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PubMed2006

Testing for segregation distortion in genetic scoring data from backcross or doubled haploid populations.

It is important that breeders have the means to assess genetic scoring data for segregation distortion because of its probable effect on the design of efficient breeding strategies. Scoring data is usually assessed for segregation distortion by separate nonindependent chi2 tests at each locus in a set of marker loci. This analysis gives the loci most affected by selection if it exists, but it cannot give a statistically correct test for the presence or absence of selection in a linkage group as a whole. I have used a combined test based on the statistic, which is the most significant P-value from the above tests, called the single locus test. I have also derived mathematically a new combined statistical test, the overall test, for segregation distortion that requires genetic scoring data for a single linkage group. This test also takes genetic linkage into account. Using a range of marker densities and population sizes, simulations were carried out, to compare the power of these two statistical tests to detect the effect of selection at one or two loci. The single locus test was always found to be more powerful than the overall test, but the single locus test required a more complicated P-value correction. For the single locus test, approximate correction factors for the P-values are given for a range of marker densities and genetic lengths.

Chi-Square Distribution↗

PubMed2004

The maintenance (or not) of polygenic variation by soft selection in heterogeneous environments.

On the basis of single-locus models, spatial heterogeneity of the environment coupled with strong population regulation within each habitat (soft selection) is considered an important mechanism maintaining genetic variation. We studied the capacity of soft selection to maintain polygenic variation for a trait determined by several additive loci, selected in opposite directions in two habitats connected by dispersal. We found three main types of stable equilibria. Extreme equilibria are characterized by extreme specialization to one habitat and loss of polymorphism. They are analogous to monomorphic equilibria in singe-locus models and are favored by similar factors: high dispersal, weak selection, and low marginal average fitness of intermediate genotypes. At the remaining two types of equilibria the population mean is intermediate but variance is very different. At fully polymorphic equilibria all loci are polymorphic, whereas at low-variance equilibria at most one locus remains polymorphic. For most parameters only one type of equilibrium is stable; the transition between the domains of fully polymorphic and low-variance equilibria is typically sharp. Low-variance equilibria are favored by high marginal average fitness of intermediate genotypes, in contrast to single-locus models, in which marginal overdominance is particularly favorable for maintenance of polymorphism. The capacity of soft selection to maintain polygenic variation is thus more limited than extrapolation from single-locus models would suggest, in particular if dispersal is high and selection weak. This is because in a polygenic model, variance can evolve independently of the mean, whereas in the single-locus two-allele case, selection for an intermediate mean automatically leads to maintenance of polymorphism.

Animals↗

PubMed2001

Genome-wide linkage analysis of pulse pressure in Mexican Americans.

Pulse pressure, a measure of aortic stiffness, is a strong predictor of cardiovascular mortality. To locate genes that affect pulse pressure, we performed genetic analysis on randomly ascertained families in the San Antonio Family Heart Study. Pulse pressure was defined as the difference between systolic and diastolic blood pressures. Likelihood methods were used to construct a model that had both single-locus and polygenic components for 46 families (1308 individuals). The single-locus component included sex-specific and genotype-specific effects of both age and body mass index. Using this model, we then performed 2-point linkage analysis in 10 families (440 individuals) that were among the largest of the 46 families and that had been genotyped for 399 polymorphic markers. The model that contained only the polygenic component and simple effects of the covariates showed pulse pressure heritability of 0.21. When the single-locus component was added, the sex-specific and genotype-specific effects of age and body mass index were highly significant (P<0.002). The full model accounted for 73% of the total variation of pulse pressure. Linkage analysis using this model with each marker revealed 4 markers with lod scores >1.9, which is the Lander-Kruglyak suggestive linkage standard. D21S1440 had a lod score of 2.78 with a recombination fraction (theta) of 0.02. D7S1799 had a lod score of 2.04 (theta=0.01), D8S1100 had a lod score of 1.98 (theta=0.08), and D18S844 had a lod score of 1.95 (theta=0.11). These results are highly correlated with results involving systolic blood pressure, indicating that pulse pressure may not be genetically distinct from systolic blood pressure.

