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ABSTRACT: Estimation of match probabilities for singleton haplotypes of lineage markers, i.e. for haplotypes observed only once in a reference database augmented by a suspect profile, is an important problem in forensic genetics. We compared the performance of four estimators of singleton match probabilities for Y-STRs, namely the count estimate, both with and without Brenner's so-called 'kappa correction', the surveying estimate, and a previously proposed, but rarely used, coalescent-based approach implemented in the BATWING software. Extensive simulation with BATWING of the underlying population history, haplotype evolution and subsequent database sampling revealed that the coalescent-based approach is characterized by lower bias and lower mean squared error than the uncorrected count estimator and the surveying estimator. Moreover, in contrast to the two count estimators, both the surveying and the coalescent-based approach exhibited a good correlation between the estimated and true match probabilities. However, although its overall performance is thus better than that of any other recognized method, the coalescent-based estimator is still computation-intense on the verge of general impracticability. Its application in forensic practice therefore will have to be limited to small reference databases, or to isolated cases of particular interest, until more powerful algorithms for coalescent simulation have become available.
Forensic science international. Genetics 12/2012; · 2.42 Impact Factor
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ABSTRACT: Our study demonstrates that the genetic investigation of forkhead box O3A gene (FOXO3A), a validated human longevity gene, is greatly hampered by the fact that its exonic regions have 99% sequence homology with the FOXO3B pseudogene. If unaccounted for, this high degree of homology can cause serious genotyping or sequencing errors. Here, we present an experimental set-up that allows reliable data generation for the highly homologous regions and that can be used for the evaluation of assay specificity. Using this design, we exemplarily showed FOXO3A-specific results for two single-nucleotide polymorphisms (SNPs) (rs4945816 and rs4946936) that are significantly associated with longevity in our centenarian-control sample (P(each)=0.0008). Because both SNPs are located in the 3' untranslated region of FOXO3A, they could be of functional relevance for the longevity phenotype. Our experimental set-up can be used for reliable and reproducible data generation for further sequencing and genotyping studies of FOXO3A with the aim of discovering new SNPs of functional relevance.European Journal of Human Genetics advance online publication, 16 May 2012; doi:10.1038/ejhg.2012.83.
European journal of human genetics: EJHG 05/2012; · 3.56 Impact Factor
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ABSTRACT: The rate of microsatellite mutation is dependent upon both the allele length and the repeat motif, but the exact nature of this relationship is still unknown. We analyzed data on the inheritance of human Y-chromosomal microsatellites in father-son duos, taken from 24 published reports and comprising 15,285 directly observable meioses. At the six microsatellites analyzed (DYS19, DYS389I, DYS390, DYS391, DYS392, and DYS393), a total of 162 mutations were observed. For each locus, we employed a maximum-likelihood approach to evaluate one of several single-step mutation models on the basis of the data. For five of the six loci considered, a novel logistic mutation model was found to provide the best fit according to Akaike's information criterion. This implies that the mutation probability at the loci increases (nonlinearly) with allele length at a rate that differs between upward and downward mutations. For DYS392, the best fit was provided by a linear model in which upward and downward mutation probabilities increase equally with allele length. This is the first study to empirically compare different microsatellite mutation models in a locus-specific fashion.
Genetics 12/2011; 189(4):1403-11. · 4.01 Impact Factor
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ABSTRACT: Haemodynamic optimisation is a fundamental goal of post-cardiac arrest therapy. Therefore, predicting volume responsiveness is a key issue in therapy of these high-risk patients and transoesophageal echocardiography (TEE) may provide helpful information. The aim of the present study was to evaluate the performance of visual evaluation (eyeballing) of standardised TEE-loops to predict volume responsiveness during post-cardiac arrest period.
