Sequencing errors or SNPs at splice-acceptor guanines in dbSNP?
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Artifacts↗
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Results for “statistical genetics”
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Evidence that enzyme polymorphisms are not selectively neutral.
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Alleles↗
A genome scan for loci influencing anti-atherogenic serum bilirubin levels.
Epidemiological studies have shown an association of decreased serum bilirubin levels with coronary artery disease. Two segregation analyses in large pedigrees have suggested a major gene responsible for high bilirubin levels occurring in about 12% of the population. Based on a recessive model from a previous segregation analysis, we performed a genome scan using 587 markers genotyped in 862 individuals from 48 Utah pedigrees to detect loci linked to high bilirubin levels. As a complementary approach, non-parametric linkage (NPL) analysis was performed. These two methods identified four regions showing evidence for linkage. The first region is on chromosome 2q34-37 with multipoint LOD and NPL scores of 3.01 and 3.22, respectively, for marker D2S1363. This region contains a previously described gene, uridine diphosphate glycosyltransferase 1, which has been associated with high bilirubin levels. A polymorphism in the promoter of this gene was recently shown to be responsible for Gilbert syndrome which is associated with mild hyperbilirubinemia. The other regions were found on chromosomes 9q21, 10q25-26, and 18q12 with maximum NPL scores of 2.39, 1.55, and 2.79, respectively. Furthermore, we investigated in these pedigrees the association between bilirubin levels and coronary artery disease. One-hundred and sixty-one male and 41 female subjects had already suffered a coronary artery disease event. Male patients showed significantly lower bilirubin concentrations than age-matched controls. This association, however, was not observed in females. These results provide evidence that loci influencing bilirubin variation exist on chromosomes 2q34-37, 9q21, 10q25-26, and 18q12 and confirms the association of low bilirubin levels with coronary artery disease in males.
Adult↗
Combined high resolution linkage and association mapping of quantitative trait loci.
In this paper, we investigate variance component models of both linkage analysis and high resolution linkage disequilibrium (LD) mapping for quantitative trait loci (QTL). The models are based on both family pedigree and population data. We consider likelihoods which utilize flanking marker information, and carry out an analysis of model building and parameter estimations. The likelihoods jointly include recombination fractions, LD coefficients, the average allele substitution effect and allele dominant effect as parameters. Hence, the model simultaneously takes care of the linkage, LD or association and the effects of the putative trait locus. The models clearly demonstrate that linkage analysis and LD mapping are complementary, not exclusive, methods for QTL mapping. By power calculations and comparisons, we show the advantages of the proposed method: (1) population data can provide information for LD mapping, and family pedigree data can provide information for both linkage analysis and LD mapping; (2) using family pedigree data and a sparse marker map, one may investigate the prior suggestive linkage between trait locus and markers to obtain low resolution of the trait loci, because linkage analysis can locate a broad candidate region; (3) with the prior knowledge of suggestive linkage from linkage analysis, both population and family pedigree data can be used simultaneously in high resolution LD mapping based on a dense marker map, since LD mapping can increase the resolution for candidate regions; (4) models of high resolution LD mappings using two flanking markers have higher power than that of models of using only one marker in the analysis; (5) excluding the dominant variance from the analysis when it does exist would lose power; (6) by performing linkage interval mappings, one may get higher power than by using only one marker in the analysis.
Chromosome Mapping↗
Heterozygote deficiencies in small lacustrine populations of brook charr Salvelinus Fontinalis Mitchill (Pisces, Salmonidae): a test of alternative hypotheses.
Empirical studies of natural populations have commonly reported departures from Hardy-Weinberg expected proportions of heterozygote individuals. Recent advances in statistical population genetics now offer the potential to exploit individual multilocus genotypic information to test more rigorously for possible sources of heterozygote deficiencies. In a previous study in lacustrine brook charr (Salvelinus fontinalis), we reported stronger deficits in small than in large lakes. In the present paper, we propose a methodology for empirically testing alternative hypotheses to identify the cause of the deficits observed in three of the smallest lakes (85, 109 and 182 ha) analysed. First, as in several salmonid species, brook charr may exhibit a trophic polymorphism in north temperate lakes. If morphs are genetically divergent, indiscriminate sampling of both forms would result in less heterozygote individuals than expected in a randomly mating population (Wahlund effect). Using an individual-based method aiming at detecting cryptic population structure, we can reject this explanation as the sole source of deficits for all three lakes. Secondly, mating among relatives could also be frequent in small lakes and lead to heterozygote deficiencies. Significantly more fish than expected at random had low individual multilocus heterozygosity in two of the lakes, suggesting that inbred fish may have been present. Thirdly, sampling of genetically related fish would also lead to departures from Hardy-Weinberg proportions. In the same two lakes, the distribution of pairwise relatedness coefficients departed from its random expectation, suggesting that non-random sampling of kin may have occurred.
