Week 5: Learning goals and objectives

In Week 5 you will be learning about the:

  • The varieties of different types and broad spectrum of uses embedded in the descriptor, “genetic test;”
  • The pros and cons of genetic testing;
  • How an individual genome is technically analyzed by a genetic testing company;
  • Ancestry testing: Recreational or Educational?
  • Pharmacogenomics and its relevance to Adverse Drug Reactions (ADR);
  • International research efforts to understand the complex biological interactions of genetic variants (SNPs) and their relationship to human disease;
  • The world’s only open-access genomic data set  

Your objectives are to:

  • Compare and contrast the aims of the 1,000 and 100,000 Genomes Projects in light of what they will seek to contribute to the quest of personalize medicine



Scientifically, a genetic (or DNA) test is defined as an analysis performed on human DNA, RNA, genes, and/or chromosomes to detect heritable or acquired genotypes, mutations, phenotypes, or karyotypes (the number and visual appearance of the chromosomes in the cell nuclei of an organism or species) that cause or are likely to cause a specific disease or condition. Testing can also involve analysis of proteins or metabolites that are the products of genes.

Genetic testing is done to predict risk of disease, screen newborns for disease, identify carriers of genetic disease, establish prenatal or clinical diagnoses or prognoses and direct clinical care. Testing can be done using many different biological samples, including blood, saliva, amniotic fluid (from which fetal cells are obtained) or individual embryonic cells.

Genetic tests also look for large changes, such as a gene that has a section missing or added, or small changes, such as a missing, added, or altered chemical base (subunit) within the DNA strand. Gene tests may also detect genes with too many copies (cytogenetic testing) individual genes that are too active, genes that are turned off, or genes that are lost entirely (molecular genetic testing).

Some tests use DNA probes. A probe is a short string of DNA with base sequence complementary to (able to bind with) the sequence of an altered gene. These probes usually have fluorescent tags attached to them. During the test, a probe looks for its complement within a person’s genome. If the altered gene is found, the complementary probe binds to it, and the fluorescent label can be used to identify the presence of the alteration using a technology called a Tissue Microarray (TMA) analysis. This is the technique which direct-to-consumer (DTC) testing companies use to analyze an individual’s genome and the means by which thousands of human tissue samples obtained at the 9/11disaster site have been identified, the video for which can be found on the “Resources” list.

Genetic testing can also be used to determine a child’s parentage (genetic mother and father) or, in general, a person’s ancestry.

DTC DNA ancestry testing is currently enjoying tremendous interest among the public. As a source of entertainment, genetic ancestry tests are quite benign. But beyond their curiosity-driven motives, and reported successes in finding relatives, DTC DNA ancestry testing is not always so innocuous. One of the fundamental issues is the conflation of DNA and self-identity, the idea that the results of an ancestry test will help you to better understand who you are. If you find a surprising result, should you think differently of yourself?

Another is privacy. Compared with health-based genetic testing, consumers are generally less wary of privacy risks associated with swabbing their cheeks to find cousins. And this willingness to dive into DNA ancestry testing has been a boon for the field of genealogy.

In general, however, the American Society of Human Genetics has released a statement which points out what’s perhaps the biggest problem with ancestry testing services: “There’s no objective way to evaluate the results they produce. The services may use any of a variety of methods—mitochondrial and/or Y-chromosome DNA, scans of the entire genome, etc.—any of which could potentially produce contradictory results, all of which are valid within the limits of the DNA being looked at. Since all of them are “right,” as it were, the only thing that’s left to discriminate among such services is price.”

Normally, every person carries two copies of every gene with the exception of genes related to sex-linked trait (e.g., Hemophilia). Genetic testing identifies changes in chromosomes which are only inherited from the mother by males, one inherited from their mother, one inherited from their father. A number of Internet companies worldwide, notably Ancestry.com and Family tree DNA offer this test on demand for which costs vary widely and with variably useful results. Compounding this weakness, is the matter of how to interpret the results of the tests they receive. (See: DNA Ancestry for All) Accordingly, the “gold standard” for family history, however, remains the “Family Tree.”