After approval of the local animal investigation committee, TEE mid-oesophageal long-axis views were recorded before a 5 ml/kg volume bolus at baseline and both 1 and 4h after return of spontaneous circulation (ROSC) from 8 min electrically induced cardiac arrest. Post-hoc, TEE loops were independently presented in randomized order to 7 blinded TEE-experts and 14 blinded TEE novices who were asked to predict whether the ventricle will increase stroke volume ≥ 15% after volume loading or not. Statistics were performed calculating sensitivity and specificity for the correct evaluation and agreement of raters.
14 out of 20 pigs were successfully resuscitated, and 924 ratings from 21 echocardiographers were included into analysis. Overall, we observed a sensitivity between 71 and 100%, whereas the specificity showed rather low values between 0 and 67% for prediction of volume responsiveness. Best prediction was recorded 1h after ROSC with median sensitivity (95% CI) of 100% (89-100%) and median specificity of 67% (61-72%). No significant difference was found between ratings of experienced and inexperienced echocardiographers. The concordance rate within the two groups was comparable.
In post-cardiac arrest period, visual evaluation of long-axis TEE loops allows prediction of volume responsiveness with good sensitivity and reasonable specificity even by novice users, and may therefore be suitable for implementation into treatment protocols.
Resuscitation 07/2011; 82(12):1553-7. · 3.60 Impact Factor
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ABSTRACT: A total of 405 unique single base-pair substitutions, located within the ATG translation initiation codons (TICs) of 255 different genes, and reported to cause human genetic disease, were retrieved from the Human Gene Mutation Database (HGMD). Although these lesions comprised only 0.7% of coding sequence mutations in HGMD, they nevertheless were 3.4-fold overrepresented as compared to other missense mutations. The distance between a TIC and the next downstream in-frame ATG codon was significantly greater for genes harboring TIC mutations than for the remainder of genes in HGMD (control genes). This suggests that the absence of an alternative ATG codon in the vicinity of a TIC increases the likelihood that a given TIC mutation will come to clinical attention. An additional 42 single base-pair substitutions in 37 different genes were identified in the vicinity of TICs (positions -6 to +4, comprising the so-called "Kozak consensus sequence"). These substitutions were not evenly distributed, being significantly more abundant at position +4. Finally, contrary to our initial expectation, the match between the original TIC and the Kozak consensus sequence was significantly better (rather than worse) for genes harboring TIC mutations than for the HGMD control genes.
Human Mutation 06/2011; 32(10):1137-43. · 5.69 Impact Factor
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ABSTRACT: The gene tyrosine hydroxylase 1 (TH01) has been suggested as a candidate for human longevity. A previous study has shown an association between longevity and specific alleles of the TH01 short tandem repeat (STR) polymorphism in an Italian population. This STR locus is also widely used in forensic genetics. If the TH01-longevity association could be confirmed in independent samples, this finding would have important ramifications for the use of this polymorphism in a forensic context. In the present study, we sought to replicate the previous association result by investigating 471 long-lived individuals (96-110 years) and 462 younger controls (19-75 years) from Germany. In the analyzed samples, the association between TH01 and longevity was not replicated. However, the obtained TH01 allele frequencies were consistent with published data. We observed considerable differences in the allele distribution between Germans and Italians, in particular with regard to allele 9.3, which displayed a previously undetected decreasing West-East and North-South cline across Europe. The discrepant TH01-longevity association results in Germans and Italians could therefore be due to population-specific effects. This finding highlights the need to take into consideration population genetic data when dealing with association studies.
European journal of human genetics: EJHG 03/2011; 19(8):924-7. · 3.56 Impact Factor
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Jan Thorsten Gräsner,
Patrick Meybohm, Amke Caliebe,
Bernd W Böttiger,
Jan Wnent,
Martin Messelken,
Tanja Jantzen,
Thorsten Zeng,
Bernd Strickmann,
Andreas Bohn,
Hans Fischer,
Jens Scholz,
Matthias Fischer
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ABSTRACT: Mild therapeutic hypothermia (MTH) has been shown to result in better neurological outcome after cardiopulmonary resuscitation. Percutaneous coronary intervention (PCI) may also be beneficial in patients after out-of-hospital cardiac arrest (OHCA).
