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PubMed2004

Exploring the relationship between parental relatedness and male reproductive success in the Antarctic fur seal Arctocephalus gazella.

Recent genetic studies of natural populations have shown that heterozygosity and other genetic estimates of parental relatedness correlate with a wide variety of fitness traits, from juvenile survival and parasite resistance to male reproductive success. Many of these traits involve health and survival, where the underlying mechanism may involve changes in the effectiveness of the immune system. However, for traits such as reproductive success, the likely mechanisms remain less obvious. In this paper, we examine the relationship between heterozygosity and a range of traits that contribute to male reproductive success, including time spent on territories and competitiveness. Our analysis is based on observational and genetic data from eight consecutive breeding seasons at a colony of the Antarctic fur seal, Arctocephalus gazella. Overall, male reproductive success was found to correlate strongly with internal relatedness (IR, a form of heterozygosity). When different components of success were analyzed, we found that IR correlates independently with reproductive longevity, time spent ashore, and competitive ability per unit mating opportunity on the study beach, with more heterozygous males being more successful. Behavioral observations were sufficiently detailed to allow examination of how daily mean IR values for males present on the beach varied within seasons and from year to year. Again, significant variation was found both among and within seasons, with more homozygous males appearing less able to hold territories in poor seasons when pup production is low and, within a season, at both the start of the season and to some extent around the peak of female estrus. Finally, we tested whether the benefits of high heterozygosity are due mainly to a genomewide effect (e.g. inbreeding depression) or to single locus heterosis by asking whether the relationship between IR and male success was robust to the removal of any single locus or to any pair of loci. Since the relationship remained significant in all cases, we favor a multilocus explanation for the effects we report.

Animals↗

PubMed1994

A multilocus DNA fingerprint with built-in security devices.

An unusual case of paternity testing is reported in which determination of paternity was an essential part of a genetic diagnosis. A Y-chromosomal abnormality, observed in a 33-year-old male whose wife had experienced a series of spontaneous abortions, was not found in his alleged father. DNA fingerprinting with the oligonucleotide multilocus probe (CAC)5 yielded two aberrant bands for the proband, i.e. bands exhibited by neither parent. This finding resulted in a comparatively low paternity probability of 0.02934 which is suggestive of, but does not unequivocally prove, false paternity. Subsequent analysis with other multi- and single-locus systems, however, failed to confirm this preliminary result. The paternity probability computed on the basis of the single-locus systems was 0.99997, providing compelling evidence in favour of true paternity. The present case thus demonstrates that even when two mutations turn up in a DNA fingerprint, these may be readily recognized as such.

Abortion, Spontaneous↗

PubMed1985

The genetics of panic disorder and agoraphobia.

Panic disorder, comprising also agoraphobia for the purpose of this review, has a prevalence of 1.2-8.4 per cent, affecting females twice as frequently as males, and has a mean age of onset of 25. It is one of the more familial diseases in Psychiatry in that 2/3 of cases have relatives affected with the same condition, and the risk to first degree relatives is approximately 3-4 times the rate of the general population. Although some family studies have suggested an overlap in the transmission of panic disorders and depression, and a common diathesis hypothesis has been proposed, depression is more common in the families of depressives, as in panic disorder in the families of probands with panic disorder. Twin studies of anxiety disorders, although limited in number, report a 30-40 per cent concordance among MZ twins, against 0-4 per cent among DZ twins, which supports a genetic predisposition. The mode of transmission is uncertain. Studies which have used the 'ancestral pairs' method (which examines the incidence of the condition in maternal versus paternal forebears, on the assumption that single locus transmission is favored by unilateral clustering, and polygenic theories are favored by a more even spread) have favored single locus transmission, although such unilateral clustering can still be accommodated within a multifactorial-polygenic hypothesis. Potential biological markers for the condition are reviewed. The observation that lactate infusion can precipitate panic attacks in predisposed individuals is well established. The association with mitral valve prolapse suggests that perhaps 38 per cent of patients presenting with symptoms of panic disorders have mitral valve prolapse on echocardiography. The possibility of an endogenous anxiety-producing agent that binds to the benzodiazepine receptor is discussed.

Adolescent↗

PubMed1991

Multilocus autosomal sex determination.

The two basic one locus sex determination models, diploid individual sex determination and parental sex determination, are generalized to the multilocus framework. As in the single locus case, it is established that there are two classes of polymorphic equilibria, equilibria with even sex ratio and equilibria with equal allele frequencies in the two sexes. The condition for external stability of this second class equilibria to invasion by a "new" mutant allele is that a "new" appropriately averaged sex ratio near the equilibrium be moved closer to the even sex ratio. However, stable polymorphisms with noneven sex ratio are not those that have a sex ratio as close as possible to 1/2, in contrast to the single locus case.

