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PubMed2002

Detecting gene-gene interactions using affected sib pair analysis with covariates.

Interest has recently focussed on allowing for interactions between loci as a way to increase power to detect linkage. In this paper, a simplified logistic regression method was used to perform affected sib pair analyses allowing for the inclusion of data from other loci. A systematic search of two-locus disease models was carried out to determine the situations in which this was advantageous. If IBD information is available (e.g. from a genome scan), it is unlikely that allowing for interactions will give a large lod score in the absence of linkage evidence from sinlge-locus analysis. Furthermore, allowing for interactions rarely gave a significant increase in power to detect linkage over a single-locus analysis, except for heterogeneity models with low K(P). Conversely, the availability of disease-associated genotypes may greatly increase the power both to detect linkage to a second locus and interaction between the loci. These results indicate that when only IBD information is available, two-locus analysis of genome scan data should be restricted to regions giving peaks under single-locus analysis. If disease-associated genotypes are available, it may be worth re-analysing the whole genome.

Genetic Linkage↗

PubMed1990

Mapping an origin of DNA replication at a single-copy locus in exponentially proliferating mammalian cells.

A general method for determining the physical location of an origin of bidirectional DNA replication has been developed recently and shown to be capable of correctly identifying the simian virus 40 origin of replication (L. Vassilev and E. M. Johnson, Nucleic Acids Res. 17:7693-7705, 1989). The advantage of this method over others previously reported is that it avoids the use of metabolic inhibitors, the requirement for cell synchronization, and the need for multiple copies of the origin sequence. Application of this method to exponentially growing Chinese hamster ovary cells containing the nonamplified, single-copy dihydrofolate reductase gene locus revealed that DNA replication begins bidirectionally in an initiation zone approximately 2.5 kilobases long centered about 17 kilobases downstream of the DHFR gene, coinciding with previously described early replicating sequences. These results demonstrate the utility of this mapping protocol for identifying cellular origins of replication and suggest that the same cellular origin is used in both the normal and the amplified DHFR locus.

Animals↗

PubMed1999

The maternal DDK syndrome phenotype is determined by modifier genes that are not linked to Om.

The DDK syndrome is a polar, early embryonic lethal phenotype caused by incompatibility between a maternal factor of DDK origin and a paternal gene of non-DDK origin. Both maternal factor and paternal gene have been mapped to the Om locus on mouse Chromosome (Chr) 11. The paternal contribution to the syndrome has been shown to segregate as a single locus. Although the inheritance of the maternal contribution has not been characterized in depth, it as been assumed to segregate as a single locus. We have now characterized the segregation of the DDK fertility phenotype in over 240 females. Our results demonstrate that females require at least one DDK allele at Om to manifest the syndrome. However, the DDK syndrome inter-strain cross-fertility phenotype of heterozygous females is highly variable and spans the gamut from completely infertile to completely fertile. Our results indicate that this phenotypic variability has a genetic basis and that the modifiers of the DDK syndrome segregate independently of Om.

Animals↗

PubMedDate not supplied

Complex segregation analysis of thyroid autoantibodies: are they inherited as an autosomal dominant trait?

The presence of circulating autoantibodies (Abs) to the thyroid antigens thyroid peroxidase (TPO) and thyroglobulin (Tg) is a marker for autoimmune thyroid disease. Recent studies have suggested that the tendency to produce these Abs is inherited as an autosomal dominant characteristic. In order to confirm or refute these observations, we have carried out a complex segregation analysis using POINTER on Ab data in 86 unselected pedigrees (172 nuclear families). The overall prevalence of TPO Ab was 9.9% in men and 24.1% in women. Tg Ab was found in 11.0% of men and 23.5% of women. There was a marked tendency for both TPO Ab and Tg Ab to cluster in families and complex segregation analysis provided strong evidence for vertical transmission. However, it was not possible to distinguish between a single locus and a multifactorial model for either Ab. In the absence of strong evidence for a single locus, genetic linkage strategies are unlikely to be successful.

Adolescent↗

PubMedDate not supplied

Evidence for multigene control of cryptorchidism in swine.