When the Human Genome Project (HGP) was officially completed in 2003 its 13 year journey had fueled the discovery of about 2,200 diseases caused by defects in single genes. Ten years later (2013) that number had more than doubled to about 5,500, and continues to grow.

Prior to the completion of the HGP the relationship between genes and pharmaceuticals was only known in a handful of diseases. Now, that number is in the hundreds and more are being developed all the time as characterized by the identification of variants in particular genes which determine the ability to metabolize the drug Warfarin to determine a patient’s personalized dose to avoid serious bleeding events.

Since completing the HGP in 2003, significant insight has been achieved aimed at understanding the role that genomic variants (SNPs) play in determining who will and who won’t benefit from a particular drug, like Warfarin, that is, how much to prescribe and what adverse reactions (ADRs) to the drug might be expected when the dose for a given individual is not carefully calibrated.

DNA microarrays are the technology used in this growing field of “Pharmacogenomics.” Warfarin (Coumadin) is the most prescribed drug in the world, 3.5 million in the U.S. alone.  It is used to prevent embolisms in at-risk populations.  Thirty percent of all ADR hospital admits in patients 65 years of age, and older, are due to improper doses of the drug which, itself, is notoriously hard to control; Too much Warfarin leads to bleeding, too little can increase the likelihood of blood clots.

Differential dose responses to Warfarin varies by race occurring in approximately 30 percent of Caucasians, 20 percent in African American, and 20 percent in  Asian populations. An individual’s predicted response to the drug is largely based on variants (SNPs) in 3 genes: VKORC1, CYP2CD, and CYP4F4 inherited from an individual’s parents.

Analyses of genetic variants, and their relationship to health, is an increasingly important area of genomic research. (See: Medical genomics gather and use genetic data in health care)

Once new genetic associations are identified, researchers can use the information to develop better strategies to detect, treat and prevent the disease. Such studies are particularly useful in finding genetic variations that contribute to common, complex diseases, such as asthma, cancer, diabetes, heart disease, mental illnesses.

For example, for someone 2.5 inches shorter than average, the risk of coronary artery disease increases by about 13.5 percent, scientists found. Shorter people are more likely than taller folks to have clogged heart arteries, and a new study says part of the reason lies in the genes. The challenge is to ferret out the actual genetic variations that underlie both height and heart disease. (See: Link between heart disease and height hidden in our genes)

Hardly surprising, genetic mutations play a key role in heart attacks. Indeed, recent research has uncovered four rare gene mutations that appear to protect against heart attacks by lowering levels of a type of fat called triglycerides.  It has long been presumed that low HDL is the causal factor in heart disease and triglycerides are just along for the ride. But genetic data indicate that the true causal factor may not be HDL after all, but triglycerides, themselves. Researchers analyzed blood from nearly 4,000 participants and found that approximately, one in every 150 people carried an APOC3 (Apolipoprotein C-III) mutation and were found to have a 40 percent reduced risk of heart attacks.

With regard to gene (variant) “protectors,” a cluster of mutations in the gene that processes arsenic into a less toxic form have been analyzed. The gene is called AS3MT and its role is to add methyl groups to arsenic and convert it into a less toxic form.  So if you’re thinking to speed the time when you’ll get your inheritance (and you’re planning to use arsenic as the “go-to” method for carrying it out) you might want to talk to inhabitants of the town of San Antonio de los Cobres, Argentina. (See: Arsenic antidote hidden in our genes)

In the case of “Autism Spectrum Disorder”–a pervasive developmental disorder which affects social and communication skills and, to a greater or lesser degree, motor and language skills– scientists have isolated gene mutations that steeply raise the risk of autism. But those glitches account for only a tiny fraction of cases, and the number of them continues to increase — to about 100 now, and counting. Up to now no one has been able to tell a coherent story about causation.  It could be that common variants—i.e., gene variations that many people carry, which cause no apparent problems—can increase the dormant possibility for the disorder, in some combinations. (See: Scientists implicate more than 100 genes in causing autism)

A genetic variant may also shield Latinas from breast cancer and recent neuroscience research has demonstrated that a genetic variation in the bran makes some people inherently less anxious, and more able to forget fearful and unpleasant experiences. This lucky genetic mutation produces higher levels of anandamide, the so-called bliss molecule and our own natural marijuana—in our brains.

