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We are in the early stages of determining each person’s susceptibility for a range of diseases and developing treatments and drugs tailored to our individual genetic profiles. Personalized medicine, as the field is often called, has seen substantial growth since the early 2000s, following the sequencing of the first human genome. Once the genotypes are known, the individual’s variations can be compared by a physician or scientists with the published literature to determine likelihood of trait expression, ancestry inference and disease risk. Physicians may soon be able to go beyond the one-size-fits-all model to make more effective clinical decisions for each patient. Automated gene sequencers have increased the speed and reduced the cost of sequencing.
Our genetics can also tell us about our ancestral family trees—the genetic ‘groupings’ mapped by our male (Y chromosome inherited from father to son) and female (mitochondrial DNA inherited from mother to child)) lineages, as well as patterns in our autosomal genes—what’s on chromosomes 1-22— and the X. Direct-to-consumer ancestry DNA tests, which use genotyping, look only for a limited number of genetic variants in a person’s genome to determine ancestral ethnicity and genealogical relationships to more recent relatives.
Direct-to-consumer genetic tests, focusing specifically on ancestry and offered by companies such as Family Tree DNA, AncestryDNA, and Oxford Ancestors, emerged first, focusing almost exclusively on genealogy. The tests require the consumer to provide a DNA sample, generally by swabbing the inside of the cheek or spitting into a collection tube. The genotyping looks for specific genetic markers that are much more common among specific population groups united by shared heritage.
Depending on how many points on the genome are tested, they can crudely reveal male and female lineages, and answer other ancestral questions, such as your estimated ‘African’ or ‘European’ ancestry or your likely percentage of Neanderthal genes. The tests are only as accurate as the number of genetic markers or variants assessed and the depth and breadth of a company’s database. Many scientists consider these tests, which can cost as little as $100, mostly entertainment, and results from one company to the next often vary.
The highest profile DTC company, 23andMe, tests for ancestry but also for hundreds of other mutations throughout the genome linked to various diseases, including celiac disease, Parkinson’s and late-onset Alzheimer’s. (Other DTC ancestral testing companies, such as Family Tree DNA, also now offer some disease testing.) But simply having one of those genes doesn’t mean the person will get the disease, as gene expression is influenced by gene-gene and gene-environment interactions. These tests are often referred to as genetic health risk or predictive tests. They can tell whether a person carries a mutation associated with a particular genetic disease. Except in rare cases, such as in identifying Huntington’s disease (for which carrying the mutation leads to certain early death), they are not an actual diagnostic tool. The test doesn’t guarantee the person will or won’t develop the disorder at some point in life, but can indicate elevated risk. Many physicians are wary of these tests as consumers, acting without physician input, often assume associations are akin to a diagnosis. It is important for consumers to ask whether a particular condition being tested for is single-gene (Mendelian) one like Huntington’s disease, or a multifactorial one, like late-onset Alzheimer’s. Multifactorial conditions have several risk factors and are more difficult to predict.
Far more can be learned through a wide range of carrier screening genetic tests offered by companies that require a doctor’s approval to oversee and interpret the results. These tests identify a couple’s risk of each partner contributing a mutation in the same autosomal gene to offspring, which carries a risk of 1 in 4 of causing a single-gene disease. Such Mendelian conditions include sickle cell disease, cystic fibrosis, the thalassemias, and lysosomal storage and other metabolic diseases. Carrier tests are available for more than 1000 diseases, many of them extremely rare. Counsyl, the leading company in this area, tests for 109 of the most common single-gene disorders.
Newborn screening is required in most US states for 32 conditions, including phenylketonuria (PKU), cystic fibrosis, sickle cell disease, critical congenital heart disease, and hearing loss. Most states test for 60 or so conditions, and there is a movement to significantly expand the standard screening list. The strategy already has been used to quickly diagnose elusive illnesses in sick newborns with rare mutations and predict those that will become ill. The conditions chosen for newborn screening panels are treatable to some extent, and can inform parents that future children will be at elevated risk compared to the general population. Researchers are also studying the idea of using expanded screenings as part of the standard battery of tests administered to newborns in hopes of identifying and treating diseases earlier.
Some people conceiving using in vitro fertilization add a step, called preimplantation genetic diagnosis (PGD), that checks for embryos that have inherited a double dose of a mutation in the same gene, and these are not selected for implantation in the uterus.