Animals↗

PubMed1985

Resolving genetic models for the transmission of schizophrenia.

Although family studies have consistently reported elevated rates of schizophrenia among the relatives of schizophrenics, the exact nature of the transmission of the disorder remains uncertain. Genetic models hypothesized to explain the transmission of schizophrenia include the generalized single locus and multifactorial threshold models. Here we briefly describe these models and test their goodness-of-fit to a single data set on the pooled morbid risks of schizophrenia among the relatives of schizophrenic probands in nine different classes of relatives with five different degrees of genetic relatedness. The generalized single locus model is rejected, while a pure polygenic threshold model does fit the observed risks. Allowance for environmental sources of familial resemblance under the multifactorial threshold model significantly improved the fit of the model to the data. An application of the multifactorial model to family data on tuberculosis is also reported. For tuberculosis, a strong familial environmental but not genetic effect was found, consistent with the known infectious etiology of this condition, showing that the finding of a strong genetic effect upon schizophrenia is not a necessary bias of these methods of analysis. The implications of these results for the search for major gene effects in schizophrenia are discussed.

Alleles↗

PubMed2006

Allelic divergence precedes and promotes gene duplication.

One of the striking observations from recent whole-genome comparisons is that changes in the number of specialized genes in existing gene families, as opposed to novel taxon-specific gene families, are responsible for the majority of the difference in genome composition between major taxa. Previous models of duplicate gene evolution focused primarily on the role that neutral processes can play in evolutionary divergence after the duplicates are already fixed in the population. By instead including the entire cycle of duplication and divergence, we show that specialized functions are most likely to evolve through strong selection acting on segregating alleles at a single locus, even before the duplicate arises. We show that the fitness relationships that allow divergent alleles to evolve at a single locus largely overlap with the conditions that allow divergence of previously duplicated genes. Thus, a solution to the paradox of the origin of organismal complexity via the expansion of gene families exists in the form of the deterministic spread of novel duplicates via natural selection.

Computer Simulation↗

PubMed2005

A likelihood approach for quantitative-trait-locus mapping with selected pedigrees.

Selective sampling is a cost-effective design for mapping quantitative trait loci (QTLs). A unified framework, which naturally combines two complementary sources of linkage information in the data, is proposed for the mapping of QTLs using selected pedigrees. Score statistics for detecting linkage are introduced for single-locus models (univariate or bivariate phenotypes) and two-locus epistasis models. A computer implementation of the methods for single-locus univariate-phenotype models is provided for nuclear families with arbitrary number of sibs and is freely available.

Algorithms↗

PubMed1999

[Structure and evolution of human sub-telomeric regions].

Recent progress in the field of human genome analysis has led to the development of new concepts in the definition of subtelomeric domains. Analysis of DNA sequences from human and yeast chromosome ends have shown that short stretches of degenerate TTAGGG are found at a distance from the telomeric repeats. These stretches define a boundary between two structurally different regions. The distal domain is characterised by numerous, short segments of interrupted homology to many other human telomeric regions and to a number of ESTs. The proximal domain shows much longer uninterrupted homology to a few chromosome ends. This domain evolved quickly within primates at least, as demonstrated by the detailed study of locus DNF92 which spread very recently in humans from 17 qter to at least ten other chromosome ends. At the different sites, presence-absence polymorphisms are observed within humans. The region remained single locus at the paralogous site in higher primates. Conversely, a human and orangutan single locus telomeric domain occupies multiple chromosome ends in chimpanzee. Balanced translocation is the likely mechanism through which the spreading occurred. Some members of the olfactory receptor gene family show a similar behaviour: multiple telomeric locations, and presence-absence polymorphism. Strikingly, the set of chromosome ends occupied by the two regions is identical, except for the two ancestral sites. Moreover, the relative frequency of detection of the region at the different sites indicates some kind of competition between the two regions. Consequently, these two regions represent major new tools to investigate recent human genome evolution and human genome diversity in different populations.

Animals↗

PubMed1989

Correlation between genetic distances based on single loci and on skeletal morphology in inbred mice.

