Discovering the sequence of the human genome was only the first step in understanding how the instructions coded in DNA lead to a functioning human being. The next stage of genomic research will begin to derive meaningful knowledge from the DNA sequence. Research studies that build on the work of the Human Genome Project are under way worldwide.

The objectives of continued genomic research include the following:

• Determine the function of genes and the elements that regulate genes throughout the genome.

• Find variations in the DNA sequence among people and determine their significance. The most common type of genetic variation is known as a single nucleotide polymorphism or SNP (pronounced “snip”). These small differences may help predict a person's risk of particular diseases and response to certain medications.

• Discover the 3-dimensional structures of proteins and identify their functions.

• Explore how DNA and proteins interact with one another and with the environment to create complex living systems.

• Develop and apply genome-based strategies for the early detection, diagnosis, and treatment of disease.

• Sequence the genomes of other organisms, such as the rat, cow, and chimpanzee, in order to compare similar genes between species.

• Develop new technologies to study genes and DNA on a large scale and store genomic data efficiently.

• Continue to explore the ethical, legal, and social issues raised by genomic research.

Did you know that just knowing the genome sequence of an organism only reveals part of the story - and that it is also important to determine how that organism interprets its genome and uses that information to build and operate itself accordingly? Less than 2 percent of the human genome corresponds to "genes," but we know other parts are important for regulating and translating the genome as well as responding to environmental influences. Even still, the job of large parts of the genome remains a bit of a mystery!

When scientists started the Human Genome Project, they didn't even know how many genes were in the human genome. It then came as a big surprise to learn that human beings only require roughly 20,000 genes! Those 20,000 or so genes are encoded by less than 2 percent of our genome. What is the rest of it doing? And how does each cell read and interpret its genome?

How Your Cells Use the Genome

Although it's appealing to think of the genome sequence as the "book of life" for an organism - one that contains all of the biological instructions to develop and operate that organism - we now know that the DNA bases are only the starting point.

It can be useful to think of a genome and how it works by a set of maps. Some maps are very simple; they may represent basic information such as the locations and intersections of roads. Such a simple map would be like the sequence of a genome: it would reflect the structure of the road, but would not give information about how it's used. As genomic technology improved, more complicated maps could be developed, adding many features and layers of information to a simple genome map. For instance, we learned that the basic sequence of a genome has stop signs and start signs added to it, just like roads do, and that these additions direct the "traffic" of proteins that bind to DNA and allow the cell use the genome. Other technologies also became available to map traffic patterns, revealing the presence of high- versus low-traffic area. In a genome, a high-traffic area might be a place where many genes are turned on by proteins binding to the DNA. These areas call for multiple layers of regulation, just like in a city where you might have high-rise buildings on top of a busy street with a subway underneath. In low-traffic areas, a genome can have deserts of hundreds of thousands of bases with no genes, with little sign of proteins binding the DNA. In the 15 years since the completion of the Human Genome Project, scientists have developed better and better methods for constructing three-dimensional "satellite" maps of genomes, where we can see what proteins bind to what DNA sequences in a single cell and at a specific time. It is the different patterns of "on" and "off" genes that helps produce the different types of cells that makes you, you.

Some of the stop and start signals that direct our cells to translate the map of our genomes are called "epigenomic modifications." Epigenomic modifications are often chemical groups that are added or subtracted from DNA bases or proteins that bind to DNA that change the way genes are read. Such modifications can be passed on as cells divide, even though they are not strictly changes in the DNA itself. One of these epigenomic modifications is called methylation. As a human is developing, some early cells start to become brain cells. Specific small chemicals (called methyl groups) are added onto the DNA in front of genes that won't be needed for brain cells. Here, the methyl groups act like stop signs: in all future brain cells, the methyl groups will make sure the genes that aren't needed stay turned off. This and other cellular tools in your cells are how the body makes sure its roughly 20,000 genes are used correctly by each cell type. Did you know that your cells were so smart?

Although methyl groups are not changes in the sequence of the DNA bases, epigenomic modifications like these can act like mutations by directing if the bases are read or not.. For example, in cancer cells, methyl groups are often inappropriately added at specific places in the genome. Now the cells grow out of control because the "stop" signs have been added in front of genes that would keep the cell in check. Some cancer therapies are drugs designed to stop these methyl groups from being added where they should not be, like the medicine azacitidine which is used in some blood cancers.