The mode of inheritance of cryptorchidism was investigated in Duroc swine. Matings of cryptorchid males with females whose full-sib brothers were cryptorchids were done. Sixteen of these litters were farrowed, and 54 males were born, of which 8 were cryptorchid. Two hypotheses were examined: first, that this trait is controlled by homozygosity of a recessive gene at a single locus; second, that it is controlled by homozygosity of recessive genes at two loci. The single-locus recessive hypothesis was rejected (P less than .01), but the two-locus model was not. Culling to reduce the incidence of cryptorchidism is discussed.

Animals↗

PubMed2002

Evidence of genetic interaction between the beta-globin complex and chromosome 8q in the expression of fetal hemoglobin.

During human development, the switch from fetal to adult hemoglobin (Hb) is not complete with the residual gamma-globin expression being restricted to a subset of erythrocytes termed "F cells" (FC). Statistical analyses have shown the FC trait to be influenced by a common sequence variant (C-->T) at position -158 upstream of the Ggamma-globin gene, termed the "XmnI-Ggamma polymorphism." The XmnI-Ggamma site is believed to be involved in the expression of the Ggamma-globin gene through interaction with transcription factors, and polymorphisms in the transcription factors could be influencing fetal Hb expression, conditional on the XmnI-Ggamma site. Using a two-locus model, in which the second locus was the known quantitative-trait locus (QTL) at the XmnI-Ggamma site, we showed suggestive linkage to chromosome 8q. A maximum single-point LOD score of 4.33 and a multipoint LOD score of 4.75 were found in a 15-20 cM region of chromosome 8q. A single-locus analysis failed to show linkage of FC to the region when the XmnI-Ggamma site was accounted for by removing its effects from the data or including it as a covariate. Results of the single-locus analysis were significant when the effects of the XmnI-Ggamma site were not accounted for in any way. The results of analysis in a large Indian kindred indicate that there is an interaction between the XmnI-Ggamma site and a QTL on chromosome 8q that is influencing the production of fetal Hb.

Chromosome Mapping↗

PubMed1992

Second-order approximations for selection coefficients at polygenic loci. II. Pleiotropy.

I determine the second-order approximation for the phenotypic distribution of an arbitrary number of quantitative traits, ignoring the effects of epistasis and linkage disequilibrium, conditioned on the presence of a specified genotype at one underlying locus of small effect. Using this approximation, I determine formulae for the effects of selection at a single locus with random mating under either Gaussian stabilizing selection, or correlated selection with truncation selection for one character. These formulae apply for arbitrary phenotypic distributions, yet even with multivariate Gaussian distributions of phenotypic effects the formula for correlated selection includes a correction to the standard formula in Falconer (1989). I demonstrate that this approximation has an error that is third order in the allelic or genotypic effects, independent of the form of the phenotypic distribution. I show also that the approximation of analogous form for the phenotypic distribution conditioned on the presence of a specified allele at a single locus is also correct to second order. Both approximations allow for dominance and are consistent in the sense that computing marginal fitnesses from approximations based on genotypic deviations and those based on average allelic effect yield the same answers.

Genotype↗

PubMed2005

Multi-locus penetrance variance analysis method for association study in complex diseases.

Common heritable diseases often result from the action of several different genes, each of which contributes to the total observed variability in the disease trait. Traditional single-locus association approaches rely heavily on the marginal effects of single-locus and tend to ignore the multigenic nature of complex diseases. The increasing request for localizing genes underlying traits in multi-gene diseases has led to the development of some statistical methods. In this study, we develop a multi-locus analysis method - multi-locus penetrance variance analysis (MPVA), and conduct systematical simulation studies to evaluate its performance. Our results show that compared with other multi-locus methods, MPVA has some advantage in detecting complicated interactions under different epistatic models, and its performance is stable and robust.

Analysis of Variance↗

PubMed1993

X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus.

