-
Forensic Science International. Genetics Nov 2022The maximum allele count (MAC) across loci and the total allele count (TAC) are often used to gauge the number of contributors to a DNA mixture. Computational strategies...
The maximum allele count (MAC) across loci and the total allele count (TAC) are often used to gauge the number of contributors to a DNA mixture. Computational strategies that predict the total number of alleles in a mixture arising from a certain number of contributors of a given population have been developed. Previous work considered the restricted case where all of the contributors to a mixture are unrelated. We relax this assumption and allow mixture contributors to be related according to a pedigree. We introduce an efficient computational strategy. This strategy based on first determining a probability distribution on the number of independent alleles per locus, and then conditioning on this distribution to compute a distribution of the number of distinct alleles per locus. The distribution of the number of independent alleles per locus is obtained by leveraging the Identical by Descent (IBD) pattern distribution which can be computed from the pedigree. We explain how allelic dropout and a subpopulation correction can be accounted for in the calculations.
Topics: Humans; Alleles; DNA Fingerprinting; DNA; Probability
PubMed: 35961259
DOI: 10.1016/j.fsigen.2022.102748 -
Transfusion Medicine (Oxford, England) Aug 2018Alloantibodies against human neutrophil antigens (HNA) are associated with a variety of clinical conditions. Over the past decade, the allelic and genotypic frequencies...
BACKGROUND
Alloantibodies against human neutrophil antigens (HNA) are associated with a variety of clinical conditions. Over the past decade, the allelic and genotypic frequencies of the five HNA systems have been evaluated. Although the HNA system is less polymorphic than human leukocyte antigens (HLA), significant differences in the genotypic and allele frequencies still exist in different populations, even those living in close proximity.
OBJECTIVES
To delineate HNA genotypic and allele frequencies to provide vital information on estimating the risk of HNA-associated diseases for our local population.
METHODS
Using a validated, in-house-developed assay, genotyping for HNA-1, HNA-3, HLA-4 and HNA-5 was performed on 300 samples from Chinese blood donors from Hong Kong. In addition, the frequency of the HNA-2 c.843A > T allele was also determined.
RESULTS
The allele frequencies of HNA-1a, -1b and -1c alleles were 67·8, 31·5 and 0%, respectively, whereas the frequencies of HNA-3a and HNA-3b were 71·0 and 29·0%, respectively. The frequencies of HNA-4a and -4b alleles were 99·5 and 0·5%, respectively, and for HNA-5a and -5b, alleles were 85·2 and 14·8%, respectively. Homozygotes for the HNA-2 c.843 TT variant were absent in our population, whereas only <4% of the population were c.843AT heterozygote carriers.
CONCLUSIONS
This is the first study to define HNA genotype and allele frequencies using a validated modified in-house PCR-SSP method in the Hong Kong Chinese blood donor population. Our approach provides a cost-effective assay for conducting routine HNA typing and facilitates the incorporation of these assays into routine clinical service. Our results are comparable with those reported in the Guangzhou Chinese population, but the allele frequencies in our Hong Kong Chinese population are significantly different from the reported European frequencies, confirming that a geographical difference exists for HNA allele frequencies.
Topics: Alleles; Asian People; Blood Donors; Gene Frequency; Hong Kong; Humans; Isoantigens; Neutrophils; Polymerase Chain Reaction
PubMed: 29280200
DOI: 10.1111/tme.12494 -
Methods in Molecular Biology (Clifton,... 2017Gametic phase disequilibrium is the nonrandom association of alleles within gametes. Linkage disequilibrium (LD) describes the special case of deviation from...
Gametic phase disequilibrium is the nonrandom association of alleles within gametes. Linkage disequilibrium (LD) describes the special case of deviation from independence between alleles at two linked genetic loci. Estimation of allelic LD requires knowledge of haplotypes. Genotype-based LD measures dispense with the haplotype estimation step and avoid bias in LD estimation. In this chapter, the most important measures for allelic and genotypic LD are introduced. The use of software packages for LD estimation is illustrated.
