opportunity to select the most appropriate linkage procedure for a specific analysis. Evaluating linkage quality in this way will improve the quality and transparency of epidemiological and clinical research using linked data. © The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association.

Disequilibrium δ18O values in microbial carbonates as a tracer of metabolic production of dissolved inorganic carbon

NASA Astrophysics Data System (ADS)

Thaler, Caroline; Millo, Christian; Ader, Magali; Chaduteau, Carine; Guyot, François; Ménez, Bénédicte

2017-02-01

Carbon and oxygen stable isotope compositions of carbonates are widely used to retrieve paleoenvironmental information. However, bias may exist in such reconstructions as carbonate precipitation is often associated with biological activity. Several skeleton-forming eukaryotes have been shown to precipitate carbonates with significant offsets from isotopic equilibrium with water. Although poorly understood, the origin of these biologically-induced isotopic shifts in biogenic carbonates, commonly referred to as "vital effects", could be related to metabolic effects that may not be restricted to mineralizing eukaryotes. The aim of our study was to determine whether microbially-mediated carbonate precipitation can also produce offsets from equilibrium for oxygen isotopes. We present here δ18O values of calcium carbonates formed by the activity of Sporosarcina pasteurii, a carbonatogenic bacterium whose ureolytic activity produces ammonia (thus increasing pH) and dissolved inorganic carbon (DIC) that precipitates as solid carbonates in the presence of Ca2+. We show that the 1000 lnαCaCO3-H2O values for these bacterially-precipitated carbonates are up to 24.7‰ smaller than those expected for precipitation at isotopic equilibrium. A similar experiment run in the presence of carbonic anhydrase (an enzyme able to accelerate oxygen isotope equilibration between DIC and water) resulted in δ18O values of microbial carbonates in line with values expected at isotopic equilibrium with water. These results demonstrate for the first time that bacteria can induce calcium carbonate precipitation in strong oxygen isotope disequilibrium with water, similarly to what is observed for eukaryotes. This disequilibrium effect can be unambiguously ascribed to oxygen isotope disequilibrium between DIC and water inherited from the oxygen isotope composition of the ureolytically produced CO2, probably combined with a kinetic isotope effect during CO2 hydration/hydroxylation. The fact that

A case study of the Secure Anonymous Information Linkage (SAIL) Gateway: a privacy-protecting remote access system for health-related research and evaluation.

PubMed

Jones, Kerina H; Ford, David V; Jones, Chris; Dsilva, Rohan; Thompson, Simon; Brooks, Caroline J; Heaven, Martin L; Thayer, Daniel S; McNerney, Cynthia L; Lyons, Ronan A

2014-08-01

With the current expansion of data linkage research, the challenge is to find the balance between preserving the privacy of person-level data whilst making these data accessible for use to their full potential. We describe a privacy-protecting safe haven and secure remote access system, referred to as the Secure Anonymised Information Linkage (SAIL) Gateway. The Gateway provides data users with a familiar Windows interface and their usual toolsets to access approved anonymously-linked datasets for research and evaluation. We outline the principles and operating model of the Gateway, the features provided to users within the secure environment, and how we are approaching the challenges of making data safely accessible to increasing numbers of research users. The Gateway represents a powerful analytical environment and has been designed to be scalable and adaptable to meet the needs of the rapidly growing data linkage community. Copyright © 2014 The Aurthors. Published by Elsevier Inc. All rights reserved.

Adaptive transmission disequilibrium test for family trio design.

PubMed

Yuan, Min; Tian, Xin; Zheng, Gang; Yang, Yaning

2009-01-01

The transmission disequilibrium test (TDT) is a standard method to detect association using family trio design. It is optimal for an additive genetic model. Other TDT-type tests optimal for recessive and dominant models have also been developed. Association tests using family data, including the TDT-type statistics, have been unified to a class of more comprehensive and flexable family-based association tests (FBAT). TDT-type tests have high efficiency when the genetic model is known or correctly specified, but may lose power if the model is mis-specified. Hence tests that are robust to genetic model mis-specification yet efficient are preferred. Constrained likelihood ratio test (CLRT) and MAX-type test have been shown to be efficiency robust. In this paper we propose a new efficiency robust procedure, referred to as adaptive TDT (aTDT). It uses the Hardy-Weinberg disequilibrium coefficient to identify the potential genetic model underlying the data and then applies the TDT-type test (or FBAT for general applications) corresponding to the selected model. Simulation demonstrates that aTDT is efficiency robust to model mis-specifications and generally outperforms the MAX test and CLRT in terms of power. We also show that aTDT has power close to, but much more robust, than the optimal TDT-type test based on a single genetic model. Applications to real and simulated data from Genetic Analysis Workshop (GAW) illustrate the use of our adaptive TDT.

SNP Discovery and Linkage Map Construction in Cultivated Tomato

PubMed Central

Shirasawa, Kenta; Isobe, Sachiko; Hirakawa, Hideki; Asamizu, Erika; Fukuoka, Hiroyuki; Just, Daniel; Rothan, Christophe; Sasamoto, Shigemi; Fujishiro, Tsunakazu; Kishida, Yoshie; Kohara, Mitsuyo; Tsuruoka, Hisano; Wada, Tsuyuko; Nakamura, Yasukazu; Sato, Shusei; Tabata, Satoshi

2010-01-01

Few intraspecific genetic linkage maps have been reported for cultivated tomato, mainly because genetic diversity within Solanum lycopersicum is much less than that between tomato species. Single nucleotide polymorphisms (SNPs), the most abundant source of genomic variation, are the most promising source of polymorphisms for the construction of linkage maps for closely related intraspecific lines. In this study, we developed SNP markers based on expressed sequence tags for the construction of intraspecific linkage maps in tomato. Out of the 5607 SNP positions detected through in silico analysis, 1536 were selected for high-throughput genotyping of two mapping populations derived from crosses between ‘Micro-Tom’ and either ‘Ailsa Craig’ or ‘M82’. A total of 1137 markers, including 793 out of the 1338 successfully genotyped SNPs, along with 344 simple sequence repeat and intronic polymorphism markers, were mapped onto two linkage maps, which covered 1467.8 and 1422.7 cM, respectively. The SNP markers developed were then screened against cultivated tomato lines in order to estimate the transferability of these SNPs to other breeding materials. The molecular markers and linkage maps represent a milestone in the genomics and genetics, and are the first step toward molecular breeding of cultivated tomato. Information on the DNA markers, linkage maps, and SNP genotypes for these tomato lines is available at http://www.kazusa.or.jp/tomato/. PMID:21044984

Sex-specific Linkage Scans in Opioid Dependence

PubMed Central

Yang, Bao-Zhu; Han, Shizhong; Kranzler, Henry R.; Palmer, Abraham A.; Gelernter, Joel

2017-01-01

Sex influences risk for opioid dependence (OD). We hypothesized that sex might interact with genetic loci that influence the risk for OD. Therefore we performed an analysis to identify sex-specific genomic susceptibility regions for OD using linkage. Over 6000 single nucleotide polymorphism (SNP) markers were genotyped for 1758 African- and European-American (AA and EA) individuals from 739 families, ascertained via affected sib-pairs with OD and/or cocaine dependence. Autosomewide non-parametric linkage scans, stratified by sex and population, were performed. We identified one significant linkage region, segregating with OD in EA men, at 71.1 cM on chromosome 4 (LOD=3.29; point-wise p=0.00005; empirical autosome-wide p=0.042), which significantly differed from the linkage signal at the same location in EA women (empirical p=0.002). Three suggestive linkage signals were identified at 181.3 cM on chromosome 7 (LOD=2.18), 104 cM on chromosome 11 (LOD=1.85), and 60.9 cM on chromosome 16 (LOD=1.93) in EA women. In AA men, four suggestive linkage signals were detected at 201.1 cM on chromosome 3 (LOD=2.32), 152.9 cM on chromosome 6 (LOD=1.86), 16.8 cM on chromosome 7 (LOD=1.95), and 36.1 cM on chromosome 17 (LOD=1.99). The significant region, mapping to 4q12-4q13.1, harbors several OD candidate genes with interconnected functionality, including VEGFR, CLOCK, PDCL2, NMU, NRSF, and IGFBP7. In conclusion, these results provide an evidence for the existence of sex-specific and population-specific differences in OD. Furthermore, these results provide positional information that will facilitate the use of targeted next-generation sequencing to search for genes that contribute to sex-specific differences in OD. PMID:27762075

Allelic loss and linkage studies in prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, D.R.; Bale, A.E.; Lytton, B.

1994-09-01

Prostate cancer is the most common malignancy in U.S. males. Many examples of familial aggregation have been reported, and segregration analysis suggests that an autosomal dominant gene with a penetrance of 88% by age 85 accounts for 9% of all cases. Because many dominant cancer predisposition syndromes are related to germline mutations in tumor suppressor genes, we analyzed a series of sporadic and hereditary tumors for allelic loss. High grade sporadic, paraffin-embedded, primary prostate tumors were obtained from the archival collection in the Department of Pathology at Yale and hereditary tumors from three families were obtained by an advertisement inmore » the New York Times and from referrals by urologists. PCR analysis showed loss in 4/7 informative sporadic prostate tumors with NEFL (8p21), in 8/22 informative tumors with D10S169 (10q26-qter), in 2/8 informative tumors with D10S108 (10q) and in 4/23 informative tumors with D10S89 (10p) in agreement with previous studies. PYGM on chromosome 11 and D9S127 on chromosome 9 showed no loss. Linkage analysis with NEFL in 3 prostate cancer families gave strongly negative results for close linkage (Z=-2.1 at {theta}=0.01) but LOD scores were very dependent on parameters, e.g. gene frequency, phenocopy rate, and penetrance. Linkage analysis with chromosome 10 markers and systematic analysis of the genome for other area of allelic loss are underway.« less

For the Common Good. A Guide for Developing Local Interagency Linkage Teams.

ERIC Educational Resources Information Center

Imel, Susan

Developed from the Ohio At-Risk Linkage Team experiences, this guide assists local communities in organizing and strengthening effective collaborative interagency linkage teams for at-risk youth and adults. The guide proposes a series of steps, poses a number of questions relating to each step, and provides information about additional resources.…

Disequilibrium dynamics in a Keynesian model with time delays

NASA Astrophysics Data System (ADS)

Gori, Luca; Guerrini, Luca; Sodini, Mauro

2018-05-01

The aim of this research is to analyse a Keynesian goods market closed economy by considering a continuous-time setup with fixed delays. The work compares dynamic results based on linear and nonlinear adjustment mechanisms through which the aggregate supply (production) reacts to a disequilibrium in the goods market and consumption depends on income at a preceding date. Both analytical and geometrical (stability switching curves) techniques are used to characterise the stability properties of the stationary equilibrium.

DXS10011: studies on structure, allele distribution in three populations and genetic linkage to further q-telomeric chromosome X markers.

PubMed

Hering, Sandra; Brundirs, Nicola; Kuhlisch, Eberhard; Edelmann, Jeanett; Plate, Ines; Benecke, Mark; Van, Pham Hung; Michael, Matthias; Szibor, Reinhard

2004-12-01

The hypervariable tetranucleotide STR polymorphism DXS10011 is a powerful marker for forensic purposes. Investigation of this STR led to an allele nomenclature which is in consensus with the ISFG recommendations. DXS10011 is located at Xq28 and genetically closely linked to DXS7423 and DXS8377 but is unlinked to HPRTB and more distant X-chromosomal STRs. DXS10011 is a very complex marker exhibiting some structural variants within alleles of identical length. Two types of repeat structure (regular and inter-alleles) are known and described as types A and B. Two SNPs which are in strong linkage disequilibrium to the different sequence types were found in the repeat flanking region. The type A sequence consists of a long stretch of uninterrupted homogenous repeats which is highly susceptible to slippage mutation during male meiosis.

Use of Genome Sequence Information for Meat Quality Trait QTL Mining for Causal Genes and Mutations on Pig Chromosome 17

PubMed Central

Hu, Zhi-Liang; Ramos, Antonio M.; Humphray, Sean J.; Rogers, Jane; Reecy, James M.; Rothschild, Max F.

2011-01-01

The newly available pig genome sequence has provided new information to fine map quantitative trait loci (QTL) in order to eventually identify causal variants. With targeted genomic sequencing efforts, we were able to obtain high quality BAC sequences that cover a region on pig chromosome 17 where a number of meat quality QTL have been previously discovered. Sequences from 70 BAC clones were assembled to form an 8-Mbp contig. Subsequently, we successfully mapped five previously identified QTL, three for meat color and two for lactate related traits, to the contig. With an additional 25 genetic markers that were identified by sequence comparison, we were able to carry out further linkage disequilibrium analysis to narrow down the genomic locations of these QTL, which allowed identification of the chromosomal regions that likely contain the causative variants. This research has provided one practical approach to combine genetic and molecular information for QTL mining. PMID:22303339

Phylogeography of haplotypes of five microsatellites located in a low-recombination region of the X chromosome: studies worldwide and in Brazilian populations.

PubMed

Pereira, Rinaldo Wellerson; Pena, Sérgio D J

2006-01-01

We studied five microsatellites (DXS995, DXS8076, DXS8114, DXS1002 and DXS1050) located in a region of very low recombination rate in the long arm of the human X chromosome (Xq13.3-Xq21.3). No recombination was seen in 291 meioses in CEPH families. To test whether haplotypes composed of the five microsatellites could differentiate among distinct human continental populations, we studied an international panel containing 72 males from Africa, Europe, Asia and the America. Haplotypic diversity was very high within these groups and no haplotypes were shared among them. This led to the hope that we might be able to identify continent-specific lineages. However, in a median joining network there was no clear discrimination of the different continental groups. We then tested whether we could identify X chromosomal lineages from different continental origins in Brazilians. We typed 180 white Brazilians from four different geographical regions and examined their proportions of haplotype sharing with Africans, Asians, Europeans and Amerindians. No phylogeographical patterns emerged from the data. Moreover, there were several instances of the same haplotype being shared by many (and in one instance all) groups, suggesting that recombination might be occurring. We thus studied pairwise the level of linkage disequilibrium (LD) between the microsatellites. No detectable linkage disequilibrium between the most external loci DXS995 and DXS1050 was observed. Thus, even though recombination may be absent on short time spans, as seen in the CEPH pedigrees, on a long term basis it occurs often enough to dissipate all linkage disequilibrium. On the other hand, we observed very strong linkage disequilibrium between the pairs DXS995/DXS8076 and DXS1002/DXS8114, raising the possibility of resequencing the segment between them to identify single nucleotide polymorphisms (SNPs) in their intervals. The combination of X-linked microsatellites and SNPs in strong linkage disequilibrium might

Effects of the Ordering of Natural Selection and Population Regulation Mechanisms on Wright-Fisher Models

PubMed Central

He, Zhangyi; Beaumont, Mark; Yu, Feng

2017-01-01

We explore the effect of different mechanisms of natural selection on the evolution of populations for one- and two-locus systems. We compare the effect of viability and fecundity selection in the context of the Wright-Fisher model with selection under the assumption of multiplicative fitness. We show that these two modes of natural selection correspond to different orderings of the processes of population regulation and natural selection in the Wright-Fisher model. We find that under the Wright-Fisher model these two different orderings can affect the distribution of trajectories of haplotype frequencies evolving with genetic recombination. However, the difference in the distribution of trajectories is only appreciable when the population is in significant linkage disequilibrium. We find that as linkage disequilibrium decays the trajectories for the two different models rapidly become indistinguishable. We discuss the significance of these findings in terms of biological examples of viability and fecundity selection, and speculate that the effect may be significant when factors such as gene migration maintain a degree of linkage disequilibrium. PMID:28500051

A deeper look at two concepts of measuring gene-gene interactions: logistic regression and interaction information revisited.

PubMed

Mielniczuk, Jan; Teisseyre, Paweł

2018-03-01

Detection of gene-gene interactions is one of the most important challenges in genome-wide case-control studies. Besides traditional logistic regression analysis, recently the entropy-based methods attracted a significant attention. Among entropy-based methods, interaction information is one of the most promising measures having many desirable properties. Although both logistic regression and interaction information have been used in several genome-wide association studies, the relationship between them has not been thoroughly investigated theoretically. The present paper attempts to fill this gap. We show that although certain connections between the two methods exist, in general they refer two different concepts of dependence and looking for interactions in those two senses leads to different approaches to interaction detection. We introduce ordering between interaction measures and specify conditions for independent and dependent genes under which interaction information is more discriminative measure than logistic regression. Moreover, we show that for so-called perfect distributions those measures are equivalent. The numerical experiments illustrate the theoretical findings indicating that interaction information and its modified version are more universal tools for detecting various types of interaction than logistic regression and linkage disequilibrium measures. © 2017 WILEY PERIODICALS, INC.

Combined linkage and association analyses identify a novel locus for obesity near PROX1 in Asians.

PubMed

Kim, Hyun-Jin; Yoo, Yun Joo; Ju, Young Seok; Lee, Seungbok; Cho, Sung-Il; Sung, Joohon; Kim, Jong-Il; Seo, Jeong-Sun

2013-11-01

Although genome-wide association studies (GWAS) have substantially contributed to understanding the genetic architecture, unidentified variants for complex traits remain an issue. One of the efficient approaches is the improvement of the power of GWAS scan by weighting P values with prior linkage signals. Our objective was to identify the novel candidates for obesity in Asian populations by using genemapping strategies that combine linkage and association analyses. To obtain linkage information for body mass index (BMI) and waist circumference (WC), we performed a multipoint genome-wide linkage study in an isolated Mongolian sample of 1,049 individuals from 74 families. Next, a family-based GWAS, which integrates within- and between-family components, was performed using the genotype data of 756 individuals of the Mongolian sample, and P values for association were weighted using linkage information obtained previously. For both BMI (LOD = 3.3) and WC (LOD = 2.6), the highest linkage peak was discovered at chromosome 10q11.22. In family-based GWAS combined with linkage information, six single-nucleotide polymorphisms (SNPs) for BMI and five SNPs for WC reached a significant level of association (linkage weighted P < 1 × 10(-5) ). Of these, only one of the SNPs associated with WC (rs1704198) was replicated in 327 Korean families comprising 1,301 individuals. This SNP was located in the proximity of the prosperorelated homeobox 1 (PROX1) gene, the function of which was validated previously in a mouse model. Our powerful strategic analysis enabled the discovery of a novel candidate gene, PROX1, associated with WC in an Asian population. Copyright © 2012 The Obesity Society.

Sex-specific linkage scans in opioid dependence.

PubMed

Yang, Bao-Zhu; Han, Shizhong; Kranzler, Henry R; Palmer, Abraham A; Gelernter, Joel

2017-04-01

Sex influences risk for opioid dependence (OD). We hypothesized that sex might interact with genetic loci that influence the risk for OD. Therefore we performed an analysis to identify sex-specific genomic susceptibility regions for OD using linkage. Over 6,000 single nucleotide polymorphism (SNP) markers were genotyped for 1,758 African- and European-American (AA and EA) individuals from 739 families, ascertained via affected sib-pairs with OD and/or cocaine dependence. Autosomewide non-parametric linkage scans, stratified by sex and population, were performed. We identified one significant linkage region, segregating with OD in EA men, at 71.1 cM on chromosome 4 (LOD = 3.29; point-wise P = 0.00005; empirical autosome-wide P = 0.042), which significantly differed from the linkage signal at the same location in EA women (empirical P = 0.002). Three suggestive linkage signals were identified at 181.3 cM on chromosome 7 (LOD = 2.18), 104 cM on chromosome 11 (LOD = 1.85), and 60.9 cM on chromosome 16 (LOD = 1.93) in EA women. In AA men, four suggestive linkage signals were detected at 201.1 cM on chromosome 3 (LOD = 2.32), 152.9 cM on chromosome 6 (LOD = 1.86), 16.8 cM on chromosome 7 (LOD = 1.95), and 36.1 cM on chromosome 17 (LOD = 1.99). The significant region, mapping to 4q12-4q13.1, harbors several OD candidate genes with interconnected functionality, including VEGFR, CLOCK, PDCL2, NMU, NRSF, and IGFBP7. In conclusion, these results provide an evidence for the existence of sex-specific and population-specific differences in OD. Furthermore, these results provide positional information that will facilitate the use of targeted next-generation sequencing to search for genes that contribute to sex-specific differences in OD. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The acceptability of conducting data linkage research without obtaining consent: lay people's views and justifications.

PubMed

Xafis, Vicki

2015-11-17

A key ethical issue arising in data linkage research relates to consent requirements. Patients' consent preferences in the context of health research have been explored but their consent preferences regarding data linkage specifically have been under-explored. In addition, the views on data linkage are often those of patient groups. As a result, little is known about lay people's views and their preferences about consent requirements in the context of data linkage. This study explores lay people's views and justifications regarding the acceptability of conducting data linkage research without obtaining consent. A qualitative study explored lay people's views regarding consent requirements in data linkage via four hypothetical data linkage scenarios of increasing complexity. Prior to considering the scenarios, participants were provided with information regarding best practice data linkage processes via discussion and a diagrammatic representation of the process. Lay people were able to understand the intricate processes involved in data linkage and the key protections afforded within a short amount of time. They were supportive of data linkage research and, on the whole, believed it should be conducted without consent provided a data linkage organization de-identifies the data used so that researchers do not handle identifiable data. Many thought that de-identified data holds a different status to identifiable data and should be used without specific consent in research that aims to benefit society. In weighing up conflicting values and interests, participants shifted consent preferences before arriving at their final consent preference for each scenario and provided justifications for their choices. They considered the protection of people's information, societal benefits, and the nature and constraints of research and recognized that these need to be balanced. With some exposure to the features of data linkage, lay people have the capacity to understand the

Molecular Variation of Adh and P6 Genes in an African Population of Drosophila Melanogaster and Its Relation to Chromosomal Inversions

PubMed Central

Benassi, V.; Aulard, S.; Mazeau, S.; Veuille, M.

1993-01-01

Four-cutter molecular polymorphism of Adh and P6, and chromosome inversion polymorphism of chromosome II were investigated in 95 isogenic lines of an Ivory Coast population of Drosophila melanogaster, a species assumed to have recently spread throughout the world from a West African origin. The P6 gene showed little linkage disequilibrium with the In(2L)t inversion, although it is located within this inversion. This suggests that the inversion and the P6 locus have extensively exchanged genetic information through either double crossover or gene conversion. Allozymic variation in ADH was in linkage disequilibrium with In(2L)t and In(2R)NS inversions. Evidence suggests either that inversion linkage with the Fast allele is selectively maintained, or that this allele only recently appeared. Molecular polymorphism at the Adh locus in the Ivory Coast is not higher than in North American populations. New haplotypes specific to the African population were found, some of them connect the ``Wa(s)-like'' haplotypes found at high frequencies in the United States to the other slow haplotypes. Their relation with In(2L)t supports the hypothesis that Wa(s) recently recombined away from an In(2L)t chromosome which may be the cause of its divergence from the other haplotypes. PMID:8349110

Mitochondrial FAD-glycerophosphate dehydrogenase and G-protein-coupled inwardly rectifying K+ channel: No evidence for linkage in maturity-onset diabetes of the young or NIDDM.

PubMed

Warren-Perry, M G; Stoffel, M; Saker, P J; Zhang, Y; Brown, L J; MacDonald, M J; Turner, R C

1996-05-01

Two genes that have potentially important regulatory roles in insulin secretion are both located on chromosome 2q24.1. G-protein-coupled muscarinic potassium channel (GIRK1) is an inwardly rectifying K+ channel that helps to maintain the resting potential and excitability of cells. Mitochondrial FAD-linked glycerophosphate dehydrogenase (m-GDH) catalyzes a rate-limiting step of the glycerol phosphate shuttle in pancreatic islets. Reduced m-GDH activity has been demonstrated in islets isolated from diabetic subjects compared with islets from nondiabetic control subjects and from the diabetic GK rat. To study the relationship between these candidate genes and NIDDM, we have examined a simple tandem-repeat polymorphism (STRP) close to both the KCN J3 (GIRK1) locus and the m-GDH locus. In a linkage study of three maturity-onset diabetes of the young (MODY) pedigrees, not linked to MODY1, MODY2, or MODY3, a cumulative score of - 9.6 at a recombination fraction of theta = 0 excluded linkage. In a population-association study, no linkage disequilibrium for the STRP was found between 190 unselected NIDDM patients and 60 geographically and age-matched white nondiabetic subjects (chi2 = 1.51 on 3 df, P = 0.68). Thus, mutations involving the genes for GIRK1 or FAD-glycerophosphate dehydrogenase are unlikely to cause MODY, and a common mutation in either gene is unlikely to contribute to NIDDM in whites. These data do not exclude mutations in some families or other ethnic groups.

A model that helps explain Sr-isotope disequilibrium between feldspar phenocrysts and melt in large-volume silicic magma systems

USGS Publications Warehouse

Duffield, W.A.; Ruiz, J.

1998-01-01

Feldspar phenocrysts of silicic volcanic rocks are commonly in Sr-isotopic disequilibrium with groundmass. In some cases the feldspar is more radiogenic, and in others it is less radiogenic. Several explanations have been published previously, but none of these is able to accommodate both senses of disequilibrium. We present a model by which either more- or less-radiogenic feldspar (or even both within a single eruptive unit) can originate. The model requires a magma body open to interaction with biotite- and feldspar-bearing wall rock. Magma is incrementally contaminated as wall rock melts incongruently. Biotite preferentially melts first, followed by feldspar. Such melting behavior, which is supported by both field and experimental studies, first contaminates magma with a relatively radiogenic addition, followed by a less-radiogenic addition. Feldspar phenocrysts lag behind melt (groundmass of volcanic rock) in incorporating the influx of contaminant, thus resulting in Sr-isotopic disequilibrium between the crystals and melt. The sense of disequilibrium recorded in a volcanic rock depends on when eruption quenches the contamination process. This model is testable by isotopic fingerprinting of individual feldspar crystals. For a given set of geologic boundary conditions, specific core-to-rim Sr-isotopic profiles are expectable. Moreover, phenocrysts that nucleate at different times during the contamination process should record different and predictable parts of the history. Initial results of Sr-isotopic fingerprinting of sanidine phenocrysts from the Taylor Creek Rhyolite are consistent with the model. More tests of the model are desirable.Feldspar phenocrysts of silicic volcanic rocks are commonly in Sr-isotopic disequilibrium with groundmass. In some cases the feldspar is more radiogenic, and in others it is less radiogenic. Several explanations have been published previously, but none of these is able to accommodate both senses of disequilibrium. We present a

Multiple loci on 8q24 associated with prostate cancer susceptibility.

PubMed

Al Olama, Ali Amin; Kote-Jarai, Zsofia; Giles, Graham G; Guy, Michelle; Morrison, Jonathan; Severi, Gianluca; Leongamornlert, Daniel A; Tymrakiewicz, Malgorzata; Jhavar, Sameer; Saunders, Ed; Hopper, John L; Southey, Melissa C; Muir, Kenneth R; English, Dallas R; Dearnaley, David P; Ardern-Jones, Audrey T; Hall, Amanda L; O'Brien, Lynne T; Wilkinson, Rosemary A; Sawyer, Emma; Lophatananon, Artitaya; Horwich, Alan; Huddart, Robert A; Khoo, Vincent S; Parker, Christopher C; Woodhouse, Christopher J; Thompson, Alan; Christmas, Tim; Ogden, Chris; Cooper, Colin; Donovan, Jenny L; Hamdy, Freddie C; Neal, David E; Eeles, Rosalind A; Easton, Douglas F

2009-10-01

Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility.

Ensuring Privacy When Integrating Patient-Based Datasets: New Methods and Developments in Record Linkage.

PubMed

Brown, Adrian P; Ferrante, Anna M; Randall, Sean M; Boyd, James H; Semmens, James B

2017-01-01

In an era where the volume of structured and unstructured digital data has exploded, there has been an enormous growth in the creation of data about individuals that can be used for understanding and treating disease. Joining these records together at an individual level provides a complete picture of a patient's interaction with health services and allows better assessment of patient outcomes and effectiveness of treatment and services. Record linkage techniques provide an efficient and cost-effective method to bring individual records together as patient profiles. These linkage procedures bring their own challenges, especially relating to the protection of privacy. The development and implementation of record linkage systems that do not require the release of personal information can reduce the risks associated with record linkage and overcome legal barriers to data sharing. Current conceptual and experimental privacy-preserving record linkage (PPRL) models show promise in addressing data integration challenges. Enhancing and operationalizing PPRL protocols can help address the dilemma faced by some custodians between using data to improve quality of life and dealing with the ethical, legal, and administrative issues associated with protecting an individual's privacy. These methods can reduce the risk to privacy, as they do not require personally identifying information to be shared. PPRL methods can improve the delivery of record linkage services to the health and broader research community.

Ensuring Privacy When Integrating Patient-Based Datasets: New Methods and Developments in Record Linkage

PubMed Central

Brown, Adrian P.; Ferrante, Anna M.; Randall, Sean M.; Boyd, James H.; Semmens, James B.

2017-01-01

In an era where the volume of structured and unstructured digital data has exploded, there has been an enormous growth in the creation of data about individuals that can be used for understanding and treating disease. Joining these records together at an individual level provides a complete picture of a patient’s interaction with health services and allows better assessment of patient outcomes and effectiveness of treatment and services. Record linkage techniques provide an efficient and cost-effective method to bring individual records together as patient profiles. These linkage procedures bring their own challenges, especially relating to the protection of privacy. The development and implementation of record linkage systems that do not require the release of personal information can reduce the risks associated with record linkage and overcome legal barriers to data sharing. Current conceptual and experimental privacy-preserving record linkage (PPRL) models show promise in addressing data integration challenges. Enhancing and operationalizing PPRL protocols can help address the dilemma faced by some custodians between using data to improve quality of life and dealing with the ethical, legal, and administrative issues associated with protecting an individual’s privacy. These methods can reduce the risk to privacy, as they do not require personally identifying information to be shared. PPRL methods can improve the delivery of record linkage services to the health and broader research community. PMID:28303240

Efficient Record Linkage Algorithms Using Complete Linkage Clustering

PubMed Central

Mamun, Abdullah-Al; Aseltine, Robert; Rajasekaran, Sanguthevar

2016-01-01

Data from different agencies share data of the same individuals. Linking these datasets to identify all the records belonging to the same individuals is a crucial and challenging problem, especially given the large volumes of data. A large number of available algorithms for record linkage are prone to either time inefficiency or low-accuracy in finding matches and non-matches among the records. In this paper we propose efficient as well as reliable sequential and parallel algorithms for the record linkage problem employing hierarchical clustering methods. We employ complete linkage hierarchical clustering algorithms to address this problem. In addition to hierarchical clustering, we also use two other techniques: elimination of duplicate records and blocking. Our algorithms use sorting as a sub-routine to identify identical copies of records. We have tested our algorithms on datasets with millions of synthetic records. Experimental results show that our algorithms achieve nearly 100% accuracy. Parallel implementations achieve almost linear speedups. Time complexities of these algorithms do not exceed those of previous best-known algorithms. Our proposed algorithms outperform previous best-known algorithms in terms of accuracy consuming reasonable run times. PMID:27124604

Efficient Record Linkage Algorithms Using Complete Linkage Clustering.

PubMed

Mamun, Abdullah-Al; Aseltine, Robert; Rajasekaran, Sanguthevar

2016-01-01

Data from different agencies share data of the same individuals. Linking these datasets to identify all the records belonging to the same individuals is a crucial and challenging problem, especially given the large volumes of data. A large number of available algorithms for record linkage are prone to either time inefficiency or low-accuracy in finding matches and non-matches among the records. In this paper we propose efficient as well as reliable sequential and parallel algorithms for the record linkage problem employing hierarchical clustering methods. We employ complete linkage hierarchical clustering algorithms to address this problem. In addition to hierarchical clustering, we also use two other techniques: elimination of duplicate records and blocking. Our algorithms use sorting as a sub-routine to identify identical copies of records. We have tested our algorithms on datasets with millions of synthetic records. Experimental results show that our algorithms achieve nearly 100% accuracy. Parallel implementations achieve almost linear speedups. Time complexities of these algorithms do not exceed those of previous best-known algorithms. Our proposed algorithms outperform previous best-known algorithms in terms of accuracy consuming reasonable run times.

