scholarly journals Parent-of-origin effects propagate through networks to shape metabolic traits

2021 ◽  
Author(s):  
Juan F Macias-Velasco ◽  
Celine L. St. Pierre ◽  
Jessica P Wayhart ◽  
Li Yin ◽  
Larry Spears ◽  
...  
Keyword(s):  
Complex Traits ◽  
Neurological Diseases ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Serum Glucose ◽  
Physiological Data ◽  
Imprinted Genes ◽  
Metabolic Traits ◽  
Parent Of Origin ◽  
Origin Effects

ABSTRACTParent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological diseases. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these parent-of-origin effects phenomena. We propose that non-imprinted genes can generate complex parent-of-origin effects on metabolic traits through interactions with imprinted genes. Here, we employ data from mouse populations at different levels of intercrossing (F0, F1, F2, F16) of the LG/J and SM/J inbred mouse lines to test this hypothesis. Using multiple populations and incorporating genetic, genomic, and physiological data, we leverage orthogonal evidence to identify networks of genes through which parent-of-origin effects propagate. We identify a network comprised of 3 imprinted and 6 non-imprinted genes that show parent-of-origin effects. This epistatic network forms a nutritional responsive pathway and the genes comprising it jointly serve cellular functions associated with growth. We focus on 2 genes, Nnat and F2r, whose interaction associates with serum glucose levels across generations in high fat-fed females. Single-cell RNAseq reveals that Nnat and F2r are negatively correlated in pre-adipocytes along an adipogenic trajectory, a result that is consistent with our observations in bulk white adipose tissue.

scholarly journals Epistatic Networks Associated with Parent-of-Origin Effects on Metabolic Traits

2019 ◽  
Author(s):  
Juan F Macias-Velasco ◽  
Celine L. St. Pierre ◽  
Jessica P Wayhart ◽  
Li Yin ◽  
Larry Spears ◽  
...  
Keyword(s):  
Complex Traits ◽  
Reciprocal Cross ◽  
Expression Profiles ◽  
Specific Interaction ◽  
Imprinted Genes ◽  
Cross Model ◽  
Metabolic Traits ◽  
Parent Of Origin ◽  
Origin Effects ◽  
Context Specific

ABSTRACTParent-of-origin effects (POE) are unexpectedly common in complex traits, including metabolic and neurological diseases. POE can also be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific POE on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these POE phenomena. Here, we use a simple yet powerful F1 reciprocal cross model to test the hypothesis that non-imprinted genes can generate complex POE on metabolic traits through genetic interactions with imprinted genes. Male and female mice from a F1 reciprocal cross of LG/J and SM/J strains were fed either high or low fat diets. We generated expression profiles from three metabolically-relevant tissues: hypothalamus, white adipose, and liver. We identified two classes of parent-of-origin expression biases: genes showing parent-of-origin-dependent allele-specific expression and biallelic genes that are differentially expressed by reciprocal cross. POE patterns of both gene classes are highly tissue-and context-specific, sometimes occurring only in one sex and/or diet cohort in a particular tissue. We then constructed tissue-specific interaction networks among genes from these two classes of POE. A key subset of gene pairs show significant epistasis in the F16 LG/J x SM/J advanced intercross data in cases where the biallelic gene fell within a previously-identified metabolic POE QTL interval. We highlight one such interaction in adipose, between Nnat and Mogat1, which associates with POE on multiple adiposity traits. Both genes localize to the endoplasmic reticulum of adipocytes and play a role in adipogenesis. Additionally, expression of both genes is significantly correlated in human visceral adipose tissue. The genes and networks we present here represent a set of actionable interacting candidates that can be probed to further identify the machinery driving POE on complex traits.

scholarly journals Reciprocal F1 hybrids of two inbred mouse strains reveal parent-of-origin and perinatal diet effects on behavior and expression

2018 ◽  
Author(s):  
Daniel Oreperk ◽  
Sarah A Schoenrock ◽  
Rachel McMullan ◽  
Robin Ervin ◽  
Joseph Farrington ◽  
...  
Keyword(s):  
Complex Traits ◽  
Detection System ◽  
Inbred Mouse ◽  
F1 Hybrids ◽  
Hybrid Population ◽  
Psychiatric Disease ◽  
Mouse Strains ◽  
Imprinted Genes ◽  
F1 Hybrid ◽  
Parent Of Origin