Topics: Alleles; Genome-Wide Association Study; Genotype; Haplotypes; Humans; Linkage Disequilibrium; Models, Genetic; Software
PubMed: 28980244
DOI: 10.1007/978-1-4939-7274-6_7 -
BMC Research Notes Nov 2021Allelic imbalance (AI) is the differential expression of the two alleles in a diploid. AI can vary between tissues, treatments, and environments. Methods for testing AI...
OBJECTIVE
Allelic imbalance (AI) is the differential expression of the two alleles in a diploid. AI can vary between tissues, treatments, and environments. Methods for testing AI exist, but methods are needed to estimate type I error and power for detecting AI and difference of AI between conditions. As the costs of the technology plummet, what is more important: reads or replicates?
RESULTS
We find that a minimum of 2400, 480, and 240 allele specific reads divided equally among 12, 5, and 3 replicates is needed to detect a 10, 20, and 30%, respectively, deviation from allelic balance in a condition with power > 80%. A minimum of 960 and 240 allele specific reads divided equally among 8 replicates is needed to detect a 20 or 30% difference in AI between conditions with comparable power. Higher numbers of replicates increase power more than adding coverage without affecting type I error. We provide a Python package that enables simulation of AI scenarios and enables individuals to estimate type I error and power in detecting AI and differences in AI between conditions.
Topics: Alleles; Allelic Imbalance; Bayes Theorem; Computer Simulation; Humans
PubMed: 34838135
DOI: 10.1186/s13104-021-05851-x -
HLA Jun 2018The HLA system shows the most extensive polymorphism in the human genome. Allelic and haplotypic frequencies of HLA genes vary dramatically across human populations. Due...
High-resolution HLA allele and haplotype frequencies in majority and minority populations of Costa Rica and Nicaragua: Differential admixture proportions in neighboring countries.
The HLA system shows the most extensive polymorphism in the human genome. Allelic and haplotypic frequencies of HLA genes vary dramatically across human populations. Due to a complex history of migration, populations in Latin America show a broad variety of admixture proportions, usually varying not only between countries, but also within countries. Knowledge of HLA allele and haplotype frequencies is essential for medical fields such as transplantation, but also serves as a means to assess genetic diversity and ancestry in human populations. Here, we have determined high-resolution HLA-A, -B, -C, and -DRB1 allele and haplotype frequencies in a sample of 713 healthy subjects from three Mestizo populations, one population of African descent, and Amerindians of five different groups from Costa Rica and Nicaragua and compared their profiles to a large set of indigenous populations from Iberia, Sub-Saharan Africa, and the Americas. Our results show a great degree of allelic and haplotypic diversity within and across these populations, with most extended haplotypes being private. Mestizo populations show alleles and haplotypes of putative European, Amerindian, and Sub-Saharan African origin, albeit with differential proportions. Despite some degree of gene flow, Amerindians and Afro-descendants show great similarity to other Amerindian and West African populations, respectively. This is the first comprehensive study reporting high-resolution HLA diversity in Central America, and its results will shed light into the genetic history of this region while also supporting the development of medical programs for organ and stem cell transplantation.
Topics: Alleles; Black People; Costa Rica; Gene Frequency; Genotype; HLA Antigens; Humans; Indians, South American; Linkage Disequilibrium; Nicaragua; Polymorphism, Genetic; Transplantation
PubMed: 29687625
DOI: 10.1111/tan.13280 -
Genetics Feb 2022Populations often inhabit multiple ecological patches and thus experience divergent selection, which can lead to local adaptation if migration is not strong enough to...
Populations often inhabit multiple ecological patches and thus experience divergent selection, which can lead to local adaptation if migration is not strong enough to swamp locally adapted alleles. Conditions for the establishment of a locally advantageous allele have been studied in randomly mating populations. However, many species reproduce, at least partially, through self-fertilization, and how selfing affects local adaptation remains unclear and debated. Using a two-patch branching process formalism, we obtained a closed-form approximation under weak selection for the probability of establishment of a locally advantageous allele (P) for arbitrary selfing rate and dominance level, where selection is allowed to act on viability or fecundity, and migration can occur via seed or pollen dispersal. This solution is compared to diffusion approximation and used to investigate the consequences of a shift in a mating system on P, and the establishment of protected polymorphism. We find that selfing can either increase or decrease P, depending on the patterns of dominance in the two patches, and has conflicting effects on local adaptation. Globally, selfing favors local adaptation when locally advantageous alleles are (partially) recessive, when selection between patches is asymmetrical and when migration occurs through pollen rather than seed dispersal. These results establish a rigorous theoretical background to study heterogeneous selection and local adaptation in partially selfing species.
