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Genetic Epidemiology Mar 2018Construction of multifactorial disease models from epidemiological findings and their application to disease pedigrees for risk prediction is nontrivial for all but the...
Construction of multifactorial disease models from epidemiological findings and their application to disease pedigrees for risk prediction is nontrivial for all but the simplest of cases. Multifactorial Disease Risk Calculator is a web tool facilitating this. It provides a user-friendly interface, extending a reported methodology based on a liability-threshold model. Multifactorial disease models incorporating all the following features in combination are handled: quantitative risk factors (including polygenic scores), categorical risk factors (including major genetic risk loci), stratified age of onset curves, and the partition of the population variance in disease liability into genetic, shared, and unique environment effects. It allows the application of such models to disease pedigrees. Pedigree-related outputs are (i) individual disease risk for pedigree members, (ii) n year risk for unaffected pedigree members, and (iii) the disease pedigree's joint liability distribution. Risk prediction for each pedigree member is based on using the constructed disease model to appropriately weigh evidence on disease risk available from personal attributes and family history. Evidence is used to construct the disease pedigree's joint liability distribution. From this, lifetime and n year risk can be predicted. Example disease models and pedigrees are provided at the website and are used in accompanying tutorials to illustrate the features available. The website is built on an R package which provides the functionality for pedigree validation, disease model construction, and risk prediction. Website: http://grass.cgs.hku.hk:3838/mdrc/current.
Topics: Disease; Genetic Predisposition to Disease; Humans; Internet; Models, Genetic; Multifactorial Inheritance; Pedigree; Reproducibility of Results; Risk Factors; Software
PubMed: 29178360
DOI: 10.1002/gepi.22101 -
Scientific Reports Jul 2023Nowadays, the development of diagnosis and treatment technology is constantly changing the pedigree and classification of nervous system diseases. Analyzing changes in...
Nowadays, the development of diagnosis and treatment technology is constantly changing the pedigree and classification of nervous system diseases. Analyzing changes in earlier disease pedigrees can help us understand the changes involved in disease diagnosis from a macro perspective, as well as predict changes in later disease pedigrees and the direction of diagnosis and treatment. The inpatients of the neurology department from January 2012 to December 2020 in Hunan Children's Hospital were retrospectively analyzed. There were 36,777 patients enrolled in this study. The next analysis was based on factors like age, gender, length of stay (LoS), number of patients per month and per year (MNoP and ANoP, respectively), and average daily hospital cost (ADHE). To evaluate the characteristics of neurological diseases, we applied a series of statistical tools such as numerical characteristics, boxplots, density charts, one-way ANOVA, Kruskal-Wallis tests, time-series plots, and seasonally adjusted indices. The statistical analysis of neurological diseases led to the following conclusions: First, children having neurological illnesses are most likely to develop them between the ages of 4 and 8 years. Benign intracranial hypertension was the youngest mean age of onset among the various neurologic diseases, and most patients with bacterial intracranial infection were young children. Some diseases have a similar mean age of onset, such as seizures (gastroenteritis/diarrhea) and febrile convulsions. Second, women made up most patients with autoimmune diseases of the central nervous system. Treatment options for inherited metabolic encephalopathy and epilepsy are similar, but they differ significantly for viral intracranial infection. Some neurologic diseases were found to have seasonal variations; for example, infectious diseases of the central nervous system were shown to occur more commonly in the warm season, whereas, autoimmune diseases primarily appeared in the autumn and winter months. Additionally, the number of patients admitted to hospitals with intracranial infections and encephalopathy has dramatically dropped recently, but the number of patients with autoimmune diseases of the central nervous system and hereditary metabolic encephalopathy has been rising year over year. Finally, we discovered apparent polycentric distributions in various illnesses' density distributions. The study offered an epidemiological basis for common nervous system diseases, including evidence from age of onset, number of cases, and so on. The pedigree of nervous system diseases has significantly changed. The proportion of patients with neuroimmune diseases and genetic metabolic diseases is rising while the number of patients with infection-related diseases and uncertain diagnoses is decreasing. The existence of a disease multimodal model suggests that there is still a lack of understanding of many diseases' diagnosis and treatment, which needs to be improved further because accurate diagnosis aids in the formulation of individualized treatment plans and the allocation of medical resources; additionally, there is still a lack of effective treatment for most genetic diseases. The seasonal characteristics of nervous system diseases suggest the need for the improvement of sanitation, living conditions, and awareness of daily health care.