How Epigenomics Affects You

In the last 15 years, we have learned how the environment influences how the genome works through epigenomics. Here's one example: in the winter of 1944-1945, Germany had blocked the food supply to the Netherlands, and the population suffered a terrible famine. The effects of the "Dutch Hunger Winter" could be seen in the children born from women who were pregnant during the famine. The babies from mothers who were malnourished only in the beginning of their pregnancy, but then had normal levels of food later, had a greater frequency of obesity throughout their lifetimes; they also had higher risks of chronic diseases like diabetes when compared to their siblings who were born before or after the famine. In a striking finding, the children of these babies were also found to have higher risks for the same chronic diseases. So it seemed like something could be passed down through generations, but not changes to the DNA sequence itself. Sure enough, research has shown that the methylation patterns in the DNA were altered in these children, and the altered patterns were inherited by their own children, changing their health outcomes.

We know that diet directly affects methylation because nutrients in our food provide the methyl groups themselves. This means that the diet of either parent can affect their children and grandchildren. But it's not just diet - there is strong evidence shows that smoking can change methylation patterns as well. Epigenomic patterns can also be altered by drinking alcohol during pregnancy, leading in extreme cases to fetal alcohol syndrome. While not everything is controlled through epigenomics, these modifications to our DNA play a central role in how the genome carries out its work. But they aren't the only controls we've learned about through the Human Genome Project.

What the Rest Of the Genome Does

If only 2 percent of the genome's bases are used to encode proteins, what is the other 98 percent doing? Some of the genome's bases help determine its structure. There are areas like the telomeres, the ends of each chromosome, that are very important. Just like the caps on the end of your shoelaces, telomeres keep the ends of your chromosomes from fraying. Some of the other parts of your genome position the genes in the right places to be read by the cell's machinery. So, although those bases might not encode proteins, the genome cannot function without their presence.

dark matter" or "junk DNA," we are learning that the 98 percent has all kinds of important roles. Some parts called "ultraconserved elements" have kept the exact same sequence for millions of years in mammals, even though they don't contain genes. Why would that be? Recent studies suggest that deleting these elements causes brain changes and could lead to some neurological diseases like Alzheimer disease, although we are still learning why.

Here's another fact that might be a little creepy: up to 45 percent of your genome is actually leftover DNA from viruses that infected mammals over millions of years. We haven't yet worked out what much of that old viral DNA is doing, but we know it's contributed to at least one very important mammalian trait: exchanging nutrients between mother and baby through the placenta. The rest of the genome includes regulatory elements, including areas that influence genes to be expressed at the same time in response to the environment; transcribed sequences that the cell reads but does not use for making protein; and material which acts as a hotspot for your chromosomes to exchange information with each other.

Single nucleotide polymorphisms, frequently called SNPs (pronounced “snips”), are the most common type of genetic variation among people. Each SNP represents a difference in a single DNA building block, called a nucleotide. For example, a SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA.

SNPs occur normally throughout a person’s DNA. They occur almost once in every 1,000 nucleotides on average, which means there are roughly 4 to 5 million SNPs in a person's genome. These variations may be unique or occur in many individuals; scientists have found more than 100 million SNPs in populations around the world. Most commonly, these variations are found in the DNA between genes. They can act as biological markers, helping scientists locate genes that are associated with disease. When SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene’s function.

Most SNPs have no effect on health or development. Some of these genetic differences, however, have proven to be very important in the study of human health. Researchers have found SNPs that may help predict an individual’s response to certain drugs, susceptibility to environmental factors such as toxins, and risk of developing particular diseases. SNPs can also be used to track the inheritance of disease genes within families. Future studies will work to identify SNPs associated with complex diseases such as heart disease, diabetes, and cancer.

Genome-wide association studies are a relatively new way for scientists to identify genes involved in human disease. This method searches the genome for small variations, called single nucleotide polymorphisms or SNPs (pronounced “snips”), that occur more frequently in people with a particular disease than in people without the disease. Each study can look at hundreds or thousands of SNPs at the same time. Researchers use data from this type of study to pinpoint genes that may contribute to a person’s risk of developing a certain disease.

Because genome-wide association studies examine SNPs across the genome, they represent a promising way to study complex, common diseases in which many genetic variations contribute to a person’s risk. This approach has already identified SNPs related to several complex conditions including diabetes, heart abnormalities, Parkinson disease, and Crohn disease. Researchers hope that future genome-wide association studies will identify more SNPs associated with chronic diseases, as well as variations that affect a person’s response to certain drugs and influence interactions between a person’s genes and the environment.

The International HapMap Project is a scientific effort to identify common genetic variations among people. This project represents a collaboration of scientists from public and private organizations in six countries. Data from the project is freely available to researchers worldwide. Researchers can use the data to learn more about the relationship between genetic differences and human disease.