Genetic and morphometric distances between 12 inbred strains of mice ranging from closely related substrains to a sub-species were estimated using published data on single locus polymorphisms, and on the basis of up to 44 measurements on seven different bones, respectively. Simulation was also used to investigate sampling effects for the single loci. There were strong and statistically highly significant correlations among all measures of genetic distance ranging from 0.58 for the comparison of single loci with the logarithm of the Mahalanobis distance based on 24 measurements on four bones, to 0.72 for estimates of genetic distance based on single loci and the morphology of the mandible. These findings are in sharp contrast with those of Wayne & O'Brien (1986) who claimed that 'structural gene and morphometric variation of mandible traits are uncoupled between mouse strains'. Their failure to find such a correlation is probably because their sample of inbred strains included only a single pair of closely related substrains, and no substrains separated for less than 40 years, and because they failed to correct for non-linearity between morphometric and single-locus measurement scales. Simulations and regression analysis suggested that genetic distances could be estimated with approximately equal precision using morphological data on bone measurements or about 10 cladistically informative single loci, which would usually involve sampling about 50 loci. Data based on single-gene markers is usually more informative than morphometric data for studying the similarity of independently-derived strains. However, similarities among closely related populations such as sublines of an inbred strain can usually be studied more efficiently using morphometry.

Animals↗

PubMed1994

Detection of an NAD(+)-dependent malic enzyme locus in the Atlantic salmon Salmo salar and other salmonid fish.

Electrophoretic studies of malate oxidoreductases routinely assess variation in two enzymes, malate dehydrogenase (EC 1.1.1.37) and malic enzyme (NADP+) (EC 1.1.1.40). By modification of the standard isozyme staining conditions for these enzymes, we have resolved a new NAD(+)-preferring, MgCl2-requiring malic enzyme which is indicated to be EC 1.1.1.39. The enzyme was detected in 10 salmonid fish species of the genera Salmo, Salvelinus, and Onchorynchus. Phenotypic variation indicates that the novel enzyme is tetrameric and coded by a single locus. Inheritance in S. salar follows a single-locus model and the phenotypes are unlinked to polymorphisms for sMDH-3,4* and mMEP-2*, two malate oxidoreductase loci previously shown to be variable in this species.

Animals↗

PubMed1996

Familial recurrence-pattern analysis of nonsyndromic isolated cleft palate--a Danish Registry study.

The finding of an association between genetic variation at the transforming growth-factor alpha (TGFA) locus and nonsyndromic isolated cleft palate (CP) represents a potentially important breakthrough in our understanding of this condition. The present study was undertaken to assess the feasibility of detecting linkage to putative CP-susceptibility loci, such as TGFA. To this end, the familial recurrence pattern for CP was evaluated to determine the most likely mode of inheritance for this condition. The study took advantage of the high ascertainment and uniform registration of CP in Denmark. In addition, the study utilized estimates of familial recurrence that were obtained by register linkage and, hence, were not subject to either recall bias or the potentially biasing influence of nonresponders. The recurrence risks for first-, second-, and third-degree relatives of 1,364 nonsyndromic CP probands were estimated to be 2.74% (72/2,628), 0.28% (3/1,068), and 0.00% (0/360), respectively. These estimates are close to published estimates based on questionnaire and interview data. The population prevalence for nonsyndromic CP was, however, found to be considerable higher than usually reported (0.058% [1,456/2,523,023]). Analyses of these and previously published data, using the method presented by Risch, indicated that major-locus or additive multilocus inheritance of CP is unlikely. The familial recurrence pattern was, however, consistent with CP being determined by several interacting loci. Under such a model, a single locus accounting for more than a sixfold increase in the risk to first-degree relatives of CP probands is unlikely, whereas a single locus accounting for a threefold increase provided a good fit to the data. Such a locus could be detected in a realistic sample of affected sib pairs.

Cleft Palate↗

PubMed2003

Integration of association statistics over genomic regions using Bayesian adaptive regression splines.

In the search for genetic determinants of complex disease, two approaches to association analysis are most often employed, testing single loci or testing a small group of loci jointly via haplotypes for their relationship to disease status. It is still debatable which of these approaches is more favourable, and under what conditions. The former has the advantage of simplicity but suffers severely when alleles at the tested loci are not in linkage disequilibrium (LD) with liability alleles; the latter should capture more of the signal encoded in LD, but is far from simple. The complexity of haplotype analysis could be especially troublesome for association scans over large genomic regions, which, in fact, is becoming the standard design. For these reasons, the authors have been evaluating statistical methods that bridge the gap between single-locus and haplotype-based tests. In this article, they present one such method, which uses non-parametric regression techniques embodied by Bayesian adaptive regression splines (BARS). For a set of markers falling within a common genomic region and a corresponding set of single-locus association statistics, the BARS procedure integrates these results into a single test by examining the class of smooth curves consistent with the data. The non-parametric BARS procedure generally finds no signal when no liability allele exists in the tested region (ie it achieves the specified size of the test) and it is sensitive enough to pick up signals when a liability allele is present. The BARS procedure provides a robust and potentially powerful alternative to classical tests of association, diminishes the multiple testing problem inherent in those tests and can be applied to a wide range of data types, including genotype frequencies estimated from pooled samples.

