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Genetics of sex-ratio variation inferred from parent-offspring regressions and sib correlations in the apple snail Pomacea canaliculata.

The brood sex ratio in the apple snail Pomacea canaliculata varies almost continuously from all male to all female, but the population sex ratio is nearly 1:1. In this study, regressions of the offspring sex ratio on the sex ratios of the parents' siblings as well as correlations in the brood sex ratios between sisters or brothers were investigated, in order to infer the genetic system that produces the sex-ratio pattern. There were significant positive relationships between the offspring sex ratio and the sex ratio of the mother's siblings (slope=0.28), and between the offspring sex ratios of two sisters (r=0.41). On the other hand, the father-offspring regression (slope=0.10), and the correlations between two brothers (r=-0.13) or between the brother and the sister (r=0.17) were not significant. These patterns differed from predictions using typical cytoplasmic sex factors, sex-ratio genes or sex-determining polygenes. Thus, the results suggest the involvement of either a small number of sex-determining genes or a more complicated system such as sex-ratio or sex-determining polygenes that act nonadditively.

Animals↗

Using mating designs to uncover QTL and the genetic architecture of complex traits.

Analysis of quantitative trait loci (QTL) affecting complex traits is often pursued in single-cross experiments. For most purposes, including breeding, some assessment is desired of the generalizability of the QTL findings and of the overall genetic architecture of the trait. Single-cross experiments provide a poor basis for these purposes, as comparison across experiments is hampered by segregation of different allelic combinations among different parents and by context-dependent effects of QTL. To overcome this problem, we combined the benefits of QTL analysis (to identify genomic regions affecting trait variation) and classic diallel analysis (to obtain insight into the general inheritance of the trait) by analyzing multiple mapping families that are connected via shared parents. We first provide a theoretical derivation of main (general combining ability (GCA)) and interaction (specific combining ability (SCA)) effects on F(2) family means relative to variance components in a randomly mating reference population. Then, using computer simulations to generate F(2) families derived from 10 inbred parents in different partial-diallel designs, we show that QTL can be detected and that the residual among-family variance can be analyzed. Standard diallel analysis methods are applied in order to reveal the presence and mode of action (in terms of GCA and SCA) of undetected polygenes. Given a fixed experiment size (total number of individuals), we demonstrate that QTL detection and estimation of the genetic architecture of polygenic effects are competing goals, which should be explicitly accounted for in the experimental design. Our approach provides a general strategy for exploring the genetic architecture, as well as the QTL underlying variation in quantitative traits.

Animals↗

Genetics of hypertension: from experimental models to clinical applications.

Human essential hypertension is a complex, multifactorial, quantitative trait under a polygenic control. Over the last decade several strategies have been used to dissect the genetic determinants of hypertension. Of these strategies, the study of rare monogenic forms of hypertension has been the most successful. Attempts to identify the multiple genes involved in the more common polygenic form of hypertension has been more difficult. Many laboratories use rat models of genetic hypertension where some of the complexity of studying human hypertension can be removed. Numerous crosses between hypertensive and normotensive strains have produced several quantitative trait loci (QTL) for blood pressure and other related phenotypes such as left ventricular hypertrophy, stroke, insulin resistance and kidney failure. In this review we describe established and novel strategies to dissect the susceptibility and severity loci for human essential hypertension. We also illustrate a few successful examples of a direct translation of genetic discoveries from the experimental setting to human investigation. The use of new molecular tools such as gene 'chips' or microarrays for either gene expression profiling or single nucleotide polymorphisms (SNPs)-based total genome scanning strategies will ultimately result in new diagnostics and therapeutics for human essential hypertension.

Animals↗

Dnase1l3 deficiency in lupus-prone MRL and NZB/W F1 mice.

