Advantages and Limitations of Genome Sequencing

Advantages of Genome Sequencing

There are many advantages to sequencing an entire genome, some more obvious than others. Some of the main reasons are listed below.

Scientific information with potential medical implications is obtained

The primary purpose of sequencing one’s genome is to obtain information of medical value for future care. Genomic sequencing can provide information on genetic variants that can lead to disease or can increase the risk of disease development, even in asymptomatic people. Thus genomic sequencing has the potential to increase the ability to act preemptively prior to disease development or commence treatment for a disease that has not yet been diagnosed. Another advantage of genome sequencing is that information regarding drug efficacy or adverse effects of drug use can be obtained. The relationship between drugs and the genome is called pharmacogenomics.

The information that the client receives is based on information obtained from publically available databases for human genome variation that are continuously updated with novel research findings. The presented data will be stratified from the most to the least clinically validated, with supporting evidence provided.

Nonmedical information can also be obtained, such as heritage background, nonhealth related trait information, or information with indirect medical impact, such as a predisposition to obesity.

Technical accuracy

The genome sequencing procedure and the data interpretation are performed according to the highest standards available to public consumers. Human genome sequencing is an innovative and state-of-the-art technology, and novel discoveries in improving data quality are constantly being made. Merogenomics Inc. selects service providers that can generate data of the highest quality based on the latest published supporting records. Merogenomics Inc. provides third party appraisal to ensure that these stringent criteria are met.

The third parties affiliated with Merogenomics Inc. to isolate, sequence, and interpret a subject’s genomic DNA are of established quality. These firms have set technical competency standards and demonstrated procedural analytical validity, and collaborate with leading academic and industry research institutions.

The information obtained in the genome sequencing procedure cannot provide a clinical diagnosis, as client medical information is not collected and the oversight of a medical geneticist is not provided. The data analysis is automated and would require validation with secondary technology and interpretation by a healthcare provider to be used for medical purposes. Merogenomics Inc. aims to help clients obtain data that, once validated, can be safely interpreted by a healthcare professional.

Privacy of information

Protecting the privacy of genetic information and access to informed consent are viewed as important by the general public, and are key influencing factors in public interest in direct-to-consumer genomic testing.1

Merogenomics Inc. will take all reasonable efforts to protect the privacy of the information and samples provided by the client and the confidentiality of the data generated. All data and information will be encrypted, password protected, and stored in a cloud. All tissue samples will be stored in a safe biorepository until they can be safely discarded. Merogenomics Inc. will not distribute private and sensitive information to third parties without the agreement of the client.

Merogenomics Inc. cannot absolutely guarantee the confidentiality of client information and genome sequencing and analysis data in the event of unintended data breaches such as hacking or other unforeseen events. To minimize the chance of private information being accessed by undesired third parties, all protected data will be erased within two weeks (14 days) of delivery to the client. Client contact information can be kept for future reference in the Merogenomics Inc. database with the agreement of the client.

  1. Myers MF and Bernhardt BA 2012. Direct-to-consumer genetic testing: introduction to the special issue. J Genet Couns 21(3): 357-60

Single test in a lifetime

As your genome is the same throughout all the cells in your body, and is specific to each individual, accurate whole genomic sequence need be obtained only once (genome sequence does not change unless influenced by environmental factors, for example, in the development of many cancers); it is a repository of biological information that will never have to be resequenced. Genomic information is available for interpretation in perpetuity, providing an opportunity to learn new information as more scientific knowledge of the genome emerges.

Whole genome sequencing is different from genotype screening tests or sequencing of individual genes. Whole genome sequencing looks at the entire DNA whereas genotyping or sequencing a panel of desired genes looks only at chosen fragments of the genome. Such fragments are selected to obtain specific information about a physical trait, but can run a risk of missing information important for appropriate analysis. It is also biased towards predetermined choice of which segments should be analyzed. Therefore, another important benefit of sequencing over genotyping is the discovery of rare or novel variants.

