Search

Whole genome sequences (WGS) of 185 North American Thoroughbred horses were compared to quantify the number and frequency of variants, diversity of mitotypes, and autosomal runs of homozygosity (ROH). Of the samples, 82 horses were born between 1965 and 1986 (Group 1); the remaining 103, selected to maximize pedigree diversity, were born between 2000 and 2020 (Group 2). Over 14.3 million autosomal variants were identified with 4.5-5.0 million found per horse. Mitochondrial sequences associated the North American Thoroughbreds with 9 of 17 clades previously identified among diverse breeds. Individual coefficients of inbreeding, estimated from ROH, averaged 0.266 (Group 1) and 0.283 (Group 2). When SNP arrays were simulated using subsets of WGS markers, the arrays over-estimated lengths of ROH. WGS-based estimates of inbreeding were highly correlated (r > 0.98) with SNP array-based estimates, but only moderately correlated (r = 0.40) with inbreeding based on 5-generation pedigrees. On average, Group 1 horses had more heterozygous variants (P

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. We evaluate enhancer activity for 59 elements using an in vivo transgenic assay and validate 44 (75%), demonstrating that single cell accessibility can be a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieve significant reduction in our variant search space and nominate candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 - as well as candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work delivers non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.

The Greying with age phenotype in horses involves loss of hair pigmentation whereas skin pigmentation is not reduced, and a predisposition to melanoma. The causal mutation was initially reported as a duplication of a 4.6 kb intronic sequence in Syntaxin 17. The speed of greying varies considerably among Grey horses. Here we demonstrate the presence of two different Grey alleles, G2 carrying two tandem copies of the duplicated sequence and G3 carrying three. The latter is by far the most common allele, probably due to strong selection for the striking white phenotype. Our results reveal a remarkable dosage effect where the G3 allele is associated with fast greying and high incidence of melanoma whereas G2 is associated with slow greying and low incidence of melanoma. The copy number expansion transforms a weak enhancer to a strong melanocyte-specific enhancer that underlies hair greying (G2 and G3) and a drastically elevated risk of melanoma (G3 only). Our direct pedigree-based observation of the origin of a G2 allele from a G3 allele by copy number contraction demonstrates the dynamic evolution of this locus and provides the ultimate evidence for causality of the copy number variation of the 4.6 kb intronic sequence.

Pathogenic and likely pathogenic variants in the TECRL gene are known to be associated with recessive catecholaminergic polymorphic ventricular tachycardia 3, which can include prolonged QT intervals (MIM#614021). We report a case of cardiac arrest in a previously healthy adolescent male in the community. The patient was found to have a novel maternally inherited likely pathogenic variant in TECRL (c.915T>G [p.Tyr305Ter]) and an additional 19-kb duplication encompassing multiple exons of TECRL (chr4:65165944-65185287, dup [4q13.1]) not identified in the mother. Genetic results were revealed via rapid whole-genome sequencing, which allowed appropriate treatment and prognostication.

IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease whose pathomechanisms remain poorly understood. Here, we identified gene variants in familial IgG4-RD and determined their functional consequences. All 3 affected members of the family shared variants of the transcription factor IKAROS, encoded by IKZF1, and the E3 ubiquitin ligase UBR4. The IKAROS variant increased binding to the FYN promoter, resulting in higher transcription of FYN in T cells. The UBR4 variant prevented the lysosomal degradation of the phosphatase CD45. In the presence of elevated FYN, CD45 functioned as a positive regulatory loop, lowering the threshold for T cell activation. Consequently, T cells from the affected family members were hyperresponsive to stimulation. When transduced with a low-avidity, autoreactive T cell receptor, their T cells responded to the autoantigenic peptide. In parallel, high expression of FYN in T cells biased their differentiation toward Th2 polarization by stabilizing the transcription factor JunB. This bias was consistent with the frequent atopic manifestations in patients with IgG4-RD, including the affected family members in the present study. Building on the functional consequences of these 2 variants, we propose a disease model that is not only instructive for IgG4-RD but also for atopic diseases and autoimmune diseases associated with an IKZF1 risk haplotype.

PURPOSE: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. METHODS: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. RESULTS: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. CONCLUSIONS: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Data from the distant past are fertile ground for testing social science theories of education and social mobility. In this study, we construct a dataset from 3,640 tomb epitaphs of males in Chinas Tang Dynasty (618-907 CE), which contain granular and extensive information about the ancestral origins, family background, and career histories of the deceased elites. Our statistical analysis of the complete profiles yields evidence of the transition away from an aristocratic society in three key trends: 1) family pedigree (i.e., aristocracy) mattered less for career achievement over time, 2) passing the Imperial Examination (Keju) became an increasingly important predictor of ones career achievement, and 3) fathers position always mattered throughout the Tang, especially for men who did not pass the Keju. The twilight of medieval Chinese aristocracy, according to the data, began in as early as the mid-seventh century CE.

Whole genome sequencing has been an effective tool in the discovery of variants that cause rare diseases. In this study, we determined the suitability of a novel avidity sequencing approach for rare disease applications. We built a sample to results workflow, combining this sequencing technology with standard library preparation kits, analysis workflows, and interpretation tools. We applied the workflow to ten pedigrees with inherited retinal degeneration (IRD) phenotype. Candidate variants of interest identified through whole genome sequencing were further evaluated using segregation analysis in the additional family members. Potentially causal variants in known IRD genes were detected in five of the ten cases. These high confidence variants were found in ABCA4, CERKL, MAK, PEX6 and RDH12 genes associated with retinal degeneration, that could be sufficient to cause pathology. Pending confirmatory clinical evaluation, we observed a 50% diagnostic yield, consistent with previously reported outcomes of IRD patient analysis. The study confirms that avidity sequencing is effective in detection of causal variants when used for whole genome sequencing in rare disease applications.

BACKGROUND: Equine neuroaxonal dystrophy/degenerative myeloencephalopathy (eNAD/EDM) is a neurodegenerative disease that primarily affects young, genetically predisposed horses that are deficient in vitamin E. Equine NAD/EDM has not previously been documented in Gypsy Vanner horses (GVs). OBJECTIVES: To evaluate: (1) the clinical phenotype, blood vitamin E concentrations before and after supplementation and pedigree in a cohort of GV horses with a high prevalence of neurologic disease suspicious for eNAD/EDM and (2) to confirm eNAD/EDM in GVs through postmortem evaluation. ANIMALS: Twenty-six GVs from 1 farm in California and 2 cases from the Midwestern U.S. METHODS: Prospective observational study on Californian horses; all 26 GVs underwent neurologic examination. Pre-supplementation blood vitamin E concentration was assessed in 17- GVs. Twenty-three were supplemented orally with 10 IU/kg of liquid RRR-alpha-tocopherol once daily for 28 days. Vitamin E concentration was measured in 23 GVs after supplementation, of which 15 (65%) had pre-supplementation measurements. Two clinically affected GVs from California and the 2 Midwestern cases had necropsy confirmation of eNAD/EDM. RESULTS: Pre-supplementation blood vitamin E concentration was ≤2.0 μg/mL in 16/17 (94%) of GVs from California. Post-supplementation concentration varied, with a median of 3.39 μg/mL (range, 1.23-13.87 μg/mL), but only 12/23 (52%) were normal (≥3.0 μg/mL). Normalization of vitamin E was significantly associated with increasing age (P = .02). Euthanized horses (n = 4) had eNAD/EDM confirmed at necropsy. CONCLUSIONS AND CLINICAL IMPORTANCE: GVs could have a genetic predisposition to eNAD/EDM. Vitamin E supplementation should be considered and monitored in young GVs.

