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PubMed1988

Maternal-fetal interactions and the maintenance of HLA polymorphism.

There is some empirical evidence that a fetus with an HLA antigen not present in its mother has a higher survival than a fetus sharing antigens with its mother. We have developed both single locus and two-locus theoretical models to examine this mode of selection. First, this immunologically based model appears to have the potential to maintain many alleles at a single locus and to result in an excess of heterozygotes when selection is strong. Second, substantial gametic disequilibrium is maintained between alleles at two loci for this selection mode when recombination is that observed between HLA loci A, B, and DR. Overall, it appears that this mode of selection has the potential to strongly affect genetic variation in the HLA region.

Alleles↗

PubMed1988

Molecular genetics of the single-minded locus: a gene involved in the development of the Drosophila nervous system.

The embryonic neuroepithelium of Drosophila gives rise to the central nervous system. We have studied the mutant phenotype and expression of a gene, single-minded (sim), which is involved in generating a specific region of this neuroepithelium. In sim mutant embryos, a subset of neuronal and nonneuronal precursor cells lying along the midline fail to emerge with the rest of the neuroepithelium. We have identified the sim transcription unit and have shown by in situ hybridization to embryos that the sim gene is expressed specifically in the midline neuroepithelium. Both the mutant phenotype and the temporal and spatial expression of transcripts suggest that the sim gene plays a key role in the emergence of this subset of cells along the midline of the developing central nervous system.

Animals↗

PubMed1992

Genetic determination of high-density lipoprotein-cholesterol and apolipoprotein A-1 plasma levels in a family study of cardiac catheterization patients.

Plasma levels of two lipoprotein risk factors, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-1 (apo A-1), have been shown to be negatively associated with the risk of developing coronary artery disease, and several reports have examined familial factors in HDL-C and apo A-1 levels. A number of studies suggest that shared genes influence familial resemblance of these lipoprotein levels far more than do shared environments. Possible mechanisms for the inheritance of these two risk factors (HDL-C and apo A-1 plasma levels) are explored using data from 390 individuals in 69 families ascertained through probands undergoing diagnostic cardiac catheterization. Segregation analysis was used to test a series of specific models of inheritance. Evidence for single-locus control of apo A-1 levels, with Mendelian transmission of a dominant allele leading to elevated apo A-1 levels, was seen in these families, although there was additional correlation among sibs present. This locus accounted for 48.6% and 37.2% of the total variation in apo A-1 levels in males and females, respectively. Similar evidence of segregation at a single locus controlling HDL-C levels was not seen in these families.

Adolescent↗

PubMed2005

Epidemiology and disease-control under gene-for-gene plant-pathogen interaction.

An introduction of disease-resistant variety of a crop plant often leads to the development of a virulent race in pathogen species that restores the pathogenicity to the resistant crop. This often makes disease control of crop plants extremely difficult. In this paper, we theoretically explore the optimal 'multiline' control, which makes use of several different resistant varieties, that minimizes the expected degree of crop damages caused by epidemic outbreaks of the pathogen. We examine both single-locus and two-locus gene-for-gene (GFG) systems for the compatibility relationship between host genotypes and pathogen genotypes, in which host haplotype has either susceptible or resistant allele in each resistance locus, and the pathogen haplotype has either avirulent or virulent allele in the corresponding virulence locus. We then study the optimal planting strategy of host resistant genotypes based on standard epidemiological dynamics with pathogen spore stages. The most striking result of our single-locus GFG model is that there exists an intermediate optimum mixing ratio for the susceptible and resistant crops that maximizes the final yield, in spite of the fact that the susceptible crop has no use to fight against either avirulent or virulent race of the pathogen. The intermediate mixture is optimum except when the initial pathogen spore population in the season consists exclusively of the virulent race. The optimal proportion of resistant crops is approximately 1/R(0), where R(0) is the basic reproductive ratio of pathogen--the rest (the vast majority if R(0) is large) of crops should be the susceptible genotype. By mixing susceptible and resistant crops, we can force the pathogen races to compete with each other for their available hosts. This competition between avirulent and virulent races prevents the fatal outbreak of the virulent race (the super-race) that can infect all the host genotypes. In the two-locus GFG control, there again exists the optimal mixing ratio for the fraction of universally susceptible genotype and the total fraction of various resistant genotypes, with the ratio close to 1/R(0).

Crops, Agricultural↗

PubMed1998

The population genetics of synthetic lethals.