This point can be illustrated by considering BRCA gene mutations, which confer a high risk of breast and ovarian cancer development in women. Early discovery of these mutations provides options for prophylactic action. However, it is known that not all such mutations will result in cancer development, and not all prophylactic actions will guarantee the prevention of future cancer development. Therefore, additional potentially genetic factors could play role in the outcome, and such information cannot be captured by genotyping methods.

How can a client determine the difference between genotyping and whole genome sequencing? The cost is a clue; current prices for genome sequencing are in the range of thousands of dollars whereas genotyping prices are in the range of hundreds of dollars, or less. A close investigation of the procedural details is necessary to determine the substance of the product offered. Merogenomics Inc. can help prospective clients to define the test methodology and function, and to evaluate the quality of a potential procedure. 

Staying ahead of nongenetic healthcare providers

A direct-to-consumer genome sequencing test allows an individual to obtain potentially health-related information privately, outside of the medical establishment, although a medical provider would be required to act upon pertinent information discovered through genome sequencing.

Genome sequencing is a relatively new technology. Although it is being rapidly incorporated in clinical care, the technology is not standard and it is likely to be used as a last alternative in diagnosis.

The utility and applicability of genome sequencing are not yet embraced fully in physician education. Therefore, many physicians are unable to provide information regarding the diagnostic opportunities of genome sequencing.

Merogenomics Inc. can inform the client and his or her treating physician of the potential utility and best available options to sequence a human genome. Merogenomics Inc. can also oversee that the test procedure and analyses are performed to standards appropriate for medical interpretation.

Information of value to future generations in a client’s family

The power of genomic information is compounded each time a genome sequence is obtained for an additional member of a family, especially when this occurs across generations. Direct comparisons of genome sequences of relatives for whom DNA variation is shared can infer inheritance patterns. Each additional genome sequence can make the interpretation of genomic variation easier. Therefore, genome sequence information is of value not only to the individual undertaking the procedure, but also to immediate family members and direct descendants. Such information should be treasured and safeguarded by families whose members have chosen to investigate their genomes.

Merogenomics Inc. can help clients to access multigenerational genome sequence data, and to interpret the data in the family context, even if the data have been previously obtained by different service providers. Such data should be protected by long term digital data storage, and Merogenomics Inc. can help with that.

Sense of empowerment

Genomic knowledge enables an individual to take preventive steps to minimize disease risks, and thus provides personal empowerment. Self-empowerment is one of the stated goals of The Precision Medicine Initiative, unveiled in 2015 by President Obama in his State of the Union address.1 The Precision Medicine Initiative aims to sequence the genomes of more than a million Americans.

A client empowered by access to genomic knowledge can improve his or her health management by proactively treating health complications or reduce impact of negative outcomes. Knowing a specific condition exists can allow a person to psychologically prepare for it, plan for future condition detection or treatment, and evaluate future family planning. Knowledge is a human right, and access to information that impacts both the self and one’s offspring is regarded by majority of people as valuable, even if nothing can be done to improve the condition.2-4

  1. https://www.whitehouse.gov/precision-medicine
  2. Etchegary H, et al. 2012. Public attitudes about genetic testing in the newborn period. J Obstet Gynecol Neonatal Nurs 41(2): 191-200
  3. Haga SB, et al. 2013. Public knowledge of and attitudes toward genetics and genetic testing. Genet Test Mol Biomarkers 17(4): 327-35
  4. Strong KA, et al. 2014. Views of nonmedical, health system professionals regarding the return of whole genome sequencing incidental findings. WMJ 113(5): 179-84

 

Cascade testing to other family members

If a variant with potential health implications is revealed in an individual, such information will have direct impact on closely related family members. Other family members can undergo a screening test to determine if they are at risk. This is one of the most positive effects associated with direct-to-consumer genome testing in presymptomatic individuals. Secondary testing can lead to the identification of other family members that have the variant in question.

