what would be required to prove that a phenotype is caused by an epigenetic change
Monica and Erika Hoffman stand up barefoot, adjacent near a sign that reads "Twin Studies Centre" at California State University at Fullerton. Their spectacles removed, both have auburn eyes, softly jutted chins, light freckles, and perky noses. Both clothing black shirts and small sparkly earrings (Erika's are flowers, Monica's, bows). The identical twin sisters turned 39 the day before this lab visit.
"You lot are the 101st twin pair we've had in this written report," Nancy Segal, a shrewd, spirited professor in a sequined black hoodie, tells them, equally a cluster of graduate students shadow her through the halls. Segal, a fraternal twin herself, is a walking Wikipedia of twin science. She specializes in evolutionary psychology and behavioral genetics, and has studied thousands of twins and their families around the world. Nearly three decades ago, Segal founded the Twin Studies Middle to learn what twins similar the Hoffman sisters—far from the same, despite appearances—accept to teach us most the complex interplay of forces that touch on our wellness and shape who we are.
Segal takes out a record measure and begins with Monica, then moves to Erika. "Sixty-eight inches," Segal says. "That would brand Monica three-quarters of an inch taller." At starting time glance, the Hoffman twins' physical differences are as difficult to observe every bit their slightly mismatched heights. Information technology's tricky to tell them apart at all, except that Monica wears a grayness beanie, wispy baby hairs peaking from beneath its knitted edges. Erika wears her dark-brown pilus loose, falling past her shoulders. Monica used to have the same hairstyle—before four-and-a-half months of chemotherapy and half dozen-and-a-half weeks of radiation treatments left her bald.
In September 2015, doctors discovered a tennis-ball-size tumor in Monica's left chest. It turned out that she had stage 2 breast cancer, which had already spread to her lymph nodes. But the specialists were surprised to learn that Monica had an identical twin—and three years later, they continue to be baffled. Monica is now in remission after a partial mastectomy, while Erika continues to receive regular mammograms and ultrasounds, only has never tested positive for cancer. (A year earlier Monica's diagnosis, a mammogram too detected early stage chest cancer in the twins' mother.)
Identical twins (also known as monozygotic twins) come from a single egg that splits in two, and share 100 percent of their genes. Neither Hoffman twin tested positive for BRCA gene mutations, which account for between 5 and 10 pct of breast-cancer cases. In that location are other mutations that may be involved in breast cancer, but with the Hoffman twins, the question loomed: What could accept led to their divergent diagnoses, when their bodies contain the same roughly xx,000 genes?
Twin studies accept historically been some of the virtually valuable genetic research tools in the world—contributing a century of data to our knowledge of man behavioral, medical, and physical traits.
"All twins are valuable to research," says Jeffrey Craig of the Center for Molecular and Medical Research at Deakin University in Australia. "Simply identical twins, I think they are the most valuable. Because what we control, or hold still, is the genetics. The mother, the begetter, the date of nativity, the flavour of birth, the shared surroundings, the family, the mother's diet [are all the same]."
"Twin studies are a simple, very elegant pattern," Segal adds. Holding the genetics constant allows researchers to report the age-old question of nature versus nurture—what aspects of a person come from their Dna, and which come up from their environment? In that location was a fourth dimension when scientists tended to call back i or the other factor was more of import to evolution, just they have since come to realize how limiting it is to confine our understanding of behavior, health, and identity to this either-or dichotomy. "Nature and nurture piece of work in concert," Segal says, "affecting every measurable human trait."
To her, twins are non but curious glasses, but unique individuals born in tandem, living gifts to science and to humanity. Segal has investigated some of the world's virtually fascinating twin cases. She'due south traveled to Brazil to spend fourth dimension with twins who belong to a family unit that includes 22 sets of identical twins born across five generations. Similar many researchers, Segal used to believe that while fraternal twins run in families, identical twins are only random occurrences in nature. Only cases similar the Brazil family and a report of 13 sets of identical twins in Hashemite kingdom of jordan challenge that idea, along with findings like a 2009 study that plant twins from seven different families shared similar alleles. Each of these families produced at least two pairs of identical twins.
