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Am J Hum Genet ; 108(11): 2130-2144, 2021 11 04.
Article En | MEDLINE | ID: mdl-34653363

Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs.

Congenital Disorders of Glycosylation/genetics , Genes, Dominant , Hexosyltransferases/genetics , Membrane Proteins/genetics , Musculoskeletal Diseases/genetics , Nervous System Diseases/genetics , Adolescent , Adult , Amino Acid Sequence , Catalytic Domain , Child, Preschool , Female , Heterozygote , Hexosyltransferases/chemistry , Humans , Male , Membrane Proteins/chemistry , Middle Aged , Pedigree , Sequence Homology, Amino Acid
Anim Genet ; 52(5): 749-753, 2021 Oct.
Article En | MEDLINE | ID: mdl-34403536

The dominance effect is a kind of non-additive effect due to the interaction between alleles at the same locus. Quantitative traits such as growth traits in farm animals have been found to be influenced by dominance effects. However, dominance effects are usually ignored in the genome-wide association study (GWAS) of complex traits for farm animals. In this study, we performed GWAS and genetic parameters estimation for the two traits age at 100 kg (AGE) and backfat thickness at 100 kg (BF) of 3572 Large White pigs. The pigs were from three breeding farms of China and were genotyped by an in-house designed 50k SNP chip. Our results showed significant non-zero variance for the dominance effect of AGE, while the dominance effect of BF was not significant. Using a GWAS model accounting for both additive and dominance effects, we identified three additive and two dominance significant SNPs for the trait AGE. For the trait BF, three genome-wide significant additive SNPs were detected, but no significant SNP was found for the dominance effect. In total, six important functional genes (NPAS3, USP16, PARN, ARL15, GPC3, ABHD4) near significant SNPs were identified as candidate genes associated with AGE or BF. Notably, ARL15 and PARN were associated with AGE near the dominance association signals. Overall, the newly detected SNPs and newly identified candidate genes in our study added new information about the genetic architectures of growth and fatness traits in pigs, and have the potential to be applied to the pig breeding program in the future.

Adiposity/genetics , Genes, Dominant , Sus scrofa/growth & development , Sus scrofa/genetics , Animals , China , Genetic Association Studies/veterinary , Genotype , Models, Genetic , Phenotype , Polymorphism, Single Nucleotide
Theor Appl Genet ; 134(11): 3721-3730, 2021 Nov.
Article En | MEDLINE | ID: mdl-34379146

KEY MESSAGE: AhRt1 controlling red testa color in peanut was fine-mapped to an interval of 580 kb on chromosome A03, and one gene encoding bHLH transcriptional factor was identified as the putative candidate gene. Peanut with red testa has higher nutritional and economic value than the traditional pink testa varieties. Identification of genes controlling red testa color will accelerate the breeding program and facilitate uncovering the genetic mechanism. In this study, in order to identify gene underlying the red testa color in peanut, a F2 population derived from a cross between a pink testa peanut variety "Fuhua 8" and a red testa variety "Quanhonghua 1" was constructed. The genetic analysis for the F2 population revealed that the red testa color was controlled by one single dominant locus. This locus, named as AhRt1 (Arachis hypogaea Red Testa 1), was preliminary identified in chromosome A03 by BSA-sequencing analysis. Using a segregation mapping population, AhRt1 was fine-mapped to a 580-kb genomic region by substitution mapping strategy. Gene candidate analysis suggested that one predicted gene encoding bHLH transcriptional factor may be the possible candidate gene for AhRt1. A diagnostic marker closely linked to candidate gene has been developed for validating the fine-mapping result in different populations and peanut germplasm. Our findings will benefit the breeding program for developing new varieties with red testa color and laid foundation for map-based cloning gene responsible for red testa in peanut.

