The WIRED Guide to Genetic Testing

[Karlston]

The WIRED Guide to Genetic Testing

Everything you need to know about DNA, medical breakthroughs, and genetic privacy.

Big secrets come in small packages. Take cells, like the ones shedding off the inside of your cheeks and into your saliva right now. These days it’s not that hard to crack them open, shake out the DNA coiled inside, and read the genetic code they contain. Those strings of As, Cs, Ts, and Gs can tell you any number of things you might want to know—the location of your ancestral homelands, say, or which cancer drug is going to give you the best shot at beating your diagnosis. You could also discover things you wish you hadn’t: What if your dad is actually some stranger from a sperm bank? What if you have a disease-causing mutation you could pass on to your own kids? And if you leave your genetic code lying around a crime scene, cops can trace it back to you.

 

Even 25 years ago, many of these things were unknowable. Today, obtaining such information can cost less than a Netflix subscription. For that you can thank your fellow US taxpayers and the $3 billion they pumped into the Human Genome Project during the decade best known for dial-up and Drew Barrymore. That Big Biology project turned Homo sapiens from a black box into a big fat book—262,000 pages long when printed letter by letter.

 

Ever since then, scientists have been trying to figure out what all the words mean. Some sections have been more accommodating to interpretation than others. Which is why, like the complicated chemistry and befuddling bioinformatics that power them, genetic tests can be difficult to understand. So too are the privacy risks associated with them. Still, genetic testing—whether it’s for genealogy research, assessing disease risk, or solving crimes—is only going to get cheaper, more powerful, and more popular. There’s never been a better time to learn what you’re getting into.

 

The History of Genetic Testing

 

You can divide genetic testing into two eras: B.H.G.P. and A.H.G.P., the defining event between them being the announcement of the first draft of the human genome, in 2000. People have known for centuries that traits—be it the curve of a nose or a bleeding disorder—tend to run in families, passing from parents to children through some inheritance mechanism. But technologies capable of detecting and interpreting said substance, now known to be DNA, evolved much more recently.

 

By most accounts, the prehistoric period of genetic testing begins in the 1950s with the discovery that an additional copy of chromosome 21 causes Down’s syndrome. Scientists developed methods for staining chromosomes so they could be sorted and counted, a test called karyotyping. Combined with the ability to collect fetal cells from a pregnant woman’s amniotic fluid, these early advances led to the first genetic prenatal screens. Such tests provided DNA-based diagnoses of genetic disorders caused by big biological screw-ups: too many chromosomes, too few, or chunks of them in the wrong places.

 

As these clinical tests became more common, scientists were also busy trying to drill deeper into the substance of DNA, the chemical structure of which had only been deciphered in 1953 by James Watson, Francis Crick, and Rosalind Franklin. Over the next few decades, scientists would come to understand that its helix-shaped pattern of paired bases—adenine, thymine, cytosine, and guanine—functioned like letters, spelling out words that a cell would decode into amino acids, the building blocks of proteins. They would also begin to realize that most of the human genome—about 98 percent—doesn’t actually code for proteins. In the '70s, “junk DNA” became the popularized term for these nonfunctional sections.

 

Not long after, in 1984, a British geneticist named Alec Jeffreys stumbled upon a use for all that so-called junk DNA: crime-fighting. In these regions of the genome, the DNA molecule tends to duplicate itself, like it’s stuttering over the same word over and over again. Scientists can capture and count these stutters, known as “short tandem repeats.” And because the number of STRs a person has at various locations is unique to them, they can be used to build a personally identifiable profile, or DNA fingerprint.

 

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Genetic Testing Glossary

 

Genotyping
Testing technology, often chip-based, that generates a partial list of your unique genetic differences.

 

Whole-genome sequencing
A method used to determine the exact sequence of your entire genome, all 6.4 billion letters.

 

Whole-exome sequencing
A method used to determine the exact sequence of the protein-coding portion of your genome, comprising about 22,000 genes.

 

Coverage/Depth
A measure of how many times a DNA sequence has been proofread. 30X average depth of coverage is the benchmark of a high-quality sequence.

 

Variant
A generic term referring to places in someone’s genome that differ from a reference genome

 

Single Nucleotide Polymorphism (SNP)
A variant defined by a single letter change

 

Polygenic Score (PGS)
An algorithm that adds up the effects of multiple variants to predict the likelihood of a physical or behavioral trait based on your DNA.

 

Preimplantation Genetic Diagnosis (PGD)
A method for testing IVF embryos for genetic defects prior to starting a pregnancy.

 

Non-Invasive Prenatal Testing
A method for screening a fetus for certain genetic disorders by testing the mother’s blood. Confirming a diagnosis requires more invasive procedures.

 

Carrier Screen
A test used to find out if you carry any genes for disorders that you could pass on to your children.