Adolescent↗

PubMed2006

Optimal two-stage strategy for detecting interacting genes in complex diseases.

BACKGROUND: The mapping of complex diseases is one of the most important problems in human genetics today. The rapid development of technology for genetic research has led to the discovery of millions of polymorphisms across the human genome, making it possible to conduct genome-wide association studies with hundreds of thousands of markers. Given the large number of markers to be tested in such studies, a two-stage strategy may be a reasonable and powerful approach: in the first stage, a small subset of promising loci is identified using single-locus testing, and, in the second stage, multi-locus methods are used while taking into account the loci selected in the first stage. In this report, we investigate and compare two possible two-stage strategies for genome-wide association studies: a conditional approach and a simultaneous approach. RESULTS: We investigate the power of both the conditional and the simultaneous approach to detect the disease loci for a range of two-locus disease models in a case-control study design. Our results suggest that, overall, the conditional approach is more robust and more powerful than the simultaneous approach; the conditional approach can greatly outperform the simultaneous approach when one of the two disease loci has weak marginal effect, but interacts strongly with the other, stronger locus (easily detectable using single-locus methods in the first stage). CONCLUSION: Genome-wide association studies hold the promise of finding new genes implicated in complex diseases. Two-stage strategies are likely to be employed in these large-scale studies. Therefore we compared two natural two-stage approaches: the conditional approach and the simultaneous approach. Our power studies suggest that, when doing genome-wide association studies, a two-stage conditional approach is likely to be more powerful than a two-stage simultaneous approach.

Alleles↗

PubMed1996

Segregation analysis of two lung function indices in a random sample of young families: the Humboldt Family Study.

The Humboldt Family Study was conducted in the town of Humboldt, Saskatchewan, in 1993. Familial correlations and segregation analyses of lung function were carried out in 799 individuals in 214 nuclear families that included 214 fathers, 214 mothers, and 371 children. Forced expiratory volume in 1 second (FEV1) and maximal mid-expiratory flow rate (MMFR) were first regressed on age, height, weight, and their quadratic and cubic terms as well as on smoking status in four groups separately (mothers, fathers, daughters, and sons), with terms significant at the 0.10 level being retained. Residual phenotypes were standardized within the four groups. Class D regressive models were used to perform familial correlations and segregation analyses. For both FEV1 and MMFR, father-mother correlations were not significantly different from zero, and mother-offspring, father-offspring, and sibling-sibling correlations showed no statistically significant difference from each other. Based on the "polygenic" models, the estimated intraclass correlation is 0.132 (+/- 0.035) for FEV1 and 0.171 (+/- 0.039) for MMFR, and the narrow-sense heritability is 0.264 for FEV1 and 0.342 for MMFR. Segregation analysis shows that the "mixed" model with both single locus and polygenic components had a better fit for FEV1 than single-locus or polygenic only models. However, the model which included a nontransmitted environmental factor [tau(AA) = tau(AB) = tau(BB) = qA] and polygenic loci had a better fit than the Mendelian model [tau(AA) = 1, tau(AB) = 1/2, tau(BB) = 0] [Akaike's information criterion (AIC) = 2219.47 vs. AIC = 2222.14]. For MMFR, the Mendelian "mixed" model gave a nonsignificant improvement in loge likelihood compared to the simple polygenic model. Comparison of the single-locus model and Mendelian "mixed" model shows no difference in fitting the data. This study suggests that FEV1 and MMFR are controlled by many loci with no major effects and/or common environmental factors.

Adolescent↗

PubMed1998

Restorer genes for different forms of Brassica cytoplasmic male sterility map to a single nuclear locus that modifies transcripts of several mitochondrial genes.