BACKGROUND: In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). HYPOTHESIS/OBJECTIVES: To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. ANIMALS: Twelve neurologically affected QH foals and the dams. METHODS: Genomic DNA was isolated and pedigrees were manually constructed. RESULTS: All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma-glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0-18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL IMPORTANCE: EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs

Large biobank samples provide an opportunity to integrate broad phenotyping, familial records, and molecular genetics data to study complex traits and diseases. We introduce Pearson-Aitken Family Genetic Risk Scores (PA-FGRS), a method for estimating disease liability from patterns of diagnoses in extended, age-censored genealogical records. We then apply the method to study a paradigmatic complex disorder, major depressive disorder (MDD), using the iPSYCH2015 case-cohort study of 30,949 MDD cases, 39,655 random population controls, and more than 2 million relatives. We show that combining PA-FGRS liabilities estimated from family records with molecular genotypes of probands improves three lines of inquiry. Incorporating PA-FGRS liabilities improves classification of MDD over and above polygenic scores, identifies robust genetic contributions to clinical heterogeneity in MDD associated with comorbidity, recurrence, and severity and can improve the power of genome-wide association studies. Our method is flexible and easy to use, and our study approaches are generalizable to other datasets and other complex traits and diseases. Our method, the Pearson-Aitken Family Genetic Risk Score, estimates genetic liability in a proband from patterns of disease outcomes in their relatives. The method is flexible, and the resulting scores can be used for genetic classification, describing genetic etiology, and improving power for gene mapping. [ABSTRACT FROM AUTHOR]

The present study aimed to elucidate the population structure and genetic diversity along with the estimation of genealogical parameters in Vrindavani cattle using pedigree data. The study was based on pedigree data on 12,718 animals, spread across multiple generations during a 52-year period (between 1971 and 2023). The pedigree data was used to estimate different population genealogical parameters including the generation interval; pedigree completeness; rate and level of inbreeding; effective population size; and parameters characterizing the probabilities of gene origin. The ENDOG program was used for estimation of different parameters while using population after 2010 as reference cohort. The results revealed the maximum number of generations (MG) to be 13, while the numbers of completed (CG) and equivalent generations (EqG) were 3.23 and 1.95, respectively. The mean generation interval for the population was 6.9 years. The average inbreeding coefficient of animals in the whole and reference population was 1.11 and 3.44%, respectively; with 0.68% rate of inbreeding per generation. The average additive relationship among all the animals and those in the reference population was 1.16 and 5.49%, respectively. The average effective population sizes for the maximum, equivalent, and complete generations were 115.56, 56.42, and 46.02, respectively. The effective population size on the basis of regression and log-regression on birth date was 77.40 and 71.24, respectively. The probabilities of gene origin were estimated by the effective number of founders (fe) and ancestors (fa), which was 115 and 78, respectively. The fe/fa ratio in the reference population was 1.20, indicating that occasional bottlenecks may have occurred in the population. The analysis revealed a loss of 5.3% of total heterozygosity as compared to base population, though significant variability exists in the latest generations. The results revealed that considerable genetic variability exists within the population that may be exploited through appropriate breed improvement programs targeting various economic traits. [ABSTRACT FROM AUTHOR]

Polyploidy occurs naturally across eukaryotic lineages and has been harnessed in the domestication of many crops and vertebrates. In aquaculture, triploidy can be induced as a biocontainment strategy, as it creates a reproductive barrier preventing farm‐to‐wild introgression, which is currently a major conservation issue for the industry. However, recent work suggests that triploidisation protocols may, on occasion, produce 'failed triploids' displaying diploidy, aneuploidy and aberrant inheritance. The potentially negative consequences for conservation and animal welfare motivate the need for methods to evaluate the success of ploidy‐manipulation protocols early in the production process. We developed a semi‐automated version of the MAC‐PR (microsatellite DNA allele counting – peak ratios) method to resolve the allelic configuration of large numbers of individuals across a panel of microsatellite markers that can be used to infer ploidy, pedigree and inheritance aberrations. We demonstrate an application of the approach using material from a series of Atlantic salmon (Salmo salar) breeding experiments where ploidy was manipulated using a hydrostatic pressure treatment. We validated the approach to infer ploidy against blood smears, finding a > 99% agreement between these methods, and demonstrate its potential utility to infer ploidy as early as the embryonic stage. Furthermore, we present tools to assign diploid and triploid progeny to families and to detect aberrant inheritance, which may be useful for breeding programmes that utilise ploidy manipulation techniques. The approach adds to the ploidy verification toolbox. The increased precision in detecting ploidy and inheritance aberrations will facilitate the ability of triploidisation programmes to prevent farm‐to‐wild introgression. [ABSTRACT FROM AUTHOR]

Kennel club registrations have been used in a number of studies to estimate ownership levels and fashion trends among dog breeds. They cannot, however, give a complete overview of the contemporary trade in pet dogs, and additionally, may be particularly poor at monitoring trends among some welfare-vulnerable breeds. Here, we compared data from online advertisements for the UK sales of single-breed dogs over an 18-month period, with equivalent data (including for prior and subsequent years) from the UK Kennel Club. Kennel Club registration rates and breed popularity rates online were positively correlated. However, some breeds, including the Jack Russell terrier, Border collie and Chihuahua were considerably over-represented in online advertisements when compared with Kennel Club registrations, indicating a hidden market for certain breeds. In addition, the online dataset provided information on the sale and re-homing of adult dogs, showing high rates of adult homing of the Staffordshire bull terrier, Siberian husky and Rottweiler. We conclude that online pet-sales websites are an important and complementary source of data about the market in, and popularity of, a wide range of dog breeds. [ABSTRACT FROM AUTHOR]

