Unequal crossing over at the rRNA locus as a source of quantitative genetic variation.
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Animals↗
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Results for “quantitative genetic variation”
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The nature of quantitative genetic variation in Drosophila. III. Mechanism of dosage compensation for sex-linked abdominal bristle polygenes.
Seventeen lines, each homozygous for a different X chromosome but all with a common autosomal genetic blackground, were constructed and assayed for abdominal bristle number to determine whether dosage compensation operates for sex-linked genes affecting this character. --The regression coefficient of male mean on female mean using a logarithmic scale was 0.90 +/- 0.13 and the genetic regression coefficient 0.92, neither differing significantly from unity. The genetic components of variance in males and females were also very similar (0.000234 or 0.000228, respectively). These results indicate that dosage compensation is complete (or nearly so) for sex-linked genes affecting this character. The bristle scores of females did not differ in reciprocal crosses between these lines, thus dosage compensation does not operate by paternal X inactivation. --The question of an adequate scale for abdominal bristle number had to be examined during the study. A logarithmic scale appeared to be adequate for both genotypic and environmental differences.
Animals↗
Genetic control of quantitative variation in carbonic anhydrase isozymes of mammals. I. The concentration within single erythrocytes of the mouse.
The levels of the carbonic anhydrase isozymes (CA and CA II) in single erythrocytes of DBA/2J mice were assayed by measuring the specific immunofluorescence of CA I and CA II with a microspectrofluorometric technique. Measurements of 100 randomly selected cells showed a range (in relative fluorescence units) of 21-52 (mean 31.3 +/- 7.5) for CA I and 30-80 (mean 45.6 +/- 10.7) for CA II. The CA II/CA I ratio of the means obtained by the single-cell fluorescence assay was similar to the ratios obtained for the two isozymes from hemolysates of DBA/2J mice using an immunodiffusion assay. The influence of cell age on the variation in carbonic anhydrase levels was determined by separating red cells into several fractions by a gravity sedimentation procedure. The younger cells showed higher levels of CA I and CA II than the older cells; however, the extensive overlap in the variability between the cells from the different fractions indicated that although cell age was contributing to the overall heterogeneity, its influence was not pronounced.
Animals↗
Genetic aspects of quantitative variation in the carbonic anhydrases of the pig-tailed macaque, Macaca nemestrina. I. Response to thyroxine.
Effects of thyroxine on incorporation of L-serine-C14 into four carbonic anhydrase isozymes (CA II, CA Ia, CA Ib, CA Ic) and hemoglobin were quantified in reticulocytes of Macaca nemestrian in vitro. Response to thyroxine differed significantly between CA Ia and two allelic variants (CA Ib and CA Ic) and the nonallelic isozyme (CA II). The effects of thyroxine on serine incorporation into hemoglobin and three of the carbonic anhydrase isozymes were shown to be nonlinear with thyroxine concentration.
Alleles↗
Immunochemical characterization of murine H-2 controlled Ss (serum substance) protein through identification of its human homologue as the fourth component of complement.
The S region of the mouse H-2 complex is genetically defined by a series of alleles, or pseudoalleles, which control the level of a serum globulin, Ss, and of its allotypic vairatn, Slp. In contrast with the products of other genes in the complex, no homologue of the Ss protein has been found in other species, except the rat. In the present study, a component in human plasma was identified which cross-reacts with anti-mouse Ss, and which also displays electrophoretic and size similarities to the mouse Ss protein. This component was isolated and characterized immunochemically as the fourth component of human complement (C'4 or beta1E globulin). Several antisera monospecific for human C'4 cross-react with the mouse Ss protein and detect its genetically determined quantitative variations.
Animals↗
Ectopic Gene Conversion Causing Quantitative Trait Variation.
Why is there so much non-neutral genetic variation segregating in natural populations? We dissect function and evolution of a near-cryptic quantitative trait locus (QTL) for defense metabolites in Arabidopsis using the CRISPR/Cas9 system and nucleotide polymorphism patterns. The QTL is explained by genetic variation in a family of 4 tightly linked indole-glucosinolate O-methyltransferase genes. Some of this variation appears to be maintained by balancing selection, some appears to be generated by non-reciprocal transfer of sequence, also known as ectopic gene conversion (EGC), between functionally diverged gene copies. Here, we elucidate how EGC, as an inevitable consequence of gene duplication, could be a general mechanism for generating genetic variation for fitness traits.
Quantitative Trait Loci↗
Application of cladistics to the analysis of genotype-phenotype relationships.
