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 ( ) and humans ( ; also see ), respectively.
Some Known Effects Of Exclusively Paternally Expressed DLK1 Gene On Immune Function
Known to be involved in inflammatory diseases (), 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 .
- DLK1 affects B cell development and function in mouse and human cell lines and in vivo mouse studies ( , , 12).
- DLK1 affects expression of several cytokines as well as one of their master switches, , in human cell lines ( ).
- A SNP ( ) 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 (
- 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 ( ).
- Such maternal transmission of MS risk was confirmed in an isolated Dutch population ( ) but not in UK (20) or Sweden ( ) studies.
- See figures below from 22, , .
In the case of(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 ( ).
- 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 ().
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 (). Imprinted microRNAs have target sites implicated in many autoimmune diseases (see Table below from 1).
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