With the discovery of the double helix, science began to unravel an essential mystery of life. The revelation placed researchers on the threshold of a frontier as tantalizing as the farthest reaches of space. The human race had embarked upon an exploration of itself.
Before DNA testing, there was no way to know, absolutely, the paternity of a child. Maternity, on the other hand, was never in doubt.
How could the father, biologically, compensate for his uncertainty? How could he insure that his offspring made it to maturity, no matter who was carrying the fetus? One way seems to be for him to manage the growth rate of the fetus (or at least to try to do that).
<<<The picture shows a human zygote, in the very first stages of fetal development. The sperm has penetrated the egg. What are the instructions for the developing embryo? What part of those instructions come from the mother, and what part from the father? Researchers are still learning answers to those questions.
But how can the father reach into the womb and control (try to control) the growth of the fetus? Does the mother accept this control? And if she doesn't want to, how can she possibly resist?
The mother has a definite interest in this issue. She has to carry the fetus. All the resources the fetus uses will come from her. The mother has to worry about her own survival, and about the well-being of her future children. She wants a healthy fetus, not a greedy one. It will not suit her to have the instructions from the father for a robust, rapidly growing fetus to prevail. So what happens?
Gagging the Father
Essentially, nature resolves the argument by gagging the father. Or at least his instruction for the fetus to grow at the expense of the mother. The story of how this remarkable scenario plays out is described below.
About twenty years ago it was discovered that a particular gene on chromosome 11, the H19, strongly influences the growth of a fetus. H19 is just one nexus of genetic disagreement between mother and father. Geneticists called this disagreement parental conflict. That's a refreshingly unscientific term, isn't it?
In this conflict, nature sides with the mother. That is, the father's H19 is muted and the mother's is allowed to prevail (most of the time).
The process of silencing a gene is called genomic imprinting. It falls under the heading of epigenetics...an area of exploration that is becoming important in understanding how we get to be who we are.
Hey Freud
Taking time out here for a tongue-in-cheek jibe at Sigmund Freud and classic psychoanalytic theory. One of the foundational principles of Freudian psychoanalysis is "penis envy". Freud's notion was that women covet male genitalia. Freud suggested that at some point in childhood little girls notice something is missing when they look down at their own bodies and at the bodies of little boys. Freud asserted that girls feel inadequate, because they compare the simple arrangement of their own genitalia to the more complicated configurations of their brothers'. And so, Freudian theory proposed, girls are afflicted for the rest of their lives with 'penis envy'.
Given what we know about genomic imprinting, parental conflict, and the silencing of paternal H19, we should consider Freud's penis envy theory as upside down. It is more likely that boys suffer trauma when they realize they will one day be obliged to entrust their offspring to a woman's womb. The most elemental urge of every creature--to propagate--is compromised by this loss of control. Very likely, it's a sort of genetic intelligence, an awareness of paternal impotence, that makes boys insecure from early childhood. The result is not penis envy, but womb envy.
Certainly, this proposition is no more ridiculous than Freud's.
Methylation
In the last few years, geneticists have discovered that genomic imprinting plays a significant role in inheritance. It is believed that hundreds of genes are imprinted (the number is not certain). This involves simply placing a little chemical label over a gene. The label does not alter the gene. It merely blocks the gene's expression.
The chemical process by which a gene is imprinted is called methylation.
Picture of a DNA molecule, (a Visual Molecular Dynamics rendering program was used, and Photoshop) methylated on two strands.
It's Not That Simple
As time passes and research continues, it has become obvious that the simple parental conflict scenario does not present an accurate impression of genomic imprinting. Where once it was thought that this occurred in a couple of clusters on chromosomes 11 and 15, now it is known that it is also spread throughout the genome. The most recently discovered imprinted gene was found on chromosome 21. Imprinting can have subtle or profound effects.
Take, for example, H19, the growth gene at the center of parental conflict discussed earlier. We've established that the mother's H19 is expressed and the father's is not. But H19 is not the only growth gene. There's another gene, IGF2, which is very close to H19 on chromosome 11. This is also a growth gene. But it is silenced in the mother and expressed in the father.
