Personal genomics

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Personal genomics or consumer genetics is the branch of genomics concerned with the sequencing, analysis and interpretation of the genome of an individual. The genotyping stage employs different techniques, including single-nucleotide polymorphism (SNP) analysis chips (typically 0.02% of the genome), or partial or full genome sequencing. Once the genotypes are known, the individual's variations can be compared with the published literature to determine likelihood of trait expression, ancestry inference and disease risk.

Contents

Automated high-throughput sequencers have increased the speed and reduced the cost of sequencing, making it possible to offer whole genome sequencing including interpretation to consumers since 2015 for less than $1,000. The emerging market of direct-to-consumer genome sequencing services has brought new questions about both the medical efficacy and the ethical dilemmas associated with widespread knowledge of individual genetic information.

In personalized medicine

Personalized medicine is a medical method that targets treatment structures and medicinal decisions based on a patient's predicted response or risk of disease. [1] The National Cancer Institute or NCI, an arm of the National Institutes of Health, lists a patient's genes, proteins, and environment as the primary factors analyzed to prevent, diagnose, and treat disease through personalized medicine. [1] 123jili

There are various subcategories of the concept of personalized medicine such as predictive medicine, precision medicine and stratified medicine. Although these terms are used interchangeably to describe this practice, each carries individual nuances. Predictive medicine describes the field of medicine that utilizes information, often obtained through personal genomics techniques, to both predict the possibility of disease, and institute preventative measures for a particular individual. [2] Precision medicine is a term very similar to personalized medicine in that it focuses on a patient's genes, environment, and lifestyle; however, it is utilized by National Research Council to avoid any confusion or misinterpretations associated with the broader term. Stratified medicine is a version of personalized medicine which focuses on dividing patients into subgroups based on specific responses to treatment, and identifying effective treatments for the particular group. [3]

Examples of the use of personalized medicine include oncogenomics and pharmacogenomics. Oncogenomics is a field of study focused on the characterization of cancer–related genes. With cancer, specific information about a tumor is used to help create a personalized diagnosis and treatment plan. [4] Pharmacogenomics is the study of how a person's genome affects their response to drugs. [5] This field is relatively new but growing fast due in part to an increase in funding for the NIH Pharmacogenomics Research Network. Since 2001, there has been an almost 550% increase in the number of research papers in PubMed related to the search terms pharmacogenomics and pharmacogenetics . [6] This field allows researchers to better understand how genetic differences will influence the body's response to a drug and inform which medicine is most appropriate for the patient. These treatment plans will be able to prevent or at least minimize the adverse drug reactions which are a, "significant cause of hospitalizations and deaths in the United States." Overall, researchers believe pharmacogenomics will allow physicians to better tailor medicine to the needs of the individual patient. [5] As of November 2016, the FDA has approved 204 drugs with pharmacogenetics information in its labeling. These labels may describe genotype-specific dosing instructions and risk for adverse events amongst other information. [7]

Disease risk may be calculated based on genetic markers and genome-wide association studies for common medical conditions, which are multifactorial and include environmental components in the assessment. Diseases which are individually rare (less than 200,000 people affected in the USA) are nevertheless collectively common (affecting roughly 8-10% of the US population [8] ). Over 2500 of these diseases (including a few more common ones) have predictive genetics of sufficiently high clinical impact that they are recommended as medical genetic tests available for single genes (and in whole genome sequencing) and growing at about 200 new genetic diseases per year. [9]

Cost of sequencing an individual's genome

Typical cost of sequencing a human-sized genome, on a logarithmic scale. Note the drastic trend faster than Moore's law beginning in January 2008 as post-Sanger sequencing came online at sequencing centers. Cost per Genome.png
Typical cost of sequencing a human-sized genome, on a logarithmic scale. Note the drastic trend faster than Moore's law beginning in January 2008 as post-Sanger sequencing came online at sequencing centers.

The cost of sequencing a human genome is dropping rapidly, due to the continual development of new, faster, cheaper DNA sequencing technologies such as "next-generation DNA sequencing".