Ecological disequilibrium drives insect pest and pathogen accumulation in non-native trees

PubMed Central

Burgess, Treena I.; Le Roux, Johannes J.; Richardson, David M.; Slippers, Bernard; Wingfield, Michael J.

2017-01-01

Abstract Non-native trees have become dominant components of many landscapes, including urban ecosystems, commercial forestry plantations, fruit orchards and as invasives in natural ecosystems. Often, these trees have been separated from their natural enemies (i.e. insects and pathogens) leading to ecological disequilibrium, that is, the immediate breakdown of historically co-evolved interactions once introduced into novel environments. Long-established, non-native tree plantations provide useful experiments to explore the dimensions of such ecological disequilibria. We quantify the status quo of non-native insect pests and pathogens catching up with their tree hosts (planted Acacia, Eucalyptus and Pinus species) in South Africa, and examine which native South African enemy species utilize these trees as hosts. Interestingly, pines, with no confamilial relatives in South Africa and the longest residence time (almost two centuries), have acquired only one highly polyphagous native pathogen. This is in contrast to acacias and eucalypts, both with many native and confamilial relatives in South Africa that have acquired more native pathogens. These patterns support the known role of phylogenetic relatedness of non-native and native floras in influencing the likelihood of pathogen shifts between them. This relationship, however, does not seem to hold for native insects. Native insects appear far more likely to expand their feeding habits onto non-native tree hosts than are native pathogens, although they are generally less damaging. The ecological disequilibrium conditions of non-native trees are deeply rooted in the eco-evolutionary experience of the host plant, co-evolved natural enemies and native organisms from the introduced range. We should expect considerable spatial and temporal variation in ecological disequilibrium conditions among non-native taxa, which can be significantly influenced by biosecurity and management practices. PMID:28013250

Uranium disequilibrium in groundwater: An isotope dilution approach in hydrologic investigations

USGS Publications Warehouse

Osmond, J.K.; Rydell, H.S.; Kaufman, M.I.

1968-01-01

The distribution and environmental disequilibrium patterns of naturally occurring uranium isotopes (U234 and U238) in waters of the Floridan aquifer suggest that variations in the ratios of isotopic activity and concentrations can be used quantitatively to evaluate mixing proportions of waters from differing sources. Uranium is probably unique in its potential for this approach, which seems to have general usefulness in hydrologic investigations.

Allele-sharing models: LOD scores and accurate linkage tests.

PubMed

Kong, A; Cox, N J

1997-11-01

Starting with a test statistic for linkage analysis based on allele sharing, we propose an associated one-parameter model. Under general missing-data patterns, this model allows exact calculation of likelihood ratios and LOD scores and has been implemented by a simple modification of existing software. Most important, accurate linkage tests can be performed. Using an example, we show that some previously suggested approaches to handling less than perfectly informative data can be unacceptably conservative. Situations in which this model may not perform well are discussed, and an alternative model that requires additional computations is suggested.

Allele-sharing models: LOD scores and accurate linkage tests.

PubMed Central

Kong, A; Cox, N J

1997-01-01

Starting with a test statistic for linkage analysis based on allele sharing, we propose an associated one-parameter model. Under general missing-data patterns, this model allows exact calculation of likelihood ratios and LOD scores and has been implemented by a simple modification of existing software. Most important, accurate linkage tests can be performed. Using an example, we show that some previously suggested approaches to handling less than perfectly informative data can be unacceptably conservative. Situations in which this model may not perform well are discussed, and an alternative model that requires additional computations is suggested. PMID:9345087

Linkage and association of haplotypes at the APOA1/C3/A4/A5 genecluster to familial combined hyperlipidemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eichenbaum-Voline, Sophie; Olivier, Michael; Jones, Emma L.

2002-09-15

Combined hyperlipidemia (CHL) is a common disorder of lipidmetabolism that leads to an increased risk of cardiovascular disease. Thelipid profile of CHL is characterised by high levels of atherogeniclipoproteins and low levels of high-density-lipoprotein-cholesterol.Apolipoprotein (APO) A5 is a newly discovered gene involved in lipidmetabolism located within 30kbp of the APOA1/C3/A4 gene cluster. Previousstudies have indicated that sequence variants in this cluster areassociated with increased plasma lipid levels. To establish whethervariation at the APOA5 gene contributes to the transmission of CHL, weperformed linkage and linkage disequilibrium (LD) tests on a large cohortof families (n=128) with familial CHL (FCHL). The linkage datamore » producedevidence for linkage of the APOA1/C3/A4/A5 genomic interval to FCHL (NPL= 1.7, P = 0.042). The LD studies substantiated these data. Twoindependent rare alleles, APOA5c.56G and APOC3c.386G of this gene clusterwere over-transmitted in FCHL (P = 0.004 and 0.007, respectively), andthis was associated with a reduced transmission of the most commonAPOA1/C3/A4/A5 haplotype (frequency 0.4425) to affected subjects (P =0.013). The APOA5c.56G allele was associated with increased plasmatriglyceride levels in FCHL probands, whereas the second, andindependent, APOC3c.386G allele was associated with increased plasmatriglyceride levels in FCHL pedigree founders. Thus, this allele (or anallele in LD) may mark a quantitative trait associated with FCHL, as wellas representing a disease susceptibility locus for the condition. Thisstudy establishes that sequence variation in the APOA1/C3/A4/A5 genecluster contributes to the transmission of FCHL in a substantialproportion of affected families, and that these sequence variants mayalso contribute to the lipid abnormalities of the metabolic syndrome,which is present in up to 40 percent of persons with cardiovasculardisease.« less

Linkage analysis of the Nail-patella syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Campeau, E.; Watkins, D.; Rouleau, G.A.

1995-01-01

Nail-patella syndrome (NPS) is an autosomal dominant disorder characterized by dysplasia of nails and patella, decreased mobility of the elbow, iliac horns, and, in some cases, nephropathy. The disorder has been mapped to the long arm of chromosome 9, but the precise localization and identity of the NPS gene are unknown. Linkage analysis in three NPS families, using highly informative dinucleotide repeat polymorphisms on 9q33-q34, confirmed linkage of NPS to this chromosome. Recombinations were detected, by two-point linkage analysis, between NPS and the centromeric markers D9S60 and the gelsolin gene and the telomeric markers D9S64 and D9S66, in one ofmore » the families. Haplotype analysis suggested an additional recombination between NPS and the argininosuccinate synthetase (ASS) gene. These results localize the NPS gene to an interval on 9q34.1, distal to D9S60 an proximal to ASS, comprising a genetic distance of {approximately}9 cM. This represents a significant refinement in the localization of the NPS gene. 25 refs., 2 figs., 1 tab.« less

Increased risk of suicide in schizophrenia patients with linkage to chromosome 13q.

PubMed

Malherbe, P J; Karayiorgou, M; Ehlers, R; Roos, J L

2017-05-01

We link schizophrenia in families from the genetically isolated South African Afrikaner population to chromosome 13q (n =51), 1p (n =23) and combined 13q & 1p (n =18). Patients with linkages to chromosome 13q were 4.16 times more likely to meet diagnostic criteria for schizoaffective disorder compared to patients with linkage to 1p. A third of patients with linkage to both 13q &1p met diagnostic criteria for SAD. There was a significant positive relationship between suicidality and a diagnosis of schizoaffective disorder. Identifying linkage to chromosome 13q may be informative in identifying suicide risk early and prevent morbidity and mortality in schizophrenia patients. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Toward allotetraploid cotton genome assembly: integration of a high-density molecular genetic linkage map with DNA sequence information

PubMed Central

2012-01-01

Background Cotton is the world’s most important natural textile fiber and a significant oilseed crop. Decoding cotton genomes will provide the ultimate reference and resource for research and utilization of the species. Integration of high-density genetic maps with genomic sequence information will largely accelerate the process of whole-genome assembly in cotton. Results In this paper, we update a high-density interspecific genetic linkage map of allotetraploid cultivated cotton. An additional 1,167 marker loci have been added to our previously published map of 2,247 loci. Three new marker types, InDel (insertion-deletion) and SNP (single nucleotide polymorphism) developed from gene information, and REMAP (retrotransposon-microsatellite amplified polymorphism), were used to increase map density. The updated map consists of 3,414 loci in 26 linkage groups covering 3,667.62 cM with an average inter-locus distance of 1.08 cM. Furthermore, genome-wide sequence analysis was finished using 3,324 informative sequence-based markers and publicly-available Gossypium DNA sequence information. A total of 413,113 EST and 195 BAC sequences were physically anchored and clustered by 3,324 sequence-based markers. Of these, 14,243 ESTs and 188 BACs from different species of Gossypium were clustered and specifically anchored to the high-density genetic map. A total of 2,748 candidate unigenes from 2,111 ESTs clusters and 63 BACs were mined for functional annotation and classification. The 337 ESTs/genes related to fiber quality traits were integrated with 132 previously reported cotton fiber quality quantitative trait loci, which demonstrated the important roles in fiber quality of these genes. Higher-level sequence conservation between different cotton species and between the A- and D-subgenomes in tetraploid cotton was found, indicating a common evolutionary origin for orthologous and paralogous loci in Gossypium. Conclusion This study will serve as a valuable genomic resource

Young people's views about consenting to data linkage: findings from the PEARL qualitative study.

PubMed

Audrey, Suzanne; Brown, Lindsey; Campbell, Rona; Boyd, Andy; Macleod, John

2016-03-21

Electronic administrative data exist in several domains which, if linked, are potentially useful for research. However, benefits from data linkage should be considered alongside risks such as the threat to privacy. Avon Longitudinal Study of Parents and Children (ALSPAC) is a birth cohort study. The Project to Enhance ALSPAC through Record Linkage (PEARL) was established to enrich the ALSPAC resource through linkage between ALSPAC participants and routine sources of health and social data. Qualitative research was incorporated in the PEARL study to examine participants' views about data linkage and inform approaches to information sharing. This paper focusses on issues of consent. Digitally recorded interviews were conducted with 55 participants aged 17-19 years. Terms and processes relating to consent, anonymization and data linkage were explained to interviewees. Scenarios were used to prompt consideration of linking different sources of data, and whether consent should be requested. Interview recordings were fully transcribed. Thematic analysis was undertaken using the Framework approach. Participant views on data linkage appeared to be most influenced by: considerations around the social sensitivity of the research question, and; the possibility of tangible health benefits in the public interest. Some participants appeared unsure about the effectiveness of anonymization, or did not always view effective anonymization as making consent unnecessary. This was related to notions of ownership of personal information and etiquette around asking permission for secondary use. Despite different consent procedures being explained, participants tended to equate consent with 'opt-in' consent through which participants are 'asked' if their data can be used for a specific study. Participants raising similar concerns came to differing conclusions about whether consent was needed. Views changed when presented with different scenarios, and were sometimes inconsistent. Findings

Unconsciously Indigenous Leadership: The Role of Cognitive Disequilibrium in Preparing Democratic Educational Leaders

ERIC Educational Resources Information Center

Farmer, Tod Allen

2008-01-01

This paper focuses on the role of cognitive disequilibrium in preparing democratic educational leaders. Followers emerge into leaders with what are many times unconsciously socialized norms and values indigenous to their local culture. One of the roles of a democratic leadership preparation program is to challenge these unconsciously accepted…

A comparison of accuracy and computational feasibility of two record linkage algorithms in retrieving vital status information from HIV/AIDS patients registered in Brazilian public databases.

PubMed

de Paula, Adelzon Assis; Pires, Denise Franqueira; Filho, Pedro Alves; de Lemos, Kátia Regina Valente; Barçante, Eduardo; Pacheco, Antonio Guilherme

2018-06-01

While cross-referencing information from people living with HIV/AIDS (PLWHA) to the official mortality database is a critical step in monitoring the HIV/AIDS epidemic in Brazil, the accuracy of the linkage routine may compromise the validity of the final database, yielding to biased epidemiological estimates. We compared the accuracy and the total runtime of two linkage algorithms applied to retrieve vital status information from PLWHA in Brazilian public databases. Nominally identified records from PLWHA were obtained from three distinct government databases. Linkage routines included an algorithm in Python language (PLA) and Reclink software (RlS), a probabilistic software largely utilized in Brazil. Records from PLWHA 1 known to be alive were added to those from patients reported as deceased. Data were then searched into the mortality system. Scenarios where 5% and 50% of patients actually dead were simulated, considering both complete cases and 20% missing maternal names. When complete information was available both algorithms had comparable accuracies. In the scenario of 20% missing maternal names, PLA 2 and RlS 3 had sensitivities of 94.5% and 94.6% (p > 0.5), respectively; after manual reviewing, PLA sensitivity increased to 98.4% (96.6-100.0) exceeding that for RlS (p < 0.01). PLA had higher positive predictive value in 5% death proportion. Manual reviewing was intrinsically required by RlS in up to 14% register for people actually dead, whereas the corresponding proportion ranged from 1.5% to 2% for PLA. The lack of manual inspection did not alter PLA sensitivity when complete information was available. When incomplete data was available PLA sensitivity increased from 94.5% to 98.4%, thus exceeding that presented by RlS (94.6%, p < 0.05). RlS spanned considerably less processing time compared to PLA. Both linkage algorithms presented interchangeable accuracies in retrieving vital status data from PLWHA. RlS had a considerably lesser runtime but

Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait.

PubMed

Dubé, M P; Mlodzienski, M A; Kibar, Z; Farlow, M R; Ebers, G; Harper, P; Kolodny, E H; Rouleau, G A; Figlewicz, D A

1997-03-01

Hereditary spastic paraplegia (HSP) is a degenerative disorder of the motor system, defined by progressive weakness and spasticity of the lower limbs. HSP may be inherited as an autosomal dominant (AD), autosomal recessive, or an X-linked trait. AD HSP is genetically heterogeneous, and three loci have been identified so far: SPG3 maps to chromosome 14q, SPG4 to 2p, and SPG4a to 15q. We have undertaken linkage analysis with 21 uncomplicated AD families to the three AD HSP loci. We report significant linkage for three of our families to the SPG4 locus and exclude several families by multipoint linkage. We used linkage information from several different research teams to evaluate the statistical probability of linkage to the SPG4 locus for uncomplicated AD HSP families and established the critical LOD-score value necessary for confirmation of linkage to the SPG4 locus from Bayesian statistics. In addition, we calculated the empirical P-values for the LOD scores obtained with all families with computer simulation methods. Power to detect significant linkage, as well as type I error probabilities, were evaluated. This combined analytical approach permitted conclusive linkage analyses on small to medium-size families, under the restrictions of genetic heterogeneity.

Environmental Scientists' Perceptions of the Science-Policy Linkage.

ERIC Educational Resources Information Center

Alm, Leslie R.; Simon, Marc

2001-01-01

Describes the criticisms coming from scientists on the assessment report on acid rain released by the National Acid Preparation Assessment Program (NAPAP) with the purpose of providing relevant information to policy makers about acid rain. Investigates n=129 scientists' point of view on the linkage of science to policy. (YDS)

Base-Catalyzed Linkage Isomerization: An Undergraduate Inorganic Kinetics Experiment.

ERIC Educational Resources Information Center

Jackson, W. G.; And Others

1981-01-01

Describes kinetics experiments completed in a single two-hour laboratory period at 25 degrees Centigrade of nitrito to nitro rearrangement, based on the recently discovered base-catalysis path. Includes information on synthesis and characterization of linkage isomers, spectrophotometric techniques, and experimental procedures. (SK)

Generalized disequilibrium test for association in qualitative traits incorporating imprinting effects based on extended pedigrees.

PubMed

Li, Jian-Long; Wang, Peng; Fung, Wing Kam; Zhou, Ji-Yuan

2017-10-16

For dichotomous traits, the generalized disequilibrium test with the moment estimate of the variance (GDT-ME) is a powerful family-based association method. Genomic imprinting is an important epigenetic phenomenon and currently, there has been increasing interest of incorporating imprinting to improve the test power of association analysis. However, GDT-ME does not take imprinting effects into account, and it has not been investigated whether it can be used for association analysis when the effects indeed exist. In this article, based on a novel decomposition of the genotype score according to the paternal or maternal source of the allele, we propose the generalized disequilibrium test with imprinting (GDTI) for complete pedigrees without any missing genotypes. Then, we extend GDTI and GDT-ME to accommodate incomplete pedigrees with some pedigrees having missing genotypes, by using a Monte Carlo (MC) sampling and estimation scheme to infer missing genotypes given available genotypes in each pedigree, denoted by MCGDTI and MCGDT-ME, respectively. The proposed GDTI and MCGDTI methods evaluate the differences of the paternal as well as maternal allele scores for all discordant relative pairs in a pedigree, including beyond first-degree relative pairs. Advantages of the proposed GDTI and MCGDTI test statistics over existing methods are demonstrated by simulation studies under various simulation settings and by application to the rheumatoid arthritis dataset. Simulation results show that the proposed tests control the size well under the null hypothesis of no association, and outperform the existing methods under various imprinting effect models. The existing GDT-ME and the proposed MCGDT-ME can be used to test for association even when imprinting effects exist. For the application to the rheumatoid arthritis data, compared to the existing methods, MCGDTI identifies more loci statistically significantly associated with the disease. Under complete and incomplete

Insights into solar nebula formation of pyrrhotite from nanoscale disequilibrium phases produced by H2S sulfidation of Fe metal

DOE PAGES

Gainsforth, Z; Lauretta, DS; Tamura, N; ...

2017-09-01

© 2017 by Walter de Gruyter Berlin/Boston. Lauretta (2005) produced sulfide in the laboratory by exposing canonical nebular metal analogs to H 2 S gas under temperatures and pressures relevant to the formation of the Solar System. The resulting reactions produced a suite of sulfides and nanophase materials not visible at the microprobe scale, but which we have now analyzed by TEM for comparison with interplanetary dust samples and comet Wild 2 samples returned by the Stardust mission. We find the unexpected result that disequilibrium formation favors pyrrhotite over troilite and also produces minority schreibersite, daubréelite, barringerite, taenite, oldhamite, andmore » perryite at the metal-sulfide interface. TEM identification of nanophases and analysis of pyrrhotite superlattice reflections illuminate the formation pathway of disequilibrium sulfide. We discuss the conditions under which such disequilibrium can occur, and implications for formation of sulfide found in extraterrestrial materials.« less

An Enhanced Linkage Map of the Sheep Genome Comprising More Than 1000 Loci

PubMed Central

Maddox, Jillian F.; Davies, Kizanne P.; Crawford, Allan M.; Hulme, Dennis J.; Vaiman, Daniel; Cribiu, Edmond P.; Freking, Bradley A.; Beh, Ken J.; Cockett, Noelle E.; Kang, Nina; Riffkin, Christopher D.; Drinkwater, Roger; Moore, Stephen S.; Dodds, Ken G.; Lumsden, Joanne M.; van Stijn, Tracey C.; Phua, Sin H.; Adelson, David L.; Burkin, Heather R.; Broom, Judith E.; Buitkamp, Johannes; Cambridge, Lisa; Cushwa, William T.; Gerard, Emily; Galloway, Susan M.; Harrison, Blair; Hawken, Rachel J.; Hiendleder, Stefan; Henry, Hannah M.; Medrano, Juan F.; Paterson, Korena A.; Schibler, Laurent; Stone, Roger T.; van Hest, Beryl

2001-01-01

A medium-density linkage map of the ovine genome has been developed. Marker data for 550 new loci were generated and merged with the previous sheep linkage map. The new map comprises 1093 markers representing 1062 unique loci (941 anonymous loci, 121 genes) and spans 3500 cM (sex-averaged) for the autosomes and 132 cM (female) on the X chromosome. There is an average spacing of 3.4 cM between autosomal loci and 8.3 cM between highly polymorphic [polymorphic information content (PIC) ≥ 0.7] autosomal loci. The largest gap between markers is 32.5 cM, and the number of gaps of >20 cM between loci, or regions where loci are missing from chromosome ends, has been reduced from 40 in the previous map to 6. Five hundred and seventy-three of the loci can be ordered on a framework map with odds of >1000 : 1. The sheep linkage map contains strong links to both the cattle and goat maps. Five hundred and seventy-two of the loci positioned on the sheep linkage map have also been mapped by linkage analysis in cattle, and 209 of the loci mapped on the sheep linkage map have also been placed on the goat linkage map. Inspection of ruminant linkage maps indicates that the genomic coverage by the current sheep linkage map is comparable to that of the available cattle maps. The sheep map provides a valuable resource to the international sheep, cattle, and goat gene mapping community. PMID:11435411

Construction of a virtual EPR and automated contextual linkage to multiple sources of support information on the Oxford Clinical Intranet.

PubMed

Kay, J D; Nurse, D

1999-01-01

We have used internet-standard tools to provide access for clinicians to the components of the electronic patient record held on multiple remote disparate systems. Through the same interface we have provided access to multiple knowledgebases, some written locally and others published elsewhere. We have developed linkage between these two types of information which removes the need for the user to drill down into each knowledgebase to search for relevant information. This approach may help in the implementation of evidence-based practice. The major problems appear to be semantic rather than technological. The intranet was developed at low cost and is now in routine use. This approach appears to be transferable across systems and organisations.

Linkage of Viral Sequences among HIV-Infected Village Residents in Botswana: Estimation of Linkage Rates in the Presence of Missing Data

PubMed Central

Carnegie, Nicole Bohme; Wang, Rui; Novitsky, Vladimir; De Gruttola, Victor

2014-01-01

Linkage analysis is useful in investigating disease transmission dynamics and the effect of interventions on them, but estimates of probabilities of linkage between infected people from observed data can be biased downward when missingness is informative. We investigate variation in the rates at which subjects' viral genotypes link across groups defined by viral load (low/high) and antiretroviral treatment (ART) status using blood samples from household surveys in the Northeast sector of Mochudi, Botswana. The probability of obtaining a sequence from a sample varies with viral load; samples with low viral load are harder to amplify. Pairwise genetic distances were estimated from aligned nucleotide sequences of HIV-1C env gp120. It is first shown that the probability that randomly selected sequences are linked can be estimated consistently from observed data. This is then used to develop estimates of the probability that a sequence from one group links to at least one sequence from another group under the assumption of independence across pairs. Furthermore, a resampling approach is developed that accounts for the presence of correlation across pairs, with diagnostics for assessing the reliability of the method. Sequences were obtained for 65% of subjects with high viral load (HVL, n = 117), 54% of subjects with low viral load but not on ART (LVL, n = 180), and 45% of subjects on ART (ART, n = 126). The probability of linkage between two individuals is highest if both have HVL, and lowest if one has LVL and the other has LVL or is on ART. Linkage across groups is high for HVL and lower for LVL and ART. Adjustment for missing data increases the group-wise linkage rates by 40–100%, and changes the relative rates between groups. Bias in inferences regarding HIV viral linkage that arise from differential ability to genotype samples can be reduced by appropriate methods for accommodating missing data. PMID:24415932

Linkage of viral sequences among HIV-infected village residents in Botswana: estimation of linkage rates in the presence of missing data.

PubMed

Carnegie, Nicole Bohme; Wang, Rui; Novitsky, Vladimir; De Gruttola, Victor

2014-01-01

Linkage analysis is useful in investigating disease transmission dynamics and the effect of interventions on them, but estimates of probabilities of linkage between infected people from observed data can be biased downward when missingness is informative. We investigate variation in the rates at which subjects' viral genotypes link across groups defined by viral load (low/high) and antiretroviral treatment (ART) status using blood samples from household surveys in the Northeast sector of Mochudi, Botswana. The probability of obtaining a sequence from a sample varies with viral load; samples with low viral load are harder to amplify. Pairwise genetic distances were estimated from aligned nucleotide sequences of HIV-1C env gp120. It is first shown that the probability that randomly selected sequences are linked can be estimated consistently from observed data. This is then used to develop estimates of the probability that a sequence from one group links to at least one sequence from another group under the assumption of independence across pairs. Furthermore, a resampling approach is developed that accounts for the presence of correlation across pairs, with diagnostics for assessing the reliability of the method. Sequences were obtained for 65% of subjects with high viral load (HVL, n = 117), 54% of subjects with low viral load but not on ART (LVL, n = 180), and 45% of subjects on ART (ART, n = 126). The probability of linkage between two individuals is highest if both have HVL, and lowest if one has LVL and the other has LVL or is on ART. Linkage across groups is high for HVL and lower for LVL and ART. Adjustment for missing data increases the group-wise linkage rates by 40-100%, and changes the relative rates between groups. Bias in inferences regarding HIV viral linkage that arise from differential ability to genotype samples can be reduced by appropriate methods for accommodating missing data.

Establishing a process for conducting cross-jurisdictional record linkage in Australia.

PubMed

Moore, Hannah C; Guiver, Tenniel; Woollacott, Anthony; de Klerk, Nicholas; Gidding, Heather F

2016-04-01

To describe the realities of conducting a cross-jurisdictional data linkage project involving state and Australian Government-based data collections to inform future national data linkage programs of work. We outline the processes involved in conducting a Proof of Concept data linkage project including the implementation of national data integration principles, data custodian and ethical approval requirements, and establishment of data flows. The approval process involved nine approval and regulatory bodies and took more than two years. Data will be linked across 12 datasets involving three data linkage centres. A framework was established to allow data to flow between these centres while maintaining the separation principle that serves to protect the privacy of the individual. This will be the first project to link child immunisation records from an Australian Government dataset to other administrative health datasets for a population cohort covering 2 million births in two Australian states. Although the project experienced some delays, positive outcomes were realised, primarily the development of strong collaborations across key stakeholder groups including community engagement. We have identified several recommendations and enhancements to this now established framework to further streamline the process for data linkage studies involving Australian Government data. © 2015 Public Health Association of Australia.

[MapDraw: a microsoft excel macro for drawing genetic linkage maps based on given genetic linkage data].

PubMed

Liu, Ren-Hu; Meng, Jin-Ling

2003-05-01

MAPMAKER is one of the most widely used computer software package for constructing genetic linkage maps.However, the PC version, MAPMAKER 3.0 for PC, could not draw the genetic linkage maps that its Macintosh version, MAPMAKER 3.0 for Macintosh,was able to do. Especially in recent years, Macintosh computer is much less popular than PC. Most of the geneticists use PC to analyze their genetic linkage data. So a new computer software to draw the same genetic linkage maps on PC as the MAPMAKER for Macintosh to do on Macintosh has been crying for. Microsoft Excel,one component of Microsoft Office package, is one of the most popular software in laboratory data processing. Microsoft Visual Basic for Applications (VBA) is one of the most powerful functions of Microsoft Excel. Using this program language, we can take creative control of Excel, including genetic linkage map construction, automatic data processing and more. In this paper, a Microsoft Excel macro called MapDraw is constructed to draw genetic linkage maps on PC computer based on given genetic linkage data. Use this software,you can freely construct beautiful genetic linkage map in Excel and freely edit and copy it to Word or other application. This software is just an Excel format file. You can freely copy it from ftp://211.69.140.177 or ftp://brassica.hzau.edu.cn and the source code can be found in Excel's Visual Basic Editor.

Demographic Disequilibrium in Early Twentieth Century Thailand: Falling Mortality, Rising Fertility, or Both?

PubMed

Carmichael, Gordon A

2008-07-17

Estimates of Thai crude birth and death rates date from 1920 when the former was around 20 per thousand higher than the latter, implying natural increase of 2 percent per annum. Such disequilibrium cannot have been the norm over the long term historical past, when population growth must have been comparatively slow. This paper explores the bases for likely past relative equilibrium between Siamese birth and death rates, then seeks to explain the disequilibrium apparent by 1920. Classic demographic transition theory postulates initially high birth and death rates, this equilibrium eventually being broken by falling mortality. In Thailand, however, there is likely to have been both significant mortality decline and appreciable fertility increase after 1850, as the virtual elimination of indigenous warfare, rapid growth of the export rice economy and the demise of slavery and corvée labour created a new domestic environment. Characterized by more dispersed, often frontier, settlement, this environment was unprecedentedly sedate and settled, afforded ordinary households a previously unknown level of control over their resources of labour, and generated optimism about prospects for the next generation.

Demographic Disequilibrium in Early Twentieth Century Thailand: Falling Mortality, Rising Fertility, or Both?

PubMed Central

Carmichael, Gordon A.

2011-01-01

Estimates of Thai crude birth and death rates date from 1920 when the former was around 20 per thousand higher than the latter, implying natural increase of 2 percent per annum. Such disequilibrium cannot have been the norm over the long term historical past, when population growth must have been comparatively slow. This paper explores the bases for likely past relative equilibrium between Siamese birth and death rates, then seeks to explain the disequilibrium apparent by 1920. Classic demographic transition theory postulates initially high birth and death rates, this equilibrium eventually being broken by falling mortality. In Thailand, however, there is likely to have been both significant mortality decline and appreciable fertility increase after 1850, as the virtual elimination of indigenous warfare, rapid growth of the export rice economy and the demise of slavery and corvée labour created a new domestic environment. Characterized by more dispersed, often frontier, settlement, this environment was unprecedentedly sedate and settled, afforded ordinary households a previously unknown level of control over their resources of labour, and generated optimism about prospects for the next generation. PMID:21966299

Equilibrium and disequilibrium chemistry of adiabatic, solar-composition planetary atmospheres

NASA Technical Reports Server (NTRS)

Lewis, J. S.

1976-01-01

The impact of atmospheric and cloud-structure models on the nonequilibrium chemical behavior of the atmospheres of the Jovian planets is discussed. Quantitative constraints on photochemical, lightning, and charged-particle production of organic matter and chromophores are emphasized whenever available. These considerations imply that inorganic chromophore production is far more important than that of organic chromophores, and that lightning is probably a negligibly significant process relative to photochemistry on Jupiter. Production of complex molecules by gas-phase disequilibrium processes on Saturn, Uranus, and Neptune is severely limited by condensation of even simple intermediates.

Neuroendocrine–immune disequilibrium and endometriosis: an interdisciplinary approach

PubMed Central

Tariverdian, Nadja; Theoharides, Theoharis C.; Siedentopf, Friederike; Gutiérrez, Gabriela; Jeschke, Udo; Rabinovich, Gabriel A.; Blois, Sandra M.

2007-01-01

Endometriosis, a chronic disease characterized by endometrial tissue located outside the uterine cavity, affects one fourth of young women and is associated with chronic pelvic pain and infertility. However, an in-depth understanding of the pathophysiology and effective treatment strategies of endometriosis is still largely elusive. Inadequate immune and neuroendocrine responses are significantly involved in the pathophysiology of endometriosis, and key findings are summarized in the present review. We discuss here the role of different immune mechanisms particularly adhesion molecules, protein–glycan interactions, and pro-angiogenic mediators in the development and progression of the disease. Finally, we introduce the concept of endometrial dissemination as result of a neuroendocrine-immune disequilibrium in response to high levels of perceived stress caused by cardinal clinical symptoms of endometriosis. PMID:17621704

Genetic Diversity of Plasmodium falciparum in Haiti: Insights from Microsatellite Markers

PubMed Central

Carter, Tamar E.; Malloy, Halley; Existe, Alexandre; Memnon, Gladys; St. Victor, Yves; Okech, Bernard A.; Mulligan, Connie J.