Synthetic lethals are variants at different loci that have little or no effect on viability singly but cause lethality in combination. The importance of synthetic lethals and, more generally, of synthetic deleterious loci (SDL) has been controversial. Here, we derive the expected frequencies for SDL under a mutation-selection balance for the complete haploid model and selected cases of the diploid model. We have also obtained simple approximations that demonstrate good fit to exact solutions based on numerical iterations. In the haploid case, equilibrium frequencies of carrier haplotypes (individuals with only a single mutation) are comparable to analogous single-locus results, after allowing for the effects of linkage. Frequencies in the diploid case, however, are much higher and more comparable to the square root of the single-locus results. In particular, when selection operates only on the double-mutant homozygote and linkage is not too tight, the expected frequency of the carriers is approximately the quartic root of the ratio between the mutation rate and the selection coefficient of the synthetics. For a reasonably wide set of models, the frequencies of carriers can be on the order of a few percent. The equilibrium frequencies of these deleterious alleles can be relatively high because, with SDL, both dominance and epistasis act to shield carriers from exposure to selection. We also discuss the possible role of SDL in maintaining genetic variation and in hybrid breakdown.

Diploidy↗

PubMed1996

Is there a paradigm shift in genetics? Lessons from the study of human diseases.

The flood of genetic data made possible by recent technological advances has led to a number of important changes in our conceptual model, or working "paradigm," of genetics. Among these changes are recognition that (1) most mutations are unique; (2) there are many alleles at every locus, not just two; (3) these alleles have a hierarchical, or cladistic, history-dependent structure and geographic distribution; (3) the genotype-to-phenotype relationship is complex and quantitative, even for single-locus traits; (4) genotype-phenotype relationships often depend on the organization of the genome into linkage groups, gene families, and the like; and (5) genes affecting quantitative traits can be individually identified rather than solely being viewed as a polygenic aggregate, and these genes each have the same characteristics as genes for single-locus phenotypes. The latter provides a profound unifying impact on biology by reconciling long-standing conceptual differences on qualitative vis-a-vis quantitative phenotypes and their relative importance and evolution. Many of the data that have led to these advances have been generated in the study of genes associated with diseases in human populations. The conceptual changes affect all of biology, but are especially important in the human context, because the amount, complexity, and historical dependence of the variation in the human genome have serious societal implications regarding the epistemology of genetic causation and applications in public health. But whether these changes constitute a real "paradigm shift" in genetics, or are merely adjustments in the classical models developed early in this century, is unclear.

Alleles↗

PubMed2005

Multidimensional genome scans identify the combinations of genetic loci linked to diabetes-related phenotypes in mice.

Most quantitative trait loci (QTL) studies have focused on detecting the genetic effects of individual QTLs. This study thoroughly dissected the genetic components of type 2 diabetic mice, including a search for epistatic interactions and multi-locus additive effects that result in variation in diabetes-related phenotypes. F2 population was generated from BKS.Cg-Leprdb+/+m and DBA/2 intercross and separated into six subpopulations by sex and the db-dependent diabetes severity. Single-locus and pairwise genome scans first identified the QTLs in these F2 subpopulations, and next covariate-dependent scans confirmed their sex-, db- and sex-by-db-specific effects in the combined populations. Single-locus genome scans detected four QTLs (QBIS1, QBIS2, QBIS3 and QBIS4) that presented their genetic effects beyond sex, but most QTLs showed their effects specifically in limited conditions. This highly conditional feature of the QTLs was accentuated in the pairwise analysis. The pairwise genome scans uncovered a total of 27 significantly interacting or additively acting pairs of loci, showing a better fit to explain the total phenotypic variation of the traits. These significant pairs affected the traits under constantly varying combinations of loci in a time series or in both sexes. In addition, pairwise analysis indicated the appropriate genetic background in constructing congenic strains to obtain the maximum power in the replication of phenotypes. Our study showed high degree of complexity in the genetics of type 2 diabetes in mice, and it suggested that a comprehensive understanding of the multi-locus effects was essential to disentangle the complex genetics of diabetes and obesity in humans.

Animals↗

PubMed1996

Analysis of the recurrence patterns for nonsyndromic cleft lip with or without cleft palate in the families of 3,073 Danish probands.

