A catalogue of imprinted genes and parent-of-origin effects in humans and animals

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.

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

10.1101/2021.08.10.455860 ◽

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.

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Imprinted Genes and Multiple Sclerosis: What Do We Know?

International Journal of Molecular Sciences ◽

10.3390/ijms22031346 ◽

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.

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Parent-of-origin effect rough endosperm mutants in maize

10.1101/054338 ◽

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.

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

Diabetologie und Stoffwechsel ◽

10.1055/s-0034-1375033 ◽

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

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Genomic imprinting in mouse blastocysts is predominantly associated with H3K27me3

Nature Communications ◽

10.1038/s41467-021-23510-4 ◽

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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Parent-of-origin effects on voluntary exercise levels and body composition in mice

Physiological Genomics ◽

10.1152/physiolgenomics.00139.2009 ◽

2010 ◽

Vol 40 (2) ◽

pp. 111-120 ◽

Cited By ~ 17

Author(s):

Scott A. Kelly ◽

Derrick L. Nehrenberg ◽

Kunjie Hua ◽

Ryan R. Gordon ◽

Theodore Garland ◽

...

Keyword(s):

Body Composition ◽

Body Fat ◽

Wheel Running ◽

Voluntary Exercise ◽

Phenotypic Variance ◽

In Utero Environment ◽

Dependent Activity ◽

Health Related ◽

Parent Of Origin ◽

Origin Effects

Despite the health-related benefits of exercise, many people do not engage in enough activity to realize the rewards, and little is known regarding the genetic or environmental components that account for this individual variation. We created and phenotyped a large G4 advanced intercross line originating from reciprocal crosses between mice with genetic propensity for increased voluntary exercise (HR line) and the inbred strain C57BL/6J. G4 females (compared to males) ran significantly more when provided access to a running wheel and were smaller with a greater percentage of body fat pre- and postwheel access. Change in body composition resulting from a 6-day exposure to wheels varied between the sexes with females generally regulating energy balance more precisely in the presence of exercise. We observed parent-of-origin effects on most voluntary wheel running and body composition traits, which accounted for 3–13% of the total phenotypic variance pooled across sexes. G4 individuals descended from progenitor (F0) crosses of HR♀ and C57BL/6J♂ ran greater distances, spent more time running, ran at higher maximum speeds/day, and had lower percent body fat and higher percent lean mass than mice descended from reciprocal progenitor crosses (C57BL/6J♀ × HR♂). For some traits, significant interactions between parent of origin and sex were observed. We discuss these results in the context of sex dependent activity and weight loss patterns, the contribution of parent-of-origin effects to predisposition for voluntary exercise, and the genetic (i.e., X-linked or mtDNA variations), epigenetic (i.e., genomic imprinting), and environmental (i.e., in utero environment or maternal care) phenomena potentially modulating these effects.

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