Phenotype Definition - Relationship to Genotype

In summary, our work elucidates a mechanistic basis for the strongest genetic association with obesity. Our results indicate that the SNV rs1421085 underlies the genetic association between the locus and obesity. The SNV disrupts an evolutionarily conserved motif for the ARID5B repressor, which leads to loss of binding, derepression of a potent preadipocyte superenhancer, and activation of downstream targets and during early differentiation of mesenchymal progenitors into adipocyte subtypes. This results in a cell-autonomous shift from white adipocyte browning to lipid-storage gene expression programs and to repression of basal mitochondrial respiration, a decrease in thermogenesis in response to stimulus, and an increase in adipocyte size. Manipulation of the uncovered pathway, including knockdown or overexpression of the upstream regulator genome editing of the predicted causal variant rs1421085, and knockdown or overexpression of target genes and had a significant effect on obesity phenotypes.

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FTO Obesity Variant Circuitry and Adipocyte Browning …

Panel A shows gene annotations and LD with array tag variant rs9930506 in a 2.5-Mb window; LD is expressed as r2 values in the CEU population. Arrows indicate the direction of transcription of annotated genes in the locus. Panel B shows chromosome conformation capture (Hi-C) interactions contact probabilities in human IMR90 myofibroblasts, revealing a 2-Mb topologically associating domain, and LD mean r2 statistics for all SNV pairs at 40-kb resolution. Panel C shows box plots for expression levels, after 2 days of differentiation, in human adipose progenitors isolated from 20 risk-allele carriers and 18 nonrisk-allele carriers, evaluated by means of a quantitative polymerase-chain-reaction analysis for all genes in the 2.5-Mb locus. The horizontal line within each box represents the median, the top and bottom of each box indicate the 75th and 25th percentile, and I bars indicate the range.

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On the basis of epigenomic annotations across 127 human cell types, we predicted the cell type in which the genetic variant was likely to act, and we validated the prediction with the use of haplotype-specific enhancer assays. We analyzed long-range chromatin interactions in the region surrounding to define potential target genes, and to validate genetic targets, we conducted an expression quantitative-trait-locus (eQTL) analysis in primary human adipocytes from risk-allele carriers and nonrisk-allele carriers. We predicted the cellular processes affected by the obesity-associated variants on the basis of correlated expression with the target genes across participants, and we validated their genetic control with the use of a trans-eQTL analysis of energy-balance genes (i.e., an eQTL analysis of energy-balance genes at large genomic distances from the locus) in adipocytes, as well as by measuring cellular phenotypes in risk-allele carriers and nonrisk-allele carriers. To examine the causal roles for the predicted target genes, we first used knockdown and overexpression of each target gene in primary human adipocytes from the subcutaneous fat of risk-allele carriers and nonrisk-allele carriers, followed by cellular phenotyping; second, we used generation of mice with a dominant negative allele of one of the target genes expressed in adipose tissue, followed by organism-level phenotyping, histologic measurements, and gene-expression profiling in major fat stores; and third, we used knockdown, overexpression, and knockout in three mouse adipocyte models.

Production of different phenotypes from the same genotype in the same environment by developmental variation Günter Vogt, Martin Huber, Markus Thiemann, Gerald van den Boogaart, Oliver J. Schmitz, Christoph D. Schubart
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The apparent genetic link between obesity and cell-autonomous adipocyte browning suggests a central role of beige adipocyte thermogenesis in whole-body energy metabolism in humans, a role that is consistent with that suggested in recent reports on PRDM16 in mice. and have evolutionarily conserved roles, and the ARID5B motif lies in a module that is functionally conserved across multiple mammalian species; this indicates that adaptive thermogenesis circuits are conserved, and and probably play both UCP1-dependent and UCP1-independent roles. Even though and dysregulation by rs1421085 was restricted to early differentiation, their effects persisted in mature adipocytes, and the targeting of these genes can have broader effects.

What is genotype? What is phenotype? – pgEd

Last, we evaluated the role of rs1421085 editing in cellular signatures of obesity by quantifying phenotypic differences between edited and unedited adipocytes. A causal role in the regulation of energy balance was indicated by the fact that C-to-T rescue of rs1421085 in edited adipocytes resulted in a reduction in gene expression for lipid storage and lipolytic markers (Fig. S2E and S8A in the ), an increase by a factor of 4 in basal metabolic rate and β-adrenergic oxygen consumption, and an increase by a factor of 7 in thermogenesis (, and Fig. S7B in the ). In particular, rescue of the ARID5B motif in C-to-T edited preadipocytes restored the strong dependence of mitochondrial respiration on ARID5B that is seen in nonrisk-allele carriers (Fig. S7C in the ).

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Panel A shows the mitochondrial and FXR and RXR activation genes with strongest positive (in red) or negative (in green) correlation with and in human perirenal adipose tissue from 10 participants. Panels B and C show box plots of the increased adipocyte diameter and decreased mitochondrial DNA content in isolated differentiated adipocytes from risk-allele carriers (16 and 8 participants, respectively) relative to nonrisk-allele carriers (26 and 8, respectively). The vertical line within each box represents the median, the left and right margins of each box indicate the interquartile range, and I bars indicate the range. Panel D shows box plots of the altered basal and isoproterenol-stimulated oxygen consumption rate (OCR) on small interfering RNA (siRNA) knockdown and doxycycline (DOX)–mediated overexpression of and in 8 risk-allele carriers and 10 nonrisk-allele carriers. The siRNA efficiency was 62% for and 71% for . The horizontal line within each box represents the median, the top and bottom of each box indicate the interquartile range, and I bars indicate the range.