The oilseed rape plant, Brassica napus, possesses two endogenous male sterile cytoplasms, nap and pol. Previous studies have shown that nuclear restoration of pol cytoplasmic male sterility (CMS) is conditioned by a gene, Rfp, that is also involved in modifying transcripts of the pol CMS-associated orf224/atp6 mtDNA region. We now find that the nap nuclear restorer gene Rfn apparently is identical to Mmt, a gene that conditions the modification of transcripts from several different mtDNA regions, including one that is associated with nap CMS and contains orf222, a chimeric gene related to orf224. Mmt, in turn, is found to be allelic to Rfp, suggesting that restorer genes for the two cytoplasms represent different alleles or haplotypes of a single nuclear locus. This view is supported by restriction fragment length polymorphism mapping studies that indicate that Rfn and Rfp map to the same chromosomal position. Thus, in contrast to CMS in other species, different forms of Brassica CMS are restored by alleles of a single nuclear locus, and the restoration properties of these alleles reflect their involvement in the modification of transcripts of corresponding CMS-associated mtDNA regions. A survey of 51 varieties from 8 Brassica and Sinapis species failed to find evidence of Rfn(Mmt) in other than fertility-restored, nap cytoplasm B. napus. This suggests that Rfn(Mmt) arose in Brassica with nap cytoplasm and that the necessity for fertility restoration may have provided the selective pressure for its origin and maintenance.

Journal Article↗

PubMed1984

Simulation studies of segregation analysis: application to two-locus models.

We tested the power of a segregation analysis method (first proposed by Elandt-Johnson) to distinguish between single-locus and two-locus models, with and without environmentally caused reduced penetrance. We also looked at the effect of ascertainment probability on the analysis and at the proband-conditioned ascertainment correction proposed by Cannings and Thompson. We found that: (1) the segregation analysis has sufficient power to distinguish between the fully-penetrant double-recessive (RR) model and the fully-penetrant single-locus dominant and recessive models; (2) the method can also distinguish fairly well between the dominant-recessive (DR) and RR models, even when one does not take into account the population prevalence; (3) the method has much less power to distinguish between the fully-penetrant RR model and the single-locus models with reduced penetrance; (4) when environmental penetrance is taken account of in the analysis, the power of the method to distinguish between the one- and two-locus models improved substantially; (5) the estimates of ascertainment probability, pi, were robust, regardless of the model under which the data were generated; and (6) the Cannings-Thompson approach to ascertainment correction worked well only when the pi used to generate the data was less than .1.

Adult↗

PubMed1982

Induction of liver microsomal cytochrome P-450 and associated monooxygenases by octachlorostyrene in inbred strains of mice. Lack of correlation with the murine Ah locus.

Single intraperitoneal injections of octachlorostyrene (OCS) and hexachlorobenzene in genetically polycyclic aromatic hydrocarbon "responsive' C57/BL/6 (B6) mice led to a time- and dose-dependent increase in the levels of liver microsomal cytochromes P-450 and b5 as well as in the activities of NADPH cytochrome P-450 (cytochrome c) reductase, ethylmorphine (EM) N-demethylase, 4-nitroanisole (PNA) O-demethylase and acetanilide 4-hydroxylase (AcA hydroxylase). No, or only a very moderate, increase in the activity of aryl hydrocarbon hydroxylase was seen after OCS and HCB, respectively. Pretreatments with phenobarbital (PB) or 3-methylcholanthrene (MC) both increased AcA hydroxylase activity to a similar degree, whereas pretreatment with polychlorinated biphenyls (Aroclor 1254) had an effect equal to the sum of PB and MC. Judged from sodium dodecylsulfate polyacrylamide gel electrophoresis studies, OCS and HCB predominantly increased a microsomal polypeptide of apparent mol. wt 52,000, similar to PB. A reduced response was seen after OCS or HCB treatment of aromatic hydrocarbon "non-responsive' DBA/2 (D2) mice compared to B6 mice, both with respect to AcA hydroxylase as well as EM demethylase and PNA demethylase activities. OCS treatment of B6D2F1 mice resulted in a doubling of AcA hydroxylase activity, but in mice of the (B6D2)D2 backcross no distinct subgrouping of individual AcA hydroxylase activities were apparent. These results demonstrate that OCS is an inducer of the PB-type in mice and that induction of AcA hydroxylase by OCS is not regulated by the Ah locus.