Loss of deoxyribonuclease I (Dnase1) function is associated with systemic lupus erythematosus (SLE) in humans and mice; however, no coding mutations in Dnase1 are found in polygenic murine models. Instead, both MRL-lpr strains and NZB/W F1 hybrids are homozygous for T89I missense in the macrophage-DNASE, desoxyribonuclease I-like 3 (Dnase1l3). By in vitro expression studies, this substitution decreases this enzyme's nuclease activity against free DNA by only approximately twofold; however, the mutation has a greater effect on the capacity of media conditioned with Dnase1l3 to confer a barrier to liposomal gene transfection to HeLa cells. The 89I substitution decreases the Dnase1l3 barrier function in vitro by eightfold (P < 0.01). In splenocytes and BM-derived macrophages of SLE mice, while cellular Dnase1l3 levels are induced relative to C57BL/6 (control) mice, levels of FD-nuclease activity are similar. Finally, media conditioned by MRL and NZB/W F1 macrophages, relative to control, contains a weak interferon-gamma (IFN-gamma) inducible Dnase1l3-associated barrier to transfection. This barrier function is hypothesized to reflect the inability of SLE mice to degrade membrane-enveloped DNA-associated antigens, such as apoptotic bodies, which are predicted to stimulate the characteristic autoimmunity of SLE. Our results for these two generally independent models strongly suggest that Dnase1l3 deficiency increases the susceptibility of these mice to polygenic SLE.

Animals↗

Polyandry in Lepidoptera: a heritable trait in Spodoptera exigua Hübner.

The genetic basis as well as the mode of inheritance of polyandry in Spodoptera exigua Hübner was studied in the laboratory by using a simple divergent selection experiment followed by F1 reciprocal crosses, F2 and backcrosses. There was an effective response to artificial selection for high (H line) and low (L line) female mating frequency with significant separation of the lines by the second generation of selection. The mean female mating frequency in the parental generation (1.57 matings per female) reached plateaus of 2.50 and 1.25 matings per female in the H and L lines, respectively, after six generations of selection. Selection response becomes saturated at about 90% and 25% levels of polyandry (percentage females re-mating) in the H and L lines, respectively, and consequently mono- and polyandric pure strains were not obtained. Polyandry levels in offspring from the H and L lines and their hybrids in F1, F2 and backcrosses consistently indicate that female mating frequency was more or less proportional to the relative amounts of genes derived from the H and L lines. Such a clear pattern of hybrid responses, together with the gradual selective changes under artificial selection, suggests the involvement of a polygenic system. Female mating frequencies from progeny of the two reciprocal F1 crosses were not significantly different, which suggest that the trait was autosomally inherited. Moreover, female mating frequency of F1 (pooled) progeny was not significantly different from the mid-parental value, which suggest no dominance. The computation of the Cavalli's joint scaling test consistently confirmed these results yielding values of d = 0.51 +/- 0.10 and h = 0.12 +/- 0.21. The broad sense heritability estimate was H2 = 0.73. It is concluded that polyandry in S. exigua is a polygenic, autosomal heritable trait and that additive genetic variance is available for selection for female mating frequency. The implications of the genetic basis of polyandry are briefly discussed in the context of current theories about this crucial insect mating system.

Animals↗

Ethics and genetic selection in purebred dogs.

