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Nature Communications Sep 2023An important challenge in genetics, evolution and biotechnology is to understand and predict how mutations combine to alter phenotypes, including molecular activities,...
An important challenge in genetics, evolution and biotechnology is to understand and predict how mutations combine to alter phenotypes, including molecular activities, fitness and disease. In diploids, mutations in a gene can combine on the same chromosome or on different chromosomes as a "heteroallelic combination". However, a direct comparison of the extent, sign, and stability of the genetic interactions between variants within and between alleles is lacking. Here we use thermodynamic models of protein folding and ligand-binding to show that interactions between mutations within and between alleles are expected in even very simple biophysical systems. Protein folding alone generates within-allele interactions and a single molecular interaction is sufficient to cause between-allele interactions and dominance. These interactions change differently, quantitatively and qualitatively as a system becomes more complex. Altering the concentration of a ligand can, for example, switch alleles from dominant to recessive. Our results show that intra-molecular epistasis and dominance should be widely expected in even the simplest biological systems but also reinforce the view that they are plastic system properties and so a formidable challenge to predict. Accurate prediction of both intra-molecular epistasis and dominance will require either detailed mechanistic understanding and experimental parameterization or brute-force measurement and learning.
Topics: Alleles; Epistasis, Genetic; Ligands; Protein Folding; Biophysics
PubMed: 37689712
DOI: 10.1038/s41467-023-41188-8 -
Genome Biology Mar 2023There is widespread interest in the three-dimensional chromatin conformation of the genome and its impact on gene expression. However, these studies frequently do not...
BACKGROUND
There is widespread interest in the three-dimensional chromatin conformation of the genome and its impact on gene expression. However, these studies frequently do not consider parent-of-origin differences, such as genomic imprinting, which result in monoallelic expression. In addition, genome-wide allele-specific chromatin conformation associations have not been extensively explored. There are few accessible bioinformatic workflows for investigating allelic conformation differences and these require pre-phased haplotypes which are not widely available.
RESULTS
We developed a bioinformatic pipeline, "HiCFlow," that performs haplotype assembly and visualization of parental chromatin architecture. We benchmarked the pipeline using prototype haplotype phased Hi-C data from GM12878 cells at three disease-associated imprinted gene clusters. Using Region Capture Hi-C and Hi-C data from human cell lines (1-7HB2, IMR-90, and H1-hESCs), we can robustly identify the known stable allele-specific interactions at the IGF2-H19 locus. Other imprinted loci (DLK1 and SNRPN) are more variable and there is no "canonical imprinted 3D structure," but we could detect allele-specific differences in A/B compartmentalization. Genome-wide, when topologically associating domains (TADs) are unbiasedly ranked according to their allele-specific contact frequencies, a set of allele-specific TADs could be defined. These occur in genomic regions of high sequence variation. In addition to imprinted genes, allele-specific TADs are also enriched for allele-specific expressed genes. We find loci that have not previously been identified as allele-specific expressed genes such as the bitter taste receptors (TAS2Rs).
CONCLUSIONS
This study highlights the widespread differences in chromatin conformation between heterozygous loci and provides a new framework for understanding allele-specific expressed genes.
Topics: Humans; Alleles; Chromatin; Genome, Human; Multigene Family; Genomic Imprinting
PubMed: 36869353
DOI: 10.1186/s13059-023-02876-2 -
PloS One 2022Sweet corn has become a popular food worldwide. It possesses six-times more sugar than field corn due to the presence of recessive shrunken2 (sh2) gene. Despite...
