Inheritance: How Our Genes Change Our Lives--and Our Lives Change Our Genes

by Moalem MD PhD, Sharon

  In a world in which the simplistic binary laws of genetic inheritance written by Gregor Mendel in the mid-1800s have long been treated as dogma, many physicians feel unprepared as the fast-emerging world of twenty-first-century genetics whizzes by like a bullet train speeding past a horse-drawn carriage.

  Medicine will catch up eventually. It always does. But until that happens (and, frankly, even after it happens), wouldn’t you like to be armed with as much information as possible?

  Good. That’s why I’m going to do for you what I did for Jeff when I first met him. I’m going to give you an examination.

  I’ve always found the best way to learn something is by just getting in there and doing it.

  So let’s roll up our sleeves and get started.

  No, really—I’d actually like you to roll up your sleeve. Don’t worry—I’m not going to poke you with a needle to extract your blood. That’s not what I’m after. My patients often think that’s the first place I’ll go, but they’re wrong. I just want to take a good look at your arm. I’d like to feel the texture of your skin and watch you flex your elbow. And I’d like to run my fingers along your wrist and stare deep into the crevices of your palm.

  With that and nothing else—no blood, no saliva, no hair sample—your first genetic examination has begun. And I already know quite a bit about you.

  People sometimes figure that when physicians are interested in your genes, the first thing to examine would be your DNA. While some cytogeneticists, people who study how your genome is physically packaged, do use microscopes to take a peek at a person’s DNA, that’s generally only to make sure all the volumes of chromosomes in your genome are there in their entirety and in the right number and order.

  Chromosomes are small—a few millionths of a meter across—but we can see them under the right circumstances. It’s even possible to see if you have a small part of one of your chromosomes missing, duplicated, or even inverted. But individual genes—the teeny-tiny, super-specific sequences of DNA that help to make you who you are? That’s tougher. Even under extreme magnification, DNA appears as a twisted piece of string—maybe a bit like the curled ribbon on a beautifully wrapped birthday present.

  There are ways to unwrap that gift and take a look at all those little bits and pieces inside. That generally involves a process that includes heating strands of DNA to make them separate, using an enzyme to make them duplicate and terminate at a certain place, and adding chemicals to make them visible. What materializes is a picture of you that has the potential to be more revealing than any photograph, X-ray, or MRI could ever be. And that’s important, because processes that get us that deep into your DNA have a vital place in medicine.

  That’s not what I’m interested in right now, however. Because if you know what to look for—a small horizontal crease on the earlobe or a certain curve of the eyebrow—you can quickly make a medical diagnosis by connecting a physical characteristic to a specific genetic or congenital condition.

  Which is why, right now, I’m just looking at you.

  If you’d like to see yourself as I see you, go grab a mirror or walk over to the bathroom and take a look at your beautiful face. We all know our faces pretty well, or at least we think we do, so let’s start there.

  Is your face symmetrical? Are your eyes the same color? Are they deep set? Do you have thin or full lips? Is your forehead broad? Are your temples narrow? Is your nose prominent? Do you have a very small chin?

  Now look closely at the space between your eyes. Can you fit an imaginary eye between your actual eyes? If you can, you may have an anatomical feature called orbital hypertelorism.

  Remain calm. Sometimes in the process of identifying a certain condition or physical characteristic—and certainly whenever we give something an “ism”—doctors set off alarm bells in their patients. But if your eyes are a bit hyperteloric, there’s no need to worry. In fact, if your eyes happen to be a bit farther apart than most, you’re in pretty company. Jackie Kennedy Onassis and Michelle Pfeiffer are among the famous people whose hyperteloric eyes set them apart from the pack.

  When we are looking at faces, eyes that are ever so slightly more widely spaced are one of the things we often subconsciously think of as attractive. Social psychologists have shown that both men and women tend to rate the faces of other people as more pleasing when those people’s eyes are a bit farther apart.3 In fact, modeling agencies purposefully seek out this trait when looking for new talent, and they have for decades.4

  Why do we equate beauty with mild hypertelorism? Well, a good explanation comes in the form of a nineteenth-century Frenchman named Louis Vuitton Malletier.