We seek to understand the relative contribution of allelic variations of a particular gene to the determination of an individual's risk of atherosclerosis or hypertension. Work in progress is focusing on the identification and characterization of mutations in candidate genes that are known to be involved in determining the phenotypic expression of intermediate biochemical and physiological traits that are in the pathway of causation between genetic variation and variation in risk of disease. The statistical strategy described in this paper is designed to aid geneticists and molecular biologists in their search to find the DNA sequences responsible for the genetic component of variation in these traits. With this information we will have a more complete understanding of the nature of the organization of the genetic variation responsible for quantitative variation in risk of disease. It will then be possible to fully evaluate the utility of measured genetic information in predicting the risk of common diseases having a complex multifactorial etiology, such as atherosclerosis and hypertension.
Alleles↗
Species-wide quantitative transcriptomes and proteomes reveal distinct genetic control of gene expression variation in yeast.
Gene expression varies between individuals and corresponds to a key step linking genotypes to phenotypes. However, our knowledge regarding the species-wide genetic control of protein abundance, including its dependency on transcript levels, is very limited. Here, we have determined quantitative proteomes of a large population of 942 diverse natural Saccharomyces cerevisiae yeast isolates. We found that mRNA and protein abundances are weakly correlated at the population gene level. While the protein coexpression network recapitulates major biological functions, differential expression patterns reveal proteomic signatures related to specific populations. Comprehensive genetic association analyses highlight that genetic variants associated with variation in protein (pQTL) and transcript (eQTL) levels poorly overlap (3%). Our results demonstrate that transcriptome and proteome are governed by distinct genetic bases, likely explained by protein turnover. It also highlights the importance of integrating these different levels of gene expression to better understand the genotype-phenotype relationship.
Saccharomyces cerevisiae↗
[Genetic diversity analysis of Forsythia suspensa germplasm resources in Shanxi based on phenotypic traits and SNP molecular markers].
This study aimed to clarify the degree of fruit phenotypic variation and the characteristics of genetic diversity, population structure, and genetic differentiation of Forsythia suspensa resources in Shanxi, providing an important basis for germplasm conservation and breeding of superior varieties. A total of 46 F. suspensa fruits were collected, and 12 agronomic traits were measured and analyzed. The population genetic structure and genetic diversity of F. suspensa germplasm were evaluated using simplified genome sequencing technology. For the five quality traits of the 46 fruits, the Shannon-Wiener index ranged from 0.631 to 1.074, and the Simpson index ranged from 0.379 to 0.560. The seven quantitative traits exhibited abundant genetic variation, with coefficients of variation ranging from 9.764%(fruit shape index) to 45.494%(forsythin content). Principal component analysis reduced the 12 phenotypic traits to four factors, with a cumulative variance contribution of 74.547%. Sequencing data showed mean Q20 and Q30 values of 98.13% and 94.33%, respectively, with an average GC content of 35.95%. After filtering, a total of 12 347 327 high-quality single nucleotide polymorphism(SNP) loci were obtained. Based on these high-quality SNPs, principal component analysis, population structure analysis, and phylogenetic tree construction were carried out. The 46 germplasm resources were divided into four groups; however, grouping showed little relationship with geographic origin, and intermixing occurred among regions. Mantel test revealed a significant but weak positive correlation between phenotypic and genetic distances(r=0.159, P=0.001). At the molecular level, the four groups exhibited moderate genetic diversity overall, and the genetic differentiation index among populations ranged from 0.027 to 0.084, indicating low to moderate differentiation. The rich genetic diversity of the main phenotypic traits provides a solid material basis for screening superior germplasm and genetic breeding of F. suspensa.
Forsythia↗
Selection among males for the genetic improvement of female fertility.
The quantitative physiological study of genetic variation in reproductive performance has shown that differences in the litter size and incidence of lambing in sheep are associated with variation in the release of LH. This variation is detectable in young animals of both sexes, and the injection of LHRH may aid its recognition. In the male it is associated with variation in mating behavior and testis growth. The ovarian activity of both sheep and mice has been shown to change following selection for testis growth. The use of measures of testis growth as criteria for selection to improve the reproductive performance of females is discussed.
Animals↗
An endothelial RNA splicing atlas catalogs effects of IL-1β and identifies an alternative PROCR isoform with genetic links to pleiotropic vascular disease.