A selected cohort study of 2,973 prospectively documented adult OHCA patients within the German Resuscitation Registry between 2004 and 2010. Data were analyzed by backwards stepwise binary logistic regression to identify the impact of MTH and PCI on both 24-hour survival and neurological outcome that was based on cerebral performance category (CPC) at hospital discharge. Odds ratios (95% confidence intervals) were calculated adjusted for the following confounding factors: age, location of cardiac arrest, presumed etiology, bystander cardiopulmonary resuscitation, witnessing, first electrocardiogram rhythm, and thrombolysis.
The Preclinical care dataset included 2,973 OHCA patients with 44% initial return of spontaneous circulation (n = 1,302) and 35% hospital admissions (n = 1,040). Seven hundred and eleven out of these 1,040 OHCA patients (68%) were also registered within the Postresuscitation care dataset. Checking for completeness of datasets required the exclusion of 127 Postresuscitation care cases, leaving 584 patients with complete data for final analysis. In patients without PCI (n = 430), MTH was associated with increased 24-hour survival (8.24 (4.24 to 16.0), P < 0.001) and the proportion of patients with CPC 1 or CPC 2 at hospital discharge (2.13 (1.17 to 3.90), P < 0.05) as an independent factor. In normothermic patients (n = 405), PCI was independently associated with increased 24-hour survival (4.46 (2.26 to 8.81), P < 0.001) and CPC 1 or CPC 2 (10.81 (5.86 to 19.93), P < 0.001). Additional analysis of all patients (n = 584) revealed that 24-hour survival was increased by MTH (7.50 (4.12 to 13.65), P < 0.001) and PCI (3.88 (2.11 to 7.13), P < 0.001), while the proportion of patients with CPC 1 or CPC 2 was significantly increased by PCI (5.66 (3.54 to 9.03), P < 0.001) but not by MTH (1.27 (0.79 to 2.03), P = 0.33), although an unadjusted Fisher exact test suggested a significant effect of MTH (unadjusted odds ratio 1.83 (1.23 to 2.74), P < 0.05).
PCI may be an independent predictor for good neurological outcome (CPC 1 or CPC 2) at hospital discharge. MTH was associated with better neurological outcome, although subsequent logistic regression analysis did not show statistical significance for MTH as an independent predictor for good neurological outcome. Thus, postresuscitation care on the basis of standardized protocols including coronary intervention and hypothermia may be beneficial after successful resuscitation. One of the main limitations may be a selection bias for patients subjected to PCI and MTH.
Critical care (London, England) 02/2011; 15(1):R61. · 4.61 Impact Factor
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ABSTRACT: Continuous cardiac output monitoring is used for early detection of hemodynamic instability and guidance of therapy in critically ill patients. Recently, the accuracy of pulse contour-derived cardiac output (PCCO) has been questioned in different clinical situations. In this study, we examined agreement between PCCO and transcardiopulmonary thermodilution cardiac output (COTCP) in critically ill patients, with special emphasis on norepinephrine (NE) administration and the time interval between calibrations.
This prospective, observational study was performed with a sample of 73 patients (mean age, 63 ± 13 years) requiring invasive hemodynamic monitoring on a non-cardiac surgery intensive care unit. PCCO was recorded immediately before calibration by COTCP. Bland-Altman analysis was performed on data subsets comparing agreement between PCCO and COTCP according to NE dosage and the time interval between calibrations up to 24 hours. Further, central artery stiffness was calculated on the basis of the pulse pressure to stroke volume relationship.
A total of 330 data pairs were analyzed. For all data pairs, the mean COTCP (±SD) was 8.2 ± 2.0 L/min. PCCO had a mean bias of 0.16 L/min with limits of agreement of -2.81 to 3.15 L/min (percentage error, 38%) when compared to COTCP. Whereas the bias between PCCO and COTCP was not significantly different between NE dosage categories or categories of time elapsed between calibrations, interchangeability (percentage error <30%) between methods was present only in the high NE dosage subgroup (≥0.1 μg/kg/min), as the percentage errors were 40%, 47% and 28% in the no NE, NE < 0.1 and NE ≥ 0.1 μg/kg/min subgroups, respectively. PCCO was not interchangeable with COTCP in subgroups of different calibration intervals. The high NE dosage group showed significantly increased central artery stiffness.
