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

Macias-Velasco, Juan F; Pierre, Celine L. St.; Wayhart, Jessica P; Li, Yin; Spears, Larry D.; Miranda, Mario A.; Carson, Caryn; Funai, Katsuhiko; Cheverud, James M.; Semenkovich, Clay F.; Lawson, Heather A.

doi:10.1101/2021.08.10.455860

Cited by 4 publications

(5 citation statements)

References 78 publications

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“…8). These findings are consistent with previous studies, in which many ASE genes in humans were associated with the immune response 28 , while parent-of-origin effects were enriched on metabolic traits in mouse 29 . The allelic gene activation during embryogenesis of hybrid Ciona showed that 72% ASE genes were species-of-origin effects, the other 28% ASE genes were parent-of-origin effects.…”

Section: Resultssupporting

confidence: 93%

Spatiotemporal dynamics of zygotic genome activation in basal chordates revealed by interspecific hybrids

Wei

Zhang

Leng

et al. 2022

Preprint

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Zygotic genome activation (ZGA), a universal process in early embryogenesis that occurs during the maternal-to-zygotic transition, involves reprogramming in the zygotic nucleus that initiates global transcription. In recent decades, knowledge of this process has been acquired from research on various model organisms; however, a consensus explanation of the mechanism underlying the process, especially in relation to housekeeping gene reactivation, is lacking. Here, we used hybrids derived from two ascidian species (Ciona robusta and C. savignyi), which diverged >120 Mya with significant divergence among most orthologous genes, to symmetrically document the unique dynamics of ZGA in urochordates. We found two co-ordinated waves of ZGA, representing early developmental and housekeeping gene reactivation, during the 8-cell to 110-cell stage. Comparative analysis revealed the regulatory connection between maternal and zygotic genes as well as allelic-specific expression in a species-rather than parental-related manner, which was attributed to the divergence of cis-regulatory elements. Single-cell RNA sequencing revealed that spatial differential reactivation of paternal housekeeping genes was significantly correlated with the mechanical property of each cell type. These findings potentially provide a new system for understanding the evolution and adaptation of strategies regulating ZGA in basal chordates.

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Section: Resultssupporting

confidence: 93%

Spatiotemporal dynamics of zygotic genome activation in basal chordates revealed by interspecific hybrids

Wei

Zhang

Leng

et al. 2022

Preprint

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“…Conversely, parent-of-origin dependent ASE genes (excluding the 171 snoRNA cluster in the PWS/AS domain) were not enriched in the 76 F 16 QTLs showing imprinting effects (p = 0.47, Figure 6B ). Tissue-specific ASE gene sets were also not enriched in the QTL sets for any metabolic trait category (p > 0.05, Supplemental Figure S16 ), supporting previous work that shows parental expression biases are often not the direct source of imprinting QTL effects (Macias-Velasco et al 2021).…”

Section: Resultssupporting

confidence: 79%

“…Tissue-specific ASE gene sets were also not enriched in the QTL sets for any metabolic trait category (p > 0.05, Supplemental Figure S16), supporting previous work that shows parental expression biases are often not the direct source of imprinting QTL effects (Macias-Velasco et al 2021).…”

Section: Ase Genes Are Enriched In Qtls For Metabolic and Anatomical ...supporting

confidence: 79%

“…27% of parent-of-origin dependent ASE genes have diet- and/or sex-specific biases in a less extreme manner than the other profiles. Most genes have no clear connection to imprinting, suggesting another mechanism for parental ASE outside of traditional imprinting that is sensitive to environmental perturbations (Wolf et al 2008; Morcos et al 2011; Macias-Velasco et al 2021). Surprisingly, over half of sequence dependent ASE genes (52%) have diet- and/or sex-specific biases, indicating these intrinsic and extrinsic environmental factors interact with strain-specific genetic variation to cause a sequence bias.…”

Section: Discussionmentioning

confidence: 99%

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Genetic, epigenetic, and environmental mechanisms govern allele-specific gene expression