Background: Cascade testing can offer improved surveillance and timely introduction of clinical management for the at-risk biological relatives. Data on cascade testing and costs in mitochondrial diseases are lacking. To address this gap, we performed a cross-sectional retrospective study to provide a framework for cascade testing in mitochondrial diseases, to estimate the eligibility versus real-time uptake of cascade testing and to evaluate the cost of the genetic diagnosis of index cases and the cost of predictive cascade testing. Methods: Data was collected through retrospective chart review. The variant inheritance pattern guided the identification of eligible first-degree relatives: (i) Males with mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) – siblings and mothers. (ii) Females with mtDNA SNVs – siblings, mothers and offspring. (iii) Autosomal Dominant (AD) nuclear DNA (nDNA) variants – siblings, offspring and both parents. (iv) Autosomal Recessive (AR) nDNA variants – siblings. Results: We recruited 99 participants from the Adult Mitochondrial Disease Clinic in Sydney. The uptake of cascade testing was 55.2% in the mtDNA group, 55.8% in the AD nDNA group and 0% in AR nDNA group. Of the relatives in mtDNA group who underwent cascade testing, 65.4% were symptomatic, 20.5% were oligosymptomatic and 14.1% were asymptomatic. The mean cost of cascade testing for eligible first-degree relatives (mtDNA group: $694.7; AD nDNA group: $899.1) was lower than the corresponding index case (mtDNA group: $4578.4; AD nDNA group: $5715.1) (p < 0.001). Conclusion: The demand for cascade testing in mitochondrial diseases varies according to the genotype and inheritance pattern. The real-time uptake of cascade testing can be influenced by multiple factors. Early diagnosis of at-risk biological relatives of index cases through cascade testing, confirms the diagnosis in those who are symptomatic and facilitates implementation of surveillance strategies and clinical care at an early stage of the disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Inbreeding increases homozygosity, often leading to the co-expression of recessive deleterious alleles and a reduction in genetic diversity. Traditional methods involve pedigree-based analysis, but high-density arrays have enabled precise estimations using genomic markers. A study comparing genomic inbreeding coefficients from DNA marker data with conventional coefficients from pedigree information in Korean commercial pig breeds reveals differences in inbreeding levels and trends among breeds. The finding highlights differences in inbreeding levels and trends among breeds, emphasizing the importance of using both genomic and conventional methods for a comprehensive understanding of inbreeding, which is crucial for effective breeding programs and maintaining genetic diversity. The purpose of this study was to estimate the homozygosity distribution and compute genomic and conventional inbreeding coefficients in three genetically diverse pig breed populations. The genomic and pedigree data of Duroc (1586), Landrace (2256), and Yorkshire (3646) were analyzed. We estimated and compared various genomic and pedigree inbreeding coefficients using different models and approaches. A total of 709,384 ROH segments in Duroc, 816,898 in Landrace, and 1,401,781 in Yorkshire, with average lengths of 53.59 Mb, 56.21 Mb, and 53.46 Mb, respectively, were identified. Relatively, the Yorkshire breed had the shortest ROH segments, whereas the Landrace breed had the longest mean ROH segments. Sus scrofa chromosome 1 (SSC1) had the highest chromosomal coverage by ROH across all breeds. Across breeds, an absolute correlation (1.0) was seen between FROH total and FROH1–2Mb, showing that short ROH were the primary contributors to overall FROH values. The overall association between genomic and conventional inbreeding was weak, with values ranging from 0.058 to 0.140. In contrast, total genomic inbreeding (FROH) and ROH classes showed a strong association, ranging from 0.663 to 1.00, across the genotypes. The results of genomic and conventional inbreeding estimates improve our understanding of the genetic diversity among genotypes. [ABSTRACT FROM AUTHOR]

Abstract Background Cascade testing can offer improved surveillance and timely introduction of clinical management for the at-risk biological relatives. Data on cascade testing and costs in mitochondrial diseases are lacking. To address this gap, we performed a cross-sectional retrospective study to provide a framework for cascade testing in mitochondrial diseases, to estimate the eligibility versus real-time uptake of cascade testing and to evaluate the cost of the genetic diagnosis of index cases and the cost of predictive cascade testing. Methods Data was collected through retrospective chart review. The variant inheritance pattern guided the identification of eligible first-degree relatives: (i) Males with mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) – siblings and mothers. (ii) Females with mtDNA SNVs – siblings, mothers and offspring. (iii) Autosomal Dominant (AD) nuclear DNA (nDNA) variants – siblings, offspring and both parents. (iv) Autosomal Recessive (AR) nDNA variants – siblings. Results We recruited 99 participants from the Adult Mitochondrial Disease Clinic in Sydney. The uptake of cascade testing was 55.2% in the mtDNA group, 55.8% in the AD nDNA group and 0% in AR nDNA group. Of the relatives in mtDNA group who underwent cascade testing, 65.4% were symptomatic, 20.5% were oligosymptomatic and 14.1% were asymptomatic. The mean cost of cascade testing for eligible first-degree relatives (mtDNA group: $694.7; AD nDNA group: $899.1) was lower than the corresponding index case (mtDNA group: $4578.4; AD nDNA group: $5715.1) (p

The single-step approach has become the most widely-used methodology for genomic evaluations when only a subset of phenotyped individuals in the pedigree are genotyped, where the genotypes for non-genotyped individuals are imputed based on gene contents (i.e., genotypes) of genotyped individuals through their pedigree relationships. We proposed a new method named single-step neural network with mixed models (NNMM) to represent single-step genomic evaluations as a neural network of three sequential layers: pedigree, genotypes, and phenotypes. These three sequential layers of information create a unified network instead of two separate steps, allowing the unobserved gene contents of non-genotyped individuals to be sampled based on pedigree, observed genotypes of genotyped individuals, and phenotypes. In addition to imputation of genotypes using all three sources of information, including phenotypes, genotypes, and pedigree, single-step NNMM provides a more flexible framework to allow nonlinear relationships between genotypes and phenotypes, and for individuals to be genotyped with different single-nucleotide polymorphism (SNP) panels. The single-step NNMM has been implemented in the software package JWAS.

Understanding somatic mutations and structural variations in domestic pigs (Sus scrofa domestica) is critical due to their increasing importance as model organisms in biomedical research. In this study, we conducted a comprehensive analysis through whole-genome sequencing of skin, organs, and blood samples. By examining two pig pedigrees, we investigated the inheritance and sharedness of structural variants among fathers, mothers, and offsprings. Utilizing single-cell clonal expansion techniques, we observed significant variations in the number of somatic mutations across different tissues. An in-house developed pipeline enabled precise filtering and analysis of these mutations, resulting in the construction of individual phylogenetic trees for two pigs. These trees explored the developmental relationships between different tissues, revealing insights into clonal expansions from various anatomical locations. This study enhances the understanding of pig genomes, affirming their increasing value in clinical and genomic research, and provides a foundation for future studies in other animals, paralleling previous studies in mice and humans. This approach not only deepens our understanding of mammalian genomic variations but also strengthens the role of pigs as a crucial model in human health and disease research. [ABSTRACT FROM AUTHOR]

Objective To address the difficulties faced in the industrial design of rail transit passenger vehicles, it is necessary to integrate innovative industrial design thinking and concepts to establish a comprehensive method for modular and pedigree applications in rail transit passenger vehicle design. Method First, a modularization analysis of passenger vehicle design components is conducted, dividing the compartment into fixed, optional, and custom modules, and categorizing the exterior into color and shape modules. Then, a pedigree analysis of passenger vehicle design contents is performed, establishing an industrial design pedigree from three dimensions: design requirements, evolutionary context, and product characteristics. Finally, based on passenger vehicle design characteristics, a passenger vehicle industrial design method for modularization and pedigree comprehensive applications is constructed, comprising three steps: sorting out modules based on design requirements, adjusting modules oriented by evolutionary context, and organizing modules based on product characteristics. Result & Conclusion The industrial design method is applied to a passenger vehicle design by a subsidiary manufacturer of CRRC (China Railway Rolling Stock Corporation). The design example verifies the feasibility of the constructed method. The modularization design allows for quick and flexible adjustments of design contents according to user needs, while pedigree design enhances design coherence and systematicity. Combining these approaches enables the completion of both exterior and interior passenger vehicle designs within a shorter design cycle, thereby improving design quality and reflecting brand features.