2015-01-01

Hispaniola, comprising Haiti and the Dominican Republic, has been identified as a candidate for malaria elimination. However, incomplete surveillance data in Haiti hamper efforts to assess the impact of ongoing malaria control interventions. Characteristics of the genetic diversity of Plasmodium falciparum populations can be used to assess parasite transmission, which is information vital to evaluating malaria elimination efforts. Here we characterize the genetic diversity of P. falciparum samples collected from patients at seven sites in Haiti using 12 microsatellite markers previously employed in population genetic analyses of global P. falciparum populations. We measured multiplicity of infections, level of genetic diversity, degree of population geographic substructure, and linkage disequilibrium (defined as non-random association of alleles from different loci). For low transmission populations like Haiti, we expect to see few multiple infections, low levels of genetic diversity, high degree of population structure, and high linkage disequilibrium. In Haiti, we found low levels of multiple infections (12.9%), moderate to high levels of genetic diversity (mean number of alleles per locus = 4.9, heterozygosity = 0.61), low levels of population structure (highest pairwise Fst = 0.09 and no clustering in principal components analysis), and moderate linkage disequilibrium (ISA = 0.05, P<0.0001). In addition, population bottleneck analysis revealed no evidence for a reduction in the P. falciparum population size in Haiti. We conclude that the high level of genetic diversity and lack of evidence for a population bottleneck may suggest that Haiti’s P. falciparum population has been stable and discuss the implications of our results for understanding the impact of malaria control interventions. We also discuss the relevance of parasite population history and other host and vector factors when assessing transmission intensity from genetic diversity data. PMID:26462203

Quantification of NSW Ambulance Record Linkages with Multiple External Datasets.

PubMed

Carroll, Therese; Muecke, Sandy; Simpson, Judy; Irvine, Katie; Jenkins, André

2015-01-01

This study has two aims: 1) to describe linkage rates between ambulance data and external datasets for "episodes of care" and "patient only" linkages in New South Wales (NSW), Australia; and 2) to detect and report any systematic issues with linkage that relate to patients, and operational or clinical variables that may introduce bias in subsequent studies if not adequately addressed. During 2010-11, the Centre for Health Record Linkage (CHeReL) in NSW, linked the records for patients attended by NSW Ambulance paramedics for the period July 2006 to June 2009, with four external datasets: Emergency Department Data Collection; Admitted Patient Data Collection; NSW Registry of Births, Deaths and Marriages death registration data; and the Australian Bureau of Statistics mortality data. This study reports linkage rates in terms of those "expected" to link and those who were "not expected" to link with external databases within 24 hours of paramedic attendance. Following thorough data preparation processes, 2,041,728 NSW Ambulance care episodes for 1,116,509 patients fulfilled the inclusion criteria. The overall episode-specific hospital linkage rate was 97.2%. Where a patient was not transported to hospital following paramedic care, 8.6% of these episodes resulted in an emergency department attendance within 24 hours. For all care episodes, 5.2% linked to a death record at some time within the 3-year period, with 2.4% of all death episodes occurring within 7 days of a paramedic encounter. For NSW Ambulance episodes of care that were expected to link to an external dataset but did not, nonlinkage to hospital admission records tended to decrease with age. For all other variables, issues relating to rates of linkage and nonlinkage were more indiscriminate. This quantification of the limitations of this large linked dataset will underpin the interpretation and results of ensuing studies that will inform future clinical and operational policies and practices at NSW Ambulance.

Identification of Genetic Loci Associated with Quality Traits in Almond via Association Mapping

PubMed Central

Font i Forcada, Carolina; Oraguzie, Nnadozie; Reyes-Chin-Wo, Sebastian; Espiau, Maria Teresa; Socias i Company, Rafael; Fernández i Martí, Angel

2015-01-01

To design an appropriate association study, we need to understand population structure and the structure of linkage disequilibrium within and among populations as well as in different regions of the genome in an organism. In this study, we have used a total of 98 almond accessions, from five continents located and maintained at the Centro de Investigación y Tecnología Agroalimentaria de Aragón (CITA; Spain), and 40 microsatellite markers. Population structure analysis performed in ‘Structure’ grouped the accessions into two principal groups; the Mediterranean (Western-Europe) and the non-Mediterranean, with K = 3, being the best fit for our data. There was a strong subpopulation structure with linkage disequilibrium decaying with increasing genetic distance resulting in lower levels of linkage disequilibrium between more distant markers. A significant impact of population structure on linkage disequilibrium in the almond cultivar groups was observed. The mean r2 value for all intra-chromosomal loci pairs was 0.040, whereas, the r2 for the inter-chromosomal loci pairs was 0.036. For analysis of association between the markers and phenotypic traits, five models comprising both general linear models and mixed linear models were selected to test the marker trait associations. The mixed linear model (MLM) approach using co-ancestry values from population structure and kinship estimates (K model) as covariates identified a maximum of 16 significant associations for chemical traits and 12 for physical traits. This study reports for the first time the use of association mapping for determining marker-locus trait associations in a world-wide almond germplasm collection. It is likely that association mapping will have the most immediate and largest impact on the tier of crops such as almond with the greatest economic value. PMID:26111146

Identification of Genetic Loci Associated with Quality Traits in Almond via Association Mapping.

PubMed

Font i Forcada, Carolina; Oraguzie, Nnadozie; Reyes-Chin-Wo, Sebastian; Espiau, Maria Teresa; Socias i Company, Rafael; Fernández i Martí, Angel

2015-01-01

To design an appropriate association study, we need to understand population structure and the structure of linkage disequilibrium within and among populations as well as in different regions of the genome in an organism. In this study, we have used a total of 98 almond accessions, from five continents located and maintained at the Centro de Investigación y Tecnología Agroalimentaria de Aragón (CITA; Spain), and 40 microsatellite markers. Population structure analysis performed in 'Structure' grouped the accessions into two principal groups; the Mediterranean (Western-Europe) and the non-Mediterranean, with K = 3, being the best fit for our data. There was a strong subpopulation structure with linkage disequilibrium decaying with increasing genetic distance resulting in lower levels of linkage disequilibrium between more distant markers. A significant impact of population structure on linkage disequilibrium in the almond cultivar groups was observed. The mean r2 value for all intra-chromosomal loci pairs was 0.040, whereas, the r2 for the inter-chromosomal loci pairs was 0.036. For analysis of association between the markers and phenotypic traits, five models comprising both general linear models and mixed linear models were selected to test the marker trait associations. The mixed linear model (MLM) approach using co-ancestry values from population structure and kinship estimates (K model) as covariates identified a maximum of 16 significant associations for chemical traits and 12 for physical traits. This study reports for the first time the use of association mapping for determining marker-locus trait associations in a world-wide almond germplasm collection. It is likely that association mapping will have the most immediate and largest impact on the tier of crops such as almond with the greatest economic value.

Major strengths and weaknesses of the lod score method.

PubMed

Ott, J

2001-01-01

Strengths and weaknesses of the lod score method for human genetic linkage analysis are discussed. The main weakness is its requirement for the specification of a detailed inheritance model for the trait. Various strengths are identified. For example, the lod score (likelihood) method has optimality properties when the trait to be studied is known to follow a Mendelian mode of inheritance. The ELOD is a useful measure for information content of the data. The lod score method can emulate various "nonparametric" methods, and this emulation is equivalent to the nonparametric methods. Finally, the possibility of building errors into the analysis will prove to be essential for the large amount of linkage and disequilibrium data expected in the near future.

Breed relationships facilitate fine-mapping studies: A 7.8-kb deletion cosegregates with Collie eye anomaly across multiple dog breeds

PubMed Central

Parker, Heidi G.; Kukekova, Anna V.; Akey, Dayna T.; Goldstein, Orly; Kirkness, Ewen F.; Baysac, Kathleen C.; Mosher, Dana S.; Aguirre, Gustavo D.; Acland, Gregory M.; Ostrander, Elaine A.

2007-01-01

The features of modern dog breeds that increase the ease of mapping common diseases, such as reduced heterogeneity and extensive linkage disequilibrium, may also increase the difficulty associated with fine mapping and identifying causative mutations. One way to address this problem is by combining data from multiple breeds segregating the same trait after initial linkage has been determined. The multibreed approach increases the number of potentially informative recombination events and reduces the size of the critical haplotype by taking advantage of shortened linkage disequilibrium distances found across breeds. In order to identify breeds that likely share a trait inherited from the same ancestral source, we have used cluster analysis to divide 132 breeds of dog into five primary breed groups. We then use the multibreed approach to fine-map Collie eye anomaly (cea), a complex disorder of ocular development that was initially mapped to a 3.9-cM region on canine chromosome 37. Combined genotypes from affected individuals from four breeds of a single breed group significantly narrowed the candidate gene region to a 103-kb interval spanning only four genes. Sequence analysis revealed that all affected dogs share a homozygous deletion of 7.8 kb in the NHEJ1 gene. This intronic deletion spans a highly conserved binding domain to which several developmentally important proteins bind. This work both establishes that the primary cea mutation arose as a single disease allele in a common ancestor of herding breeds as well as highlights the value of comparative population analysis for refining regions of linkage. PMID:17916641

Securizing data linkage in french public statistics.

PubMed

Guesdon, Maxence; Benzenine, Eric; Gadouche, Kamel; Quantin, Catherine

2016-10-06

Administrative records in France, especially medical and social records, have huge potential for statistical studies. The NIR (a national identifier) is widely used in medico-social administrations, and this would theoretically provide considerable scope for data matching, on condition that the legislation on such matters was respected.The law, however, forbids the processing of non-anonymized medical data, thus making it difficult to carry out studies that require several sources of social and medical data.We would like to benefit from computer techniques introduced since the 70 s to provide safe linkage of anonymized files, to release the current constraints of such procedures.We propose an organization and a data workflow, based on hashing and cyrptographic techniques, to strongly compartmentalize identifying and not-identifying data.The proposed method offers a strong control over who is in possession of which information, using different hashing keys for each linkage. This allows to prevent unauthorized linkage of data, to protect anonymity, by preventing cumulation of not-identifying data which can become identifying data when linked.Our proposal would make it possible to conduct such studies more easily, more regularly and more precisely while preserving a high enough level of anonymity.The main obstacle to setting up such a system, in our opinion, is not technical, but rather organizational in that it is based on the existence of a Key-Management Authority.

Cytonuclear disequilibrium and genetic drift in a natural population of ponderosa pine.

PubMed Central

Latta, R G; Linhart, Y B; Mitton, J B

2001-01-01

We measured the cytonuclear disequilibrium between 11 nuclear allozyme loci and both mitochondrial and chloroplast DNA haplotypes in a natural population of ponderosa pine (Pinus ponderosa, Laws). Three allozyme loci showed significant associations with mtDNA variation, while two other loci showed significant association with cpDNA. However, the absolute number of individuals involved in any of the associations was small, such that in none of the nuclear-organellar combinations was the difference between observed and expected numbers >11 individuals. Patterns of association were not consistent across loci or organellar genomes, suggesting that they are not the result of mating patterns, which would act uniformly on all loci. This pattern of disequilibria is consistent with the action of genetic drift and with existing knowledge of the structure of this population and thus does not imply the action of other evolutionary processes. The overall magnitude (normalized disequilibrium) of associations was greater for maternally inherited mtDNA than for paternally inherited cpDNA, though this difference was neither large nor significant. Such significant disequilibria involving the paternally inherited organelle indicate that not only are there a limited number of seed parents, but the effective number of pollen parents is also limited. PMID:11404345

Th-230 - U-238 series disequilibrium of the Olkaria rhyolites Gregory Rift Valley, Kenya: Residence times

NASA Technical Reports Server (NTRS)

Black, S.; Macdonald, R.; Kelly, M.

1993-01-01

U-series disequilibrium analyses have been conducted on samples from Olkaria rhyolite centers with ages being available for all but one center using both internal and whole rock isochrons. 67 percent of the rhyolites analyzed show U-Th disequilibrium, ranging from 27 percent excess thorium to 36 percent excess uranium. Internal and whole rock isochrons give crystallization/formation ages between 65 ka and 9 ka, in every case these are substantially older than the eruptive dates. The residence times of the rhyolites (U-Th age minus the eruption date) have decreased almost linearly with time, from 45 ka to 7 Ka suggesting a possible increase of activity within the system related to increased basaltic input. The long residence times are mirrored by large Rn-222 fluxes from the centers which cannot be explained by larger U contents.

Apprenticeship - School Linkage Implementation Manual.

ERIC Educational Resources Information Center

Martin, Sharon T.; And Others

Developed to assist interested sponsors in implementing apprenticeship-school linkage projects, this guide is intended to organize the collective experiences of those who have implemented the demonstration projects to highlight the day-to-day mechanics involved. Section 1 overviews apprenticeship-school linkage. In section 2 factors are described…

Who Are the Okinawans? Ancestry, Genome Diversity, and Implications for the Genetic Study of Human Longevity From a Geographically Isolated Population

PubMed Central

Hsueh, Wen-Chi; He, Qimei; Willcox, D. Craig; Nievergelt, Caroline M.; Donlon, Timothy A.; Kwok, Pui-Yan; Suzuki, Makoto; Willcox, Bradley J.

2014-01-01

Isolated populations have advantages for genetic studies of longevity from decreased haplotype diversity and long-range linkage disequilibrium. This permits smaller sample sizes without loss of power, among other utilities. Little is known about the genome of the Okinawans, a potential population isolate, recognized for longevity. Therefore, we assessed genetic diversity, structure, and admixture in Okinawans, and compared this with Caucasians, Chinese, Japanese, and Africans from HapMap II, genotyped on the same Affymetrix GeneChip Human Mapping 500K array. Principal component analysis, haplotype coverage, and linkage disequilibrium decay revealed a distinct Okinawan genome—more homogeneity, less haplotype diversity, and longer range linkage disequilibrium. Population structure and admixture analyses utilizing 52 global reference populations from the Human Genome Diversity Cell Line Panel demonstrated that Okinawans clustered almost exclusively with East Asians. Sibling relative risk (λs) analysis revealed that siblings of Okinawan centenarians have 3.11 times (females) and 3.77 times (males) more likelihood of centenarianism. These findings suggest that Okinawans are genetically distinct and share several characteristics of a population isolate, which are prone to develop extreme phenotypes (eg, longevity) from genetic drift, natural selection, and population bottlenecks. These data support further exploration of genetic influence on longevity in the Okinawans. PMID:24444611

Sexual selection and sex linkage.

PubMed

Kirkpatrick, Mark; Hall, David W

2004-04-01

Some animal groups, such as birds, seem prone to extreme forms of sexual selection. One contributing factor may be sex linkage of genes affecting male displays and female preferences. Here we show that sex linkage can have substantial effects on the genetic correlation between these traits and consequently for Fisher's runaway and the good-genes mechanisms of sexual selection. Under some kinds of sex linkage (e.g. Z-linked preferences), a runaway is more likely than under autosomal inheritance, while under others (e.g., X-linked preferences and autosomal displays), the good-genes mechanism is particularly powerful. These theoretical results suggest empirical tests based on the comparative method.

Validity of deterministic record linkage using multiple indirect personal identifiers: linking a large registry to claims data.

PubMed

Setoguchi, Soko; Zhu, Ying; Jalbert, Jessica J; Williams, Lauren A; Chen, Chih-Ying

2014-05-01

Linking patient registries with administrative databases can enhance the utility of the databases for epidemiological and comparative effectiveness research. However, registries often lack direct personal identifiers, and the validity of record linkage using multiple indirect personal identifiers is not well understood. Using a large contemporary national cardiovascular device registry and 100% Medicare inpatient data, we linked hospitalization-level records. The main outcomes were the validity measures of several deterministic linkage rules using multiple indirect personal identifiers compared with rules using both direct and indirect personal identifiers. Linkage rules using 2 or 3 indirect, patient-level identifiers (ie, date of birth, sex, admission date) and hospital ID produced linkages with sensitivity of 95% and specificity of 98% compared with a gold standard linkage rule using a combination of both direct and indirect identifiers. Ours is the first large-scale study to validate the performance of deterministic linkage rules without direct personal identifiers. When linking hospitalization-level records in the absence of direct personal identifiers, provider information is necessary for successful linkage. © 2014 American Heart Association, Inc.

On computation of p-values in parametric linkage analysis.

PubMed

Kurbasic, Azra; Hössjer, Ola

2004-01-01

Parametric linkage analysis is usually used to find chromosomal regions linked to a disease (phenotype) that is described with a specific genetic model. This is done by investigating the relations between the disease and genetic markers, that is, well-characterized loci of known position with a clear Mendelian mode of inheritance. Assume we have found an interesting region on a chromosome that we suspect is linked to the disease. Then we want to test the hypothesis of no linkage versus the alternative one of linkage. As a measure we use the maximal lod score Z(max). It is well known that the maximal lod score has asymptotically a (2 ln 10)(-1) x (1/2 chi2(0) + 1/2 chi2(1)) distribution under the null hypothesis of no linkage when only one point (one marker) on the chromosome is studied. In this paper, we show, both by simulations and theoretical arguments, that the null hypothesis distribution of Zmax has no simple form when more than one marker is used (multipoint analysis). In fact, the distribution of Zmax depends on the number of families, their structure, the assumed genetic model, marker denseness, and marker informativity. This means that a constant critical limit of Zmax leads to tests associated with different significance levels. Because of the above-mentioned problems, from the statistical point of view the maximal lod score should be supplemented by a p-value when results are reported. Copyright (c) 2004 S. Karger AG, Basel.

Use of linkage to improve the completeness of the SIM and SINASC in the Brazilian capitals

PubMed Central

Maia, Lívia Teixeira de Souza; de Souza, Wayner Vieira; Mendes, Antonio da Cruz Gouveia; da Silva, Aline Galdino Soares

2017-01-01

ABSTRACT OBJECTIVE To analyze the contribution of linkage between databases of live births and infant mortality to improve the completeness of the variables common to the Mortality Information System (SIM) and the Live Birth Information System (SINASC) in Brazilian capitals in 2012. METHODS We studied 9,001 deaths of children under one year registered in the SIM in 2012 and 1,424,691 live births present in the SINASC in 2011 and 2012. The databases were related with linkage in two steps – deterministic and probabilistic. We calculated the percentage of incompleteness of the variables common to the SIM and SINASC before and after using the technique. RESULTS We could relate 90.8% of the deaths to their respective declarations of live birth, most of them paired deterministically. We found a higher percentage of pairs in Porto Alegre, Curitiba, and Campo Grande. In the capitals of the North region, the average of pairs was 84.2%; in the South region, this result reached 97.9%. The 11 variables common to the SIM and SINASC had 11,278 incomplete fields cumulatively, and we could recover 91.4% of the data after linkage. Before linkage, five variables presented excellent completeness in the SINASC in all Brazilian capitals, but only one variable had the same status in the SIM. After applying this technique, all 11 variables of the SINASC became excellent, while this occurred in seven variables of the SIM. The city of birth was significantly associated with the death component in the quality of the information. CONCLUSIONS Despite advances in the coverage and quality of the SIM and SINASC, problems in the completeness of the variables can still be identified, especially in the SIM. In this perspective, linkage can be used to qualify important information for the analysis of infant mortality. PMID:29211201

The effect of using genealogy-based haplotypes for genomic prediction.

PubMed

Edriss, Vahid; Fernando, Rohan L; Su, Guosheng; Lund, Mogens S; Guldbrandtsen, Bernt

2013-03-06

Genomic prediction uses two sources of information: linkage disequilibrium between markers and quantitative trait loci, and additive genetic relationships between individuals. One way to increase the accuracy of genomic prediction is to capture more linkage disequilibrium by regression on haplotypes instead of regression on individual markers. The aim of this study was to investigate the accuracy of genomic prediction using haplotypes based on local genealogy information. A total of 4429 Danish Holstein bulls were genotyped with the 50K SNP chip. Haplotypes were constructed using local genealogical trees. Effects of haplotype covariates were estimated with two types of prediction models: (1) assuming that effects had the same distribution for all haplotype covariates, i.e. the GBLUP method and (2) assuming that a large proportion (π) of the haplotype covariates had zero effect, i.e. a Bayesian mixture method. About 7.5 times more covariate effects were estimated when fitting haplotypes based on local genealogical trees compared to fitting individuals markers. Genealogy-based haplotype clustering slightly increased the accuracy of genomic prediction and, in some cases, decreased the bias of prediction. With the Bayesian method, accuracy of prediction was less sensitive to parameter π when fitting haplotypes compared to fitting markers. Use of haplotypes based on genealogy can slightly increase the accuracy of genomic prediction. Improved methods to cluster the haplotypes constructed from local genealogy could lead to additional gains in accuracy.

Accommodating Chromosome Inversions in Linkage Analysis

PubMed Central

Chen, Gary K.; Slaten, Erin; Ophoff, Roel A.; Lange, Kenneth

2006-01-01

This work develops a population-genetics model for polymorphic chromosome inversions. The model precisely describes how an inversion changes the nature of and approach to linkage equilibrium. The work also describes algorithms and software for allele-frequency estimation and linkage analysis in the presence of an inversion. The linkage algorithms implemented in the software package Mendel estimate recombination parameters and calculate the posterior probability that each pedigree member carries the inversion. Application of Mendel to eight Centre d'Étude du Polymorphisme Humain pedigrees in a region containing a common inversion on 8p23 illustrates its potential for providing more-precise estimates of the location of an unmapped marker or trait gene. Our expanded cytogenetic analysis of these families further identifies inversion carriers and increases the evidence of linkage. PMID:16826515

SNP identification from RNA sequencing and linkage map construction of rubber tree for anchoring the draft genome.

PubMed

Shearman, Jeremy R; Sangsrakru, Duangjai; Jomchai, Nukoon; Ruang-Areerate, Panthita; Sonthirod, Chutima; Naktang, Chaiwat; Theerawattanasuk, Kanikar; Tragoonrung, Somvong; Tangphatsornruang, Sithichoke

2015-01-01

Hevea brasiliensis, or rubber tree, is an important crop species that accounts for the majority of natural latex production. The rubber tree nuclear genome consists of 18 chromosomes and is roughly 2.15 Gb. The current rubber tree reference genome assembly consists of 1,150,326 scaffolds ranging from 200 to 531,465 bp and totalling 1.1 Gb. Only 143 scaffolds, totalling 7.6 Mb, have been placed into linkage groups. We have performed RNA-seq on 6 varieties of rubber tree to identify SNPs and InDels and used this information to perform target sequence enrichment and high throughput sequencing to genotype a set of SNPs in 149 rubber tree offspring from a cross between RRIM 600 and RRII 105 rubber tree varieties. We used this information to generate a linkage map allowing for the anchoring of 24,424 contigs from 3,009 scaffolds, totalling 115 Mb or 10.4% of the published sequence, into 18 linkage groups. Each linkage group contains between 319 and 1367 SNPs, or 60 to 194 non-redundant marker positions, and ranges from 156 to 336 cM in length. This linkage map includes 20,143 of the 69,300 predicted genes from rubber tree and will be useful for mapping studies and improving the reference genome assembly.

Irish study of high-density Schizophrenia families: Field methods and power to detect linkage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kendler, K.S.; Straub, R.E.; MacLean, C.J.

Large samples of multiplex pedigrees will probably be needed to detect susceptibility loci for schizophrenia by linkage analysis. Standardized ascertainment of such pedigrees from culturally and ethnically homogeneous populations may improve the probability of detection and replication of linkage. The Irish Study of High-Density Schizophrenia Families (ISHDSF) was formed from standardized ascertainment of multiplex schizophrenia families in 39 psychiatric facilities covering over 90% of the population in Ireland and Northern Ireland. We here describe a phenotypic sample and a subset thereof, the linkage sample. Individuals were included in the phenotypic sample if adequate diagnostic information, based on personal interview and/ormore » hospital record, was available. Only individuals with available DNA were included in the linkage sample. Inclusion of a pedigree into the phenotypic sample required at least two first, second, or third degree relatives with non-affective psychosis (NAP), one of whom had schizophrenia (S) or poor-outcome schizoaffective disorder (PO-SAD). Entry into the linkage sample required DNA samples on at least two individuals with NAP, of whom at least one had S or PO-SAD. Affection was defined by narrow, intermediate, and broad criteria. 75 refs., 6 tabs.« less

A second-generation genetic linkage map of the domestic dog, Canis familiaris.

PubMed Central

Neff, M W; Broman, K W; Mellersh, C S; Ray, K; Acland, G M; Aguirre, G D; Ziegle, J S; Ostrander, E A; Rine, J

1999-01-01

Purebred strains, pronounced phenotypic variation, and a high incidence of heritable disease make the domestic dog uniquely suited to complement genetic analyses in humans and mice. A comprehensive genetic linkage map would afford many opportunities in dogs, ranging from the positional cloning of disease genes to the dissection of quantitative differences in size, shape, and behavior. Here we report a canine linkage map with the number of mapped loci expanded to 276 and 10-cM coverage extended to 75-90% of the genome. Most of the 38 canine autosomes are likely represented in the collection of 39 autosomal linkage groups. Eight markers were sufficiently informative to detect linkage at distances of 10-13 cM, yet remained unlinked to any other marker. Taken together, the results suggested a genome size of about 27 M. As in other species, the genetic length varied between sexes, with the female autosomal distance being approximately 1.4-fold greater than that of male meioses. Fifteen markers anchored well-described genes on the map, thereby serving as landmarks for comparative mapping in dogs. We discuss the utility of the current map and outline steps necessary for future map improvement. PMID:9927471

GUILD: GUidance for Information about Linking Data sets†

PubMed Central

Gilbert, Ruth; Lafferty, Rosemary; Hagger-Johnson, Gareth; Zhang, Li-Chun; Smith, Peter; Dibben, Chris; Goldstein, Harvey

2018-01-01

Abstract Record linkage of administrative and survey data is increasingly used to generate evidence to inform policy and services. Although a powerful and efficient way of generating new information from existing data sets, errors related to data processing before, during and after linkage can bias results. However, researchers and users of linked data rarely have access to information that can be used to assess these biases or take them into account in analyses. As linked administrative data are increasingly used to provide evidence to guide policy and services, linkage error, which disproportionately affects disadvantaged groups, can undermine evidence for public health. We convened a group of researchers and experts from government data providers to develop guidance about the information that needs to be made available about the data linkage process, by data providers, data linkers, analysts and the researchers who write reports. The guidance goes beyond recommendations for information to be included in research reports. Our aim is to raise awareness of information that may be required at each step of the linkage pathway to improve the transparency, reproducibility, and accuracy of linkage processes, and the validity of analyses and interpretation of results. PMID:28369581

African-specific variability in the acetylcholine muscarinic receptor M4: association with cocaine and heroin addiction.

PubMed

Levran, Orna; Randesi, Matthew; Peles, Einat; Correa da Rosa, Joel; Ott, Jurg; Rotrosen, John; Adelson, Miriam; Kreek, Mary Jeanne

2016-06-01

This study was designed to determine whether polymorphisms in acetylcholine receptors contribute to opioid dependence and/or cocaine dependence. The sample (n = 1860) was divided by drug and ancestry, and 55 polymorphisms (nine genes) were analyzed. Of the 20 SNPs that showed nominally significant associations, the association of the African-specific CHRM4 SNP rs2229163 (Asn417=) with cocaine dependence survived correction for multiple testing (Pcorrected = 0.047). CHRM4 is located in a region of strong linkage disequilibrium on chromosome 11 that includes genes associated with schizophrenia. CHRM4 SNP rs2229163 is in strong linkage disequilibrium with several African-specific SNPs in DGKZ and AMBRA1. Cholinergic receptors' variants may contribute to drug addiction and have a potential role as pharmacogenetic markers.

Siblings versus Parents and Friends: Longitudinal Linkages to Adolescent Externalizing Problems

ERIC Educational Resources Information Center

Defoe, Ivy N.; Keijsers, Loes; Hawk, Skyler T.; Branje, Susan; Dubas, Judith Semon; Buist, Kirsten; Frijns, Tom; van Aken, Marcel A. G.; Koot, Hans M.; van Lier, Pol A. C.; Meeus, Wim

2013-01-01

Background: It is well documented that friends' externalizing problems and negative parent-child interactions predict externalizing problems in adolescence, but relatively little is known about the role of siblings. This four-wave, multi-informant study investigated linkages of siblings' externalizing problems and sibling-adolescent negative…

A novel metadata management model to capture consent for record linkage in longitudinal research studies.

PubMed

McMahon, Christiana; Denaxas, Spiros

2017-11-06

Informed consent is an important feature of longitudinal research studies as it enables the linking of the baseline participant information with administrative data. The lack of standardized models to capture consent elements can lead to substantial challenges. A structured approach to capturing consent-related metadata can address these. a) Explore the state-of-the-art for recording consent; b) Identify key elements of consent required for record linkage; and c) Create and evaluate a novel metadata management model to capture consent-related metadata. The main methodological components of our work were: a) a systematic literature review and qualitative analysis of consent forms; b) the development and evaluation of a novel metadata model. We qualitatively analyzed 61 manuscripts and 30 consent forms. We extracted data elements related to obtaining consent for linkage. We created a novel metadata management model for consent and evaluated it by comparison with the existing standards and by iteratively applying it to case studies. The developed model can facilitate the standardized recording of consent for linkage in longitudinal research studies and enable the linkage of external participant data. Furthermore, it can provide a structured way of recording consent-related metadata and facilitate the harmonization and streamlining of processes.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hellsten, E.; Vesa, J.; Peltonen, L.

Infantile neuronal ceroid lipofuscinosis, INCL, CLN1, is an autosomally inherited progressive neuro-generative disorder. The disease results in the massive death of cortical neurons, suggesting an essential role for the CLN1 gene product in the normal neuronal maturation during the first years of life. Identification of new multiallelic markers has now made possible the construction of a refined genetic map encompassing the CLN1 locus at 1p32. Strong allelic association was detected with a new, highly polymorphic HY-TM1 marker. The authors incorporated this observed linkage disequilibrium into multipoint linkage analysis, which significantly increased the informativeness of the limited family material and facilitatedmore » refined assignment of the CLN1 locus. 23 refs., 2 figs., 4 tabs.« less

Tests for a disease-susceptibility locus allowing for an inbreeding coefficient (F).

PubMed

Song, Kijoung; Elston, Robert C

2003-11-01

We begin by discussing the false positive test results that arise because of cryptic relatedness and population substructure when testing a disease susceptibility locus. We extend and evaluate the Hardy-Weinberg disequilibrium (HWD) method, allowing for an inbreeding coefficient (F) in a similar way that Devlin and Roeder (1999) allowed for inbreeding in a case-control study. Then we compare the HWD measure and the common direct measure of linkage disequilibrium, both when there is no population substructure (F = 0) and when there is population substructure (F not = 0), for a single marker. The HWD test statistic gives rise to false positives caused by population stratification. These false positives can be controlled by adjusting the test statistic for the amount of variance inflation caused by the inbreeding coefficient (F). The power loss for the HWD test that arises when controlling for population structure is much less than that which arises for the common direct measure of linkage disequilibrium. However, in the multiplicative model, the HWD test has virtually no power even when allowing for non-zero F.

Particle swarm optimization with recombination and dynamic linkage discovery.

PubMed

Chen, Ying-Ping; Peng, Wen-Chih; Jian, Ming-Chung

2007-12-01

In this paper, we try to improve the performance of the particle swarm optimizer by incorporating the linkage concept, which is an essential mechanism in genetic algorithms, and design a new linkage identification technique called dynamic linkage discovery to address the linkage problem in real-parameter optimization problems. Dynamic linkage discovery is a costless and effective linkage recognition technique that adapts the linkage configuration by employing only the selection operator without extra judging criteria irrelevant to the objective function. Moreover, a recombination operator that utilizes the discovered linkage configuration to promote the cooperation of particle swarm optimizer and dynamic linkage discovery is accordingly developed. By integrating the particle swarm optimizer, dynamic linkage discovery, and recombination operator, we propose a new hybridization of optimization methodologies called particle swarm optimization with recombination and dynamic linkage discovery (PSO-RDL). In order to study the capability of PSO-RDL, numerical experiments were conducted on a set of benchmark functions as well as on an important real-world application. The benchmark functions used in this paper were proposed in the 2005 Institute of Electrical and Electronics Engineers Congress on Evolutionary Computation. The experimental results on the benchmark functions indicate that PSO-RDL can provide a level of performance comparable to that given by other advanced optimization techniques. In addition to the benchmark, PSO-RDL was also used to solve the economic dispatch (ED) problem for power systems, which is a real-world problem and highly constrained. The results indicate that PSO-RDL can successfully solve the ED problem for the three-unit power system and obtain the currently known best solution for the 40-unit system.

