Skeptophilia (skep-to-fil-i-a) (n.) - the love of logical thought, skepticism, and thinking critically. Being an exploration of the applications of skeptical thinking to the world at large, with periodic excursions into linguistics, music, politics, cryptozoology, and why people keep seeing the face of Jesus on grilled cheese sandwiches.

Wednesday, December 29, 2021

The battle of the sexes

Today I'm going to tell you about the latest weird and fascinating research in genetics, but first, a brief refresher from high school biology to set the context.

You may recall that back in the 1800s, an Austrian monk named Gregor Mendel made the first serious stab at trying to figure out how inheritance works.  Prior to this, about all they knew was "like begets like," which sometimes works and sometimes leads you to think that there's such thing as "royal blood," despite evidence to the contrary such as the fact that a lot of those royals were nuttier than squirrel shit.

Anyhow, Mendel studied some traits in pea plants that seemed to obey a few statistical rules.  He made the understandable error of concluding that all traits inherit according to those rules, which turned out to be wrong; actually "Mendelian" traits, that obey all four of Mendel's Laws, are in the minority.  But for a first-order approximation, it wasn't bad. 

One trait in humans that is Mendelian is the Rh blood group gene.  Some people have a gene that makes the Rh protein; in others, the gene is defective, and makes nothing.  You only need one copy of the Rh-producing gene to have the Rh protein in your blood ("Rh-positive"), so the Rh-producing gene is said to be dominant; you only lack the protein ("Rh negative") if both of your copies of the gene are defective, so the non-functional gene is said to be recessive.

Since everyone has two copies of every gene -- one came from your mother, the other from your father -- this makes the inheritance pattern for Rh pretty simple.  (The "everyone has two copies" rule is broken by sex-linked genes, but this doesn't affect today's topic and is a subject for another day.)  Let's say, for example, that parent 1 is Rh-negative (so both copies are defective), and parent 2 is Rh-positive but has one defective and one normal copy.  Their kids inherit a defective copy from parent 1 (that's all (s)he's got), and the one that inherits from parent 2 has a 50/50 probability of being the normal or the defective one.  So the kids each have a 50% chance of being negative or positive.

The important part here is that I didn't stipulate which parent was which; in fact, it doesn't matter.  It works exactly the same way if the mom is parent 1 as it does if the dad is parent 1.

Okay, here's the second bit of background.  There's a group of terrible genetic defects called deletions, in which one of the patient's chromosomes broke somewhere along the process, and is missing a big chunk of genetic information.  You're supposed to have 23 matched pairs, one of each pair from dad and one from mom (again, ignoring the sex chromosomes).  In a deletion, when you match them up (a process called karyotyping) you find that one of the pairs isn't matched, because one member of the pair has a piece missing.

A karyotype for an individual with a deletion on the long arm of chromosome 4 (indicated by the arrow)

Each chromosome contains genes that guide development, and a person with a deletion only has a single copy of the genes in the deleted segment rather than the usual two.  The result is that (s)he only produces half the normal amount of the product made by that gene, and fetal development goes seriously awry.  Most deletions are so bad that they result in death of the embryo and miscarriage; the ones who survive to birth usually have drastic physical and mental abnormalities.

Once again, in the description of deletion, there's no indication which parent the broken chromosome came from.  In the above karyotype, you can't tell if the abnormal copy of chromosome 4 came from the mom or from the dad.  Shouldn't matter, right?  Mendel showed that the trait expresses the same way regardless which parent contributed what to the offspring.

With me so far?  Because here's where it gets a little weird.

The first inkling we had that there was more to the story came from a pair of genetic disorders that seemed, on first glance, to have absolutely nothing in common.  Angelman syndrome results in severe physical and developmental problems, including jerky or spastic movement of the limbs, little capacity for speech, cognitive impairment, and difficulty gaining and keeping on weight.  They often have no interest in food, so their diet has to be carefully managed.  Prader-Willi syndrome causes abnormal skull and brain growth, weak muscles, small hands and feet, and -- most strikingly -- an insatiable fixation on eating.  A friend of mine who worked in a home for the developmentally disabled once told me about a teenager who lived there who suffered from Prader-Willi syndrome, and he was so unable to control his hunger that he'd raid people's desks for food, and if that didn't work, he'd eat inedible things like chalk.