Abstract Background Inbreeding and relationship coefficients are essential for conservation and breeding programs. Whether dealing with a small conserved population or a large commercial population, monitoring the inbreeding rate and designing mating plans that minimize the inbreeding rate and maximize the effective population size is important. Free, open-source, and efficient software may greatly contribute to conservation and breeding programs and help students and researchers. Efficient methods exist for calculating inbreeding coefficients. Therefore, an efficient way of calculating the numerator relationship coefficients is via the inbreeding coefficients. i.e., the relationship coefficient between parents is twice the inbreeding coefficient of their progeny. A dummy progeny is introduced where no progeny exists for a pair of individuals. Calculating inbreeding coefficients is very fast, and finding whether a pair of individuals has a progeny and picking one from multiple progenies is computationally more demanding. Therefore, the R package introduces a dummy progeny for any pair of individuals whose relationship coefficient is of interest, whether they have a progeny or not. Results Runtime and peak memory usage were benchmarked for calculating relationship coefficients between two sets of 250 and 800 animals (200,000 dummy progenies) from a pedigree of 2,721,252 animals. The program performed efficiently (200,000 relationship coefficients, which involved calculating 2,721,252 + 200,000 inbreeding coefficients) within 3:45 (mm:ss). Providing the inbreeding coefficients (for real animals), the runtime was reduced to 1:08. Furthermore, providing the diagonal elements of D in $$\textbf{A} = \textbf{TDT}^{\prime }$$ A = TDT ′ (d), the runtime was reduced to 54s. All the analyses were performed on a machine with a total memory size of 1 GB. Conclusions The R package FnR is free and open-source software with implications in conservation and breeding programs. It proved to be time and memory efficient for large populations and many dummy progenies. Calculation of inbreeding coefficients can be resumed for new animals in the pedigree. Thus, saving the latest inbreeding coefficient estimates is recommended. Calculation of d coefficients (from scratch) was very fast, and there was limited value in storing those for future use.

Abstract Background Haemochromatosis is a genetic disease characterized by the excessive deposition of iron in various tissues and organs, eventually results in organ damage including cirrhosis, diabetes, cardiomyopathy, etc. SLC40A1-related haemochromatosis is associated with gain-of-function mutations in the SLC40A1 gene, which encodes ferroportin. While sporadic reports of this condition exist in mainland China, the understanding of the phenotype and genetic pattern associated with the SLC40A1 p.Y333H mutation remains incomplete. Case presentation We report a pedigree with heterozygous p.Y333H mutation in Chinese Han population. The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. He displayed markedly elevated serum ferritin level and transferrin saturation. Magnetic resonance imaging showed iron deposition in the liver, spleen, and pancreas, along with cirrhosis and splenomegaly. Whole exome sequencing identified a heterozygous allelic variant c.997T > C (p.Y333H). Genetic screening of family members identified four first-degree relatives and three second-degree relatives having the same mutation. Additional cases with this mutation from two published studies were included. Among the probands and screened relatives, all eight males aged over 30 y had ferritin level > 1000 µg/L, transferrin saturation > 90%. Four patients with organ damage in the present study received therapeutic phlebotomy, alleviating clinical symptoms and improving in transferrin saturation and serum ferritin. Conclusions This study reports the largest pedigree with heterozygous SLC40A1 p.Y333H mutation in the Chinese population to date. In Chinese families, males over 30 years old with hemochromatosis due to SLC40A1 p.Y333H mutation exhibit severe iron overload phenotypes.

Joint association analysis of multiple traits with multiple genetic variants can provide insight into genetic architecture and pleiotropy, improve trait prediction, and increase power for detecting association. Furthermore, some traits are naturally high-dimensional, e.g., images, networks, or longitudinally measured traits. Assessing significance for multitrait genetic association can be challenging, especially when the sample has population sub-structure and/or related individuals. Failure to adequately adjust for sample structure can lead to power loss and inflated type 1 error, and commonly used methods for assessing significance can work poorly with a large number of traits or be computationally slow. We developed JASPER, a fast, powerful, robust method for assessing significance of multitrait association with a set of genetic variants, in samples that have population sub-structure, admixture, and/or relatedness. In simulations, JASPER has higher power, better type 1 error control, and faster computation than existing methods, with the power and speed advantage of JASPER increasing with the number of traits. JASPER is potentially applicable to a wide range of association testing applications, including for multiple disease traits, expression traits, image-derived traits, and microbiome abundances. It allows for covariates, ascertainment, and rare variants and is robust to phenotype model misspecification. We apply JASPER to analyze gene expression in the Framingham Heart Study, where, compared to alternative approaches, JASPER finds more significant associations, including several that indicate pleiotropic effects, most of which replicate previous results, while others have not previously been reported. Our results demonstrate the promise of JASPER for powerful multitrait analysis in structured samples. We developed JASPER, a fast, robust method for multitrait association testing with a set of genetic variants. JASPER accommodates population structure and relatedness, while handling diverse trait types, making it a powerful tool for uncovering pleiotropic effects, as demonstrated in our analysis of gene expression traits in the Framingham cohort. [ABSTRACT FROM AUTHOR]

Pigeonpea [Cajanus cajan (L.) Mill.] may have cross- or self-pollination that allows the use of hybrids or improved genotypes by conventional breeding approaches in pigeonpea production. The objectives of this research were to: 1) compare the agronomic performance of a hybrid vs. breeding lines (BLs) developed by pedigree and bulk methods, and 2) determine if there were average and useful heterosis and heterobeltiosis for quantitative traits. The hybrid 13KLAF1 and UPE-1, UPE-2, UPE-3, UPE-4, UPE-5 BLs, their parents (13KPP-264-05 and 'Lázaro'), and one early maturity check 'ICPL 86012' were evaluated in field trials in Isabela and Lajas, PR. Data of plant height, days to flowering and harvest, seed yield, and weight of 100 dry-seeds were noted for all genotypes. There were no significant differences between 13KLAF1 and UPE BLs for plant height in both locations. 'Lázaro' was late maturity in Isabela (157 days) and Lajas (124 days), as expected. The weight of 100 seeds for all genotypes did not reach values more than 18.5 and 16.3 g such as those observed for 13KPP-264-05 in Isabela and Lajas, respectively. The higher seed yields were observed for 13KLAF1 (3112 kg·ha-1), UPE-4 (2970 kg·ha-1), and 'ICPL 86012' (2739 kg·ha-1) in Isabela, whereas 13KLAF1 (1599 kg·ha-1) and 'ICPL 86012' (1450 kg·ha-1) produced the higher yields in Lajas. The 13KLAF1 showed an average heterosis and heterobeltiosis of 87% and 60%, and 78% and 30% for seed yield in Isabela and Lajas, respectively. The useful heterosis was >125% in both locations. [ABSTRACT FROM AUTHOR]

