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Genetics Jul 2022Multigene families-immunity genes or sensory receptors, for instance-are often subject to diversifying selection. Allelic diversity may be favored not only through...
Multigene families-immunity genes or sensory receptors, for instance-are often subject to diversifying selection. Allelic diversity may be favored not only through balancing or frequency-dependent selection at individual loci but also by associating different alleles in multicopy gene families. Using a combination of analytical calculations and simulations, we explored a population genetic model of epistatic selection and unequal recombination, where a trade-off exists between the benefit of allelic diversity and the cost of copy abundance. Starting from the neutral case, where we showed that gene copy number is Gamma distributed at equilibrium, we derived also the mean and shape of the limiting distribution under selection. Considering a more general model, which includes variable population size and population substructure, we explored by simulations mean fitness and some summary statistics of the copy number distribution. We determined the relative effects of selection, recombination, and demographic parameters in maintaining allelic diversity and shaping the mean fitness of a population. One way to control the variance of copy number is by lowering the rate of unequal recombination. Indeed, when encoding recombination by a rate modifier locus, we observe exactly this prediction. Finally, we analyzed the empirical copy number distribution of 3 genes in human and estimated recombination and selection parameters of our model.
Topics: Alleles; Humans; Models, Genetic; Recombination, Genetic; Selection, Genetic
PubMed: 35460227
DOI: 10.1093/genetics/iyac052 -
British Journal of Haematology Mar 2020
Topics: Adult; Alleles; Cohort Studies; Humans; Leukemia, Myeloid, Acute; Nuclear Proteins; Nucleophosmin
PubMed: 31580476
DOI: 10.1111/bjh.16240 -
Epigenetics 2016While DNA methylation is usually thought to be symmetrical across both alleles, there are some notable exceptions. Genomic imprinting and X chromosome inactivation are...
While DNA methylation is usually thought to be symmetrical across both alleles, there are some notable exceptions. Genomic imprinting and X chromosome inactivation are two well-studied sources of allele-specific methylation (ASM), but recent research has indicated a more complex pattern in which genotypic variation can be associated with allelically-skewed DNA methylation in cis. Given the known heterogeneity of DNA methylation across tissues and cell types we explored inter- and intra-individual variation in ASM across several regions of the human brain and whole blood from multiple individuals. Consistent with previous studies, we find widespread ASM with > 4% of the ∼220,000 loci interrogated showing evidence of allelically-skewed DNA methylation. We identify ASM flanking known imprinted regions, and show that ASM sites are enriched in DNase I hypersensitivity sites and often located in an extended genomic context of intermediate DNA methylation. We also detect examples of genotype-driven ASM, some of which are tissue-specific. These findings contribute to our understanding of the nature of differential DNA methylation across tissues and have important implications for genetic studies of complex disease. As a resource to the community, ASM patterns across each of the tissues studied are available in a searchable online database: http://epigenetics.essex.ac.uk/ASMBrainBlood.
Topics: Alleles; Brain; DNA Methylation; Epigenesis, Genetic; Female; Genome, Human; Genomic Imprinting; Genotype; Humans; Male; Oligonucleotide Array Sequence Analysis; Organ Specificity; Polymorphism, Single Nucleotide; Sequence Analysis, DNA
PubMed: 26786711
DOI: 10.1080/15592294.2015.1127479 -
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 Biology Aug 2023Autopolyploidy is a valuable model for studying whole-genome duplication (WGD) without hybridization, yet little is known about the genomic structural and functional...
BACKGROUND
Autopolyploidy is a valuable model for studying whole-genome duplication (WGD) without hybridization, yet little is known about the genomic structural and functional changes that occur in autopolyploids after WGD. Cyclocarya paliurus (Juglandaceae) is a natural diploid-autotetraploid species. We generated an allele-aware autotetraploid genome, a chimeric chromosome-level diploid genome, and whole-genome resequencing data for 106 autotetraploid individuals at an average depth of 60 × per individual, along with 12 diploid individuals at an average depth of 90 × per individual.
RESULTS
Autotetraploid C. paliurus had 64 chromosomes clustered into 16 homologous groups, and the majority of homologous chromosomes demonstrated similar chromosome length, gene numbers, and expression. The regions of synteny, structural variation and nonalignment to the diploid genome accounted for 81.3%, 8.8% and 9.9% of the autotetraploid genome, respectively. Our analyses identified 20,626 genes (69.18%) with four alleles and 9191 genes (30.82%) with one, two, or three alleles, suggesting post-polyploid allelic loss. Genes with allelic loss were found to occur more often in proximity to or within structural variations and exhibited a marked overlap with transposable elements. Additionally, such genes showed a reduced tendency to interact with other genes. We also found 102 genes with more than four copies in the autotetraploid genome, and their expression levels were significantly higher than their diploid counterparts. These genes were enriched in enzymes involved in stress response and plant defense, potentially contributing to the evolutionary success of autotetraploids. Our population genomic analyses suggested a single origin of autotetraploids and recent divergence (~ 0.57 Mya) from diploids, with minimal interploidy admixture.