There is an ongoing revolution in medicine that is changing the way that veterinarians will be counselling clients regarding inherited disorders. Clinical applications will emerge rapidly in veterinary medicine as we obtain new information from canine and comparative genome projects (Meyers-Wallen 2001: Relevance of the canine genome project to veterinary medical practice. International Veterinary Information Service, New York). The canine genome project is described by three events: mapping markers on canine chromosomes, mapping gene locations on canine chromosomes (Breen et al. 2001: Genome Res. 11, 1784-1795), and obtaining the nucleotide sequence of the entire canine genome. Information from such research has provided a few DNA tests for single gene mutations [Aguirre 2000: DNA testing for inherited canine diseases. In: Bonagura, J (ed), Current Veterinary Therapy XIII. Philadelphia WB Saunders Co, 909-913]. Eventually it will lead to testing of thousands of genes at a time and production of DNA profiles on individual animals. The DNA profile of each dog could be screened for all known genetic disease and will be useful in counselling breeders. As part of the pre-breeding examination, DNA profiles of prospective parents could be compared, and the probability of offspring being affected with genetic disorders or inheriting desirable traits could be calculated. Once we can examine thousands of genes of individuals easily, we have powerful tools to reduce the frequency of, or eliminate, deleterious genes from a population. When we understand polygenic inheritance, we can potentially eliminate whole groups of deleterious genes from populations. The effect of such selection on a widespread basis within a breed could rapidly improve health within a few generations. However, until we have enough information on gene interaction, we will not know whether some of these genes have other functions that we wish to retain. And, other population effects should not be ignored. At least initially it may be best to use this new genetic information to avoid mating combinations that we know will produce affected animals, rather than to eliminate whole groups of genes from a population. This is particularly important for breeds with small gene pools, where it is difficult to maintain genetic diversity. Finally, we will eventually have enough information about canine gene function to select for specific genes encoding desirable traits and increase their frequencies in a population. This is similar to breeding practices that have been applied to animals for hundreds of years. The difference is that we will have a large pool of objective data that we can use rapidly on many individuals at a time. This has great potential to improve the health of the dog population as a whole. However, if we or our breeder clients make an error, we can inadvertently cause harm through massive, rapid selection. Therefore, we should probably not be advising clients on polygenic traits or recommend large scale changes in gene frequencies in populations until much more knowledge of gene interaction is obtained. By then it is likely that computer modelling will be available to predict the effect of changing one or several gene frequencies in a dog population over time. And as new mutations are likely to arise in the future, these tools will be needed indefinitely to detect, treat and eliminate genetic disorders from dog populations. Information available from genetic research will only be useful in improving canine health if veterinarians have the knowledge and skills to use it ethically and responsibly. There is not only a great potential to improve overall canine health through genetic selection, but also the potential to do harm if we fail to maintain genetic diversity. Our profession must be in a position to correctly advise clients on the application of this information to individual dogs as well as to populations of dogs, and particularly purebred dogs.

Animals↗

Evidence for a major gene accounting for mild elevation in LDL cholesterol: the NHLBI Family Heart Study.

Studies of rare Mendelian disorders of low density lipoprotein cholesterol (LDL-C) metabolism have identified specific genetic mutations in the LDL receptor and apolipoprotein B. Although these rare mutations account for a small proportion of LDL-C variation, twin and adoption studies indicate that at least 50% of the overall LDL-C observed variation is genetically determined. In a heterogeneous sample of 3227 subjects from the NHLBI Family Heart Study collected from four US centres, we find evidence for a common major gene accounting for mild elevations (1.25 standard deviations) in LDL-C. The analysis favored a recessive model with a frequency of 0.52 for the gene influencing elevated LDL-C, phenotypic means of 113 mg/dl for the normal genotypes and 146 mg/dl for the abnormal genotype, and a significant polygenic heritability. This statistically-inferred major gene accounted for 24% of the variation in LDL-C, with polygenes accounting for another 28% of the variation. Using parameters for major gene transmission estimated in the segregation analysis, LDL-C showed no linkage to the LDL receptor gene (LDLR), nor to the apolipoprotein E gene (APOE), nor to the cholesterol 7alpha-hydroxylase gene (CYP7A1), indicating the major gene effect influencing mild elevation in LDL-C is not explained by any of these candidate loci.

Adult↗

Possible association of the human KCNE1 (minK) gene and QT interval in healthy subjects: evidence from association and linkage analyses in Israeli families.

QT interval prolongation is associated with increased risk of sudden and non-sudden cardiac death. Potassium channel gene variants are associated with inherited long QT syndromes. Using linkage and association analyses, we investigated whether variants in the potassium channel subunit KCNE1 are associated with QTc intervals in an unselected population sample of 80 kindreds living in kibbutz settlements in Israel. Variance-component linkage analysis revealed weak evidence of linkage of KCNE1 polymorphisms with QTc intervals. Family-based association analysis showed a significant association between the G38S polymorphism and QTc interval. Further quantitative trait association analysis demonstrated a significant residual heritability component (h(2)= 0.33), and that the effect of the G38S variant allele is modified by gender. Estimated maximum likelihood parameters from these models indicated that male gender, age, hypertension, diabetes, hypercholesterolemia, fibrinogen and BMI were positively associated with QTc interval; level of education and cigarette smoking showed an inverse association. Both erythrocyte membrane n-6 and n-3 fatty acids showed a significant inverse association with QTc interval. While more than 15.8% of QTc variability was contributed by covariates, another 4.7% was explained by dietary factors, the G38S polymorphism explained 2.2%, and approximately 36% was explained by polygenes. An in silico analysis showed also that the novel V80 SNP, another KCNE1 synonymous variant, abolishes the recognition for a splicing enhancer, which may lead to an increased effect of the G38S mutation. These results demonstrate that, in addition to polygenic background, dietary factors and other covariables, the KCNE1 G38S variant is involved in determining QTc levels in this population-based sample of families.

