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Neurological Sciences : Official... Sep 2020Wilson's disease (WD) is an autosomal recessive disorder of ATP7B gene leading to impaired copper metabolism. Brain imaging, such as magnetic resonance (MR) and...
PURPOSE
Wilson's disease (WD) is an autosomal recessive disorder of ATP7B gene leading to impaired copper metabolism. Brain imaging, such as magnetic resonance (MR) and transcranial sonography (TCS) in WD patients, shows changes mostly in the basal ganglia. Heterozygotic carriers of one faulty ATP7B gene should not exhibit symptoms of WD, but one in three heterozygotes has copper metabolism abnormalities. This study examined heterozygote ATP7B mutation carriers using TCS to assess any basal ganglia changes compared with healthy controls.
METHODS
Heterozygote carriers and healthy volunteers underwent the same standard MR and TCS imaging protocols. Heterozygotes were followed for 5 years and monitored for the development of neurological symptoms.
RESULTS
The study assessed 34 heterozygotes (21 women), with mean age of 43 years (range of 18 to 74 years) and 18 healthy controls (13 women), with mean age of 47 years (range of 20 to 73 years). Bilateral lenticular nucleus (LN) hyperechogenicity was found in 25 heterozygotes, but none of the controls (p < 0.001). Bilateral substantia nigra (SN) hyperechogenicity was found in 8 heterozygotes and one control; another 3 heterozygotes had unilateral SN hyperechogenicity (p = 0.039 for the right; p = 0.176 for the left). Heterozygotes had larger SN area on both sides compared with controls (p = 0.005 right; p = 0.008 left).
CONCLUSIONS
SN and LN hyperechogenicity were more frequent in heterozygotes than in controls, probably due to copper accumulation, but it remains unknown if this predisposes to brain neurodegeneration.
Topics: Adolescent; Adult; Aged; Basal Ganglia; Female; Hepatolenticular Degeneration; Heterozygote; Humans; Middle Aged; Substantia Nigra; Ultrasonography; Ultrasonography, Doppler, Transcranial; Young Adult
PubMed: 32270360
DOI: 10.1007/s10072-020-04378-6 -
Proceedings. Biological Sciences Mar 2024Beneficial reversals of dominance reduce the costs of genetic trade-offs and can enable selection to maintain genetic variation for fitness. Beneficial dominance... (Review)
Review
Beneficial reversals of dominance reduce the costs of genetic trade-offs and can enable selection to maintain genetic variation for fitness. Beneficial dominance reversals are characterized by the beneficial allele for a given context (e.g. habitat, developmental stage, trait or sex) being dominant in that context but recessive where deleterious. This context dependence at least partially mitigates the fitness consequence of heterozygotes carrying one non-beneficial allele for their context and can result in balancing selection that maintains alternative alleles. Dominance reversals are theoretically plausible and are supported by mounting empirical evidence. Here, we highlight the importance of beneficial dominance reversals as a mechanism for the mitigation of genetic conflict and review the theory and empirical evidence for them. We identify some areas in need of further research and development and outline three methods that could facilitate the identification of antagonistic genetic variation (dominance ordination, allele-specific expression and allele-specific ATAC-Seq (assay for transposase-accessible chromatin with sequencing)). There is ample scope for the development of new empirical methods as well as reanalysis of existing data through the lens of dominance reversals. A greater focus on this topic will expand our understanding of the mechanisms that resolve genetic conflict and whether they maintain genetic variation.