Animals↗
Effective size of populations with heritable variation in fitness.
The effective size of monogamous populations with heritable variation in fitness is formulated, and the expression obtained is compared with a published equation. It is shown that the published equation for dioecious populations is inappropriate for most animal and human populations, because the derivation is implicitly based on the assumption that zygotes are produced by random union of gametes, each from conceptual male and female gametic pools. A convenient equation for practical use is proposed, and the application is illustrated with the estimation of the effective size of a rural human community in Japan.
Data Interpretation, Statistical↗
The T-allele of the C825T polymorphism is associated with higher arterial stiffness in young healthy males.
Arterial stiffening is the major cause of increasing systolic blood pressure in arterial hypertension. Increased arterial stiffness is one major mechanism responsible for morbidity and mortality in hypertension. A C825T polymorphism was identified in the gene encoding the G-protein beta3 subunit (GNB3), and an association of the T-allele with hypertension was demonstrated in several studies. In order to identify a pathogenetic link between hypertension and arterial stiffness, we compared two indices of arterial stiffness, pulse wave velocity (PWV) and augmentation index, in young, healthy men with and without the 825T-allele under resting conditions. PWV was determined from pressure tracing over carotid and femoral arteries in 99 subjects (CC: n=43; CT&TT: n=56). Augmentation index was derived in 72 subjects (CC: n=30; CT&TT: n=42) by pulse wave analysis using radial applanation tonometry. Carriers of the 825T-allele exhibited a significantly higher PWV compared to subjects with the CC genotype (6.0+/-0.1 m/s (TC&TT) vs 5.7+/-0.1 m/s (CC); P=0.0251). There was also a significant difference (P = 0.0448) in augmentation index between carriers of the T-allele (CT&TT: 3.4+/-2.9%) and controls with the CC -genotype (-5.0+/-4.1 %). There was no difference in any other anthropometric (age, height, weight, body mass index) or haemodynamic (heart rate, peripheral and central blood pressure). In summary, the C825T polymorphism is associated with higher arterial stiffness in young, healthy males. Arterial stiffening may pathogenetically contribute to the development of hypertension in carriers of the T-allele.
Adult↗
Indigenous domestic breeds as reservoirs of genetic diversity: the Argentinean Creole cattle.
Contrary to highly selected commercial breeds, indigenous domestic breeds are composed of semi-wild or feral populations subjected to reduced levels of artificial selection. As a consequence, many of these breeds have become locally adapted to a wide range of environments, showing high levels of phenotypic variability and increased fitness under natural conditions. Genetic analyses of three loci associated with milk production (alpha(S1)-casein, kappa-casein and prolactin) and the locus BoLA-DRB3 of the major histocompatibility complex indicated that the Argentinean Creole cattle (ACC), an indigenous breed from South America, maintains high levels of genetic diversity and population structure. In contrast to the commercial Holstein breed, the ACC showed considerable variation in heterozygosity (H(e)) and allelic diversity (A) across populations. As expected, bi-allelic markers showed extensive variation in He whereas the highly polymorphic BoLA-DRB3 showed substantial variation in A, with individual populations having 39-74% of the total number of alleles characterized for the breed. An analysis of molecular variance (AMOVA) of nine populations throughout the distribution range of the ACC revealed that 91.9-94.7% of the total observed variance was explained by differences within populations whereas 5.3-8.1% was the result of differences among populations. In addition, the ACC breed consistently showed higher levels of genetic differentiation among populations than Holstein. Results from this study emphasize the importance of population genetic structure within domestic breeds as an essential component of genetic diversity and suggest that indigenous breeds may be considered important reservoirs of genetic diversity for commercial domestic species.
Alleles↗
Relationship between bleeding time, aspirin and the PlA1/A2 polymorphism of platelet glycoprotein IIIa.
A single nucleotide T to C transition of the gene encoding glycoprotein IIIa leads to a common diallelic polymorphism Leu-33-->Pro (PLA1/A2). We studied the relationship between the PlA1/A2 polymorphism and platelet function in 80 healthy men, aged 20-25 years. Before aspirin ingestion, bleeding time (BT) was shorter in carriers of the PlA2 than in carriers of the PlA1/A1 allele. At 4 h after ingestion of 300 mg of aspirin, BT became prolonged, and the intergroup difference was enhanced. In seven out of 26 PLA2 allele carriers, aspirin shortened BT on average by 30 s, compared with only one among 54 subjects with the PlA1/A1 genotype. Thus, BT both at baseline and after aspirin depends on the PlA1/A2 polymorphism of glycoprotein IIIa. Carriers of the PlA2 allele appear to be more resistant to the antithrombotic action of aspirin.