Arachis/genetics , Genes, Dominant , Genes, Plant , Pigmentation/genetics , Anthocyanins , Basic Helix-Loop-Helix Transcription Factors/genetics , Chromosome Mapping , Color , Genetic Markers , Polymorphism, Single Nucleotide
Eur J Med Genet ; 64(10): 104311, 2021 Oct.
Article En | MEDLINE | ID: mdl-34416374

Hereditary hearing loss (HL) has high genetic and phenotypical heterogeneity including the overlapping and variable phenotypic features. For sporadic HL without a family history, it is more difficult to indicate the contribution of genetic factors to define a pattern of inheritance. We assessed the contribution of genetic variants and patterns of inheritance by a family trio-based sequencing and provided new insight into genetics. We conducted an analysis of data from unrelated sporadic patients with HL (n = 404) who underwent trio-based whole-exome sequencing (trio-WES) or proband-only WES (p-WES) or targeted exome sequencing (TES), and the samples of their unaffected-parents (n = 808)were validated. A molecular diagnosis was rendered for 191 of 404 sporadic HL patients (47.3%) in multiple modes of inheritance, including autosomal recessive (AR), autosomal dominant (AD) caused by de novo variants, copy-number variants (CNVs), X-linked recessive, and dual genetic diagnosis. Among these patients, 83 (43.5%) cases were diagnosed with variants in rare genes. Sporadic HL patients were identified by multiple modes of transmission. Observed variations in rare genes and multiple modes of inheritance can strikingly emphasize the important etiological contribution of recessive and de novo genetic variants to a large cohort of sporadic HL cases plus their parents.

Genes, Recessive , Hearing Loss, Sensorineural/genetics , Mutation , Adolescent , Adult , DNA Copy Number Variations , Female , Gene Frequency , Genes, Dominant , Genetic Testing/methods , Genetic Testing/statistics & numerical data , Humans , Male , Pedigree
Genes (Basel) ; 12(6)2021 06 17.
Article En | MEDLINE | ID: mdl-34204324

Hemp (Cannabis sativa L.) has recently become an important crop due to the growing market demands for products containing cannabinoids. Unintended cross-pollination of C. sativa crops is one of the most important threats to cannabinoid production and has been shown to reduce cannabinoid yield. Ploidy manipulation has been used in other crops to improve agronomic traits and reduce fertility; however, little is known about the performance of C. sativa polyploids. In this study, colchicine was applied to two proprietary, inbred diploid C. sativa inbred lines, 'TS1-3' and 'P163', to produce the tetraploids 'TS1-3 (4x)' and 'P163 (4x)'. The diploid, triploid, and tetraploid F1 hybrids from 'TS1-3' × 'P163', 'TS1-3 (4x)' × 'P163', and 'TS1-3 (4x)' × 'P163 (4x)' were produced to test their fertilities, crossing compatibilities, and yields. The results indicated a reduction in fertility in the triploids and the tetraploids, relative to their diploid counterparts. When triploids were used as females, seed yields were less than 2% compared to when diploids were used as females; thus, triploids were determined to be female infertile. The triploids resulting from the crosses made herein displayed increases in biomass and inflorescence weight compared to the diploids created from the same parents in a field setting. Statistical increases in cannabinoid concentrations were not observed. Lastly, asymmetric crossing compatibility was observed between the diploids and the tetraploids of the genotypes tested. The results demonstrate the potential benefits of triploid C. sativa cultivars in commercial agriculture.

Cannabinoids/metabolism , Cannabis/genetics , Hybridization, Genetic , Plant Breeding , Polyploidy , Cannabinoids/genetics , Cannabis/physiology , Genes, Dominant , Plant Infertility/genetics
Biomed Res Int ; 2021: 5574136, 2021.
Article En | MEDLINE | ID: mdl-34250087