Small populations of endangered species risk losing already eroded genetic diversity, important for adaptive potential, through the effects of genetic drift. The magnitude of drift can be mitigated by maximising the effective population size, as is the goal of genetic management strategies. Different mating systems, specifically those leading to reproductive skew, exacerbate genetic drift by distorting contributions. In the absence of an active management strategy, reproductive skew will have long-term effects on the genetic composition of a population, particularly where admixture is present. Here we examine the contrasting effects of conservation management strategies in two ex situ populations of the Critically Endangered eastern black rhino (Diceros bicornis michaeli), one managed as a semi-wild population in South Africa (SAx), and one managed under a mean-kinship breeding strategy in European zoos. We use molecular data to reconstruct pedigrees for both populations and validate the method using the zoo studbook. Using the reconstructed pedigree and studbook we show there is male sex-specific skew in both populations. However, the zoo's mean-kinship breeding strategy effectively reduces reproductive skew in comparison to a semi-wild population with little genetic management. We also show that strong male reproductive skew in SAx has resulted in extensive admixture, which may require a re-evaluation of the population's original intended role in the black rhino meta-population. With a high potential for admixture in many ex situ populations of endangered species, molecular and pedigree data remain vital tools for populations needing to balance drift and selection. [ABSTRACT FROM AUTHOR]

Copyright of Urban Mass Transit is the property of Urban Mass Transit Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Serbia preserves a high number of local grape varieties, which have been cultivated across thecountry forcenturies.Now, these ancient varieties are in the spotlight, and there is a global trend towards their recovery and characterization because they can revitalize regional, national and international grape and wine sectors. In addition, their genetic study can be useful to find new pedigree relationships to reveal how local varietal assortment evolve dover time. Here, thegeneticcharacterizationof138 grapevines from old Serbian vineyards revealed 59 different genetic profiles, 49 of which were identified as grapevine varieties whose origin in the country could be linked to some major Serbian historical periods.Most of the genetic profiles found in this work arranged in a complex pedigree network that integrates numerous grapevine varieties from diverse Balkan countries, agreeing with an intense exchange of plant material among Balkan regions for centuries. This analysis identified some varieties as important founders of Balkan genetic resources, like 'Alba Imputotato', 'Braghina Rosie', 'Coarna Alba', and 'Vulpea'. After deepening into their genealogy, these major direct founders might have ultimately derived from 'Visparola', an ancient variety of likely Balkan origin with a major founding role in some European regions. Our results also indicated the genetic singularity of the grapevine resources fromthe Balkanswhen compared to those fromother relevant winemaking regions, supporting the interest of their detailed study to evaluate their oenological potential and for the eventual identification of useful traits tocounteract current viticulture challenges. [ABSTRACT FROM AUTHOR]

The preferred tool for conceptualizing, determining, and claiming relations of kinship, ancestry, and descent among humans are diagrams. For this reason, and at the same time to avoid a reduction to biology as transported by terms such as kinship, ancestry, and descent, we introduce the expression diagrammatics of relatedness. We seek to understand the enormous influence that especially tree diagrams have had as a way to express and engage with human relatedness, but hold that this success can only be adequately understood by attending to what in fact are broader diagrammatic practices. These practices bring to light that diagrams of relatedness do not simply make visible natural connections, but create or deny relations in particular ways and for particular reasons. In this special section, contributors investigate diagrams of relatedness in genealogy, heredity, as well as biological and social anthropology. Conceiving of diagrams as techniques that transcend such binaries as 'thought and action' and 'image and text', we aim at an understanding of how they were constructed and how they functioned in particular epistemic, cultural, and political contexts. [ABSTRACT FROM AUTHOR]

The marmoset is a fundamental nonhuman primate model for the study of aging, neurobiology, and many other topics. Genetic management of captive marmoset colonies is complicated by frequent chimerism in the blood and other tissues, a lack of tools to enable cost‐effective, genome‐wide interrogation of variation, and historic mergers and migrations of animals between colonies. We implemented genotype‐by‐sequencing (GBS) of hair follicle derived DNA (a minimally chimeric DNA source) of 82 marmosets housed at the Southwest National Primate Research Center (SNPRC). Our primary goals were the genetic characterization of our marmoset population for pedigree verification and colony management and to inform the scientific community of the functional genetic makeup of this valuable resource. We used the GBS data to reconstruct the genetic legacy of recent mergers between colonies, to identify genetically related animals whose relationships were previously unknown due to incomplete pedigree information, and to show that animals in the SNPRC colony appear to exhibit low levels of inbreeding. Of the >99,000 single‐nucleotide variants (SNVs) that we characterized, >9800 are located within gene regions known to harbor pathogenic variants of clinical significance in humans. Overall, we show the combination of low‐resolution (sparse) genotyping using hair follicle DNA is a powerful strategy for the genetic management of captive marmoset colonies and for identifying potential SNVs for the development of biomedical research models. Research Highlights: Genotype‐by‐sequencing of hair follicle DNA allows effective genetic characterization of captive marmosets for colony management.Ancestry analysis of genetic data reflects recent colony mergers and site‐specific genetic characteristics.Genetic data augments pedigree records to reveal previously unknown relationships in a captive population. [ABSTRACT FROM AUTHOR]

For species of management concern, accurate estimates of inbreeding and associated consequences on reproduction are crucial for predicting their future viability. However, few studies have partitioned this aspect of genetic viability with respect to reproduction in a group-living social mammal. We investigated the contributions of foundation stock lineages, putative fitness consequences of inbreeding, and genetic diversity of the breeding versus nonreproductive segment of the Yellowstone National Park gray wolf population. Our dataset spans 25 years and seven generations since reintroduction, encompassing 152 nuclear families and 329 litters. We found more than 87% of the pedigree foundation genomes persisted and report influxes of allelic diversity from two translocated wolves from a divergent source in Montana. As expected for group-living species, mean kinship significantly increased over time but with minimal loss of observed heterozygosity. Strikingly, the reproductive portion of the population carried a significantly lower genome-wide inbreeding coefficients, autozygosity, and more rapid decay for linkage disequilibrium relative to the nonbreeding population. Breeding wolves had significantly longer lifespans and lower inbreeding coefficients than nonbreeding wolves. Our model revealed that the number of litters was negatively significantly associated with heterozygosity (R  = −0.11). Our findings highlight genetic contributions to fitness, and the importance of the reproductively active individuals in a population to counteract loss of genetic variation in a wild, free-ranging social carnivore. It is crucial for managers to mitigate factors that significantly reduce effective population size and genetic connectivity, which supports the dispersion of genetic variation that aids in rapid evolutionary responses to environmental challenges. [ABSTRACT FROM AUTHOR]