This study shows that NE dosage, but not the time interval between calibrations, has an impact on the agreement between PCCO and COTCP. Only in the measurements with high NE dosage (representing the minority of measurements) was PCCO interchangeable with COTCP.
Critical care (London, England) 01/2011; 15(1):R22. · 4.61 Impact Factor
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ABSTRACT: Twin studies have shown that longevity in humans is moderately heritable with a genetic component of 25-32%. Experimental model organisms point to the existence of core survival and anti-ageing pathways that have been conserved throughout evolution. It has been shown that mutations in single genes involved in these pathways can either delay or accelerate the ageing process and that many of these genes and pathways are also present in humans. Here, we performed a targeted investigation of selected genes (i) involved in longevity pathways (insulin receptor/insulin-like growth factor-I signaling and energy metabolism, intracellular signaling, apoptosis and stress response) and (ii) in which mutations lead to genetic perturbations in animal models or human diseases. Altogether, we tested 500 nonsynonymous single nucleotide polymorphisms (SNPs) in 343 candidate genes for association with the longevity phenotype in a German sample comprising about 400 centenarians and an equal number of younger control subjects. Thus, this study presents one of the largest candidate studies in human genetic longevity research conducted to-date. The three top-ranking markers, which are located in the genes DUSP6, NALP1 and PERP, revealed p-values≤0.01 in the allelic case-control comparisons. Although the association signals in Germans were not replicated in an independent French sample, the large number of analysis results is deemed a valuable reference point for further genetic studies.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 12/2010; 694(1-2):13-9. · 2.85 Impact Factor
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ABSTRACT: The stepwise mutation model (SMM) is a simple, widely used model to describe the evolutionary behaviour of microsatellites. We apply a Markov chain description of the SMM and derive the marginal and joint properties of this process. In addition to the standard SMM, we also consider the normalised allele process. In contrast to the standard process, the normalised process converges to a stationary distribution. We show that the marginal stationary distribution is unimodal. The standard and normalised processes capture the global and the local behaviour of the SMM, respectively.
Journal of Theoretical Biology 09/2010; 266(2):336-42. · 2.21 Impact Factor
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ABSTRACT: The common 4977-bp deletion in mitochondrial DNA (dmtDNA(4977)) occurs frequently in tissues of high oxygen demand and low mitotic activity, e.g. brain, heart and skeletal muscle, where it appears to show an age-related accumulation. Although dmtDNA(4977) can also be detected in very low amounts in fast replicating tissues such as blood, it is still unclear whether an age-dependent distribution of dmtDNA(4977) occurs in blood. In view of these uncertainties, we investigated the presence of the mutation and changes in the dmtDNA(4977) level in whole blood samples from 473 individuals who belong to two different age groups, i.e. elderly (aged 61-75 years) and long-lived individuals (LLI, aged 95-109 years). We applied a highly sensitive and reliable duplex-PCR method that allowed relative quantification of dmtDNA(4977). For validation, we additionally performed absolute quantification on a subset of samples using real time-PCR. Our results showed that the proportion of dmtDNA(4977) carriers was very similar in both groups, but that the individual mutational load was on average much lower in the nonagenarians and centenarians than in the elderly. The finding was independent of smoking habits, gender or variation in APOE and FOXO3A but could be caused by other environmental and/or genetic factors.