Background: The pathogenic variant, POU class 4 transcription factor 3 (POU4F3), is reported to cause autosomal dominant nonsyndromic hearing loss (ADNSHL). Previously, we have examined a four-generation midfrequency sensorineural hearing loss (MFSNHL) family (no. 6126) and established POU4F3 c.602T>C (p.Leu201Pro) as a potential disease-causing variant. Objectives: We explored the structural and functional alterations that the c.602T>C (p.Leu201Pro) variant enforces on the POU4F3 protein. Methods: We utilized wild-type (WT) and mutant (MUT) POU4F3 c.602T>C plasmid incorporation into HeLa cells to assess functional changes, by immunofluorescence and luciferase assays. To predict protein structural alterations in the MUT versus WT POU4F3, we also generated 3D structures to compare both types of POU4F3 proteins. Results: The WT POU4F3 is ubiquitously present in the nucleus, whereas the MUT form of POU4F3 exhibits a more restricted nuclear presence. This finding is different from other publications, which report a cytoplasmic localization of the MUT POU4F3. We also demonstrated that, as opposed to WT POU4F3, the MUT POU4F3 had 40% reduced luciferase activity. Conclusions: The reduced nuclear presence, combined with reduced transcriptional activity, suggests that the POU4F3 c.602T>C variant alters cellular activity and may contribute to the pathogenicity of POU4F3-related hearing loss. It, also, provides more evidence of the pathophysiological characteristics of MFSNHL.

Cell Nucleus/metabolism , Genes, Dominant , Hearing Loss, Sensorineural/genetics , Homeodomain Proteins/genetics , Mutation, Missense/genetics , Transcription Factor Brn-3C/genetics , Transcription, Genetic , Base Sequence , HeLa Cells , Homeodomain Proteins/chemistry , Humans , Models, Molecular , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/metabolism , Protein Transport , Transcription Factor Brn-3C/chemistry
Biomed Res Int ; 2021: 6624744, 2021.
Article En | MEDLINE | ID: mdl-34258273

Objective: Genetic variants in the WFS1 gene can cause Wolfram syndrome (WS) or autosomal dominant nonsyndromic low-frequency hearing loss (HL). This study is aimed at investigating the molecular basis of HL in an affected Chinese family and the genotype-phenotype correlation of WFS1 variants. Methods: The clinical phenotype of the five-generation Chinese family was characterized using audiological examinations and pedigree analysis. Target exome sequencing of 129 known deafness genes and bioinformatics analysis were performed among six patients and four normal subjects to screen suspected pathogenic variants. We built a complete WFS1 protein model to assess the potential effects of the variant on protein structure. Results: A novel heterozygous pathogenic variant NM_006005.3 c.2020G>T (p.Gly674Trp) was identified in the WFS1 gene, located in the C-terminal domain of the wolframin protein. We further showed that HL-related WFS1 missense variants were mainly concentrated in the endoplasmic reticulum (ER) domain. In contrast, WS-related missense variants are randomly distributed throughout the protein. Conclusions: In this family, we identified a novel variant p.Gly674Trp of WFS1 as the primary pathogenic variant causing the low-frequency sensorineural HL, enriching the mutational spectrum of the WFS1 gene.

Endoplasmic Reticulum/metabolism , Genes, Dominant , Hearing Loss/genetics , Membrane Proteins/genetics , Mutation, Missense/genetics , Adult , Aged, 80 and over , Base Sequence , Female , Humans , Male , Middle Aged , Models, Molecular , Pedigree , Phenotype
Nat Genet ; 53(7): 1006-1021, 2021 07.
Article En | MEDLINE | ID: mdl-34211179

SPTBN1 encodes ßII-spectrin, the ubiquitously expressed ß-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal ßII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect ßII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of ßII-spectrin in the central nervous system.

Genes, Dominant , Genetic Predisposition to Disease , Genetic Variation , Neurodevelopmental Disorders/genetics , Spectrin/genetics , Animals , Genetic Association Studies/methods , Heterozygote , Humans , Mice , Neurodevelopmental Disorders/diagnosis , Phenotype , Spectrin/metabolism
Int J Mol Sci ; 22(13)2021 Jun 29.
Article En | MEDLINE | ID: mdl-34209661