The HapMap (short for “haplotype map”) is a catalog of common genetic variants called single nucleotide polymorphisms or SNPs (pronounced “snips”). Each SNP represents a difference in a single DNA building block, called a nucleotide. These variations occur normally throughout a person’s DNA. When several SNPs cluster together on a chromosome, they are inherited as a block known as a haplotype. The HapMap describes haplotypes, including their locations in the genome and how common they are in different populations throughout the world.

The human genome contains roughly 10 million SNPs. It would be difficult, time-consuming, and expensive to look at each of these changes and determine whether it plays a role in human disease. Using haplotypes, researchers can sample a selection of these variants instead of studying each one. The HapMap will make carrying out large-scale studies of SNPs and human disease (called genome-wide association studies) cheaper, faster, and less complicated.

The main goal of the International HapMap Project is to describe common patterns of human genetic variation that are involved in human health and disease. Additionally, data from the project will help researchers find genetic differences that can help predict an individual’s response to particular medicines or environmental factors (such as toxins.)

The ENCODE Project was planned as a follow-up to the Human Genome Project. The Human Genome Project sequenced the DNA that makes up the human genome; the ENCODE Project seeks to interpret this sequence. Coinciding with the completion of the Human Genome Project in 2003, the ENCODE Project began as a worldwide effort involving more than 30 research groups and more than 400 scientists.

The approximately 20,000 genes that provide instructions for making proteins account for only about 1 percent of the human genome. Researchers embarked on the ENCODE Project to figure out the purpose of the remaining 99 percent of the genome. Scientists discovered that more than 80 percent of this non-gene component of the genome, which was once considered “junk DNA,” actually has a role in regulating the activity of particular genes (gene expression).

Researchers think that changes in the regulation of gene activity may disrupt protein production and cell processes and result in disease. A goal of the ENCODE Project is to link variations in the expression of certain genes to the development of disease.

The ENCODE Project has given researchers insight into how the human genome functions. As researchers learn more about the regulation of gene activity and how genes are expressed, the scientific community will be able to better understand how the entire genome can affect human health.

Pharmacogenomics is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup.

Many drugs that are currently available are “one size fits all,” but they don't work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions). Adverse drug reactions are a significant cause of hospitalizations and deaths in the United States. With the knowledge gained from the Human Genome Project, researchers are learning how inherited differences in genes affect the body’s response to medications. These genetic differences will be used to predict whether a medication will be effective for a particular person and to help prevent adverse drug reactions. Conditions that affect a person’s response to certain drugs include clopidogrel resistance, warfarin sensitivity, warfarin resistance, malignant hyperthermia, Stevens-Johnson syndrome/toxic epidermal necrolysis, and thiopurine S-methyltransferase deficiency.

The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but new approaches are under study in clinical trials. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.

​​​What is pharmacogenomics?

Pharmacogenomics (sometimes called pharmacogenetics) is a field of research that studies how a person’s genes affect how he or she responds to medications. Its long-term goal is to help doctors select the drugs and doses best suited for each person. It is part of the field of precision medicine, which aims to treat each patient individually.

What role do genes play in how medicines work?

Just as our genes determine our hair and eye color, they partly affect how our bodies respond to medicine.

Genes are instructions, written in DNA, for building protein molecules. Different people can have different versions of the same gene. Each version has a slightly different DNA sequence. Some of these variants are common, and some are rare. And some affect health, such as those gene variants linked to certain diseases.

Scientists know that certain proteins affect how drugs work. Pharmacogenomics looks at variations in genes for these proteins. Such proteins include liver enzymes that chemically change drugs. Sometimes chemical changes can make the drugs more—or less—active in the body. Even small differences in the genes for these liver enzymes can have a big impact on a drug’s safety or effectiveness.

One liver enzyme, known as CYP2D6, acts on a quarter of all prescription drugs. For example, it converts the painkiller codeine into its active form, morphine. There are more than 160 versions of the CYP2D6 gene. Many vary by only a single difference in their DNA sequence. Others have larger changes. Most of these variants don’t affect how people respond to the drug.

Typically, people have two copies of each gene. However, some people have hundreds or even thousands of copies of the CYP2D6 gene. Those with extra copies produce too much of the CYP2D6 enzyme and process the drug very fast. As a result, their bodies may convert codeine to morphine so quickly and completely that a standard dose can be an overdose. In contrast, some variants of CYP2D6 create an enzyme that doesn’t work. People with these variants process codeine slowly, if at all, leading to little, if any, pain relief. For them, doctors can prescribe a different drug.

How is pharmacogenomics affecting drug design, development, and prescribing guidelines?

The Food and Drug Administration (FDA) monitors drug safety in the United States. It now includes pharmacogenomic information on the labels of around 200 medications. This information can help doctors tailor drug prescriptions for individual patients by providing guidance on dose, possible side effects, or differences in effectiveness for people with certain gene variants.