Psychological benefit

Certain individuals might undergo distress over a perceived disease risk if family history indicates inheritance of a disease. Although an individual deemed nonhigh risk for a specific disease might not be eligible to receive confirmatory medical testing, such individual can turn to direct-to-consumer testing to determine his or her genetic condition. Studies indicate that removal of disease risk uncertainty has a beneficial impact on reduction of anxiety associated with the uncertainty.1

  1. Sivell S, et al. 2008. How risk is perceived, constructed and interpreted by clients in clinical genetics, and the effects on decision making: systematic review. J Genet Couns 17(1): 30-63

 

Cost savings

A whole genome sequencing procedure produces data that can be analyzed and interpreted in perpetuity. Once a genome is decoded it becomes a multigenerational repository of information. This replaces the current clinical approach of sequencing individual genes, or of genotyping specific areas of the genome that might or might not be informative. Access to a genome sequence reduces or removes the trial and error that frequent diagnostic tests that search for clues for undesirable and elusive health conditions and drug prescriptions that seek to alleviate such conditions. Thus, genome sequencing can result in substantial cost saving, especially when measured over the lifespan of an individual. Stanek et al. (2012) reported that 98% of surveyed U.S. physicians expected that patient genetic profiles would influence drug therapy, resulting in reduced treatment costs.1

  1. Stanek EJ, et al. 2012. Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clin Pharmacol Ther 91(3): 450-8

 

Limitations

Limitations can be expected in any technology, especially in a novel one. Clients should be familiar with the limitations of genome sequencing.

Analytical validity

How accurately and reliably genome sequencing measures genome variants is termed “analytical validity.” Analytic validity depends on how many times a nucleotide base is read by the sequencing platform during the sequencing process. The more times a particular base is read, the higher the accuracy that it was measured, or “called,” correctly at that particular position. The number of times a particular base is called is the “read depth” or “coverage depth.” The coverage depth can be affected by the quantity and quality of DNA available for sequencing, as well as the computational capabilities of the software selected to determine the DNA sequence. A certain minimum coverage depth is required as the acceptable threshold to be confident that the nucleotide base was called correctly.

Because the DNA is not read at uniform coverage across the genome, it is possible that segments of the genome could be read below the minimum coverage depth. If the depth coverage is not sufficient, it is possible that a base will be identified that is not actually present in a person’s genome. For example, if a mutation that leads to a disease is mistaken for a normal gene (a false negative), the person could think they have been successfully tested for a condition and found to be “negative” for it, whereas that might not be the case. Conversely, a gene could be misread as a mutation that is expected to lead to an adverse condition, whereas in reality, the person is not harbouring such a mutation in their genome (a false positive). A small fraction of the genome might not be sequenced if it reads below the minimum coverage depth.

It is therefore important to remember that information obtained from genome sequencing is not to be used for medical interpretation unless it is validated by additional means. It is the first step only in unravelling biological information from personal DNA.

For example, recent data analysis of two different competing sequencing platforms indicated that a median of 10–19% (depending on the platform) of genes associated with inherited diseases (including genes recommended for pathogenic variant discovery by the American College of Medical Genetics and Genomics) contained segments that were not read at the minimum threshold required to confidently determine a variant.1 These areas of the genome, albeit small, would not be of sufficient quality to use for clinical diagnostic purposes.

The technical performance of sequencing platforms and data analysis tools has continuously improved since, but the example described above indicates the potential limitations of genomic sequencing in the context of diagnostics. In summary, genome depth coverage varies throughout, and the lower the depth, the lower the probability that base was measured correctly. Conversely, the higher the coverage, the higher the probability of accurate base calling. The current standard expected is a minimum of 95% of the genome being sequenced with 95% or greater accuracy.