All in all, the hunt is on for “unexpected genetic heros” That is, with most inherited diseases, only some family members will develop the disease, while others who carry the same genetic risks dodge it (AKA “the heros”). In this TED Talk Stephen Friend suggests we start studying those family members who stay healthy, not those who are sick. (See: The hunt for unexpected genetic heroes)

As already discussed in Week 2, the objective of the ENCODE (Encyclopedia for DNA Elements) Project is, itself, designed to understand how genetic variation affects human traits and diseases. For example, compared to the person sitting next to you, or across the room, there are from 3-5 million places (variants) in your 6-billion base pairs of DNA (3 billion from each of your parents) where a single nucleotide is different, labeled as single nucleotide polymorphisms, or “SNPS,” as well as tens of thousands of structural differences in your chromosomes in the form of deletions, additions, and breaks.

As we know now, many of these variants are, metaphorically speaking, “time bombs” that can lead to an increase in the risk of disease, and others which are more attributable to positive phenotypic features (“good” variants).  But, presently, we don’t yet know which are which.  We also share a lot of variants in common, so we need to catalogue these millions of variants scattered over our 23 pairs of chromosomes in each somatic cell, to get a handle on all of this information, the rationale for three other international efforts currently underway.

One major step toward such comprehensive understanding has been the development in 2005 of the HapMap Project, a map of the human genome which will describe the common patterns of human variation and their relationship to human diseases such as single gene disorders (like Huntington’s and Cystic Fibrosis), as well as the more complex gene disorders like hypertension, diabetes, and heart disease.  Variants appear to be clustered together and inherited from one generation to the next in “haplotype blocks,” thus, the name, “HapMap.”

In 2010, the third phase of the HapMap project was published with data from 11 global populations, the largest survey of human genetic variation performed to date. Previously, it has not been feasible to scan the genomes of thousands of people and millions of variants, so 1-2 variants in each haplotype block are used as proxies for the entire block in order to look for an association of, say, hypertension, in the presence (or absence) of these variants (and others also associated with rare and common diseases).

The “1000 Genomes Project”  is using “New Generation” sequencing techniques to get deeper and deeper catalogues of human variation, aimed at getting a fix on which of the millions of genetic variants in the human genome play a role in human disease. That approach is about to be expanded in the near future.

An ambitious genome project launched in the United Kingdom in 2013 (aptly dubbed “Genomics England”) aims to sequence the DNA of 100,000 people by 2017 and publish that information as a free research resource that will be able to be accessed by anyone. The genetic information will be linked to medical and other phenotypic information about the donors to enable researchers to use the material to help identify genes linked to medical conditions, develop new treatments, and facilitate improvements in personalized medicine.  In March 2015 Genomics England delivered on its promises when three British men were diagnosed with rare diseases after having their complete genomes sequenced as part of the project.  Even lacking a cure, the findings will primarily be a source of relief for the men; “It’s quite frustrating to not find out what’s wrong with you.” (See: 100,000 Genomes Project leads to first diagnoses)

Researchers at Decode, an Icelandic genetics firm owned by Amgen, is making impressive strides in its pursuit of the holy grail of associating gene mutations with diseases as diverse as Alzheimer’s disease, heart disease, and gallstones. In a series of papers published in March of 2015–with data drawn from the complete DNA of 2,636 Icelanders, the largest collection ever analyzed in a single human population—a trove of genetic information enabling scientists to accurately infer the genomes of more than 100,000 other Icelanders, or almost a third of the entire country! (See: In Iceland’s DNA clues to what genes may cause disease)

When thousands of genetic variants are researched across an entire human genome it is identified as Genome-Wide Association Studies (GWAS), a genome-wide approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease.