Drug companies are also using pharmacogenomics to develop and market medicines for people with specific genetic profiles.By studying a drug only in people likely to benefit from it, drug companies might be able to speed up the drug’s development and maximize its therapeutic benefit.

In addition, if scientists can identify genes that cause serious side effects, doctors could prescribe those drugs only to people who do not have those genes. This would allow some individuals to receive potentially lifesaving medicines that otherwise might be banned because they pose a risk for other people.

How is pharmacogenomics affecting medical treatment?

Currently, doctors prescribe drugs based mostly on factors such as a patient’s age, weight, sex, and liver and kidney function. For a few drugs, researchers have identified gene variants that affect how people respond. In these cases, doctors can select the best medication and dose for each patient.

Additionally, learning how patients respond to medications helps to discern the different forms of their diseases.

What is pharmacogenomics?

Pharmacogenomics uses information about a person's genetic makeup, or genome, to choose the drugs and drug doses that are likely to work best for that particular person. This new field combines the science of how drugs work, called pharmacology, with the science of the human genome, called genomics.

What might pharmacogenomics mean for you?

Until recently, drugs have been developed with the idea that each drug works pretty much the same in everybody. But genomic research has changed that "one size fits all" approach and opened the door to more personalized approaches to using and developing drugs.

Depending on your genetic makeup, some drugs may work more or less effectively for you than they do in other people. Likewise, some drugs may produce more or fewer side effects in you than in someone else. In the near future, doctors will be able to routinely use information about your genetic makeup to choose those drugs and drug doses that offer the greatest chance of helping you.

Pharmacogenomics may also help to save you time and money. By using information about your genetic makeup, doctors soon may be able to avoid the trial-and-error approach of giving you various drugs that are not likely to work for you until they find the right one. Using pharmacogenomics, the "best-fit" drug to help you can be chosen from the beginning.

How is pharmacogenomic information being used today?

Doctors are starting to use pharmacogenomic information to prescribe drugs, but such tests are routine for only a few health problems. However, given the field's rapid growth, pharmacogenomics is soon expected to lead to better ways of using drugs to manage heart disease, cancer, asthma, depression and many other common diseases.

One current use of pharmacogenomics involves people infected with the human immunodeficiency virus (HIV). Before prescribing the antiviral drug abacavir (Ziagen), doctors now routinely test HIV-infected patients for a genetic variant that makes them more likely to have a bad reaction to the drug.

Another example is the breast cancer drug trastuzumab (Herceptin). This therapy works only for women whose tumors have a particular genetic profile that leads to overproduction of a protein called HER2.

The U.S. Food and Drug Administration (FDA) also recommends genetic testing before giving the chemotherapy drug mercaptopurine (Purinethol) to patients with acute lymphoblastic leukemia. Some people have a genetic variant that interferes with their ability to process the drug. This processing problem can cause severe side effects and increase risk of infection, unless the standard dose is adjusted according to the patient's genetic makeup.

The FDA also advises doctors to test colon cancer patients for certain genetic variants before administering irinotecan (Camptosar), which is part of a combination chemotherapy regimen. The reasoning is that patients with one particular variant may not be able to clear the drug from their bodies as quickly as others, resulting in severe diarrhea and increased infection risk. Such patients may need to receive lower doses of the drug.

What other uses of pharmacogenomics are being studied?

Much research is underway to understand how genomic information can be used to develop more personalized and cost-effective strategies for using drugs to improve human health.

In 2007, the FDA revised the label on the common blood-thinning drug warfarin (Coumadin) to explain that a person's genetic makeup might influence response to the drug. Some doctors have since begun using genetic information to adjust warfarin dosage. Still, more research is needed to conclusively determine whether warfarin dosing that includes genetic information is better than the current trial-and-error approach.

The FDA also is considering genetic testing for another blood-thinner, clopidogrel bisulfate (Plavix), used to prevent dangerous blood clots. Researchers have found that Plavix may not work well in people with a certain genetic variant.

Cancer is another very active area of pharmacogenomic research. Studies have found that the chemotherapy drugs, gefitinib (Iressa) and erlotinib (Tarceva), work much better in lung cancer patients whose tumors have a certain genetic change. On the other hand, research has shown that the chemotherapy drugs cetuximab (Erbitux) and panitumumab (Vecitibix) do not work very well in the 40 percent of colon cancer patients whose tumors have a particular genetic change.

Pharmacogenomics may also help to quickly identify the best drugs to treat people with certain mental health disorders. For example, while some patients with depression respond to the first drug they are given, many do not, and doctors have to try another drug. Because each drug takes weeks to take its full effect, patients' depression may grow worse during the time spent searching for a drug that helps.

