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Parent-of-origin describes phenotype depending on whether its associated allele is inherited from the mother or father, i.e., non-Mendelian inheritance, unlike Mendelian which assumes genes from either maternal or paternal genomes have equal chance of being expressed in the offspring.

  • Such effects ensue from a variety of genetic and epigenetic mechanisms, and their combinations.
  • Mechanisms include mitochondrial genes, sex chromosomes, i.e., sex-linked traits, and genomic imprinting, i.e., ‘allele-specific expression of a gene depending on its parental origin‘ (1).
  • Since DNA sequences of the two parental copies of autosomes are theoretically identical, difference in expression usually occurs via epigenetic processes.
  • Epigenetics refers to heritable changes not involving changes in DNA nucleotide sequence.
  • Genomic imprinting essentially reduces portions of the genome to ‘a functionally haploid state‘ (2).
  • DNA methylation, histone modification, long non-coding RNAs, long-range chromatin interactions and microRNAs are the best known mechanisms for preferential imprinting of parental genes.
  • The 1st imprinted genes were discovered in mice in 1991 (3, 4, 5, 6).
  • ~7 clusters of imprinted genes are known to exist in mice, namely, Dlk1, Gnas, Grb10, Igf2, Igf2r, Kcnq1 and PWS.
  • So far ~200 and ~60 imprinted genes have been described in mice (7) and humans (8; also see Geneimprint : Home), respectively.

Some Known Effects Of Exclusively Paternally Expressed DLK1 Gene On Immune Function

Known to be involved in inflammatory diseases (9), the exclusively paternally expressed DLK1 gene on human chromosome 14 encodes for an EGF (Epidermal Growth Factor) containing protein, similar to molecules involved in the Notch signaling pathway.

  • DLK1 affects B cell development and function in mouse and human cell lines and in vivo mouse studies (10, 11, 12).
  • DLK1 affects expression of several cytokines as well as one of their master switches, NF-κB, in human cell lines (13).
  • A SNP (Single-nucleotide polymorphism) in the DLK1 cluster, rs941576, associates with paternally inherited risk of developing type I diabetes (14).

Obviously, such Parent-of-origin effects on immune responses are difficult to discern in normal circumstances but easier to do so in diseases, especially autoimmune diseases so that’s where the majority of such effects are being studied. However, given the multi-factorial nature of these diseases and the complexity of gene interactions involved, such studies haven’t yet identified individual genes. Rather, they strongly imply involvement of parentally imprinted genes.

Parent-of-origin effects in MS (Multiple Sclerosis)

  • A Canadian study of 1567 MS patients found (15)
    • Maternal half-siblings (34 of 1859, crude risk 1.83%, age-adjusted risk 2.35%) have a significantly higher MS risk compared to paternal half-siblings (15 of 1577, crude risk 0.95%, age-adjusted risk 1.31%).
    • However, maternal half-sibling risk did not differ significantly from that of full siblings (71 of 2706, crude risk 2.62%, age-adjusted risk 3.11%), implying parent-of-origin effect plays a major role in familial risk for MS.
  • Aunt/uncle and niece/nephew pairs were more likely connected through an unaffected mother rather than father (16).
  • This effect was also observed in inter-racial matings (17) as well as in a Canadian timing of birth study (18).
  • Such maternal transmission of MS risk was confirmed in an isolated Dutch population (19) but not in UK (20) or Sweden (21) studies.
  • See figures below from 22, 23, 24.

In the case of Human leukocyte antigen (HLA) haplotypes linked to MS predisposition,

  • A Canadian study found the haplotype HLA-DRB1*15 bestowed greater risk when inherited from mothers compared to fathers (25).
  • A Canadian study on 7334 individuals from 1515 MS families found HLA-DRB1*15 was preferentially transmitted by mothers rather than fathers (26).
  • The HLA haplotype, HLA-DRB1*1501, shows a stronger disease association in female MS patients of Northern European descent (27).

Such data imply parent-of-origin effects in the HLA locus influence MS susceptibility. One hypothesis for this HLA association with MS is that it might be part of a network of imprinted and non-imprinted genes whose expressions become coordinated in response to specific immune dysregulation (9).

Imprinted MicroRNAs Involved In Autoimmune Diseases

MicroRNAs are small (22 to 23 nucleotides), noncoding RNA molecules that post-transcriptionally regulate gene expression. Such regulation is critical for all kinds of normal cellular functions such as cell cycle, differentiation and death. Each microRNA has multiple mRNA targets and ~30% of all mRNAs are estimated to be regulated by miRNAs (28). Imprinted microRNAs have target sites implicated in many autoimmune diseases (see Table below from 1).


1. Camprubí, Cristina, and David Monk. “Does genomic imprinting play a role in autoimmunity?.” Epigenetic Contributions in Autoimmune Disease. Springer US, 2011. 103-116.

2. Guilmatre, A., and A. J. Sharp. “Parent of origin effects.” Clinical genetics 81.3 (2012): 201-209.

3. Barlow, Denise P., et al. “The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus.” Nature 349.6304 (1991): 84-87.

4. Bartolomei, Marisa S., Sharon Zemel, and Shirley M. Tilghman. “Parental imprinting of the mouse H19 gene.” Nature 351.6322 (1991): 153-155.

