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

by Moalem MD PhD, Sharon

  But it wasn’t until researchers removed a tiny piece of bone from Ötzi’s left hip that the real genomic fun began. Genetic analysis of DNA preserved in the bone showed that although Ötzi was discovered in Italy’s frigid mountainous north, it seems his closest living genetic relatives today are islanders from Sardinia and Corsica—more than 300 miles away. He also likely was light-skinned, had brown eyes, had type O blood, was lactose intolerant, and was at increased genetic risk for dying from cardiovascular disease, meaning that if we could go back in time and keep him away from milk, meat, and murderers, Ötzi might have lasted a bit longer than his estimated 45 years.12

  For Ötzi, it’s a little too late for any of that genetic information to help. But if we can discover that much about someone who died roaming the Alps more than 5,000 years ago, just imagine what we could learn about ourselves today.

  For those who may not have access to comprehensive genetic testing and sequencing, there’s still another low-tech option that doesn’t require you to subject yourself to the same sort of posthumous rigorous genetic testing that Ötzi endured. A routine climb up your family tree can help you get a lot of valuable information. Asking your relatives if they’ve ever had an acute drug reaction, for example, just might save your life.

  And when trying to parcel out a complex disease that results from myriad genetic interactions, any bit of information can be crucial. The truth is, there’s really no replacement for a good family medical history. And that’s why, when it comes to genetic health in the decades to come, the Mormons may be leading the way.

  You might know Mormons as members of the fast-growing international Church of Jesus Christ of Latter-day Saints. And you might have occasionally encountered them directly—in teams of two, their hair cropped and gelled back, dressed in dark slacks and white shirts with black name tags—at your doorstep.

  What you might not know, though, is that some Mormons also engage in a practice known as baptism for the dead, under the belief that people who died without having had the opportunity to be baptized by a proper authority can get a second shot at salvation, so to speak, if they receive a proxy baptism from a living Mormon.

  That rite gave rise to the modern Mormon practice of sophisticated, computer-based genealogy research, which is a key reason why many members of the church can recite the names and life stories of their ancestors going back for hundreds of years—even for lines of the family complicated by a single husband and multiple wives. This is to ensure that no Mormon soul is left behind.

  For doctors trying to link genetic conditions with family histories, that kind of detailed information can be an absolute gold mine. Today, the church makes many of its genealogy records available to the public over the Internet,13 and many non-Mormons take advantage of that, but for church members, it’s literally something to be done religiously.

  And since Mormons have long sustained a rather strict set of guidelines about what they put into their bodies (many don’t drink caffeine, most eschew alcohol, and illicit drugs are particularly shunned), they might have fewer complicating factors to deal with when sorting through the genetic, epigenetic, and environmental issues at play in their lives.

  ***

  You don’t have to be a Mormon to give your siblings, children, and grandchildren a better shot at having the important information they’ll need to make better sense of their genomes, and thus their personal health. One of the best gifts you can provide them with is a thorough genealogical history, starting with what you know about the health of your own parents and moving on up and across the family tree as far as you can.

  Make it as detailed as possible: You never know how some seemingly inconsequential detail of one generation, like sensitivity to a specific drug, can lead to a useful bounty of familial medical information. So knowing more about your own inheritance, either through a detailed family history or from direct genetic testing, can serve as an important reminder about your own unique individuality.

  It’s a reminder that tells you that it’s time to step away and leave the crowd behind by starting to ask questions like these: What’s the best drug and dosage for my genotype? How can I avoid the Prevention Paradox? What nutritional and lifestyle strategies should I be trying to employ to best serve my genetic needs? And what genetic life lessons can I learn from a frozen 5,000-year-old Italian mummy?

  You may not find all the answers to these key questions right away, but by asking them you’ll come closer to getting a picture of some of the most important genetic qualities that make you incomparably original.

  * A few of the prescribed medications that are impacted by your genes include chloroquine, codeine, dapsone, diazepam, esomeprazole, mercaptopurine, metoprolol, omeprazole, paroxetine, phenytoin, propranolol, risperidone, tamoxifen, and warfarin.

  Chapter 7

  Picking Sides

  How Genes Help Us Decide Between Left and Right

  The raging bull was done. He’d been put out to pasture. That’s what they said.

  And it wasn’t just the critics—although there were many of those too. It was fellow surfers. They’d known for a long time that Mark Occhilupo’s demons were getting the best of him. They knew the drugs had taken their toll. They could see him getting bigger around the waist and falling further and further behind the other top surfers of the day.

  In 1992, it all came to an explosive apogee. At the Rip Curl Pro competition on southeast France’s famed Hossegor Beach, the man known around the world as Occy reportedly attempted to push over the judges’ booth, threw a board at his opponent, and even chowed down on some beach sand before announcing he would be swimming home to Australia.1

  The self-assured, swaggering Aussie had never won a world title. And when Occhilupo abandoned the Association of Surfing Professionals championship tour that year, it seemed clear he never would.