X linked hereditary spastic paraplegia is a rare condition that has been divided into two forms (the pure spastic form and the complicated form) as a function of clinical course and severity. A gene for pure hereditary spastic paraplegia (SPG2) has been mapped to the proximal long arm of the X chromosome (Xq21) by linkage to the DXS17 locus, while a gene for a complicated form of the disease has been mapped to the distal long arm by linkage to the DXS52 locus (Xq28). Here we report on the mapping of a gene for complicated hereditary spastic paraplegia to the Xq21 region by linkage to the probe S9 at the DXS17 locus (Z = 5 at theta = 0.04) in a three generation pedigree. Multipoint linkage analysis supports the distal location of the disease gene with respect to the DXYS1-DXS17 block (cen-DXYS1-DXS3-DXS17-SPG2-tel). The observation of a complicated form of spastic paraplegia mapping to Xq21 raises the difficult issue of variable phenotypic expression, allelic heterogeneity, or even close proximity of two genes for hereditary spastic paraplegia in this region. However, since our study provides clinical evidence for intrafamilial heterogeneity in complicated X linked spastic paraplegia, the present data support the hypothesis of variable clinical expression of a single gene at the SPG2 locus, as previously suggested for SPG1. Finally, we report here what we believe to be the first evidence of clinical expression in heterozygous carriers, a feature that is relevant to genetic counselling in at risk females.

Adolescent↗

PubMed1999

Population structure and dynamics of Magnaporthe grisea in the Indian Himalayas.

The population genetics of Magnaporthe grisea, the rice blast pathogen, were analyzed in a center of rice diversity (the Uttar Pradesh hills of the Indian Himalayas) using multilocus and single-, or low-copy, DNA markers. Based on DNA fingerprinting with the multilocus probe MGR586 and single-locus probes, 157 haplotypes clustered into 56 lineages (at >/=70% MGR586 band similarity, each with unique single-locus profiles) and high diversity indices were detected among 458 isolates collected from 29 sites during 1992-1995. Most valleys sampled had distinct populations (73% of the lineages were site specific) with some containing one or a few lineages, confirming the importance of clonal propagation, and others were very diverse. Widely distributed lineages suggested that migration occurs across the region and into the Indo-Gangetic plains. Repeated sampling at one site, Matli, (170 isolates, 1992-1995) yielded 19 lineages and diversity significantly greater than that reported from similar samples from Colombia and the Philippines. Analysis of allelic associations using pairwise comparisons and multilocus variance analysis failed to reject the hypothesis of gametic phase equilibrium. The Matli population shifted from highly diverse in 1992 to almost complete dominance by one lineage in 1995. Such population dynamics are consistent with recombination followed by differential survival of clonal descendants of recombinant progeny. At another site, Ranichauri, population (n = 84) composition changed from 2 to 11 lineages over 2 yr and yielded additional evidence for equilibrium. Sexually fertile and hermaphrodite isolates of both mating types were recovered from rice in both Matli and Ranichauri. We demonstrate that Himalayan M. grisea populations are diverse and dynamic and conclude that the structure of some populations may be affected to some extent by sexual recombination.

Crosses, Genetic↗

PubMed1995

Genetic analysis of kifafa, a complex familial seizure disorder.

Kifafa is the Swahili name for an epileptic seizure disorder, first reported in the early 1960s, that is prevalent in the Wapogoro tribe of the Mahenge region of Tanzania in eastern Africa. A 1990 epidemiological survey of seizure disorders in this region reported a prevalence in the range of 19/1,000-36/1,000, with a mean age at onset of 11.6 years; 80% of those affected had onset prior to 20 years of age. A team of investigators returned to Tanzania in 1992 and collected data on > 1,600 relatives of 26 probands in 20 kifafa families. We have undertaken a genetic analysis of these data in order to detect the presence of familial clustering and whether such aggregation could be attributed to genetic factors. Of the 127 affected individuals in these pedigrees, 23 are first-degree relatives (parent, full sibling, or offspring) of the 26 probands; 20 are second-degree relatives (half-sibling, grandparent, uncle, or aunt). When corrected for age, the risk to first-degree relatives is .15; the risk to second-degree relatives is .063. These risks are significantly higher than would be expected if there were no familial clustering. Segregation analysis, using PAP (rev.4.0), was undertaken to clarify the mode of inheritance. Among the Mendelian single-locus models, an additive model was favored over either a dominant, recessive, or codominant model. The single-locus model could be rejected when compared with the mixed Mendelian model (inclusion of a polygenic background), although the major-gene component tends to be recessive.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2003

Chalcone isomerase gene from rice (Oryza sativa) and barley (Hordeum vulgare): physical, genetic and mutation mapping.