Inbreeding depression results in a decrease in the average phenotypic values of affected traits. It has been traditionally estimated from pedigree‐based inbreeding coefficients. However, with the development of single‐nucleotide polymorphism arrays, novel methods were developed for calculating the inbreeding coefficient, and consequently, inbreeding depression. The aim of the study was to analyse inbreeding depression in 6 growth and 2 reproductive traits in the Asturiana de los Valles cattle breed using both genealogical and molecular information. The pedigree group comprised 225,848 records and an average equivalent number of complete generations of 2.3. The molecular data comprised genotypes of 2693 animals using the Affymetrix medium‐density chip. Using the pedigree information, three different inbreeding coefficients were estimated for the genotyped animals: the full pedigree coefficient (FPED), and the recent and ancient inbreeding coefficients based on the information of the last three generations (FPED<3G) and until the last three generations (FPED>3G), respectively. Using the molecular data, seven inbreeding coefficients were calculated. Four of them were estimated based on runs of homozygosity (ROH), considering (1) the total length (FROH), (2) segments shorter than 4 megabases (FROH<4), (3) between 4 and 17 megabases (FROH4‐17), and (4) longer than 17 Mb (FROH>17). Additionally, the three inbreeding coefficients implemented in the Plink software (FHAT1‐3) were estimated. Inbreeding depression was estimated using linear mixed‐effects model with inbreeding coefficients used as covariates. All analysed traits (birth weight, preweaning average daily gain, weaning weight adjusted at 180 days, carcass weight, calving ease, age at first calving, calving interval) showed a statistically significant non‐zero effect of inbreeding depression estimated from the pedigree group, except for the Postweaning Average Daily Gain trait. When inbreeding coefficients were based on the genomic group, statistically significant inbreeding depression was observed for two traits, Preweaning Average Daily Gain and Weaning Weight based on FROH, FROH>17, and FHAT3 inbreeding coefficients. Nevertheless, similar to inbreeding depression estimated based on pedigree information, estimates of inbreeding depression based on genomic information had no relevant economic impact. Despite this, from a long‐term perspective, genotyped data could be included to maximize genetic progress in genetic programs following an optimal genetic contribution strategy and to consider individual inbreeding load instead global inbreeding. ROH islands were identified on chromosomes 2, 3, 8, 10, and 16. Such regions contain several candidate genes for growth development, intramuscular fat, body weight and lipid metabolism that are related to production traits selected in Asturiana de los Valles breed. [ABSTRACT FROM AUTHOR]

Background: Haemochromatosis is a genetic disease characterized by the excessive deposition of iron in various tissues and organs, eventually results in organ damage including cirrhosis, diabetes, cardiomyopathy, etc. SLC40A1-related haemochromatosis is associated with gain-of-function mutations in the SLC40A1 gene, which encodes ferroportin. While sporadic reports of this condition exist in mainland China, the understanding of the phenotype and genetic pattern associated with the SLC40A1 p.Y333H mutation remains incomplete. Case presentation: We report a pedigree with heterozygous p.Y333H mutation in Chinese Han population. The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. He displayed markedly elevated serum ferritin level and transferrin saturation. Magnetic resonance imaging showed iron deposition in the liver, spleen, and pancreas, along with cirrhosis and splenomegaly. Whole exome sequencing identified a heterozygous allelic variant c.997T > C (p.Y333H). Genetic screening of family members identified four first-degree relatives and three second-degree relatives having the same mutation. Additional cases with this mutation from two published studies were included. Among the probands and screened relatives, all eight males aged over 30 y had ferritin level > 1000 µg/L, transferrin saturation > 90%. Four patients with organ damage in the present study received therapeutic phlebotomy, alleviating clinical symptoms and improving in transferrin saturation and serum ferritin. Conclusions: This study reports the largest pedigree with heterozygous SLC40A1 p.Y333H mutation in the Chinese population to date. In Chinese families, males over 30 years old with hemochromatosis due to SLC40A1 p.Y333H mutation exhibit severe iron overload phenotypes. [ABSTRACT FROM AUTHOR]

Changes in wool prices, labour costs and animal welfare have sparked interest in several new sheep traits. Shedding, the ability of moulting or seasonal wool loss in sheep, is one of them. Here, we aimed to develop breeding values for shedding using existing data from New Zealand flocks. We used breeder-collected shedding scores, 0 = 'no shedding on any part of the body' to 10 = 'wool shed fully from all the body', for Wiltshire and Wiltshire-composite lambs born between 2003 and 2022. After QC, 20,653 phenotypic records from 25,066 animals with pedigree information (393 sires and 7439 dams from 12 flocks) were included in the analyses. Genetic parameters and breeding values were obtained using a genetic additive model with pedigree data (BLUP model), assuming shedding scores were quantitative. The genetic model incorporated the following variables: date of birth, sex, birth and rearing rank, age of dam and contemporary group. We found a high heritability for lamb shedding, 0.54 (0.02), and estimated a low-to-moderate prediction accuracy of breeding values (ranging from 0.09 to 0.36) using forward-validation. Our results confirmed that shedding can be subject to selection and that pedigree-based breeding values for this trait can be a useful tool for breeders. [ABSTRACT FROM AUTHOR]

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.

Assessing the genetic diversity of local breeds is essential for conserving these unique breeds, which may possess unique traits. This study provides the genomic characterisation of eight indigenous sheep breeds in Belgium based on pedigree and single nucleotide polymorphism (SNP) analysis. A total of 687 sheep were genotyped and were subjected to a rigorous quality control, resulting in a set of 45 978 autosomal SNPs. Pedigree analysis showed breed-average inbreeding estimates between 3.3% and 11.3%. The genomic analysis included an assessment of runs of homozygosity (ROH) to examine the genomic inbreeding coefficient, with breed-average inbreeding coefficients estimated between 4.1% and 8.5%. Runs of homozygosity islands were identified in six of the eight breeds studied, with some exhibiting an incidence of up to 58%. Interestingly, several ROH islands overlapped with other breeds included in this study, as well as with international sheep breeds. Pedigree-based effective population sizes were estimated below 100 for all breeds, whereas genomic-based effective population sizes were below 24, indicating that these eight local sheep breeds are endangered. Principal component analysis, admixture analyses, and Fst computations were used to study the population structure and genetic differences. A neighbour−joining tree using 95 international sheep breeds positioned the eight local breeds in the group of milksheep, Texel sheep and the Scandinavian breeds. Additionally, the investigation of paternal oY1 genotypes revealed diverse lineage origins within the Belgian sheep population. This study refines and deepens our knowledge about the local sheep breeds in Belgium, thereby improving their management and conservation. Moreover, as these breeds are linked to other international breeds, these insights are significant for the global scientific community.