Mechanisms of ageing and development 03/2010; 131(3):179-84. · 4.18 Impact Factor
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Amke Caliebe,
Rabea Kleindorp,
Hélène Blanché,
Lene Christiansen,
Annibale Alessandro Puca,
Irene Maeve Rea,
Eline Slagboom,
Friederike Flachsbart,
Kaare Christensen,
Gerald Rimbach,
Stefan Schreiber,
Almut Nebel
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ABSTRACT: Paraoxonase 1 (PON1) has been suggested as a plausible candidate gene for human longevity due to its modulation of cardiovascular disease risk, by preventing oxidation of atherogenic low-density lipoprotein. The role of the PON1 192 Q/R polymorphism has been analyzed for association with survival at old age in several populations, albeit with controversial results. To reconcile the conflicting evidence, we performed a large association study with two samples of 2357 Germans and 1025 French, respectively. We combined our results with those from seven previous studies in the largest and most comprehensive meta-analysis on PON1 192 Q/R and longevity to-date, to include a total of 9580 individuals. No significant association of PON1 192 Q/R with longevity was observed, for either R allele or carriership. This finding relied on very large sample sizes, is supported by different analysis methods and is therefore considered very robust. Moreover, we have investigated a potential interaction of PON1 192 Q/R with APOE epsilon4 using data from four populations. Whereas a significant result was found in the German sample, this could not be confirmed in the other examined groups. Our large-scale meta-analysis provided no evidence that the PON1 192 Q/R polymorphism is associated with longevity, but this does not exclude the possibility of population-specific effects due to the influence of, and interaction between, different genetic and/or environmental factors (e.g. diet).
Ageing research reviews 03/2010; 9(3):238-44. · 5.62 Impact Factor
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Almut Nebel,
Friederike Flachsbart,
Andreas Till, Amke Caliebe,
Hélène Blanché,
Alexander Arlt,
Robert Häsler,
Gunnar Jacobs,
Rabea Kleindorp,
Andre Franke,
Binghui Shen,
Susanna Nikolaus,
Michael Krawczak,
Philip Rosenstiel,
Stefan Schreiber
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ABSTRACT: Human longevity is heritable with a genetic component of 25-32%. Variation in genes regulating the levels of somatic maintenance and DNA repair functions is thought to modulate the aging process and to contribute to survival at advanced age. We tested 92 non-synonymous SNPs in 49 DNA repair genes for a possible association with longevity in a sample of 395 German centenarians and 411 controls. The obtained association signal in exonuclease 1 (EXO1) was further investigated by fine mapping and mutation detection, leading to the identification of the functionally relevant SNP rs1776180. Our detailed analyses revealed that the C allele of this promoter SNP is significantly enriched in female centenarians. This finding replicated in 455 female French centenarians and 109 controls. The C allele leads to the loss of a binding site for the basic helix-loop-helix transcription factor E47, resulting in higher EXO1 expression. Thus, we have detected a hitherto undescribed role for E47 as a negative regulator of EXO1 transcription and a genetic variant in the EXO1 promoter that counteracts the E47-mediated repression of the gene. Given the survival advantage that is associated with the C allele of rs1776180, EXO1 can be considered a candidate for a novel longevity-enabling gene.
Mechanisms of ageing and development 09/2009; 130(10):691-9. · 4.18 Impact Factor
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ABSTRACT: Risk alleles for age-related diseases are expected to decrease in frequency in the population strata of increasing age. Consistent with this hypothesis, earlier studies showed a depletion of the Alzheimer's disease risk factor APOE*epsilon4 in long-lived individuals (LLIs). To evaluate whether this observation also holds for a previously suggested Alzheimer's disease risk haplotype in the A2M gene, we analyzed this particular haplotype in 1042 German LLIs (aged 95-100 years) and 1040 younger individuals (aged 60-75 years). Our results show a significant depletion of this haplotype in LLIs, thus confirming it as a mortality factor in the elderly. Consequently, our data support an involvement of the suggested A2M risk haplotype in the pathogenesis of Alzheimer's disease and adds new evidence to the risk-allele depletion hypothesis.