The barley and rice chalcone flavonone isomerase (Cfi) genes were isolated and identified by homology to the maize Cfi gene. Structure analysis indicated high similarity except that the barley gene lacked intron 3. The maize Cfi gene has been mapped to three loci, but only a single locus was detected in barley and rice. This explains the lack of observed mutants in maize while a single locus anthocyanin-less 30 (ant30), with four alleles ant30-245, ant30-310, ant30-272 and ant30-287 has been described in barley. Based on biochemical analysis it has been suggested that these mutants are in the Cfi gene resulting in absence of anthocyanin. In order to provide molecular evidence for or against this hypothesis we sequenced the four ant30 alleles and compared them to their respective wild-type alleles. The three sodium azide induced mutants ant30-245, ant30-272 and ant30-287 showed single base changes resulting in two non-sense and one mis-sense mutations affecting the protein function. The 1-nitroso-5,6-dihydrouracil induced mutant ant30-310 had one base substitution and a 25 bp deletion. These observations are in accordance with the conclusion that the ant30 phenotype is caused by mutations in the Cfi gene. The nature of the mutants induced is in line with the proposed mechanism of action for the mutagens used.

Chromosome Mapping↗

PubMed1984

No evidence for linkage between an insulin-dependent diabetes mellitus-susceptibility locus and immunoglobulin loci KM or GM.

We studied 52 families having more than one member affected with insulin-dependent diabetes mellitus (IDDM) for linkage of an IDDM-susceptibility locus to the immunoglobulin loci KM and GM. Linkage was analyzed by the LOD score method using single-locus recessive and dominant models of IDDM inheritance, with penetrances of the disease-susceptible genotypes being dependent on age and reaching a maximum of 20% by age 40. We found no evidence for linkage of IDDM to KM or GM. Close linkage (recombination fraction less than 5%) was rejected for KM under the recessive model and for GM under both models. These results suggest either that there are no IDDM-susceptibility loci closely linked to KM or GM or that use of a single-locus model of IDDM (which ignores the effects of the susceptibility locus in the HLA region) is inadequate for their detection.

Adult↗

PubMed2006

The G protein-coupled receptor kinase 4 gene affects blood pressure in young normotensive twins.

BACKGROUND: G protein-coupled receptor kinase 4 (GRK4) is involved in activity of dopamine receptors in renal proximal tubules and thus mediates sodium reabsorption and blood pressure (BP) regulation. The present study evaluated the impact of the GRK4 gene variants on BP levels in normotensive adolescents and young adults. METHODS: Three functional polymorphisms of R65L, A142V, and A486V were genotyped in 934 white and African American (44.2%) twin subjects (17.4 +/- 3.4 years of age). A number of association approaches including single-locus analyses, haplotype trend regression analyses, and sib-pair transmission disequilibrium tests were carried out. RESULTS: Single-locus analyses revealed a significant interaction between R65L and age for SBP (P = .019) with an obvious gene-dose effect. In L65L homozygotes SBP showed the steepest increase with age (beta = 0.85, P = .003), R65L heterozygotes showed the next steepest increase (beta = 0.54, P < .001), and the effect of age on SBP was absent in R65R homozygotes. Stratified analyses showed that the SBP increasing effect of the 65L allele was significant only in the older group of subjects (114.1 +/- 11.1 mm Hg v 110.1 +/- 9.6 mm Hg, P = .024). Sib-pair transmission disequilibrium tests analyses in 72 informative dizygotic twin pairs confirmed the significant effect of the 65L on SBP; carriers of the 65L allele had a higher SBP compared with noncarriers (110.3 +/- 8.2 v 107.3 +/- 7.8 mm Hg, P = .047). Haplotype analyses uncovered an interaction between haplotype 65L-142V-486A and age for SBP (P = .017); individuals who were homozygous for haplotype 65L-142V-A486 showed a 1.05-mm Hg steeper increase in SBP per year increase in age compared with those homozygous for the most common R65-A142-A486 haplotype. CONCLUSION: Our data indicate that the R65L polymorphism of the GRK4 gene plays a role in BP regulation in adolescents and young adults.

Adolescent↗

PubMed1986

Affinities between contemporary and skeletal Jewish and non-Jewish groups based on tooth morphology.