ABSTRACTParent-of-origin effects (POEs) in mammals typically arise from maternal effects or from imprinting. Mutations in imprinted genes have been associated with psychiatric disorders, as well as with changes in a handful of animal behaviors. Nonetheless, POEs on complex traits such as behavior remain largely uncharacterized. Furthermore, although perinatal environmental exposures, such as nutrient deficiency, are known to modify both behavior and epigenetic effects generally, the architecture of environment-by-POE is almost completely unexplored. To study POE and environment-by-POE, we employ a relatively neglected but maximally powerful POE-detection system: a reciprocal F1 hybrid population. We exposed female NOD/ShiLtJxC57Bl/6J and C57Bl/6JxNOD/ShiLtJ mice, in utero, to one of four different diets, then after weaning recorded their whole-brain gene expression, as well as a set of behaviors that model psychiatric disease. Microarray expression data revealed an imprinting-enriched set of over a dozen genes subject to POE; the POE on the most significantly affected gene, Carmil1 (a.k.a. Lrrc16a), was validated using qPCR in the same and in a new set of mice. Several behaviors, especially locomotor behaviors, also showed POE. Interestingly, Bayesian mediation analysis suggests Carmil1 expression suppresses behavioral POE, and Airn suppresses POE on Carmil1 expression. A significant diet-by-POE was observed on one behavior, one imprinted gene, and over a dozen non-imprinted genes. Beyond our particular results, our study demonstrates a reciprocal F1 hybrid framework for studying POE and environment-by-POE on behavior.

scholarly journals Genomic imprinting and parent-of-origin effects on complex traits

2013 ◽  
Vol 14 (9) ◽  
pp. 609-617 ◽  
Author(s):  
Heather A. Lawson ◽  
James M. Cheverud ◽  
Jason B. Wolf
Keyword(s):  
Genomic Imprinting ◽  
Complex Traits ◽  
Parent Of Origin ◽  
Origin Effects

scholarly journals Coping-Style Behavior Identified by a Survey of Parent-of-Origin Effects in the Rat

2018 ◽  
Author(s):  
Carme Mont ◽  
Polinka Hernandez Pilego ◽  
Toni Cañete ◽  
Ignasi Oliveras ◽  
Cristóbal Río-Álamos ◽  
...  
Keyword(s):  
Complex Traits ◽  
Coping Style ◽  
Additive Genetic Variance ◽  
Shared Environment ◽  
Parental Origin ◽  
Impulsive Behavior ◽  
Develop Theory ◽  
Parent Of Origin ◽  
Origin Effects ◽  
F1 Cross

AbstractWe develop theory, based on earlier work, to partition heritability into a component due to a combination of parent of origin, maternal, paternal and shared environment, and another component that estimates classical additive genetic variance. We then investigate the effects on heritability of the parental origin of alleles in outbred heterogeneous stock rats across 199 complex traits. Parent-of-origin-like heritability was on average 2.7-fold larger than classical additive heritability. Among the phenotypes with the most enhanced parent-of-origin heritability were 10 coping style behaviors, with average 3.2-fold heritability enrichment. To confirm these findings on coping behaviour, and to eliminate the possibility that the parent of origin effects are due to confounding with shared environment, we performed a reciprocal F1 cross between the behaviourally divergent RHA and RLA rat strains. We observed parent-of-origin effects on F1 rat anxiety/coping-related behavior in the Elevated Zero Maze test. Our results are the first to assess genetic parent-of-origin effects in rats, and confirm earlier findings in mice that such effects influence mammalian coping and impulsive behavior.

scholarly journals Imprinted Genes and Multiple Sclerosis: What Do We Know?

2021 ◽  
Vol 22 (3) ◽  
pp. 1346
Author(s):  
Natalia Baulina ◽  
Ivan Kiselev ◽  
Olga Favorova
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Molecular Mechanisms ◽  
Imprinted Genes ◽  
Factors Affecting ◽  
Phenotypic Differences ◽  
The Central Nervous System ◽  
Parent Of Origin ◽  
Origin Effects

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disease of the central nervous system that arises from interplay between non-genetic and genetic risk factors. The epigenetics functions as a link between these factors, affecting gene expression in response to external influence, and therefore should be extensively studied to improve the knowledge of MS molecular mechanisms. Among others, the epigenetic mechanisms underlie the establishment of parent-of-origin effects that appear as phenotypic differences depending on whether the allele was inherited from the mother or father. The most well described manifestation of parent-of-origin effects is genomic imprinting that causes monoallelic gene expression. It becomes more obvious that disturbances in imprinted genes at the least affecting their expression do occur in MS and may be involved in its pathogenesis. In this review we will focus on the potential role of imprinted genes in MS pathogenesis.