Algorithms↗

PubMed1995

Heterozygosity and fitness: no association in Scots pine.

The association of six quantitative traits related to fitness with heterozygosity at 12 allozyme loci has been examined in three populations of Scots pine, Pinus sylvestris. Because of several characteristics of this organism and of this extensive data set, it appeared that this study would show a positive association between heterozygosity and these traits if indeed heterozygotes had higher values for these quantitative traits. Using several different statistical techniques including analysis of variance, regression with the scaling recommended from the adaptive distance model, and multiple regression, no evidence of an association was found. For example, only between 7 and 8% of the regression tests were significant at the 5% level and half of these showed a positive association and half showed a negative association. Further, the multiple regression analysis explained on average only 5.8% of the variation observed in the six different traits and only 1.5% of this variation was explained by a positive association. Power analysis was carried out (for the first time on these type of data), both for the single locus heterozygous advantage and the association of individual multiple locus heterozygosity and the quantitative traits. For diameter and height, two traits often used in similar studies, the average power to detect a single locus heterozygous advantage of 0.10 was 0.737 and the average power to detect a mean heterozygote advantage of 0.05 per locus for multiple loci was 0.797. As a result of this study and an examination of the published results from other studies, it appears that what positive associations have been observed are probably not, in large part, due to the presence of intrinsic heterozygote advantage.

Genes, Plant↗

PubMed1979

On the use of multiple thresholds for the determination of the mode of inheritance of semi-continuous traits.

In this article we reconsider the analysis proposed by Reich et al. (1972) for determining the mode of inheritance for semi-continuous traits from intrafamilial data. We consider both the (general) multifactorial and the single-locus model formulation. We show (numerically), by using a much improved numerical analysis technique for the parameter estimation, that there may be many single-locus models that could have given rise to a particular data set, dependent on its size and nature. Finally we question whether the use of monozygotic twins data, or data obtained from defining further levels of severity of the disease, would improve the discrimination between these two types of models.

Alleles↗

PubMed2005

Searching for epistatic interactions in nuclear families using conditional linkage analysis.

BACKGROUND: Genomic screens generally employ a single-locus strategy for linkage analysis, but this may have low power in the presence of epistasis. Ordered subsets analysis (OSA) is a method for conditional linkage analysis using continuous covariates. METHODS: We used OSA to evaluate two-locus interactions in the simulated Genetic Analysis Workshop 14 dataset. We used all nuclear families ascertained by Aipotu, Karangar, and Danacaa. Using the single-nucleotide polymorphism map, multipoint affected-sibling-pair (ASP) linkage analysis was performed on all 100 replicates for each chromosome using SIBLINK. OSA was used to examine linkage on each chromosome using LOD scores at each 3-cM location on every other chromosome as covariates. Two methods were used to identify positive results: one searching across the entire covariate chromosome, the other conditioning on location of known disease loci. RESULTS: Single-locus linkage analysis revealed very high LOD scores for disease loci D1 through D4, with mean LOD scores over 100 replicates ranging from 4.0 to 7.8. Although OSA did not obscure this linkage evidence, it did not detect the simulated interactions between any of the locus pairs. We found inflated type I error rates using the first OSA method, highlighting the need to correct for multiple comparisons. Therefore, using "null chromosome pairs" without simulated disease loci, we calculated a corrected alpha-level. CONCLUSION: We were unable to detect two-locus interactions using OSA. This may have been due to lack of incorporation of phenotypic subgroups, or because linkage evidence as summarized by LOD scores performs poorly as an OSA covariate. We found inflated type I error rates, but were able to calculate a corrected alpha-level for future analyses employing this strategy to search for two-locus interactions.

Chromosome Mapping↗

PubMed1984

The detection of major loci by segregation and linkage analysis: a simulation study.