Topics: Humans; Child; Female; Child, Preschool; Male; Retrospective Studies; Pedigree; Epilepsy; Hospitalization; Autoimmune Diseases
PubMed: 37407586
DOI: 10.1038/s41598-023-35571-0 -
Bioinformatics (Oxford, England) Feb 2024Pedigree-based analyses' prime role is to unravel relationships between individuals in breeding programs and germplasms. This is critical information for decoding the...
SUMMARY
Pedigree-based analyses' prime role is to unravel relationships between individuals in breeding programs and germplasms. This is critical information for decoding the genetics underlying main inherited traits of relevance, and unlocking the genotypic variability of a species to carry out genomic selections and predictions. Despite the great interest, current lineage visualizations become quite limiting in terms of public display, exploration, and tracing of traits up to ancestral donors. PERSEUS is a user-friendly, intuitive, and interactive web-based tool for pedigree visualizations represented as directed graph networks distributed using a force-repulsion method. The visualizations do not only showcase individual relationships among accessions, but also facilitate a seamless search and download of phenotypic traits along the pedigrees. PERSEUS is a promising tool for breeders and scientists, advantageous for evolutionary, genealogy, and diversity analyses among related accessions and species.
AVAILABILITY AND IMPLEMENTATION
PERSEUS is freely accessible at https://bioinformatics.cragenomica.es/perseus and GitHub code is available at https://github.com/aranzana-lab/PERSEUS.
Topics: Humans; Software; Pedigree; Genomics; Genome; Internet
PubMed: 38310342
DOI: 10.1093/bioinformatics/btae060 -
BMC Plant Biology Jan 2020Apple (Malus x domestica Borkh.) is one of the most important fruit tree crops of temperate areas, with great economic and cultural value. Apple cultivars can be...
BACKGROUND
Apple (Malus x domestica Borkh.) is one of the most important fruit tree crops of temperate areas, with great economic and cultural value. Apple cultivars can be maintained for centuries in plant collections through grafting, and some are thought to date as far back as Roman times. Molecular markers provide a means to reconstruct pedigrees and thus shed light on the recent history of migration and trade of biological materials. The objective of the present study was to identify relationships within a set of over 1400 mostly old apple cultivars using whole-genome SNP data (~ 253 K SNPs) in order to reconstruct pedigrees.
RESULTS
Using simple exclusion tests, based on counting the number of Mendelian errors, more than one thousand parent-offspring relations and 295 complete parent-offspring families were identified. Additionally, a grandparent couple was identified for the missing parental side of 26 parent-offspring pairings. Among the 407 parent-offspring relations without a second identified parent, 327 could be oriented because one of the individuals was an offspring in a complete family or by using historical data on parentage or date of recording. Parents of emblematic cultivars such as 'Ribston Pippin', 'White Transparent' and 'Braeburn' were identified. The overall pedigree combining all the identified relationships encompassed seven generations and revealed a major impact of two Renaissance cultivars of French and English origin, namely 'Reinette Franche' and 'Margil', and one North-Eastern Europe cultivar from the 1700s, 'Alexander'. On the contrary, several older cultivars, from the Middle Ages or the Roman times, had no, or only single, identifiable offspring in the set of studied accessions. Frequent crosses between cultivars originating from different European regions were identified, especially from the nineteenth century onwards.