Topics: Adaptation, Physiological; Alleles; Fertilization; Models, Genetic; Self-Fertilization
PubMed: 34791199
DOI: 10.1093/genetics/iyab201 -
HLA Jan 2023A synonymous nucleotide substitution in exon 3 results in the novel HLA-DQA1*02:01:09:01 allele.
A synonymous nucleotide substitution in exon 3 results in the novel HLA-DQA1*02:01:09:01 allele.
Topics: Humans; Alleles
PubMed: 36086921
DOI: 10.1111/tan.14810 -
Human Reproduction (Oxford, England) Apr 2021Does pituitary response to a GnRH stimulation test differ according to the different FSHB-211 G/T genotypes?
STUDY QUESTION
Does pituitary response to a GnRH stimulation test differ according to the different FSHB-211 G/T genotypes?
SUMMARY ANSWER
The promoter polymorphism FSHB-211 G > T affects the pituitary response to exogenous GnRH stimulation by reducing FSH and increasing LH outputs.
WHAT IS KNOWN ALREADY
The FSHB-211 G > T single nucleotide polymorphism (SNP) is known to affect pituitary FSH output by impairing the transcriptional activity of FSHB.
STUDY DESIGN, SIZE, DURATION
This was a cross-sectional, retrospective study on 67 male subjects (mean age: 24.6 ± 10.3 years) undergoing a GnRH stimulation test for diagnostic purposes in cases of secondary hypogonadism.
PARTICIPANTS/MATERIALS, SETTING, METHODS
A GnRH stimulation test was performed by administering an i.v. bolus of 100 µg of the GnRH-analogue gonadorelin acetate to all patients, with blood samples drawn from the cubital vein immediately prior to injection (T0) and 30 (T1) and 45 minutes (T2) after. Clinical and genetic data were retrieved from a computerized database. Linear longitudinal mixed-effect models were used to assess the effects of SNP genotype on FSH and LH levels over time via additive and recessive models.
MAIN RESULTS AND THE ROLE OF CHANCE
An overall marked increase in serum FSH and LH following administration i.v. of 100 µg of an LHRH-analogue was found (P < 0.0001 for linear trend, both models). Peak levels of LH were significantly higher in TT carriers than in GT and GG carriers (P = 0.012); no significant between-groups difference was found concerning stimulated FSH levels. In both the additive and recessive model, the main effect of T allele(s) did not reach statistical significance concerning FSH levels (P = 0.9502 and P = 0.8576, respectively), yet interaction effects over time demonstrated an attenuated response in T-allele carriers compared to the GG-allele carriers (P = 0.0219 and P = 0.0276). Main and interaction effects for LH were significant in both the additive (P = 0.0022 and P = 0.0013, respectively) and recessive model (P = 0.0025 and P = 0.0016, respectively).
LIMITATIONS, REASONS FOR CAUTION
Given the retrospective nature of the study and the small number of TT carriers, results should be interpreted with caution.
WIDER IMPLICATIONS OF THE FINDINGS
The FSHB c.-211G>T polymorphism might result in an impaired response to endogenous, as well as exogenous, GnRH stimulation. This finding might contribute to the clinical phenotype of reduced testicular volume and sperm count for patients carrying one or two T alleles.
STUDY FUNDING/COMPETING INTEREST(S)
Parts of the study were supported by the German Research Foundation (CRU326 Male Germ Cells). On behalf of all authors, the corresponding author states that there is no conflict of interest.
TRIAL REGISTRATION NUMBER
NA.