Animals↗

PubMed1993

[Two unusual cases of half-sibling test with DNA polymorphism].

In usual paternity cases, the putative man and the mother-child couple are alive. However, there are some cases in which putative man and mother were deceased and only children were available for analyses. It is difficult to determine the presence or absence of half-sibling relationship from analyses of conventional blood group markers (CBGM). In this study, five kinds of single locus DNA probes were applied to 2 half-sibling cases. To decide usefulness of single locus DNA probes, we defined likelihood ratio of half-sibling (LRHS) based on the likelihood ratio of paternity (LRP) and also investigated the distribution curves of log10 LRHS in cases of unrelated combinations and half-sibling combinations. Distribution curves of log10 LRHS from DNA analyses in the cases of unrelated combinations and half-sibling combinations is more clearly separated than from CBGM. Single locus DNA probes are considered to be more informative for half-sibling cases.

Blood Group Antigens↗

PubMed1997

Further evidence for elevated human minisatellite mutation rate in Belarus eight years after the Chernobyl accident.

Analysis of germline mutation rate at human minisatellites among children born in areas of the Mogilev district of Belarus heavily polluted after the Chernobyl accident has been extended, both by recruiting more families from the affected region and by using five additional minisatellite probes, including multi-locus probe 33.6 and four hypervariable single-locus probes. These additional data confirmed a twofold higher mutation rate in exposed families compared with non-irradiated families from the United Kingdom. An elevated rate was seen at all three independent sets of minisatellites (detected separately by multi-locus probes 33.15, 33.6 and six single-locus probes), indicating a generalised increase in minisatellite germline mutation rate in the Belarus families. Within the Belarus cohort, mutation rate was significantly greater in families with higher parental radiation dose estimated for chronic external and internal exposure to caesium-137, consistent with radiation induction of germline mutation. The spectra of mutation seen in the unexposed and exposed families were indistinguishable, suggesting that increased mutation observed over multiple loci arises indirectly by some mechanism that enhances spontaneous minisatellite mutation.

Adult↗

PubMed2005

The effect of Wolbachia versus genetic incompatibilities on reinforcement and speciation.

Wolbachia is a widespread group of intracellular bacteria commonly found in arthropods. In many insect species, Wolbachia induce a cytoplasmic mating incompatibility (CI). If different Wolbachia infections occur in the same host species, bidirectional CI is often induced. Bidirectional CI acts as a postzygotic isolation mechanism if parapatric host populations are infected with different Wolbachia strains. Therefore, it has been suggested that Wolbachia could promote speciation in their hosts. In this article we investigate theoretically whether Wolbachia-induced bidirectional CI selects for premating isolation and therefore reinforces genetic divergence between parapatric host populations. To achieve this we combined models for Wolbachia dynamics with a well-studied reinforcement model. This new model allows us to compare the effect of bidirectional CI on the evolution of female mating preferences with a situation in which postzygotic isolation is caused by nuclear genetic incompatibilities (NI). We distinguish between nuclear incompatibilities caused by two loci with epistatic interactions, and a single locus with incompatibility among heterozygotes in the diploid phase. Our main findings are: (1) bidirectional CI and single locus NI select for premating isolation with a higher speed and for a wider parameter range than epistatic NI; (2) under certain parameter values, runaway sexual selection leads to the increase of an introduced female preference allele and fixation of its preferred male trait allele in both populations, whereas under others it leads to divergence in the two populations in preference and trait alleles; and (3) bidirectional CI and single locus NI can stably persist up to migration rates that are two times higher than seen for epistatic NI. The latter finding is important because the speed with which mutants at the preference locus spread increases exponentially with the migration rate. In summary, our results show that bidirectional CI selects for rapid premating isolation and so generally support the view that Wolbachia can promote speciation in their hosts.