CONCLUSIONS
The availability of over 1400 apple genotypes, previously filtered for genetic uniqueness and providing a broad representation of European germplasm, has been instrumental for the success of this large pedigree reconstruction. It enlightens the history of empirical selection and recent breeding of apple cultivars in Europe and provides insights to speed-up future breeding and selection.
Topics: Breeding; Europe; Genome, Plant; Genotype; Genotyping Techniques; Malus; Pedigree; Polymorphism, Single Nucleotide; Whole Genome Sequencing
PubMed: 31898487
DOI: 10.1186/s12870-019-2171-6 -
Animal : An International Journal of... May 2024Inbreeding plays a crucial role in livestock breeding, influencing genetic diversity and phenotypic traits. Genomic data have helped address limitations posed by...
Inbreeding plays a crucial role in livestock breeding, influencing genetic diversity and phenotypic traits. Genomic data have helped address limitations posed by incomplete pedigrees, providing deeper insights into breed genetic diversity. This study assesses inbreeding levels via pedigree and genomic approaches and analyzes old and recent inbreeding using runs of homozygosity (ROH), and selection signals in Alpine Grey cattle. Pedigree data from 165 575 individuals, analyzed with INBUPGF90 software, computed inbreeding coefficients. Genomic-based coefficients derived from PLINK v1.9. or DetectRUNS R package analyses of 1 180 individuals' genotypes. Common single nucleotide polymorphisms within ROH pinpointed genomic regions, aggregating into "ROH islands" indicative of selection pressure. Overlaps with USCS Genome Browser unveiled gene presence. Moderate correlations (0.20-0.54) existed between pedigree and genomic coefficients, with most genomic estimators having higher (>0.8) correlation values. Inbreeding averaged 0.04 in < 8 Mb ROH segments, and 0.03 in > 16 Mb segments; > 90% of ROHs were < 8 Mb, indicating ancient inbreeding prevalence. Recent inbreeding proved less detrimental than in cosmopolitan breeds. Two major ROH islands on chromosomes 6 and 7 harbored genes linked to immune response, disease resistance (PYURF, HERC3), and fertility (EIF4EBP3, SRA1). This study underscores the need for detailed inbreeding analyses to understand genetic characteristics and historical changes in local breeds like Alpine Grey cattle. Genomic insights, especially from ROH, facilitated overcoming pedigree limitations, illuminating breed genetic diversity. Our findings reveal ancient inbreeding's enduring genetic impact and ROH islands potential for selective sweeps, elucidating traits in Alpine Grey cattle.
Topics: Animals; Cattle; Inbreeding; Pedigree; Polymorphism, Single Nucleotide; Female; Selection, Genetic; Genotype; Male; Homozygote; Genetic Variation; Genomics; Breeding; Genome; Phenotype
PubMed: 38718700
DOI: 10.1016/j.animal.2024.101159 -
Genes Feb 2024Y-chromosomal short tandem repeats (Y-STRs) are widely used in forensic, genealogical, and population genetics. With the recent increase in the number of rapidly...
Y-chromosomal short tandem repeats (Y-STRs) are widely used in forensic, genealogical, and population genetics. With the recent increase in the number of rapidly mutating (RM) Y-STRs, an unprecedented level of male differentiation can be achieved, widening and improving the applications of Y-STRs in various fields, including forensics. The growing complexity of Y-STR data increases the need for automated data analyses, but dedicated software tools are scarce. To address this, we present the Male Pedigree Toolbox (MPT), a software tool for the automated analysis of Y-STR data in the context of patrilineal genealogical relationships. The MPT can estimate mutation rates and male relative differentiation rates from input Y-STR pedigree data. It can aid in determining ancestral haplotypes within a pedigree and visualize the genetic variation within pedigrees in all branches of family trees. Additionally, it can provide probabilistic classifications using machine learning, helping to establish or prove the structure of the pedigree and the level of relatedness between males, even for closely related individuals with highly similar haplotypes. The tool is flexible and easy to use and can be adjusted to any set of Y-STR markers by modifying the intuitive input file formats. We introduce the MPT software tool v1.0 and make it publicly available with the goal of encouraging and supporting forensic, genealogical, and other geneticists in utilizing the full potential of Y-STRs for both research purposes and practical applications, including criminal casework.