Adult↗
Approaches to meta analysis in genetic disorders.
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Family↗
Population genetic structure in a Robertsonian race of house mice: evidence from microsatellite polymorphism.
Genetic evidence was assessed for inbreeding and population subdivision in a Robertsonian fusion (Rb) race of the western European form of house mouse, Mus musculus domesticus, in central Belgium. Inbreeding, and the factors responsible for subdivision (genetic drift and extinction-recolonization) can theoretically influence the fixation of underdominant Rb variants. The data consisted of allele frequencies of eight microsatellite loci and of the Rb(4.12) and Rb(5.10) chromosomes. Six populations were sampled once, and a seventh was sampled successively over 3 years. No evidence for inbreeding within populations was found. Levels of between-population subdivision were high (theta = 0.15-0.39), and showed no association with either karyotype or geographical distance over 8-60 km. In addition, low values of effective size were found in the successively sampled population (Ne = 5-20). Cases of significant two-locus disequilibria were associated with the most closely linked pair of microsatellite loci (r = 0.15): also consistent with small effective sizes. These results suggest that both the lack of inbreeding, and the combined effects of genetic drift and extinction-recolonization, may promote Rb polymorphism in M. m. domesticus.
Animals↗
The evolutionary dynamics of male-killers and their hosts.
Male-killing bacteria are cytoplasmic sex-ratio distorters that are transmitted vertically through females of their insect hosts. The killing of male hosts by their bacteria is thought to be an adaptive bacterial trait because it augments the fitness of female hosts carrying clonal relatives of those bacteria. Here we attempt to explain observations of multiple male-killers in natural host populations. First we show that such male-killer polymorphism cannot be explained by a classical model of male-killing. We then show that more complicated models incorporating the evolution of resistance in hosts can explain male-killer polymorphism. However, this is only likely if resistance genes are very costly. We also consider the long-term evolutionary dynamics of male-killers, and show that evolution towards progressively more 'efficient' male-killers can be thwarted by the appearance of host resistance. The presence of a resistance gene can allow a less efficient male-killer to outcompete its rival and hence reverse the trend towards more efficient transmission and reduced metabolic load on the host.
Animals↗
Mitotic counting in surgical pathology: sampling bias, heterogeneity and statistical uncertainty.
Mitotic counting in surgical pathology: sampling bias, heterogeneity and statistical uncertainty Although several articles on the methodological aspects of mitotic counting have been published, the effects of macroscopic sampling and tumour heterogeneity have not been discussed in any detail. In this review the essential elements for a standardized mitotic counting protocol are described, including microscopic calibration, specific morphological criteria, macroscopic selection, counting procedure, effect of biological variation, threshold, and the setting of an area of uncertainty ('grey area'). We propose that the use of a standard area for mitotic quantification and of a grey area in mitotic counting protocols will facilitate the application of mitotic counting in diagnostic and prognostic pathology.
Data Interpretation, Statistical↗
Hypothesis testing with the similarity index.
Multilocus DNA fingerprinting methods have been used extensively to address genetic issues in wildlife populations. Hypotheses concerning population subdivision and differing levels of diversity can be addressed through the use of the similarity index (S), a band-sharing coefficient, and many researchers construct hypothesis tests with S based on the work of Lynch. It is shown in the present study, through mathematical analysis and through simulations, that estimates of the variance of a mean S based on Lynch's work are downwardly biased. An unbiased alternative is presented and mathematically justified. It is shown further, however, that even when the bias in Lynch's estimator is corrected, the estimator is highly imprecise compared with estimates based on an alternative approach such as 'parametric bootstrapping' of allele frequencies. Also discussed are permutation tests and their construction given the interdependence of Ss which share individuals. A simulation illustrates how some published misuses of these tests can lead to incorrect conclusions in hypothesis testing.
DNA Fingerprinting↗
Microsatellite analysis of genetic variation among and within Alpine marmot populations in the French Alps.