Recently, researchers identified genetic variations that influence the response of depressed people to citalopram (Celexa), which belongs to a widely used class of antidepressant drugs called selective serotonin re-uptake inhibitors (SSRIs). Clinical trials are now underway to learn whether genetic tests that predict SSRI response can improve patients' outcomes.

Can pharmacogenomics be used to develop new drugs?

Yes. Besides improving the ways in which existing drugs are used, genome research will lead to the development of better drugs. The goal is to produce new drugs that are highly effective and do not cause serious side effects.

Until recently, drug developers usually used an approach that involved screening for chemicals with broad action against a disease. Researchers are now using genomic information to find or design drugs aimed at subgroups of patients with specific genetic profiles. In addition, researchers are using pharmacogenomic tools to search for drugs that target specific molecular and cellular pathways involved in disease.

Pharmacogenomics may also breathe new life into some drugs that were abandoned during the development process. For example, development of the beta-blocker drug bucindolol (Gencaro) was stopped after two other beta-blocker drugs won FDA approval to treat heart failure. But interest in Gencaro revived after tests showed that the drug worked well in patients with two genetic variants that regulate heart function. If Gencaro is approved by the FDA, it could become the first new heart drug to require a genetic test before prescription.

Did you know that the sequence of your genome can determine how you respond to certain medications? Understanding pharmacogenomics, or tailoring a person's medications based on their genome, would not be possible without sequencing the genomes of many people and comparing their responses to medicines.

One of the most important uses for DNA sequencing is not to just sequence one human genome - but rather to sequence many human genomes to understand how genomic differences relate to different traits. Some such traits reflect physical characteristics (like eye color), whereas others can be used to help in the clinical care of patients. Scientists in the field of pharmacogenomics study how specific variants in your genome sequence influence your response to medications.

Influencing How Medicines Work

In order for our bodies to use some medicines properly, the cells in our bodies must make a few chemical changes that convert them into an active form, just like we do when we eat food. Then, these active forms of the medicine must get to the right places in the body or inside cells to do the job that we want them to do. If we want to make sure this happens, it makes sense that we would target our bodies' pathways involved in changing the medicine's form or in getting medicines to the right places. For example, you probably know someone who takes an antidepressant. Many of these medicines get to the right places by interacting with a protein called ABCB1, which works like a traffic cop on the outside of your cells.

Given ABCB1's important role in controlling traffic, you might imagine that if someone has a genomic variant that changes the shape or function of their ABCB1 protein, they might have a different response than usual to any number of medicines. We now know that is the case for some antidepressants, as well as other medications like statins for cholesterol and certain chemotherapy medicines. As a result, there are at least 18 pharmacogenomic tests for variants in ABCB1 listed in the NIH's Genetic Test Registry, with suggestions that you be tested for these variants to help determine the correct dose for certain medications.

Stopping Dangerous Side Effects

Healthcare professionals and researchers are constantly seeking both to optimize medical treatments and to avoid adverse (or negative) reactions to treatments, which are estimated to affect between 7 percent and 14 percent of hospitalized patients. This makes adverse reactions a large cause of added days spent in a hospital, and the fourth leading cause of death in the United States.

One scary example of such an adverse reaction is Stevens-Johnson syndrome (SJS), a severe allergic reaction also called "scalded skin syndrome." It can be caused by infections, but also by very common medications like ibuprofen, anti-seizure medicines, or antibiotics. Patients may go from taking two pain pills to ending up in the hospital burn unit fighting for their lives if SJS progresses to a worse condition called toxic epidermal necrolysis (TEN). TEN is diagnosed when patients have shed at least one-third of the skin off of their bodies. Needless to say, anything we can do to prevent this allergic reaction is vitally important.

In Taiwan, married scientists Wen-Hung Chung (a physician) and Shuen-Iu Hung (an immunologist) noticed that SJS/TEN was much more common in patients taking carbamazepine, used to treat epilepsy and seizures, or allopurinol, used to treat gout. They showed that this was due to genomic variants in the HLA-B gene. Not surprisingly, this gene helps control the immune response. As a result of their work, the country of Thailand has implemented genomic testing before these medications are prescribed. The results of this "pharmacogenomic test" are used to decide whether it is safe to give a specific patient certain medicines, like carbamazepine or allopurinol. Thailand's government even covers the cost of this testing, and the frequency of SJS/TEN has been drastically reduced. We have since learned that different ancestries are associated with different HLA-B genomic variants, so countries may need to take different approaches to monitor which medications are most likely to be linked to SJS/TEN.