 

Short Tandem Repeat (STR)
A pattern of repeating sequences in the noncoding part of your genome used in forensic DNA testing

 

CODIS

A national database of genetic profiles collected from criminals and crime scenes, maintained by the US government.

 

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In 1987, this technique was used for the first time in a police investigation, leading to the arrest and conviction of Colin Pitchfork for the rape and murder of two young women in the UK. That same year, Tommie Lee Andrews, who raped and stabbed to death a woman in Florida, became the first person in the US to be convicted as a result of DNA evidence. Since then, forensic DNA testing has put millions of criminals behind bars. In 1994, Congress signed the DNA Identification Act, giving the US Federal Bureau of Investigation authority to maintain a national database of genetic profiles collected from criminal offenders. As of September 2019, this database, known as CODIS, contains DNA from nearly 14 million people convicted of crimes, as well as 3.7 million arrestees, and 973,000 samples gathered at crime scenes.

 

Throughout the '80s and '90s, while cops were rushing to use DNA to catch rapists and murderers, geneticists were slowly doing detective work of their own. By linking health records, family pedigrees, disease registries, and STR locations and lengths, scientific sleuths painstakingly began to map traits onto chromosomes, eventually identifying the genes responsible for a number of inherited conditions, including Huntington’s disease, cystic fibrosis, and sickle-cell anemia. These diseases linked to single genes, so-called monogenic conditions, are basically binary—if you have the genetic mutation you’re almost certain to develop the disease. And once the sequences for these faulty genes were revealed, it wasn’t too hard to test for their presence. All you had to do was design a probe—a single strand of DNA attached to a signal molecule, that would send out a fluorescent burst or some other chemical flare when it found its matching sequence.

 

As the new millennium approached, companies were beginning to pilot such tests in various clinical settings, i.e. with a doctor’s order. That included testing amniotic fluid as part of prenatal screening, testing the blood of prospective parents (what’s known as carrier screening), and testing the cells of embryos created by in vitro fertilization, in a process called pre-implantation diagnosis. These tests were expensive and targeted only at people with family histories of so-called monogenic diseases. Developing tests to assess a healthy person’s risk of developing more complex conditions caused by the interaction of multiple genes—things like heart disease, diabetes, and cancer—would require a more detailed map of human DNA than the fragmented picture scientists had so far decoded. Luckily, that was just around the corner.

 

In 2000, a rough draft of the human genome sequence was made freely available online, followed three years later by a more complete, high-resolution version. With it, scientists and engineers now had enough information to load up chips with not one or two DNA probes but thousands, even hundreds of thousands. These microarrays made it possible to simultaneously scan a person’s genome for thousands of SNPs, or single nucleotide polymorphisms—single changes in the arrangement of DNA letters that make people unique. These SNPs, or variants as they’re alternatively known, can be tallied up to rank a person’s susceptibility to various illnesses.

 

And because this SNP snapshot technology, known as genotyping, could be done much cheaper than full sequencing—in 2006 it cost $1,000 as opposed to $1 million for a full-genome scan—it launched not only a new wave of research but a new industry: direct-to-consumer DNA testing.

 

Starting in the mid-2000s, dozens of companies began selling people a new genetic experience that didn’t have to take place in a doctor’s office. They would take a sample of your DNA—a few laboriously salivated milliliters of drool sent through the mail—scan it, and peer into your ancestral past as well as forecast your genetic future. In the early days, these tests could provide only a limited amount of information. And many companies went under while waiting for researchers to amass more knowledge about the links between certain genes and human traits. But one deep-pocketed Silicon Valley startup weathered the creeping adoption curve (and a spat with the US Food and Drug Administration) to become synonymous with the retail genomics business: 23andMe.

 

Today though, as costs sink even further and the internet makes the exchange of cheek cells for genetic insights virtually frictionless, 23andMe again has plenty of competition. A recent study identified nearly 250 companies offering DNA tests that people can buy online. Most of these are tests for disease predisposition, ancestry, and paternity. But others offer biological inheritance as infotainment—tests offering matchmaking services, predicting children’s talents, recommending the right diet, or even identifying wines you might be genetically inclined to enjoy.

 

Customers should be aware though, that many of these recreational tests offer results with little relationship to reality—the science is still just too premature to be truly predictive for most complicated traits. They might be fun, but don’t take them too seriously. (And if you care about genetic privacy, don’t take them at all!) Even the more medically focused tests, like 23andMe’s health reports, should be taken with a grain of salt. Its testing formula for breast cancer risk, for example, is built around just three genetic variants in the BRCA genes, common in Ashkenazi Jewish populations and known to be associated with cancer. But there are thousands of other variants in those genes that can also raise your risk of breast cancer. It’s just that 23andMe’s DNA chip isn’t set up to capture them. In other words, a clean bill of health from 23andMe shouldn’t be taken as definitive. The company emphasizes that its tests are probability readings, they’re not meant to be diagnostic. So if anything does come up, you still have to go see a doctor for confirmatory clinical testing.