The genetic structure of the Alpine marmot, Marmota marmota, was studied by an analysis of five polymorphic microsatellite loci. Eight locations were sampled in the French Alps, one from Les Ecrins valley (n = 160), another from La Sassière valley (n = 289) and the six others from the Maurienne valley (n = 139). Information on social group structure was available for both Les Ecrins and La Sassière but not for the other samples. The high levels of genetic diversity observed are at odds with the results obtained using microsatellites, minisatellites and allozymes on Alpine marmots from Germany, Austria and Switzerland. Strong deficits in heterozygotes were found in Les Ecrins and La Sassière. They are caused by a Wahlund effect due to the family structure (i.e. differentiation between the family groups). The family groups exhibit excess of heterozygotes rather than deficits. This may be caused by outbreeding and this is compatible with recent results from the genetics of related social species when information on the social structure is taken into account. The observed outbreeding could be the result of females mating with transient males or males coming from neighbouring colonies. Both indicate that the species may not be as monogamous as is usually believed. The results are also compatible with a male-biased dispersal but do not allow us to exclude some female migration. We also found a significant correlation between geographical and genetic distance indicating that isolation by distance could be an issue in marmots. This study is the first that analysed populations of marmots taking into account the social structure within populations and assessing inbreeding at different levels (region, valley, population, and family groups). Our study clearly demonstrated that the sampling strategy and behavioural information can have dramatic effects on both the results and interpretation of the genetic data.
Animals↗
Genetic structure and phylogeography of European catfish (Silurus glanis) populations.
The genetic structure of Silurus glanis (Europe's largest freshwater fish species) across most of its natural distribution was investigated using 10 microsatellite loci. The revealed levels of genetic diversity were much higher than previous allozyme and restriction fragment length polymorphism mitochondrial DNA analyses had shown; relative levels of variability among populations were however, in good agreement with the previous studies. Populations from large basins (Volga and Danube rivers) were the most polymorphic, while samples from the smaller Greek rivers, which are more prone to genetic bottleneck, exhibited the lowest levels of genetic diversity. Microsatellite multilocus genotyping permitted the assignment of individual fish to their population of origin with a score as high as 98.3%. Despite the great genetic differentiation of S. glanis populations, no consistent pattern of geographical structuring was revealed, in contrast to previous studies of European freshwater fish species. A model of isolation by distance seems more probable and a hypothesis of recent dispersion from only one glacial refugium is proposed. The discovery of the highest levels of microsatellite and mitochondrial diversity in the Volga sample and the presence of river connections, during the Pleistocene, between this area and all major areas of the present catfish distribution, place this refugium around the Ponto-Caspian region. Combining these data with those from previous studies, a number of markers are now available to monitor wild and hatchery populations even at the individual level.
Animals↗
AFLP utility for population assignment studies: analytical investigation and empirical comparison with microsatellites.
Individual-based population assignment tests have thus far mainly relied on the use of microsatellite loci. However, the logistic difficulty of screening large numbers of loci required to reach sufficient statistical power hampers the usefulness of microsatellites in situations of weak population structuring. Amplified fragment length polymorphisms (AFLP) represents an alternative for overcoming this logistical issue as the technique allows the user to characterize a much larger number of loci with a comparable analytical effort. In this study, an assignment test based on maximum likelihood for dominant markers was used to investigate the potential usefulness of AFLP for population assignment. We also compared assignment success achieved with AFLP with that obtained using microsatellites in a case study of low population differentiation involving whitefish (Coregonus clupeaformis) sympatric ecotypes. The analytical investigation showed that the minimum number of AFLP loci required to reach an assignment success of 95% stood within values that are easily achievable in many situations. This also showed how assignment success varied according to the number of AFLP loci used, their absolute frequency and their frequency differential and sampling errors, as well as the number of putative source populations. The case study showed that given a comparable analytical effort in the laboratory, AFLP were much more efficient than the microsatellite loci in discriminating the source of an individual among putative populations. AFLP resulted in higher assignment success at all levels of stringency and the log-likelihood differences between populations obtained with AFLP for each individual were much larger than those obtained with microsatellites. These results indicate that research involving individual-based population assignment methods should benefit importantly from the use of AFLP markers, especially in systems characterized by weak population structuring.
Data Interpretation, Statistical↗
Flowering time plasticity in Arabidopsis thaliana: a reanalysis of Westerman & Lawrence (1970).
Environmental variation in temperature can have dramatic effects on plant morphology, phenology, and fitness, and for this reason it is important to understand the evolutionary dynamics of phenotypic plasticity in response to temperature. We investigated constraints on the evolution of phenotypic plasticity in response to a temperature gradient in the model plant Arabidopsis thaliana by applying modern analytical tools to the classic data of Westerman & Lawrence (1970). We found significant evidence for two types of constraints. First, we detected numerous significant genetic correlations between plastic responses to temperature and the mean value of a trait across all environments, which differed qualitatively in pattern between the set of ecotypes and the set of mutant lines in the original sample. Secondly, we detected significant costs of flowering time plasticity in two of the three experimental environments, and a net pattern of selection against flowering time plasticity in the experiment overall. Thus, when explored with contemporary methods, the prescient work of Westerman & Lawrence (1970) provides new insights about evolutionary constraints on the evolution of plasticity.
Arabidopsis↗