Relationships are Complicated

Understanding pharmacogenomics would not be possible without sequencing the genomes of many people and comparing them, and then comparing their response to medicines. But we have also learned that a person's genome sequence is not everything when it comes to medication responses. The human body is a very complicated machine, and the instructions written in our DNA are just part of the process.

There are some cases, as with the breast cancer treatment tamoxifen, where a small study showed that there might be a relationship between someone's response to the medicine and a variant in the CYP2D6 gene. However, this finding did not appear to be true in a larger study that involved many more people. That's why at this time, the U.S. Food and Drug Administration (FDA) labeling for tamoxifen does not recommend CYP2D6 pharmacogenomic testing, but the issue is still being reviewed as more research is conducted.

Another gene in the same CYP family, called CYP2C19, has variations which affect how your body can use clopidogrel (more commonly known as Plavix). This medication is a "blood thinner" which helps prevent blood clots, and thus reduces your risk of strokes or some heart attacks. If your CYP2C19 protein is not working properly due to a mutation in the gene, then you will not be able to process clopidogrel, and you need either a different dose or a different medication. As it turns out, these variants in CYP2C19 are also more common in those with Asian ancestry. Although testing for variants in this gene is also not routinely recommended, you may wish to speak with your healthcare provider about the test if you are given a prescription for clopidogrel, particularly if you have East Asian family members.

Genome editing (also called gene editing) is a group of technologies that give scientists the ability to change an organism's DNA. These technologies allow genetic material to be added, removed, or altered at particular locations in the genome. Several approaches to genome editing have been developed. A well-known one is called CRISPR-Cas9, which is short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9. The CRISPR-Cas9 system has generated a lot of excitement in the scientific community because it is faster, cheaper, more accurate, and more efficient than other genome editing methods.

CRISPR-Cas9 was adapted from a naturally occurring genome editing system that bacteria use as an immune defense. When infected with viruses, bacteria capture small pieces of the viruses' DNA and insert them into their own DNA in a particular pattern to create segments known as CRISPR arrays. The CRISPR arrays allow the bacteria to "remember" the viruses (or closely related ones). If the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays that recognize and attach to specific regions of the viruses' DNA. The bacteria then use Cas9 or a similar enzyme to cut the DNA apart, which disables the virus.

Researchers adapted this immune defense system to edit DNA. They create a small piece of RNA with a short "guide" sequence that attaches (binds) to a specific target sequence in a cell's DNA, much like the RNA segments bacteria produce from the CRISPR array. This guide RNA also attaches to the Cas9 enzyme. When introduced into cells, the guide RNA recognizes the intended DNA sequence, and the Cas9 enzyme cuts the DNA at the targeted location, mirroring the process in bacteria. Although Cas9 is the enzyme that is used most often, other enzymes (for example Cpf1) can also be used. Once the DNA is cut, researchers use the cell's own DNA repair machinery to add or delete pieces of genetic material, or to make changes to the DNA by replacing an existing segment with a customized DNA sequence.

Genome editing is of great interest in the prevention and treatment of human diseases. Currently, genome editing is used in cells and animal models in research labs to understand diseases. Scientists are still working to determine whether this approach is safe and effective for use in people. It is being explored in research and clinical trials for a wide variety of diseases, including single-gene disorders such as cystic fibrosis, hemophilia, and sickle cell disease. It also holds promise for the treatment and prevention of more complex diseases, such as cancer, heart disease, mental illness, and human immunodeficiency virus (HIV) infection.

Ethical concerns arise when genome editing, using technologies such as CRISPR-Cas9, is used to alter human genomes. Most of the changes introduced with genome editing are limited to somatic cells, which are cells other than egg and sperm cells (germline cells). These changes are isolated to only certain tissues and are not passed from one generation to the next. However, changes made to genes in egg or sperm cells or to the genes of an embryo could be passed to future generations. Germline cell and embryo genome editing bring up a number of ethical challenges, including whether it would be permissible to use this technology to enhance normal human traits (such as height or intelligence). Based on concerns about ethics and safety, germline cell and embryo genome editing are currently illegal in the United States and many other countries.

Genomics is establishing more robust methods for DNA-based forensic analyses.

Did you know that forensic analyses of DNA were being used well before the completion of the Human Genome Project, but newer approaches are speeding up and greatly improving the process, and larger DNA databases are making searches more powerful and more widely available? The National DNA Index in the United States now contains information from over 16 million people and has been used to aid in over 387,000 investigations.