The National Human Genome Research Institute, an arm of the U.S. National Institutes of Health, has reported that the cost to sequence a whole human-sized genome has dropped from about $14 million in 2006 to below $1,500 by late 2015. [11]

There are 6 billion base pairs in the diploid human genome. Statistical analysis reveals that a coverage of approximately ten times is required to get coverage of both alleles in 90% human genome from 25 base pair reads with shotgun sequencing. [12] This means a total of 60 billion base pairs that must be sequenced. An Applied Biosystems SOLiD, Illumina or Helicos [13] sequencing machine can sequence 2 to 10 billion base pairs in each $8,000 to $18,000 run. The cost must also take into account personnel costs, data processing costs, legal, communications and other costs. One way to assess this is via commercial offerings. The first such whole diploid genome sequencing (6 billion bp, 3 billion from each parent) was from Knome and their price dropped from $350,000 in 2008 to $99,000 in 2009. [14] [15] This inspects 3000-fold more bases of the genome than SNP chip-based genotyping, identifying both novel and known sequence variants, some relevant to personal health or ancestry. [16] In June 2009, Illumina announced the launch of its own Personal Full Genome Sequencing Service at a depth of 30X for $48,000 per genome. [17] In 2010, they cut the price to $19,500. [18]

In 2009, Complete Genomics of Mountain View announced that it would provide full genome sequencing for $5,000, from June 2009. [19] This will only be available to institutions, not individuals. [20] Prices are expected to drop further over the next few years through economies of scale and increased competition. [21] [22] As of 2014, nearly complete exome sequencing was offered by Gentle for less than $2,000, including personal counseling along with the results. [23] As of late 2018, over a million human genomes have been nearly completely sequenced for as little as $200 per person, [24] and even under certain circumstances ultra-secure personal genomes for $0 each. [25] In those two cases, the actual cost is reduced because the data can be monetized for researchers.

The decreasing cost in general of genomic mapping has permitted genealogical sites to offer it as a service, [26] to the extent that one may submit one's genome to crowd sourced scientific endeavours such as OpenSNP [27] or DNA.land at the New York Genome Center, as examples of citizen science. [28] The Corpas family, led by scientist Manuel Corpas, developed the Corpasome project, [29] and encouraged by the low prices in genome sequencing, was the first example of citizen science crowd sourced analysis of personal genomes. [30]

The opening of genomic medical clinics at major US hospitals has raised questions about whether these services broaden existing inequities in the US healthcare system, including from practitioners such as Robert C. Green, director of the Preventive Genomics Clinic at Brigham and Women's Hospital. [31] [32]

Ethical issues

Genetic discrimination is discriminating on the basis of information obtained from an individual's genome. Genetic non-discrimination laws have been enacted in some US states [33] and at the federal level, by the Genetic Information Nondiscrimination Act (GINA). The GINA legislation prevents discrimination by health insurers and employers, but does not apply to life insurance or long-term care insurance. The passage of the Affordable Care Act in 2010 strengthened the GINA protections by prohibiting health insurance companies from denying coverage because of patient's "pre-existing conditions" and removing insurance issuers' ability to adjust premium costs based on certain factors such as genetic diseases. [34] Given the ethical concerns about pre-symptomatic genetic testing of minors, [35] [36] [37] [38] it is likely that personal genomics will first be applied to adults who can provide consent to undergo such testing, although genome sequencing is already proving valuable for children if any symptoms are present. [39]

There are also concerns regarding human genome research in developing countries. The tools for conducting whole genome analyses are generally found in high-income nations, necessitating partnerships between developed and developing countries in order to study the patients affected by certain diseases. The relevant tools for sharing access to the collected data are not equally accessible across low-income nations and without an established standard for this type of research, concerns over fairness to local researchers remain unsettled. [40]

Other issues

Genetic privacy

In the United States, biomedical research containing human subjects is governed by a baseline standard of ethics known as The Common Rule, which aims to protect a subject's privacy by requiring "identifiers" such as name or address to be removed from collected data. [41] A 2012 report by the Presidential Commission for the Study of Bioethical Issues stated, however, that "what constitutes 'identifiable' and 'de-identified' data is fluid and that evolving technologies and the increasing accessibility of data could allow de-identified data to become re-identified." [41] In fact, research has already shown that it is "possible to discover a study participant's identity by cross-referencing research data about him and his DNA sequence … [with] genetic genealogy and public-records databases." [42] This has led to calls for policy-makers to establish consistent guidelines and best practices for the accessibility and usage of individual genomic data collected by researchers. [43]