Alternative splicing (AS) alters the sequence and dynamics of mRNA but has not been comprehensively annotated in human endothelial cells (ECs). EC dysfunction is a hallmark of complex inflammatory diseases, including cancer and atherosclerosis. Therefore, we modeled inflammation in vitro using 53 genetically distinct human aortic EC lines exposed to interleukin-1β (IL-1β) or control media. This identified 1,224 differentially spliced transcripts (DSTs). DSTs were enriched for alternative first (AF) exon usage, including isoforms of several disease-associated and metabolic genes. To confirm that IL-1β-dependent AF exons were produced by alternative promoters, a quantitative measure of promoter activity was defined using epigenetic data. Ratios of histone 3 lysine 27 acetylation and binding of ERG and RELA between alternative promoters correlated RNA levels of AF exons, confirming our hypothesis. Finally, the effects of genetic variation on AS were investigated by mapping splicing quantitative trait loci (sQTLs). Significant sQTLs were tested for genetic colocalization with cardiovascular risk loci from genome-wide association studies. This identified 66 colocalized signals corresponding to 30 genes and 39 lead variants. The sQTLs identified here provide testable mechanisms explaining some of the genetic risk for vascular disease. For example, genetic association for a previously undescribed isoform of endothelial protein C receptor (PROCR) colocalized with genetic risk for deep vein thrombosis and coronary artery disease with opposing risk alleles. This study demonstrates the prevalence of inducible promoters upon inflammatory stimuli and shows that genetic risk for vascular disease may be in part governed through AS in ECs.
Humans↗
Tonsillar expression quantitative trait loci verify and expand genetic contributors to childhood atopic diseases.
BACKGROUND: The spectrum of causal variants, mechanisms, and immunologic gene networks that influence pediatric atopic traits is not completely understood. Human genetic variation associated with transcript abundance (expression quantitative trait loci [eQTLs]) can help to advance our understanding, yet prior work has focused on profiling immune cell populations collected from peripheral blood primarily in adult populations, leaving tissue-resident lymphocytes collected from children uncharacterized. OBJECTIVE: We sought to characterize gene expression of 4 populations of tonsil-derived immune cell types collected from pediatric patients. METHODS: We collected naive B, germinal center B, naive T, and T follicular helper cells from the discarded tonsils of 103 children across development (age range 1-19). Following genotyping and RNA sequencing of samples, we performed differential expression and eQTL analysis, then statistically linked eQTL signals to relevant atopic traits via colocalization. RESULTS: We found differentially expressed genes across cell types and identified 13,393 expression genes (eGenes) (1,793 eGenes not previously reported in similar datasets) influenced by 27,603 eQTLs (5,199 eQTLs not previously reported). We linked eQTLs to associations identified in pediatric and adult asthma and atopy traits, nominating 78 eGenes including TRAF3, ZBTB10, and JAZF1 in disease-relevant cell types. CONCLUSIONS: Our freely available resource exemplifies the importance of discovery in native tissues and across human development.
Expression quantitative trait locus↗
Network-based drug repurposing for psychiatric disorders using single-cell genomics.
Neuropsychiatric disorders lack effective treatments due to a limited understanding of the underlying cellular and molecular mechanisms. To address this, we integrated population-scale single-cell genomics data and analyzed 23 cell-type-level gene regulatory networks across schizophrenia, bipolar disorder, and autism. Our analysis revealed potential druggable transcription factors co-regulating known risk genes that converge into cell-type-specific co-regulated modules. We applied graph neural networks on those modules to prioritize novel risk genes and leveraged them in a network-based drug repurposing framework to identify 220 drug molecules with the potential for targeting specific cell types. We found evidence for 37 of these drugs in reversing disorder-associated transcriptional phenotypes. Additionally, we discovered 335 drug-cell quantitative trait loci (eQTLs), revealing genetic variation's influence on drug target expression at the cell-type level. Our results provide a single-cell network medicine resource that provides potential mechanistic insights for advancing treatment options for neuropsychiatric disorders.
Drug Repositioning↗
Genetic studies in outpatients: plasma cholesterol in family and twin studies.
Quantitative genetic studies have much potential in partitioning the causes of variation of quantitative traits such as risk factors for atherosclerosis. Only if specific causes of variation are identified can specific therapy be developed to modify risks. There have been extensive family studies of plasma cholesterol which reveal that the level of plasma cholesterol is correlated in family members. However, except for the relatively rare familial hypercholesterolemia the evidence is not convincing that correlations of relatives are due to genetic rather than environmental factors. Early twin studies were interpreted as supporting the hypothesis that levels of plasma cholesterol were strongly influenced by genetic factors. However a recent large study of twins cast doubt upon this hypothesis by finding no significant genetic variance of plasma cholesterol after correcting for differences in total variance of monozygotic and dizygotic twins.
Arteriosclerosis↗
Complex and Dynamic Gene-by-Age and Gene-by-Environment Interactions Underlie Functional Morphological Variation in Adaptive Divergence in Arctic Charr (Salvelinus alpinus).
