A global evolutionary and metabolic analysis of human obesity gene risk variants

Castillo, Joseph; Hazlett, Zachary; Orlando, Robert A.; Garver, William S.

doi:10.1016/j.gene.2017.07.002

Cited by 8 publications

(4 citation statements)

References 52 publications

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“…Given its function, it is expected to be differentially selected in the wild vs. domestic environment, and by varying energy requirements during the upstream spawning migration (when Atlantic salmon do not feed). Several other obesity‐associated genes are candidate selective targets, including negr1 ; four copies of neurexin 3 ( nrxn3 ) on a large candidate haploblock on Ssa09 (Table ; Supporting information: Figure ); lingo2 (Ssa05 and Ssa09); and arid5b (Ssa01; Claussnitzer et al., ; Castillo, Hazlett, Orlando, & Garver, ; Heard‐Costa et al., ; Supporting information: Table ). The observation of these genes as selective candidates conforms to a model in which different Teno Atlantic salmon subpopulations are adapted to different energy‐balance optima.…”

Section: Discussionmentioning

confidence: 99%

Genomic signatures of fine‐scale local selection in Atlantic salmon suggest involvement of sexual maturation, energy homeostasis and immune defence‐related genes

et al. 2018

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Elucidating the genetic basis of adaptation to the local environment can improve our understanding of how the diversity of life has evolved. In this study, we used a dense SNP array to identify candidate loci potentially underlying fine-scale local adaptation within a large Atlantic salmon (Salmo salar) population. By combining outlier, gene-environment association and haplotype homozygosity analyses, we identified multiple regions of the genome with strong evidence for diversifying selection. Several of these candidate regions had previously been identified in other studies, demonstrating that the same loci could be adaptively important in Atlantic salmon at subdrainage, regional and continental scales. Notably, we identified signals consistent with local selection around genes associated with variation in sexual maturation, energy homeostasis and immune defence. These included the large-effect age-at-maturity gene vgll3, the known obesity gene mc4r, and major histocompatibility complex II. Most strikingly, we confirmed a genomic region on Ssa09 that was extremely differentiated among subpopulations and that is also a candidate for local selection over the global range of Atlantic salmon. This region colocalized with a haplotype strongly associated with spawning ecotype in sockeye salmon (Oncorhynchus nerka), with circumstantial evidence that the same gene (six6) may be the selective target in both cases. The phenotypic effect of this region in Atlantic salmon remains cryptic, although allelic variation is related to upstream catchment area and covaries with timing of the return spawning migration. Our results further inform management of Atlantic salmon and open multiple avenues for future research.

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Section: Discussionmentioning

confidence: 99%

Genomic signatures of fine‐scale local selection in Atlantic salmon suggest involvement of sexual maturation, energy homeostasis and immune defence‐related genes

et al. 2018

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“…Several other obesity-associated genes are candidate selective targets: four copies of neurexin 3 ( nrxn3 , Heard-Costa et al 2009) on a large candidate haploblock on Ssa09 (Table 2, Fig. S5.6); negr1 (discussed above); lingo2 (Ssa05 and Ssa09); arid5b (Ssa01); and kcdt15 (Ssa11) (Claussnitzer et al, 2015; Castillo, Hazlett & Orlando, 2017; Table S4). The observation of these genes as selective candidates conforms to a model in which different Teno Atlantic salmon sub-populations are adapted to different energy-balance optima.…”

Section: Discussionmentioning

confidence: 99%

Genomic Signatures of Fine-Scale Local Adaptation in Atlantic Salmon Suggest Involvement of Sexual Maturation, Energy Homeostasis, Behaviour, and Immune Defence-Related Genes

Pritchard

Mäkinen

Vähä

et al. 2018

Preprint

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Elucidating the genetic basis of adaptation to the local environment can improve our understanding of how the diversity of life has evolved. In this study we used a dense SNP array to identify candidate loci underlying fine-scale local adaptation within a large Atlantic salmon (Salmo salar) population. By combining outlier, gene-environment association, and haplotype homozygosity analyses, we identified multiple regions of the genome with strong evidence for diversifying selection. Several of these candidate regions had previously been identified in other studies, demonstrating that the same loci be adaptively important in Atlantic salmon at sub-drainage, regional and continental scales. Notably, we identified signals consistent with local selection around genes associated with variation in sexual maturation, energy homeostasis, behaviour, and immune defence. These included the large-effect age-at-matunty gene vgll3, the known obesity gene mc4r, and major histocompatibility complex II. Most strikingly, we confirmed a genomic region on Ssa09 that was extremely differentiated among subpopulations, and that is also a candidate for local selection over the global range of Atlantic salmon. This region co-localized with a genomic region strongly associated with spawning ecotype in sockeye salmon (Oncorhynchus nerka), with circumstantial evidence that the same gene (six6) may be the selective target in both cases. The phenotypic effect of this region in Atlantic salmon remains cryptic, although allelic variation is related to river flow volume and co-vanes with timing of the return spawning migration. Our results further inform management of Atlantic salmon and open multiple avenues for future research.

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“…Type 2 diabetes (T2D) is a multifactorial metabolic disease, which, as shown by a large number of studies including genome-wide association studies (GWAS) [1] , [2] , [3] as well as numerous large scale metabolite screens [4] , [5] depends on complex gene and environment interactions. To date, single nucleotide polymorphisms (SNPs) in more than 100 genes have been described to contribute to the development of T2D [3] .…”

Section: Introductionmentioning

confidence: 99%

Chronic d-serine supplementation impairs insulin secretion

Suwandhi

Hausmann

Braun

et al. 2018

Molecular Metabolism

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ObjectiveThe metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis.MethodsWe apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding. Moreover, we identify SNPs in SRR, the enzyme converting L-to d-serine and two subunits of the NMDA receptor to associate with insulin secretion in humans, based on the analysis of 2760 non-diabetic Caucasian individuals.ResultsWe show that chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. Inhibition of alpha 2-adrenergic receptors rapidly restores glycemia and glucose tolerance in d-serine supplemented mice. Moreover, we show that single nucleotide polymorphisms (SNPs) in SRR as well as in individual NMDAR subunits are associated with insulin secretion in humans.ConclusionThus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.

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A global evolutionary and metabolic analysis of human obesity gene risk variants

Cited by 8 publications

References 52 publications

Genomic signatures of fine‐scale local selection in Atlantic salmon suggest involvement of sexual maturation, energy homeostasis and immune defence‐related genes

Genomic signatures of fine‐scale local selection in Atlantic salmon suggest involvement of sexual maturation, energy homeostasis and immune defence‐related genes

Genomic Signatures of Fine-Scale Local Adaptation in Atlantic Salmon Suggest Involvement of Sexual Maturation, Energy Homeostasis, Behaviour, and Immune Defence-Related Genes

Chronic d-serine supplementation impairs insulin secretion

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