H19 on Chromosome 11: Influences Fetal Growth
However, that's not the end of the story.
Let's say something happens to the mother's H19 and she does not have this growth gene to guide the fetus. It seems that the imprinting (silencing) of her nearby IGF2 growth gene will be "relaxed" to compensate (this information was derived from a mouse study, not a human study). If this sounds complicated, it is. And geneticists are just figuring out how the complex system of genomic imprinting works.
Not only are maternal and paternal genes imprinted, but the imprinted genes are programmed to be silent or active at different stages of life.
What Can Go Wrong?
Plenty
Diploid Insurance Policy
The normal human genome is diploid-- it has 46 chromosomes, 23 from the mother and 23 from the father. This pairing allows for a backup in case something happens to one of the genes in a pair. In that case, a gene on the corresponding, paired chromosome can compensate for the loss.
However, if one of the genes in a pair is imprinted, there is no backup, no insurance policy. Or, if somehow the imprinted gene is mislabeled or misread, then there can be negative consequences.
Some Consequences Related to Imprinting
Angelman Syndrome
This is a commonly cited example of an imprinting disorder. The gene responsible for this disorder is UBE3A, on chromosome 15. Apparently both maternal and paternal copies of this gene are active throughout the body--everywhere except the brain. In the brain, the father's gene is imprinted and only the mother's gene is active. But sometimes maternal UBE3A gets deleted, or damaged. The father's gene is imprinted (silenced) and cannot compensate, so a constellation of abnormalities result. These include movement disorders, seizures and developmental disorders.
This sixteenth-century picture, by Giovanni Francesco Caroto, was painted long before Angelman Syndrome was understood. But the child in the picture looks like some people who are diagnosed with Angelman syndrome. Harry Angelman (pediatrician after whom the disorder is named) actually used the picture to help describe clinical features of the syndrome. Children with Angelman syndrome often appear to be very happy.
Prader-Willi Syndrome
This is another commonly cited imprinting disorder related to chromosome 15. In this case, the affected area of the chromosome is active in the father and imprinted in the mother. If there is a deletion on the father's chromosome, the mother's corresponding chromosome cannot compensate. People with Prader Willi have stunted growth (sometimes treatable by growth hormone), insatiable appetites as they grow older, weak muscle tone and certain developmental or personality issues.
Cancer
Epigenetics--genomic imprinting--offers a promising area of cancer research. Two genes that have been the focus of research are the previously discussed H19 and IGF2. Since both genes affect growth, they have been implicated in the development of tumors. According to an article in Biometrical Central, these two genes have been studied especially in regard to colorectal cancers. The authors of the journal article suggest that looking at peculiarities in the methylation of these genes may help in diagnosing cancers and also in offering prognosis.
Assisted Reproductive Technologies (Artificial Insemination)
Picture shows human sperm being injected into a human egg.
Studies have shown that there is a higher incidence of imprinting errors in children who are the result of assisted reproductive technologies. Research seems to indicate that certain, imprinting related, "major malformations" occur more commonly in children who are born with this assistance.
Consider this blog an introduction. I have learned a great deal about inheritance and genetics from reading the research on genomic imprinting. Besides rethinking Freud's (ridiculous) theory about penis envy, I'm fascinated by the implications for the nature vs. nurture argument. I am left wondering, how far can the apple really fall from the tree? Epigenetics may provide part of that answer.
Credits/Sources
The picture at the start of the post was from Pixabay clipart. Other, not credited, accents in the piece (apple, for example) came from Paint 3D. I made the GIFs.
There are many more sources I read, for background, in order to become familiar with this topic.