Adult↗

[Sex-specific depression risk].

Major depression displays significant heritability, and its genetic background has been extensively explored by genome-wide association studies. On the whole, these results indicate a highly polygenic landscape with significant sex-linked differences revealing a higher and more polygenic genetic influence in females than in males.

Humans↗

Mapping loci causing susceptibility to anal atresia in pigs, using a resource pedigree.

BACKGROUND/PURPOSE: Very little information on the genetic background for anal atresia (anorectal malformations; AA) in humans has been described. A strikingly similar natural anomaly occurs in piglets. The authors have used this as an animal model for various research purposes. The affected piglets were treated surgically soon after birth, raised, and used for breeding. The authors have generated a resource pedigree segregating for this naturally occurring nonsyndromal AA and describe here the first attempt to map susceptibility loci by marker analysis. METHODS: A pig pedigree with a high incidence of AA has been established by selective breeding using 3 probands from the Landrace and Large White breeds. It has been maintained by intrafamilial crossing for more than 15 years. A backcross pedigree has now been generated by mating 4 AA females to an unaffected male from the Chinese Meishan breed. F(1) animals were both intercrossed and backcrossed to affected AA animals. A genome scan was carried out using the F(0), F(1), and affected backcross progeny. Ninety-two microsatellite loci were analyzed using fluorescently labelled primers and an ABI377 sequencer. Linkage analysis was done with the CRI-MAP 2.4 software. RESULTS: Crossing affected parents increased the incidence of abnormalities from 30% to 61.9%. All 39 F(1) pigs were unaffected. In the F(1) intercross, only 3 of 205 (1.5%) were affected, whereas 42 of 523 (8.0%) backcross progeny were affected. The marked difference in the incidence of affected progeny in the F(1) intercross and in the backcross indicates the presence of multiple genes causing AA. The genome scan showed suggestive evidence for the presence of a susceptibility locus on pig chromosome 15 (lod score 2.7 for a pig microsatellite marker SW2072). CONCLUSIONS: The results clearly show that AA has a oligogenic or polygenic background. The genome scan showed one suggestive locus causing AA on pig chromosome 15. The long-term goal is to identify causative genes for this malformation by comparative positional candidate cloning. This study provides, for the first time, linkage mapping of nonsyndromal anorectal malformations with a polygenic inheritance.

Animals↗

EEG longitudinal studies in febrile convulsions. Genetic aspects.

It was the purpose of the study to obtain viewpoints on the genetics of febrile convulsions and their relationship to epilepsy by EEG long term follow up. 89 children with febrile convulsions could be followed up to the age of 11 to 13 years (in total 1046 EEG records). The study was concentrated on genetically determined EEG patterns: bilaterally synchronous spikes and waves, photosensitivity and 4-7 cps rhythms. The statistical evaluation was based on standards derived from known strict age dependence of the different patterns. Theta rhythms were found in 54%, spikes and waves of the resting record in 49% and photosensitivity in 42%. In total, genetically determined EEG patterns were found in 81% of the cases which were sufficiently investigated according to given standards. Spikes and waves are strongly age dependent with a maximum at the age of 5-6 years and appear very inconstantly. Theta rhythms and spikes and waves are closely correlated. Spikes and waves are a heterogeneous phenomenon. The type described here must be interpreted as a facultative symptom of the same functional anomaly which forms the basis of 4-7 cps rhythms. The possible pathophysiological basis of the pattern is discussed.--Photosensitivity is interpreted as the symptom of a genetically independent pathogenetic mechanism, which can lead to additive effects by interaction with other genetic abnormalities as well as exogenous factors.--The pathogenesis of febrile convulsions is multifactorial in the strict sense. While the exogenous pathogenetic factors are rather uniform, the genetic predisposition apparently is not. It is based on different genetic anomalies. Each of them is polygenically determined. In the individual case one or different factors can be involved. The genetic predisposition to febrile convulsions is definitely not only polygenic, but of heterogeneous nature. Finally the genetic relationship between febrile convulsions and epilepsy is discussed.