The evolution of adaptive phenotypic divergence requires heritable genetic variation. However, it is underappreciated that trait heritability is molded by developmental processes interacting with the environment. We hypothesized that the genetic architecture of divergent functional traits was dependent on age and foraging environment. Thus, we induced plasticity in full-sib families of Arctic charr (Salvelinus alpinus) morphs from two Icelandic lakes by mimicking prey variation in the wild. We characterized variation in body shape and size at two ages and investigated their genetic architecture with quantitative trait locus (QTL) analysis. Age had a greater effect on body shape than diet in most families, suggesting that development strongly influences phenotypic variation available for selection. Consistent with our hypothesis, multiple QTL were detected for all traits and their location depended on age and diet. Many of the genome-wide QTL were located within a subset of duplicated chromosomal regions suggesting that ancestral whole genome duplication events have played a role in the genetic control of functional morphological variation in the species. Moreover, the detection of two body shape QTL after controlling for the effects of age provides additional evidence for genetic variation in the plastic response of morphological traits to environmental variation. Thus, functional morphological traits involved in phenotypic divergence are molded by complex genetic interactions with development and environment.
Animals↗
CYClones: a highly powered, fully genotyped, eight-parent yeast mapping population.
The budding yeast Saccharomyces cerevisiae is a remarkably adaptable organism that thrives in diverse environments. Global sequencing of natural isolates has revealed extensive genetic diversity within the species. Here, we describe the construction and characterization of CYClones (Collaborative Yeast Cross clones), a library of 11,392 segregants generated from a multiparent funnel cross of eight genetically diverse parental strains. To enable the genetic dissection of complex traits, we imputed whole-genome sequences for all segregants and show that CYClones captures a substantial fraction of the global genetic diversity of S. cerevisiae. Haplotype representation is well maintained, with each parental haplotype present at >5% frequency across >95% of the genome. Simulations demonstrate that CYClones has ≥95% power to detect variants with heritability as low as 0.36%, with mapping resolution often finer than the length of a single gene. In summary, CYClones is a powerful community resource for dissecting the genetic architecture of complex and quantitative traits, uncovering context-dependent mutational effects, and identifying causal variants underlying phenotypic diversity.
Saccharomyces cerevisiae↗
The evolution of separate sexes in waterhemp is associated with surprising chromosomal diversity and complexity.
The evolution of separate sexes is hypothesized to occur through distinct pathways involving few large-effect or many small-effect alleles. However, we lack empirical evidence for how these different genetic architectures shape the transition from quantitative variation in sex expression to distinct male and female phenotypes. To explore these processes, we leveraged the recent transition of Amaranthus tuberculatus to dioecy within a predominantly monoecious genus, along with a sex-phenotyped population genomic dataset, and six newly generated chromosome-level haplotype phased assemblies. We identify a ~3 Mb region strongly associated with sex through complementary SNP genotype and sequence-depth-based analyses. Comparative genomics of these proto-sex chromosomes within the species and across the Amaranthus genus demonstrates remarkable variability in their structure and genic content, including numerous polymorphic inversions. No such inversion underlies the extended linkage we observe associated with sex determination. Instead, we identify a complex presence/absence polymorphism reflecting substantial Y-haplotype variation-structured by ancestry, geography, and habitat-but only partially explaining phenotyped sex. Just over 10% of sexed individuals show phenotype-genotype mismatch in the sex-linked region, and along with observation of leakiness in the phenotypic expression of sex, suggest additional modifiers of sex and dynamic gene content within and between the proto-X and Y. Together, this work reveals a complex genetic architecture of sex determination in A. tuberculatus characterized by the maintenance of substantial haplotype diversity, and variation in the expression of sex.
Haplotypes↗
[Enzyme deficiencies of blood cells in bone marrow insufficiency (author's transl].
Numerous enzyme defects-deficiency of pyruvate kinase, phosphofructo-kinase, glocosephosphate isomerase, adenylate kinase, 2,3-diphosphoglycerate mutase and glutathione reductase--in red blood cells have been described to be connected with dyserythropoietic or refractory anemias and panmyelopathies of different origin. These enzyme deficiencies also have been demonstrated in red cells of patients with acute leukemia. Most likely the enzyme deficiencies are acquired and are not important for the origin of anemia or bone marrow insufficiency. Partial derepression of fetal genes, qualitative and quantitative perturbations of genetic expression, and posttranslational variations of the enzyme protein by low molecular factors from plasma, erythrocytes or leukemic cells have been discussed as a reason of enzyme deficiency. The decrease of glutathione reductase deficiency is dependent of FAD deficiency.
Acetylcholinesterase↗