Topics: Selection, Genetic; Phenotype; Heterozygote; Alleles; Genetic Variation; Models, Genetic; Genetic Fitness
PubMed: 38471544
DOI: 10.1098/rspb.2023.2816 -
BMC Genetics Aug 2008In studies where microsatellite markers are employed, it is essential that the primers designed will reliably and consistently amplify target loci. In populations... (Comparative Study)
Comparative Study
BACKGROUND
In studies where microsatellite markers are employed, it is essential that the primers designed will reliably and consistently amplify target loci. In populations conforming to Hardy-Weinberg equilibrium (HWE), screening for unreliable markers often relies on the identification of heterozygote deficiencies and subsequent departures from HWE. However, since many populations naturally deviate from HWE, such as many marine invertebrates, it can be difficult to distinguish heterozygote deficiencies resulting from unreliable markers from natural processes. Thus, studies of populations that are suspected to deviate from HWE naturally would benefit from a method to validate genotype data-sets and test the reliability of the designed primers. Levels of heterozygosity are reported for the prosobranch mollusc Hydrobia ulvae (Pennant) together with a method of genotype validation and primer assessment that utilises two primer sets for each locus. Microsatellite loci presented are the first described for the species Hydrobia ulvae; the five loci presented will be of value in further study of populations of H. ulvae.
RESULTS
We have developed a novel method of testing primer reliability in naturally heterozygote deficient populations. After the design of an initial primer set, genotyping in 48 Hydrobia ulvae specimens using a single primer set (Primer set_A) revealed heterozygote deficiency in six of the seven loci examined. Redesign of six of the primer pairs (Primer set_B), re-genotyping of the successful individuals from Primer set_A using Primer set_B, and comparison of genotypes between the two primer sets, enabled the identification of two loci (Hulv-06 & Hulv-07) that showed a high degree of discrepancy between primer sets A and B (0% & only 25% alleles matching, respectively), suggesting unreliability in these primers. The discrepancies included changes from heterozygotes to homozygotes or vice versa, and some individuals who also displayed new alleles of unexpected sizes. Of the other four loci examined (Hulv-01, Hulv-03, Hulv-04, & Hulv-05), all showed more than 95% agreement between primer sets. Hulv-01, Hulv-03, & Hulv-05 displayed similar levels of heterozygosity with both primer sets suggesting that these loci are indeed heterozygote deficient, while Hulv-08 showed no deficiency in either primer set.
CONCLUSION
The simple method described to identify unreliable markers will prove a useful technique for many population studies, and also emphasises the dangers in using a single primer set and assuming marker reliability in populations shown to naturally deviate from HWE.
Topics: Alleles; Animals; DNA Primers; Gastropoda; Gene Library; Genotype; Heterozygote; Microsatellite Repeats; Polymerase Chain Reaction
PubMed: 18713472
DOI: 10.1186/1471-2156-9-55 -
Fertility and Sterility Feb 2019
Topics: Fertility Preservation; Heterozygote; Humans; Neoplasms; Reproduction
PubMed: 30611548
DOI: 10.1016/j.fertnstert.2018.11.009 -
Journal of Evolutionary Biology Mar 2021Maintenance of genetic polymorphism remains one of the big questions of evolutionary biology, which for a long time tended to be explained by balancing selection. This...
Maintenance of genetic polymorphism remains one of the big questions of evolutionary biology, which for a long time tended to be explained by balancing selection. This explanation was later criticized, but now is again accepted as an important mechanism in evolution. Human blood group systems seem affected by balancing selection especially strongly. In this preregistered study, we focused on stable coexistence of RhD-positive and RhD-negative subjects in a population. This is an evolutionary conundrum, because carriers of the less frequent negative allele suffer from lower fecundity due to haemolytic disease of the newborn affecting RhD-positive infants born to RhD-negative women. One explanation of persisting stability of RhD polymorphism points to heterozygote advantage. Over the past decade, numerous studies demonstrated that RhD-positive subjects score better than RhD-negative homozygotes in psychomotor tests and physical health-related variables. Still, evidence of better health and performance of heterozygotes is scarce and merely indirect. We compared the physical and mental health of 2,539 subjects whose RhD genotype was estimated based on their and their parents' RhD phenotype. We confirmed that RhD-negative homozygotes fare worse in terms of physical and mental health than subjects with RhD-positive phenotype and that RhD-positive heterozygotes enjoy better health than both homozygotes. For the first time, we demonstrated that RhD-positive homozygotes might suffer from worse health than RhD-negative homozygotes. Our results strongly support the hypothesis that RhD polymorphism is maintained by heterozygote advantage and that balancing selection may have played an important role in human evolution in this context and in general.