Animals↗

PubMed1991

A genetic study of platelet adenylate cyclase activity: evidence for a single major locus effect in fluoride-stimulated activity.

The activity of membrane-bound platelet adenylate cyclase, when stimulated in vitro by several compounds (including fluoride), is significantly reduced in alcoholics compared with control subjects. We have begun a study of the genetics of this enzyme activity. Complex segregation analysis of basal (unstimulated) platelet adenylate cyclase activity in families reveals a mode of inheritance that cannot be accounted for by a simple mixed model of transmission. By contrast, adenylate cyclase activity stimulated by fluoride ion reveals a single major locus effect with a modest multifactorial background. These results suggest that a single factor in the second-messenger pathway may (a) account for the majority of individual differences in stimulation of adenylate cyclase of fluoride and (b) help explain the reduced activities previously observed in alcoholics.

Adenylyl Cyclases↗

PubMed1997

Dissection of a synthesized quantitative trait to characterize transgene interactions.

Six transgenic tobacco lines, each homozygous for the beta-glucuronidase (GUS) gene at a different locus, and wild type were selfed and intercrossed to evaluate GUS activity in all possible hemizygous, homozygous and dihybrid combinations of GUS alleles. The transgenic lines are characterized by their GUS activity (two low, three intermediate, one high), T-DNA complexity (four single-copy, two more complex single-locus) and the presence of the chicken lysozyme matrix-associated region (MAR) around the full T-DNA (two lines). Gene action and interaction was analyzed by weighted linear regression with parameters for additivity, dominance and epistasis. The analysis showed that each of the four single-copy lines acted fully additively. In contrast, the two complex single-locus lines showed classical single-locus overdominance and were epistatic dominant over all other GUS alleles. The latter is manifested in severe suppression of GUS activity in dihybrid lines, irrespective of the presence of MAR elements around the GUS gene. Such elements apparently do not protect against epistatic dominance. The quantitative data suggested that the epistatic dominance and overdominance are based on the same molecular mechanism. Our approach of a genetic analysis of quantitative variation in well-characterized transgenic lines provides a powerful tool to gain insight into complex plant traits.

Alleles↗

PubMed2002

An evaluation of the variance components approach: type I error, power and size of the estimated effect.

In order to evaluate the statistical properties of the variance components method implemented in SOLAR and GENEHUNTER2, the type I error rate, power and estimated size of modelled effects were determined using computer simulation. Results suggested that the type I error rate was quite conservative when the variance was completely due to random effects. However, when either a polygenic effect or an unlinked single locus component effect was included in the generating models the type I error rate was closer to the nominal level. The size of the polygenic or single locus effect appeared to influence the type I error rate. Results suggested that the variance components method underestimated the variance attributed to a single locus effect and overestimated the variance attributed to a polygenic effect in the models considered regardless of the source of variation.

Analysis of Variance↗

PubMed1997

Effect of genetic heterogeneity and assortative mating on linkage analysis: a simulation study.

Linkage studies of complex genetic traits raise questions about the effects of genetic heterogeneity and assortative mating on linkage analysis. To further understand these problems, I have simulated and analyzed family data for a complex genetic disease in which disease phenotype is determined by two unlinked disease loci. Two models were studied, a two-locus threshold model and a two-locus heterogeneity model. Information was generated for a marker locus linked to one of the disease-defining loci. Random-mating and assortative-mating samples were generated. Linkage analysis was then carried out by use of standard methods, under the assumptions of a single-locus disease trait and a random-mating population. Results were compared with those from analysis of a single-locus homogeneous trait in samples with the same levels of assortative mating as those considered for the two-locus traits. The results show that (1) introduction of assortative mating does not, in itself, markedly affect the estimate of the recombination fraction; (2) the power of the analysis, reflected in the LOD scores, is somewhat lower with assortative rather than random mating. Loss of power is greater with increasing levels of assortative mating; and (3) for a heterogeneous genetic disease, regardless of mating type, heterogeneity analysis permits more accurate estimate of the recombination fraction but may be of limited use in distinguishing which families belong to each homogeneous subset. These simulations also confirmed earlier observations that linkage to a disease "locus" can be detected even if the disease is incorrectly defined as a single-locus (homogeneous) trait, although the estimated recombination fraction will be significantly greater than the true recombination fraction between the linked disease-defining locus and the marker locus.