Once new genetic associations are identified, researchers can use the information to develop better strategies to detect, treat and prevent the disease. Such studies are particularly useful in finding genetic variations that contribute to common, complex diseases, such as asthma, cancer, diabetes, heart disease and mental illnesses.

The availability of the human genome sequence and the data collected by the HapMap, 1,000, 100,000, and GWAS DNA sequencing projects are key resources for researchers to find genetic variants affecting health, disease and responses to drugs and environmental factors. While this research is by no means a straight path toward better public health, improved knowledge of the genetic linkages has the potential to change fundamentally the way health professionals and public health practitioners approach the prevention and treatment of disease.

Eric Green, Director of the National Human Genome Research Institute, NIH

Eric Green, Director of the National Human Genome Research Institute, NIH

Realizing this potential will require greater sophistication in the interpretation of genetic tests, new training for physicians and other diagnosticians, and new approaches to communicating findings to the public. As this rapidly growing field matures, all of these questions require attention from a variety of perspectives, both pro and con.  Indeed, in the words of Eric Green, “The biggest bottleneck to the realization of the ‘genomic revolution’ in health care is the capacity of health professionals to make meaningful use of these new tools.” 

For those tests that are already in regular use, like paternity or pre-natal genetic testing, there are well-documented positive outcomes.  They put people in control of information that helps them make solid decisions about their future, medically, financially, and legally. Having that kind of definitive knowledge is a definite pro for many people.

This is also true for those genetic tests that are in use for some disease predictions, such Jolie(BreastCancer)as the BRCA testing.  Women (like Angelina Jolie) who learn they have specific indicators and a good chance that they will develop the disease can make decisions based on that information.  And that is the most important “pro” for any genetic testing— the accumulation of knowledge.

For example, did Angelina Jolie’s famous editorial in the New York Times a year ago induce an overemphasis on genetic risk in breast cancer? Or has it saved lives by bringing the issue out into the open? (See: Podcast: Relative Risk – Breast Cancer and Genetics and The Angelina Effect)

One other positive outcome is that by having your genes screened, your information will be put into a database of information which can be shared by researchers and scientists around the world.  In fact, some people are willing to undergo testing simply to further science in hopes it will benefit their descendants and/or give them some historical sense of where they came from.


Resources and Discussion

Questions for Discussion

  • Genomic knowledge in the form of genetic test results is generated by research paid for by tax dollars, but does that mean that companies should be allowed to provide it directly to consumers with no medical personnel acting as a filter?
  • What are some advantages and limitations of direct-to-consumer genetic tests for health and ancestry?
  • Would you want to know your future if science could tell it to you?
  • What do genetic variants mean in terms of health? Do they play some important role(s) or are they phenotypically neutral?
  • Let’s say you send a tube of your saliva off to one of the many companies advertising direct-to-consumer genetic testing and the results showed you had a huge risk of a fatal disease. Would that freak you out? Would you want to get this news in a letter sent by overnight mail? Would you prefer to have someone available to counsel you about what negative findings mean and what to do about them?
  • Would you want to know you may have a higher than average risk of Alzheimer’s Disease?
  • Since most diseases are caused by an inextricable mix of genetic and environmental components how accurate can any test be?
  • How long do you think it will be before health insurance companies start hiking up premiums for disease with an increased risk for diseases like Huntington’s?
  • Should we screen embryos for genes which carry a risk factor for a disease which, if it develops at all, is unlikely to do so until middle age or beyond?
  • In light of recent large-scale initiatives: “Genomics England” and the “Personal Genome Project,” to sequence the DNA of 100,000 individuals, should genes be public?