  1. Dewey FE, et al. 2014. Clinical interpretation and implications of whole-genome sequencing. JAMA 311(10): 1035-45

 

Structural variants

While technologies used to sequence DNA are highly accurate at deciphering the sequence, the majority of available technologies have limited scope in being able to determine so called structural variants. These are alterations that affect large segments of DNA at a time, such as duplications, deletions, and inversions. Such structural variants can still have important impact on health, but due to the limited scope in determining such structural genomic rearrangements by current sequencing technologies, such biological events might not be interpretable for the benefit of a client. Instead, current genome sequencing allows for analysis of potential impact of individual base changes. The American College of Medical Genetics and Genomics guidelines for mandatory returns of incidental findings have also been set up with this limitation in mind, and the guidelines do not recommend a search for structural variants in the list of genes they recommend.1

  1. Green RC, et al. 2013. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15(7): 565-74

 

Interpretation

Although genome sequencing has the potential to reduce morbidity and mortality by enabling early identification of risk factors for various health conditions, and to aid identification of an appropriate treatment course, it is not an all-encompassing screen for every possible disease. The interpretation of sequencing results is limited by the current state of medical knowledge, and can range from almost certain clinical significance to almost certainly no significance. In some instances the data might even present contradictory evidence. Even if the interpretation of genome sequencing results is straightforward, such information might not lead to a useful ameliorative intervention for a specific condition or disease. However, since the human genome we are born with is static (it does not change unless influenced by environmental factors, for example, in the development of many cancers), it means that obtained sequence can always be reinterpreted in the future as the scientific potential expands.

A related issue is that the amount of data that need to be analyzed and curated prior to a genome sequence being delivered to a client requires considerable computer and human resources. The bioinformatics capabilities of genome sequence analysis are continuously improving by incorporating new information, and the process is increasingly automated. As the demand for clinical interpretation of the genome increases, so does the demand for appropriate platforms to deliver a higher performance standard. However, without human oversight, there is no guarantee that such automated algorithms will always be accurate, as no database is error-free.

Clinical validity and utility

Another often cited limitation is the lack of clinical validity and utility for systematic mass scale use of genomic sequencing technology for public’s benefit, and is only being currently investigated at clinical research institutions around the world.1 Simply put, currently there is no gold standard against which the performance of population genomic screening can be judged.2 Whether application of next generation sequencing will reduce mortality and morbidity in the population the way it has been demonstrated in individual studies is yet to be established. Numerous large scale population studies have been undertaken throughout the world to examine this issue. Increasing number of academic medical centers performing genome sequencing for human diagnostics under a Clinical Laboratory Improvement Amendments license highlights the expanding role of genomics in medical practice.1 Development of metrics that measure the healthcare outcomes of genomic sequencing to validate the clinical utility of genomic medicine toward effective patient care currently remains a top challenge and a priority.1

  1. Crawford JM, et al. 2014. The business of genomic testing: a survey of early adopters. Genet Med 16(12): 954-61
  2. Wilson BJ and Nicholls SG 2015. The Human Genome Project, and recent advances in personalized genomics. Risk Manag Healthc Policy 8: 9-20

 

Test failure

Factors outside the control of the service provider tasked with isolation and sequencing of DNA can negatively influence the quality of the genome sequence and therefore its interpretation. This can include the quality of the DNA sample provided for analysis, such as low quantity, high bacterial contamination, or sample degradation. Such factors can even prevent the procedure from being undertaken. In such a circumstance, the client might be obliged to deliver a new sample.

Psychological impact

Genome sequencing can uncover data that have potential negative psychological consequences to the client and the client’s family. Some examples of data that fit this description are: the discovery of a pathogenic variant, the receipt of indecisive results with regard to certain health conditions, difficulty assimilating information that contradicts prior beliefs, and the information that the subject of the genome sequencing is not biologically related to family members as previously believed. Sharing discovered information with other individuals, especially with family members, can be an additional source of distress if all individuals are not adequately prepared.