Topics: Male; Humans; Pedigree; Haplotypes; Mutation Rate; Genetics, Population; Chromosomes, Human, Y
PubMed: 38397216
DOI: 10.3390/genes15020227 -
Journal of Neurosurgery Jul 2023Inherited variants predisposing patients to type 1 or 1.5 Chiari malformation (CM) have been hypothesized but have proven difficult to confirm. The authors used a unique...
OBJECTIVE
Inherited variants predisposing patients to type 1 or 1.5 Chiari malformation (CM) have been hypothesized but have proven difficult to confirm. The authors used a unique high-risk pedigree population resource and approach to identify rare candidate variants that likely predispose individuals to CM and protein structure prediction tools to identify pathogenicity mechanisms.
METHODS
By using the Utah Population Database, the authors identified pedigrees with significantly increased numbers of members with CM diagnosis. From a separate DNA biorepository of 451 samples from CM patients and families, 32 CM patients belonging to 1 or more of 24 high-risk Chiari pedigrees were identified. Two high-risk pedigrees had 3 CM-affected relatives, and 22 pedigrees had 2 CM-affected relatives. To identify rare candidate predisposition gene variants, whole-exome sequence data from these 32 CM patients belonging to 24 CM-affected related pairs from high-risk pedigrees were analyzed. The I-TASSER package for protein structure prediction was used to predict the structures of both the wild-type and mutant proteins found here.
RESULTS
Sequence analysis of the 24 affected relative pairs identified 38 rare candidate Chiari predisposition gene variants that were shared by at least 1 CM-affected pair from a high-risk pedigree. The authors found a candidate variant in HOXC4 that was shared by 2 CM-affected patients in 2 independent pedigrees. All 4 of these CM cases, 2 in each pedigree, exhibited a specific craniocervical bony phenotype defined by a clivoaxial angle less than 125°. The protein structure prediction results suggested that the mutation considered here may reduce the binding affinity of HOXC4 to DNA.
CONCLUSIONS
Analysis of unique and powerful Utah genetic resources allowed identification of 38 strong candidate CM predisposition gene variants. These variants should be pursued in independent populations. One of the candidates, a rare HOXC4 variant, was identified in 2 high-risk CM pedigrees, with this variant possibly predisposing patients to a Chiari phenotype with craniocervical kyphosis.
Topics: Humans; Genetic Predisposition to Disease; Genotype; Homeodomain Proteins; Mutation; Pedigree; Phenotype; Risk Factors; Brain
PubMed: 36433874
DOI: 10.3171/2022.10.JNS22956 -
Genetic Epidemiology Apr 2019The transmission disequilibrium test (TDT) is the gold standard for testing the association between a genetic variant and disease in samples consisting of affected... (Comparative Study)
Comparative Study
The transmission disequilibrium test (TDT) is the gold standard for testing the association between a genetic variant and disease in samples consisting of affected individuals and their parents. In practice, more complex pedigree structures, that is siblings with no parents, or three-generational pedigrees with possibly missing genotypes, are common. There are several generalizations of the TDT that are suitable for use with arbitrary pedigree structures. We consider three such frequently used generalizations, family-based association test, pedigree disequilibrium test, and generalized disequilibrium test, that have accompanying software and compare them regarding validity and power in the single variant setting. We use simulations to study the effects of population admixture, populations whose genotypes are not in Hardy-Weinberg equilibrium (HWE), different pedigree structures, and the presence of linkage. Whereas our results show that some TDT generalizations can have a substantially increased Type 1 error, these tests are often used in substantive research without caveats about the validity of their Type 1 error. For the association analysis of rare variants in sequencing studies, region-based extensions of the TDT generalizations, that rely on the postulated robustness of the single variant tests, have been proposed. We discuss the implications of our results for these region-based extensions.