  Out of the limelight, though, Occy set to work righting his life. He got sober. Got back into shape. He swore off the fried chicken, which had been a staple of his diet for way too long. He started surfing again, this time for fun and fitness rather than fame and financial gain.

  Then in 1999 Occhilupo grinded his way, wave by wave, win by win, to the Association of Surfing Professionals World Tour Title. At 33, he was the oldest champion ever.

  Years later, Occy was still at it. After yet another retirement—this one came about on easier terms than the first—the raging bull was raring for another shot at the world circuit. It was then, on a stunning Hawaiian morning on the island of Oahu, that I watched Occhilupo dive headfirst into the crashing waves, emerging not long afterward over the frothy crest and dropping into the trough with all the effort that any of the rest of us might put into laughing at a great joke.

  I’m not a pro surfer, but one thing really stood out to me as I watched Occhilupo ply his trade that day: He’s goofy.

  Some people call left-handers southpaws. Others call them mollydookers or corky dobbers. Scientists still often call lefties sinister, which in Latin originally just meant “left” but later came to be associated with evil.2

  Wondering about the medical implications of being born a corky dobber? It may surprise you that left-handed women were found to be twice or more likely to develop premenopausal breast cancer than right-handers. And a few researchers believe this effect may be linked to exposure to certain chemicals in utero, affecting your genes and then setting the stage for both left-handedness and cancer susceptibility,3 thus opening up another probability of nurture changing nature.

  When it comes to our hands, feet, and even our eyes, most human beings are right-side dominant. Now, you might think that footedness and handedness are always aligned, but as it turns out that’s not always the case for right-handed people, and it’s even more infrequent for left-handed people. Lots of people aren’t congruent.

  In board sports, though, the term is goofy, and it refers to which foot is planted toward the back of the board, and thus which foot dominates when it comes to turn
control. Occy stands with his left foot back.

  There are an amazing number of theories as to why some of us are goofy-footed. But the term itself is often said to have originated with an eight-minute long Walt Disney animated short, called Hawaiian Holiday, that was first released to theaters in 1937. The color cartoon stars the usual suspects: Mickey and Minnie, Pluto and Donald, and, of course, Goofy. During the gang’s vacation in Hawaii, Goofy attempts to surf, and when he finally catches a wave and heads back to shore atop its short-lived crest, he’s standing with his right foot forward and his left foot back.4

  If you’re wondering if you might be goofy and would like to find out before hitting the beach, then imagine yourself at the bottom of a staircase that you’re about to ascend. Which foot moves first? If you’re taking that first imaginary step with your left foot, then it’s likely that you’re a member of the goofy-footed club. And if you find out that you aren’t goofy, then you’re in the majority.

  Why some of us are born left-handed, right-handed, or goofy-footed is thought to relate to an important and early time in the formation of our brain. One of the most popular explanations for lateralization, which is the term given to this phenomenon, is that each side of our brain has evolved for functional specialization. This division of labor allows us to perform multiple complex tasks.

  Do you whistle while you’re at work? Your coworkers can thank your brain’s remarkable lateralization for that. Are you able to drive and talk on the phone at the same time? That’s lateralization, too.*

  So why the predominance of righties? For our species, one of the most important tasks is communication, which is generally processed on the left side of the brain. And some scientists think that’s the reason why we’re right-side dominant, because, as you’ve probably heard, the left side of the brain generally controls the muscles on the right side of the body (which is why a stroke suffered on the left side of your brain is more likely to result in impairment to the arm and leg on the right side of the body).

  So why should you care if you’re goofy? Well, it’s the same question that many people have posed to Amar Klar, a senior investigator of the Gene Regulation and Chromosome Biology Laboratory at the National Cancer Institute. He has been interested in the genetics of handedness for more than a decade.

  Klar is a proponent of a direct genetic cause for handedness, perhaps even a single gene—a discovery we’ve thus far managed to miss as we’ve combed the human genome. The theory, which Klar’s team has backed with a predictive model of dominant and recessive traits that would make Gregor Mendel proud, even explains the fact that monozygotic twins don’t always share the same handedness. This might seem to be an argument against genetic inheritance, but what Klar and several other respected geneticists have proposed is that this theoretical gene carries two alleles, a dominant one that orders up right-handedness and a recessive one. Someone who inherits a pair of recessive alleles has a 50-50 chance of going either way. More than a decade after he started looking for that elusive gene, Klar hasn’t found it yet, but he’s still holding out hope.