European journal of human genetics: EJHG 08/2009; 18(1):59-61. · 3.56 Impact Factor
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ABSTRACT: The human forkhead box O3A gene (FOXO3A) encodes an evolutionarily conserved key regulator of the insulin-IGF1 signaling pathway that is known to influence metabolism and lifespan in model organisms. A recent study described 3 SNPs in the FOXO3A gene that were statistically significantly associated with longevity in a discovery sample of long-lived men of Japanese ancestry [Willcox et al. (2008) Proc Natl Acad Sci USA 105:13987-13992]. However, this finding required replication in an independent population. Here, we have investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provide evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age. The FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research. Our study extended the initial finding observed in Japanese men to women and indicates that both genders were likely to be equally affected by variation in FOXO3A. Replication in a French centenarian sample generated a trend that supported the previous results. Our findings confirmed the initial discovery in the Japanese sample and indicate FOXO3A as a susceptibility gene for prolonged survival in humans.
Proceedings of the National Academy of Sciences 03/2009; 106(8):2700-5. · 9.68 Impact Factor
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Timothy Tehua Lu,
Oscar Lao,
Michael Nothnagel,
Olaf Junge,
Sandra Freitag-Wolf, Amke Caliebe,
Miroslava Balascakova,
Jaume Bertranpetit,
Laurence Albert Bindoff,
David Comas, [......],
André Gerardus Uitterlinden,
Christian Gieger,
Heinz-Erich Wichmann,
Andreas Ruether,
Stefan Schreiber,
Christian Becker,
Peter Nürnberg,
Matthew Roberts Nelson,
Manfred Kayser,
Michael Krawczak
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ABSTRACT: Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene-disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309,790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.
European journal of human genetics: EJHG 02/2009; 17(7):967-75. · 3.56 Impact Factor
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Andreas Wolf,
David S Millar, Amke Caliebe,
Martin Horan,
Vicky Newsway,
Dorothea Kumpf,
Katharina Steinmann,
Ik-Seung Chee,
Young-Ho Lee,
Apiwat Mutirangura,
Guglielmina Pepe,
Olga Rickards,
Jörg Schmidtke,
Werner Schempp,
Nadia Chuzhanova,
Hildegard Kehrer-Sawatzki,
Michael Krawczak,
David N Cooper
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ABSTRACT: To assess the evolutionary importance of nonallelic (or interlocus) gene conversion for the highly polymorphic human growth hormone (GH1) gene promoter, sequence variation in this region was studied in four different ethnic groups. For 14 SNPs in the proximal GH1 promoter (535 bp), 60 different haplotypes were observed in 577 individuals (156 Britons, 116 Spaniards, 163 West-Africans, 142 Asians). Using a novel coalescence-based statistical test, significant evidence was found in the British, Spanish, and African groups for GH1 having acted as an acceptor of gene conversion, with at least one of the four paralogous GH gene promoters serving as the donor (and specifically GH2 in the Britons and Spaniards). The average gene conversion tract length was estimated to be 84 bp. A gene conversion hotspot was identified, spanning the GH1 transcriptional initiation site (positions -6 to +25). Although these findings serve to highlight the importance of gene conversion for the recent evolution of the human GH1 promoter, its relative frequency does not appear to be related simply to the presence of specific DNA sequence motifs or secondary structures, the degree of homology between GH paralogs, the distance between them, or their transcriptional orientation. The GH1 promoter was also found to be highly polymorphic in chimpanzee but not in macaque. This may reflect the lower degree of pair-wise similarity between the GH1 promoter and its paralogs in macaque (mean, 92.0%) as compared to chimpanzee (93.5%) and human (94.0%), and hence provides further support for the idea of a threshold (perhaps around 92%) below which gene conversion is reduced or abolished.