Simulated multigenerational pedigrees were analyzed using the program GENPED and POINTER to examine the 1) limits of segregation analysis for detecting single locus, two-allele transmission of a dichotomous trait and 2) accuracy of the parameter estimates. Ten data sets of 30 pedigrees each (approximately 25 persons per pedigree) were simulated. The genotypic penetrance values were varied but the population prevalence of the trait was kept constant at 2%. For some data sets a linked marker locus was also simulated. Previous results had shown that a single major locus could be easily detected when the heterozygote penetrance (f1) was high or midway between the two homozygote penetrances. In this study, we found a single major locus could not be consistently detected by either method of segregation analysis when f1 was "low" to "intermediate." Accuracy of the parameter estimates depended on assumptions about the population prevalence. In those cases where the major locus could not be detected by segregation analysis, linkage to a marker locus could be detected as long as the marker was closely linked and there were not phenocopies in the population. Owing to the limited number of simulations in this study, we cannot generalize these findings. However, they provide a basis for further testing of methods of segregation analysis when factors such as the parameter values, family structure, and ascertainment scheme are varied.

Biometry↗

PubMed2006

Parsing the genetic heterogeneity of chromosome 12q susceptibility genes for Alzheimer disease by family-based association analysis.

Previous linkage studies have suggested that chromosome 12 may harbor susceptibility genes for late-onset Alzheimer disease (LOAD). No risk genes on chromosome 12 have been conclusively identified yet. We have reported that the linkage evidence for LOAD in a 12q region was significantly increased in autopsy-confirmed families particularly for those showing no linkage to alpha-T catenin gene, a LOAD candidate gene on chromosome 10 [LOD score increased from 0.1 in the autopsy-confirmed subset to 4.19 in the unlinked subset (optimal subset); p<0.0001 for the increase in LOD score], indicating a one-LOD support interval spanning 6 Mb. To further investigate this finding and to identify potential candidate LOAD risk genes for follow-up analysis, we analyzed 99 single nucleotide polymorphisms in this region, for the overall sample, the autopsy-confirmed subset, and the optimal subset, respectively, for comparison. We saw no significant association (p<0.01) in the overall sample. In the autopsy-confirmed subset, the best finding was obtained in the activation transcription factor 7 (ATF7) gene (single-locus association, p=0.002; haplotype association global, p=0.007). In the optimal subset, the best finding was obtained in the hypothetical protein FLJ20436 (FLJ20436) gene (single-locus association, p=0.0026). These results suggest that subset and covariate analyses may be one approach to help identify novel susceptibility genes on chromosome 12q for LOAD.

Alzheimer Disease↗

PubMed2005

High-resolution mapping of a new brown planthopper (BPH) resistance gene, Bph18(t), and marker-assisted selection for BPH resistance in rice (Oryza sativa L.).

Brown planthopper (BPH) is a destructive insect pest of rice in Asia. Identification and the incorporation of new BPH resistance genes into modern rice cultivars are important breeding strategies to control the damage caused by new biotypes of BPH. In this study, a major resistance gene, Bph18(t), has been identified in an introgression line (IR65482-7-216-1-2) that has inherited the gene from the wild species Oryza australiensis. Genetic analysis revealed the dominant nature of the Bph18(t) gene and identified it as non-allelic to another gene, Bph10 that was earlier introgressed from O. australiensis. After linkage analysis using MapMaker followed by single-locus ANOVA on quantitatively expressed resistance levels of the progenies from an F2 mapping population identified with marker allele types, the Bph18(t) gene was initially located on the subterminal region of the long arm of chromosome 12 flanked by the SSR marker RM463 and the STS marker S15552. The corresponding physical region was identified in the Nipponbare genome pseudomolecule 3 through electronic chromosome landing (e-landing), in which 15 BAC clones covered 1.612 Mb. Eleven DNA markers tagging the BAC clones were used to construct a high-resolution genetic map of the target region. The Bph18(t) locus was further localized within a 0.843-Mb physical interval that includes three BAC clones between the markers R10289S and RM6869 by means of single-locus ANOVA of resistance levels of mapping population and marker-gene association analysis on 86 susceptible F2 progenies based on six time-point phenotyping. Using gene annotation information of TIGR, a putative resistance gene was identified in the BAC clone OSJNBa0028L05 and the sequence information was used to generate STS marker 7312.T4A. The marker allele of 1,078 bp completely co-segregated with the BPH resistance phenotype. STS marker 7312.T4A was validated using BC2F2 progenies derived from two temperate japonica backgrounds. Some 97 resistant BC2F2 individuals out of 433 screened completely co-segregated with the resistance-specific marker allele (1,078 bp) in either homozygous or heterozygous state. This further confirmed a major gene-controlled resistance to the BPH biotype of Korea. Identification of Bph18(t) enlarges the BPH resistance gene pool to help develop improved rice cultivars, and the PCR marker (7312.T4A) for the Bph18(t) gene should be readily applicable for marker-assisted selection (MAS).

Alleles↗