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."

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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!]

The eyes have it

A friend of mine has characterized the teaching of science in elementary school, middle school, high school, and college as follows:

1. Elementary school: Here's how it works!  There are a couple of simple rules.
2. Middle school: Okay, it's not quite that simple.  Here are a few exceptions to the simple rules.
3. High school: Those exceptions aren't actually exceptions, it's just that there are a bunch more rules.
4. College: Here are papers written studying each of those "rules," and it turns out some are probably wrong, and analysis of the others has raised dozens of other questions.

This is pretty close to spot-on. The universe is a complicated place, and it's inevitable that to introduce children to science you have to simplify it considerably.  A seventh grader could probably understand and be able to apply F = ma, but you wouldn't get very far if you started out the with the equations of quantum electrodynamics.

But there are good ways to do this and bad ways.  Simplifying concepts and omitting messy complications is one thing; telling students something that is out-and-out false because it's familiar and sounds reasonable is quite another.  And there is no example of this that pisses me off more than the intro-to-genetics standard that brown eye color in humans is a Mendelian dominant allele, and the blue-eyed allele is recessive.

How many of you had your first introduction to Mendel's laws from a diagram like this one?

This is one of those ideas that isn't so much an oversimplification as it is ridiculously wrong.  Any reasonably intelligent seventh-grader would see this and immediately realize that not only do different people's brown and blue eyes vary in hue and darkness, there are hazel eyes, green eyes, gray eyes, and various combos -- hazel eyes with green flecks, for example.  Then there's heterochromia -- far more common in dogs than in humans -- where the iris of the right eye has a dramatically different color than the left.

[Image licensed under the Creative Commons AWeith, Sled dog on Svalbard with heterochromia, CC BY-SA 4.0]

When I taught genetics, I found that the first thing I usually had to get my students to do was to unlearn the things they'd been taught wrong, with eye color inheritance at the top of the list.  (Others were that right-handedness is dominant -- in fact, we have no idea how handedness is inherited; that red hair is caused by a recessive allele; and that dark skin color is dominant.)  In fact, even some traits that sorta-kinda-almost follow a Mendelian pattern, such as hitchhiker's thumb, cleft chin, and attached earlobes, aren't as simple as they might seem.

But there's nowhere that the typical middle-school approach to genetics misses the mark quite as badly as it does with eye color.  While it's clearly genetic in origin -- most physical traits are -- the actual mechanism should rightly be put in that unfortunate catch-all stuffed away in the science attic:

"Complex and poorly understood."

The good news, though, and what prompted me to write this, is a paper this week in Science Advances that might at least deal with some of the "poorly understood" part.  A broad-ranging study of people from across Europe and Asia found that eye color in the people studied was caused by no fewer than sixty-one different gene loci.  Each of these controls some part of pigment creation and/or deposition, and the variation in these loci from population to population is why the variation in eye appearance seems virtually infinite.

The authors write:

Human eye color is highly heritable, but its genetic architecture is not yet fully understood.   We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations.  We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified.  We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure.  Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes.  Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms.  Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.

And note that even this analysis only explained a little more than half of the observed variation in human eye color.

Like I said, it's not that middle-school teachers should start their students off with a paper from Science Advances.  I usually began with a few easily-observable traits from the sorta-kinda-Mendelian list, like tongue rolling and hitchhiker's thumb.  These aren't quite as simple as they're usually portrayed, but at least calling them Mendelian isn't so ridiculously wrong that when students find out the correct model -- most often in college -- they could accuse their teachers of lying outright.

Eye color, though.  That one isn't even Mendelian on a superficial level.  Teaching it that way is a little akin to teaching elementary students that 2+2=5 and figuring that's close enough for now and can be refined later.  So to teachers who still use brown vs. blue eye color as their canonical example of a dominant and recessive allele:

Please find a different one.

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Last week's Skeptophilia book-of-the-week was about the ethical issues raised by gene modification; this week's is about the person who made CRISPR technology possible -- Nobel laureate Jennifer Doudna.