Have you ever wondered how those detectives on TV and in the movies actually use DNA analyses to match a person to a crime or to determine the identity of a person by their remains? This is how it works behind the scientific scenes. In the 0.1 percent of the human genome sequence that differs between people [see Human Genomic Variation] are a number of areas where very short stretches of DNA are repeated over and over. These regions arecalled "short tandem repeats" (or STRs). As these stretches of DNA are passed from one generation to the next, they often experience a gain or loss of one of their repeats. At a specific place in the gene TPOX, for example, there are a series of repeats of the four bases GAAT. You might have 10 copies of that GAAT in your genome, while your neighbor might have 14. Since the repeat doesn't affect whether TPOX works or not, it doesn't matter to you or your DNA how many repeats are present. But these changes from one generation to the next lead to differences among STRs across the human population. The British scientist Sir Alec Jeffreys realized in 1984 that by determining the repeat numbers at enough of these STRs across the genome, he could generate a "DNA fingerprint" that was almost unique to each individual's genome.

DNA Analysis For Human Identification

As new, more powerful technologies for amplifying and sequencing tiny amounts of DNA became available, scientists teamed up with law enforcement officials to improve the use of DNA analyses for crime solving. In the United States, the Federal Bureau of Investigation created the Combined DNA Index System (CODIS) in 1990. Today, a CODIS forensic profile combines information from analyzing 20 different STRs across the human genome. In theory, the combined data generated for this panel is specific enough to identify one person on earth.

In practice, gathering samples and accurately analyzing the DNA can be problematic. We leave our own DNA behind us all the time, through stray hairs, skin cells, or other materials. This means that samples collected from a crime scene might be a mix of multiple people, and could potentially lead to the real perpetrator of a crime to not be identified. Or, in cases of mass casualties or environmental disasters, many samples might be mixed together or subjected to high pressure, moisture, or temperature. Advances in genomic technologies, including DNA sequencing, are allowing for more precise identification, in some cases using DNA samples collected years ago. For instance, forensic scientists are still working to use DNA analyses for identifying remains from the World Trade Center site after September 11, 2001 and soldiers from the Vietnam war.

DNA forensic analyses are only as good as the people performing the tests. In some cases, samples might get mixed up in the laboratory or statistical calculations may lead to erroneous conclusions. Groups like The Innocence Project use DNA analyses to exonerate people accused of crimes by showing years later that their DNA does not match the sample(s) collected years earlier at the scene.

Finding Missing Persons with DNA Analyses

When DNA evidence is being used in missing persons case, the generated DNA profile will often include markers from mitochondrial DNA and the Y chromosome. Children only inherit mitochondrial DNA from their mother, and sons only inherit the Y chromosome from their father. One example of the use of mitochondrial DNA is the work of Dr. Mary-Claire King with the Grandmothers (Abuelas) of the Plaza de Mayo in Argentina. A group of grandmothers whose children and grandchildren were taken and given to other families donated their own DNA to help find their family members. These abuelas have been working for over 30 years; in 2014, one of the founders named Estela de Carlotto was reunited with her own grandson, marking the 114th child found through their efforts.

DNA-Based Predictions

As we improve our ability to analyze ancient DNA samples [see Human Origins and Ancestry] and to understand how our genomes encode our traits, we are gaining interesting insights about what humans looked like in the past and now. Recently, genomic analyses of a set of 10,000-year-old human remains in the United Kingdom (called "Cheddar Man" because he was found in the Cheddar Gorge), allowed scientists to predict what some of the first Britons might have looked like. According to the researchers, Cheddar Man and his relatives would have likely had dark skin, dark hair and light eyes. More recently, scientists have been working towards developing a "police sketch" based on analyses of DNA collected at a crime scene. While DNA variation cannot yet predict an exact facial appearance of a person, it can suggest some traits that can be useful for investigating a crime, like hair color and eye color. The limits of this technology have been explored in an art installation where DNA from discarded chewing gum and cigarette butts was analyzed and used to create sculptures of what the person might have looked like. While still highly speculative, forensic scientists may be able to add such an approach to their toolkit along with other lines of evidence for deducing some elements of a suspect's physical appearance.

Do you know what the slogan "it's in your DNA" is really all about? Our ever improving ability to read anyone's genome sequence raises many issues regarding the social context of genomics. Information about our genomes is starting to become part of our everyday life. Genomic information shapes societal messages about DNA in how we think about ourselves and how others view us.

Companies, universities, nonprofits, and many other organizations have used the slogan "it's in our DNA" to mean that something is part of their core mission or values. Our understanding of our DNA also extends to our understanding of ourselves: what is in your DNA? Is it the chin that looks like your mother's or the eye color that is just like your grandfather's? What story does your DNA tell about the hundreds or thousands of ancestors before you? What continents did they migrate through in times long past? How does your DNA contribute to who you are, or how you are treated within your society?

Continued studies of the ethical, legal, and social implications of genomic advances can help to break down barriers and yield a better appreciation of what truly is, and is not, in our DNA - and what that means to us, our families, and communities and society.