Self-incompatibility (SI) is conserved among members of the Brassicaceae plant family. This trait is controlled epigenetically by the dominance hierarchy of the male determinant alleles. We previously demonstrated that a single small RNA (sRNA) gene is sufficient to control the linear dominance hierarchy in Brassica rapa and proposed a model in which a homology-based interaction between sRNAs and target sites controls the complicated dominance hierarchy of male SI determinants. In Arabidopsis halleri, male dominance hierarchy is reported to have arisen from multiple networks of sRNA target gains and losses. Despite these findings, it remains unknown whether the molecular mechanism underlying the dominance hierarchy is conserved among Brassicaceae. Here, we identified sRNAs and their target sites that can explain the linear dominance hierarchy of Arabidopsis lyrata, a species closely related to A. halleri. We tested the model that we established in Brassica to explain the linear dominance hierarchy in A. lyrata. Our results suggest that the dominance hierarchy of A. lyrata is also controlled by a homology-based interaction between sRNAs and their targets.

Arabidopsis/genetics , Epistasis, Genetic , Gene Expression Regulation, Plant , Genes, Dominant , Homologous Recombination , RNA, Plant , Social Dominance , Alleles , Genotype , Haplotypes , Nucleic Acid Conformation
PLoS One ; 16(7): e0254947, 2021.
Article En | MEDLINE | ID: mdl-34288964

An additive genetic model is usually employed in case-control-based genome-wide association studies. The model usually encodes "AA", "Aa" and "aa" ("a" represents the minor allele) as three different numbers, implying the contribution of genotype "Aa" to the phenotype is different from "AA" and "aa". From the perspective of biological phenomena, the coding is reasonable since the phenotypes of lives are not "black and white". A case-control based study, however, has only two phenotypes, case and control, which means that the phenotypes are "black and white". It suggests that a recessive/dominant model may be an alternative to the additive model. In order to investigate whether the alternative is feasible, we conducted comparative experiments on several models used in those studies through chi-square test and logistic regression. Our simulation experiments demonstrate that a recessive model is better than the additive model. The area under the curve of the former has increased by 5% compared with the latter, the discrimination of identifying risk single nucleotide polymorphisms has been improved by 61%, and the precision has also reached 1.10 times that of the latter. Furthermore, the real data experiments show that the precision and area under the curve of the former are 16% and 20% higher than the latter respectively, and the area under the curve of dominant model of the former is 13% higher than the latter. The results indicate a recessive/dominant model may be an alternative to the additive model and suggest a new route for case-control-based studies.

Coronary Artery Disease/genetics , Databases, Nucleic Acid , Genes, Dominant , Genes, Recessive , Models, Genetic , Polymorphism, Single Nucleotide , Case-Control Studies , Genome-Wide Association Study , Humans
J Exp Med ; 218(8)2021 08 02.
Article En | MEDLINE | ID: mdl-34137790

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.

Genes, Dominant , Job Syndrome/genetics , Mutation/genetics , STAT3 Transcription Factor/genetics , Adolescent , Adult , Alleles , Alternative Splicing/genetics , Child , Child, Preschool , Codon, Nonsense/genetics , Evolution, Molecular , Family , Female , Frameshift Mutation/genetics , Genetics, Population , HEK293 Cells , Humans , Infant , Infant, Newborn , Male , Middle Aged , Pedigree , Protein Biosynthesis , RNA, Messenger/genetics , RNA, Messenger/metabolism
Int J Mol Sci ; 22(11)2021 May 30.
Article En | MEDLINE | ID: mdl-34070858

Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.

Frontotemporal Dementia/genetics , Genes, Dominant , Genes, Recessive , Spinocerebellar Ataxias/genetics , Ubiquitin-Protein Ligases , Adult , Age of Onset , Aged , Family , Female , Frontotemporal Dementia/diagnosis , Frontotemporal Dementia/metabolism , Frontotemporal Dementia/pathology , Gene Expression , Heterozygote , Humans , Male , Middle Aged , Mutation , Pedigree , Protein Folding , Spinocerebellar Ataxias/diagnosis , Spinocerebellar Ataxias/metabolism , Spinocerebellar Ataxias/pathology
Int J Mol Sci ; 22(11)2021 May 28.
Article En | MEDLINE | ID: mdl-34071252