The purpose of this article is to determine the cause of Leber congenital amaurosis (LCA) in Chuuk state, Federated States of Micronesia (FSM). In this prospective observational case series, five patients with early-onset vision loss were examined in Chuuk state, FSM, during an ocular genetics visit to study the elevated incidence of microphthalmia. Because of their low vision these patients were incorrectly assumed to have microphthalmia. A complete ophthalmological exam established a clinical diagnosis of LCA. Candidate gene exons were sequenced with a targeted retinal dystrophy panel. Five subjects in three related families were diagnosed with LCA. All five were from Tonoas Island, within the Chuuk Lagoon, with ages ranging from 6 months to 16 years. DNA sequencing of affected individuals revealed a homozygous CRB1 NM_201253.3:c.3134del pathogenic variant, which was heterozygous in their parents. CRB1 genotypes were confirmed by a PCR restriction assay. We report identification of a founder pathogenic variant in CRB1 responsible for autosomal recessive LCA in this isolated community. This discovery will lead to appropriate recurrence risk counseling.

Background Primary hyperoxaluria type 2 (PH2) is a rare disorder caused by GRHPR mutations. Research on the mutation spectrum and pedigree of PH2 helps in comprehending its pathogenesis and clinical outcomes, guiding clinical diagnosis and treatment.Methods We report a case of PH2 with a three-generational pedigree. The GRHPR genotypes of the family members were confirmed by Sanger sequencing. Urine and blood samples were collected for biochemical analysis. Computational analysis was performed to assess the pathogenicity of the mutations. Cellular experiments based on site-directed mutagenesis were conducted to confirm the effect of mutations on GRHPR expression, activity, and subcellular localization.Results The proband underwent her first kidney transplantation in 2015, and experienced recurrent urinary tract infections and urolithiasis postoperatively. Graft failure occurred in 2018. Whole exome sequencing identified compound heterozygous GRHPR mutations p.G160E/p.P203Rfs*7. The patient underwent a second kidney transplantation in 2019 and maintained good graft function with urine dilution measures. Notably, her brother and sister carried the same mutations; however, only the proband progressed to renal failure. Computational analysis suggested that p.G160E reduced the affinity of GRHPR for coenzymes. Cellular experiments indicated that p.G160E reduced GRHPR activity (p

The purpose of this paper is to identify likely pathogenic non-coding variants in inherited retinal dystrophy (IRD) genes, using genome sequencing (GS). Patients with IRD were recruited to the study and underwent comprehensive ophthalmological evaluation and GS. The results of GS were investigated through virtual gene panel analysis, and plausible pathogenic variants and clinical phenotype evaluated by the multidisciplinary team (MDT) discussion. For unsolved patients in whom a specific gene was suspected to harbor a missed pathogenic variant, targeted re-analysis of non-coding regions was performed on GS data. Candidate variants were functionally tested by messenger RNA analysis, minigene or luciferase reporter assays. Previously unreported, likely pathogenic, non-coding variants in 7 genes (PRPF31, NDP, IFT140, CRB1, USH2A, BBS10 and GUCY2D), were identified in 11 patients. These were shown to lead to mis-splicing (PRPF31, IFT140, CRB1 and USH2A) or altered transcription levels (BBS10 and GUCY2D). MDT-led, phenotype-driven, non-coding variant re-analysis of GS is effective in identifying the missing causative alleles.

Dilated cardiomyopathy (DCM) is characterized by decreased systolic function and dilation of one or both ventricles, often leading to heart failure or sudden death. Two 10-month-old sibling Nova Scotia Duck Tolling Retrievers (NSDTR) died acutely with evidence of dilated cardiomyopathy with myocardial fibrosis. Association analysis using two cases and 35 controls identified three candidate regions homozygous in the two cases. Whole genome sequencing identified a frameshift deletion in the LMNA gene (NC_049228.1:g.41688530del, NP_001274080:p.(Asp576ThrfsTer124)). Three retrospectively identified NSDTRs with sudden death before 2 years of age and severe myocardial fibrosis were also homozygous for the deletion. One 5 year old with sudden death and myocardial fibrosis was heterozygous for the deletion. This variant was not identified in 722 dogs of other breeds, nor was it identified to be homozygous in 784 NSDTR. LMNA codes for lamin A/C proteins, which are type V intermediate filaments that provide structural support to the nuclear membrane. In humans, LMNA variants can cause DCM with sudden death as well as diseases of striated muscles, lipodystrophy, neuropathies, and accelerated aging disorders. This frameshift deletion is predicted to affect processing of prelamin A into lamin A. Pedigree analysis in the NSDTR and functional evaluation of heterozygotes is consistent with a predominantly recessive mode of inheritance and possibly low penetrance in heterozygotes in contrast to people, where most pathogenic LMNA variants are dominantly inherited.

Pathogenic variants in more than 14 genes have been implicated in monogenic diabetes; however, a significant fraction of individuals with young-onset diabetes and a strong family history of diabetes have unknown genetic etiology. To identify novel pathogenic alleles for monogenic diabetes, we performed whole-genome sequencing (WGS) on four related individuals with type 2 diabetes - including one individual diagnosed at the age of 31 years - that were negative for mutations in known monogenic diabetes genes. The individuals were ascertained from a large case-control study and had a multi-generation family history of diabetes. Identity-by-descent (IBD) analysis revealed that the four individuals represent two sib-pairs that are third-degree relatives. A novel missense mutation (p.P81S) in the PAX6 gene was one of eight rare coding variants across the genome shared IBD by all individuals and was inherited from affected mothers in both sib-pairs. The mutation affects a highly conserved amino acid located in the paired-domain of PAX6 - a hotspot for missense mutations that cause aniridia and other eye abnormalities. However, no eye-related phenotype was observed in any individual. The well-established functional role of PAX6 in glucose-induced insulin secretion and the co-segregation of diabetes in families with aniridia provide compelling support for the pathogenicity of this mutation for diabetes. The mutation could be classified as "likely pathogenic" with a posterior probability of 0.975 according to the ACMG/AMP guidelines. This is the first PAX6 missense mutation that is likely pathogenic for autosomal-dominant adult-onset diabetes without eye abnormalities.

CDKN2A at chromosome positon 9p21 is a tumour suppressor gene encoding the cell cycle regulators p16 and p14ARF. While melanoma is associated with variants affecting both transcripts, families with mutations involving the p14ARF-specific exon 1B may be predisposed to central nervous system tumours. We describe a family with a deletion of exon 1B in CDKN2A, who had multiple cutaneous melanomas, neural tumours and various malignancies.