Scitable "Discovery of DNA Structure and Function: Watson and Crick"
https://www.nature.com/scitable/topicpage/discovery-of-dna-structure-and-function-watson-397
The Psychologist "he genetic battle of the sexes"
https://thepsychologist.bps.org.uk/volume-29/october-2016/genetic-battle-sexes
Plos Genetics "The Importance of Imprinting in the Human Placenta"
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1001015
Journal of the American Psychoanalytic Association "Penis Envy: from childhood wish to developmental metaphor"
https://www.researchgate.net/publication/22351033_Penis_envy_from_childhood_wish_to_developmental_metaphor
Oxford Journal: Human Molecular Genetics "Genome-wide survey of parent-of-origin effects on DNA methylation identifies candidate imprinted loci in humans"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077796/
Cold Spring Harbor: Perspectives in Biology: Genomic Imprinting in Mammals
https://cshperspectives.cshlp.org/content/6/2/a018382.full
European Journal Human Genetics "A genome-wide search for new imprinted genes in the human placenta identifies DSCAM as the first imprinted gene on chromosome 2"
https://www.ncbi.nlm.nih.gov/pubmed/30206355
Proceedings of the National Academy of Science "Loss of the maternal H19 gene induces changes in Igf2 methylation in both cis and trans"
https://www.researchgate.net/publication/13927403_Loss_of_the_maternal_H19_gene_induces_changes_in_Igf2_methylation_in_both_cis_and_trans
Genetics Home Reference "Angelman syndrome"
https://ghr.nlm.nih.gov/condition/angelman-syndrome#genes
JAMA Pedtatrics "Angelman Syndrome and the Portrait of a Child with a Drawing by Giovanni F. Caroto (ca. 1480 - 1555)"
https://www.researchgate.net/publication/296020335_Angelman_Syndrome_and_the_Portrait_of_a_Child_with_a_Drawing_by_Giovanni_F_Caroto_ca_1480_-_1555
National Organization for Rare Diseases "Prader-Willi Syndrome"
https://rarediseases.org/rare-diseases/prader-willi-syndrome/
Nucleic Acids Research "Epigenetic instability of imprinted genes in human cancers"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678850/
BMC Clinical Epigenetics "Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorectal cancer"
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-018-0578-9#Abs1
Pediatric International "DNA methylation errors in imprinting disorders and assisted reproductive technology"
https://www.researchgate.net/publication/255688140_DNA_methylation_errors_in_imprinting_disorders_and_assisted_reproductive_technology
Journal of Assisted Reproductive Technology "Comprehensive meta-analysis reveals association between multiple imprinting disorders and conception by assisted reproductive technology"https://www.ncbi.nlm.nih.gov/pubmed/29696471
Euroean Journal of Medical Genetics Assisted Reproductive Technologies and imprinting disorders: Results of a study from a French congenital malformations registry
https://www.ncbi.nlm.nih.gov/pubmed/29775803
Genetics Home Reference "What are genomic imprinting and uniparental disomy?"
https://ghr.nlm.nih.gov/primer/inheritance/updimprinting
Plant Physiology "Characterization of Imprinted Genes in Rice Reveals Conservation of Regulation and Imprinting with Other Plant Species"
http://www.plantphysiol.org/content/177/4/1754
Nature Reviews, Genetics "Genomic imprinting disorders: lessons on how genome, epigenome and environment interact"
https://www.nature.com/articles/s41576-018-0092-0
eLife "The discovery and importance of genomic imprinting"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197852/
Science Direct "Influences of genomic imprinting on brain function and behavior"
https://www.sciencedirect.com/science/article/pii/S2352154618301153
PLOS Genetics"The Importance of Imprinting in the Human Placenta"
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1001015
Learn.Genetics "Genomic Imprinting"
https://learn.genetics.utah.edu/content/epigenetics/imprinting/
Biology Pages Info "Imprinted Genes"
http://www.biology-pages.info/I/Imprinting.html
Journal of Cell Science "Paxillin-dependent regulation of IGF2 and H19 gene cluster expression "
http://jcs.biologists.org/content/128/16/3106
American Journal of Obstetric Gynecology "Alterations in expression of imprinted genes from the H19/IGF2 loci in a multigenerational model of intrauterine growth restriction (IUGR)"
https://www.ncbi.nlm.nih.gov/pubmed/26880735
NCBI Resources "H19 imprinted maternally expressed transcript [ Homo sapiens (human)]"
https://www.ncbi.nlm.nih.gov/gene/283120