Topics: Computer Simulation; Family; Female; Gene Frequency; Genetic Association Studies; Genetic Linkage; Humans; Linkage Disequilibrium; Male; Models, Genetic; Parents; Pedigree; Software
PubMed: 30609057
DOI: 10.1002/gepi.22181 -
Frontiers in Public Health 2023We initiated the Fujian Tulou Pedigree-based Cohort (FTPC) as the integration of extended pedigrees and prospective cohort to clarify the genetic and environmental risk...
BACKGROUND
We initiated the Fujian Tulou Pedigree-based Cohort (FTPC) as the integration of extended pedigrees and prospective cohort to clarify the genetic and environmental risk factors of cardiometabolic diseases.
METHODS
FTPC was carried out in Nanjing County, Fujian Province, China from August 2015 to December 2017 to recruit probands with the same surnames and then enroll their first-degree and more distant relatives. The participants were asked to complete questionnaire interview, physical examination, and blood collection. According to the local genealogical booklets and family registry, we reconstructed extended pedigrees to estimate the heritability of cardiometabolic traits. The follow-up of FTPC is scheduled every 5 years in the future.
RESULTS
The baseline survey interviewed 2,727 individuals in two clans. A total of 1,563 adult subjects who completed all baseline examinations were used to reconstruct pedigrees and 452 extended pedigrees were finally identified, including one seven-generation pedigree, two five-generation pedigrees, 23 four-generation pedigrees, 186 three-generation pedigrees, and 240 two-generation pedigrees. The average age of the participants was 57.4 years, with 43.6% being males. The prevalence of hypertension, diabetes and dyslipidemia in FTPC were 49.2, 10.0, and 45.2%, respectively. Based on the pedigree structure, the heritability of systolic blood pressure, diastolic blood pressure, fast blood glucose, total cholesterol, triglyceride, high-density lipoprotein, and low-density lipoprotein was estimated at 0.379, 0.306, 0.386, 0.452, 0.568, 0.852, and 0.387, respectively.
CONCLUSION
As an extended pedigree cohort in China, FTPC will provide an important source to study both genetic and environmental risk factors prospectively.
Topics: Male; Adult; Humans; Middle Aged; Female; Prospective Studies; Pedigree; Diabetes Mellitus; Hypertension; Risk Factors
PubMed: 37521988
DOI: 10.3389/fpubh.2023.1189993 -
Proceedings of the National Academy of... Feb 2019A central goal of population genetics is to understand how genetic drift, natural selection, and gene flow shape allele frequencies through time. However, the actual...
A central goal of population genetics is to understand how genetic drift, natural selection, and gene flow shape allele frequencies through time. However, the actual processes underlying these changes-variation in individual survival, reproductive success, and movement-are often difficult to quantify. Fully understanding these processes requires the population pedigree, the set of relationships among all individuals in the population through time. Here, we use extensive pedigree and genomic information from a long-studied natural population of Florida Scrub-Jays () to directly characterize the relative roles of different evolutionary processes in shaping patterns of genetic variation through time. We performed gene dropping simulations to estimate individual genetic contributions to the population and model drift on the known pedigree. We found that observed allele frequency changes are generally well predicted by accounting for the different genetic contributions of founders. Our results show that the genetic contribution of recent immigrants is substantial, with some large allele frequency shifts that otherwise may have been attributed to selection actually due to gene flow. We identified a few SNPs under directional short-term selection after appropriately accounting for gene flow. Using models that account for changes in population size, we partitioned the proportion of variance in allele frequency change through time. Observed allele frequency changes are primarily due to variation in survival and reproductive success, with gene flow making a smaller contribution. This study provides one of the most complete descriptions of short-term evolutionary change in allele frequencies in a natural population to date.
Topics: Algorithms; Animals; Birds; Gene Frequency; Genetic Variation; Genetics, Population; Models, Genetic; Pedigree; Population Dynamics
PubMed: 30598449
DOI: 10.1073/pnas.1813852116