In The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race, author Walter Isaacson describes the discovery of how the bacterial enzyme complex called CRISPR-Cas9 can be used to edit genes of other species with pinpoint precision.  Doudna herself has been fascinated with scientific inquiry in general, and genetics in particular, since her father gave her a copy of The Double Helix and she was caught up in what Richard Feynman called "the joy of finding things out."  The story of how she and fellow laureate Emmanuelle Charpentier developed the technique that promises to revolutionize our ability to treat genetic disorders is a fascinating exploration of the drive to understand -- and a cautionary note about the responsibility of scientists to do their utmost to make certain their research is used ethically and responsibly.

If you like biographies, are interested in genetics, or both, check out The Code Breaker, and find out how far we've come into the science-fiction world of curing genetic disease, altering DNA, and creating "designer children," and keep in mind that whatever happens, this is only the beginning.

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

Altering the message

It's always a little startling when something is discovered that ends up explaining... well, damn near everything.

If I exaggerate, it's not by much.  I'm referring to epigenetics, which is the modification of DNA or RNA by chemical changes that don't alter the gene sequence itself.  Usually this is accomplished by adding various "markers" to the strand that then change how it is expressed.  These alterations are at least sometimes inheritable; in 2008, a group of geneticists at Cold Spring Harbor came up with the definition of epigenetics as a "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence," and that's pretty much the one that still is used today.

[Image is in the Public Domain]

It has led to some pretty startling discoveries.  In a paper in Nature in 2014, geneticist Moshe Szyl showed evidence that mice that were taught (using mild electric shocks) to fear an odor gave birth to offspring that feared the odor as well -- and that heightened fear response lasted for two further generations.  Szyl found that a particular olfactory gene was "demethylated" by the conditioning -- had a marker called a methyl group removed -- and this enhanced the mice's ability to detect the odor, and modified their response to it.  This led to some serious speculation that the children and grandchildren of people who had been through atrocities like the Holocaust might inherit similar enhancements, leading to significant changes in behavior.

If you think this sounds Lamarckian, you're not wrong.  It turns out there is a way to inherit acquired characteristics.  It doesn't work the way Lamarck thought it did, but there was a grain of truth in what the man said.

This comes up because of a paper in Science this week describing evidence that epigenetic marking influences everything from embryonic development to cancer susceptibility to memory formation.  In fact, one such modification -- called m6a -- can do all three depending on which RNA strand it's acting on.  The last one is the most interesting to me; a team led by Chuan He of the University of Chicago found that if you knocked out an enzyme that reads m6a in mice, they have memory defects but are otherwise normal.  They then injected a virus carrying the normal reader gene into the mice -- and the defects went away.

This sounds to me like the basis of as much of a revolution as Mendel's discovery of the gene itself, and the discovery of DNA's structure and function by Rosalind Franklin, Marshall Nirenberg, James Watson, Francis Crick, and Maurice Wilkins.  The idea that a relatively small alteration to our DNA could create inheritable changes without altering the base sequence runs so contrary to both Mendelian inheritance and the "Central Dogma of Molecular Biology" that it looks like it'll force significant revisions to every bit of genetics we thought we understood.

My guess is that they're only beginning to test the depth of this discovery.  "We just need … a lot more knowledge about these things,” He said.  "We need to stay open-minded. The field is still very young."

So maybe I need to change my declaration in yesterday's post that "the twentieth century was [past tense] the century of the gene."  If my intuition is right, we might be on the brink of a whole new chapter -- hell, a whole new textbook -- in our understanding of how genes work.  All of which reiterates something I've believed for years -- that if you're interested in science, you'll never run out of new discoveries to be amazed at.

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This week's Skeptophilia book recommendation is about a subject near and dear to me: sleep.

I say this not only because I like to sleep, but for two other reasons; being a chronic insomniac, I usually don't get enough sleep, and being an aficionado of neuroscience, I've always been fascinated by the role of sleep and dreaming in mental health.  And for the most up-to-date analysis of what we know about this ubiquitous activity -- found in just about every animal studied -- go no further than Matthew Walker's brilliant book Why We Sleep: Unlocking the Power of Sleep and Dreams.

Walker, who is a professor of neuroscience at the University of California - Berkeley, tells us about what we've found out, and what we still have to learn, about the sleep cycle, and (more alarmingly) the toll that sleep deprivation is taking on our culture.  It's an eye-opening read (pun intended) -- and should be required reading for anyone interested in the intricacies of our brain and behavior.

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