SNP Identification from RNA Sequencing and Linkage Map Construction of Rubber Tree for Anchoring the Draft Genome

PubMed Central

Shearman, Jeremy R.; Sangsrakru, Duangjai; Jomchai, Nukoon; Ruang-areerate, Panthita; Sonthirod, Chutima; Naktang, Chaiwat; Theerawattanasuk, Kanikar; Tragoonrung, Somvong; Tangphatsornruang, Sithichoke

2015-01-01

Hevea brasiliensis, or rubber tree, is an important crop species that accounts for the majority of natural latex production. The rubber tree nuclear genome consists of 18 chromosomes and is roughly 2.15 Gb. The current rubber tree reference genome assembly consists of 1,150,326 scaffolds ranging from 200 to 531,465 bp and totalling 1.1 Gb. Only 143 scaffolds, totalling 7.6 Mb, have been placed into linkage groups. We have performed RNA-seq on 6 varieties of rubber tree to identify SNPs and InDels and used this information to perform target sequence enrichment and high throughput sequencing to genotype a set of SNPs in 149 rubber tree offspring from a cross between RRIM 600 and RRII 105 rubber tree varieties. We used this information to generate a linkage map allowing for the anchoring of 24,424 contigs from 3,009 scaffolds, totalling 115 Mb or 10.4% of the published sequence, into 18 linkage groups. Each linkage group contains between 319 and 1367 SNPs, or 60 to 194 non-redundant marker positions, and ranges from 156 to 336 cM in length. This linkage map includes 20,143 of the 69,300 predicted genes from rubber tree and will be useful for mapping studies and improving the reference genome assembly. PMID:25831195

Filtering genetic variants and placing informative priors based on putative biological function.

PubMed

Friedrichs, Stefanie; Malzahn, Dörthe; Pugh, Elizabeth W; Almeida, Marcio; Liu, Xiao Qing; Bailey, Julia N

2016-02-03

High-density genetic marker data, especially sequence data, imply an immense multiple testing burden. This can be ameliorated by filtering genetic variants, exploiting or accounting for correlations between variants, jointly testing variants, and by incorporating informative priors. Priors can be based on biological knowledge or predicted variant function, or even be used to integrate gene expression or other omics data. Based on Genetic Analysis Workshop (GAW) 19 data, this article discusses diversity and usefulness of functional variant scores provided, for example, by PolyPhen2, SIFT, or RegulomeDB annotations. Incorporating functional scores into variant filters or weights and adjusting the significance level for correlations between variants yielded significant associations with blood pressure traits in a large family study of Mexican Americans (GAW19 data set). Marker rs218966 in gene PHF14 and rs9836027 in MAP4 significantly associated with hypertension; additionally, rare variants in SNUPN significantly associated with systolic blood pressure. Variant weights strongly influenced the power of kernel methods and burden tests. Apart from variant weights in test statistics, prior weights may also be used when combining test statistics or to informatively weight p values while controlling false discovery rate (FDR). Indeed, power improved when gene expression data for FDR-controlled informative weighting of association test p values of genes was used. Finally, approaches exploiting variant correlations included identity-by-descent mapping and the optimal strategy for joint testing rare and common variants, which was observed to depend on linkage disequilibrium structure.

Saturation of an Intra-Gene Pool Linkage Map: Towards a Unified Consensus Linkage Map for Fine Mapping and Synteny Analysis in Common Bean

PubMed Central

Galeano, Carlos H.; Fernandez, Andrea C.; Franco-Herrera, Natalia; Cichy, Karen A.; McClean, Phillip E.; Vanderleyden, Jos; Blair, Matthew W.

2011-01-01

Map-based cloning and fine mapping to find genes of interest and marker assisted selection (MAS) requires good genetic maps with reproducible markers. In this study, we saturated the linkage map of the intra-gene pool population of common bean DOR364×BAT477 (DB) by evaluating 2,706 molecular markers including SSR, SNP, and gene-based markers. On average the polymorphism rate was 7.7% due to the narrow genetic base between the parents. The DB linkage map consisted of 291 markers with a total map length of 1,788 cM. A consensus map was built using the core mapping populations derived from inter-gene pool crosses: DOR364×G19833 (DG) and BAT93×JALO EEP558 (BJ). The consensus map consisted of a total of 1,010 markers mapped, with a total map length of 2,041 cM across 11 linkage groups. On average, each linkage group on the consensus map contained 91 markers of which 83% were single copy markers. Finally, a synteny analysis was carried out using our highly saturated consensus maps compared with the soybean pseudo-chromosome assembly. A total of 772 marker sequences were compared with the soybean genome. A total of 44 syntenic blocks were identified. The linkage group Pv6 presented the most diverse pattern of synteny with seven syntenic blocks, and Pv9 showed the most consistent relations with soybean with just two syntenic blocks. Additionally, a co-linear analysis using common bean transcript map information against soybean coding sequences (CDS) revealed the relationship with 787 soybean genes. The common bean consensus map has allowed us to map a larger number of markers, to obtain a more complete coverage of the common bean genome. Our results, combined with synteny relationships provide tools to increase marker density in selected genomic regions to identify closely linked polymorphic markers for indirect selection, fine mapping or for positional cloning. PMID:22174773

The quantitative LOD score: test statistic and sample size for exclusion and linkage of quantitative traits in human sibships.

PubMed

Page, G P; Amos, C I; Boerwinkle, E

1998-04-01

We present a test statistic, the quantitative LOD (QLOD) score, for the testing of both linkage and exclusion of quantitative-trait loci in randomly selected human sibships. As with the traditional LOD score, the boundary values of 3, for linkage, and -2, for exclusion, can be used for the QLOD score. We investigated the sample sizes required for inferring exclusion and linkage, for various combinations of linked genetic variance, total heritability, recombination distance, and sibship size, using fixed-size sampling. The sample sizes required for both linkage and exclusion were not qualitatively different and depended on the percentage of variance being linked or excluded and on the total genetic variance. Information regarding linkage and exclusion in sibships larger than size 2 increased as approximately all possible pairs n(n-1)/2 up to sibships of size 6. Increasing the recombination (theta) distance between the marker and the trait loci reduced empirically the power for both linkage and exclusion, as a function of approximately (1-2theta)4.

Structural synthesis of linkages for quadruped bio-robot legs

NASA Astrophysics Data System (ADS)

Antonescu, O.; Robu, C.; Antonescu, P.

2016-08-01

The paper presents a few kinematic schemes of planar mechanisms with bars (linkages) used as part of the quadruped robot legs. The Dunshee linkage having only four elements as crank-rocker mechanism is analyzed. Further, the Klann linkage, which is accomplished by amplifying the crank-rocker mechanism with a dyadic kinematic chain, is also presented. More than that, the Jansen linkage, which is obtained by extending and amplifying the crank-rocker mechanism with two dyadic kinematic chains, is also analyzed. At the end of the paper, the authors present a novel linkage application consisting of a quadric kinematic chain.

Heritability and linkage analysis of personality in bipolar disorder.

PubMed

Greenwood, Tiffany A; Badner, Judith A; Byerley, William; Keck, Paul E; McElroy, Susan L; Remick, Ronald A; Dessa Sadovnick, A; Kelsoe, John R

2013-11-01

The many attempts that have been made to identify genes for bipolar disorder (BD) have met with limited success, which may reflect an inadequacy of diagnosis as an informative and biologically relevant phenotype for genetic studies. Here we have explored aspects of personality as quantitative phenotypes for bipolar disorder through the use of the Temperament and Character Inventory (TCI), which assesses personality in seven dimensions. Four temperament dimensions are assessed: novelty seeking (NS), harm avoidance (HA), reward dependence (RD), and persistence (PS). Three character dimensions are also included: self-directedness (SD), cooperativeness (CO), and self-transcendence (ST). We compared personality scores between diagnostic groups and assessed heritability in a sample of 101 families collected for genetic studies of BD. A genome-wide SNP linkage analysis was then performed in the subset of 51 families for which genetic data was available. Significant group differences were observed between BD subjects, their first-degree relatives, and independent controls for all but RD and PS, and all but HA and RD were found to be significantly heritable in this sample. Linkage analysis of the heritable dimensions produced several suggestive linkage peaks for NS (chromosomes 7q21 and 10p15), PS (chromosomes 6q16, 12p13, and 19p13), and SD (chromosomes 4q35, 8q24, and 18q12). The relatively small size of our linkage sample likely limited our ability to reach genome-wide significance in this study. While not genome-wide significant, these results suggest that aspects of personality may prove useful in the identification of genes underlying BD susceptibility. © 2013 Elsevier B.V. All rights reserved.

Evaluation of forensic genetic parameters of 12 STR loci in the Korean population using the InvestigatorⓇ HDplex kit.

PubMed

Jung, Ju Yeon; Kim, Eun Hye; Oh, Yu-Li; Park, Hyun-Chul; Hwang, Jung Ho; Lim, Si-Keun

2017-09-01

We genotyped and calculated the forensic parameters of 10 non-CODIS loci and 2 CODIS loci of 990 Korean individuals using the Investigator Ⓡ HDplex kit. No significant deviations from Hardy-Weinberg equilibrium (after Bonferroni correction for multiple testing) or genetic linkage disequilibrium were observed. The calculated matching probability and power of discrimination ranged from 0.0080 to 0.2014, and 0.7986 to 0.9920, respectively. We conclude that the markers of the kit are highly informative corroborative tools for forensic DNA analysis.

Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q.

PubMed

Holmans, Peter; Zubenko, George S; Crowe, Raymond R; DePaulo, J Raymond; Scheftner, William A; Weissman, Myrna M; Zubenko, Wendy N; Boutelle, Sandra; Murphy-Eberenz, Kathleen; MacKinnon, Dean; McInnis, Melvin G; Marta, Diana H; Adams, Philip; Knowles, James A; Gladis, Madeleine; Thomas, Jo; Chellis, Jennifer; Miller, Erin; Levinson, Douglas F

2004-06-01

A genome scan was performed on the first phase sample of the Genetics of Recurrent Early-Onset Depression (GenRED) project. The sample consisted of 297 informative families containing 415 independent affected sibling pairs (ASPs), or, counting all possible pairs, 685 informative affected relative pairs (555 ASPs and 130 other pair types). Affected cases had recurrent major depressive disorder (MDD) with onset before age 31 years for probands or age 41 years for other affected relatives; the mean age at onset was 18.5 years, and the mean number of depressive episodes was 7.3. The Center for Inherited Disease Research genotyped 389 microsatellite markers (mean spacing of 9.3 cM). The primary linkage analysis considered allele sharing in all possible affected relative pairs with the use of the Z(lr) statistic computed by the ALLEGRO program. A secondary logistic regression analysis considered the effect of the sex of the pair as a covariate. Genomewide significant linkage was observed on chromosome 15q25.3-26.2 (Zlr=4.14, equivalent LOD = 3.73, empirical genomewide P=.023). The linkage was not sex specific. No other suggestive or significant results were observed in the primary analysis. The secondary analysis produced three regions of suggestive linkage, but these results should be interpreted cautiously because they depended primarily on the small subsample of 42 male-male pairs. Chromosome 15q25.3-26.2 deserves further study as a candidate region for susceptibility to MDD.

Molecular Characterization of the Lipid Genome-Wide Association Study Signal on Chromosome 18q11.2 Implicates HNF4A-Mediated Regulation of the TMEM241 Gene.

PubMed

Rodríguez, Alejandra; Gonzalez, Luis; Ko, Arthur; Alvarez, Marcus; Miao, Zong; Bhagat, Yash; Nikkola, Elina; Cruz-Bautista, Ivette; Arellano-Campos, Olimpia; Muñoz-Hernández, Linda L; Ordóñez-Sánchez, Maria-Luisa; Rodriguez-Guillen, Rosario; Mohlke, Karen L; Laakso, Markku; Tusie-Luna, Teresa; Aguilar-Salinas, Carlos A; Pajukanta, Päivi

2016-07-01

We recently identified a locus on chromosome 18q11.2 for high serum triglycerides in Mexicans. We hypothesize that the lead genome-wide association study single-nucleotide polymorphism rs9949617, or its linkage disequilibrium proxies, regulates 1 of the 5 genes in the triglyceride-associated region. We performed a linkage disequilibrium analysis and found 9 additional variants in linkage disequilibrium (r(2)>0.7) with the lead single-nucleotide polymorphism. To select the variants for functional analyses, we annotated the 10 variants using DNase I hypersensitive sites, transcription factor and chromatin states and identified rs17259126 as the lead candidate variant for functional in vitro validation. Using luciferase transcriptional reporter assay in liver HepG2 cells, we found that the G allele exhibits a significantly lower effect on transcription (P<0.05). The electrophoretic mobility shift and ChIPqPCR (chromatin immunoprecipitation coupled with quantitative polymerase chain reaction) assays confirmed that the minor G allele of rs17259126 disrupts an hepatocyte nuclear factor 4 α-binding site. To find the regional candidate gene, we performed a local expression quantitative trait locus analysis and found that rs17259126 and its linkage disequilibrium proxies alter expression of the regional transmembrane protein 241 (TMEM241) gene in 795 adipose RNAs from the Metabolic Syndrome In Men (METSIM) cohort (P=6.11×10(-07)-5.80×10(-04)). These results were replicated in expression profiles of TMEM241 from the Multiple Tissue Human Expression Resource (MuTHER; n=856). The Mexican genome-wide association study signal for high serum triglycerides on chromosome 18q11.2 harbors a regulatory single-nucleotide polymorphism, rs17259126, which disrupts normal hepatocyte nuclear factor 4 α binding and decreases the expression of the regional TMEM241 gene. Our data suggest that decreased transcript levels of TMEM241 contribute to increased triglyceride levels in Mexicans. �

An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees

DOE Office of Scientific and Technical Information (OSTI.GOV)

Freimer, N.B.; Reus, V.I.; Vinogradov, S.

1996-05-31

Despite the evidence that major gene effects exist for bipolar disorder (BP), efforts to map BP loci have so far been unsuccessful. A strategy for mapping BP loci is described, focused on investigation of large pedigrees from a genetically homogenous population, that of Costa Rica. This approach is based on the use of a conservative definition of the BP phenotype in preparation for whole genome screening with polymorphic markers. Linkage simulation analyses are utilized to indicate the probability of detecting evidence suggestive of linkage, using these pedigrees. These analyses are performed under a series of single locus models, ranging formmore » recessive to nearly dominant, utilizing both lod score and affected pedigree member analyses. Additional calculations demonstrate that with any of the models employed, most of the information for linkage derives from affected rather than unaffected individuals. 26 refs., 2 figs., 5 tabs.« less

Linkages to Public Land Framework: toward embedding humans in ecosystem analyses by using “inside-out social assessment.”

Treesearch

Joanna Endter-Wada; Dale J. Blahna

2011-01-01

This article presents the " Linkages to Public Land" (LPL) Framework, a general but comprehensive data-gathering and analysis approach aimed at informing citizen and agency decision making about the social environment of public land. This social assessment and planning approach identifies and categorizes various types of linkages that people have to public...

Roadmap for Early Childhood and K-12 Data Linkages: Key Focus Areas to Ensure Quality Implementation. Quality Implementation Roadmaps

ERIC Educational Resources Information Center

Data Quality Campaign, 2016

2016-01-01

Every state can create secure, robust linkages between early childhood and K-12 data systems, and effectively use the information from these linkages to implement initiatives to support programs and children, answer key policy questions, and be transparent about how the state's early childhood investments prepare students for success in school and…

Genotype calling from next-generation sequencing data using haplotype information of reads

PubMed Central

Zhi, Degui; Wu, Jihua; Liu, Nianjun; Zhang, Kui

2012-01-01

Motivation: Low coverage sequencing provides an economic strategy for whole genome sequencing. When sequencing a set of individuals, genotype calling can be challenging due to low sequencing coverage. Linkage disequilibrium (LD) based refinement of genotyping calling is essential to improve the accuracy. Current LD-based methods use read counts or genotype likelihoods at individual potential polymorphic sites (PPSs). Reads that span multiple PPSs (jumping reads) can provide additional haplotype information overlooked by current methods. Results: In this article, we introduce a new Hidden Markov Model (HMM)-based method that can take into account jumping reads information across adjacent PPSs and implement it in the HapSeq program. Our method extends the HMM in Thunder and explicitly models jumping reads information as emission probabilities conditional on the states of adjacent PPSs. Our simulation results show that, compared to Thunder, HapSeq reduces the genotyping error rate by 30%, from 0.86% to 0.60%. The results from the 1000 Genomes Project show that HapSeq reduces the genotyping error rate by 12 and 9%, from 2.24% and 2.76% to 1.97% and 2.50% for individuals with European and African ancestry, respectively. We expect our program can improve genotyping qualities of the large number of ongoing and planned whole genome sequencing projects. Contact: dzhi@ms.soph.uab.edu; kzhang@ms.soph.uab.edu Availability: The software package HapSeq and its manual can be found and downloaded at www.ssg.uab.edu/hapseq/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID:22285565

Posterior probability of linkage and maximal lod score.

PubMed

Génin, E; Martinez, M; Clerget-Darpoux, F

1995-01-01

To detect linkage between a trait and a marker, Morton (1955) proposed to calculate the lod score z(theta 1) at a given value theta 1 of the recombination fraction. If z(theta 1) reaches +3 then linkage is concluded. However, in practice, lod scores are calculated for different values of the recombination fraction between 0 and 0.5 and the test is based on the maximum value of the lod score Zmax. The impact of this deviation of the test on the probability that in fact linkage does not exist, when linkage was concluded, is documented here. This posterior probability of no linkage can be derived by using Bayes' theorem. It is less than 5% when the lod score at a predetermined theta 1 is used for the test. But, for a Zmax of +3, we showed that it can reach 16.4%. Thus, considering a composite alternative hypothesis instead of a single one decreases the reliability of the test. The reliability decreases rapidly when Zmax is less than +3. Given a Zmax of +2.5, there is a 33% chance that linkage does not exist. Moreover, the posterior probability depends not only on the value of Zmax but also jointly on the family structures and on the genetic model. For a given Zmax, the chance that linkage exists may then vary.

A reference linkage map for Eucalyptus

PubMed Central

2012-01-01

Background Genetic linkage maps are invaluable resources in plant research. They provide a key tool for many genetic applications including: mapping quantitative trait loci (QTL); comparative mapping; identifying unlinked (i.e. independent) DNA markers for fingerprinting, population genetics and phylogenetics; assisting genome sequence assembly; relating physical and recombination distances along the genome and map-based cloning of genes. Eucalypts are the dominant tree species in most Australian ecosystems and of economic importance globally as plantation trees. The genome sequence of E. grandis has recently been released providing unprecedented opportunities for genetic and genomic research in the genus. A robust reference linkage map containing sequence-based molecular markers is needed to capitalise on this resource. Several high density linkage maps have recently been constructed for the main commercial forestry species in the genus (E. grandis, E. urophylla and E. globulus) using sequenced Diversity Arrays Technology (DArT) and microsatellite markers. To provide a single reference linkage map for eucalypts a composite map was produced through the integration of data from seven independent mapping experiments (1950 individuals) using a marker-merging method. Results The composite map totalled 1107 cM and contained 4101 markers; comprising 3880 DArT, 213 microsatellite and eight candidate genes. Eighty-one DArT markers were mapped to two or more linkage groups, resulting in the 4101 markers being mapped to 4191 map positions. Approximately 13% of DArT markers mapped to identical map positions, thus the composite map contained 3634 unique loci at an average interval of 0.31 cM. Conclusion The composite map represents the most saturated linkage map yet produced in Eucalyptus. As the majority of DArT markers contained on the map have been sequenced, the map provides a direct link to the E. grandis genome sequence and will serve as an important reference for

Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas.

PubMed

Sun, Xiangqing; Elston, Robert; Falk, Gary W; Grady, William M; Faulx, Ashley; Mittal, Sumeet K; Canto, Marcia I; Shaheen, Nicholas J; Wang, Jean S; Iyer, Prasad G; Abrams, Julian A; Willis, Joseph E; Guda, Kishore; Markowitz, Sanford; Barnholtz-Sloan, Jill S; Chandar, Apoorva; Brock, Wendy; Chak, Amitabh

2016-07-01

Familial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett's esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC). We genotyped 144 individuals in 42 multiplex pedigrees chosen from 1000 singly ascertained BE/EAC pedigrees, and performed both model-based and model-free linkage analyses, using S.A.G.E. and other software. Segregation models were fitted, from the data on both the 42 pedigrees and the 1000 pedigrees, to determine parameters for performing model-based linkage analysis. Model-based and model-free linkage analyses were conducted in two sets of pedigrees: the 42 pedigrees and a subset of 18 pedigrees with female affected members that are expected to be more genetically homogeneous. Genome-wide associations were also tested in these families. Linkage analyses on the 42 pedigrees identified several regions consistently suggestive of linkage by different linkage analysis methods on chromosomes 2q31, 12q23, and 4p14. A linkage on 15q26 is the only consistent linkage region identified in the 18 female-affected pedigrees, in which the linkage signal is higher than in the 42 pedigrees. Other tentative linkage signals are also reported. Our linkage study of BE/EAC pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to BE and EAC.

Linkage and Association Mapping for Two Major Traits Used in the Maritime Pine Breeding Program: Height Growth and Stem Straightness

PubMed Central

Bink, Marco CAM; van Heerwaarden, Joost; Chancerel, Emilie; Boury, Christophe; Lesur, Isabelle; Isik, Fikret; Bouffier, Laurent; Plomion, Christophe

2016-01-01

Background Increasing our understanding of the genetic architecture of complex traits, through analyses of genotype-phenotype associations and of the genes/polymorphisms accounting for trait variation, is crucial, to improve the integration of molecular markers into forest tree breeding. In this study, two full-sib families and one breeding population of maritime pine were used to identify quantitative trait loci (QTLs) for height growth and stem straightness, through linkage analysis (LA) and linkage disequilibrium (LD) mapping approaches. Results The populations used for LA consisted of two unrelated three-generation full-sib families (n = 197 and n = 477). These populations were assessed for height growth or stem straightness and genotyped for 248 and 217 markers, respectively. The population used for LD mapping consisted of 661 founders of the first and second generations of the breeding program. This population was phenotyped for the same traits and genotyped for 2,498 single-nucleotide polymorphism (SNP) markers corresponding to 1,652 gene loci. The gene-based reference genetic map of maritime pine was used to localize and compare the QTLs detected by the two approaches, for both traits. LA identified three QTLs for stem straightness and two QTLs for height growth. The LD study yielded seven significant associations (P ≤ 0.001): four for stem straightness and three for height growth. No colocalisation was found between QTLs identified by LA and SNPs detected by LD mapping for the same trait. Conclusions This study provides the first comparison of LA and LD mapping approaches in maritime pine, highlighting the complementary nature of these two approaches for deciphering the genetic architecture of two mandatory traits of the breeding program. PMID:27806077

Linkage and Association Mapping for Two Major Traits Used in the Maritime Pine Breeding Program: Height Growth and Stem Straightness.

PubMed

Bartholomé, Jérôme; Bink, Marco Cam; van Heerwaarden, Joost; Chancerel, Emilie; Boury, Christophe; Lesur, Isabelle; Isik, Fikret; Bouffier, Laurent; Plomion, Christophe

2016-01-01

Increasing our understanding of the genetic architecture of complex traits, through analyses of genotype-phenotype associations and of the genes/polymorphisms accounting for trait variation, is crucial, to improve the integration of molecular markers into forest tree breeding. In this study, two full-sib families and one breeding population of maritime pine were used to identify quantitative trait loci (QTLs) for height growth and stem straightness, through linkage analysis (LA) and linkage disequilibrium (LD) mapping approaches. The populations used for LA consisted of two unrelated three-generation full-sib families (n = 197 and n = 477). These populations were assessed for height growth or stem straightness and genotyped for 248 and 217 markers, respectively. The population used for LD mapping consisted of 661 founders of the first and second generations of the breeding program. This population was phenotyped for the same traits and genotyped for 2,498 single-nucleotide polymorphism (SNP) markers corresponding to 1,652 gene loci. The gene-based reference genetic map of maritime pine was used to localize and compare the QTLs detected by the two approaches, for both traits. LA identified three QTLs for stem straightness and two QTLs for height growth. The LD study yielded seven significant associations (P ≤ 0.001): four for stem straightness and three for height growth. No colocalisation was found between QTLs identified by LA and SNPs detected by LD mapping for the same trait. This study provides the first comparison of LA and LD mapping approaches in maritime pine, highlighting the complementary nature of these two approaches for deciphering the genetic architecture of two mandatory traits of the breeding program.

DNA linkage studies of degenerative retinal diseases.

PubMed

Daiger, S P; Heckenlively, J R; Lewis, R A; Pelias, M Z

1987-01-01

DNA linkage studies of human genetic diseases have led to rapid characterization of a number of otherwise intractable disease loci. Detection of a linked DNA marker, the first step in "reverse genetics", has permitted cloning of the genes for Duchenne muscular dystrophy, retinoblastoma and chronic granulomatosis disease, among others. Thus, the case for applying these techniques to retinitis pigmentosa and related diseases, and the urgency in capitalizing on molecular developments, is justified and compelling. The first major success regarding RP was in demonstrating linkage of the DNA marker DXS7 (L1.28) to XRP. For autosomal forms of the disease, conventional linkage studies have provided tentative evidence for linkage of ADRP to the Rh blood group on chromosome lp and for linkage of Usher's syndrome to Gc and 4q. These provisional assignments are, at least, an important starting point for DNA analysis. The Support Program for DNA Linkage Studies of Degenerative Retinal Diseases was established to provide access for the scientific community to appropriate families, using the resources of the Human Genetic Mutant Cell Repository to prepare, store and distribute lymphoblast lines. To date, two extensive, well-characterized families are included in the program: the autosomal dominant RP family UCLA-RP01, and the Usher's syndrome families LSU-US01. It is highly likely that rapid progress will be made in mapping and characterizing the inherited retinal dystrophies. We believe the support program will facilitate this progress.

Linkage Disequilibrium And Genome-Wide Association Studies In O. sativa

USDA-ARS?s Scientific Manuscript database

There is increasing evidence that genome-wide association studies provide a powerful approach to find the genetic basis of complex phenotypic variation in all kinds of species. For this purpose, we developed the first generation 44K Affymetrix SNP array in rice (see Tung et al. poster). We genotyped...

Dynamics of a durable commodity market involving trade at disequilibrium

NASA Astrophysics Data System (ADS)

Panchuk, A.; Puu, T.

2018-05-01

The present work considers a simple model of a durable commodity market involving two agents who trade stocks of two different types. Stock commodities, in contrast to flow commodities, remain on the market from period to period and, consequently, there is neither unique demand function nor unique supply function exists. We also set up exact conditions for trade at disequilibrium, the issue being usually neglected, though a fact of reality. The induced iterative system has infinite number of fixed points and path dependent dynamics. We show that a typical orbit is either attracted to one of the fixed points or eventually sticks at a no-trade point. For the latter the stock distribution always remains the same while the price displays periodic or chaotic oscillations.

The effect of using genealogy-based haplotypes for genomic prediction

PubMed Central

2013-01-01

Background Genomic prediction uses two sources of information: linkage disequilibrium between markers and quantitative trait loci, and additive genetic relationships between individuals. One way to increase the accuracy of genomic prediction is to capture more linkage disequilibrium by regression on haplotypes instead of regression on individual markers. The aim of this study was to investigate the accuracy of genomic prediction using haplotypes based on local genealogy information. Methods A total of 4429 Danish Holstein bulls were genotyped with the 50K SNP chip. Haplotypes were constructed using local genealogical trees. Effects of haplotype covariates were estimated with two types of prediction models: (1) assuming that effects had the same distribution for all haplotype covariates, i.e. the GBLUP method and (2) assuming that a large proportion (π) of the haplotype covariates had zero effect, i.e. a Bayesian mixture method. Results About 7.5 times more covariate effects were estimated when fitting haplotypes based on local genealogical trees compared to fitting individuals markers. Genealogy-based haplotype clustering slightly increased the accuracy of genomic prediction and, in some cases, decreased the bias of prediction. With the Bayesian method, accuracy of prediction was less sensitive to parameter π when fitting haplotypes compared to fitting markers. Conclusions Use of haplotypes based on genealogy can slightly increase the accuracy of genomic prediction. Improved methods to cluster the haplotypes constructed from local genealogy could lead to additional gains in accuracy. PMID:23496971

Key practices for implementing geospatial technologies for a planning and environment linkages (PEL) approach

DOT National Transportation Integrated Search

2008-07-01

This report presents three case studies that illustrate how geographic information systems (GIS) have been used to implement the Federal Highway Administrations (FHWA) Planning and Environment Linkages (PEL) approach. The PEL approach provides inf...

A study of disequilibrium between 220Rn and 216Po for 220Rn measurements using a flow-through Lucas scintillation cell.

PubMed

Sathyabama, N; Datta, D; Gaware, J J; Mayya, Y S; Tripathi, R M

2014-01-01

Lucas-type scintillation cells (LSCs) are commonly used for rapid measurements of (220)Rn concentrations in flow-through mode in field and for calibration experiments in laboratories. However, in those measurements, equilibrium between (220)Rn and (216)Po is generally assumed and two alpha particles are considered to be emitted per (220)Rn decay due to very short half-life of (216)Po. In this paper, a small, yet significant disequilibrium existing between (220)Rn and (216)Po has been examined and shown that less than two alpha particles are actually emitted per (220)Rn decay in the cell when flow is maintained. A theoretical formula has been derived for the first time for a correction factor (CF) to be applied to this measured concentration to account for the disequilibrium. The existence of this disequilibrium has been verified experimentally and is found to increase with the increase in the ratio of flow rate to cell volume. The reason for the disequilibrium is attributed to the flushing out of (216)Po formed in the cell before its decay due to the flow. Uncertainties in measured concentrations have been estimated and the estimated CF values have been found to be significant for the flow rates considered above 5 dm(3) min(-1) for a cell of volume 0.125 dm(3). The calculated values of the CF are about 1.055 to 1.178 in the flow rate range of 4 to 15 dm(3) min(-1) for the cell of volume 0.125 dm(3), while the corresponding experimental values are 1.023 to 1.264. This is a systematic error introduced in (220)Rn measurements using a flow-through LSC, which can be removed either by correct formulation or by proper design of a measurement set-up.

Army Active Duty Members’ Linkage to Veterans Health Administration Services After Deployments to Iraq or Afghanistan and Following Separation

PubMed Central

Vanneman, Megan E.; Harris, Alex H. S.; Chen, Cheng; Mohr, Beth A.; Adams, Rachel Sayko; Williams, Thomas V.; Larson, Mary Jo

2015-01-01

This study described the rate and predictors of Operation Enduring Freedom/Operation Iraqi Freedom active duty Army members’ enrollment in and use of Veterans Health Administration (VHA) services (linkage), as well as variation in linkage rates by VHA facility. We used a multivariate mixed effect regression model to predict linkage to VHA, and also calculated linkage rates in the catchment areas of each facility (n = 158). The sample included 151,122 active duty members who deployed to Iraq or Afghanistan and then separated from the Army between fiscal years 2008 and 2012. Approximately 48% of the active duty members separating utilized VHA as an enrollee within one year. There was significant variation in linkage rates by VHA facilities (31–72%). The most notable variables associated with greater linkage included probable serious injury during index deployment (odds ratio = 1.81), separation because of disability (odds ratio = 2.86), and various measures of receipt of VHA care before and after separation. Information about the individual characteristics that predict greater or lesser linkage to VHA services can be used to improve delivery of health care services at VHA as well as outreach efforts to active duty Army members. PMID:26444467

A High-Density Linkage Map for Astyanax mexicanus Using Genotyping-by-Sequencing Technology

PubMed Central

Carlson, Brian M.; Onusko, Samuel W.; Gross, Joshua B.