Sweet corn has become a popular food worldwide. It possesses six-times more sugar than field corn due to the presence of recessive shrunken2 (sh2) gene. Despite availability of diverse sweet corn germplasm, comprehensive characterization of sh2 has not been undertaken so far. Here, entire Sh2 gene (7320 bp) among five field corn-(Sh2Sh2) and six sweet corn-(sh2sh2) inbreds was sequenced. A total of 686 SNPs and 372 InDels were identified, of which three SNPs differentiated the wild-(Sh2) and mutant-(sh2) allele. Ten InDel markers were developed to assess sh2 gene-based diversity among 23 sweet corn and 25 field corn lines. Twenty-five alleles and 47 haplotypes of sh2 were identified among 48 inbreds. Among markers, MGU-InDel-2, MGU-InDel-3, MGU-InDel-5 and MGU-InDel-8 had PIC>0.5. Major allele frequency varied from 0.458-0.958. The gene sequence of these maize inbreds was compared with 25 orthologues of monocots. Sh2 gene possessed 15-18 exons with 6-225bp among maize, while it was 6-21 exons with 30-441bp among orthologues. While intron length across maize genotypes varied between 67-2069bp, the same among orthologues was 57-2713 bp. Sh2-encoded AGPase domain was more conserved than NTP transferase domain. Nucleotide and protein sequences of sh2 in maize and orthologues revealed that rice orthologue was closer to maize than other monocots. The study also provided details of motifs and domains present in sh2 gene, physicochemical properties and secondary structure of SH2 protein in maize inbreds and orthologues. This study reports detailed characterization and diversity analysis in sh2 gene of maize and related orthologues in various monocots.
Topics: Alleles; Nucleotides; Sugars; Transferases; Zea mays
PubMed: 36136965
DOI: 10.1371/journal.pone.0274732 -
Tropical Animal Health and Production Dec 2022The present study has analyzed the allelic-specific expression in Purebred Sistani (Bos Indicus) and their crossbreed with Holstein, Simmental, and Montbeliarde breeds...
The present study has analyzed the allelic-specific expression in Purebred Sistani (Bos Indicus) and their crossbreed with Holstein, Simmental, and Montbeliarde breeds (Bos Taurus). The blood samples were taken from the caudal vein of purebred Sistani cows and crossbreed Sistani's with Holstein, Simental, and Montbeliarde (4 treatments). We discovered 152,496 (Purebred Sistani), 134,285 (Sistani × Simmental), 163,362 (Sistani × Montbeliarde), and 177,042 (Sistani × Holstein) SNPs on the assembled transcriptomes. In the Purebred Sistani, 8295 (5%), Sistani × Holstein crossbreed 11,900 (7%), Sistani × Simmental crossbreed 13,187 (10%), and Sistani × Montbeliarde crossbreed 16,666 (10%) number of SNPs were identified as ASE-SNPs. In the present study, 12 SNPs types identify, of which four were transition and eight were transversion. The most common SNPs were transition types. These SNPs were present in purebred Sistani 71.84%, Sistani × Holstein crossbreed 72.65%, Sistani × Simmental crossbreed 72.60%, and Sistani × Montbeliarde crossbreed 71.94%. Ontology analysis of the expressed genes in these cows revealed the involvement of these genes in different Biological classifications. Conducting such studies in parts of the world, such as the Sistan region, where it is not possible to record accurate records of cows, is a suitable and economical method for identifying genes with different expressions.
Topics: Female; Cattle; Animals; Alleles; Hybridization, Genetic
PubMed: 36525098
DOI: 10.1007/s11250-022-03422-1 -
Psychiatry Research Mar 2017Serotonergic neurotransmission dysfunctions have been well documented in patients with suicidal behaviour. We investigated monoamine oxidase A (MAOA: rs2064070, rs6323,...
Serotonergic neurotransmission dysfunctions have been well documented in patients with suicidal behaviour. We investigated monoamine oxidase A (MAOA: rs2064070, rs6323, rs909525) and B (MAOB: rs1799836, rs2311013, rs2205655) genetic modulation of personality traits (Temperament and Character Inventory, TCI) as endophenotype for suicidal behaviour. 108 suicide attempters and 286 healthy controls of German origin were screened. Among females, allelic analyses revealed associations between MAOA rs6323 A allele and higher Harm Avoidance in suicide attempters and MAOB rs2205655 A allele and higher Cooperativeness scores in healthy controls. Among males, MAOA rs909525 A allele was associated with higher Reward Dependence in suicide attempters. Multivariate analyses controlling for age and educational level mainly confirmed results. Case-control analyses in this subsample do not differ from our previously reported one. Despite of the small sample size, a possible involvement of these genes in the modulation of personality traits closely related to suicidal behaviour cannot be excluded.