Adolescent↗

Profound defects in pancreatic beta-cell function in mice with combined heterozygous mutations in Pdx-1, Hnf-1alpha, and Hnf-3beta.

Defects in pancreatic beta-cell function contribute to the development of type 2 diabetes, a polygenic disease that is characterized by insulin resistance and compromised insulin secretion. Hepatocyte nuclear factors (HNFs) -1alpha, -3beta, -4alpha, and Pdx-1 contribute in the complex transcriptional circuits within the pancreas that are involved in beta-cell development and function. In mice, a heterozygous mutation in Pdx-1 alone, but not Hnf-1alpha(+/-), Hnf-3beta(+/-), or Hnf-4alpha(+/-), causes impaired glucose-stimulated insulin secretion in mice. To investigate the possible functional relationships between these transcription factors on beta-cell activity in vivo, we generated mice with the following combined heterozygous mutations: Pdx-1(+/-)/Hnf-1alpha(+/-), Pdx-1(+/-)/Hnf-3beta(+/-), Pdx-1(+/-)/Hnf-4alpha(+/-), Hnf-1alpha(+/-)/Hnf-4alpha(+/-), and Hnf-3beta(+/-)/Hnf-4alpha(+/-). The greatest loss in function was in combined heterozygous null alleles of Pdx-1 and Hnf-1alpha (Pdx-1(+/-)/Hnf-1alpha(+/-)), or Pdx-1 and Hnf-3beta (Pdx-1(+/-)/Hnf-3beta(+/-)). Both double mutants develop progressively impaired glucose tolerance and acquire a compromised first- and second-phase insulin secretion profile in response to glucose compared with Pdx-1(+/-) mice alone. The loss in beta-cell function in Pdx-1(+/-)/Hnf-3beta(+/-) mice was associated with decreased expression of Nkx-6.1, glucokinase (Gck), aldolase B (aldo-B), and insulin, whereas Nkx2.2, Nkx-6.1, Glut-2, Gck, aldo-B, the liver isoform of pyruvate kinase, and insulin expression was reduced in Pdx-1(+/-)/Hnf-1alpha(+/-) mice. The islet cell architecture was also abnormal in Pdx-1(+/-)/Hnf-3beta(+/-) and Pdx-1(+/-)/Hnf-1alpha(+/-) mice, with glucagon-expressing cells scattered throughout the islet, a defect that may be connected to decreased E-cadherin expression. Our data suggest that functional interactions between key islet regulatory factors play an important role in maintaining islet architecture and beta-cell function. These studies also established polygenic mouse models for investigating the mechanisms contributing to beta-cell dysfunction in diabetes.

Animals↗

Spontaneous mutation rates at enzyme loci in Drosophila melanogaster.

In a marked-inversion-balanced lethal system mutations were accumulated at a minimum pressure of natural selection on 2000 second chromosomes of Drosophila melanogaster that originated from 4 stem chromosomes. Five enzyme loci were tested: alpha-glycerol-3-phosphate dehydrogenase (EC 1.1.1.8), malate dehydrogenase (Mdh, EC 1.1.1.37), alcohol dehydrogenase (EC 1.1.1.1), hexokinase-C (Hex-C tentative name), and alpha-amylase (Amy, EC 3.2.1.1). Three band-morph mutants, one at the Mdh locus, one at the Hex-C locus, and one at the Amy locus, were detected out of 1,658,308 allele replications. In addition, 17 null mutants were found. Accepting that the number of structural genes is the same as that of bands in the salivary gland chromosomes, the total mutation rate per generation for all the structural genes in the second chromosomes is estimated to be 0.008-0.040, which is much smaller than that estimated for viability polygenes (0.12-0.17). Thus, it is speculated that most viability and other fitness polygenes are located in controlling regions outside the structural genes.