  You likely know Louis Vuitton as the maker of some of the world’s most expensive and beautiful handbags as well as the founder of a fashion empire that today has become one of the world’s most valuable luxury brands. When young Louis first arrived in Paris, in 1837, he had far more modest ambitions. At the age of 16 he found work as a luggage packer for rich Parisian travelers while apprenticing for a local merchant who was known for making sturdy travel trunks—the well-stickered sort that you may recall seeing in a grandparent’s attic.5

  You might think that today’s baggage handlers are rough with your luggage, but by historical comparison they treat your suitcases with kid gloves. In the days of ship travel, when inexpensive new suitcases couldn’t be bought at any local department store, luggage had to be able to take a really good beating. Before Louis’ trunks, most were not waterproof, and they had to be made with a rounded top to promote water runoff. That made them tough to stack and even less durable. One of Louis’ clever innovations was to use waxed canvas instead of leather. This not only made the trunks waterproof but easily allowed for the switch to a flat-top design, which kept the clothing and goods packed inside dry—not a small feat given the shipping conditions of the time.

  But Louis had a problem: How would he make sure people not familiar with the challenges and costs associated with his trunk design knew whether the luggage they were purchasing was of quality construction? While that wasn’t a big issue in Paris, where word of mouth was the only marketing a good luggage maker needed, growing the business outside of La Ville Lumière was a markedly tougher job.

  Compounding that dilemma was a challenge that has never gone away for Louis and his progeny—knockoffs. When rival luggage makers began copying his boxy designs, sans the quality, his son Georges came up with the illustrious interlocking LV logo, one of the first brand emblems to be trademarked in France.

  With that, he reasoned, buyers could know at a glance whether they were getting the real deal. The logo was shorthand for quality.

  But when it comes to biological quality, people aren’t born with obvious logos. And so, over the course of millions of years of evolution, we’ve developed other, crude ways to size someone up—ways that tell us at a glance the three important things we need to know: kinship, health, and parental suitability.

  Beyond facial similarities denoting blood relations—“you know, he looks so much like his dad”—we usually give very little thought to where our faces come from. Yet the story of the formation of our facial features is a fascinating tale—a complex embryological ballet—and any small developmental misstep is forever etched in our faces for all to see. Starting around the fourth week of our embryological lives, the external part of our face begins to develop from five swellings (imagine that these are like pieces of clay that will be shaped into what will become our future face) that will eventually merge, mold, fuse, and be fashioned into a continuous surface. When these areas don’t fuse smoothly and attach, an open space remains that results in a cleft.

  Some clefts are more serious than others. Sometimes a cleft results in nothing more than a small divot visible on the tip of the chin. (The actors Ben Affleck, Cary Grant, and Jessica Simpson are just a few of the people who have a cleft or “dimpled” chin.) This can also happen on the nose. (Think Steven Spielberg and Gérard Depardieu.) Other times, th
ough, a cleft can leave a large gap in the skin exposing muscle, tissue, and bone and providing an entry point for infections.

  Because they are so multifaceted, our faces serve as our most important biological trademark. Just like the Louis Vuitton logo, our faces speak volumes about our genes and the genetic workmanship that went into our fetal development. For this reason, our species learned to pay attention to these clues before we even knew what they really meant, because they also provided the fastest way of assessing, ranking, and relating to the people around us. Far more than just a superficial perspective, the reason we give so much importance to how our faces look is that, whether we like it or not, they can divulge our developmental and genetic history. Your face can also tell us a lot about your brain.

  Facial formation can signal whether or not your brain developed under normal conditions. In the genetic game of sizing people up, millimeters matter. That could help explain why, across many cultures and generations, we’ve developed a special attraction to eyes that are ever so subtly farther apart than most people’s. The spacing between our eyes is a feature of more than 400 genetic conditions.