Topics: Adult; Alleles; Endophenotypes; Female; Humans; Male; Middle Aged; Monoamine Oxidase; Personality; Personality Inventory; Polymorphism, Single Nucleotide; Suicide, Attempted
PubMed: 28119174
DOI: 10.1016/j.psychres.2017.01.020 -
Genes and Immunity Apr 2022The IMGT database profiles the TR germline alleles for all four TR loci (TRA, TRB, TRG and TRD), however, it does not comprise of the information regarding population...
The IMGT database profiles the TR germline alleles for all four TR loci (TRA, TRB, TRG and TRD), however, it does not comprise of the information regarding population specificity and allelic frequencies of these germline alleles. The specificity of allelic variants to different human populations can, however, be a rich source of information when studying the genetic basis of population-specific immune responses in disease and in vaccination. Therefore, we meticulously identified true germline alleles enriched with complete TR allele sequences and their frequencies across 26 different human populations, profiled by "1000 Genomes data". We identified 205 TRAV, 249 TRBV, 16 TRGV and 5 TRDV germline alleles supported by at least four haplotypes. The diversity of germline allelic variants in the TR loci is the highest in Africans, while the majority of the Non-African alleles are specific to the Asian populations, suggesting a diverse profile of TR germline alleles in different human populations. Interestingly, the alleles in the IMGT database are frequent and common across all five super-populations. We believe that this new set of germline TR sequences represents a valuable new resource which we have made available through the new population-matched TR (pmTR) database, accessible via https://pmtrig.lumc.nl/ .
Topics: Alleles; Germ Cells; Humans; Receptors, Antigen, T-Cell
PubMed: 35436998
DOI: 10.1038/s41435-022-00171-x -
Forensic Science International. Genetics Nov 2019Peaks in an electropherogram could represent alleles, stutter product, or a combination of allele and stutter. Continuous probabilistic genotyping (PG) systems model the...
Peaks in an electropherogram could represent alleles, stutter product, or a combination of allele and stutter. Continuous probabilistic genotyping (PG) systems model the heights of peaks in an additive manner: for a shared or composite peak, PG models assume that the peak height is the sum of the allelic component and the stutter component. In this work we examine the assumption that the heights of overlapping alleles from a minor contributor and stutter peaks from a major contributor are additive. Any peak below the analytical threshold is considered unobserved; hence, in any dataset and particularly in low-template DNA profiles, some or many peaks may be unobserved or missing. Using simulation and empirical data, we show that an additive model can explain the heights of overlapping alleles from a minor contributor and stutter peaks from a major contributor as long as missing data are carefully considered. We use a naive method of imputation for the missing data which appears to perform adequately in this case. If missing data are ignored then the sum of stutter and allelic peaks is expected to be an overestimate of the average height of the composite peaks, as was observed in this study.
Topics: Alleles; DNA; DNA Fingerprinting; Electrophoresis; Humans; Models, Genetic; Models, Statistical
PubMed: 31586815
DOI: 10.1016/j.fsigen.2019.102166 -
Methods in Molecular Biology (Clifton,... 2023Research on the evolutionary fate of duplicated genes in recurrent polyploids is scarce due to the difficulties in disentangling the different homeologs and alleles of...
Research on the evolutionary fate of duplicated genes in recurrent polyploids is scarce due to the difficulties in disentangling the different homeologs and alleles of duplicated genes. This chapter describes the detailed procedures to identify different homeologs and alleles of duplicated genes, to analyze their molecular characteristics, and to reveal their functional divergence by gene editing with CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9). Using the gene editing approach, we efficiently constructed multiple knockout mutant lines with single or simultaneously disrupted different homeologs or alleles in a recurrent polyploid fish, demonstrating its usability for targeting and mutating multiple divergent homeologs and alleles in recurrent duplicated genomes.