2014-01-01

The Mexican tetra, Astyanax mexicanus, is a unique model system consisting of cave-adapted and surface-dwelling morphotypes that diverged >1 million years (My) ago. This remarkable natural experiment has enabled powerful genetic analyses of cave adaptation. Here, we describe the application of next-generation sequencing technology to the creation of a high-density linkage map. Our map comprises more than 2200 markers populating 25 linkage groups constructed from genotypic data generated from a single genotyping-by-sequencing project. We leveraged emergent genomic and transcriptomic resources to anchor hundreds of anonymous Astyanax markers to the genome of the zebrafish (Danio rerio), the most closely related model organism to our study species. This facilitated the identification of 784 distinct connections between our linkage map and the Danio rerio genome, highlighting several regions of conserved genomic architecture between the two species despite ∼150 My of divergence. Using a Mendelian cave-associated trait as a proof-of-principle, we successfully recovered the genomic position of the albinism locus near the gene Oca2. Further, our map successfully informed the positions of unplaced Astyanax genomic scaffolds within particular linkage groups. This ability to identify the relative location, orientation, and linear order of unaligned genomic scaffolds will facilitate ongoing efforts to improve on the current early draft and assemble future versions of the Astyanax physical genome. Moreover, this improved linkage map will enable higher-resolution genetic analyses and catalyze the discovery of the genetic basis for cave-associated phenotypes. PMID:25520037

Simulating a base population in honey bee for molecular genetic studies.

PubMed

Gupta, Pooja; Conrad, Tim; Spötter, Andreas; Reinsch, Norbert; Bienefeld, Kaspar

2012-06-27

Over the past years, reports have indicated that honey bee populations are declining and that infestation by an ecto-parasitic mite (Varroa destructor) is one of the main causes. Selective breeding of resistant bees can help to prevent losses due to the parasite, but it requires that a robust breeding program and genetic evaluation are implemented. Genomic selection has emerged as an important tool in animal breeding programs and simulation studies have shown that it yields more accurate breeding value estimates, higher genetic gain and low rates of inbreeding. Since genomic selection relies on marker data, simulations conducted on a genomic dataset are a pre-requisite before selection can be implemented. Although genomic datasets have been simulated in other species undergoing genetic evaluation, simulation of a genomic dataset specific to the honey bee is required since this species has a distinct genetic and reproductive biology. Our software program was aimed at constructing a base population by simulating a random mating honey bee population. A forward-time population simulation approach was applied since it allows modeling of genetic characteristics and reproductive behavior specific to the honey bee. Our software program yielded a genomic dataset for a base population in linkage disequilibrium. In addition, information was obtained on (1) the position of markers on each chromosome, (2) allele frequency, (3) χ(2) statistics for Hardy-Weinberg equilibrium, (4) a sorted list of markers with a minor allele frequency less than or equal to the input value, (5) average r(2) values of linkage disequilibrium between all simulated marker loci pair for all generations and (6) average r2 value of linkage disequilibrium in the last generation for selected markers with the highest minor allele frequency. We developed a software program that takes into account the genetic and reproductive biology specific to the honey bee and that can be used to constitute a genomic

A Test of Outreach and Drop-in Linkage Versus Shelter Linkage for Connecting Homeless Youth to Services.

PubMed

Slesnick, Natasha; Feng, Xin; Guo, Xiamei; Brakenhoff, Brittany; Carmona, Jasmin; Murnan, Aaron; Cash, Scottye; McRee, Annie-Laurie

2016-05-01

Outreach and service linkage are key for engaging marginalized populations, such as homeless youth, in services. Research to date has focused primarily on engaging individuals already receiving some services through emergency shelters, clinics, or other programs. Less is known about those who are not connected to services and, thus, likely the most vulnerable and in need of assistance. The current study sought to engage non-service-connected homeless youth (N = 79) into a strengths-based outreach and advocacy intervention. Youth were randomly assigned to receive 6 months of advocacy that focused on linking youth to a drop-in center (n = 40) or to a crisis shelter (n = 39). All youth were assessed at baseline and 3, 6, and 9 months post-baseline. Findings indicated that youth prefer drop-in center services to the shelter. Also, the drop-in center linkage condition was associated with more service linkage overall (B = 0.34, SE = 0.04, p < 0.01) and better alcohol-l [B = -0.39, SE = 0.09, t(75) = -4.48, p < 0.001] and HIV-related outcomes [B = 0.62, SE = 0.10, t(78) = 6.34, p < 0.001] compared to the shelter linkage condition. Findings highlight the importance of outreach and service linkage for reconnecting service-marginalized youth, and drop-in centers as a primary service option for homeless youth.

Linkage analysis in a Dutch family with X-linked recessive congenital stationary night blindness (XL-CSNB).

PubMed

Berger, W; van Duijnhoven, G; Pinckers, A; Smits, A; Ropers, H H; Cremers, F

1995-01-01

Linkage analysis has been performed in a large Dutch pedigree with X-linked recessive congenital stationary night blindness (CSNB) by utilizing 16 DNA markers from the proximal short arm of the human X chromosome (Xp21.1-11.2). Thirteen polymorphic markers are at least partially informative and have enabled pairwise and multipoint linkage analysis. For three loci, i.e. DXS228, the monoamine oxidase B gene and the Norrie disease gene (NDG), multipoint linkage studies have yielded maximum lod scores of > 3.0 at a recombination fraction of zero. Analysis of recombination events has enabled us to rule out the possibility that the underlying defect in this family is allelic to RP3; the gene defect could also be excluded from the proximal part of the region known to carry RP2. Linkage data are consistent with a possible involvement of the NDG but mutations in the open reading frame of this gene have not been found.

Family genome browser: visualizing genomes with pedigree information.

PubMed

Juan, Liran; Liu, Yongzhuang; Wang, Yongtian; Teng, Mingxiang; Zang, Tianyi; Wang, Yadong

2015-07-15

Families with inherited diseases are widely used in Mendelian/complex disease studies. Owing to the advances in high-throughput sequencing technologies, family genome sequencing becomes more and more prevalent. Visualizing family genomes can greatly facilitate human genetics studies and personalized medicine. However, due to the complex genetic relationships and high similarities among genomes of consanguineous family members, family genomes are difficult to be visualized in traditional genome visualization framework. How to visualize the family genome variants and their functions with integrated pedigree information remains a critical challenge. We developed the Family Genome Browser (FGB) to provide comprehensive analysis and visualization for family genomes. The FGB can visualize family genomes in both individual level and variant level effectively, through integrating genome data with pedigree information. Family genome analysis, including determination of parental origin of the variants, detection of de novo mutations, identification of potential recombination events and identical-by-decent segments, etc., can be performed flexibly. Diverse annotations for the family genome variants, such as dbSNP memberships, linkage disequilibriums, genes, variant effects, potential phenotypes, etc., are illustrated as well. Moreover, the FGB can automatically search de novo mutations and compound heterozygous variants for a selected individual, and guide investigators to find high-risk genes with flexible navigation options. These features enable users to investigate and understand family genomes intuitively and systematically. The FGB is available at http://mlg.hit.edu.cn/FGB/. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Linkage studies in primary open angle glaucoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Avramopoulos, D.; Grigoriadu, M.; Kitsos, G.

1994-09-01

Glaucoma is a leading cause of blindness worldwide. The majority of glaucoma is associated with an open, normal appearing anterior chamber angle and is termed primary open angle glaucoma (POAG, MIM 137760). It is characterized by elevated intraocular pressure and onset in middle age or later. A subset of POAG with juvenile onset has recently been linked to chromosome 1q in two families with autosomal dominant inheritance. Eleven pedigrees with autosomal dominant POG (non-juvenile-onset) have been identified in Epirus, Greece. In the present study DNA samples have been collected from 50 individuals from one large pedigree, including 12 affected individuals.more » Preliminary results of linkage analysis with chromosome 1 microsatellites using the computer program package LINKAGE Version 5.1 showed no linkage with the markers previously linked to juvenile-onset POAG. Further linkage analysis is being pursued, and the results will be presented.« less

PERMANENT GENETIC RESOURCES: Isolation and characterization of polymorphic microsatellite loci in common evening primrose (Oenothera biennis).

PubMed

Larson, E L; Bogdanowicz, S M; Agrawal, A A; Johnson, M T J; Harrison, R G

2008-03-01

We developed nine polymorphic microsatellite loci for evening primrose (Oenothera biennis). These loci have two to 18 alleles per locus and observed heterozygosities ranging from 0 to 0.879 in a sample of 34 individuals. In a pattern consistent with the functionally asexual reproductive system of this species, 17/36 pairs of loci revealed significant linkage disequilibrium and three loci showed significant deviations from Hardy-Weinberg equilibrium. The loci will be informative in identifying genotypes in multigenerational field studies to assess changes in genotype frequencies. © 2007 The Authors.

Systematic Assessment of Linkage to Care for Persons with HIV Released from Corrections Facilities Using Existing Datasets

PubMed Central

Montague, Brian T.; Rosen, David L.; Sammartino, Cara; Costa, Michael; Gutman, Roee; Solomon, Liza; Rich, Josiah

2016-01-01

Abstract Populations in corrections continue to have high prevalence of HIV. Expanded testing and treatment programs allow persons to be identified and stabilized on treatment while incarcerated. However, these gains and frequently lost on reentry. Systemic frameworks are needed to monitor linkage to care to guide programs supporting linkage to care. To assess the adequacy of linkage to care on reentry, incarceration data from the National Corrections Reporting Program and data from the Ryan White Services Report from 2010 to 2012 were linked using an encrypted client identification (eUCI). Time from release to the first visit and presence of detectable HIV RNA at linkage were assessed. Multivariate survival analyses were performed to identify associations between patient characteristics and time to linkage. Among those linking, only 43% in Rhode Island and 49% in North Carolina linked within 90 days, and 33% in both states had detectable viremia at the first visit. Those not previously in care and with shorter incarceration experiences longer linkage times. Persons identified as black, had median times greater than 1 year. Using existing datasets, significant gaps in linkage to care for persons with HIV on release from corrections were demonstrated in Rhode Island and North Carolina. Systemically implementing this monitoring to evaluate changes over time would provide important information to support interventions to improve linkage in high-risk populations. Using national datasets for both corrections and clinical data, this framework equally could be used to evaluate experiences of persons with HIV linking to care on release from corrections facilities nationwide. PMID:26836237

Annotated genetic linkage maps of Pinus pinaster Ait. from a Central Spain population using microsatellite and gene based markers.

PubMed

de Miguel, Marina; de Maria, Nuria; Guevara, M Angeles; Diaz, Luis; Sáez-Laguna, Enrique; Sánchez-Gómez, David; Chancerel, Emilie; Aranda, Ismael; Collada, Carmen; Plomion, Christophe; Cabezas, José-Antonio; Cervera, María-Teresa

2012-10-04

Pinus pinaster Ait. is a major resin producing species in Spain. Genetic linkage mapping can facilitate marker-assisted selection (MAS) through the identification of Quantitative Trait Loci and selection of allelic variants of interest in breeding populations. In this study, we report annotated genetic linkage maps for two individuals (C14 and C15) belonging to a breeding program aiming to increase resin production. We use different types of DNA markers, including last-generation molecular markers. We obtained 13 and 14 linkage groups for C14 and C15 maps, respectively. A total of 211 and 215 markers were positioned on each map and estimated genome length was between 1,870 and 2,166 cM respectively, which represents near 65% of genome coverage. Comparative mapping with previously developed genetic linkage maps for P. pinaster based on about 60 common markers enabled aligning linkage groups to this reference map. The comparison of our annotated linkage maps and linkage maps reporting QTL information revealed 11 annotated SNPs in candidate genes that co-localized with previously reported QTLs for wood properties and water use efficiency. This study provides genetic linkage maps from a Spanish population that shows high levels of genetic divergence with French populations from which segregating progenies have been previously mapped. These genetic maps will be of interest to construct a reliable consensus linkage map for the species. The importance of developing functional genetic linkage maps is highlighted, especially when working with breeding populations for its future application in MAS for traits of interest.

Annotated genetic linkage maps of Pinus pinaster Ait. from a Central Spain population using microsatellite and gene based markers

PubMed Central

2012-01-01

Background Pinus pinaster Ait. is a major resin producing species in Spain. Genetic linkage mapping can facilitate marker-assisted selection (MAS) through the identification of Quantitative Trait Loci and selection of allelic variants of interest in breeding populations. In this study, we report annotated genetic linkage maps for two individuals (C14 and C15) belonging to a breeding program aiming to increase resin production. We use different types of DNA markers, including last-generation molecular markers. Results We obtained 13 and 14 linkage groups for C14 and C15 maps, respectively. A total of 211 and 215 markers were positioned on each map and estimated genome length was between 1,870 and 2,166 cM respectively, which represents near 65% of genome coverage. Comparative mapping with previously developed genetic linkage maps for P. pinaster based on about 60 common markers enabled aligning linkage groups to this reference map. The comparison of our annotated linkage maps and linkage maps reporting QTL information revealed 11 annotated SNPs in candidate genes that co-localized with previously reported QTLs for wood properties and water use efficiency. Conclusions This study provides genetic linkage maps from a Spanish population that shows high levels of genetic divergence with French populations from which segregating progenies have been previously mapped. These genetic maps will be of interest to construct a reliable consensus linkage map for the species. The importance of developing functional genetic linkage maps is highlighted, especially when working with breeding populations for its future application in MAS for traits of interest. PMID:23036012

Rapid genotyping with DNA micro-arrays for high-density linkage mapping and QTL mapping in common buckwheat (Fagopyrum esculentum Moench)

PubMed Central

Yabe, Shiori; Hara, Takashi; Ueno, Mariko; Enoki, Hiroyuki; Kimura, Tatsuro; Nishimura, Satoru; Yasui, Yasuo; Ohsawa, Ryo; Iwata, Hiroyoshi

2014-01-01

For genetic studies and genomics-assisted breeding, particularly of minor crops, a genotyping system that does not require a priori genomic information is preferable. Here, we demonstrated the potential of a novel array-based genotyping system for the rapid construction of high-density linkage map and quantitative trait loci (QTL) mapping. By using the system, we successfully constructed an accurate, high-density linkage map for common buckwheat (Fagopyrum esculentum Moench); the map was composed of 756 loci and included 8,884 markers. The number of linkage groups converged to eight, which is the basic number of chromosomes in common buckwheat. The sizes of the linkage groups of the P1 and P2 maps were 773.8 and 800.4 cM, respectively. The average interval between adjacent loci was 2.13 cM. The linkage map constructed here will be useful for the analysis of other common buckwheat populations. We also performed QTL mapping for main stem length and detected four QTL. It took 37 days to process 178 samples from DNA extraction to genotyping, indicating the system enables genotyping of genome-wide markers for a few hundred buckwheat plants before the plants mature. The novel system will be useful for genomics-assisted breeding in minor crops without a priori genomic information. PMID:25914583

Rapid genotyping with DNA micro-arrays for high-density linkage mapping and QTL mapping in common buckwheat (Fagopyrum esculentum Moench).

PubMed

Yabe, Shiori; Hara, Takashi; Ueno, Mariko; Enoki, Hiroyuki; Kimura, Tatsuro; Nishimura, Satoru; Yasui, Yasuo; Ohsawa, Ryo; Iwata, Hiroyoshi

2014-12-01

For genetic studies and genomics-assisted breeding, particularly of minor crops, a genotyping system that does not require a priori genomic information is preferable. Here, we demonstrated the potential of a novel array-based genotyping system for the rapid construction of high-density linkage map and quantitative trait loci (QTL) mapping. By using the system, we successfully constructed an accurate, high-density linkage map for common buckwheat (Fagopyrum esculentum Moench); the map was composed of 756 loci and included 8,884 markers. The number of linkage groups converged to eight, which is the basic number of chromosomes in common buckwheat. The sizes of the linkage groups of the P1 and P2 maps were 773.8 and 800.4 cM, respectively. The average interval between adjacent loci was 2.13 cM. The linkage map constructed here will be useful for the analysis of other common buckwheat populations. We also performed QTL mapping for main stem length and detected four QTL. It took 37 days to process 178 samples from DNA extraction to genotyping, indicating the system enables genotyping of genome-wide markers for a few hundred buckwheat plants before the plants mature. The novel system will be useful for genomics-assisted breeding in minor crops without a priori genomic information.

Estimating parameters for probabilistic linkage of privacy-preserved datasets.

PubMed

Brown, Adrian P; Randall, Sean M; Ferrante, Anna M; Semmens, James B; Boyd, James H

2017-07-10

Probabilistic record linkage is a process used to bring together person-based records from within the same dataset (de-duplication) or from disparate datasets using pairwise comparisons and matching probabilities. The linkage strategy and associated match probabilities are often estimated through investigations into data quality and manual inspection. However, as privacy-preserved datasets comprise encrypted data, such methods are not possible. In this paper, we present a method for estimating the probabilities and threshold values for probabilistic privacy-preserved record linkage using Bloom filters. Our method was tested through a simulation study using synthetic data, followed by an application using real-world administrative data. Synthetic datasets were generated with error rates from zero to 20% error. Our method was used to estimate parameters (probabilities and thresholds) for de-duplication linkages. Linkage quality was determined by F-measure. Each dataset was privacy-preserved using separate Bloom filters for each field. Match probabilities were estimated using the expectation-maximisation (EM) algorithm on the privacy-preserved data. Threshold cut-off values were determined by an extension to the EM algorithm allowing linkage quality to be estimated for each possible threshold. De-duplication linkages of each privacy-preserved dataset were performed using both estimated and calculated probabilities. Linkage quality using the F-measure at the estimated threshold values was also compared to the highest F-measure. Three large administrative datasets were used to demonstrate the applicability of the probability and threshold estimation technique on real-world data. Linkage of the synthetic datasets using the estimated probabilities produced an F-measure that was comparable to the F-measure using calculated probabilities, even with up to 20% error. Linkage of the administrative datasets using estimated probabilities produced an F-measure that was higher

Association of the widespread A149P hereditary fructose intolerance mutation with newly identified sequence polymorphisms in the aldolase B gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brooks, C.C.; Tolan, D.R.

1993-04-01

Hereditary fructose intolerance (HFI) is a potentially fatal autosomal recessive disease resulting from the catalytic deficiency of fructose 1-phosphate aldolase (aldolase B) in fructose-metabolizing tissues. The A149P mutation in exon 5 of the aldolase B gene, located on chromosome 9q2l.3-q22.2, is widespread and the most common HFI mutation, accounting for 57% of HFI chromosomes. The possible origin of this mutation was studied by linkage to polymorphisms within the aldolase B gene. DNA fragments of the aldolase B gene containing the polymorphic marker loci from HFI patients homozygous for the A149P allele were amplified by PCR. Absolute linkage to a commonmore » Pvull RFLP allele was observed in 10 A149P homozygotes. In a more informative study, highly heterozygous polymorphisms were detected by direct sequence determination of a PCR-amplified aldolase B gene fragment. Two two-allele, single-base-pair polymorphisms, themselves in absolute linkage disequilibrium, in intron 8 (C at nucleotide 84 and A at nucleotide 105, or T at 84 and G at 105) of the aldolase B gene were identified. Mendelian segregation of these polymorphisms was confirmed in three families. Allele-specific oligonucleotide (ASO) hybridizations with probes for both sequence polymorphisms showed that 47% of 32 unrelated individuals were heterozygous at these loci; the calculated PIC value was .37. Finally, ASO hybridizations of PCR-amplified DNA from 15 HFI patients homozygous for the A149P allele with probes for these sequence polymorphisms revealed absolute linkage disequilibrium between the A149P mutation and the 84T/105G allele. These results are consistent with a single origin of the A149P allele and subsequent spread by genetic drift. 32 refs., 4 figs., 3 tabs.« less

Robustness of linkage strategy that leads to large-scale cooperation.

PubMed

Inaba, Misato; Takahashi, Nobuyuki; Ohtsuki, Hisashi

2016-11-21

One of the most well-known models to characterize cooperation among unrelated individuals is Social dilemma (SD). However there is no consensus about how to solve the SD by itself. Since SDs are often embedded in other social interactions, including indirect reciprocity games (IR), human can coordinate their behaviors across multiple games. Such coordination is called 'linkage'. Recently linkage has been considered as a promising solution to resolve SDs, since excluding SD defectors (i.e. those who defected in SD) from indirectly reciprocal relationships functions as a costless sanction. A previous study performed mathematical modeling and revealed that a linkage strategy, which cooperates in SD and engages in the Standing strategy in IR based on the recipients' behaviors in both SD and IR, was an ESS against a non-linkage strategy which defects in SD and engages in the Standing strategy in IR based on recipients' behaviors only in IR (Panchanathan and Boyd, 2004). In order to investigate the robustness of the linkage strategy, we devised a non-linkage strategy, which cooperates in SD but does not link two games. First, we conducted a mathematical analysis and demonstrated that the linkage strategy was not an ESS against cooperating non-linkage strategy. Second, we conducted a series of agent-based computer simulations to examine how the strategies perform in situations in which various types of errors can occur. Our results showed that the linkage strategy was an ESS only when there are implementation errors in SD. However, the equilibrium of the linkage strategy was unstable when there are perception errors. Since we know that humans are not free from perception errors in their social life, future studies will need to show how perception errors can be overcome in order to provide support for the conclusion that linkage is a plausible solution to SDs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Automated assembly of oligosaccharides containing multiple cis-glycosidic linkages

NASA Astrophysics Data System (ADS)

Hahm, Heung Sik; Hurevich, Mattan; Seeberger, Peter H.

2016-09-01

Automated glycan assembly (AGA) has advanced from a concept to a commercial technology that rapidly provides access to diverse oligosaccharide chains as long as 30-mers. To date, AGA was mainly employed to incorporate trans-glycosidic linkages, where C2 participating protecting groups ensure stereoselective couplings. Stereocontrol during the installation of cis-glycosidic linkages cannot rely on C2-participation and anomeric mixtures are typically formed. Here, we demonstrate that oligosaccharides containing multiple cis-glycosidic linkages can be prepared efficiently by AGA using monosaccharide building blocks equipped with remote participating protecting groups. The concept is illustrated by the automated syntheses of biologically relevant oligosaccharides bearing various cis-galactosidic and cis-glucosidic linkages. This work provides further proof that AGA facilitates the synthesis of complex oligosaccharides with multiple cis-linkages and other biologically important oligosaccharides.

Sex versus asex: An analysis of the role of variance conversion.

PubMed

Lewis-Pye, Andrew E M; Montalbán, Antonio

2017-04-01

The question as to why most complex organisms reproduce sexually remains a very active research area in evolutionary biology. Theories dating back to Weismann have suggested that the key may lie in the creation of increased variability in offspring, causing enhanced response to selection. Under appropriate conditions, selection is known to result in the generation of negative linkage disequilibrium, with the effect of recombination then being to increase genetic variance by reducing these negative associations between alleles. It has therefore been a matter of significant interest to understand precisely those conditions resulting in negative linkage disequilibrium, and to recognise also the conditions in which the corresponding increase in genetic variation will be advantageous. Here, we prove rigorous results for the multi-locus case, detailing the build up of negative linkage disequilibrium, and describing the long term effect on population fitness for models with and without bounds on fitness contributions from individual alleles. Under the assumption of large but finite bounds on fitness contributions from alleles, the non-linear nature of the effect of recombination on a population presents serious obstacles in finding the genetic composition of populations at equilibrium, and in establishing convergence to those equilibria. We describe techniques for analysing the long term behaviour of sexual and asexual populations for such models, and use these techniques to establish conditions resulting in higher fitnesses for sexually reproducing populations. Copyright © 2017 Elsevier Inc. All rights reserved.

Common variants of the EPDR1 gene and the risk of Dupuytren’s disease.

PubMed

Dębniak, T; Żyluk, A; Puchalski, P; Serrano-Fernandez, P

2013-10-01

The object of this study was the investigation of 3 common variants of single nucleotide polymorphisms of the ependymin-related gene 1 and its association with the occurrence of Dupuytren's disease. DNA samples were obtained from the peripheral blood of 508 consecutive patients. The control group comprised 515 healthy adults who were age-matched with the Dupuytren's patients. 3 common variants were analysed using TaqMan® genotyping assays and sequencing. The differences in the frequencies of variants of single nucleotide polymorphisms in patients and the control group were statistically tested. Additionally, haplotype frequency and linkage disequilibrium were analysed for these variants. A statistically significant association was noted between rs16879765_CT, rs16879765_TT and rs13240429_AA variants and Dupuytren's disease. 2 haplotypes: rs2722280_C+rs13240429_A+rs16879765_C and rs2722280_C+rs13240429_G+rs16879765_T were found to be statistically significantly associated with Dupuytren's disease. Moreover, we found that rs13240429 and rs16879765 variants were in strong linkage disequilibrium, while rs2722280 was only in moderate linkage disequilibrium. No significant differences were found in the frequencies of the variants of the gene between the groups with a positive and negative familial history of Dupuytren's disease. In conclusion, results of this study suggest that EPDR1 gene can be added to a growing list of genes associated with Dupuytren's disease development. © Georg Thieme Verlag KG Stuttgart · New York.

Convective Dynamics and Disequilibrium Chemistry in the Atmospheres of Giant Planets and Brown Dwarfs

NASA Astrophysics Data System (ADS)

Bordwell, Baylee; Brown, Benjamin P.; Oishi, Jeffrey S.

2018-02-01

Disequilibrium chemical processes significantly affect the spectra of substellar objects. To study these effects, dynamical disequilibrium has been parameterized using the quench and eddy diffusion approximations, but little work has been done to explore how these approximations perform under realistic planetary conditions in different dynamical regimes. As a first step toward addressing this problem, we study the localized, small-scale convective dynamics of planetary atmospheres by direct numerical simulation of fully compressible hydrodynamics with reactive tracers using the Dedalus code. Using polytropically stratified, plane-parallel atmospheres in 2D and 3D, we explore the quenching behavior of different abstract chemical species as a function of the dynamical conditions of the atmosphere as parameterized by the Rayleigh number. We find that in both 2D and 3D, chemical species quench deeper than would be predicted based on simple mixing-length arguments. Instead, it is necessary to employ length scales based on the chemical equilibrium profile of the reacting species in order to predict quench points and perform chemical kinetics modeling in 1D. Based on the results of our simulations, we provide a new length scale, derived from the chemical scale height, that can be used to perform these calculations. This length scale is simple to calculate from known chemical data and makes reasonable predictions for our dynamical simulations.

Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism.

PubMed

Kim, S-J; Young, L J; Gonen, D; Veenstra-VanderWeele, J; Courchesne, R; Courchesne, E; Lord, C; Leventhal, B L; Cook, E H; Insel, T R

2002-01-01

Impairment in social reciprocity is a central component of autism. In preclinical studies, arginine vasopressin (AVP) has been shown to increase a range of social behaviors, including affiliation and attachment, via the V(1a) receptor (AVPR1A) in the brain. Both the behavioral effects of AVP and the neural distribution of the V1a receptor vary greatly across mammalian species. This difference in regional receptor expression as well as differences in social behavior may result from a highly variable repetitive sequence in the 5' flanking region of the V1a gene (AVPR1A). Given this comparative evidence for a role in inter-species variation in social behavior, we explored whether within our own species, variation in the human AVPR1A may contribute to individual variations in social behavior, with autism representing an extreme form of social impairment. We genotyped two microsatellite polymorphisms from the 5' flanking region of AVPR1A for 115 autism trios and found nominally significant transmission disequilibrium between autism and one of the microsatellite markers by Multiallelic Transmission/Disequilibrium test (MTDT) that was not significant after Bonferroni correction. We also screened approximately 2 kb of the 5' flanking region and the coding region and identified 10 single nucleotide polymorphisms.

Quantifying the Correctness, Computational Complexity, and Security of Privacy-Preserving String Comparators for Record Linkage

PubMed Central

Durham, Elizabeth; Xue, Yuan; Kantarcioglu, Murat; Malin, Bradley

2011-01-01

Record linkage is the task of identifying records from disparate data sources that refer to the same entity. It is an integral component of data processing in distributed settings, where the integration of information from multiple sources can prevent duplication and enrich overall data quality, thus enabling more detailed and correct analysis. Privacy-preserving record linkage (PPRL) is a variant of the task in which data owners wish to perform linkage without revealing identifiers associated with the records. This task is desirable in various domains, including healthcare, where it may not be possible to reveal patient identity due to confidentiality requirements, and in business, where it could be disadvantageous to divulge customers' identities. To perform PPRL, it is necessary to apply string comparators that function in the privacy-preserving space. A number of privacy-preserving string comparators (PPSCs) have been proposed, but little research has compared them in the context of a real record linkage application. This paper performs a principled and comprehensive evaluation of six PPSCs in terms of three key properties: 1) correctness of record linkage predictions, 2) computational complexity, and 3) security. We utilize a real publicly-available dataset, derived from the North Carolina voter registration database, to evaluate the tradeoffs between the aforementioned properties. Among our results, we find that PPSCs that partition, encode, and compare strings yield highly accurate record linkage results. However, as a tradeoff, we observe that such PPSCs are less secure than those that map and compare strings in a reduced dimensional space. PMID:22904698

Quantifying the Correctness, Computational Complexity, and Security of Privacy-Preserving String Comparators for Record Linkage.

PubMed

Durham, Elizabeth; Xue, Yuan; Kantarcioglu, Murat; Malin, Bradley

2012-10-01

Record linkage is the task of identifying records from disparate data sources that refer to the same entity. It is an integral component of data processing in distributed settings, where the integration of information from multiple sources can prevent duplication and enrich overall data quality, thus enabling more detailed and correct analysis. Privacy-preserving record linkage (PPRL) is a variant of the task in which data owners wish to perform linkage without revealing identifiers associated with the records. This task is desirable in various domains, including healthcare, where it may not be possible to reveal patient identity due to confidentiality requirements, and in business, where it could be disadvantageous to divulge customers' identities. To perform PPRL, it is necessary to apply string comparators that function in the privacy-preserving space. A number of privacy-preserving string comparators (PPSCs) have been proposed, but little research has compared them in the context of a real record linkage application. This paper performs a principled and comprehensive evaluation of six PPSCs in terms of three key properties: 1) correctness of record linkage predictions, 2) computational complexity, and 3) security. We utilize a real publicly-available dataset, derived from the North Carolina voter registration database, to evaluate the tradeoffs between the aforementioned properties. Among our results, we find that PPSCs that partition, encode, and compare strings yield highly accurate record linkage results. However, as a tradeoff, we observe that such PPSCs are less secure than those that map and compare strings in a reduced dimensional space.

Autosomal Dominant Nonsyndromic Cleft Lip and Palate: Significant Evidence of Linkage at 18q21.1

PubMed Central

Beiraghi, Soraya ; Nath, Swapan K. ; Gaines, Matthew ; Mandhyan, Desh D. ; Hutchings, David ; Ratnamala, Uppala ; McElreavey, Ken ; Bartoloni, Lucia ; Antonarakis, Gregory S. ; Antonarakis, Stylianos E. ; Radhakrishna, Uppala 

2007-01-01

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital facial defects, with an incidence of 1 in 700–1,000 live births among individuals of European descent. Several linkage and association studies of NSCL/P have suggested numerous candidate genes and genomic regions. A genomewide linkage analysis of a large multigenerational family (UR410) with NSCL/P was performed using a single-nucleotide–polymorphism array. Nonparametric linkage (NPL) analysis provided significant evidence of linkage for marker rs728683 on chromosome 18q21.1 (NPL=43.33 and P=.000061; nonparametric LOD=3.97 and P=.00001). Parametric linkage analysis with a dominant mode of inheritance and reduced penetrance resulted in a maximum LOD score of 3.61 at position 47.4 Mb on chromosome 18q21.1. Haplotype analysis with informative crossovers defined a 5.7-Mb genomic region spanned by proximal marker rs1824683 (42,403,918 bp) and distal marker rs768206 (48,132,862 bp). Thus, a novel genomic region on 18q21.1 was identified that most likely harbors a high-risk variant for NSCL/P in this family; we propose to name this locus “OFC11” (orofacial cleft 11). PMID:17564975

Distribution of lod scores in oligogenic linkage analysis.