The identification of several putative susceptibility loci for nonsyndromic cleft lip with or without cleft palate (CL +/- P) has sparked a renewed interest in the genetics of this condition. However, prior to undertaking linkage studies for complex traits such as CL +/- P it is desirable to have some understanding of the number and nature of the loci involved in disease susceptibility. The ability to obtain valid estimates of these parameters is contingent on the availability of family data which are unbiased by factors that distort the true familial recurrence pattern. In an effort to obtain such data, 2 centralized data repositories (the Danish Central Person Registry and the Danish Facial Cleft Database), were linked and used to estimate the risks to first, second, and third-degree relatives of 3,073 CL +/- P probands born in Denmark from 1952 to 1987. Analyses of these data excluded single locus and additive multilocus inheritance of CL +/- P, and provided evidence that CL +/- P is most likely determined by the effects of multiple interacting loci. Under a multiplicative model, no single locus can account for more than a threefold increase in the risk to first-degree relatives of CL +/- P probands. These data provide further evidence that nonparametric linkage methods (ex. affected relative pair studies) are likely to represent a more realistic approach for identifying CL +/- P susceptibility loci, than are traditional pedigree-based methods. However, at least 100 and more realistically several hundred (300-500) affected sib pairs are likely to be required to detect linkage to CL +/- P susceptibility loci.

Cleft Lip↗

PubMed2003

Genomic organization of rDNA loci in natural populations of Medicago truncatula Gaertn.

Medicago truncatula Gaertn. is an annual self-pollinating species characterized by a diploid complement 2n = 16 and low DNA content. It responds very well to transformation methods so it is used as a model species for Leguminosae. In contrast with the advanced studies in molecular biology, cytogenetic research has remained limited even though it is an extremely valuable approach to the analysis of the genome structure. In the present study we examined the chromosomal distribution of rDNA sequences in five natural populations of M. truncatula, explored the genomic diversity of this species and found markers for chromosome identification. FISH experiments revealed three distribution patterns of rDNA sequences, distinguished by one, two and three loci of 5S genes; 18S-5.8S-25S genes were always localized at a single locus. The results add information to the genome structure of M. truncatula, revealing a pattern of distribution of rDNA genes unobserved previously, which consists of 5S genes clustered at a single locus. The physical mapping of rDNA sequences is a first contribution towards the construction of a detailed molecular karyotype of M. truncatula.

Chromosomes, Plant↗

PubMed1985

Gene mapping and leader polypeptide sequence of human glucocerebrosidase: implications for Gaucher disease.

Analysis of immunologic cross-reacting material in Chinese hamster-human somatic cell hybrids allowed assignment of the structural gene for glucocerebrosidase (glucosylceramidase; beta-D-glucosyl-N-acylsphingosine glucohydrolase, EC 3.2.1.45) to chromosome 1 bands q21-q32. In situ hybridization of a radiolabeled human glucocerebrosidase cDNA to high resolution human chromosomes demonstrated that a single locus encoding glucocerebrosidase is on 1q21, adjacent to a region of chromosome 1 (1qh) abundant in structural heteromorphisms. We also have identified a hydrophobic leader polypeptide encoded by this locus, permitting a more complete description of the biosynthesis of the enzyme. These results suggest that the type-specific protein polymorphisms in Gaucher disease result from mutations at this single locus, whose segregation might be followed by linkage to visible chromosomal heteromorphisms.

Animals↗

PubMed1985

Susceptibility of wild mouse cells to exogenous infection with xenotropic leukemia viruses: control by a single dominant locus on chromosome 1.

Although xenotropic murine leukemia viruses cannot productively infect cells of laboratory mice, cells from various wild-derived mice can support replication of these viruses. Although the virus-sensitive wild mice generally lack all or most of the xenotropic proviral genes characteristic of inbred strains, susceptibility to exogenous infection is unrelated to inheritance of these sequences. Instead, susceptibility is controlled by a single dominant gene, designated Sxv, which maps to chromosome 1. Sxv is closely linked to, but distinct from Bxv-1, the major locus for induction of xenotropic murine leukemia viruses in laboratory mice. Genetic experiments designed to characterize Sxv show that this gene also controls sensitivity to a wild mouse virus with the interference properties of mink cell focus-forming murine leukemia viruses, and that Sxv-mediated susceptibility to xenotropic murine leukemia viruses is restricted by the mink cell focus-forming virus resistance gene Rmcf. These data, together with genetic mapping of the mink cell focus-forming virus cell surface receptor locus to this same region of chromosome 1, suggest that Sxv may encode a wild mouse variant of the mink cell focus-forming virus receptor that allows penetration by xenotropic murine leukemia viruses.

Animals↗

PubMed1986

Genetic analysis of plasma sitosterol, apoprotein B, and lipoproteins in a large Amish pedigree with sitosterolemia.

