Out of the blue, we at GEITP received an anonymous email question in early developmental biology. In answering his/her question, this became such a major educational story — that we believe it is worthwhile sharing with all of GEITP.
Question:
Dear Colleague, I am writing to ask that you consider, or advise me on, the possibility that some complex traits may be influenced by a certain unconsidered epigenetic mechanism operating at conception; that is, the laterality of gamete origin, and their combinations. Understanding that “1 of 4” (LL; LR; RL; RR) gamete pairing takes place, NO EVIDENCE exists — explaining whether there are any detectable compatibility differences between each of the four, nor whether there could be any potential ramifications, depending on which one of the four combinations establishes. This astounds me, leaving me compelled to ask “Is this a ‘science’ topic that needs to be considered more deeply?”
As you well know, advancing discovery requires investigation and validation, and it begins by asking challenging questions, such as above. One can’t help but wonder: could there be a connection regarding what impact these combinations of lateral gametes could have on aspects of human development? Perhaps none, but also perhaps something reliable and consequential.
However, I can find NO EVIDENCE that any scientist has yet looked at this relatively simple question. This invites other associated questions such as: Can an experiment be designed to test this hypothesis? / Are you, or is anyone, interested in exploring this possibility? / What means are available, or what resources would be required, to help “kick-start” an experiment to test the hypothesis that lateral origin of gametes, and their combinations, can have some impact on the epigenetic profile of resulting cells, and traits in an organism?
Thank you for your consideration and I welcome your advice or any comments.
Given what is available today, one can isolate each of those individual (LL; LR; RL; RR) gamete cells and perform single-cell multi-omics (transcriptomics, metabolomics, WGS, WES, whole-genome DNA methylomics, whole-genome RNAi-omics, histone modifications, chromatin remodeling). ALL these things can now be carried out on individual isolated cells.
What would we be looking for??
Transcriptomics = This would show all genes in each of the one-cell embryos that are expressed — i.e., the full set of RNA transcripts produced by the genome (which shouldn’t be many, at this very early stage of development).
Metabolomics = This will show a profile of all metabolites formed by whatever genes are being expressed.
WGS (whole-genome sequencing) = In the four one-cell embryos, are all ~3 billion DNA base-pairs (bp) of their haploid genomes identical? Or has one or more undergone a de novo mutation (it can happen, but it’d be rare)…
WES (whole-genome exon sequencing) = In each of the four one-cell embryos, 1.5% of ~3 billion = one million base-pairs comprise all exons. Exons contain the nucleotides that directly encode for proteins, whereas introns are stretches of DNA between the exons and do not encode for proteins. Is every bp identical or has one or more undergone mutation (it can happen, but it’d be rare)…
Whole-genome DNA methylomics = A fundamental principle of epigenetics is DNA methylation (mostly around the 5’ end of genes). In general, heavily methylated DNA in promoter and enhancer regions means gene repression (silencing), whereas demethylated (or hypomethylated) DNA allows for gene expression (activation). This is a good place to look at those four embryo cells: there could be changes in gene expression without there being any DNA sequence changes.
Whole-genome RNAi-omics = Another fundamental principle of epigenetics is RNA-interference. (RNAi) is a biological process whereby double-stranded RNA molecules inhibit gene expression by degrading specific mRNA molecules or inhibiting their translation. Triggered by siRNAs or miRNAs, this mechanism uses the RISC complex to target complementary mRNA, preventing protein synthesis. This is another good place to look at those four embryo cells: there could be changes in RNAi expression — without there being any DNA sequence changes.
Histone modifications = This is another fundamental principle of epigenetics. Histone modifications alter gene expression by changing the physical structure of chromatin, making DNA either more accessible, or less accessible, to the transcription machinery. Chemical modifications (such as acetylation, or de-acetylation, or methylation, or de-methylation, on histone tails) dictate whether DNA is tightly packed (repressing gene expression) or loosely packed (activating gene expression). This is another good place to look at those four embryo cells: there could be changes in histone modifications, without there being any DNA sequence changes.
Chromatin remodeling = This is the fourth and last fundamental principle of epigenetics. This field of study is the least well characterized among the four principles of epigenetics. Chromatin remodeling alters gene expression by dynamically opening or closing the chromatin structure, controlling the accessibility of DNA to the transcription machinery. Using ATP for energy, remodeling complexes move, eject, or restructure nucleosomes to expose (“open”) or hide (“close”) promoter regions, allowing transcription factors and RNA polymerases to bind and activate — or inhibit — gene transcription. 😊
DwN