PubMed

Williams, J T; North, K E; Martin, L J; Comuzzie, A G; Göring, H H; Blangero, J

2001-01-01

In variance component oligogenic linkage analysis it can happen that the residual additive genetic variance bounds to zero when estimating the effect of the ith quantitative trait locus. Using quantitative trait Q1 from the Genetic Analysis Workshop 12 simulated general population data, we compare the observed lod scores from oligogenic linkage analysis with the empirical lod score distribution under a null model of no linkage. We find that zero residual additive genetic variance in the null model alters the usual distribution of the likelihood-ratio statistic.

Data Linkage: A powerful research tool with potential problems

PubMed Central

2010-01-01

Background Policy makers, clinicians and researchers are demonstrating increasing interest in using data linked from multiple sources to support measurement of clinical performance and patient health outcomes. However, the utility of data linkage may be compromised by sub-optimal or incomplete linkage, leading to systematic bias. In this study, we synthesize the evidence identifying participant or population characteristics that can influence the validity and completeness of data linkage and may be associated with systematic bias in reported outcomes. Methods A narrative review, using structured search methods was undertaken. Key words "data linkage" and Mesh term "medical record linkage" were applied to Medline, EMBASE and CINAHL databases between 1991 and 2007. Abstract inclusion criteria were; the article attempted an empirical evaluation of methodological issues relating to data linkage and reported on patient characteristics, the study design included analysis of matched versus unmatched records, and the report was in English. Included articles were grouped thematically according to patient characteristics that were compared between matched and unmatched records. Results The search identified 1810 articles of which 33 (1.8%) met inclusion criteria. There was marked heterogeneity in study methods and factors investigated. Characteristics that were unevenly distributed among matched and unmatched records were; age (72% of studies), sex (50% of studies), race (64% of studies), geographical/hospital site (93% of studies), socio-economic status (82% of studies) and health status (72% of studies). Conclusion A number of relevant patient or population factors may be associated with incomplete data linkage resulting in systematic bias in reported clinical outcomes. Readers should consider these factors in interpreting the reported results of data linkage studies. PMID:21176171

Individual Data Linkage of Survey Data with Claims Data in Germany—An Overview Based on a Cohort Study

PubMed Central

March, Stefanie

2017-01-01

Research based on health insurance data has a long tradition in Germany. By contrast, data linkage of survey data with such claims data is a relatively new field of research with high potential. Data linkage opens up new opportunities for analyses in the field of health services research and public health. Germany has comprehensive rules and regulations of data protection that have to be followed. Therefore, a written informed consent is needed for individual data linkage. Additionally, the health system is characterized by heterogeneity of health insurance. The lidA-living at work-study is a cohort study on work, age and health, which linked survey data with claims data of a large number of statutory health insurance data. All health insurance funds were contacted, of whom a written consent was given. This paper will give an overview of individual data linkage of survey data with German claims data on the example of the lidA-study results. The challenges and limitations of data linkage will be presented. Despite heterogeneity, such kind of studies is possible with a negligibly small influence of bias. The experience we gain in lidA will be shown and provide important insights for other studies focusing on data linkage. PMID:29232834

Individual Data Linkage of Survey Data with Claims Data in Germany-An Overview Based on a Cohort Study.

PubMed

March, Stefanie

2017-12-09

Research based on health insurance data has a long tradition in Germany. By contrast, data linkage of survey data with such claims data is a relatively new field of research with high potential. Data linkage opens up new opportunities for analyses in the field of health services research and public health. Germany has comprehensive rules and regulations of data protection that have to be followed. Therefore, a written informed consent is needed for individual data linkage. Additionally, the health system is characterized by heterogeneity of health insurance. The lidA-living at work-study is a cohort study on work, age and health, which linked survey data with claims data of a large number of statutory health insurance data. All health insurance funds were contacted, of whom a written consent was given. This paper will give an overview of individual data linkage of survey data with German claims data on the example of the lidA-study results. The challenges and limitations of data linkage will be presented. Despite heterogeneity, such kind of studies is possible with a negligibly small influence of bias. The experience we gain in lidA will be shown and provide important insights for other studies focusing on data linkage.

Considerations in using linkage analysis as a presymptomatic test for Huntington's disease.

PubMed

Farrer, L A; Myers, R H; Cupples, L A; Conneally, P M

1988-09-01

The polymorphic locus D4S10 that is genetically linked to the locus for Huntington's disease (HD) has made possible a presymptomatic test for those at risk. Because the symptoms of this progressively debilitating and fatal illness are not usually manifest until adulthood, the outcome of the test will influence major decisions about career, marriage, and procreation. Several differential diagnoses must be considered before using the test if HD is not confirmed in at least one family member. Review of a large number of pedigrees has shown that 40% of persons at risk do not have appropriate family structure for a linkage test. Furthermore, uncooperative or inaccessible relatives may make this test infeasible for many others who wish to be tested. Linkage phase, which must be known in the affected parent for an informative test, can be determined using one or more of 12 probe-enzyme combinations for D4S10. Although the polymorphism information content (PIC) value for any one RFLP is less than 40%, the PIC value for the haplotype of the two G8 HindIII, pK083 EcoRI, and R7 BglII RFLPs is greater than 88%. We have developed a scheme to incorporate linkage data and age at onset information adjusted for censored observations, sex of affected parent, and familial correlation for age at onset, using the computer program MLINK for calculation of risk of having HD. Simulated experiments showed that proper age at onset adjustment is crucial to the calculation of the probability of risk. A formal presymptomatic testing protocol, including pre- and post-test counselling, psychological testing, and paternity testing is recommended. Many of these considerations are illustrated in several actual test cases.

Development of 11 polymorphic microsatellite markers for the blackberry rust fungus Phragmidium violaceum

USDA-ARS?s Scientific Manuscript database

Eleven polymorphic microsatellite markers were developed for the Uredinales fungus Phragmidium violaceum, which causes leaf rust on European blackberry (Rubus fruticosus L. aggregate). Allele frequency ranged between two and seventeen alleles per locus with no evidence of linkage disequilibrium amon...

Brief report: linkage between G6PD and fragile-X syndrome.

PubMed

Filippi, G; Rinaldi, A; Archidiacono, N; Rocchi, M; Balazs, I; Siniscalco, M

1983-05-01

Eighteen Sardinian pedigrees segregating for the X-fragile site syndrome were studied with respect to the segregation of the fragile site (FS) at Xq28, mental retardation, and macro-orchidism. No exception was found in the association of this symptomatic triad (MOM-X) in 41 out of 42 patients examined. The exceptional individual had micro- rather than macro-orchidism and was found to have a 47, XXY sex chromosome complement. In six informative sibships, the MOM-X syndrome was found to segregate in close linkage association with G6PD-deficiency or protan colorblindness. The maximum likelihood estimate of recombination if 6% with 90% fiducial limits between 2.5 and 19.5% and an odds ratio in favor of measurable linkage of 428:1. However, no hint of measurable linkage was found in six pedigrees segregating for G6PD and the Renpenning syndrome or other unspecified types of X-linked mental retardation. These data give strong support to the generally held hypothesis that the FS at Zq28, characteristic of the MOM-X syndrome, is a direct expression of a genetic change in the same chromosomal region. They also clearly suggest that X-linked MR without FS may be the result of different allelic mutations at the same locus.

A High-Density Linkage Map Reveals Sexual Dimorphism in Recombination Landscapes in Red Deer (Cervus elaphus)

PubMed Central

Johnston, Susan E.; Huisman, Jisca; Ellis, Philip A.; Pemberton, Josephine M.

2017-01-01

High-density linkage maps are an important tool to gain insight into the genetic architecture of traits of evolutionary and economic interest, and provide a resource to characterize variation in recombination landscapes. Here, we used information from the cattle genome and the 50 K Cervine Illumina BeadChip to inform and refine a high-density linkage map in a wild population of red deer (Cervus elaphus). We constructed a predicted linkage map of 38,038 SNPs and a skeleton map of 10,835 SNPs across 34 linkage groups. We identified several chromosomal rearrangements in the deer lineage relative to sheep and cattle, including six chromosome fissions, one fusion, and two large inversions. Otherwise, our findings showed strong concordance with map orders in the cattle genome. The sex-averaged linkage map length was 2739.7 cM and the genome-wide autosomal recombination rate was 1.04 cM/Mb. The female autosomal map length was 1.21 longer than that of males (2767.4 cM vs. 2280.8 cM, respectively). Sex differences in map length were driven by high female recombination rates in peri-centromeric regions, a pattern that is unusual relative to other mammal species. This effect was more pronounced in fission chromosomes that would have had to produce new centromeres. We propose two hypotheses to explain this effect: (1) that this mechanism may have evolved to counteract centromeric drive associated with meiotic asymmetry in oocyte production; and/or (2) that sequence and structural characteristics suppressing recombination in close proximity to the centromere may not have evolved at neo-centromeres. Our study provides insight into how recombination landscapes vary and evolve in mammals, and will provide a valuable resource for studies of evolution, genetic improvement, and population management in red deer and related species. PMID:28667018

Bayesian linkage and segregation analysis: factoring the problem.

PubMed

Matthysse, S

2000-01-01

Complex segregation analysis and linkage methods are mathematical techniques for the genetic dissection of complex diseases. They are used to delineate complex modes of familial transmission and to localize putative disease susceptibility loci to specific chromosomal locations. The computational problem of Bayesian linkage and segregation analysis is one of integration in high-dimensional spaces. In this paper, three available techniques for Bayesian linkage and segregation analysis are discussed: Markov Chain Monte Carlo (MCMC), importance sampling, and exact calculation. The contribution of each to the overall integration will be explicitly discussed.

The use of analytical sedimentation velocity to extract thermodynamic linkage

PubMed Central

Cole, James L.; Correia, John J.; Stafford, Walter F.

2011-01-01

For 25 years, the Gibbs Conference on Biothermodynamics has focused on the use of thermodynamics to extract information about the mechanism and regulation of biological processes. This includes the determination of equilibrium constants for macromolecular interactions by high precision physical measurements. These approaches further reveal thermodynamic linkages to ligand binding events. Analytical ultracentrifugation has been a fundamental technique in the determination of macromolecular reaction stoichiometry and energetics for 85 years. This approach is highly amenable to the extraction of thermodynamic couplings to small molecule binding in the overall reaction pathway. In the 1980’s this approach was extended to the use of sedimentation velocity techniques, primarily by the analysis of tubulin-drug interactions by Na and Timasheff. This transport method necessarily incorporates the complexity of both hydrodynamic and thermodynamic nonideality. The advent of modern computational methods in the last 20 years has subsequently made the analysis of sedimentation velocity data for interacting systems more robust and rigorous. Here we review three examples where sedimentation velocity has been useful at extracting thermodynamic information about reaction stoichiometry and energetics. Approaches to extract linkage to small molecule binding and the influence of hydrodynamic nonideality are emphasized. These methods are shown to also apply to the collection of fluorescence data with the new Aviv FDS. PMID:21703752

Mobile assemblies of Bennett linkages from four-crease origami patterns

NASA Astrophysics Data System (ADS)

Zhang, Xiao; Chen, Yan

2018-02-01

This paper deals with constructing mobile assemblies of Bennett linkages inspired by four-crease origami patterns. A transition technique has been proposed by taking the thick-panel form of an origami pattern as an intermediate bridge. A zero-thickness rigid origami pattern and its thick-panel form share the same sector angles and folding behaviours, while the thick-panel origami and the mobile assembly of linkages are kinematically equivalent with differences only in link profiles. Applying this transition technique to typical four-crease origami patterns, we have found that the Miura-ori and graded Miura-ori patterns lead to assemblies of Bennett linkages with identical link lengths. The supplementary-type origami patterns with different mountain-valley crease assignments correspond to different types of Bennett linkage assemblies with negative link lengths. And the identical linkage-type origami pattern generates a new mobile assembly. Hence, the transition technique offers a novel approach to constructing mobile assemblies of spatial linkages from origami patterns.

Mobile assemblies of Bennett linkages from four-crease origami patterns.

PubMed

Zhang, Xiao; Chen, Yan

2018-02-01

This paper deals with constructing mobile assemblies of Bennett linkages inspired by four-crease origami patterns. A transition technique has been proposed by taking the thick-panel form of an origami pattern as an intermediate bridge. A zero-thickness rigid origami pattern and its thick-panel form share the same sector angles and folding behaviours, while the thick-panel origami and the mobile assembly of linkages are kinematically equivalent with differences only in link profiles. Applying this transition technique to typical four-crease origami patterns, we have found that the Miura-ori and graded Miura-ori patterns lead to assemblies of Bennett linkages with identical link lengths. The supplementary-type origami patterns with different mountain-valley crease assignments correspond to different types of Bennett linkage assemblies with negative link lengths. And the identical linkage-type origami pattern generates a new mobile assembly. Hence, the transition technique offers a novel approach to constructing mobile assemblies of spatial linkages from origami patterns.

Community-Clinical Linkages With Community Health Workers in the United States: A Scoping Review.

PubMed

Lohr, Abby M; Ingram, Maia; Nuñez, Annabelle V; Reinschmidt, Kerstin M; Carvajal, Scott C

2018-05-01

Despite the proliferation of community-clinical linkage (CCL) interventions with community health workers (CHWs), little is known about the components of these programs or how linkages are realized. In this scoping review, we synthesize evidence concerning the role of CHWs in creating and sustaining CCLs aimed at improving individual health outcomes. Our inclusion criteria included peer-reviewed articles that described a CHW intervention in the United States that used a CCL model. A total of 2,776 titles and/or abstracts were screened and 47 articles underwent full text review. Two independent reviewers rated the screened articles based on additional criteria including the CHW connection to community and evidence of linkage follow up rather than simple referral. For the 11 peer-reviewed articles included in the final review, we describe the CHW's relationship to the community, training, and role within the intervention, linkage, and outcomes. We used a standardized framework to determine commonalities in CHW roles across the interventions. CCLs with CHWs positively affect the delivery of both clinical care and community resources across a range of disease areas in a variety of contexts. To identify effective CCL models, additional information on CHW training, CCL follow-up methods, and the CHW role in CCLs is recommended.

Magnesium isotopic evidence for chemical disequilibrium among cumulus minerals in layered mafic intrusion

NASA Astrophysics Data System (ADS)

Chen, Lie-Meng; Teng, Fang-Zhen; Song, Xie-Yan; Hu, Rui-Zhong; Yu, Song-Yue; Zhu, Dan; Kang, Jian

2018-04-01

Magnesium isotopic compositions of olivine, clinopyroxene, and ilmenite from the Baima intrusion, SW China, for the first time, are investigated to constrain the magnitude and mechanisms of Mg isotope fractionation among cumulus minerals in layered mafic intrusions and to evaluate their geological implications. Olivine and clinopyroxene have limited Mg isotope variations, with δ26Mg ranging from -0.33 to +0.05‰ and from -0.29 to -0.13‰, respectively, similar to those of mantle xenolithic peridotites. By contrast, ilmenites display extremely large Mg isotopic variation, with δ26Mg ranging from -0.50 to +1.90‰. The large inter-mineral fractionations of Mg isotopes between ilmenite and silicates may reflect both equilibrium and kinetic processes. A few ilmenites have lighter Mg isotopic compositions than coexisting silicates and contain high MgO contents without compositional zoning, indicating equilibrium fractionation. The implication is that the light Mg isotopic compositions of lunar high-Ti basalts may result from an isotopically light source enriched in cumulate ilmenites. On the other hand, most ilmenites have heavy Mg isotopic compositions, coupled with high MgO concentration and chemical zoning, which can be quantitatively modeled by kinetic Mg isotope fractionations induced by subsolidus Mg-Fe exchange between ilmenite and ferromagnesian silicates during the cooling of the Baima intrusion. The extensive occurrence of kinetic Mg isotope fractionation in ilmenites implies the possibility of widespread compositional disequilibrium among igneous minerals in magma chambers. Consequently, disequilibrium effects need to be considered in studies of basaltic magma evolution, magma chamber processes, and magmatic Fe-Ti oxide ore genesis.

Genetic linkage map of the interspecific grape rootstock cross Ramsey (Vitis champinii) x Riparia Gloire (Vitis riparia).

PubMed

Lowe, K M; Walker, M A

2006-05-01

The first genetic linkage map of grape derived from rootstock parents was constructed using 188 progeny from a cross of Ramsey (Vitis champinii) x Riparia Gloire (V. riparia). Of 354 simple sequence repeat markers tested, 205 were polymorphic for at least one parent, and 57.6% were fully informative. Maps of Ramsey, Riparia Gloire, and the F1 population were created using JoinMap software, following a pseudotestcross strategy. The set of 205 SSRs allowed for the identification of all 19 Vitis linkage groups (2n=38), with a total combined map length of 1,304.7 cM, averaging 6.8 cM between markers. The maternal map consists of 172 markers aligned into 19 linkage groups (1,244.9 cM) while 126 markers on the paternal map cover 18 linkage groups (1,095.5 cM). The expected genome coverage is over 92%. Segregation distortion occurred in the Ramsey, Riparia Gloire, and consensus maps for 10, 13, and 16% of the markers, respectively. These distorted markers clustered primarily on the linkage groups 3, 5, 14 and 17. No genome-wide difference in recombination rate was observed between Ramsey and Riparia Gloire based on 315 common marker intervals. Fifty-four new Vitis-EST-derived SSR markers were mapped, and were distributed evenly across the genome on 16 of the 19 linkage groups. These dense linkage maps of two phenotypically diverse North American Vitis species are valuable tools for studying the genetics of many rootstock traits including nematode resistance, lime and salt tolerance, and ability to induce vigor.

Transcriptome Sequencing of Hevea brasiliensis for Development of Microsatellite Markers and Construction of a Genetic Linkage Map

PubMed Central

Triwitayakorn, Kanokporn; Chatkulkawin, Pornsupa; Kanjanawattanawong, Supanath; Sraphet, Supajit; Yoocha, Thippawan; Sangsrakru, Duangjai; Chanprasert, Juntima; Ngamphiw, Chumpol; Jomchai, Nukoon; Therawattanasuk, Kanikar; Tangphatsornruang, Sithichoke

2011-01-01

To obtain more information on the Hevea brasiliensis genome, we sequenced the transcriptome from the vegetative shoot apex yielding 2 311 497 reads. Clustering and assembly of the reads produced a total of 113 313 unique sequences, comprising 28 387 isotigs and 84 926 singletons. Also, 17 819 expressed sequence tag (EST)-simple sequence repeats (SSRs) were identified from the data set. To demonstrate the use of this EST resource for marker development, primers were designed for 430 of the EST-SSRs. Three hundred and twenty-three primer pairs were amplifiable in H. brasiliensis clones. Polymorphic information content values of selected 47 SSRs among 20 H. brasiliensis clones ranged from 0.13 to 0.71, with an average of 0.51. A dendrogram of genetic similarities between the 20 H. brasiliensis clones using these 47 EST-SSRs suggested two distinct groups that correlated well with clone pedigree. These novel EST-SSRs together with the published SSRs were used for the construction of an integrated parental linkage map of H. brasiliensis based on 81 lines of an F1 mapping population. The map consisted of 97 loci, consisting of 37 novel EST-SSRs and 60 published SSRs, distributed on 23 linkage groups and covered 842.9 cM with a mean interval of 11.9 cM and ∼4 loci per linkage group. Although the numbers of linkage groups exceed the haploid number (18), but with several common markers between homologous linkage groups with the previous map indicated that the F1 map in this study is appropriate for further study in marker-assisted selection. PMID:22086998

Dimensional threshold for fracture linkage and hooking

NASA Astrophysics Data System (ADS)

Lamarche, Juliette; Chabani, Arezki; Gauthier, Bertrand D. M.

2018-03-01

Fracture connectivity in rocks depends on spatial properties of the pattern including length, abundance and orientation. When fractures form a single-strike set, they hardly cross-cut each other and the connectivity is limited. Linkage probability increases with increasing fracture abundance and length as small fractures connect to each other to form longer ones. A process for parallel fracture linkage is the "hooking", where two converging fracture tips mutually deviate and then converge to connect due to the interaction of their crack-tip stresses. Quantifying the processes and conditions for fracture linkage in single-strike fracture sets is crucial to better predicting fluid flow in Naturally Fractured Reservoirs. For 1734 fractures in Permian shales of the Lodève Basin, SE France, we measured geometrical parameters in 2D, characterizing three stages of the hooking process: underlapping, overlapping and linkage. We deciphered the threshold values, shape ratios and limiting conditions to switch from one stage to another one. The hook set up depends on the spacing (S) and fracture length (Lh) with the relation S ≈ 0.15 Lh. Once the hooking is initiated, with the fracture deviation length (L) L ≈ 0.4 Lh, the fractures reaches the linkage stage only when the spacing is reduced to S ≈ 0.02 Lh and the convergence (C) is < 0.1 L. These conditions apply to multi-scale fractures with a shape ratio L/S = 10 and for fracture curvature of 10°-20°.

The Effect of Educational Disequilibrium in Field Work on Graduate Social Work Students' Self-Concept and Mental Health

ERIC Educational Resources Information Center

Ying, Yu-Wen

2011-01-01

The author used a mixed methods design to assess field work-related educational disequilibrium and its effect on the self-concept and mental health of MSW students. Twenty-eight advanced, fourth-semester MSW students were compared with 37 entering, first-semester MSW students in practice-related sense of accomplishment. Compared with first-year…

Genome-wide linkage scan for maximum and length-dependent knee muscle strength in young men: significant evidence for linkage at chromosome 14q24.3.

PubMed

De Mars, G; Windelinckx, A; Huygens, W; Peeters, M W; Beunen, G P; Aerssens, J; Vlietinck, R; Thomis, M A I

2008-05-01

Maintenance of high muscular fitness is positively related to bone health, functionality in daily life and increasing insulin sensitivity, and negatively related to falls and fractures, morbidity and mortality. Heritability of muscle strength phenotypes ranges between 31% and 95%, but little is known about the identity of the genes underlying this complex trait. As a first attempt, this genome-wide linkage study aimed to identify chromosomal regions linked to muscle and bone cross-sectional area, isometric knee flexion and extension torque, and torque-length relationship for knee flexors and extensors. In total, 283 informative male siblings (17-36 years old), belonging to 105 families, were used to conduct a genome-wide SNP-based multipoint linkage analysis. The strongest evidence for linkage was found for the torque-length relationship of the knee flexors at 14q24.3 (LOD = 4.09; p<10(-5)). Suggestive evidence for linkage was found at 14q32.2 (LOD = 3.00; P = 0.005) for muscle and bone cross-sectional area, at 2p24.2 (LOD = 2.57; p = 0.01) for isometric knee torque at 30 degrees flexion, at 1q21.3, 2p23.3 and 18q11.2 (LOD = 2.33, 2.69 and 2.21; p<10(-4) for all) for the torque-length relationship of the knee extensors and at 18p11.31 (LOD = 2.39; p = 0.0004) for muscle-mass adjusted isometric knee extension torque. We conclude that many small contributing genes rather than a few important genes are involved in causing variation in different underlying phenotypes of muscle strength. Furthermore, some overlap in promising genomic regions were identified among different strength phenotypes.

Genome-wide linkage scan for maximum and length-dependent knee muscle strength in young men: significant evidence for linkage at chromosome 14q24.3

PubMed Central

De Mars, G; Windelinckx, A; Huygens, W; Peeters, M W; Beunen, G P; Aerssens, J; Vlietinck, R; Thomis, M A I

2008-01-01

Background: Maintenance of high muscular fitness is positively related to bone health, functionality in daily life and increasing insulin sensitivity, and negatively related to falls and fractures, morbidity and mortality. Heritability of muscle strength phenotypes ranges between 31% and 95%, but little is known about the identity of the genes underlying this complex trait. As a first attempt, this genome-wide linkage study aimed to identify chromosomal regions linked to muscle and bone cross-sectional area, isometric knee flexion and extension torque, and torque–length relationship for knee flexors and extensors. Methods: In total, 283 informative male siblings (17–36 years old), belonging to 105 families, were used to conduct a genome-wide SNP-based multipoint linkage analysis. Results: The strongest evidence for linkage was found for the torque–length relationship of the knee flexors at 14q24.3 (LOD  = 4.09; p<10−5). Suggestive evidence for linkage was found at 14q32.2 (LOD  = 3.00; P = 0.005) for muscle and bone cross-sectional area, at 2p24.2 (LOD  = 2.57; p = 0.01) for isometric knee torque at 30° flexion, at 1q21.3, 2p23.3 and 18q11.2 (LOD  = 2.33, 2.69 and 2.21; p<10−4 for all) for the torque–length relationship of the knee extensors and at 18p11.31 (LOD  = 2.39; p = 0.0004) for muscle-mass adjusted isometric knee extension torque. Conclusions: We conclude that many small contributing genes rather than a few important genes are involved in causing variation in different underlying phenotypes of muscle strength. Furthermore, some overlap in promising genomic regions were identified among different strength phenotypes. PMID:18178634

A SNP based high-density linkage map of Apis cerana reveals a high recombination rate similar to Apis mellifera.

PubMed

Shi, Yuan Yuan; Sun, Liang Xian; Huang, Zachary Y; Wu, Xiao Bo; Zhu, Yong Qiang; Zheng, Hua Jun; Zeng, Zhi Jiang

2013-01-01

The Eastern honey bee, Apis cerana Fabricius, is distributed in southern and eastern Asia, from India and China to Korea and Japan and southeast to the Moluccas. This species is also widely kept for honey production besides Apis mellifera. Apis cerana is also a model organism for studying social behavior, caste determination, mating biology, sexual selection, and host-parasite interactions. Few resources are available for molecular research in this species, and a linkage map was never constructed. A linkage map is a prerequisite for quantitative trait loci mapping and for analyzing genome structure. We used the Chinese honey bee, Apis cerana cerana to construct the first linkage map in the Eastern honey bee. F2 workers (N = 103) were genotyped for 126,990 single nucleotide polymorphisms (SNPs). After filtering low quality and those not passing the Mendel test, we obtained 3,000 SNPs, 1,535 of these were informative and used to construct a linkage map. The preliminary map contains 19 linkage groups, we then mapped the 19 linkage groups to 16 chromosomes by comparing the markers to the genome of A. mellfiera. The final map contains 16 linkage groups with a total of 1,535 markers. The total genetic distance is 3,942.7 centimorgans (cM) with the largest linkage group (180 loci) measuring 574.5 cM. Average marker interval for all markers across the 16 linkage groups is 2.6 cM. We constructed a high density linkage map for A. c. cerana with 1,535 markers. Because the map is based on SNP markers, it will enable easier and faster genotyping assays than randomly amplified polymorphic DNA or microsatellite based maps used in A. mellifera.

Syphilis in pregnancy and congenital syphilis in Amazonas State, Brazil: an evaluation using database linkage.

PubMed

Soeiro, Claudia Marques de Oliveira; Miranda, Angélica Espinosa; Saraceni, Valeria; Santos, Marcelo Cordeiro dos; Talhari, Sinesio; Ferreira, Luiz Carlos de Lima

2014-04-01

This study analyzes notification of syphilis in pregnancy and congenital syphilis in Amazo- nas State, Brazil, from 2007 to 2009 and verifies underreporting in databases in the National Information System on Diseases of Notification (SINAN) and the occurrence of perinatal deaths associated with congenital syphilis and not reported in the Mortality Information System (SIM). This was a cross-sectional study with probabilistic record linkage between the SINAN and SIM. There were 666 reports of syphilis in pregnant women, including 224 in 2007 (3.8/1,000), 244(4.5/1,000) in 2008, and 198(4.0/1,000) in 2009. The study found 486 cases of congenital syphilis, of which 153 in 2007 (2.1/1,000), 193 in 2008 (2.6/1,000), and 140 in 2009 (2.0/1,000). After linkage of the SINAN databases, 237 pregnant women (35.6%) had cases of congenital syphilis reported. The SIM recorded 4,905 perinatal deaths, of which 57.8% were stillbirths. Probabilistic record linkage between SIM and SINAN-Congenital Syphilis yielded 13 matched records. The use of SINAN and SIM may not reflect the total magnitude of syphilis, but provide the basis for monitoring and analyzing this health problem, with a view towards planning and management.

Genome-wide association study of acute post-surgical pain in humans

PubMed Central

Kim, Hyungsuk; Ramsay, Edward; Lee, Hyewon; Wahl, Sharon; Dionne, Raymond A

2009-01-01

Aims Testing a relatively small genomic region with a few hundred SNPs provides limited information. Genome-wide association studies (GWAS) provide an opportunity to overcome the limitation of candidate gene association studies. Here, we report the results of a GWAS for the responses to an NSAID analgesic. Materials & methods European Americans (60 females and 52 males) undergoing oral surgery were genotyped with Affymetrix 500K SNP assay. Additional SNP genotyping was performed from the gene in linkage disequilibrium with the candidate SNP revealed by the GWAS. Results GWAS revealed a candidate SNP (rs2562456) associated with analgesic onset, which is in linkage disequilibrium with a gene encoding a zinc finger protein. Additional SNP genotyping of ZNF429 confirmed the association with analgesic onset in humans (p = 1.8 × 10−10, degrees of freedom = 103, F = 28.3). We also found candidate loci for the maximum post-operative pain rating (rs17122021, p = 6.9 × 10−7) and post-operative pain onset time (rs6693882, p = 2.1 × 10−6), however, correcting for multiple comparisons did not sustain these genetic associations. Conclusion GWAS for acute clinical pain followed by additional SNP genotyping of a neighboring gene suggests that genetic variations in or near the loci encoding DNA binding proteins play a role in the individual variations in responses to analgesic drugs. PMID:19207018

Quantifying sources of bias in longitudinal data linkage studies of child abuse and neglect: measuring impact of outcome specification, linkage error, and partial cohort follow-up.

PubMed

Parrish, Jared W; Shanahan, Meghan E; Schnitzer, Patricia G; Lanier, Paul; Daniels, Julie L; Marshall, Stephen W

2017-12-01

Health informatics projects combining statewide birth populations with child welfare records have emerged as a valuable approach to conducting longitudinal research of child maltreatment. The potential bias resulting from linkage misspecification, partial cohort follow-up, and outcome misclassification in these studies has been largely unexplored. This study integrated epidemiological survey and novel administrative data sources to establish the Alaska Longitudinal Child Abuse and Neglect Linkage (ALCANLink) project. Using these data we evaluated and quantified the impact of non-linkage misspecification and single source maltreatment ascertainment use on reported maltreatment risk and effect estimates. The ALCANLink project integrates the 2009-2011 Alaska Pregnancy Risk Assessment Monitoring System (PRAMS) sample with multiple administrative databases through 2014, including one novel administrative source to track out-of-state emigration. For this project we limited our analysis to the 2009 PRAMS sample. We report on the impact of linkage quality, cohort follow-up, and multisource outcome ascertainment on the incidence proportion of reported maltreatment before age 6 and hazard ratios of selected characteristics that are often available in birth cohort linkage studies of maltreatment. Failure to account for out-of-state emigration biased the incidence proportion by 12% (from 28.3% w to 25.2% w ), and the hazard ratio (HR) by as much as 33% for some risk factors. Overly restrictive linkage parameters biased the incidence proportion downwards by 43% and the HR by as much as 27% for some factors. Multi-source linkages, on the other hand, were of little benefit for improving reported maltreatment ascertainment. Using the ALCANLink data which included a novel administrative data source, we were able to observe and quantify bias to both the incidence proportion and HR in a birth cohort linkage study of reported child maltreatment. Failure to account for out

Hierarchical Naive Bayes for genetic association studies.