Topics: Adult; Biological Evolution; Cross-Sectional Studies; Female; Health Status; Heterozygote; Humans; Male; Middle Aged; Polymorphism, Genetic; Rh-Hr Blood-Group System; Selection, Genetic
PubMed: 33244840
DOI: 10.1111/jeb.13745 -
Journal of Genetics Dec 2018George Shull's 1908 seminal article 'The composition of a field of maize' marked the 'exploitation of heterosis in plant breeding, surely one of genetics' greatest...
George Shull's 1908 seminal article 'The composition of a field of maize' marked the 'exploitation of heterosis in plant breeding, surely one of genetics' greatest triumphs'. Hybrid corn became a 'symbol of American agriculture' and 'the paradigm for all developments of F hybrid crop varieties and more generally breeding. But there is still no consensus on the definition of heterosis while its biological basis, causal factors and genetic mechanisms remain 'unknown', or at best 'poorly understood'. It is thus logical to reverse the usual approach from the exploitation of a mysterious heterosis to the triumph of hybrid corn and focus on what breeders and geneticists do rather than on the theoretical reasons for their success. This factual approach produces surprising results: (i) hybrid corn extends the isolation technique of autogamous cereals to the allogamous maize; (ii) a 'hybrid' is an ordinary corn plantmade reproducible by the breeder and only the breeder. It is proprietary rather than 'hybrid'; (iii) for all practical purposes, heterosis is irrelevant; (iv) Shull justified his 'hybrid' breeding method by the argument of maize 'hybrid vigour' which in 1914, he conflated under the name of heterosis with Edward East's concept of physiological stimulation due to heterozygosity; (v) hybrid corn can increase yield only once and by a small margin and (vi) the huge yield gains of the last 80 years came from mass selection, a process inconsistent with the theory of heterosis. In conclusion, the enduring success of 'hybrid' corn was achieved at the expense of farmers, common welfare and biodiversity and dovetails with the industrial agriculture requirements of crop uniformity and breeder monopoly over reproduction. This critical understanding of the paradigm of plant breeding could have important implications for breeders and geneticists.
Topics: Heterozygote; Hybrid Vigor; Phenotype; Plant Breeding; Zea mays
PubMed: 30555057
DOI: No ID Found -
Genetics Aug 1995Currently used tests of Hardy-Weinberg proportions do not take into account the nature of the alternative hypothesis, which is generally a heterozygote deficiency....
Currently used tests of Hardy-Weinberg proportions do not take into account the nature of the alternative hypothesis, which is generally a heterozygote deficiency. Different exact tests, appropriate for small sample size and large number of alleles, are proposed in this perspective, and their properties are evaluated by power comparisons. Some tests are found to be close to optimal for the detection of inbreeding or heterozygote excess, one of which is a score test closely related to Robertson and Hill's estimator of the inbreeding coefficient. This test is also easily applied to multiple samples. Such tests are not always the most appropriate if alternative hypotheses differ from those considered here.
Topics: Alleles; Crosses, Genetic; Genetics, Population; Heterozygote; Models, Genetic; Statistics as Topic
PubMed: 7498780
DOI: 10.1093/genetics/140.4.1413 -
The Turkish Journal of Pediatrics 2022Monocarboxylate transporter 1 (MCT1) deficiency (MIM #616095) is a relatively new identified cause of recurrent ketoacidosis triggered by fasting or infections. MCT1 was...
BACKGROUND
Monocarboxylate transporter 1 (MCT1) deficiency (MIM #616095) is a relatively new identified cause of recurrent ketoacidosis triggered by fasting or infections. MCT1 was first described in 2014 by van Hasselt et al. to result from both homozygous and heterozygous mutations in the SLC16A1 gene. Patients with homozygous mutations are known to have a more severe phenotype with developmental delay and epilepsy. Thirteen patients with MCT1 deficiency with ketoacidosis have been reported in the literature to date.
