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

Nature Reviews Genetics volume 14, pages 609–617 (2013)Cite this article

Subjects

Key Points

  • Parent-of-origin effects probably contribute to the genetic architecture of complex traits, but they are rarely included in studies of genetic architecture.

  • It is crucial to distinguish between reciprocal heterozygotes when identifying parent-of-origin effects, but several phenomena besides genomic imprinting can potentially produce phenotypic differences between reciprocal heterozygotes.

  • In human studies, large-scale samples that incorporate pedigree information will be important for developing models and tools that can accommodate parent-of-origin effects into analyses.

  • Animal studies will be essential for developing a framework of DNA sequence–imprint–function relationships, particularly because parent-of-origin effects can be context dependent.

  • Research that integrates complex trait mapping results with next-generation sequencing data to identify patterns that have predictive power will be essential to advance the field.

Abstract

Parent-of-origin effects occur when the phenotypic effect of an allele depends on whether it is inherited from the mother or the father. Several phenomena can cause parent-of-origin effects, but the best characterized is parent-of-origin-dependent gene expression associated with genomic imprinting. The development of new mapping approaches applied to the growing abundance of genomic data has demonstrated that imprinted genes can be important contributors to complex trait variation. Therefore, to understand the genetic architecture and evolution of complex traits, including complex diseases and traits of agricultural importance, it is crucial to account for these parent-of-origin effects. Here, we discuss patterns of phenotypic variation associated with imprinting, evidence supporting its role in complex trait variation and approaches for identifying its molecular signatures.

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Figure 1: The line-cross design and the appearance of pseudo-imprinted loci.
Figure 2: Molecular mechanisms that generate complex phenotypic patterns associated with genomic imprinting.

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Acknowledgements

H.A.L. is supported by the US National Institute of Diabetes and Digestive and Kidney Diseases of the US National Institutes of Health (awards K01DK095003 to H.A.L. and P30DK056341 to the Washington University School of Medicine Nutrition and Obesity Research Center). J.B.W. is supported by grant support from the UK Biotechnology and Biological Sciences Research Council (BBSRC).

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Authors and Affiliations

  1. Department of Genetics, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Heather A. Lawson

  2. Department of Biology, Loyola University, Chicago, 60660, Illinois, USA

    James M. Cheverud

  3. Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK

    Jason B. Wolf

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Correspondence to Jason B. Wolf.

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PowerPoint slides

Glossary

Epigenetic

Pertaining to a difference in phenotype resulting from variations in DNA chemistry rather than DNA sequence. Epigenetic changes can be cell specific, can be modified by environmental factors, can affect gene expression and may underlie some parent-of-origin effects on complex traits.

Genomic imprinting

An epigenetic phenomenon in which the expression of a gene occurs in a parent-of-origin-dependent manner.

Complex traits

Quantitative traits that are influenced by many genetic, epigenetic and environmental factors and their interactions.

Line-cross design

An approach to quantitative trait locus mapping in which two non-inbred lines are crossed to produce a mapping population. The approach assumes that the two lines are fixed for different quantitative trait locus alleles, but there is variation at marker loci segregating within the lines.

Quantitative trait locus

(QTL). A region of the genome in which genetic variation at a marker locus is significantly correlated with phenotypic variation for a complex trait.

Parental genetic effects

Effects that occur when genes expressed in the mother or father have a causal influence on the phenotype of the offspring.

Parental imprinting

A phenomenon that occurs when either only the maternally or only the paternally inherited allele affects a phenotype. In a two-allele system, genotypes will group into two phenotypic classes based on the maternally or paternally expressed allele.

Advanced intercross

The result of continued random mating of a population derived from a cross between inbred lines. Advanced intercrosses provide higher resolution for quantitative trait loci than traditional (for example, F2) mapping approaches because of the accumulation of recombination through each generation of random mating.

Dominance imprinting

A complex imprinting pattern in which the parent of origin of alleles affects dominance at a locus. For example, bipolar dominance imprinting occurs when one heterozygote shows overdominance and the reciprocal heterozygote shows underdominance.

Allele-specific biases

Biases that occur when the two alleles in a heterozygote are not functionally equivalent. This situation can arise from an expression bias wherein one allele is expressed at a higher level than the other (the null expectation being that both alleles will be expressed at approximately the same level). There can also be methylation biases, wherein one allele is preferentially methylated (or unmethylated); this can underlie allele-specific expression biases.

Differentially methylated regions

(DMRs). Genomic regions in which the pattern of methylation (the ratio of methylated to unmethylated sequence) is different between two alleles at the same locus.

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Lawson, H., Cheverud, J. & Wolf, J. Genomic imprinting and parent-of-origin effects on complex traits. Nat Rev Genet 14, 609–617 (2013). https://doi.org/10.1038/nrg3543

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