 

The fact that companies have amassed so much DNA data on so many people—more than 26 million by recent estimates—has triggered public concern over genetic ownership and privacy. Especially as the lines between these different kinds of testing begin to blur, as in the case of the Golden State Killer. In April 2018, California police arrested Joseph James DeAngelo, accusing him of being the man behind 12 murders and more than 50 rapes that terrorized the state throughout the '70s and '80s. After nearly four decades, the tip that gave police what they believe is the Golden State Killer’s real name wasn’t a stakeout or fingerprints or cell phone records. It was a genealogy website.

 

Ever since companies like 23andMe and Ancestry have been offering DNA test kits that tell people what regions of the world their great-great-great relatives hail from, hobby genealogists have been building tools to make it easier to turn that DNA data into family trees. A public website called GEDMatch is one such tool. Law enforcement agencies realized it could also be a powerful tool for solving crimes.

 

Traditional forensic DNA tests, as you’ll remember, line up STRs in noncoding regions of the genome to find a match. That kind of data can tell you if two samples came from the same person. What STRs can’t tell you is if a person has green eyes, what their ethnic background is, or who their third cousin might be. Direct-to-consumer tests, on the other hand, do collect that kind of information. And that’s the data that DNA companies and third-party sites like GEDMatch use to build trees of genetically related people. DeAngelo never took a DNA test. But his relatives did. And when they partially matched to samples collected at Golden State Killer crime scenes, police worked with genealogists to zero in on him as a suspect.

 

Since then, law enforcement agencies have rushed to apply the method to other unsolved mysteries. To date, investigators have used genetic genealogy to identify suspects in more than 70 cases. But unlike DNA fingerprinting, this kind of police work has until very recently progressed virtually unregulated. The Department of Justice only issued its interim policy on the procedure in September. It stipulates that police agencies must exhaust all other options, including traditional forensic DNA testing, before accessing genealogy databases. It also requires that any personal genetic information that generates a lead not be downloaded or retained by law enforcement. (A final policy will be issued in 2020.)

 

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5 Things to Know Before Taking an At-Home DNA Test

 

Expect the unexpected. DNA tests may tell you things that aren’t welcome or positive. And the odds of this happening are higher than you might think. About one in 10 people discover they’re not actually related to one or both parents. Be sure you’re ready for all potential outcomes before you start.

 

Your genes are not your future. At-home tests can inform you of your genetic risk for various diseases, but not your overall risk. Lifestyle choices and environmental factors also matter. This is even more true for complex behavioral and social traits.

 

You won’t be the only one with access to your genetic code. Most DNA testing companies allow for de-identified genetic information to be shared with other companies, researchers, and databases. Personally identifiable information can also be shared with law enforcement. Always look carefully through your provider’s privacy policy to find out how your data might be used.

 

If you’re worried about privacy, take steps to divorce your DNA data from your personal identity. These include using encrypted email, a VPN, a PO box, and a preloaded credit card to order your DNA test. Only fill out necessary profile information, and turn off features that connect you to genetic relatives.

 

DNA testing will always carry some privacy risks. Your genetic code is, after all, a string of letters unique to you and only you. And unlike a credit card number, it can’t be changed.

 

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In this regulatory vacuum, consumers have had to rely on companies’ terms of service and privacy policies to keep their genetic information from being accessed by police against their will. But that hasn’t always worked. In January, customers of FamilyTreeDNA learned via news reports that the company had opened its database to the FBI. It had also changed its terms of service to allow searches by law enforcement, without alerting customers. GEDMatch’s policies too, have gone through an evolution over the past year. Following the Golden State Killer case, the company changed its terms to allow police searches for serious crimes—rapes and murders. But after Utah police used it in a case of aggravated assault, and amid the ensuing backlash, the terms were changed again to opt out all its users by default. That might have given some privacy-minded users peace of mind.

 

Then everything changed again. This summer, a Florida judged granted a warrant to search all of GEDMatch for a genetic lead in a murder case. Not just the 185,000 who’d so far opted in to police searches. But the whole database, all 1.3 million profiles. Now, legal experts worry the case will be used as precedent to open up all consumer DNA sites, even closed ones—like 23andMe and Ancestry, which together house the genetic profiles of at least 20 million people—to routine police searches. Both companies have long pledged to keep law enforcement out of their customers’ genetic data. Their terms prohibit police from submitting forensic samples, and each company publishes transparency reports with the number of subpoenas and search warrants received and the number of instances in which data was produced. So far, they’ve been successful in resisting any requests for genetic information, which have been few. But as cops become more willing to pursue court orders, those circumstances, like the companies’ terms of service, are subject to change. Which means the question going forward isn’t just how much do we want to know about ourselves at a genetic level, but how much of our DNA do we want to share with other people?