  Holoprosencephaly, for instance, is a condition in which the two hemispheres of the brain don’t form properly. Besides being more likely to have seizures and intellectual disability, people with holoprosencephaly are also likely to have orbital hypotelorism—eyes that are very closely spaced. Hypotelorism has also been associated with Fanconi anemia, another fairly common genetic condition in people of Ashkenazi Jewish or black South African descent.6 This condition often causes progressive bone marrow failure and an increased risk for malignancies.

  Hyper- and hypotelorism are just two road signs along a developmental highway that brings together our genetic inheritance and our physical environment, but there are other indicators to look for as well.

  Let’s go find some of those things.

  Take another look in the mirror. Are the outer corners of your eyes lower than the inner corners? Are they higher? We call the separation between the upper and lower eyelids the palpebral fissure. If the outer corners of your eyes are higher than the inner, we describe that as upslanting palpebral fissures. In many people of Asian ancestry this is completely normal and a defining feature, but in individuals of other ancestries, substantially upslanting palpebral fissures may be one of the specific signs or indications of a genetic condition such as Trisomy 21 or Down syndrome.

  When the outer corners of the eyes are lower than the inner, the term for this is downslanting palpebral fissures, which again may mean nothing on its own. But it could also be an indicator of Marfan syndrome, a genetic connective tissue disorder, as it was in the case of the late actor Vincent Schiavelli, who played Fredrickson in the film One Flew Over the Cuckoo’s Nest and Mr. Vargas in Fast Times at Ridgemont High. For casting agents, Schiavelli was “the man with the sad eyes.” For those who know the clues, though, those eyes were a marker that pointed, along with flat feet, a small lower jaw, and several other physical signs, to a genetic condition that when left untreated can result in heart conditions and shortened lifespans.

  Another, less debilitating condition in which the same principle of discovery applies is heterochromia iridum, an anatomical feature in which a person’s irises don’t match in color. It’s often the result of an uneven migration of melanocytes, the cells that produce melanin. You might immediately think of David Bowie, since much has been made of the strikingly different appearance of his eyes. If you look closely, though, you’ll see that Bowie’s eyes aren’t different colors but rather that one of his pupils is fully dilated—the result, it turns out, of a high school fight over a girl.

  Mila Kunis, Kate Bosworth, Demi Moore, and Dan Aykroyd are a few of the people who are true members of the heterochromia club. Even though you’re probably familiar with some or all of those people, you might not have noticed it before, since heterochromia is often subtle.

  You probably know some people with heterochromia and never even realized it. Ordinarily, we don’t spend a lot of time looking deep into the eyes of our friends and acquaintances. Nonetheless, there’s probably someone in your life whose eyes are burned into your psyche.

  Aside from our most significant others, though, we often only remember people’s eyes if they are strikingly and brilliantly blue, like a perfectly cut aquamarine gemstone—a pretty consequence of a complete failure of pigmentation cells to go where they are supposed to go during fetal development.

  And if those blue eyes are accompanied by a white forelock, I think immediately of Waardenburg syndrome. If you have a streak of hair without pigment, heterochromatic eyes, a wide nasal bridge, and hearing problems, then chances are good that you have this condition.

  There are a few different types of Waardenburg syndrome, but the most common is Type 1. This variety of Waardenburg syndrome is caused by changes in a gene called PAX3, which plays a critical role in the way cells migrate as they make their way out of the fetal spinal cord.

  Studying the way the gene works in people with Waardenburg syndrome may provide insights that can be used to understand other, much more common conditions as well. PAX3 is also thought to be involved in melanomas, the deadliest type of skin cancer—an example of how the hidden inner workings of our bodies become apparent through rare genetic conditions.7

  Now let’s move onto eyelashes. While some of us take them for granted, there’s actually a whole industry to make us better endowed in this department. If you’re looking for fuller lashes, you could consider getting extensions or even try using an eyelash-enhancing drug by the trade name Latisse.