5. DeChiara, Thomas M., Elizabeth J. Robertson, and Argiris Efstratiadis. “Parental imprinting of the mouse insulin-like growth factor II gene.” Cell 64.4 (1991): 849-859.

6. Ferguson-Smith, Anne C., et al. “Embryological and molecular investigations of parental imprinting on mouse chromosome 7.” (1991): 667-670.

7. Wang, Xu, Paul D. Soloway, and Andrew G. Clark. “A survey for novel imprinted genes in the mouse placenta by mRNA-seq.” Genetics 189.1 (2011): 109-122. https://www.researchgate.net/pro…

8. Yuen, Ryan KC, et al. “Genome-wide mapping of imprinted differentially methylated regions by DNA methylation profiling of human placentas from triploidies.” Epigenetics & chromatin 4.1 (2011): 1-16. Genome-wide mapping of imprinted differentially methylated regions by DNA methylation profiling of human placentas from triploidies

9. Ruhrmann, Sabrina, et al. “Genomic imprinting: a missing piece of the multiple sclerosis puzzle?.” The international journal of biochemistry & cell biology 67 (2015): 49-57. https://www.researchgate.net/pro…

10. Bauer, Steven R., et al. “Modulated expression of the epidermal growth factor-like homeotic protein dlk influences stromal-cell–pre-B-cell interactions, stromal cell adipogenesis, and pre-B-cell interleukin-7 requirements.” Molecular and cellular biology 18.9 (1998): 5247-5255. Modulated Expression of the Epidermal Growth Factor-Like Homeotic Protein dlk Influences Stromal-Cell-Pre-B-Cell Interactions, Stromal Cell Adipogenesis, and Pre-B-Cell Interleukin-7 Requirements

11. Sakajiri, S., et al. “Dlk1 in normal and abnormal hematopoiesis.” Leukemia 19.8 (2005): 1404-1410. https://www.researchgate.net/pro…

12. Raghunandan, Ramadevi, et al. “Dlk1 influences differentiation and function of β lymphocytes.” Stem cells and development 17.3 (2008): 495-508.

13. Abdallah, Basem M., et al. “dlk1/FA1 regulates the function of human bone marrow mesenchymal stem cells by modulating gene expression of pro-inflammatory cytokines and immune response-related factors.” Journal of Biological chemistry 282.10 (2007): 7339-7351. https://www.researchgate.net/pro…

14. Wallace, Chris, et al. “The imprinted DLK1-MEG3 gene region on chromosome 14q32. 2 alters susceptibility to type 1 diabetes.” Nature genetics 42.1 (2010): 68-71.

15. Ebers, G. C., et al. “Parent-of-origin effect in multiple sclerosis: observations in half-siblings.” The Lancet 363.9423 (2004): 1773-1774. https://www.researchgate.net/pro…

16. Herrera, B. M., et al. “Parent-of-origin effects in MS Observations from avuncular pairs.” Neurology 71.11 (2008): 799-803.

17. Ramagopalan, S. V., et al. “Parent-of-origin effect in multiple sclerosis. Observations from interracial matings.” Neurology 73.8 (2009): 602-605.

18. Willer, Cristen J., et al. “Timing of birth and risk of multiple sclerosis: population based study.” Bmj 330.7483 (2005): 120. http://www.direct-ms.org/sites/d…

19. Hoppenbrouwers, Ilse A., et al. “Maternal transmission of multiple sclerosis in a Dutch population.” Archives of neurology 65.3 (2008): 345-348. http://archsurg.jamanetwork.com/…

20. Hupperts, R., et al. “Patterns of disease in concordant parent–child pairs with multiple sclerosis.” Neurology 57.2 (2001): 290-295.

21. Westerlind, Helga, et al. “Modest familial risks for multiple sclerosis: a registry-based study of the population of Sweden.” Brain 137.3 (2014): 770-778. http://brain.oxfordjournals.org/…

22. Handel, Adam E., et al. “Environmental factors and their timing in adult-onset multiple sclerosis.” Nature Reviews Neurology 6.3 (2010): 156-166.

23. Ramagopalan, Sreeram V., et al. “Multiple sclerosis: risk factors, prodromes, and potential causal pathways.” The Lancet Neurology 9.7 (2010): 727-739. https://www.researchgate.net/pro…

24. Willer, C. J., et al. “Twin concordance and sibling recurrence rates in multiple sclerosis.” Proceedings of the National Academy of Sciences 100.22 (2003): 12877-12882. https://www.researchgate.net/pro…

25. Chao, Michael J., et al. “Epigenetics in multiple sclerosis susceptibility: difference in transgenerational risk localizes to the major histocompatibility complex.” Human molecular genetics 18.2 (2009): 261-266. difference in transgenerational risk localizes to the major histocompatibility complex

26. Ramagopalan, Sreeram V., et al. “Parental transmission of HLA-DRB1* 15 in multiple sclerosis.” Human genetics 122.6 (2008): 661-663.

27. Pennell, Leesa M., Carole L. Galligan, and Eleanor N. Fish. “Sex affects immunity.” Journal of autoimmunity 38.2 (2012): J282-J291.

28. Wienholds, Erno, and Ronald HA Plasterk. “MicroRNA function in animal development.” FEBS letters 579.26 (2005): 5911-5922. http://onlinelibrary.wiley.com/d…