Gene-expression programs modulated by transcription factors (TFs) mediate key developmental events. Here, we show that the synthetic transcriptional repressor (TR; ZF6-DB), designed to treat Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP), does not perturb murine retinal development, while maintaining its ability to block Rho expression transcriptionally. To express ZF6-DB into the developing retina, we pursued two approaches, (i) the retinal delivery (somatic expression) of ZF6-DB by Adeno-associated virus (AAV) vector (AAV-ZF6-DB) gene transfer during retinogenesis and (ii) the generation of a transgenic mouse (germ-line transmission, TR-ZF6-DB). Somatic and transgenic expression of ZF6-DB during retinogenesis does not affect retinal function of wild-type mice. The P347S mouse model of RHO-adRP, subretinally injected with AAV-ZF6-DB, or crossed with TR-ZF6-DB or shows retinal morphological and functional recovery. We propose the use of developmental transitions as an effective mode to challenge the safety of retinal gene therapies operating at genome, transcriptional, and transcript levels.

Genetic Therapy/methods , Retina/metabolism , Retinitis Pigmentosa/genetics , Animals , Dependovirus/genetics , Disease Models, Animal , Female , Gene Expression , Genes, Dominant , Genetic Vectors , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Retinitis Pigmentosa/metabolism , Rhodopsin/genetics , Transcription Factors , Transcriptome , Zinc Fingers
Hum Genet ; 140(8): 1183-1200, 2021 Aug.
Article En | MEDLINE | ID: mdl-34076780

Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD = 2.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the SEMA3C gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. SEMA3C encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a cis-regulatory effect on SEMA3C expression, making a contribution to dyslexia susceptibility in this family.

Dyslexia/genetics , Genetic Predisposition to Disease , Inheritance Patterns , Polymorphism, Single Nucleotide , Semaphorins/genetics , Base Sequence , Cell Movement , Chromosomes, Human, Pair 7 , Dyslexia/diagnostic imaging , Dyslexia/metabolism , Dyslexia/physiopathology , Family , Female , Gene Expression , Genes, Dominant , Genetic Linkage , Genetic Loci , Genome-Wide Association Study , Haplotypes , Humans , Introns , Lod Score , Male , Neuroimaging , Neurons/metabolism , Neurons/pathology , Pedigree , Phenotype , Semaphorins/deficiency , Whole Genome Sequencing
Nat Med ; 27(7): 1197-1204, 2021 Jul.
Article En | MEDLINE | ID: mdl-34059824

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease.

Amyotrophic Lateral Sclerosis/metabolism , Sphingolipids/biosynthesis , Adolescent , Adult , Alleles , Amino Acid Sequence , Amyotrophic Lateral Sclerosis/enzymology , Amyotrophic Lateral Sclerosis/genetics , CRISPR-Cas Systems , Child , Female , Genes, Dominant , HEK293 Cells , Humans , Male , Middle Aged , Mutation , Serine C-Palmitoyltransferase/genetics , Serine C-Palmitoyltransferase/metabolism , Young Adult
PLoS Genet ; 17(5): e1009548, 2021 05.
Article En | MEDLINE | ID: mdl-34014919

Fisher's partitioning of genotypic values and genetic variance is highly relevant in the current era of genome-wide association studies (GWASs). However, despite being more than a century old, a number of persistent misconceptions related to nonadditive genetic effects remain. We developed a user-friendly web tool, the Falconer ShinyApp, to show how the combination of gene action and allele frequencies at causal loci translate to genetic variance and genetic variance components for a complex trait. The app can be used to demonstrate the relationship between a SNP effect size estimated from GWAS and the variation the SNP generates in the population, i.e., how locus-specific effects lead to individual differences in traits. In addition, it can also be used to demonstrate how within and between locus interactions (dominance and epistasis, respectively) usually do not lead to a large amount of nonadditive variance relative to additive variance, and therefore, that these interactions usually do not explain individual differences in a population.

Genes/genetics , Genetic Variation , Genome-Wide Association Study , Internet , Software , Epistasis, Genetic , Gene Frequency , Genes, Dominant , Genetic Loci/genetics , Genotype , Humans , Models, Genetic , Polymorphism, Single Nucleotide