  But before you do any of those things, I’d like you to get a good look at your eyelashes and see if you can count more than one row. If you find a few extra eyelashes or an entire row, you have a condition called distichiasis. You’re also in pretty famous company, Elizabeth Taylor is only one example of someone who shares your condition. Interestingly, it’s thought that having an extra row of eyelashes is part of a syndrome called lymphedema-distichiasis syndrome, LD for short, which is associated with mutations in a gene called FOXC2.

  The lymphedema in the disease name refers to what happens when there’s less than normal fluid drainage, as when you’ve been sitting on a long flight and your shoes no longer fit. In this condition it’s especially pronounced in the legs.

  Not everyone with an extra row of eyelashes is symptomatic for swelling, though, and it’s not exactly clear why. You or someone you love may have an extra row of eyelashes and never noticed it until now.

  You never know what you’ll find when you start looking at people in this way. Which is exactly what happened to me last year while sitting at the dinner table with my wife. I always thought that it was mascara that was giving her a very full-looking set of upper eyelashes. But I was wrong. My wife has distichiasis.

  Although she doesn’t have any of the other associated symptoms of LD, I couldn’t believe that it took me more than five years of marriage to notice. Which puts a whole new genetic spin on the idea of finding new qualities in our spouse, even after many years. I just never thought that I could actually miss an extra row of eyelashes.

  This proves that our faces can be vast and unexplored genetic landscapes. You just need to know how to look.

  By now you might have identified at least one feature on your face that may be connected to a genetic condition. But chances are good that you don’t, in fact, have that condition. The truth is that everyone is “abnormal” in some way, so it’s rare to be able to link a single physical characteristic with a correlating condition. When such characteristics are analyzed piece by piece and combined—the spacing and slant of your eyes, the shape of your nose, the number of rows of eyelashes—a tremendous amount of information can be gained about people. And it’s this gestalt that can lead us to a genetic diagnosis—one we can reach without ever having to take an in-depth look into your genome. True, the confirmation of a clinical suspicion is often done through direct genetic
testing, but combing through a person’s entire genome without a specific target is like sifting through every grain of sand on a beach looking for a grain that is just slightly different from the others. A daunting and onerous computational task, to be sure.

  So, in short, it helps to know what you’re looking for.

  Recently, I was at a dinner party with some of my wife’s friends whom I hadn’t met before. And I just couldn’t stop staring at the hostess.

  Susan had eyes that were slightly spread apart (hyperteloric)—just enough to be noticeable. Her nose was just a bit flatter across the bridge than most people’s. She had a rather distinct, wide peak to her vermillion border (doctor shoptalk to describe the shape of her upper lip). She was also a little on the short side.

  And as her hair danced along her shoulders, I was fixated on the prospect of getting a glimpse of her neck. While pretending to admire a rare French poster on the wall for François Truffaut’s 1959 film The 400 Blows and craning my neck as inconspicuously as possible, I tried to sneak a peek.

  It didn’t take long for my wife to notice my blatant gawking, and she pulled me aside in a quiet hallway.

  “Come on! Are you looking again?” she asked. “If you don’t stop staring at Susan people are going to get the wrong idea.”

  “I can’t help it. Remember the other day with your eyelashes?” I said. “Sometimes I just can’t turn it off. Seriously, though, I think Susan has Noonan syndrome.”

  My wife rolled her eyes, knowing full well where this was going. I would be awful company for the rest of the night, ruminating on the various diagnostic possibilities presented by our host’s physical appearance.

  Here’s the thing: Once you learn how to look, manners easily go out the window, and it becomes almost impossible not to. You might have heard that many doctors believe they have an ethical duty to stop and render aid to those in immediate need—at the scene of an accident before paramedics arrive, for instance. What then of those physicians who have been trained to see the possibility of serious, even life-threatening conditions, where others might not see anything unusual at all?