Privacy

Genome sequencing provides information about the subject of the procedure, but also about individuals who are closely related to the subject. Thus the genomic information has the potential to impact relationships with other family members. Other family members might not desire to know such information, or there could be information that the client might wish to keep private. However, such information might have important implications to the wellbeing of family members and the client might be faced with the difficult task of deciding what information to disclose and what information to conceal.

Discrimination

While many countries have implemented laws that ban discrimination based on genetic information, often such laws do not protect an individual in the case of a life insurance policy. It is natural for new technology to be accepted slowly, and the accurate interpretation of new laws can take time. That is why there is a lingering (and disproportionate) public fear of discrimination based on genetic information. Such discrimination can be imposed by an insurance company, an employer, or a medical, educational or financial institution. Disputing such discrimination might require an appeal to the judicial system, and that action could have unpredictable results.

Additional limitations of prenatal tests

In postnatal genome sequencing the DNA is isolated from cells present in a saliva or blood sample. In a prenatal genome sequencing test, the sequencing must be performed on DNA fragments that are circulating cell-free in the mother’s blood sample. Accurate determination of the fetal genome depends on the amount of DNA in the mother’s blood sample, and the test can fail if sufficient fetal DNA is not present in the mother’s blood sample.

In a sample population of nearly 150,000 pregnant women who underwent prenatal testing, repeat blood sampling was required in 2.2% of the women due to quality control failure, assay failure, or low fetal DNA fraction. Only 0.1% of the cases provided no informative results.1

Fetal cell-free DNA is derived from the placenta and therefore might not accurately represent the genomic information of the fetus. Extraembryonic tissue mosaicism, or a vanishing twin/cotwin demise are events that result in a mixture of genomes, which can lead to false results. Maternal chromosome abnormality, or maternal metastatic disease can also complicate interpretation of the genomic data and lead to false results.2

The mother’s blood sample can harbor cell-free DNA released from cancerous cells. Such DNA contains identifiable mutant variant signatures. Therefore, women undergoing prenatal testing run a risk of incidental finding of cancer discovery.

Prenatal testing cannot be used to obtain the following information: evaluation of placental dysfunction, preterm delivery risk, fetal growth restriction, preeclampsia, placental abruption, intrauterine fetal demise, and perinatal death.3

  1. Zhang H, et al. 2015. Non-invasive prenatal testing for trisomies 21, 18 and 13: clinical experience from 146,958 pregnancies. Ultrasound Obstet Gynecol 45(5): 530-8
  2. Cao Y, et al. 2016. False Negative Cell-Free DNA Screening Result in a Newborn with Trisomy 13. Case Rep Genet 2016: 7397405
  3. Keller NA and Rijshinghani A 2016. Advantages of the Quadruple Screen over noninvasive prenatal testing. Clin Case Rep 4(3): 244-6

 

Additional limitations of cancer sample tests

Cancer biopsy samples are typically a mixture of normal cells and cells at different stages of cancer development. Therefore, variable amounts of cancerous DNA might be available for genome sequencing in a cancer sample, increasing the chance of test failure. Depending on the cancer type and sequencing procedure, > 10% of samples might contain an inadequate mass of DNA to obtain a reliable DNA sequence.1, 2 Up to 20% of these samples can require either multiple attempts at preparation or sequencing to obtain sufficient depth coverage of DNA.2 Such difficulties can delay results and increase costs, and in some cases more sample must be provided. The final depth coverage determines the degree to which different genomic alterations can be identified.

The test results can provide no information of value if molecular profiling does not indicate a personalized therapy that can perform beyond standard treatment options.

  1. Tsimberidou AM, et al. 2014. Personalized medicine for patients with advanced cancer in the phase I program at MD Anderson: validation and landmark analyses. Clin Cancer Res 20(18): 4827-36
  2. Uzilov AV, et al. 2016. Development and clinical application of an integrative genomic approach to personalized cancer therapy. Genome Med 8(1): 62

 

Related Information:

Procedure Overview

Considerations Before the Purchase 

Action After Procedure Completion

Genomic Education


This site contains images generated by emovie combined with pymol software.