Samples from five Jewish and six non-Jewish populations were compared in terms of the frequencies of 19 dental morphological variables. All but one of the samples came from Europe, North Africa, or the Middle East. Nine were from contemporary populations, and two were skeletal. Of the skeletal groups, one was Jewish, excavated on Mount Zion, Jerusalem, and dated at around 3,000 years old; and the other non-Jewish, excavated on the east coast of Australia, and dated at between 1,000 and 200 years old. Assessment of affinity between the different groups was based on smallest space analysis and cluster analysis. The results demonstrated relative proximity of the Jewish groups (with one exception), despite the fact that they came from a wide geographical area. In particular, the sample from Mount Zion showed greater affinity with three of the four living Jewish populations than with most non-Jewish groups. The skeletal Australian sample formed a cluster of its own, distinct from all the other groups. For six of the groups, the relationships based on tooth morphology showed good correspondence with known relationships based on single locus polymorphisms. The similarity of the Jewish groups to each other in terms of both tooth morphology and single locus polymorphisms was of special interest, since differences in other morphological and anthropometric characteristics, thought to be the result of selection, are known to exist between the Jewish populations.

Africa, Northern↗

PubMed1997

Optimal weighting scheme for affected sib-pair analysis of sibship data.

Application of the affected sib-pair method of linkage analysis to sibships with variable numbers of affected and unaffected members requires a scheme for weighting the contributions from the sibships in the calculation of an overall test statistic. Currently accepted weighting schemes are based on the concepts of independent pairs and Shannon information content. Here, we show that the weighting scheme with maximum power to detect linkage can be determined from the theoretical means and variances of the sibship contributions under the null and alternative hypotheses. We derive the theoretical means and variances of the contributions from different types of sibships under a generalized single locus model. We use these theoretical means and variances to obtain the optimal weights for a variety of single locus models, and compare the power of existing weighting schemes relative to the optimum. The results suggest that, under a range of plausible assumptions, optimal power is nearly obtained by weighting to all sibpairs equally, except those occurring in sibships with so many affected siblings (usually five or more) that the probability of parental homozygosity for the disease allele becomes substantial. A corollary is that, in affected sib-pair analysis, the 'informativeness' of a sibship is more nearly proportional to the number of affected sib-pairs than to the number of affected siblings, up to about five affected siblings.

Alleles↗

PubMed1989

Genes encoding the major surface glycoprotein in Leishmania are tandemly linked at a single chromosomal locus and are constitutively transcribed.

The major surface glycoprotein of Leishmania, gp63, is encoded by a small multi-gene family of tandemly linked genes which map to a single chromosome. For Leishmania major, there are five 3.1 kilobasepair (kb) direct repeat units which include a 1.8-kb open reading frame and a 1.3-kb intergenic or spacer region. In addition, there is a single gene copy linked as a direct repeat but separated from the tandem array of gp63 genes by about 8 kb. The restriction enzyme map of the repeat unit is highly conserved among the gene copies. The regions which flank the tandemly repeated genes diverge outside of the 3.1-kb repeat unit. Transcription of the gp63 gene locus is constitutive as the 3-kb transcript was present in promastigotes as well as in amastigotes. A minor 6-kb gp63 gene transcript was also detected in Northern blot analysis which could signify the transcription of the genes as a polycistronic or multigene precursor RNA.

Animals↗

PubMedDate not supplied

Genetic quality control of laboratory animals used in aging studies.

Laboratory rodents provide a useful model for aging processes in humans. Various genetic "types" of stock are available, including outbred stocks and inbred strains and their derivatives. Inbred strains, which can be regarded as clones of genetically identical individuals, provide a powerful research tool for studies in many disciplines, including gerontology. However, some form of genetic quality control is essential to ensure that the strains are authentic. Single gene polymorphisms, particularly those detected by electrophoresis and immunological methods, provide a powerful tool for such quality control, though these methods are expensive and require considerable expertise. Methods based on several loci studied simultaneously include skin grafting and polyvalent alloantisera. These methods are often quick and technically relatively easy, but are less flexible than the single locus methods. Methods based on DNA restriction fragment length polymorphisms (RFLPs) fall into both categories depending on whether a single locus or a multilocus probe, such as the fingerprinting probes, is used. These DNA-based methods have many advantages, and are likely to be the methods of choice in the future.

Aging↗