We previously reported the finding of phytosterolemia, xanthomatosis, and hyperapobetalipoproteinemia (hyperapoB) in five siblings in a large Amish pedigree ascertained through a 13-year-old boy who died suddenly from advanced coronary atherosclerosis. Here, we present further analyses of the plasma levels of the plant sterol, sitosterol, of low density (beta) lipoprotein (LDL) sterol, and of LDL B protein. Of 254 relatives and spouses of the proband, 90.5% were examined. A series of genetic models were explored using a pedigree analysis where parameters reflecting frequency, transmission, and penetrance of putative genotypes were examined simultaneously using a maximum likelihood approach. Segregation analysis of the sitosterol levels showed that the phenotype of sitosterolemia was controlled by a rare autosomal recessive gene. There was also significant familial correlation in plasma sitosterol levels that was attributed to a polygenic component under a mixed model but could also be due to shared environments such as diets. The recessive model was supported by our finding that the plasma sitosterol levels in the parents and in six children born to three of the five sitosterolemics were less than 1 mg/dl, well within the normal range. The phenotype of hyperapoB is based on an elevated level of LDL B protein in the presence of a normal LDL cholesterol level (low LDL sterol to LDL B ratio). For both LDL sterol and LDL B, a polygenic model showed a slightly greater improvement in ln likelihood than did the Mendelian single locus model when both were compared to a sporadic model. Similar results were obtained for sterol levels of high density (alpha) lipoprotein (HDL) sterol. When segregation analysis was performed using the ratio of LDL sterol to LDL B, the Mendelian single locus model gave a slightly better fit to the data than did the polygenic model. While the analyses presented here provided unequivocal evidence for the recessive phenotype of phytosterolemia, we also identified a possible single gene factor that could account for the major portion of the strong familial aggregation in the ratio of LDL sterol to LDL B, and to a lesser extent LDL B. However, there is clear evidence of familial aggregation for these traits in this pedigree beyond that due to Mendelian components.

Adolescent↗

PubMed1993

Linkage analysis by two-dimensional DNA typing.

In two-dimensional (2-D) DNA typing, genomic DNA fragments are separated, first according to size by electrophoresis in a neutral polyacrylamide gel and second according to sequence by denaturing gradient gel electrophoresis, followed by hybridization analysis using micro- and minisatellite core probes. The 2-D DNA typing method generates a large amount of information on polymorphic loci per gel. Here we demonstrate the potential usefulness of 2-D DNA typing in an empirical linkage study on the red factor in cattle, and we show an example of the 2-D DNA typing analysis of a human pedigree. The power efficiency of 2-D DNA typing in general is compared with that of single-locus typing by simulation. The results indicate that, although 2-D DNA typing is very efficient in generating data on polymorphic loci, its power to detect linkage is lower than single-locus typing, because it is not obvious whether a spot represents the presence of one or two alleles. It is possible to compensate for this lower informativeness by increasing the sample size. Genome scanning by 2-D DNA typing has the potential to be more efficient than current genotyping methods in scoring polymorphic loci. Hence, it could become a method of choice in mapping genetic traits in humans and animals.

Alleles↗

PubMed1988

Genetic variability in white-tailed deer.

Genetic variability at 36 loci was studied in white-tailed deer (Odocoileus virginianus) populations, on the Savannah River Plant (SRP) in South Carolina. Mean multilocus heterozygosity (H), percentage of polymorphic loci (P) and average number of alleles per locus (A) for white-tailed deer were calculated and compared with values for white-tailed deer from several locations (SRP deer: H = 9.9 per cent, P0.05 = 30.6 per cent, A = 1.89; white-tailed deer overall: H = 10.4 per cent, P0.05 = 32.3 per cent, A = 1.94). Frequency distributions for single locus heterozygosity values (h) and the number of alleles per locus for white-tailed deer were found to be significantly different from those of mammals in general. Analysis of single-locus data based on quaternary structure and functional groups of proteins failed to demonstrate expected differences as predicted from the literature. White-tailed deer have a high level of heterozygosity, but they do not exhibit many of the life history and environmental characteristics associated with high heterozygosity in other animals.

Animals↗

PubMed1999

A comparison of multilocus clines maintained by environmental adaptation or by selection against hybrids.