PubMed

Malovini, Alberto; Barbarini, Nicola; Bellazzi, Riccardo; de Michelis, Francesca

2012-01-01

Genome Wide Association Studies represent powerful approaches that aim at disentangling the genetic and molecular mechanisms underlying complex traits. The usual "one-SNP-at-the-time" testing strategy cannot capture the multi-factorial nature of this kind of disorders. We propose a Hierarchical Naïve Bayes classification model for taking into account associations in SNPs data characterized by Linkage Disequilibrium. Validation shows that our model reaches classification performances superior to those obtained by the standard Naïve Bayes classifier for simulated and real datasets. In the Hierarchical Naïve Bayes implemented, the SNPs mapping to the same region of Linkage Disequilibrium are considered as "details" or "replicates" of the locus, each contributing to the overall effect of the region on the phenotype. A latent variable for each block, which models the "population" of correlated SNPs, can be then used to summarize the available information. The classification is thus performed relying on the latent variables conditional probability distributions and on the SNPs data available. The developed methodology has been tested on simulated datasets, each composed by 300 cases, 300 controls and a variable number of SNPs. Our approach has been also applied to two real datasets on the genetic bases of Type 1 Diabetes and Type 2 Diabetes generated by the Wellcome Trust Case Control Consortium. The approach proposed in this paper, called Hierarchical Naïve Bayes, allows dealing with classification of examples for which genetic information of structurally correlated SNPs are available. It improves the Naïve Bayes performances by properly handling the within-loci variability.

Genome-wide differentiation of various melon horticultural groups for use in genome wide association study for fruit firmness and construction of a high resolution genetic map

USDA-ARS?s Scientific Manuscript database

We generated 13,789 single nucleotide plymorphism (SNP) markers from 97 melon accessions using genotyping by sequencing and anchored them to chromosomes to understand genome-wide fixation index between various melon morphotypes and linkage disequilibrium (LD) decay for inodorus and cantalupensis, th...

Pharmacogenetic testing through the direct-to-consumer genetic testing company 23andMe.

PubMed

Lu, Mengfei; Lewis, Cathryn M; Traylor, Matthew

2017-06-19

Rapid advances in scientific research have led to an increase in public awareness of genetic testing and pharmacogenetics. Direct-to-consumer (DTC) genetic testing companies, such as 23andMe, allow consumers to access their genetic information directly through an online service without the involvement of healthcare professionals. Here, we evaluate the clinical relevance of pharmacogenetic tests reported by 23andMe in their UK tests. The research papers listed under each 23andMe report were evaluated, extracting information on effect size, sample size and ethnicity. A wider literature search was performed to provide a fuller assessment of the pharmacogenetic test and variants were matched to FDA recommendations. Additional evidence from CPIC guidelines, PharmGKB, and Dutch Pharmacogenetics Working Group was reviewed to determine current clinical practice. The value of the tests across ethnic groups was determined, including information on linkage disequilibrium between the tested SNP and causal pharmacogenetic variant, where relevant. 23andMe offers 12 pharmacogenetic tests to their UK customers, some of which are in standard clinical practice, and others which are less widely applied. The clinical validity and clinical utility varies extensively between tests. The variants tested are likely to have different degrees of sensitivity due to different risk allele frequencies and linkage disequilibrium patterns across populations. The clinical relevance depends on the ethnicity of the individual and variability of pharmacogenetic markers. Further research is required to determine causal variants and provide more complete assessment of drug response and side effects. 23andMe reports provide some useful pharmacogenetics information, mirroring clinical tests that are in standard use. Other tests are unspecific, providing limited guidance and may not be useful for patients without professional interpretation. Nevertheless, DTC companies like 23andMe act as a powerful

DHLAS: A web-based information system for statistical genetic analysis of HLA population data.

PubMed

Thriskos, P; Zintzaras, E; Germenis, A

2007-03-01

DHLAS (database HLA system) is a user-friendly, web-based information system for the analysis of human leukocyte antigens (HLA) data from population studies. DHLAS has been developed using JAVA and the R system, it runs on a Java Virtual Machine and its user-interface is web-based powered by the servlet engine TOMCAT. It utilizes STRUTS, a Model-View-Controller framework and uses several GNU packages to perform several of its tasks. The database engine it relies upon for fast access is MySQL, but others can be used a well. The system estimates metrics, performs statistical testing and produces graphs required for HLA population studies: (i) Hardy-Weinberg equilibrium (calculated using both asymptotic and exact tests), (ii) genetics distances (Euclidian or Nei), (iii) phylogenetic trees using the unweighted pair group method with averages and neigbor-joining method, (iv) linkage disequilibrium (pairwise and overall, including variance estimations), (v) haplotype frequencies (estimate using the expectation-maximization algorithm) and (vi) discriminant analysis. The main merit of DHLAS is the incorporation of a database, thus, the data can be stored and manipulated along with integrated genetic data analysis procedures. In addition, it has an open architecture allowing the inclusion of other functions and procedures.

History of the Rochester Epidemiology Project: Half a Century of Medical Records Linkage in a US Population

PubMed Central

Rocca, Walter A.; Yawn, Barbara P.; St. Sauver, Jennifer L.; Grossardt, Brandon R.; Melton, L. Joseph

2012-01-01

The Rochester Epidemiology Project (REP) has maintained a comprehensive medical records linkage system for nearly half a century for almost all persons residing in Olmsted County, Minnesota. Herein, we provide a brief history of the REP before and after 1966, the year in which the REP was officially established. The key protagonists before 1966 were Henry Plummer, Mabel Root, and Joseph Berkson, who developed a medical records linkage system at Mayo Clinic. In 1966, Leonard Kurland established collaborative agreements with other local health care providers (hospitals, physician groups, and clinics [primarily Olmsted Medical Center]) to develop a medical records linkage system that covered the entire population of Olmsted County, and he obtained funding from the National Institutes of Health to support the new system. In 1997, L. Joseph Melton III addressed emerging concerns about the confidentiality of medical record information by introducing a broad patient research authorization as per Minnesota state law. We describe how the key protagonists of the REP have responded to challenges posed by evolving medical knowledge, information technology, and public expectation and policy. In addition, we provide a general description of the system; discuss issues of data quality, reliability, and validity; describe the research team structure; provide information about funding; and compare the REP with other medical information systems. The REP can serve as a model for the development of similar research infrastructures in the United States and worldwide. PMID:23199802

Three Degree of Freedom Parallel Mechanical Linkage

NASA Technical Reports Server (NTRS)

Adelstein, Bernard D. (Inventor)

1998-01-01

A three degree of freedom parallel mechanism or linkage that couples three degree of freedom translational displacements at an endpoint, such as a handle, a hand grip, or a robot tool, to link rotations about three axes that are fixed with respect to a common base or ground link. The mechanism includes a three degree of freedom spherical linkage formed of two closed loops, and a planar linkage connected to the endpoint. The closed loops are rotatably interconnected, and made of eight rigid links connected by a plurality of single degree of freedom revolute joints. Three of these revolute joints are base joints and are connected to a common ground. such that the axis lines passing through the revolute joints intersect at a common fixed center point K forming the center of a spherical work volume in which the endpoint is capable of moving. 'Me three degrees of freedom correspond to the spatial displacement of the endpoint, for instance. The mechanism provides a new overall spatial kinematic linkage composed of a minimal number of rigid links and rotary joints. The mechanism has improved mechanical stiffness, and conveys mechanical power bidirectionally between the human operator and the electromechanical actuators. It does not require gears, belts. cable, screw or other types of transmission elements, and is useful in applications requiring full backdrivability. Thus, this invention can serve as the mechanical linkage for actively powered devices such as compliant robotic manipulators and force-reflecting hand controllers, and passive devices such as manual input devices for computers and other systems.

210Pb in the western Indian Ocean: distribution, disequilibrium, and partitioning between dissolved and particulate phases

NASA Astrophysics Data System (ADS)

Chung, Y.

1987-09-01

Dissolved 210Pb profiles are presented for 13 GEOSECS stations in the western Indian Ocean. In surface water away from high southern latitudes, 210Pb is in excess over 226Ra due to the atmospheric fallout from decay of 222Rn. Except in the Circumpolar region, the dissolved 210Pb profiles display a gentle mid-depth maximum similar to the corresponding 226Ra profiles. The 210Pb/ 226Ra activity ratio ranges from 1.6 in the surface water east of Madagascar to 0.4 or less in the bottom water of all the basins. The lowest ratio observed was 0.1 in the Gulf of Aden very close to the continental land mass. A ratio of 0.6 divides the western Indian Ocean horizontally into two portions, with the contour at shallower depth in the north than in the south. The deep water disequilibrium is thus more extensive north of Madagascar than south of it. It appears that locality and bottom topography play a strong role in controlling the distributions of 210Pb and 226Ra as well as their extent of disequilibrium in the water column. The mean residence time for Pb with respect to particulate and boundary scavenging in the deep water ranges from about 15 to 75 years.

[Linkage to care among new human immunodeficiency virus diagnoses in Spain].

PubMed

Oliva, Jesús; Malo, Carmen; Fernández, Ana; Izquierdo, Ana; Marcos, Henar; Cevallos, Carlos; Castilla, Jesús; García, Rocio; Díez, Mercedes

2014-03-01

To describe linkage to care among new HIV diagnoses in Spain; and to estimate factors associated to linkage to care within three months after diagnosis. The distribution of the time elapsing between the date of HIV diagnosis and the date of first determination of CD4 (considered to be the date of linkage to care) was calculated among new HIV diagnoses in 2010 in the seven Autonomous Regions participating, where data on date of CD4 count was available. Linkage to care was considered «correct» if done within three months after diagnosis. Factors associated to correct linkage to care were estimated using logistic regression. A total of 1769 new HIV diagnoses were included. Of them, 83.1% had evidence of linkage to care within a year, and 75.7% were linked within three months after diagnosis. Being an injectable drug user (IDU) was the only factor inversely associated with linkage to care within 3 months (OR = 0.3; 95% CI: 0.2-0.6). In Spain linkage to care after HIV diagnosis is good, but there is still room for improvement, especially among IDUs. Copyright © 2013 Elsevier España, S.L. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Phase-Division-Based Dynamic Optimization of Linkages for Drawing Servo Presses

NASA Astrophysics Data System (ADS)

Zhang, Zhi-Gang; Wang, Li-Ping; Cao, Yan-Ke

2017-11-01

Existing linkage-optimization methods are designed for mechanical presses; few can be directly used for servo presses, so development of the servo press is limited. Based on the complementarity of linkage optimization and motion planning, a phase-division-based linkage-optimization model for a drawing servo press is established. Considering the motion-planning principles of a drawing servo press, and taking account of work rating and efficiency, the constraints of the optimization model are constructed. Linkage is optimized in two modes: use of either constant eccentric speed or constant slide speed in the work segments. The performances of optimized linkages are compared with those of a mature linkage SL4-2000A, which is optimized by a traditional method. The results show that the work rating of a drawing servo press equipped with linkages optimized by this new method improved and the root-mean-square torque of the servo motors is reduced by more than 10%. This research provides a promising method for designing energy-saving drawing servo presses with high work ratings.

Student-Teacher Linkage Verification: Model Process and Recommendations

ERIC Educational Resources Information Center

Watson, Jeffery; Graham, Matthew; Thorn, Christopher A.

2012-01-01

As momentum grows for tracking the role of individual educators in student performance, school districts across the country are implementing projects that involve linking teachers to their students. Programs that link teachers to student outcomes require a verification process for student-teacher linkages. Linkage verification improves accuracy by…

Prospective Industrial Linkage at Aqaba University College, Jordan

ERIC Educational Resources Information Center

Abu-Hamatteh, Zeid; Al-Amyan, Mozfi; Al-Azzam, Farouq

2008-01-01

The present study intends to examine the overall situation and the environment of Aqaba University College (AUC) in relation to industrial-educational interaction, and to discuss existing and possible future industrial linkage strategies. This article presents observations from AUC, as well as suggestions for action on industrial linkage. The…

Privacy-preserving genome-wide association studies on cloud environment using fully homomorphic encryption

PubMed Central

2015-01-01

Objective Developed sequencing techniques are yielding large-scale genomic data at low cost. A genome-wide association study (GWAS) targeting genetic variations that are significantly associated with a particular disease offers great potential for medical improvement. However, subjects who volunteer their genomic data expose themselves to the risk of privacy invasion; these privacy concerns prevent efficient genomic data sharing. Our goal is to presents a cryptographic solution to this problem. Methods To maintain the privacy of subjects, we propose encryption of all genotype and phenotype data. To allow the cloud to perform meaningful computation in relation to the encrypted data, we use a fully homomorphic encryption scheme. Noting that we can evaluate typical statistics for GWAS from a frequency table, our solution evaluates frequency tables with encrypted genomic and clinical data as input. We propose to use a packing technique for efficient evaluation of these frequency tables. Results Our solution supports evaluation of the D′ measure of linkage disequilibrium, the Hardy-Weinberg Equilibrium, the χ2 test, etc. In this paper, we take χ2 test and linkage disequilibrium as examples and demonstrate how we can conduct these algorithms securely and efficiently in an outsourcing setting. We demonstrate with experimentation that secure outsourcing computation of one χ2 test with 10, 000 subjects requires about 35 ms and evaluation of one linkage disequilibrium with 10, 000 subjects requires about 80 ms. Conclusions With appropriate encoding and packing technique, cryptographic solutions based on fully homomorphic encryption for secure computations of GWAS can be practical. PMID:26732892

Privacy-preserving genome-wide association studies on cloud environment using fully homomorphic encryption.

PubMed

Lu, Wen-Jie; Yamada, Yoshiji; Sakuma, Jun

2015-01-01

Developed sequencing techniques are yielding large-scale genomic data at low cost. A genome-wide association study (GWAS) targeting genetic variations that are significantly associated with a particular disease offers great potential for medical improvement. However, subjects who volunteer their genomic data expose themselves to the risk of privacy invasion; these privacy concerns prevent efficient genomic data sharing. Our goal is to presents a cryptographic solution to this problem. To maintain the privacy of subjects, we propose encryption of all genotype and phenotype data. To allow the cloud to perform meaningful computation in relation to the encrypted data, we use a fully homomorphic encryption scheme. Noting that we can evaluate typical statistics for GWAS from a frequency table, our solution evaluates frequency tables with encrypted genomic and clinical data as input. We propose to use a packing technique for efficient evaluation of these frequency tables. Our solution supports evaluation of the D' measure of linkage disequilibrium, the Hardy-Weinberg Equilibrium, the χ2 test, etc. In this paper, we take χ2 test and linkage disequilibrium as examples and demonstrate how we can conduct these algorithms securely and efficiently in an outsourcing setting. We demonstrate with experimentation that secure outsourcing computation of one χ2 test with 10, 000 subjects requires about 35 ms and evaluation of one linkage disequilibrium with 10, 000 subjects requires about 80 ms. With appropriate encoding and packing technique, cryptographic solutions based on fully homomorphic encryption for secure computations of GWAS can be practical.

A microsatellite-based consensus linkage map for species of Eucalyptus and a novel set of 230 microsatellite markers for the genus

PubMed Central

Brondani, Rosana PV; Williams, Emlyn R; Brondani, Claudio; Grattapaglia, Dario

2006-01-01

Background Eucalypts are the most widely planted hardwood trees in the world occupying globally more than 18 million hectares as an important source of carbon neutral renewable energy and raw material for pulp, paper and solid wood. Quantitative Trait Loci (QTLs) in Eucalyptus have been localized on pedigree-specific RAPD or AFLP maps seriously limiting the value of such QTL mapping efforts for molecular breeding. The availability of a genus-wide genetic map with transferable microsatellite markers has become a must for the effective advancement of genomic undertakings. This report describes the development of a novel set of 230 EMBRA microsatellites, the construction of the first comprehensive microsatellite-based consensus linkage map for Eucalyptus and the consolidation of existing linkage information for other microsatellites and candidate genes mapped in other species of the genus. Results The consensus map covers ~90% of the recombining genome of Eucalyptus, involves 234 mapped EMBRA loci on 11 linkage groups, an observed length of 1,568 cM and a mean distance between markers of 8.4 cM. A compilation of all microsatellite linkage information published in Eucalyptus allowed us to establish the homology among linkage groups between this consensus map and other maps published for E. globulus. Comparative mapping analyses also resulted in the linkage group assignment of other 41 microsatellites derived from other Eucalyptus species as well as candidate genes and QTLs for wood and flowering traits published in the literature. This report significantly increases the availability of microsatellite markers and mapping information for species of Eucalyptus and corroborates the high conservation of microsatellite flanking sequences and locus ordering between species of the genus. Conclusion This work represents an important step forward for Eucalyptus comparative genomics, opening stimulating perspectives for evolutionary studies and molecular breeding applications

Sample selection and spatial models of housing price indexes, and, A disequilibrium analysis of the U.S. gasoline market using panel data

NASA Astrophysics Data System (ADS)

Hu, Haixin

This dissertation consists of two parts. The first part studies the sample selection and spatial models of housing price index using transaction data on detached single-family houses of two California metropolitan areas from 1990 through 2008. House prices are often spatially correlated due to shared amenities, or when the properties are viewed as close substitutes in a housing submarket. There have been many studies that address spatial correlation in the context of housing markets. However, none has used spatial models to construct housing price indexes at zip code level for the entire time period analyzed in this dissertation to the best of my knowledge. In this paper, I study a first-order autoregressive spatial model with four different weighing matrix schemes. Four sets of housing price indexes are constructed accordingly. Gatzlaff and Haurin (1997, 1998) study the sample selection problem in housing index by using Heckman's two-step method. This method, however, is generally inefficient and can cause multicollinearity problem. Also, it requires data on unsold houses in order to carry out the first-step probit regression. Maximum likelihood (ML) method can be used to estimate a truncated incidental model which allows one to correct for sample selection based on transaction data only. However, convergence problem is very prevalent in practice. In this paper I adopt Lewbel's (2007) sample selection correction method which does not require one to model or estimate the selection model, except for some very general assumptions. I then extend this method to correct for spatial correlation. In the second part, I analyze the U.S. gasoline market with a disequilibrium model that allows lagged-latent variables, endogenous prices, and panel data with fixed effects. Most existing studies (see the survey of Espey, 1998, Energy Economics) of the gasoline market assume equilibrium. In practice, however, prices do not always adjust fast enough to clear the market

Detecting local haplotype sharing and haplotype association

USDA-ARS?s Scientific Manuscript database

A novel haplotype association method is presented, and its power is demonstrated. Relying on a statistical model for linkage disequilibrium (LD), the method first infers ancestral haplotypes and their loadings at each marker for each individual. The loadings are then used to quantify local haplotype...

The use of analytical sedimentation velocity to extract thermodynamic linkage.

PubMed

Cole, James L; Correia, John J; Stafford, Walter F

2011-11-01

For 25 years, the Gibbs Conference on Biothermodynamics has focused on the use of thermodynamics to extract information about the mechanism and regulation of biological processes. This includes the determination of equilibrium constants for macromolecular interactions by high precision physical measurements. These approaches further reveal thermodynamic linkages to ligand binding events. Analytical ultracentrifugation has been a fundamental technique in the determination of macromolecular reaction stoichiometry and energetics for 85 years. This approach is highly amenable to the extraction of thermodynamic couplings to small molecule binding in the overall reaction pathway. In the 1980s this approach was extended to the use of sedimentation velocity techniques, primarily by the analysis of tubulin-drug interactions by Na and Timasheff. This transport method necessarily incorporates the complexity of both hydrodynamic and thermodynamic nonideality. The advent of modern computational methods in the last 20 years has subsequently made the analysis of sedimentation velocity data for interacting systems more robust and rigorous. Here we review three examples where sedimentation velocity has been useful at extracting thermodynamic information about reaction stoichiometry and energetics. Approaches to extract linkage to small molecule binding and the influence of hydrodynamic nonideality are emphasized. These methods are shown to also apply to the collection of fluorescence data with the new Aviv FDS. Copyright © 2011 Elsevier B.V. All rights reserved.

A Population Genetics Model of Marker-Assisted Selection

PubMed Central

Luo, Z. W.; Thompson, R.; Woolliams, J. A.

1997-01-01

A deterministic two-loci model was developed to predict genetic response to marker-assisted selection (MAS) in one generation and in multiple generations. Formulas were derived to relate linkage disequilibrium in a population to the proportion of additive genetic variance used by MAS, and in turn to an extra improvement in genetic response over phenotypic selection. Predictions of the response were compared to those predicted by using an infinite-loci model and the factors affecting efficiency of MAS were examined. Theoretical analyses of the present study revealed the nonlinearity between the selection intensity and genetic response in MAS. In addition to the heritability of the trait and the proportion of the marker-associated genetic variance, the frequencies of the selectively favorable alleles at the two loci, one marker and one quantitative trait locus, were found to play an important role in determining both the short- and long-term efficiencies of MAS. The evolution of linkage disequilibrium and thus the genetic response over several generations were predicted theoretically and examined by simulation. MAS dissipated the disequilibrium more quickly than drift alone. In some cases studied, the rate of dissipation was as large as that to be expected in the circumstance where the true recombination fraction was increased by three times and selection was absent. PMID:9215918

Intragroup Emotions: Physiological Linkage and Social Presence.

PubMed

Järvelä, Simo; Kätsyri, Jari; Ravaja, Niklas; Chanel, Guillaume; Henttonen, Pentti

2016-01-01

We investigated how technologically mediating two different components of emotion-communicative expression and physiological state-to group members affects physiological linkage and self-reported feelings in a small group during video viewing. In different conditions the availability of second screen text chat (communicative expression) and visualization of group level physiological heart rates and their dyadic linkage (physiology) was varied. Within this four person group two participants formed a physically co-located dyad and the other two were individually situated in two separate rooms. We found that text chat always increased heart rate synchrony but HR visualization only with non-co-located dyads. We also found that physiological linkage was strongly connected to self-reported social presence. The results encourage further exploration of the possibilities of sharing group member's physiological components of emotion by technological means to enhance mediated communication and strengthen social presence.

A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16.

PubMed

Asherson, P; Zhou, K; Anney, R J L; Franke, B; Buitelaar, J; Ebstein, R; Gill, M; Altink, M; Arnold, R; Boer, F; Brookes, K; Buschgens, C; Butler, L; Cambell, D; Chen, W; Christiansen, H; Feldman, L; Fleischman, K; Fliers, E; Howe-Forbes, R; Goldfarb, A; Heise, A; Gabriëls, I; Johansson, L; Lubetzki, I; Marco, R; Medad, S; Minderaa, R; Mulas, F; Müller, U; Mulligan, A; Neale, B; Rijsdijk, F; Rabin, K; Rommelse, N; Sethna, V; Sorohan, J; Uebel, H; Psychogiou, L; Weeks, A; Barrett, R; Xu, X; Banaschewski, T; Sonuga-Barke, E; Eisenberg, J; Manor, I; Miranda, A; Oades, R D; Roeyers, H; Rothenberger, A; Sergeant, J; Steinhausen, H-C; Taylor, E; Thompson, M; Faraone, S V

2008-05-01

As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, approximately 95 cM) and Dutch (LOD>1, approximately 100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.

Using the structure-function linkage database to characterize functional domains in enzymes.

PubMed

Brown, Shoshana; Babbitt, Patricia

2014-12-12

The Structure-Function Linkage Database (SFLD; http://sfld.rbvi.ucsf.edu/) is a Web-accessible database designed to link enzyme sequence, structure, and functional information. This unit describes the protocols by which a user may query the database to predict the function of uncharacterized enzymes and to correct misannotated functional assignments. The information in this unit is especially useful in helping a user discriminate functional capabilities of a sequence that is only distantly related to characterized sequences in publicly available databases. Copyright © 2014 John Wiley & Sons, Inc.

Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Villard, E.; Soubrier, F.; Tiret, L.

1996-06-01

Plasma angiotensin I-converting enzyme (ACE) levels are highly genetically determined. A previous segregation-linkage analysis suggested the existence of a functional mutation located within or close to the ACE locus, in almost complete linkage disequilibrium (LD) with the ACE insertion/deletion (I/D) polymorphism and accounting for half the ACE variance. In order to identify the functional variant at the molecular level, we compared ACE gene sequences between four subjects selected for having contrasted ACE levels and I/D genotypes. We identified 10 new polymorphisms, among which 8 were genotyped in 95 healthy nuclear families, in addition to the I/D polymorphism. These polymorphisms couldmore » be divided into two groups: five polymorphisms in the 5{prime} region and three in the coding sequence and the 3{prime} UTR. Within each group, polymorphisms were in nearly complete association, whereas polymorphisms from the two groups were in strong negative LD. After adjustment for the I/D polymorphism, all polymorphisms of the 5{prime} group remained significantly associated with ACE levels, which suggests the existence of two quantitative trait loci (QTL) acting additively on ACE levels. Segregation-linkage analyses including one or two ACE-linked QTLs in LD with two ACE markers were performed to test this hypothesis. The two QTLs and the two markers were assumed to be in complete LD. Results supported the existence of two ACE-linked QTLs, which would explain 38% and 49% of the ACE variance in parents and offspring, respectively. One of these QTLs might be the I/D polymorphism itself or the newly characterized 4656(CT){sub 2/3} polymorphism. The second QTL would have a frequency of {approximately}.20, which is incompatible with any of the yet-identified polymorphisms. More extensive sequencing and extended analyses in larger samples and in other populations will be necessary to characterize definitely the functional variants. 30 refs., 1 fig., 6 tabs.« less

The Educational Information Consultant. Skills in Disseminating Educational Information. Training Manual.

ERIC Educational Resources Information Center

Banathy, Bela H.; And Others

This instructional system is designed to train individuals in the role of Educational Information Consultant (EIC). The EIC serves as a linkage agent between the worlds of educational research and practice by (1) negotiating with a client concerning information need, (2) retrieving pertinent information, (3) transforming the information, (4)…

Temperature and precipitation records from stalagmites grown under disequilibrium conditions: A model approach.

NASA Astrophysics Data System (ADS)

Mühlinghaus, C.; Scholz, D.; Mangini, A.

2009-04-01

To reconstruct past variations in Earth's climate, a variety of climate archives are studied. During the last decades stalagmites came into focus due to their long, continuous growth and absolute dating techniques. In this study a numerical model was developed, which calculates variations in temperature and precipitation during the growth period of stalagmites grown under isotopic disequilibrium conditions using the isotope profiles both along the growth axis and individual growth layers as well as the growth depth relation. The model is based on the inversion and combination of existing models (Dreybrodt 1999, Kaufmann et al. 2004, Mühlinghaus et al. 2007, Scholz et al. 2008, Mühlinghaus et al. 2008b) and incorporates important parameters describing the cave and the overlying soil. Beside the dependence on temperature and water supply it depends on the isotopic composition of the drip water, the pCO2 pressure of the soil and the cave atmosphere as well as on the mixing coefficient, which describes mixing between the impinging drop and the existing solution layer. To determine the characteristics of temperature and precipitation, in a first step all other parameters are assumed to remain constant over the whole growth period to simplify calculations. This allows to run the model with only two input variables: the isotopic composition ^13C of the drip water and a temperature information at any point of time during the growth period of the stalagmite (e.g. the recent cave temperature). All other parameters are determined by the model. The CSM (Combined Stalagmite Model, Mühlinghaus et al. 2008a) was applied to three stalagmites from the Marcelo Arévalo cave in Southern Patagonia, Chile (Schimpf 2005, Kilian et al. 2006, Schimpf et al. in prep). These stalagmites grew in a small cave next to each other during the last 4500 years. However, their isotopic profiles along the growth axis show different kinetic influences. Despite these conditions, the temperature

Linkages Between Patient-centered Medical Homes and Addiction Treatment Organizations: Results From a National Survey.

PubMed

D'Aunno, Thomas; Pollack, Harold; Chen, Qixuan; Friedmann, Peter D

2017-04-01

To meet their aims of providing comprehensive and coordinated care, patient-centered medical homes (PCMHs) need to coordinate services for individuals with substance use disorders. Yet, the 14,000 addiction treatment (AT) organizations across the United States that provide services for more than 1 million individuals daily are generally ill-prepared to work with PCMHs (eg, AT organizations often lack electronic health records). To examine the extent to which AT organizations have formal linkages through contracts with PCMHs; to identify key dimensions of linkages between PCMHs and AT organizations (eg, shared use of electronic health records); to identify characteristics of AT organizations and their environments associated with these linkages. We draw on data from a 2014 nationally representative survey of directors and clinical supervisors from 695 AT organizations (n=1390 survey respondents). Thirty-eight percent of patients across the nation are receiving treatment in AT organizations linked by contracts to PCMHs. This number increases to 51% in states that expanded Medicaid (vs. only 6.2% of patients in non-Medicaid expansion states). Yet, the great majority of linkages are relatively weak; they do not include the exchange of patient information. Results from multivariable analyses show that larger, nonprofit and publicly owned AT organizations, as well as those located in the northeast and in states that expanded Medicaid coverage, are more likely to have contracts with PCMHs. Without stronger linkages between AT organizations and PCMHs or the development of other models that integrate services, individuals with substance abuse disorders may continue to receive uncoordinated care.

Equilibrium and Disequilibrium of River Basins: Effects on Stream Captures in Serra do Mar and Serra da Mantiqueira, Brazil

NASA Astrophysics Data System (ADS)

DA Silva, L. M.

2015-12-01

Landscapes are mainly driven by river processes that control the dynamic reorganization of networks. Discovering and identifying whether river basins are in geometric equilibrium or disequilibrium requires an analysis of water divides, channels that shift laterally or expand upstream and river captures. Issues specifically discussed include the variation of drainage area change and erosion rates of the basins. In southeastern Brazil there are two main escarpments with extensive geomorphic surfaces: Serra do Mar and Serra da Mantiqueira Mountains. These landscapes are constituted of Neoproterozoic and early Paleozoic rocks, presenting steep escarpments with low-elevation coastal plains and higher elevation interior plateaus. To identify whether river basins and river profiles are in equilibrium or disequilibrium in Serra do Mar and Serra da Mantiqueira Mountains, we used the proxy (χ), evaluating the effect of drainage area change and erosion rates. We selected basins that drain both sides of these two main escarpments (oceanic and continental sides) and have denudation rates derived from pre-existing cosmogenic isotopes data (Rio de Janeiro, Paraná and Minas Gerais). Despite being an ancient and tectonically stable landscape, part of the coastal plain of Serra do Mar Mountain in Rio de Janeiro and Paraná is in geometric disequilibrium, with water divides moving in the direction of higher χ values. To achieve equilibrium, some basins located in the continental side are retracting and disappearing, losing area to the coastal basins. On the contrary, there are some adjacent sub-basins that are close to equilibrium, without strong contrasts in χ values. The same pattern was observed in Serra da Mantiqueira (Minas Gerais state), with stream captures and river network reorganization in its main rivers. The initial results suggest a strong contrast between erosion rates in the continental and the oceanic portions of the escarpments.

Linkage of autosomal recessive lamellar ichthyosis to chromosome 14q

DOE Office of Scientific and Technical Information (OSTI.GOV)

Russell, L.J.; Compton, J.G.; Bale, S.J.

The authors have mapped the locus for lamellar ichthyosis (LI), an autosomal recessive skin disease characterized by abnormal cornification of the epidermis. Analysis using both inbred and outbred families manifesting severe LI showed complete linkage to several markers within a 9.3-cM region on chromosome 14q11. Affected individuals in inbred families were also found to have striking homozygosity for markers in this region. Linkage-based genetic counseling and prenatal diagnosis is now available for informative at-risk families. Several transcribed genes have been mapped to the chromosome 14 region containing the LI gene. The transglutaminase 1 gene (TGM1), which encodes one of themore » enzymes responsible for cross-linking epidermal proteins during formation of the stratum corneum, maps to this interval. The TGM1 locus was completely linked to LI (Z = 9.11), suggesting that TGM1 is a good candidate for further investigation of this disorder. The genes for four serine proteases also map to this region but are expressed only in hematopoietic or mast cells, making them less likely candidates.« less

Linkages between ACE Vocational Provision and Mainstream VET.