  As an alternative to an exclusively genetic cause of handedness, a different line of thinking suggests that left-handed individuals experienced some neurological insult, or damage, during development or delivery that affected the way their brains are wired. Marshaling evidence for “the insult theory,” some people have pointed to studies that found a correlation between children who are born premature and left-handedness. A Swedish meta-analysis* found an almost twofold increase in left-handed children who were born premature.5

  Discovering more of the biology behind handedness, tracing it to genetics, exposures, or both, could give us a lot more knowledge as to whether we should line up our kids on the left or right side of the tee-ball batter’s box. That’s because left-handedness has also been associated with higher rates of dyslexia, schizophrenia, attention deficit hyperactivity disorder, some mood disorders, and, as we’ve discussed, even cancer.6 Indeed, adding handedness into the mix has helped Danish researchers identify which children who had symptoms of ADHD at the age of eight (when, let’s face it, just about every kid is a little bit on the rambunctious side) would still have it at the age of 16.7

  Unlike handedness, though, we’re a lot closer to understanding the genetic reasoning behind the anatomical planning that happens during the development of our body—the genes that work hard to ensure our hearts and spleens end up on the left and our livers on the right. This genetic understanding helps us answer the following question.

  Does it really matter which side does what? If you’ve ever experienced the joy of a hot tap marked cold, then you’ve experienced the pain of laterality gone wrong. When our bodies don’t work as labeled or expected, things can get dangerous—or at least a little goofy.

  But first, to really understand how genes help your body pick sides, we’re going to need to travel back in time to when you were just starting out your life’s adventure as an embryo in your mother’s womb. As we begin our development in three dimensions, there’s an exquisite balance of growth that needs to be struck to make sure we can maintain what will become our future bodily proportions.

  The funny thing about imbalance is that it doesn’t take a whole lot of it to throw everything out of whack. So while a little biological one-sidedness might be good for life, just a little more can cause things to go seriously awry. And quickly, too.

  If you’ve ever been on a small boat—a canoe, perhaps, during a camping trip—you know how this goes. With everyone seated and rowing in perfect coordination, a canoe is an incredibly stable way to move across the water. But all it takes is for one person to stand up at the wrong time and the whole thing capsizes.

  I thought about this as I stood on the beach on Oahu’s North Shore and watched Occhilupo burst out of the barrel of a wave as it crested to the left, then cut back sharply, always one step ahead of the break, manipulating the water like a Japanese chef cutting up a piece of chicken breast sizzling on a teppanyaki.

  Occhilupo’s a master craftsman, but even he couldn’t have done that if not for something that happened back in the 1930s.

  If you watch that Hawaiian Holiday cartoon, you might notice that Goofy’s surfboard looks a bit like an ironing board. It’s long, flat, and tapered at one end—and it has nothing on the bottom. That’s because Goofy’s board hadn’t yet met a guy named Tom Blake, an inventor and surfboard maker who, just a few short years before that cartoon was made, had introduced the world of surfing to the skeg, a fin attached to the underside of the board that helps maintain balance and provide improved maneuverability. As the story goes, Blake’s first prototype was part of a motorboat’s keel that had washed up on shore.

  At first no one really understood what good such an appendage on a surfboard would do. Within a decade, though, nearly every surfboard in the world was outfitted with one or more fins.8

  How does surfing relate to genes and our own development? We humans don’t have a skeg, per se, but a similar sort of structure coded deep within our genes plays an absolutely vital role in our development and sets up the environment for the right genes to be expressed at the right time. Chances are, though, you’ve never heard of them. They are called nodal cilia, and they show up during embryonic development—at a point in which we more or less resemble a squashed piece of gum within our mother’s uterus. At that all-important juncture, nodal cilia stick up from what will be our heads, like little protein antennae.

  And just like a skeg that helps a surfer steer his surfboard in the water and shred some decent waves, our cilia are crucial for moving (and in some situations sensing) the fluid around our developing embryonic selves and creating a necessary spatial chemical concentration gradient. In this way, cilia are simple but vital: Moving the fluid in a specific direction, creating a current like a whirlpool around the embryo. That changes the amount of proteins that are floating in just the right order, which then directs your body’s development, through genetic express
ion, at just the right time.

  Our developing embryo uses these protein signals, which are encoded by our genes, to make sure that our liver forms on what will become the right side of our body and that the spleen will develop on the left.

  In the grand battle fought between competing sides of a human body as to which side gets which organ, our genes code for aptly named proteins like Lefty2, Sonic Hedgehog, and Nodal that duke it out for supremacy in the realm of laterality.

  But when cilia are not working well due to a genetic change, our developmental balance can go completely awry. Like a surfer whose skeg has been broken off by an offshore reef or an unexpected tide swell, misbehaving cilia can cause an imbalance in the amount of proteins that wash over the embryo.

  And if more of the protein Sonic Hedgehog flows beyond its usual borders, it can, metaphorically speaking of course, eat your spleen, leaving you spleenless. Not to be outdone by Sonic Hedgehog, when proteins like Lefty2 are not working, you can end up with more than one spleen, a condition we call polysplenia.

  Confused cilia can even flip our organs goofy. Spin the whirlpool the wrong way and you can end up with some of your major organs on the complete opposite side of the body—the heart on the right, the liver on the left, the spleen on the right.

  Far from being benign, if the proper placement of our internal organs gets lost during development, it can affect almost everything, from our vascular plumbing to our neurological wiring. And what has been done anatomically and neurologically cannot easily be undone. Often, it cannot be undone at all.