Ethical and Social Questions

The scientists who launched the Human Genome Project recognized immediately that having a complete human genome sequence would raise many ethical and social issues. In 1990, the Ethical, Legal, and Social Implications (ELSI) Research Program was formally established at the National Institutes of Health (NIH) as an integral part of the Human Genome Project. The research supported by this program, ranges from genomics and health disparities to inclusion of diverse populations in genomics research, to whether people should have the right to refuse to know genomic testing results. Over the last 15 years, this research has greatly advanced our understanding and appreciation of the complex societal implications of genomics.

Consent and Privacy

Among the major areas of study in ELSI research are questions about consent and privacy. For example, what do you need to know about a research study that will use your DNA before you agree to participate? That's called "informed consent." As new areas of genomics have developed in recent years (like learning about microbiomes), researchers have needed to continually update their guidelines, so as to help people understand the relevant risks and benefits before signing up to be a research participant. Such studies are overseen by Institutional Review Boards (or IRBs), and these boards are made up of scientists, ethicists, and members of the community. An IRB must approve any research projects involving humans.

The widespread availability of genomic data has brought changes to privacy considerations as well. When a test is performed on your DNA, either through a research or clinical program, how is the privacy of your genomic data maintained and does that align with how you want those data to be protected? Since you share half of your genome with each of your parents, and half with each of your children, the information is not just about your genome. Should you be able to stop your relatives from revealing genomic information that could be relevant to you as well? And does that answer change based on what the test is for? Let's say that one of your parents learns from a genetic test that they have Huntington's disease, which is often diagnosed quite late in life. This gives you a 50-50 chance of carrying the same genetic mutation for this fatal neurological disease. Some people react to such information by wanting to know right away what their future might be, while others do not want to know.

Another privacy issue that has arisen in the genomics era is when are you entitled to receive all of your data back from a DNA-based research study or a clinical test. In the case of genomic tests, this can often be a lot of data! Research studies do not often return data to their participants, whereas patients are more often provided the results of clinical tests. If you have had direct-to-consumer (or DTC) genomic testing, the companies might have let you download your entire dataset. You might want to share such data with other research groups in order to further science or with other healthcare professionals for your medical care. There are also many questions about what the companies might do with the data, and most companies have user agreements which you must agree to, where they specify their plans up front. This may include sharing your data with others, including pharmaceutical companies and law enforcement. As President Obama noted in 2016, there is a difficult balance in making your data available for some purposes while still keeping them private for other reasons.

Discrimination

Concerns also exist about potential discrimination based on information about a person's DNA. In 2008, President Bush signed into law the Genetic Information Nondiscrimination Act (or GINA for short). This law is now enforced by multiple federal agencies, including the United States Equal Employment Opportunity Commission. You might have seen posters saying, "Equal Employment Opportunity is THE LAW" - those posters point out that GINA now specifically protects job applicants and current employees from discrimination based on their genetic information. GINA also prohibits health insurers from discriminating against anyone based on their genetic information when determining coverage or rates. At this time, GINA does not cover life insurance, disability insurance, or long-term care insurance. As in all potential discrimination areas, even though legal protections are in place under GINA, it is important to be knowledgeable about your rights and to know if and when they might be abused.

Race

The broad availability of genomic ancestry testing is influencing the way we think about the concept of race in America (see Human Origins and Ancestry). We now understand that skin color, as one component of how we think of ourselves, is due to a complex interaction of genes and the environment (see Human Genomic Variation). When we can see the genomic patterns of our ancestors in our own DNA, it might not be the same as how we describe ourselves (or how they described themselves). Large studies of African Americans in the United States have shown that their genomes contain an average of 25 percent European DNA sequences; in the same studies, Latino genomes in the United States show a mix of DNA from African, Native American, and European sources. It turns out that two people who call themselves the same race may be quite different at the genomic level. With our emerging understanding of genomics, we can combine genomic information with historical records and social data in order to study the shaping of concepts such as race.

Other characteristics often associated with race are part of culture but are not written in our DNA. Racial terms change over time, sometimes even multiple times within one person's life. For example, the categories used by the national census in the United States have also contributed to what we think of as "race," but they have changed quite substantially over time. The term "Hispanic" was not offered as a way that a person could describe themselves until the 1970 census, but by 2010, people could answer whether they were "of Hispanic, Latino, or Spanish origin." Genomics is helping us understand the complex and intertwined relationships between a person's or groups' ancestry, ethnicity, and racial identity. The National Human Genome Research Institute is also monitoring the use of race and ethnicity in biomedical research, including any influence on health disparities and inclusion/engagement of underrepresented populations in genomics.