CASE
We describe a developmentally normal male patient with heterozygous missense variation in the SLC16A1 gene. Our patient who presented with cyclic vomiting and ketoacidosis episodes was found to have a heterozygous c.303T > G (p.Ile101Met) missense mutation.
CONCLUSIONS
It is crucial to take early preventive measures and to minimize the harmful effects of ketoacidotic episodes. MCT1 deficiency should be considered in the differential diagnosis of ketoacidosis in patients with normal SCOT and ACAT1 activities.
Topics: Heterozygote; Homozygote; Humans; Ketosis; Male; Mutation; Phenotype
PubMed: 36082648
DOI: 10.24953/turkjped.2021.4915 -
Molecular Biology and Evolution May 2022Recombination is critical both for accelerating adaptation and purging deleterious mutations. Chromosomal inversions can act as recombination modifiers that suppress...
Recombination is critical both for accelerating adaptation and purging deleterious mutations. Chromosomal inversions can act as recombination modifiers that suppress local recombination in heterozygotes and thus, under some conditions, are predicted to accumulate such mutations. In this study, we investigated patterns of recombination, transposable element abundance, and coding sequence evolution across the genomes of 1,445 individuals from three sunflower species, as well as within nine inversions segregating within species. We also analyzed the effects of inversion genotypes on 87 phenotypic traits to test for overdominance. We found significant negative correlations of long terminal repeat retrotransposon abundance and deleterious mutations with recombination rates across the genome in all three species. However, we failed to detect an increase in these features in the inversions, except for a modest increase in the proportion of stop codon mutations in several very large or rare inversions. Consistent with this finding, there was little evidence of overdominance of inversions in phenotypes that may relate to fitness. On the other hand, significantly greater load was observed for inversions in populations polymorphic for a given inversion compared to populations monomorphic for one of the arrangements, suggesting that the local state of inversion polymorphism affects deleterious load. These seemingly contradictory results can be explained by the low frequency of inversion heterozygotes in wild sunflower populations, apparently due to divergent selection and associated geographic structure. Inversions contributing to local adaptation represent ideal recombination modifiers, acting to facilitate adaptive divergence with gene flow, while largely escaping the accumulation of deleterious mutations.
Topics: Chromosome Inversion; Gene Flow; Helianthus; Heterozygote; Mutation
PubMed: 35535689
DOI: 10.1093/molbev/msac101 -
Bioinformatics (Oxford, England) Nov 2019Detection of somatic mutations from tumor and matched normal sequencing data has become among the most important analysis methods in cancer research. Some existing...
MOTIVATION
Detection of somatic mutations from tumor and matched normal sequencing data has become among the most important analysis methods in cancer research. Some existing mutation callers have focused on additional information, e.g. heterozygous single-nucleotide polymorphisms (SNPs) nearby mutation candidates or overlapping paired-end read information. However, existing methods cannot take multiple information sources into account simultaneously. Existing Bayesian hierarchical model-based methods construct two generative models, the tumor model and error model, and limited information sources have been modeled.
RESULTS
We proposed a Bayesian model integration framework named as partitioning-based model integration. In this framework, through introducing partitions for paired-end reads based on given information sources, we integrate existing generative models and utilize multiple information sources. Based on that, we constructed a novel Bayesian hierarchical model-based method named as OHVarfinDer. In both the tumor model and error model, we introduced partitions for a set of paired-end reads that cover a mutation candidate position, and applied a different generative model for each category of paired-end reads. We demonstrated that our method can utilize both heterozygous SNP information and overlapping paired-end read information effectively in simulation datasets and real datasets.
AVAILABILITY AND IMPLEMENTATION
https://github.com/takumorizo/OHVarfinDer.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Bayes Theorem; Heterozygote; High-Throughput Nucleotide Sequencing; Mutation; Polymorphism, Single Nucleotide
PubMed: 30924874
DOI: 10.1093/bioinformatics/btz233