So nothing alike, are they?  Imagine researchers' puzzlement when they found out that both disorders were caused by the same deletion -- the loss of a chunk of the long arm of chromosome 15.

How could the same genetic damage result in such differing outcomes?  You're probably already guessing, given what I said earlier, that it has to do with which parent the damaged chromosome came from, and if so, you're right.  If the deletion was on the maternal copy of the chromosome, the child gets Prader-Willi syndrome; if it's the paternal copy, (s)he gets Angelman syndrome.

This was the first example ever discovered of the phenomenon of genomic imprinting -- where the gene expresses differently depending which parent it comes from.  But there's an even more curious part of the Prader-Willi/Angelman situation, and it has to do with hunger.

Let's say you're a male proto-hominid on the African savanna, and your significant other has just told you that you're gonna be a proud proto-hominid father.  The fetus is surviving inside the mom by obtaining nutrients through the placenta, so in essence, the baby is existing as a parasite on the mom (which continues even after birth, because of breastfeeding).  The dad's interest is (in the pure evolutionary sense) having the baby feed as much as possible, even at the expense of the mother; after all, the baby is his genes' way of surviving, and if the mom weakens, he can always find another mate.  The mom, on the other hand, certainly wants the baby to survive (half the baby's genes come from her, after all), but for her to survive is actually more important.  It's the opposite of the dad's situation; if the baby dies, she can have another baby, but if she dies, she's done for.

So the dad's imprint on the genes is to have the baby feed insatiably; the mom's imprint is to limit the baby's feeding to a level that isn't deleterious to her.  The system all works fine as long as the baby inherits copies of the imprinted genes from both parents; the competing interests of the mother and father balance each other out.  

But in a chromosome 15 deletion, that balance doesn't happen.  A baby with Angelman syndrome only has the maternal copy of a gene called UBE3A, and during egg formation, this gene is imprinted, with the result that it pushes the baby toward the mother's end of the spectrum, feeding-wise.  Thus the lack of interest in food you seen in kids with Angelman syndrome.  In Prader-Willi syndrome, the baby only has the paternal copy -- so the father's interest wins, and the kid wants to eat continuously.

All of this is lead-up to the research that came out last week in the journal Developmental Cell, in which a team of geneticists at Cambridge University found out that the missing chunk of chromosome 15 doesn't just cause opposite behavioral disorders depending on which parent it comes from; it actually changes the number of blood vessels that develop in the placenta long before the baby is born.  A gene called IGF2 (also in the target region of chromosome 15) controls the rate of blood vessel growth, and once again, it's in the dad's interest to have as many blood vessels as possible (favoring the baby at the expense of the mother) and in the mom's interest to inhibit blood vessel growth (favoring the mother at the expense of the baby).  And once again, if both copies are present and work correctly, the competing interests balance out, and the placenta develops normally -- resulting in an at-term overall length of blood vessels of 320 kilometers if you stretched them out end to end.  The genomic imprinting shows up, though, if one of the copies of the genes is defective or missing, because then the parent that contributed the working copy "wins."

So that's another odd twist on inheritance and development, for your morning entertainment.  It all brings to mind the comment made by my genetics professor, Dr. Lemmon, when I was an undergraduate.  "It's not strange when something goes wrong with our developmental genetics," she told us.  "There are a million ways things could go wrong.  What's phenomenal is how often everything goes right."


Neil deGrasse Tyson has become deservedly famous for his efforts to bring the latest findings of astronomers and astrophysicists to laypeople.  Not only has he given hundreds of public talks on everything from the Big Bang to UFOs, a couple of years ago he launched (and hosted) an updated reboot of Carl Sagan's wildly successful 1980 series Cosmos.

He has also communicated his vision through his writing, and this week's Skeptophilia book-of-the-week is his 2019 Letters From an Astrophysicist.  A public figure like Tyson gets inundated with correspondence, and Tyson's drive to teach and inspire has impelled him to answer many of them personally (however arduous it may seem to those of us who struggle to keep up with a dozen emails!).  In Letters, he has selected 101 of his most intriguing pieces of correspondence, along with his answers to each -- in the process creating a book that is a testimony to his intelligence, his sense of humor, his passion as a scientist, and his commitment to inquiry.

[Note: if you purchase this book using the image/link below, part of the proceeds goes to support Skeptophilia!]

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