There has recently been considerable debate over the relative importance of selection against hybrids ("endogenous" selection) vs. adaptation to different environments ("exogenous") in maintaining stable hybrid zones and hence in speciation. Single-locus models of endogenous and exogenous viability selection generate clines of similar shape, but the comparison has not been extended to multilocus systems, which are both quantitatively and qualitatively very different from the single-locus case. Here we develop an analytical multilocus model of differential adaptation across an environmental transition and compare it to previous heterozygote disadvantage models. We show that the shape of clines generated by exogenous selection is indistinguishable from that generated by endogenous selection. A stochastic simulation model is used to test the robustness of the analytical description to the effects of drift and strong selection, and confirms the prediction that pairwise linkage disequilibria are predominantly generated by migration. However, although analytical predictions for the width of clines maintained by heterozygote disadvantage fit well with the simulation results, those for environmental adaptation are consistently too narrow; reasons for the discrepancy are discussed. There is a smooth transition between a system in which a set of loci effectively act independently of each other and one in which they act as a single nonrecombining unit.

Adaptation, Physiological↗

PubMed1994

Structure and function of selectable and non-selectable transgenes in maize after introduction by particle bombardment.

Zea mays transformants produced by particle bombardment of embryogenic suspension culture cells of the genotype A188 x B73 and selected on kanamycin or bialaphos were characterized with respect to transgene integration, expression, and inheritance. Selection on bialaphos, mediated by the bar or pat genes, was more efficient than selection on kanamycin, mediated by the nptII gene. Most transformants contained multicopy, single locus, transgene insertion events. A transgene expression cassette was more likely to be rearranged if expression of that gene was not selected for during callus growth. Not all plants regenerated from calli representing single transformation events expressed the transgenes, and a non-selectable gene (uidA) was expressed in fewer plants than was the selectable transgene. Mendelian inheritance of transgenes consistent with transgene insertion at a single locus was observed for approximately two thirds of the transformants assessed. Transgene expression was typically, but not always, predictable in progeny plants--transgene silencing, as well as poor transgene transmission to progeny was observed in some plant lines in which the parent plants had expressed the transgene.

Cells, Cultured↗

PubMed2005

TAFI gene haplotypes, TAFI plasma levels and future risk of coronary heart disease: the PRIME Study.

OBJECTIVES: To evaluate the association of thrombin-activatable fibrinolysis inhibitor (TAFI) gene polymorphisms with the risk of coronary heart disease (CHD) and with TAFI levels measured by a newly developed enzyme-linked immunosorbent assay (ELISA) (TAFI-1B1), shown to be a reliable method for detecting quantitative variations in circulating TAFI. PATIENTS/METHODS: Six polymorphisms (C-2599G, G-438A, Ala147Thr, Thr325Ile, C + 1542G and T + 1583A) were genotyped and baseline plasma concentrations of TAFI were measured in a nested case-control design as part of the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study. Participants from France and Northern Ireland who had developed a CHD event during a 5-year follow-up (n = 321) were compared with 645 population- and age-matched control subjects. RESULTS: In France, the Thr147 allele was more frequent in cases than in controls (0.41 vs. 0.32; P = 0.02), whereas the reverse was observed in Northern Ireland (0.33 vs. 0.38; P = 0.19) (P = 0.01 for interaction). No other polymorphism was associated with CHD risk. Consistent with the results derived from the single-locus analysis, haplotype analysis revealed that the haplotype carrying the Thr147 allele was associated with increased risk of CHD in France while the reverse tended to hold in the Northern Ireland population. Single-locus and haplotype analyses revealed that two polymorphisms, C-2599G and Ala147Thr (or T + 1583A that is in nearly complete association with it), had additive effects on TAFI levels and explained >18% of TAFI variability. This effect was homogeneous in France and Northern Ireland, and in cases and controls who exhibited similar TAFI levels. CONCLUSIONS: Thrombin-activatable fibrinolysis inhibitor gene polymorphisms are strongly associated to plasma TAFI levels, but the relation to CHD risk is less clear.

Alleles↗

PubMed2000

Context-dependent genetic effects in hypertension.

There is a growing frustration with the limitations and inconsistencies of single locus candidate gene association and linkage studies. This frustration is exacerbated by the knowledge that a large influx of genotypic and gene expression data is expected to emerge over the next 5 years, and we are not prepared for the type of multigenic conceptual framework that will be necessary to analyze that data. A review of the hypertension genetic literature reveals substantial evidence for the importance of both genetic and environmental contexts on the mapping between single locus polymorphisms and risk of disease. These trends indicate that the current reliance on simple single gene studies to elucidate the complex etiology of hypertension needs to undergo some kind of transformation. It is suggested that even a minor shift to a more systematic investigation of context-dependent effects will increase our understanding of the multidimensional genetic and environmental realities underneath current studies. This shift is also necessary if we are to gain a deeper understanding of the specific ways in which an individual's risk of hypertension is a consequence of the inter- actions among genes and environments.

Causality↗