CONCLUSIONS
Our results indicate the potential for genomic and functional reorganization, which may contribute to evolutionary success in autotetraploid C. paliurus.
Topics: Humans; Alleles; Tetraploidy; Gene Duplication; Polyploidy; Genomics
PubMed: 37553642
DOI: 10.1186/s12915-023-01668-1 -
Heredity Jan 2019The transition from outcrossing to selfing through the breakdown of distyly to homostyly has occurred repeatedly among families of flowering plants. Homostyles can...
The transition from outcrossing to selfing through the breakdown of distyly to homostyly has occurred repeatedly among families of flowering plants. Homostyles can originate by major gene changes at the S-locus linkage group, or by unlinked polygenic modifiers. Here, we investigate the inheritance of distyly and homostyly in Primula oreodoxa, a subalpine herb endemic to Sichuan, China. Controlled self- and cross-pollinations confirmed that P. oreodoxa unlike most heterostylous species is fully self-compatible. Segregation patterns indicated that the inheritance of distyly is governed by a single Mendelian locus with the short-styled morph carrying at least one dominant S-allele (S-) and long-styled plants homozygous recessive (ss). Crossing data were consistent with a model in which homostyly results from genetic changes at the distylous linkage group, with the homostylous allele (S) dominant to the long-styled allele (s), but recessive to the short-styled allele (S). Progeny tests of open-pollinated seed families revealed high rates of intermorph mating in the L-morph but considerable selfing and possibly intramorph mating in the S-morph and in homostyles. S-morph plants homozygous at the S-locus (SS) occurred in several populations but may experience viability selection. The crossing data from distylous and homostylous plants are consistent with either recombination at the S-locus governing distyly, or mutation at gene(s) controlling sex-organ height; both models predict the same patterns of segregation. Recent studies on the molecular genetics of distyly in Primula demonstrating the hemizygous nature of genes at the S-locus make it more likely that homostyles have resulted from mutation rather than recombination.
Topics: Alleles; Crosses, Genetic; Genetic Linkage; Homozygote; Mutation; Pollen; Pollination; Primula; Reproduction
PubMed: 29728676
DOI: 10.1038/s41437-018-0081-2 -
Molecular Biology and Evolution Jan 2021The detection of introgression from genomic data is transforming our view of species and the origins of adaptive variation. Among the most widely used approaches to...
The detection of introgression from genomic data is transforming our view of species and the origins of adaptive variation. Among the most widely used approaches to detect introgression is the so-called ABBA-BABA test or D-statistic, which identifies excess allele sharing between nonsister taxa. Part of the appeal of D is its simplicity, but this also limits its informativeness, particularly about the timing and direction of introgression. Here we present a simple extension, D frequency spectrum or DFS, in which D is partitioned according to the frequencies of derived alleles. We use simulations over a large parameter space to show how DFS carries information about various factors. In particular, recent introgression reliably leads to a peak in DFS among low-frequency derived alleles, whereas violation of model assumptions can lead to a lack of signal at low frequencies. We also reanalyze published empirical data from six different animal and plant taxa, and interpret the results in the light of our simulations, showing how DFS provides novel insights. We currently see DFS as a descriptive tool that will augment both simple and sophisticated tests for introgression, but in the future it may be usefully incorporated into probabilistic inference frameworks.
Topics: Alleles; Gene Flow; Gene Frequency; Genetic Introgression; Genetic Techniques
PubMed: 32941617
DOI: 10.1093/molbev/msaa239 -
European Review For Medical and... Jun 2022In animal models and humans, mutations in voltage-dependent calcium channel gamma-2 subunit gene (CACNG2) have been associated with neuronal hyperexcitability, including...
OBJECTIVE
In animal models and humans, mutations in voltage-dependent calcium channel gamma-2 subunit gene (CACNG2) have been associated with neuronal hyperexcitability, including neuropathic pain. The objective of this study was to determine the allelic and genotypic frequencies of CACNG2 polymorphisms (rs4820242, rs2284015 and rs2284017) and their association with the risk of chronic peripheral neuropathic pain (CPNP) in the Mexican population.
PATIENTS AND METHODS
Single nucleotide polymorphisms (SNPs) were determined by real-time PCR, and allelic and genotypic frequencies were compared between healthy Mexican subjects and CPNP patients. The risk of association of CACNG2 SNPs with the presence of CPNP and its characteristics was evaluated.
RESULTS
The allele G (OR 2.08, p = 0.01) of rs2284015 was observed as a risk factor for developing CPNP. The allele A of rs4820442 showed a risk of association with a history of surgery (OR 3.92, p = 0.04), radiculopathy (OR 4.29, p = 0.0001), bilateral presentation of pain (OR 3.15, p = 0.003), and neuropraxia (OR 0.36, p = 0.01). The allele C of rs2284015 was associated with an increased risk of burning and allodynia. In the analysis of the association of genotype frequencies and inheritance patterns, as well as in the analysis of interaction with sex, a modification of risk was observed.