Concerns over the average consumer’s ability to differentiate between risk and certainty have shaped the ongoing debate since 2013, when the US Food and Drug Administration put a stop to disease-specific mutation testing being offered by 23andMe, which started business in 2006. According to Nature, the FDA concluded: “The agency was worried that people might take drastic medical measures on the basis of their test results, such as deciding to change the dosage of their medications without consulting a doctor or undergoing unnecessary surgery, such as a mastectomy, or treatment based on false positives.” These restrictions were a sharp blow to 23andMe’s revenue model.
The landscape shifted again in April 2017, when DTC testing companies were given permission to reveal genetic markers for a list of 10 diseases. Then, in November 2017, the FDA announced plans to cut back on its regulation of genetic health risk tests—those that inform consumers about risk associations for various diseases, but don’t actually diagnose DNA-disease links. According to GenomeWeb: “The agency also specified that the same exemption didn’t extend to diagnostic genetic tests that inform treatment decisions, such as hereditary cancer tests that analyze BRCA1 and BRCA2 genes, the results from which can lead women to have prophylactic mastectomies or oophorectomies.”
Researchers are increasingly using genetic sequencing and screening to learn more about diseases and how individual genetics might alter the way such medical conditions are treated. The new field of pharmacogenomics, pioneered by such companies as Assurex Health, explores the way genes affect a person’s response to drugs. It helps physicians tailor treatments to specific people, instead of a one-size-fits-all approach.
Pharmacogenomics is use to select treatments for many types of cancer. This is the case for lung cancer. According to the National Cancer Institute, mutations in the EGFR gene can cause cells to divide more rapidly. Drugs called EGFR inhibitors can slow cell division in patients whose cancer cells have that mutation.
Whole genome sequencing determines the order of the four chemical building blocks (called bases) making up the DNA of any organism. The four bases are adenine (A), cytosine (C), guanine (G), and thymine (T). A pairs with T and G pairs with C, forming the rungs of the long ladder that is the DNA double helix. Those four letters are like a chemical alphabet that extends some 3 billion base pairs long to form the instructions to build a functioning human body.
Whole exome sequencing analyzes only the approximately 1.5 percent of the genome that codes for proteins, but which nevertheless accounts for 85% of gene-related diseases. Whole exome sequencing is used to diagnose patients, typically children, with sets of symptoms that are unfamiliar to physicians. If a child has a dominant mutation not seen in either parent, she or he has a “new” (or de novo) case and future children are not at elevated risk. Or, exome sequencing finds the same recessive mutation carried in each parent that, as a double dose in the child, causes disease. In this case, siblings are at a 25% risk of inheriting the family’s disease too.
Exome sequencing does not detect DNA sequences that control gene expression or the many repeated sequences that are in the human genome. We still do not know what some parts of our genomes do. This process ignores the vast area of the genome that has been referred to as “genomic dark matter” based on beliefs (now being challenged) that this area was unimportant.
The first human genomes were sequenced in 2003, one effort as part of the $2.7 billion Human Genome Project, launched in 1990, and the other from Celera Genomics, led at the time by J. Craig Venter. While that’s often the price tag associated with the first successful human sequence, the National Human Genome Research Institute says it doesn’t accurately reflect the price of the actual sequence. Instead, the institute estimates that cost to be somewhere between $500 million and $1 billion.
By 2006, the cost of sequencing had fallen to an estimated $14 million. And a decade later, the cost was dramatically lower, According to the institute: “The cost to generate a high-quality ‘draft’ whole human genome sequence in mid-2015 was just above $4,000; now it’s under $1,000. The cost to generate a whole exome sequence is also generally below $1,000.”
A growing concern among privacy advocates is what happens to people’s genetic information after they pay for genotyping or take part in research that involves genome sequencing.
On one level, the public is afforded some protection by the Genetic Information Nondiscrimination Act (GINA), which makes it illegal for employers or health insurers from requiring genetic information from individuals or their family members. The act doesn’t cover life or disability insurance.
But there is little regulation when it comes to the fast-moving world of DTC commercial genetic tests. And these companies generally stake a claim to the genetic data they collect—with the idea that it can or will be sold to researchers. According to Peter Pitts, president of the Center for Medicine in the Public Interest: “23andMe customers have to wade through pages of fine print before finding out that their information may be ‘shared with research partners, including commercial partners.’ AncestryDNA’s contract claims a ‘perpetual, royalty-free, worldwide, transferable license to use your DNA.’”
There are even questions about guarantees of anonymity for those who take part in scientific studies involving the collection of genetic data. Researchers have shown that it’s possible to identify anonymous study participants by cross referencing their genetic data against publicly available data. Such concerns prompted Senator Chuck Schumer to call on the Federal Trade Commission to review the privacy policies of DTC genetic testing companies.