Pierre

Macias-Velasco²,

Wayhart³

et al. 2021

Preprint

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Allele-specific expression (ASE) is a phenomenon where one allele is preferentially expressed over the other. Genetic and epigenetic factors cause ASE by altering the final allelic composition of a gene's product, leading to expression imbalances that can have functional consequences on phenotypes. Environmental signals also impact allele-specific gene regulation, but how they contribute to this crosstalk remains understudied. Here, we explored how allelic genotype, parent-of-origin, tissue type, sex, and dietary fat simultaneously influence ASE biases in a F1 reciprocal cross mouse model. Male and female mice from a F1 reciprocal cross of the LG/J and SM/J strains were fed a high-fat or low-fat diet. We harnessed strain-specific variants to distinguish between two classes of ASE: parent-of-origin dependent (unequal expression based on an allele's parental origin) and sequence dependent (unequal expression based on an allele's nucleotide identity). We present a comprehensive genome-wide map of ASE patterns across three metabolically-relevant tissues and nine environmental contexts. We find that both ASE classes are highly dependent on tissue type and environmental context. They vary across metabolic tissues, between males and females, and in response to dietary fat levels. Surprisingly, we also find several genes with inconsistent ASE biases that switched direction across tissues and/or contexts (e.g. SM/J biased in one cohort, LG/J biased in another). Together, our results provide novel insights into how genetic, epigenetic, and environmental mechanisms govern allele-specific gene regulation, which is an essential step towards deciphering the genotype to phenotype map.

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“…Therefore, it can be used to efficiently identify divergent gene expression regulated by cis variation. For example, by comparing expression originated from the two alleles in an interspecific F1 hybrid of Drosophila, genes subject to cis and trans regulation were identified, providing a genome-wide characterization of the regulatory landscape 13,14 . A special case of allele specific expression (ASE) is the parent-of-origin effect, where expression is biased towards a particular allele according to its paternal or maternal origin.…”

Section: Introductionmentioning

confidence: 99%

Multi-omic characterization of allele-specific regulatory variation in hybrid pigs

Quan,

Yang,

Wang

et al. 2024

Preprint

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Genetic variation in the regulation of gene expression contributes substantially to phenotypic variation. Understanding how variation in DNA sequences and epigentic modifications leads to gene expression variation remains a challenging task. In hybrid animals where cellular environments are homogeneous, differences between the expression of paternal and maternal alleles must be due to cis sequence or epigenic differences. Therefore, hybrid mapping is a powerful approach to efficiently identify and characterize genes under regulation through mechanisms in cis. In this study, using reciprocal crosses of the phenotypically divergent Duroc and Lulai pig breeds, we performed a comprehensive multi-omic characterization of regulatory variation across brain, liver, muscle, and placenta in four developmental stages. We produced one of the largest multi-omic datasets to date in pigs, including 16 whole genome sequenced genomes, 48 whole genome bisulfite sequencing, 168 ATAC-Seq and 168 RNA-Seq samples. We developed a novel read count-based method to reliably assess allele-specific methylation, chromatin accessibility, and RNA expression. We showed that tissue specificity was much stronger than developmental stage specificity in all of DNA methylation, chromatin accessibility, and gene expression. We identified 573 genes showing allele specific expression, including those influenced by parent-of-origin as well as allele genotype effects. By integrating methylation, chromatin accessibility, and gene expression data, many of these allele specific expression can be explained by allele specific methylation and/or chromatin accessibility. This study provides one of the most comprehensive characterizations of regulatory variation across multiple tissues and developmental stages in pigs and offers new opportunity of genetic improvement for this important food animal species.

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

Cited by 4 publications

References 78 publications

Spatiotemporal dynamics of zygotic genome activation in basal chordates revealed by interspecific hybrids

Spatiotemporal dynamics of zygotic genome activation in basal chordates revealed by interspecific hybrids

Genetic, epigenetic, and environmental mechanisms govern allele-specific gene expression

Multi-omic characterization of allele-specific regulatory variation in hybrid pigs

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