The Future of Genetic Testing

 

On June 26, 2000, upon announcing the first draft of the human genome, President Bill Clinton proclaimed it would “revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases.” Now, two decades on, that promise is still only just beginning to be fulfilled. Rooting out the genetic causes of the most common medical conditions and turning those insights into blockbuster treatments turned out to be far more complicated than anyone had imagined. But genetic testing is radically changing some corners of medicine. And more are sure to follow.

 

Take cancer care. Decades of research into the genes that turn normal cells into cancerous ones mean that doctors can use new and existing drugs to target tumor-specific mutations. So today, if you find a lump or a radiologist sees something blurry on a scan, it’s likely that doctors will extract some cancerous tissue to run through a gene panel test and match you up with the best available treatment option. As more of these targeted treatments, including a promising new class of living drugs, called immunotherapy, make their way through FDA approval, cancer care will only get more personalized. It’ll also get proactive. It’s now possible to scan people’s blood for bits of DNA shed by cancerous cells—an emerging technology known as liquid biopsy—meaning that doctors can attack tumors before they get big enough to be felt or seen on an X-ray. For many patients that might be enough to shift the odds in their favor.

 

Treating diseases is one thing. Preventing them is another. But that’s an area where genetic testing has a lot of room to make an impact, thanks to the emergence of a powerful new kind of prediction: polygenic scores. Heart disease, for instance, is a complicated condition. There’s no single gene that predisposes you to the big one. Instead, it’s underpinned by a constellation of thousands of genes, each with tiny effects that either boost or lower your odds of having a healthy heart. A polygenic score adds up all these effects and puts you on a continuum of risk. Conceptually, they’ve been around for a while. But only recently, as genetic data on millions of people have become available to lend them a power boost, have they become accurate enough to begin to be useful. Polygenic score-based tests are just starting to hit the market for things like heart disease and breast cancer.

 

Such tests can guide doctors to take extra precautions for high-risk patients, like putting them on cholesterol-lowering statins or recommending a prophylactic double mastectomy. The idea being to catch diseases before symptoms start, when they’re easier to manage. Of course, this is only helpful for illnesses you can do something about. Polygenic scores also have a race problem; they work best in people of the same ethnicity as the data they were built on. And most of the DNA catalogued to date comes from white people. But as efforts to diversify the world’s DNA make these predictions more powerful and more treatments become available, it’s not impossible to imagine a paradigm shift—where people take pills to stave off disease based on their genetic risk report cards.

 

Such report cards are just now starting to show up in another place: the IVF clinic. At least one company has begun offering embryo-grading services for prospective parents. In addition to providing risk scores for diseases that might develop later in life, it also ranks embryos for complex traits like height and intelligence. Scientists warn that these tests aren’t especially predictive, likely adding only a few centimeters and a couple IQ points. But they too will get more accurate with more data. Then it will be up to different societies to decide exactly where to put the line between eliminating serious disease and offering wealthy parents the opportunity to give their kids yet another leg up.

 

Of course, most babies are still made the old-fashioned way, and probably will be for the foreseeable future. (At least until artificial eggs and sperm really take off.) And that’s why hospital systems and governments are beginning to look into screening programs that would sequence the DNA of every child at birth. Not just a genotype, like what you’d get with 23andMe, but a full genome sequence—all 6.4 billion letters of genetic code that make a human. Until recently, the technology to read out a full genome was too expensive to be practical as part of routine health care. But that’s changing. A $100 genome is now just a few years away. And a full sequence makes it possible to gain new insights about yourself every time a scientist makes a genetic discovery—with the help of literature-crawling AI to translate it all. Some companies are even talking about offering whole-genome prenatal screens for expectant parents.

 

But will all that knowledge make people healthier? Happier? The truth is, it’s hard to imagine how societies will rearrange around the ubiquity of genetic information. There are plenty of potential dystopian futures (insert mandatory Gattaca reference here). China has already begun using surreptitiously collected DNA to detain its ethnic Uighur population in reeducation camps. Even in the US the potential for genetic discrimination is only becoming more real, a fact the nation’s aging legal structure is going to have to catch up with, and soon. Optimists though, hold out hope that all this genetic testing can get us to a fairer place, a place with less suffering. If the last 70 years have been about breaking through the biological, chemical, and computational boundaries on understanding our genetic code, the next 70 will be about defining the moral, ethical, and societal boundaries around how we use that information.

 

 

Source: The WIRED Guide to Genetic Testing (Wired)