Only Segal may be most known for her studies on twins separated or switched at birth, such equally the case involving Begoña and Delia from the Canary Islands in Spain. Equally a baby, Delia was accidentally switched with another infant in the hospital, and the girls and their families grew up oblivious that it had e'er happened until they were 28. They were the sixth switched-at-nascence pair of twins ever identified.
In 2014, Segal stumbled on the eighth and 9th publicly known switched-at-nativity cases, an even more bizarre story of two sets of brothers in Colombia. Each family believed their ii sons were fraternal twins. But everything the men thought they knew about their families and selves blew up when a co-worker of one of the brothers, Jorge, in Bogotá went to the butcher shop on the far side of town. She was certain she saw Jorge working behind the meat counter, which was peculiarly odd because she knew Jorge worked at an applied science company, designing gas and water lines. It was actually Jorge's identical twin, William, who he'd never met.
This mistaken identity led to the discovery that two of the iv brothers had been switched at birth. The young men were actually office of two identical twin sets. 2 of them had been raised in the wrong families altogether, about 150 miles abroad from their identical brothers. Segal traveled to Colombia to written report the four young men, and write about their journeys in a new volume, Adventitious Brothers.
Though switched-at-birth twins are exceedingly rare, there are more instances of twins who are separated at nascency. Since 1922, in that location have been 1,894 cases of sets of twins reared apart, according to a study by Segal. Today, at that place are more documented cases of twins separated at nascence and later reunited than ever before, largely considering the internet has helped connect these siblings. Segal has studied 150 reared-apart twin pairs, and is currently studying 22 cases, mostly from People's republic of china, whose ane-child policy of the 1970s led to the abandonment of tens of thousands of infants. Over a dozen twin sets from Prc were adopted (since the 1990s) and raised separately.
Though all twins, through their similarities and differences, offering insight into the effects of genetics and the surround, twins who were reared autonomously offer peculiarly powerful example studies.
In 1979, Jim Springer and Jim Lewis, "the Jim twins," were reunited at historic period 39 after non knowing the other existed. Every bit described in Segal'due south book on the identical Jim twins, Born Together—Reared Autonomously, both had been adopted and raised by different families in Ohio, only 40 miles apart from each other. Despite their carve up upbringings, information technology turned out that both twins got terrible migraines, scrap their nails, smoked Salem cigarettes, drove light blueish Chevrolets, did poorly in spelling and math, and had worked at McDonald'south and every bit part-time deputy sheriffs. But the weirdest part was that one of the Jim twins had named his first son James Alan. The other had named his first son James Allan. Both had named their pet dogs "Toy." Both had also married women named Linda—then they got divorced, and both married women named Betty.
The Jim twins inspired the Minnesota Twins Reared Autonomously study, which Segal also worked on from 1982 to 1992. This inquiry once more showed surprising similarities in identical twins' habits, interests, intelligence, and religion despite their split up upbringings. Still, even the Jim twins had differences. For starters, one divorced Betty and married a adult female named Sandy, which, as Segal jokes, must take caused worry for the other still-married Betty.
Even the most strikingly similar identical siblings tin can too differ in deeper ways. In the 1960s, researchers studied a set of four identical sisters known as the Genain Quadruplets, all of whom were diagnosed with schizophrenia at 24. Equally a graduate educatee at the University of Chicago, Segal worked on the case one summer at the National Institutes of Mental Wellness in Bethesda, Maryland. The quads' shared diagnoses might take seemed like a vote for nature over nurture. Merely it wasn't so simple. "The Genains did have a very calumniating, paranoid father," Segal says. But the quads were specially remarkable because "despite their identical genes, they all showed varying symptoms."
One sis, known as Myra in the study, had mild features, and might not have even been diagnosed with schizophrenia had it non been for her three sisters whose symptoms ranged in paranoia, hallucinations, catatonia, and incoherence. Genetics obviously played a role. Merely how the affliction manifested within each sister may have been influenced by something else.
The reasons why identical twins have differences at all—non just in health outcomes, simply temperament, taste, and physical traits—can come up down to random chance. But it can also be traced to how each sibling's (identical) genes are expressed. These microscopic variations can lead to radical differences in a person'south health, personality, and fifty-fifty appearance. The written report of how this works is known as epigenetics.