scholarly journals Parent-of-origin effect rough endosperm mutants in maize

2016 ◽  
Author(s):  
Fang Bai ◽  
Mary Daliberti ◽  
Alyssa Bagadion ◽  
Miaoyun Xu ◽  
Yubing Li ◽  
...  
Keyword(s):  
Female Parent ◽  
Mendelian Inheritance ◽  
Endosperm Development ◽  
Paternal Allele ◽  
Imprinted Genes ◽  
Incomplete Penetrance ◽  
Starchy Endosperm ◽  
Parent Of Origin ◽  
Origin Effects ◽  
Origin Effect

ABSTRACTParent-of-origin effect loci have non-Mendelian inheritance in which phenotypes are determined by either the maternal or paternal allele alone. In angiosperms, parent-of-origin effects can be caused by loci required for gametophyte development or by imprinted genes needed for seed development. Few parent-of-origin effect loci have been identified in maize (Zea mays) even though there are a large number of imprinted genes known from transcriptomics. We screened rough endosperm (rgh) mutants for parent-of-origin effects using reciprocal crosses with inbred parents. Six maternal rough endosperm (mre) and three paternal rough endosperm (pre) mutants were identified with three mre loci mapped. When inherited from the female parent, mre/+ seeds reduce grain-fill with a rough, etched, or pitted endosperm surface. Pollen transmission of pre mutants results in rgh endosperm as well as embryo lethality. Eight of the loci had significant distortion from the expected one-to-one ratio for parent-of-origin effects. Linked markers for mre1, mre2, and mre3 indicated that the mutant alleles have no bias in transmission. Histological analysis of mre1, mre2, mre3, and pre*-949 showed altered timing of starch grain accumulation and basal endosperm transfer cell layer (BETL) development. The mre1 locus delays BETL and starchy endosperm development, while mre2 and pre*-949 cause ectopic starchy endosperm differentiation. We conclude that many parent-of-origin effects in maize have incomplete penetrance of kernel phenotypes and that there is a large diversity of endosperm developmental roles for parent-of-origin effect loci.

Analysis of parent of origin effects in Sorbs using long range phasing algorithms

2014 ◽  
Vol 9 (S 01) ◽  
Author(s):  
X Liu ◽  
M Scholz ◽  
A Tönjes ◽  
M Stumvoll ◽  
PF Stadler ◽  
...  
Keyword(s):  
Long Range ◽  
Parent Of Origin ◽  
Origin Effects

scholarly journals Genomic imprinting in mouse blastocysts is predominantly associated with H3K27me3

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Laura Santini ◽  
Florian Halbritter ◽  
Fabian Titz-Teixeira ◽  
Toru Suzuki ◽  
Maki Asami ◽  
...  
Keyword(s):  
Bisulfite Sequencing ◽  
Blastocyst Stage ◽  
Preimplantation Embryos ◽  
Imprinted Genes ◽  
Specific Expression ◽  
Histone 3 ◽  
Complex Program ◽  
Genome Bisulfite Sequencing ◽  
Mammalian Genomes ◽  
Parent Of Origin

AbstractIn mammalian genomes, differentially methylated regions (DMRs) and histone marks including trimethylation of histone 3 lysine 27 (H3K27me3) at imprinted genes are asymmetrically inherited to control parentally-biased gene expression. However, neither parent-of-origin-specific transcription nor imprints have been comprehensively mapped at the blastocyst stage of preimplantation development. Here, we address this by integrating transcriptomic and epigenomic approaches in mouse preimplantation embryos. We find that seventy-one genes exhibit previously unreported parent-of-origin-specific expression in blastocysts (nBiX: novel blastocyst-imprinted expressed). Uniparental expression of nBiX genes disappears soon after implantation. Micro-whole-genome bisulfite sequencing (µWGBS) of individual uniparental blastocysts detects 859 DMRs. We further find that 16% of nBiX genes are associated with a DMR, whereas most are associated with parentally-biased H3K27me3, suggesting a role for Polycomb-mediated imprinting in blastocysts. nBiX genes are clustered: five clusters contained at least one published imprinted gene, and five clusters exclusively contained nBiX genes. These data suggest that early development undergoes a complex program of stage-specific imprinting involving different tiers of regulation.

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