CONCLUSIONS
The allele G of rs2284015 and the AGC haplotype of CACNG2 rs4820242, rs2284015 and rs2284017, regardless of sex and etiology could contribute to the risk of CPNP. Certain alleles and genotypes could constitute severity markers in CPNP with sex-biased effects; however, further studies are required to confirm these observations.
Topics: Alleles; Calcium Channels; Genotype; Haplotypes; Humans; Neuralgia; Polymorphism, Single Nucleotide
PubMed: 35776036
DOI: 10.26355/eurrev_202206_29074 -
The Turkish Journal of Pediatrics 2018Gümüş E, Aras BD, Çilingir O, Yarar C, Çarman KB, Laçiner-Gürlevik S, Koçak O, Artan S. Apolipoprotein E allelic variants and cerebral palsy. Turk J Pediatr...
Gümüş E, Aras BD, Çilingir O, Yarar C, Çarman KB, Laçiner-Gürlevik S, Koçak O, Artan S. Apolipoprotein E allelic variants and cerebral palsy. Turk J Pediatr 2018; 60: 361-371. Cerebral palsy (CP) is the most frequent cause of mobility restriction and posture disturbance in childhood. Against the complexity in disease etiology, genetic factors, including Apolipoprotein E allelic distribution in this patient population, are worthy targets for investigation. ApoE is a lipoprotein of central nervous system encoded by ApoE gene with its 3 main co-dominant alleles, 2, 3 and 4. We aimed to evaluate the allelic frequencies of ApoE gene and its association with coexisting clinical entities such as vision and hearing impairment, cognitive problems, seizures and MRI findings in a pediatric patient population native to middle Anatolian region. Seventy-eight children with CP and 60 healthy controls were genotyped. Genotypic variations along with coexisting clinical conditions and CP-related medical findings were compared between the patient and control groups. The Denver Developmental Screening Test for all, the Wechsler Intelligence Scale for Children-IV (short form WISC-IV; Turkish version) for the patients > 6y and the Stanford-Binet Intelligence Scale (SB-5) for those who aged 2-6 years old were employed to evaluate cognitive and mental abilities of the patients. ApoE 2 and 4 alleles were more frequent in the patient group (p < 0.05), whereas ApoE 3 allele was more frequent in the healthy controls. ApoE 2/4 genotype has been determined 29% in the case group, but none in healthy control group. In the patient group with apolipoprotein 4 or 2 alleles, the rate of emergency cesarean section was found being significantly higher than the group with 3 allele. Brain MRI findings were not significantly different among ApoE allelic variants within the patient group. Our data show that the ApoE alleles may be effective in the development of cerebral palsy and may be associated with some clinical manifestations in those patients.
Topics: Alleles; Apolipoproteins E; Cerebral Palsy; Child; Child, Preschool; Female; Gene Frequency; Genotype; Humans; Magnetic Resonance Imaging; Male; Pregnancy; Turkey
PubMed: 30859759
DOI: 10.24953/turkjped.2018.04.002 -
Genome Research Jun 2014Though sequence differences between alleles are often limited to a few polymorphisms, these differences can cause large and widespread allelic variation at the...
Though sequence differences between alleles are often limited to a few polymorphisms, these differences can cause large and widespread allelic variation at the expression level. Such allele-specific expression (ASE) has been extensively explored at the level of transcription but not translation. Here we measured ASE in the diploid yeast Candida albicans at both the transcriptional and translational levels using RNA-seq and ribosome profiling, respectively. Since C. albicans is an obligate diploid, our analysis isolates ASE arising from cis elements in a natural, nonhybrid organism, where allelic effects reflect evolutionary forces. Importantly, we find that ASE arising from translation is of a similar magnitude as transcriptional ASE, both in terms of the number of genes affected and the magnitude of the bias. We further observe coordination between ASE at the levels of transcription and translation for single genes. Specifically, reinforcing relationships--where transcription and translation favor the same allele--are more frequent than expected by chance, consistent with selective pressure tuning ASE at multiple regulatory steps. Finally, we parameterize alleles based on a range of properties and find that SNP location and predicted mRNA-structure stability are associated with translational ASE in cis. Since this analysis probes more than 4000 allelic pairs spanning a broad range of variations, our data provide a genome-wide view into the relative impact of cis elements that regulate translation.
Topics: Alleles; Candida albicans; Gene Expression Regulation, Fungal; Genome, Fungal; Polymorphism, Single Nucleotide; Protein Biosynthesis; RNA Processing, Post-Transcriptional; Transcription, Genetic
PubMed: 24732588
DOI: 10.1101/gr.166322.113