This research field is often misunderstood. Defoliation over gene expression contributed to contempo widespread fake news claiming that the identical twin astronauts Mark and Scott Kelly no longer had identical Deoxyribonucleic acid, after Scott'due south record-length stay on the International Space Station.
What actually happened to the astronaut? "Some of Scott's genes inverse their expression while he was in space, and seven percent of those genes didn't return to their preflight states months afterward he came back," every bit Marina Koren writes in The Atlantic. "If 7 percent of Scott's genetic code changed, as some of the stories suggested, he'd come up back an entirely different species." Gene expression would be expected to change as one'due south trunk reacts to life in space, a drastically different surround from earth. But genetic code itself would not.
With epigenetics, gene action reacts in response to various mechanisms at the cellular level. In Greek, the prefix "epi" ways "on summit of" or "higher up." So referring to "epigenetics" or the "epigenome" implies a process occurring on peak of the genes. A common analogy used to depict the epigenome is to consider genes as instruments in the "symphony" of life. But they don't play themselves. They need musicians. Epigenetics would be the musicians that help limited (or silence) the operation of our genes. Exercise, slumber, trauma, aging, stress, illness, and diet have all shown significant effects on the epigenome.
Studies advise that some changes to the epigenome may be passed on to our hereafter grandchildren. Meanwhile, scientists are actively working on epigenetic editing—finding a way to hack cistron expression. Others are developing drug treatments that target the epigenome. In that location is promise that the science of epigenetics will one day help doctors detect and disrupt diseases earlier and more than effectively.
Whether a gene is agile or not tin can depend on chemical compounds that click onto the Dna construction, toggling the gene'south on-off switch (think of it as a biological lock and key). These changes can be clicked into identify, and they can also be undone. Environment and lifestyle can influence cistron activity, and it is within this segment of the field of epigenetics that twin studies can play a key role.
My own identical twin boys are now 16 months one-time. One has a strawberry-shaped birthmark on his left talocrural joint. The other has a thick em-nuance-shaped birthmark on the back of his right thigh. 1 has a hair whorl that swoops to the correct. The other's swoops left. Without those defining markers—for the first vi months of their lives particularly—my husband and I might take mixed them upwardly and never straightened out the mistake.
It is not as hard to tell my sons apart now, only we oftentimes recognize them more based on personality differences than looks. One is audacious, daring—the first to nosedive off a sofa, the first to fall down stairs. He as well crawled, stood, cruised, and walked showtime. He hollers and cries when nosotros leave the room. Our other boy is an observer. He tin can be laser-focused, able to spend 30 minutes trying to click together a buckle every bit his brother marches effectually with his chest puffed, in need of constant movement and entertainment.
In life, they've shared bottles, diets, sleep schedules, and common colds. In the womb, they shared a placenta (simply not umbilical cords). Notwithstanding, they were starkly different long before most of these experiences, from the instant the doctor sliced me open and yanked them out. Ane screamed all dark long in those first days on Earth. The other, in the aforementioned bassinet, dozed right through his brother's cries.
I wondered: What the heck then was going on inside my body that may accept influenced their different personalities in their start shared year of life? No physician or scientist tin can perchance tell us for certain. Merely the epigenetic changes that can take two identical strands of Deoxyribonucleic acid and turn them into ii unique individuals are thought to start in the womb. Some studies of twin newborns have shown that intrauterine and postnatal environments lead to differences in cistron expression, and some of these divergent patterns are detectable at birth.
These differences may widen equally twins grow upwards. While baby identical twins can exist virtually indistinguishable, some can begin to look more unique as they age (though friends and family all the same misfile adult twins all the time, Segal says, equally with the Colombian sets). Just Segal studied a pair in which one twin was ever heavier growing up. "Mom said he ever ate more—and then there is a subset of twins like that. And adverse prenatal factors tin can intervene, making identical twins somewhat dissimilar in height—the average difference is two inches," she says. For some pairs, their different environments modify them. One may spend more fourth dimension in the sun. One may smoke or experience greater stress. All of these things could influence their epigenomes.
Twins share many environments—a room, a faith, a family. But for twin researchers, understanding what they call "not-shared environments" is of special significance. In life, a non-shared environment "could be a college course. A great teacher. A trauma," says Segal. "Say 1 twin took an exotic trip around the world, or one twin had a terrible disease, or won the lottery, or had an accident. Information technology's those unshared experiences that affect behavior."