Introduction: Knowing a person's family tree or origin is one means of identifying a person. The DNA (Deoxyribonucleic Acid) to determine the origin of a person is a trend in the United States and Europe now. DNA examinations had the capabilities to identify eye color, skin color, and hair color from bone samples. In Indonesia, the identification process for bone remains is still less informative. The implementation of DNA identification is not widely used due to high operational costs and requires a huge database. Purposed: Explore the literature regarding the use of DNA for identifying individuals and tracing their lineages. Methods: This study uses a systematic review. Data is obtained between 2017 - 2022 on PubMed searches. Extract data with search keys in the form of genealogy remains' 'human' and 'DNA' The review of the discussion is only for journals included in the free full text. Results: Articles that match the search key are 22 articles. Nine articles are free full text and human subjects. The journal discusses hereditary diseases, DNA databases, case reports, and DNA research methods. Most research uses the Y chromosome to measure the pedigrees, but it could be using other chromosomes. Conclusions: DNA examination could be used to measure heredity in great detail, especially in bone samples, but there are still many limitations like the application in society is very lacking. [ABSTRACT FROM AUTHOR]

Knowledge of the parental origin of crop species is a prerequisite for formulating effective strategies for genetic conservation, management, and utilisation of genotypes in breeding programmes and genetic studies. In the case of the potato, although pedigree information is well documented, the possible lack of accurate pedigree data for certain cultivars constitutes a loss of opportunity to exploit the selection gain, the precise targeting of a market niche, or other breeding objectives. In this study, the genetic profiles of 1249 varieties were examined using a set of 35 polymorphic simple sequence repeats (SSR) markers with the available pedigree information to achieve pedigree validation. The maximum likelihood (LOD) was used to validate pedigree information of potato accessions for which the genetic data of at least one parent was available in the dataset. Our results showed that among the accessions for which both parents were genotyped, 81.7% presented a validated pedigree, while 18.3% presented a pedigree conflict (for at least one parent). Among the accessions for which only one parent was available in the dataset, 91.3% presented a validated pedigree, while 8.7% presented a pedigree conflict. Then, pedigree reconstruction was investigated to determine the most likely parent candidates for varieties whose pedigree is either questionable or lacking information. [ABSTRACT FROM AUTHOR]

Genomic data in Gossypium provide numerous data resources for the cotton genomics community. However, to fill the gap between genomic analysis and breeding field work, detecting the featured genomic items of a subset cohort is essential for geneticists. We developed FPFinder v1.0 software to identify a subset of the cohort's fingerprint genomic sites. The FPFinder was developed based on the term frequency–inverse document frequency algorithm. With the short-read sequencing of an elite cotton pedigree, we identified 453 pedigree fingerprint genomic sites and found that these pedigree-featured sites had a role in cotton development. In addition, we applied FPFinder to evaluate the geographical bias of fiber-length-related genomic sites from a modern cotton cohort consisting of 410 accessions. Enriching elite sites in cultivars from the Yangtze River region resulted in the longer fiber length of Yangze River-sourced accessions. Apart from characterizing functional sites, we also identified 12,536 region-specific genomic sites. Combining the transcriptome data of multiple tissues and samples under various abiotic stresses, we found that several region-specific sites contributed to environmental adaptation. In this research, FPFinder revealed the role of the cotton pedigree fingerprint and region-specific sites in cotton development and environmental adaptation, respectively. The FPFinder can be applied broadly in other crops and contribute to genetic breeding in the future. [ABSTRACT FROM AUTHOR]

Academia today is deeply hierarchical and continues to be centered around perceptions of prestige and symbolic capital. The symbolic capital, or pedigree, associated with the training one receives at the graduate level greatly informs how academics navigate their careers and how they advance professionally. In investigating the formation of the professional habitus of Indonesian academics, we are interested in how their graduate training informs both their career progression and their teaching practices. We theorize graduate training using the terms 'hybrid' for the participants who have a mix of overseas and domestic training and 'homegrown' for those who were educated solely in Indonesia. The data suggests that hybrid academics in Indonesia are more open to innovating their teaching practice and advance at a quicker pace than homegrown academics. [ABSTRACT FROM AUTHOR]

Pigeonpea [Cajanus cajan (L.) Mill.] may have cross- or self-pollination that allows the use of hybrids or improved genotypes by conventional breeding approaches in pigeonpea production. The objectives of this research were to: 1) compare the agronomic performance of a hybrid vs. breeding lines (BLs) developed by pedigree and bulk methods, and 2) determine if there were average and useful heterosis and heterobeltiosis for quantitative traits. The hybrid 13KLAF1 and UPE-1, UPE-2, UPE-3, UPE-4, UPE-5 BLs, their parents (13KPP-264-05 and ‘Lázaro’), and one early maturity check ‘ICPL 86012’ were evaluated in field trials in Isabela and Lajas, PR. Data of plant height, days to flowering and harvest, seed yield, and weight of 100 dry-seeds were noted for all genotypes. There were no significant differences between 13KLAF1 and UPE BLs for plant height in both locations. ‘Lázaro’ was late maturity in Isabela (157 days) and Lajas (124 days), as expected. The weight of 100 seeds for all genotypes did not reach values more than 18.5 and 16.3 g such as those observed for 13KPP-264-05 in Isabela and Lajas, respectively. The higher seed yields were observed for 13KLAF1 (3112 kg·ha−1), UPE-4 (2970 kg·ha−1), and ‘ICPL 86012’ (2739 kg·ha−1) in Isabela, whereas 13KLAF1 (1599 kg·ha−1) and ‘ICPL 86012’ (1450 kg·ha−1) produced the higher yields in Lajas. The 13KLAF1 showed an average heterosis and heterobeltiosis of 87% and 60%, and 78% and 30% for seed yield in Isabela and Lajas, respectively. The useful heterosis was >125% in both locations.

Serbia preserves a high number of local grape varieties, which have been cultivated across the country for centuries. Now, these ancient varieties are in the spotlight, and there is a global trend towards their recovery and characterization because they can revitalize regional, national and international grape and wine sectors. In addition, their genetic study can be useful to find new pedigree relationships to reveal how local varietal assortment evolved over time. Here, the genetic characterization of 138 grapevines from old Serbian vineyards revealed 59 different genetic profiles, 49 of which were identified as grapevine varieties whose origin in the country could be linked to some major Serbian historical periods. Most of the genetic profiles found in this work arranged in a complex pedigree network that integrates numerous grapevine varieties from diverse Balkan countries, agreeing with an intense exchange of plant material among Balkan regions for centuries. This analysis identified some varieties as important founders of Balkan genetic resources, like ‘Alba Imputotato’, ‘Braghina Rosie’, ‘Coarna Alba’, and ‘Vulpea’. After deepening into their genealogy, these major direct founders might have ultimately derived from ‘Visparola’, an ancient variety of likely Balkan origin with a major founding role in some European regions. Our results also indicated the genetic singularity of the grapevine resources from the Balkans when compared to those from other relevant winemaking regions, supporting the interest of their detailed study to evaluate their oenological potential and for the eventual identification of useful traits to counteract current viticulture challenges.