Alcohol Oxidoreductases↗

Recognition of female kin by male bees through olfactory signals.

After males of Lasioglossum zephyrum (Hymenoptera: Halictidae) have first been exposed to a conspecific female, the attractiveness of a second female diminishes with increasing genealogical relationship between the two females. The most parsimonious explanation for this is a polygenically controlled female sex pheromone. Nonrandom mating preferences may markedly affect gene flow within and between natural populations. Polygenically controlled sex pheromones probably also enhance kin recognition among females and, thus, influence the evolution of eusocial behavior in bees and wasps.

Journal Article↗

Artificial selection for a secondary sexual character in males of Drosophila silvestris from Hawaii.

Drosophila silvestris is endemic to the rain forests of Hawaii Island. In populations from the northeast side, the male foreleg tibia bears about 100 long cilia; these are used as a brush to stimulate the female during courtship. Cyclical family selection for high and low cilia number was carried out on progeny of lines started from single wild isofemales collected at a single site. Significant response in both directions was obtained; in the third generation the lines differed by a mean of 25 cilia. Despite much effort to save them, both lines died out without further advance; the low cilia number line died after five and the high cilia number line died after nine generations. The data are compatible with the view that the cilia character is polygenic and is maintained in nature by a stabilizing sexual selection that also favors a polygenic heterozygous state. Although selection in these experiments resulted in dysgenesis, such a result is not inevitable. Disorganization and reorganization of such a genetic system following a population bottleneck might be important as a predisposing condition for the emergence of a specifically novel and possibly isolating mode of courtship.

Journal Article↗

Detection of a major gene for resistance to fusiform rust disease in loblolly pine by genomic mapping.

Genomic mapping has been used to identify a region of the host genome that determines resistance to fusiform rust disease in loblolly pine where no discrete, simply inherited resistance factors had been previously found by conventional genetic analysis over four decades. A resistance locus, behaving as a single dominant gene, was mapped by association with genetic markers, even though the disease phenotype deviated from the expected Mendelian ratio. The complexity of forest pathosystems and the limitations of genetic analysis, based solely on phenotype, had led to an assumption that effective long-term disease resistance in trees should be polygenic. However, our data show that effective long-term resistance can be obtained from a single qualitative resistance gene, despite the presence of virulence in the pathogen population. Therefore, disease resistance in this endemic coevolved forest pathosystem is not exclusively polygenic. Genomic mapping now provides a powerful tool for characterizing the genetic basis of host pathogen interactions in forest trees and other undomesticated, organisms, where conventional genetic analysis often is limited or not feasible.

Chromosome Mapping↗

The inheritance of height in a Finnish population.

Although height is widely cited as the classic polygenic trait, there have been few large-scale studies of its inheritance since that of Pearson and Lee 80 years ago (Pearson and Lee 1903). Values of heritability derived in many standard genetics texts are based on those data. The data of Rissanen and Nikkila (1977) on 2869 individuals in 392 three-generation families provide an opportunity to make comparisons in a contemporary European population. We examine here height differences between regions, sexes and generations, and consider the form of the population distribution. Analysing the data within the classic polygenic framework we obtain a much higher spouse correlation in height than shown by earlier studies, a smaller heritability, and only a small effect of common-sib environment or genetic dominance deviations.

Body Height↗

Path analysis of family resemblance for cranio-facial traits in Andhra Pradesh nuclear families and twins.

Path analysis of 12 cranio-facial measurements from a sample of nuclear families and twins from Andhra Pradesh, India is used to test hypotheses about the familial transmission of these traits. For bigonial breadth and ear dimensions, the transmission from parent to child is consistent with simple autosomal polygenic inheritance, but length, breadth and circumference of the head, facial breadth and nose dimensions show evidence of transmission in excess of polygenic expectations. Additional non-transmissible resemblance of sibling pairs is not significant for any of the variables, but twin pairs do exhibit significant additional resemblance for head circumference, head length, minimum frontal breadth, bizygomatic breadth and ear dimensions. The effect of interobserver measurement differences can be detected for head breadth, minimum frontal breadth, bigonial breadth, total facial height and nose dimensions.

Adolescent↗