In the womb, non-shared experiences could exist slight differences in placenta size, or in umbilical cords, and the fetuses' placement in the womb. "If it'south a really long cord, the idea is that you lot demand more than pressure to actually get the nutrients and oxygen from mother to babe," says Craig, of Deakin University, who believes this is one area of research that is understudied but potentially very important.
"There are some twins in Brazil, where one twin has microcephaly due to the Zika virus infection and the does other not," he adds. "And you'd really remember, 'Concur on a minute, how does that happen if the female parent gets infected, why does only one twin become infected?'" Equally a recent written report on twins exposed to Zika in pregnancy suggested, infection risk could be related to epigenetic mechanisms.
In 2015, Segal collected cheek-swab samples from the Colombian twins doubly switched at birth, and sent them to Craig's lab for an epigenetic assay. This was the first published epigenetic comparison of identical twins raised apart.
2 of the identical twins raised apart (Jorge and William) shared the same bump on the same spot on the bridge of their nose, and until they were reunited both had been convinced that it was from an injury. They also both preferred only eating the drumsticks of chicken. But one wore glasses and the other did not. The other identical pair (Carlos and Wilber) had both been smokers, and both had a speech impediment (Carlos's was corrected but Wilber's was not). Segal also noticed that Wilber is more strongly right-handed than Carlos, who borders in ambidexterity.
Two of the young men grew up in the city of Bogotá, where they had admission to strong educational resources and were working toward graduate degrees when Segal met them. The other two grew upwardly on a remote farm in Vereda El Recreo, and left schoolhouse after 5th form. "The Colombian twins really made me think hard about the environment," Segal says. "The separated twins were raised in extremely different environments, more so than nearly separated pairs."
Craig specializes in reading one kind of epigenetic marker known as methylation patterns. With the Colombian twins, it turned out that one identical pair was still epigenetically similar, despite being raised apart. But with the other pair, the epigenome of one brother raised in the city seemed to differ significantly from his identical twin raised in the country. This could exist because of genes afflicted by ultraviolet rays, radiation, or pesticides—factors that may accept differed from city to state, Craig and Segal hypothesized in their report, published in Dec 2016. But it'south unclear why these twins diverged so greatly while the other pair—who also grew up in these different environments—had such similar epigenomes.
One possibility is that epigenetic changes could have been triggered long before the twins were separated. "What happens if one had a large placenta, and other had a pocket-sized one? Or a sparse umbilical cord, and the other had a fat ane?" Craig asks. There is also, as Craig and other researchers emphasize, happenstance. In that location are spontaneous, unpredictable variations between all cells, and all people, including identical twins.
For twins raised together in similar settings who share the aforementioned genetic profiles, it isn't surprising that 1'south illness could befall the other, like identical twin girls diagnosed with a rare leukemia at 3 months old; or identical twin brothers who each received an ALS diagnosis inside weeks of each other; or the tragic story of identical teen boys who adult a deadly class of liver cirrhosis last year (one survived and his twin did not).
Just by comparing differing gene expressions in identical twins, researchers are beginning to sympathize a diversity of conditions. Rare pairs like the Hoffman sisters with "discordant" diagnoses (in which one has a disease, merely the other does not) may help physicians determine gamble factors for diabetes, autism, schizophrenia, cerebral palsy, thyroid affliction, and ALS.
Manel Esteller, the manager of the Cancer Epigenetics and Biology Program at the Bellvitge Biomedical Research Institute in Barcelona led one of the earliest efforts to identify differences in gene-expression "portraits" of monozygotic twins. "Nosotros saw that different lifestyles were able to create divergent epigenomes," Esteller says. And the changes grew more than contrasting in the twins as they aged.
Esteller'southward lab then fix out to look for epigenetic markers of cancer run a risk. They studied twin pairs with discordant breast-cancer diagnoses, and constitute that epigenetic changes signaling college chest-cancer hazard could exist detected in the sick twin several years before doctors would be able to make an actual clinical diagnosis. (The sample had been previously studied earlier the diagnosis, which allowed Esteller to await at their epigenomes over time.) These changes "can exist detected by a biopsy of the breast. Sometimes the epigenetic defects can likewise exist observed in DNA circulating in the blood," Esteller says. "Present it is widely accustomed that in all human being disorders in that location is a genetic and epigenetic component."