Topics: Adolescent; Adult; Alleles; Cross-Sectional Studies; Follicle Stimulating Hormone; Genotype; Gonadotropin-Releasing Hormone; Humans; Male; Retrospective Studies; Young Adult
PubMed: 33704441
DOI: 10.1093/humrep/deab033 -
The Journal of Allergy and Clinical... Aug 2023Nearly 50 pathogenic genes and hundreds of pathogenic variants have been identified in monogenic autoinflammatory diseases (AIDs). Nonetheless, there are still many...
BACKGROUND
Nearly 50 pathogenic genes and hundreds of pathogenic variants have been identified in monogenic autoinflammatory diseases (AIDs). Nonetheless, there are still many genes for which the pathogenic mechanisms are poorly understood, and the pathogenicity of many candidate variants needs to be determined.
OBJECTIVE
Monogenic AIDs are a group of rare genetic diseases characterized by inflammation as the phenotype. With the development of next-generation sequencing, pathogenic genes have been widely reported and used for clinical screening and diagnosis. The International Society for Systemic Autoinflammatory Diseases has recognized approximately 50 pathogenic genes and hundreds of related pathogenic variants in monogenic AIDs. We plan to investigate these pathogenic variants by conducting a variant burden analysis to determine whether or not there are consistent characteristics.
METHODS
We performed a variant burden analysis on the Genome Aggregation Database cohort using the currently reported genetic variants in monogenic AIDs, analyzing the enrichment of allelic signatures and deleterious predictions at the variants. Allelic signatures were extracted from Genome Aggregation Database, and the deleterious predictions were extracted from existing tools. The features obtained from the variant burden analysis were applied to the Random Forest model to classify the pathogenicity of novel mutations.
RESULTS
Functional enrichment and network analysis of AID pathogenic genes have hinted at the possible involvement of unsuspected signals. The variant burden analysis demonstrated that the pathogenicity of a variant could not be reliably classified using only its allele frequency and deleterious predictions. However, variants of varying classifications of pathogenicity exhibited strikingly different patterns of the allelic signature in the upstream and downstream regions surrounding the variants. Furthermore, the distribution of deleterious variants surrounding the variants in the cohort varied significantly across pathogenicity categories. Finally, the cohort-based features extracted from the alleles were applied to the prediction of pathogenicity in monogenic AIDs, achieving superior prediction performance compared with other tools. The cohort-based features have potential applications across a more extensive variety of disease categories.
CONCLUSIONS
The pathogenicity of a variant can be effectively classified on the basis of variant frequency and deleterious prediction of the allele in the cohort, and this information can be used to improve the accuracy of the current classification of the pathogenicity of the variant.
Topics: Humans; Virulence; Gene Frequency; Phenotype; Alleles; Rare Diseases; Hereditary Autoinflammatory Diseases
PubMed: 37030591
DOI: 10.1016/j.jaci.2023.03.028 -
Genome Research Feb 2022Polyploidy is widespread in plants, allowing the different copies of genes to be expressed differently in a tissue-specific or developmentally specific way. This...
Polyploidy is widespread in plants, allowing the different copies of genes to be expressed differently in a tissue-specific or developmentally specific way. This allele-specific expression (ASE) has been widely reported, but the proportion and nature of genes showing this characteristic have not been well defined. We now report an analysis of the frequency and patterns of ASE at the whole-genome level in the highly polyploid sugarcane genome. Very high depth whole-genome sequencing and RNA sequencing revealed strong correlations between allelic proportions in the genome and in expressed sequences. This level of sequencing allowed discrimination of each of the possible allele doses in this 12-ploid genome. Most genes were expressed in direct proportion to the frequency of the allele in the genome with examples of polymorphisms being found with every possible discrete level of dose from 1:11 for single-copy alleles to 12:0 for monomorphic sites. The rarer cases of ASE were more frequent in the expression of defense-response genes, as well as in some processes related to the biosynthesis of cell walls. ASE was more common in genes with variants that resulted in significant disruption of function. The low level of ASE may reflect the recent origin of polyploid hybrid sugarcane. Much of the ASE present can be attributed to strong selection for resistance to diseases in both nature and domestication.
Topics: Alleles; Gene Expression; Polymorphism, Single Nucleotide; Polyploidy; Saccharum; Sequence Analysis, RNA
PubMed: 34949669
DOI: 10.1101/gr.275904.121