Human Mutation 10/2008; 30(2):239-47. · 5.69 Impact Factor
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Oscar Lao,
Timothy T Lu,
Michael Nothnagel,
Olaf Junge,
Sandra Freitag-Wolf, Amke Caliebe,
Miroslava Balascakova,
Jaume Bertranpetit,
Laurence A Bindoff,
David Comas, [......],
André G Uitterlinden,
Christian Gieger,
Heinz-Erich Wichmann,
Andreas Rüther,
Stefan Schreiber,
Christian Becker,
Peter Nürnberg,
Matthew R Nelson,
Michael Krawczak,
Manfred Kayser
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ABSTRACT: Understanding the genetic structure of the European population is important, not only from a historical perspective, but also for the appropriate design and interpretation of genetic epidemiological studies. Previous population genetic analyses with autosomal markers in Europe either had a wide geographic but narrow genomic coverage [1, 2], or vice versa [3-6]. We therefore investigated Affymetrix GeneChip 500K genotype data from 2,514 individuals belonging to 23 different subpopulations, widely spread over Europe. Although we found only a low level of genetic differentiation between subpopulations, the existing differences were characterized by a strong continent-wide correlation between geographic and genetic distance. Furthermore, mean heterozygosity was larger, and mean linkage disequilibrium smaller, in southern as compared to northern Europe. Both parameters clearly showed a clinal distribution that provided evidence for a spatial continuity of genetic diversity in Europe. Our comprehensive genetic data are thus compatible with expectations based upon European population history, including the hypotheses of a south-north expansion and/or a larger effective population size in southern than in northern Europe. By including the widely used CEPH from Utah (CEU) samples into our analysis, we could show that these individuals represent northern and western Europeans reasonably well, thereby confirming their assumed regional ancestry.
Current Biology 09/2008; 18(16):1241-8. · 9.65 Impact Factor
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ABSTRACT: To evaluate whether ABCC2 gene polymorphisms are associated with expression and/or function of the efflux pump.
We investigated the allele frequency of ABCC2 -24C>T, -23G>A, c.1249G>A, c.1446C>G, c.1457C>T, c.2302C>T, c.2366C>T, c.3542G>T, c.3561G>A, c.3563T>A, c.3972C>T, c.4348G>A, and 4544G>A in 374 nonrelated German healthy volunteers and determined the impact on duodenal mRNA and protein content of ABCC2. For functional analysis, the disposition of intravenously (30 mg) and orally administered talinolol (100 mg) was measured among 31 individuals. Moreover, the effects of rifampicin-type induction (600 mg, 8 days) of duodenal ABCC2 were quantified in 22 participants with regard to genetic polymorphisms.
The allele frequencies were 18.3% (-24T), 21.1% (1249A), 1.4% (1446G), 0.1% (3542T), 4.5% (3563A), 34.2% (3972T), and 4.4% (4544A); carriers of -23G>A, 1457C>T, 2302C>T, 2366C>T, 3561G>A, and 4348G>A were not identified. The -24T allele was in strong linkage with 3972T, and 3563A with 4544A, whereas 1249A was weakly linked with other variant alleles. None of the single nucleotide polymorphisms investigated influenced significantly intestinal ABCC2 mRNA and protein content. The variant ABCC2 1249G>A (V417I), however, was associated with lower oral bioavailability (P=0.001), and increased residual clearance of intravenous talinolol (P=0.021). Intestinal ABCC2 mRNA and protein expression were upregulated by rifampicin treatment, a genetic influence could be detected in only four cases heterozygote for 3563T>A or 4544G>A.
The 1249G>A (V417I) polymorphism is obviously associated with higher activity of the intestinal transporter.
Pharmacogenetics and Genomics 04/2008; 18(4):357-65. · 3.48 Impact Factor
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ABSTRACT: Let Z(n) denote the length of an external branch, chosen at random from a Kingman n-coalescent. Based on a recursion for the distribution of Z(n), we show that nZ(n) converges in distribution, as n tends to infinity, to a non-negative random variable Z with density x--> 8/(2+x)(3), x>or=0. This result facilitates the study of the time to the most recent common ancestor of a randomly chosen individual and its closest relative in a given population. This time span also reflects the maximum relatedness between a single individual and the rest of the population. Therefore, it measures the uniqueness of a random individual, a central characteristic of the genetic diversity of a population.
Theoretical Population Biology 10/2007; 72(2):245-52. · 1.65 Impact Factor