ERIC Educational Resources Information Center

Saunders, John

A study investigated linkages between adult community education (ACE) and mainstream vocational education and training (VET) in Australia, which enable people to move between the two sectors in their pursuit of vocational learning, and the ways in which linkages might be improved or new ones developed. The data from the study were derived from 69…

Validation of an instrument to measure inter-organisational linkages in general practice.

PubMed

Amoroso, Cheryl; Proudfoot, Judith; Bubner, Tanya; Jayasinghe, Upali W; Holton, Christine; Winstanley, Julie; Beilby, Justin; Harris, Mark F

2007-12-03

Linkages between general medical practices and external services are important for high quality chronic disease care. The purpose of this research is to describe the development, evaluation and use of a brief tool that measures the comprehensiveness and quality of a general practice's linkages with external providers for the management of patients with chronic disease. In this study, clinical linkages are defined as the communication, support, and referral arrangements between services for the care and assistance of patients with chronic disease. An interview to measure surgery-level (rather than individual clinician-level) clinical linkages was developed, piloted, reviewed, and evaluated with 97 Australian general practices. Two validated survey instruments were posted to patients, and a survey of locally available services was developed and posted to participating Divisions of General Practice (support organisations). Hypotheses regarding internal validity, association with local services, and patient satisfaction were tested using factor analysis, logistic regression and multilevel regression models. The resulting General Practice Clinical Linkages Interview (GP-CLI) is a nine-item tool with three underlying factors: referral and advice linkages, shared care and care planning linkages, and community access and awareness linkages. Local availability of chronic disease services has no affect on the comprehensiveness of services with which practices link, however, comprehensiveness of clinical linkages has an association with patient assessment of access, receptionist services, and of continuity of care in their general practice. The GP-CLI may be useful to researchers examining comparable health care systems for measuring the comprehensiveness and quality of linkages at a general practice-level with related services, possessing both internal and external validity. The tool can be used with large samples exploring the impact, outcomes, and facilitators of high

History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population.

PubMed

Rocca, Walter A; Yawn, Barbara P; St Sauver, Jennifer L; Grossardt, Brandon R; Melton, L Joseph

2012-12-01

The Rochester Epidemiology Project (REP) has maintained a comprehensive medical records linkage system for nearly half a century for almost all persons residing in Olmsted County, Minnesota. Herein, we provide a brief history of the REP before and after 1966, the year in which the REP was officially established. The key protagonists before 1966 were Henry Plummer, Mabel Root, and Joseph Berkson, who developed a medical records linkage system at Mayo Clinic. In 1966, Leonard Kurland established collaborative agreements with other local health care providers (hospitals, physician groups, and clinics [primarily Olmsted Medical Center]) to develop a medical records linkage system that covered the entire population of Olmsted County, and he obtained funding from the National Institutes of Health to support the new system. In 1997, L. Joseph Melton III addressed emerging concerns about the confidentiality of medical record information by introducing a broad patient research authorization as per Minnesota state law. We describe how the key protagonists of the REP have responded to challenges posed by evolving medical knowledge, information technology, and public expectation and policy. In addition, we provide a general description of the system; discuss issues of data quality, reliability, and validity; describe the research team structure; provide information about funding; and compare the REP with other medical information systems. The REP can serve as a model for the development of similar research infrastructures in the United States and worldwide. Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Delayed, disequilibrium degassing in rhyolite magma: Decompression experiments and implications for explosive volcanism

USGS Publications Warehouse

Mangan, M.; Sisson, T.

2000-01-01

Recent numerical models and analog shock tube experiments show that disequilibrium degassing during magma ascent may lead to violent vesiculation very near the surface. In this study a series of decompression experiments using crystal-free, rhyolite melt were conducted to examine the development of large supersaturations due to delayed, homogenous (spontaneous) bubble nucleation. Melts were saturated at 900??C and 200 MPa with either 5.2 wt% dissolved H2O, or with 4.2 wt% H2O and 640 ppm CO2, and isothermally decompressed at linear rates of either 0.003, 0.025, or 8.5 MPa/s to final pressures between 25 and 175 MPa. Additional isobaric saturation experiments (900??C, 200-25 MPa) using pure H2O or mixed H2O-CO2 fluids establish reference equilibrium solubility curves/values. Homogenous nucleation is triggered in both H2O-only and H2O-CO2 experiments once the supersaturation pressure (??Pss) reaches ?? 120-150 MPa and the melt contains ?? two times its equilibrium water contents. Bubble number density and nucleation rate depend on the supersaturation pressure, with values on the order of 102/cm3 and < 1/cm3/s for ??Pss~120 MPa; 106/cm3 and 103-105/cm3/s for ??Pss??~130-150 MPa; and 107/cm3 and 106/cm3/s for ??Pss??160-175 MPa. Nucleation rates are consistent with classical nucleation theory, and infer an activation energy for nucleation of 1.5 x 10-18 J/nucleus, a critical bubble radius of 2 x 10-9 m, and an effective surface tension for rhyolite at 5.2 wt% H2O and 900??C of 0.10-0.11 N/m. The long nucleation delay limits the time available for subsequent diffusion such that disequilibrium dissolved H2O and CO2 contents persist to the end of our runs. The disequilibrium degassing paths inferred from our experiments contrast markedly with the equilibrium or quasi-equilibrium paths found in other studies where bubble nucleation occurs heterogenously on crystals or other discontinuities in the melt at low ??Pss. Homogenous and heterogenous nucleation rates are

Mercury flux from salt marsh sediments: Insights from a comparison between 224Ra/228Th disequilibrium and core incubation methods

NASA Astrophysics Data System (ADS)

Shi, Xiangming; Mason, Robert P.; Charette, Matthew A.; Mazrui, Nashaat M.; Cai, Pinghe

2018-02-01

In aquatic environments, sediments are the main location of mercury methylation. Thus, accurate quantification of methylmercury (MeHg) fluxes at the sediment-water interface is vital to understanding the biogeochemical cycling of mercury, especially the toxic MeHg species, and their bioaccumulation. Traditional approaches, such as core incubations, are difficult to maintain at in-situ conditions during assays, leading to over/underestimation of benthic fluxes. Alternatively, the 224Ra/228Th disequilibrium method for tracing the transfer of dissolved substances across the sediment-water interface, has proven to be a reliable approach for quantifying benthic fluxes. In this study, the 224Ra/228Th disequilibrium and core incubation methods were compared to examine the benthic fluxes of both 224Ra and MeHg in salt marsh sediments of Barn Island, Connecticut, USA from May to August, 2016. The two methods were comparable for 224Ra but contradictory for MeHg. The radiotracer approach indicated that sediments were always the dominant source of both total mercury (THg) and MeHg. The core incubation method for MeHg produced similar results in May and August, but an opposite pattern in June and July, which suggested sediments were a sink of MeHg, contrary to the evidence of significant MeHg gradients between overlying water and porewater at the sediment-water interface. The potential reasons for such differences are discussed. Overall, we conclude that the 224Ra/228Th disequilibrium approach is preferred for estimating the benthic flux of MeHg and that sediment is indeed an important MeHg source in this marshland, and likely in other shallow coastal waters.

Estimation and test for linkage between markers: a comparison of lod score and χ (2) test in a linkage study of maritime pine (Pinus pinaster Ait.).

PubMed

Gerber, S; Rodolphe, F

1994-06-01

The first step in the construction of a linkage map involves the estimation and test for linkage between all possible pairs of markers. The lod score method is used in many linkage studies for the latter purpose. In contrast with classical statistical tests, this method does not rely on the choice of a first-type error level. We thus provide a comparison between the lod score and a χ (2) test on linkage data from a gymnosperm, the maritime pine. The lod score appears to be a very conservative test with the usual thresholds. Its severity depends on the type of data used.

Linkage mapping in sheep and deer identifies a conserved pecora ruminant linkage group orthologous to two regions of HSA16 and a portion of HSA7Q

DOE Office of Scientific and Technical Information (OSTI.GOV)

Broom, J.E.; Tate, M.L.; Dodds, K.G.

1996-05-01

Two orthologous linkage groups have been mapped in sheep and deer. Seven loci have been mapped in deer, and 12 in sheep. The sheep linkage group is assigned of ovine chromosome 24. The linkage groups consist of loci from the short arm of human chromosome 16, spanning the region containing the human Batten disease locus, and from human chromosome 7. One locus from the long arm of human chromosome 16 is also present, demonstrating a previously unknown rearrangement between human and ruminant chromosomes. There is no significant difference in marker order and distances between the two linkage groups, implying thatmore » this linkage pattern was present in the genome of the common ancestor of the pecora ruminants. 35 refs., 1 fig., 2 tabs.« less

Simulating a base population in honey bee for molecular genetic studies

PubMed Central

2012-01-01

Background Over the past years, reports have indicated that honey bee populations are declining and that infestation by an ecto-parasitic mite (Varroa destructor) is one of the main causes. Selective breeding of resistant bees can help to prevent losses due to the parasite, but it requires that a robust breeding program and genetic evaluation are implemented. Genomic selection has emerged as an important tool in animal breeding programs and simulation studies have shown that it yields more accurate breeding value estimates, higher genetic gain and low rates of inbreeding. Since genomic selection relies on marker data, simulations conducted on a genomic dataset are a pre-requisite before selection can be implemented. Although genomic datasets have been simulated in other species undergoing genetic evaluation, simulation of a genomic dataset specific to the honey bee is required since this species has a distinct genetic and reproductive biology. Our software program was aimed at constructing a base population by simulating a random mating honey bee population. A forward-time population simulation approach was applied since it allows modeling of genetic characteristics and reproductive behavior specific to the honey bee. Results Our software program yielded a genomic dataset for a base population in linkage disequilibrium. In addition, information was obtained on (1) the position of markers on each chromosome, (2) allele frequency, (3) χ2 statistics for Hardy-Weinberg equilibrium, (4) a sorted list of markers with a minor allele frequency less than or equal to the input value, (5) average r2 values of linkage disequilibrium between all simulated marker loci pair for all generations and (6) average r2 value of linkage disequilibrium in the last generation for selected markers with the highest minor allele frequency. Conclusion We developed a software program that takes into account the genetic and reproductive biology specific to the honey bee and that can be used to

Population genetics related to adaptation in elite oat germplasm

USDA-ARS?s Scientific Manuscript database

Six hundred thirty five oat lines and 2,635 SNP loci were used to evaluate population structure, linkage disequilibrium (LD) and genotype-phenotype association with heading date. The first five principal components (PC) accounted for 25.3% of genetic variation. Neither the eigenvalues of the first 2...

Intragroup Emotions: Physiological Linkage and Social Presence

PubMed Central

Järvelä, Simo; Kätsyri, Jari; Ravaja, Niklas; Chanel, Guillaume; Henttonen, Pentti

2016-01-01

We investigated how technologically mediating two different components of emotion—communicative expression and physiological state—to group members affects physiological linkage and self-reported feelings in a small group during video viewing. In different conditions the availability of second screen text chat (communicative expression) and visualization of group level physiological heart rates and their dyadic linkage (physiology) was varied. Within this four person group two participants formed a physically co-located dyad and the other two were individually situated in two separate rooms. We found that text chat always increased heart rate synchrony but HR visualization only with non-co-located dyads. We also found that physiological linkage was strongly connected to self-reported social presence. The results encourage further exploration of the possibilities of sharing group member's physiological components of emotion by technological means to enhance mediated communication and strengthen social presence. PMID:26903913

Solid-Phase Synthesis of RNA Analogs Containing Phosphorodithioate Linkages.

PubMed

Yang, Xianbin

2017-09-18

The oligoribonucleotide phosphorodithioate (PS2-RNA) modification uses two sulfur atoms to replace two non-bridging oxygen atoms at an internucleotide phosphorodiester backbone linkage. Like a natural phosphodiester RNA backbone linkage, a PS2-modified backbone linkage is achiral at phosphorus. PS2-RNAs are highly stable to nucleases and several in vitro assays have demonstrated their biological activity. For example, PS2-RNAs silenced mRNA in vitro and bound to protein targets in the form of PS2-aptamers (thioaptamers). Thus, the interest in and promise of PS2-RNAs has drawn attention to synthesizing, isolating, and characterizing these compounds. RNA-thiophosphoramidite monomers are commercially available from AM Biotechnologies and this unit describes an effective methodology for solid-phase synthesis, deprotection, and purification of RNAs having PS2 internucleotide linkages. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

Cognitive Disequilibrium and Service-Learning in Physical Education Teacher Education: Perceptions of Pre-Service Teachers in a Study Abroad Experience

ERIC Educational Resources Information Center

Ward, Stephen; Pellet, Heidi Henschel; Perez, Mark I.

2017-01-01

Purpose: The purpose of this study was to explore preservice teachers' experiences of cognitive disequilibrium (CD) theory during a service-learning project in a study abroad experience. Method: A case study with 8 participants was used. Data sources consisted of: Formal interviews, videos of planning, videos of teaching, videos of reflection…

A reliability design method for a lithium-ion battery pack considering the thermal disequilibrium in electric vehicles

NASA Astrophysics Data System (ADS)

Xia, Quan; Wang, Zili; Ren, Yi; Sun, Bo; Yang, Dezhen; Feng, Qiang

2018-05-01

With the rapid development of lithium-ion battery technology in the electric vehicle (EV) industry, the lifetime of the battery cell increases substantially; however, the reliability of the battery pack is still inadequate. Because of the complexity of the battery pack, a reliability design method for a lithium-ion battery pack considering the thermal disequilibrium is proposed in this paper based on cell redundancy. Based on this method, a three-dimensional electric-thermal-flow-coupled model, a stochastic degradation model of cells under field dynamic conditions and a multi-state system reliability model of a battery pack are established. The relationships between the multi-physics coupling model, the degradation model and the system reliability model are first constructed to analyze the reliability of the battery pack and followed by analysis examples with different redundancy strategies. By comparing the reliability of battery packs of different redundant cell numbers and configurations, several conclusions for the redundancy strategy are obtained. More notably, the reliability does not monotonically increase with the number of redundant cells for the thermal disequilibrium effects. In this work, the reliability of a 6 × 5 parallel-series configuration is the optimal system structure. In addition, the effect of the cell arrangement and cooling conditions are investigated.

Report from the Maryland epidemiology schizophrenia linkage study: No evidence for linkage between schizophrenia and a number of candidate and other genomic regions using a complex dominant model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karayiorgou, M.; Hwang, J.; Elango, R.

Our collaborative group has undertaken a linkage study of schizophrenia, using a systematic sample of patients admitted to Maryland hospitals. An initial sample of 39 families, each having two or more affecteds, was available for genotyping candidate genes, candidate regions, and highly polymorphic markers randomly distributed throughout the genome. We used a single complex dominant model (with a disease gene frequency of 0.005 and age-dependent penetrance for affected phenotype: for under 35, penetrance = .45; for 35 and older, penetrance = .85). We report here 130 markers which met the exclusion criteria of LOD score < -2.00 at theta >more » 0.01 in at least 10 informative families, and no evidence for heterogeneity. We also report here markers that were tested as candidates for linkage to the schizophrenic phenotype. They were selected based on the following criteria: (a) proximity to reported chromosomal rearrangements (both 5q and 11q), (b) suggestions of linkage from other families (5q), or (c) presence of a candidate gene (5q, 11q, 3q: dopamine receptors 1, 2, and 3, respectively). We also tested for mutations of codon 717 in exon 17 of the amyloid precursor protein (APP) gene and were unable to detect the C to T substitution in our schizophrenic group. 48 refs., 2 tabs.« less

Data Linkage in VET Research: Opportunities, Challenges and Principles. Discussion Paper

ERIC Educational Resources Information Center

Osborne, Kristen; Fowler, Craig; Circelli, Michelle

2018-01-01

This discussion paper explores the possibilities and risks that data linkage presents for the vocational education and training (VET) sector. Along with a broad overview of the nature of data linkage, it highlights possible applications for data linkage in the VET sector and examines the key challenges associated with its use. A number of case…

Appliation of rad-sequencing to linkage mapping in citrus

USDA-ARS?s Scientific Manuscript database

High density linkage maps can be developed for modest cost using high-throughput DNA sequencing to genotype a defined fraction (representation) of the genome. We developed linkage maps in two citrus populations using the RAD (Restriction site Associated DNA) genotyping method which involves restrict...

Linkage and Branch Analysis of High-Mannose Oligosaccharides Using Closed-Ring Labeling of 8-Aminopyrene-1,3,6-Trisulfonate and P-Aminobenzoic Ethyl Ester and Negative Ion Trap Mass Spectrometry

NASA Astrophysics Data System (ADS)

Chen, Shu-Ting; Her, Guor-Rong

2012-08-01

A strategy based on negative ion electrospray ionization tandem mass spectrometry and closed-ring labeling with both 8-aminopyrene-1,3,6-trisulfonate (APTS) and p-aminobenzoic acid ethyl ester (ABEE) was developed for linkage and branch determination of high-mannose oligosaccharides. X-type cross-ring fragment ions obtained from APTS-labeled oligosaccharides by charge remote fragmentation provided information on linkages near the non-reducing terminus. In contrast, A-type cross-ring fragment ions observed from ABEE-labeled oligosaccharides yielded information on linkages near the reducing terminus. This complementary information provided by APTS- and ABEE-labeled oligosaccharides was utilized to delineate the structures of the high-mannose oligosaccharides. As a demonstration of this approach, the linkages and branches of high-mannose oligosaccharides Man5GlcNAc2, Man6GlcNAc2, Man8GlcNAc2, and Man9GlcNAc2 cleaved from the ribonuclease B were assigned from MS2 spectra of ABEE- and APTS-labeled derivatives.

Metabolic Linkage and Correlations to Storage Capacity in Erythrocytes from Glucose 6-Phosphate Dehydrogenase-Deficient Donors.

PubMed

Reisz, Julie A; Tzounakas, Vassilis L; Nemkov, Travis; Voulgaridou, Artemis I; Papassideri, Issidora S; Kriebardis, Anastasios G; D'Alessandro, Angelo; Antonelou, Marianna H

2017-01-01

In glucose 6-phosphate dehydrogenase (G6PD) deficiency, decreased NADPH regeneration in the pentose phosphate pathway and subnormal levels of reduced glutathione result in insufficient antioxidant defense, increased susceptibility of red blood cells (RBCs) to oxidative stress, and acute hemolysis following exposure to pro-oxidant drugs and infections. Despite the fact that redox disequilibrium is a prominent feature of RBC storage lesion, it has been reported that the G6PD-deficient RBCs store well, at least in respect to energy metabolism, but their overall metabolic phenotypes and molecular linkages to the storability profile are scarcely investigated. We performed UHPLC-MS metabolomics analyses of weekly sampled RBC concentrates from G6PD sufficient and deficient donors, stored in citrate phosphate dextrose/saline adenine glucose mannitol from day 0 to storage day 42, followed by statistical and bioinformatics integration of the data. Other than previously reported alterations in glycolysis, metabolomics analyses revealed bioactive lipids, free fatty acids, bile acids, amino acids, and purines as top variables discriminating RBC concentrates for G6PD-deficient donors. Two-way ANOVA showed significant changes in the storage-dependent variation in fumarate, one-carbon, and sulfur metabolism, glutathione homeostasis, and antioxidant defense (including urate) components in G6PD-deficient vs. sufficient donors. The levels of free fatty acids and their oxidized derivatives, as well as those of membrane-associated plasticizers were significantly lower in G6PD-deficient units in comparison to controls. By using the strongest correlations between in vivo and ex vivo metabolic and physiological parameters, consecutively present throughout the storage period, several interactomes were produced that revealed an interesting interplay between redox, energy, and hemolysis variables, which may be further associated with donor-specific differences in the post

Disequilibrium growth of olivine in mafic magmas revealed by phosphorus zoning patterns of olivine from mafic-ultramafic intrusions

NASA Astrophysics Data System (ADS)

Xing, Chang-Ming; Wang, Christina Yan; Tan, Wei

2017-12-01

Olivine from mafic-ultramafic intrusions rarely displays growth zoning in major and some minor elements, such as Fe, Mg and Ni, due to fast diffusion of these elements at high temperatures. These elements in olivine are thus not useful in deciphering magma chamber processes, such as magma convection, multiple injection and mixing. High-resolution X-ray elemental intensity mapping reveals distinct P zoning patterns of olivine from two mafic-ultramafic intrusions in SW China. Polyhedral olivine grains from lherzolite and dunite of the Abulangdang intrusion show P-rich dendrites similar to those observed in volcanic rocks. Rounded olivine grains from net-textured Fe-Ti oxide ores of the Baima layered intrusion have irregular P-rich patches/bands crosscut and interlocked by P-poor olivine domains. P-rich patches/bands contain 250 to 612 ppm P, much higher than P-poor olivine domains with 123 to 230 ppm P. In electron backscattered diffraction (EBSD) maps, P-rich patches/bands within a single olivine grain have the same crystallographic orientation, indicating that they were remnants of the same crystal. Thus, both P-rich patches/bands and P-poor olivine domains in the same grain show a disequilibrium texture and clearly record two-stage growth. The P-rich patches/bands are likely the remnants of a polyhedral olivine crystal that formed in the first stage, whereas the P-poor olivine domains containing rounded Ti-rich magnetite and Fe-rich melt inclusions may have formed from an Fe-rich ambient melt in the second stage. The complex P zoning of olivine can be attributed to the dissolution of early polyhedral olivine and re-precipitation from the Fe-rich ambient melt. The early polyhedral olivine was in chemical disequilibrium with the ambient melt that may have been developed by silicate liquid immiscibility in a crystal mush. Our study implies that olivine crystals in igneous cumulates with an equilibrium appearance may have experienced disequilibrium growth processes

Arctic-midlatitude weather linkages in North America

NASA Astrophysics Data System (ADS)

Overland, James E.; Wang, Muyin

2018-06-01

There is intense public interest in whether major Arctic changes can and will impact midlatitude weather such as cold air outbreaks on the central and east side of continents. Although there is progress in linkage research for eastern Asia, a clear gap is conformation for North America. We show two stationary temperature/geopotential height patterns where warmer Arctic temperatures have reinforced existing tropospheric jet stream wave amplitudes over North America: a Greenland/Baffin Block pattern during December 2010 and an Alaska Ridge pattern during December 2017. Even with continuing Arctic warming over the past decade, other recent eastern US winter months were less susceptible for an Arctic linkage: the jet stream was represented by either zonal flow, progressive weather systems, or unfavorable phasing of the long wave pattern. The present analysis lays the scientific controversy over the validity of linkages to the inherent intermittency of jet stream dynamics, which provides only an occasional bridge between Arctic thermodynamic forcing and extended midlatitude weather events.

High-frequency stock linkage and multi-dimensional stationary processes

NASA Astrophysics Data System (ADS)

Wang, Xi; Bao, Si; Chen, Jingchao

2017-02-01

In recent years, China's stock market has experienced dramatic fluctuations; in particular, in the second half of 2014 and 2015, the market rose sharply and fell quickly. Many classical financial phenomena, such as stock plate linkage, appeared repeatedly during this period. In general, these phenomena have usually been studied using daily-level data or minute-level data. Our paper focuses on the linkage phenomenon in Chinese stock 5-second-level data during this extremely volatile period. The method used to select the linkage points and the arbitrage strategy are both based on multi-dimensional stationary processes. A new program method for testing the multi-dimensional stationary process is proposed in our paper, and the detailed program is presented in the paper's appendix. Because of the existence of the stationary process, the strategy's logarithmic cumulative average return will converge under the condition of the strong ergodic theorem, and this ensures the effectiveness of the stocks' linkage points and the more stable statistical arbitrage strategy.

Linkage of the National Health Interview Survey to air quality data.

PubMed

Parker, Jennifer D; Kravets, Nataliya; Woodruff, Tracey J

2008-02-01

This report describes the linkage between the National Health Interview Survey (NHIS) and air monitoring data from the U.S. Environmental Protection Agency (EPA). There have been few linkages of these data sources, partly because of restrictions on releasing geographic detail from NHIS on public-use files in order to protect participant confidentiality. Pollution exposures for NHIS respondents were calculated by averaging the annual average exposure estimates from EPA air monitors both within 5, 10, 15, and 20 miles of the respondent's block-group location (which is available on restricted NHIS data files) and by county of residence. The 1987-2005 linked data files--referred to as NHIS-EPAAnnualAir--were used to describe the percentage of NHIS respondents linked and the median exposures by linkage method, survey year, and pollutant. Using the 2005 NHIS-EPAAnnualAir data file, the percentage linked and median exposure were described by respondent characteristics, linkage method, and pollutant. Many decisions were made to define pollution exposures for NHIS respondents, including monitor selection, location assignment for NHIS respondents, and geographic linkage criteria. Geographic linkage criteria for assigning area-level exposure estimates affected the percentage and composition of respondents included in the resulting linked sample. Median exposure estimates, however, were similar among geographic linkage methods. NHIS-EPAAnnualAir data files for 1985 through 2005 are currently available to users in the NCHS Research Data Center.

A high-density SNP genetic linkage map for the silver-lipped pearl oyster, Pinctada maxima: a valuable resource for gene localisation and marker-assisted selection.

PubMed

Jones, David B; Jerry, Dean R; Khatkar, Mehar S; Raadsma, Herman W; Zenger, Kyall R

2013-11-20

The silver-lipped pearl oyster, Pinctada maxima, is an important tropical aquaculture species extensively farmed for the highly sought "South Sea" pearls. Traditional breeding programs have been initiated for this species in order to select for improved pearl quality, but many economic traits under selection are complex, polygenic and confounded with environmental factors, limiting the accuracy of selection. The incorporation of a marker-assisted selection (MAS) breeding approach would greatly benefit pearl breeding programs by allowing the direct selection of genes responsible for pearl quality. However, before MAS can be incorporated, substantial genomic resources such as genetic linkage maps need to be generated. The construction of a high-density genetic linkage map for P. maxima is not only essential for unravelling the genomic architecture of complex pearl quality traits, but also provides indispensable information on the genome structure of pearl oysters. A total of 1,189 informative genome-wide single nucleotide polymorphisms (SNPs) were incorporated into linkage map construction. The final linkage map consisted of 887 SNPs in 14 linkage groups, spans a total genetic distance of 831.7 centimorgans (cM), and covers an estimated 96% of the P. maxima genome. Assessment of sex-specific recombination across all linkage groups revealed limited overall heterochiasmy between the sexes (i.e. 1.15:1 F/M map length ratio). However, there were pronounced localised differences throughout the linkage groups, whereby male recombination was suppressed near the centromeres compared to female recombination, but inflated towards telomeric regions. Mean values of LD for adjacent SNP pairs suggest that a higher density of markers will be required for powerful genome-wide association studies. Finally, numerous nacre biomineralization genes were localised providing novel positional information for these genes. This high-density SNP genetic map is the first comprehensive linkage

Policy Makers, Information and Learning.

ERIC Educational Resources Information Center

Beers, Pieter J.; van Asselt, Marjolein B. A.; Vermunt, Jan D.; Kirschner, Paul A.

2003-01-01

Interviews explored the information needs of seven Dutch policymakers dealing with global sustainability. They sought information on cultural perspectives and linkages. Information gathering emphasized filtering to find specific information. Most used an application-oriented working style that, combined with policy-driven information seeking, was…

Assessing the value of phenotypic information from non-genotyped animals for QTL mapping of complex traits in real and simulated populations.

PubMed

Melo, Thaise P; Takada, Luciana; Baldi, Fernando; Oliveira, Henrique N; Dias, Marina M; Neves, Haroldo H R; Schenkel, Flavio S; Albuquerque, Lucia G; Carvalheiro, Roberto

2016-06-21

QTL mapping through genome-wide association studies (GWAS) is challenging, especially in the case of low heritability complex traits and when few animals possess genotypic and phenotypic information. When most of the phenotypic information is from non-genotyped animals, GWAS can be performed using the weighted single-step GBLUP (WssGBLUP) method, which permits to combine all available information, even that of non-genotyped animals. However, it is not clear to what extent phenotypic information from non-genotyped animals increases the power of QTL detection, and whether factors such as the extent of linkage disequilibrium (LD) in the population and weighting SNPs in WssGBLUP affect the importance of using information from non-genotyped animals in GWAS. These questions were investigated in this study using real and simulated data. Analysis of real data showed that the use of phenotypes of non-genotyped animals affected SNP effect estimates and, consequently, QTL mapping. Despite some coincidence, the most important genomic regions identified by the analyses, either using or ignoring phenotypes of non-genotyped animals, were not the same. The simulation results indicated that the inclusion of all available phenotypic information, even that of non-genotyped animals, tends to improve QTL detection for low heritability complex traits. For populations with low levels of LD, this trend of improvement was less pronounced. Stronger shrinkage on SNPs explaining lower variance was not necessarily associated with better QTL mapping. The use of phenotypic information from non-genotyped animals in GWAS may improve the ability to detect QTL for low heritability complex traits, especially in populations in which the level of LD is high.

Data linkage between existing healthcare databases to support hospital epidemiology.

PubMed

García Álvarez, L; Aylin, P; Tian, J; King, C; Catchpole, M; Hassall, S; Whittaker-Axon, K; Holmes, A

2011-11-01

Enhancing the use of existing datasets within acute hospitals will greatly facilitate hospital epidemiology, surveillance, the monitoring of a variety of processes, outcomes and risk factors, and the provision of alert systems. Multiple overlapping data systems exist within National Health Service (NHS) hospitals in the UK, and many duplicate data recordings take place because of the lack of linkage and interfaces. This results in hospital-collected data not being used efficiently. The objective was to create an inventory of all existing systems, including administrative, management, human resources, microbiology, patient care and other platforms, to describe the data architecture that could contribute valuable information for a hospital epidemiology unit. These datasets were investigated as to how they could be used to generate surveillance data, key performance indicators and risk information that could be shared at board, clinical programme group, specialty and ward level. An example of an output of this integrated data platform and its application in influenza resilience planning and responsiveness is described. The development of metrics for staff absence and staffing levels may also be used as key indicators for risk-monitoring for infection prevention. This work demonstrates the value of such a data inventory and linkage and the importance of more sophisticated uses of existing NHS data, and innovative collaborative approaches to support clinical care, quality improvement, surveillance, emergency planning and research. Copyright © 2011 The Healthcare Infection Society. All rights reserved.

Identification of Multiple QTL Hotspots in Sockeye Salmon (Oncorhynchus nerka) Using Genotyping-by-Sequencing and a Dense Linkage Map.

PubMed

Larson, Wesley A; McKinney, Garrett J; Limborg, Morten T; Everett, Meredith V; Seeb, Lisa W; Seeb, James E

2016-03-01

Understanding the genetic architecture of phenotypic traits can provide important information about the mechanisms and genomic regions involved in local adaptation and speciation. Here, we used genotyping-by-sequencing and a combination of previously published and newly generated data to construct sex-specific linkage maps for sockeye salmon (Oncorhynchus nerka). We then used the denser female linkage map to conduct quantitative trait locus (QTL) analysis for 4 phenotypic traits in 3 families. The female linkage map consisted of 6322 loci distributed across 29 linkage groups and was 4082 cM long, and the male map contained 2179 loci found on 28 linkage groups and was 2291 cM long. We found 26 QTL: 6 for thermotolerance, 5 for length, 9 for weight, and 6 for condition factor. QTL were distributed nonrandomly across the genome and were often found in hotspots containing multiple QTL for a variety of phenotypic traits. These hotspots may represent adaptively important regions and are excellent candidates for future research. Comparing our results with studies in other salmonids revealed several regions with overlapping QTL for the same phenotypic trait, indicating these regions may be adaptively important across multiple species. Altogether, our study demonstrates the utility of genomic data for investigating the genetic basis of important phenotypic traits. Additionally, the linkage map created here will enable future research on the genetic basis of phenotypic traits in salmon. © The American Genetic Association 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.