The number of bookish papers in the field of epigenetics has exploded since 2000, which has likewise led to hyped-upwardly promises and overblown results. It is a relatively new field, with some problematic studies, says Andrew Feinberg, who directs the Eye for Epigenetics in the Johns Hopkins Plant for Bones Biomedical Sciences. But for some diseases, similar cancer, "information technology is already well established that most of the mutations disrupt the epigenome, so epigenetics is at the very heart of malignancy."
In April'due south New England Periodical of Medicine, Feinberg called for doctors to integrate genetic and epigenetic information into their practices, arguing that the field "can lead u.s. at concluding to an era of comprehensive medical understanding, unlocking the relationships amongst the patient's genome, surroundings, prenatal exposure, and disease chance in time for us to prevent diseases or mitigate their effects before they accept their toll on health."
After Monica Hoffman's breast-cancer diagnosis, doctors probed the twins' medical and life histories, forcing them to think most where exactly their environments had diverged.
When Erika and Monica were newborns, the only way their mom could tell her babies apart was by a freckle on Monica's lip. But sleep-deprived or in the nighttime of night, it was incommunicable to go on her kids direct. "My mom was so tired that she still couldn't think who she fed, who she bathed, who she burped," Erika says. "She would just cry. So our grandparents came over. They put my mom to bed. They done both of usa. They fed both of us, and they painted Monica'due south toenails."
The red toenails kept the confusion to a minimum at dwelling. At school, classmates called Monica and Erika the "Twin Towers." They played softball and volleyball, were natural leaders, and had like gustatory modality in clothes (surfing tanks and flip-flops fifty-fifty in the winter). They both attended California State University at Long Beach. They went on to showtime a pharmacy wholesale business together and, afterwards living apart for a while, are now roommates once again in Huntington Beach, California.
The sisters wondered if stress may accept played a role in Monica'southward illness. Erika was in a long-term, stable relationship. Monica struggled to find the right romantic partner. Did it come down to diet? Monica ate salmon three times a week for a year. Erika ate far less fish. The sisters told doctors about Monica's irregular, depression-pain periods, which started when she was 10. Meanwhile, Erika had regular menstruation cycles since the age of xi, accompanied past excruciating cramps. Monica developed breasts by 5th class, much earlier than Erika.
The truth is doctors may never be able to tease out any environmental triggers that may have been involved in Monica's diagnosis. Many environmental-epigenetic findings and so far are based on correlation, not proven causation. In the field of twin studies, there is so much still left to untangle and explore, every bit the research continues to veer more toward epigenetics and also the human microbiome, Segal says.
I key question for scientists to consider may be not simply if and how the surroundings toggles with gene expression, simply how humans could flip genes on or off ourselves. This is where engineering such equally epigenetic cistron editing—which focuses on turning the volume knob of gene expression upwards or downwards without changing the underlying Deoxyribonucleic acid—holds great hope.
The Hoffman twins enrolled in Segal'southward study (which is still underway) to ameliorate understand themselves, but through their interest, they will also assistance researchers like Segal understand more most all humans. Today, the cancer-costless twin, Erika, is focusing on disease prevention. She receives regular mammograms and ultrasounds. She thinks dorsum to Monica's bouts with chemo, which acquired terrible bone pain, migraines, and neuropathy. Erika cradled her sister though sleepless nights and helped carry her when she needed to move off the couch. "I e'er idea I was a burden," Monica told her twin, to which Erika replied: "I would rather take you lot be a burden, than have you not be around."
Subsequently her battle with cancer, Monica had a hysterectomy at her doctors' advice, equally a preventative measure. It was bloodshot, considering although she is still in remission, she had always wanted to be a mother. Erika, on the other hand, knew that she did not want children. The twins yet wonder why they ended up on these contrasting trajectories.
"I suspect that at that place are some answers that will always elude us," Segal says.
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Source: https://www.theatlantic.com/science/archive/2018/05/twin-epigenetics/560189/
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