Computer Simulation↗

PubMed1992

Evolution of multilocus genetic structure in an experimental barley population.

Data from 311 selfed families isolated from four generations (F8, F13, F23, F45) of an experimental barley population were analyzed to determine patterns of change in character expression for seven quantitative traits, and in single-locus allelic frequencies, and multilocus genetic structure, for 16 Mendelian loci that code for discretely recognizable variants. The analyses showed that large changes in single-locus allelic frequencies and major reorganizations in multilocus genetic structure occurred in each of the generation-to-generation transitions examined. Although associations among a few traits persisted over generations, dynamic dissociations and reassociations occurred among several traits in each generation-transition period. Overall, the restructuring that occurred was characterized by gradual decreases in the number of clusters of associated traits and increases in the number of traits within each cluster. The observed changes in single-locus frequencies and in multilocus genetic structure were attributed to interplay among various evolutionary factors among which natural selection acting in a temporally heterogeneous environment was the guiding force.

Alleles↗

PubMed2003

Nuclear DNA sequences detect species limits in ancient moa.

Ancient DNA studies have typically used multi-copy mitochondrial DNA sequences. This is largely because single-locus nuclear genes have been difficult to recover from sub-fossil material, restricting the scope of ancient DNA research. Here, we have isolated single-locus nuclear DNA markers to assign the sex of 115 extinct moa and, in combination with a mitochondrial DNA phylogeny, tested competing hypotheses about the specific status of moa taxa. Moa were large ratite birds that showed extreme size variation both within and among species. For some taxa, this large variation was hypothesized to represent sexual dimorphism, while for others it was argued to reflect the existence of different species. Our results show that moa were characterized by extreme reverse sexual dimorphism and as a result we have been able to clarify the number of moa species. For example, we show that the three recognized 'species' of Dinornis comprised only two monophyletic groups and that two of these 'species' comprised individuals of one sex only. This study also illustrates that single-locus nuclear DNA sequences can be consistently recovered from ancient material.

Animals↗

PubMed1994

Segregation analysis of NIDDM in Caucasian families.

Non-insulin-dependent diabetes mellitus (NIDDM) has a substantial genetic component, but the mode of inheritance and the molecular basis are unknown. We have undertaken segregation analysis of NIDDM after studying 247 subjects in 59 Caucasian nuclear pedigrees ascertained without regard to family history of the disorder. The analyses were performed using POINTER and COMDS, which are computer programs which apply statistical models to the data. POINTER analysis was performed defining the phenotype as a presence or absence of hyperglycaemia. Among single locus hypothesis, the analyses rejected a recessive model and favoured a dominant model, but could not statistically show that this fitted better than a mixed model (a single locus against a polygenic background) or a polygenic model. COMDS analysis assumed a continuum of hyperglycaemia from normality to NIDDM, classified family members into a series of diathesis classes with increasing plasma glucose levels and compared the distribution with that found by screening the normal population. This analysis improved the likelihood of a dominant single locus model and suggested a gene frequency of 7.4%. It raised the possibility of a second locus, but cannot identify or exclude a polygenic model. In conclusion, two types of segregation analyses rejected a recessive model and favoured a dominant model of inheritance, although they could not statistically show that this fitted better than the polygenic model. The results raised the possibility of a common dominant gene with incomplete penetrance, but genetic analysis of NIDDM needs to take into account the likelihood of polygenic inheritance with genetic heterogeneity.

Adult↗