Topics: Animals; Alleles; Biological Evolution; Craniocerebral Trauma; Gene Editing; Polyploidy
PubMed: 36720830
DOI: 10.1007/978-1-0716-2561-3_26 -
American Journal of Botany Mar 2018Untapped information about allele diversity within populations and individuals (i.e., heterozygosity) could improve phylogenetic resolution and accuracy. Many...
PREMISE OF THE STUDY
Untapped information about allele diversity within populations and individuals (i.e., heterozygosity) could improve phylogenetic resolution and accuracy. Many phylogenetic reconstructions ignore heterozygosity because it is difficult to assemble allele sequences and combine allele data across unlinked loci, and it is unclear how reconstruction methods accommodate variable sequences. We review the common methods of including heterozygosity in phylogenetic studies and present a novel method for assembling allele sequences from target-enriched Illumina sequencing libraries.
METHODS
We performed supermatrix phylogeny reconstruction and species tree estimation of Artocarpus based on three methods of accounting for heterozygous sequences: a consensus method based on de novo sequence assembly, the use of ambiguity characters, and a novel method for incorporating read information to phase alleles. We characterize the extent to which highly heterozygous sequences impeded phylogeny reconstruction and determine whether the use of allele sequences improves phylogenetic resolution or decreases topological uncertainty.
KEY RESULTS
We show here that it is possible to infer phased alleles from target-enriched Illumina libraries. We find that highly heterozygous sequences do not contribute disproportionately to poor phylogenetic resolution and that the use of allele sequences for phylogeny reconstruction does not have a clear effect on phylogenetic resolution or topological consistency.
CONCLUSIONS
We provide a framework for inferring phased alleles from target enrichment data and for assessing the contribution of allelic diversity to phylogenetic reconstruction. In our data set, the impact of allele phasing on phylogeny is minimal compared to the impact of using phylogenetic reconstruction methods that account for gene tree incongruence.
Topics: Alleles; Artocarpus; Base Sequence; Cell Nucleus; DNA, Plant; Gene Library; Genes, Plant; Genetic Loci; Genomics; Heterozygote; Models, Genetic; Phylogeny; Species Specificity
PubMed: 29729187
DOI: 10.1002/ajb2.1068 -
Journal of the Formosan Medical... Apr 2020ABO blood system has many subgroups. In A group, A phenotype and A phenotype are more common, and A is caused by deletion or substitution in A allele (ABO*A1.01).
BACKGROUND
ABO blood system has many subgroups. In A group, A phenotype and A phenotype are more common, and A is caused by deletion or substitution in A allele (ABO*A1.01).
METHODS
Based on standard ABO serological test, the subject was identified as A phenotype. Direct sequencing and ABO gene cloning were performed to analyze the allele.
RESULTS
The subject had one A allele (ABO*A1.02) and one O allele. The haplotype sequencing analysis of each allelic clone demonstrated that allele 1 was A (ABO*A1.02) allele with nt543 variation (543 G > C) and allele 2 was O allele (ABO*O.01.02) with nt261 deletion and nt220 variation.
CONCLUSION
The 543 G > C nucleotide substitution of the present A allele (ABO*A1.02) shares the same sequence variation site with A allele (ABO*AW.33) (543 G > T), and both 543 G > C and 543 G > T nucleotide substitutions encode the same amino acid change of tryptophan to cysteine. Mechanism, such as allelic enhancement, has been proposed to explain this controversial phenotype-genotype relationship. But in present case, there has been no B allele to enhance the expression of A to that expected of A, so there could be another novel underlying mechanism to be investigated.
Topics: ABO Blood-Group System; Alleles; Exons; Genotype; Humans; Phenotype
PubMed: 31521466
DOI: 10.1016/j.jfma.2019.08.029