There is also controversy regarding the concerns with companies testing individual DNA. There are issues such as "leaking" information, the right to privacy and what responsibility the company has to ensure this does not happen. Regulation rules are not clearly laid out. What is still not determined is who legally owns the genome information: the company or the individual whose genome has been read. There have been published examples of personal genome information being exploited. [44] Additional privacy concerns, related to, e.g., genetic discrimination, loss of anonymity, and psychological impacts, have been increasingly pointed out by the academic community [44] as well as government agencies. [41]

Additional issues arise from the trade-off between public benefit from research sharing and exposure to data escape and re-identification. The Personal Genome Project (started in 2005) is among the few to make both genome sequences and corresponding medical phenotypes publicly available. [45] [46]

Personalized genome utility

Full genome sequencing holds large promise in the world of healthcare in the potential of precise and personalized medical treatments. This use of genetic information to select appropriate drugs is known as pharmacogenomics. This technology may allow treatments to be catered to the individual and the certain genetic predispositions they may have (such as personalized chemotherapy). Among the most impactful and actionable uses of personal genome information is the avoidance of hundreds of severe single-gene genetic disorders which endanger about 5% of newborns (with costs up to 20 million dollars), [47] for example elimination of Tay Sachs Disease via Dor Yeshorim. Another set of 59 genes vetted by the American College of Medical Genetics and Genomics (ACMG-59) are considered actionable in adults. [48]

At the same time, full sequencing of the genome can identify polymorphisms that are so rare and/or mild sequence change that conclusions about their impact are challenging, reinforcing the need to focus on the reliable and actionable alleles in the context of clinical care. Czech medical geneticist Eva Machácková writes: "In some cases it is difficult to distinguish if the detected sequence variant is a causal mutation or a neutral (polymorphic) variation without any effect on phenotype. The interpretation of rare sequence variants of unknown significance detected in disease-causing genes becomes an increasingly important problem." [49] In fact, researchers from the Exome Aggregation Consortium (ExAC) project estimated the average person to carry 54 genetic mutations that previously were assumed pathogenic, i.e. having 100% penetrance, but without any apparent negative health presentation. [50]

As with other new technologies, doctors can order genomic tests for which some are not correctly trained to interpret the results. Many are unaware of how SNPs respond to one another. This results in presenting the client with potentially misleading and worrisome results which could strain the already overloaded health care system. In theory, this might antagonize an individual to make uneducated decisions such as unhealthy lifestyle choices and family planning modifications. Negative results which may potentially be inaccurate, theoretically decrease the quality of life and mental health of the individual (such as increased depression and extensive anxiety).

Direct-to-consumer genetics

Using microarrays for genotyping. The video shows the process of extracting genotypes from a human spit sample using microarrays as is done by most major direct-to-consumer genetics companies.

There are also three potential problems associated with the validity of personal genome kits. The first issue is the test's validity. Handling errors of the sample increases the likelihood for errors which could affect the test results and interpretation. The second affects the clinical validity, which could affect the test's ability to detect or predict associated disorders. The third problem is the clinical utility of personal genome kits and associated risks, and the benefits of introducing them into clinical practices. [51]

People need to be educated on interpreting their results and what they should be rationally taking from the experience. Concerns about customers misinterpreting health information was one of the reasons for the 2013 shutdown by the FDA of 23&Me's health analysis services. [52] It is not only the average person who needs to be educated in the dimensions of their own genomic sequence but also professionals, including physicians and science journalists, who must be provided with the knowledge required to inform and educate their patients and the public. [53] [54] [55] Examples of such efforts include the Personal Genetics Education Project (pgEd), the Smithsonian collaboration with NHGRI, and the MedSeq, BabySeq and MilSeq projects of Genomes to People, an initiative of Harvard Medical School and Brigham and Women's Hospital.

A major use of personal genomics outside the realm of health is that of ancestry analysis (see Genetic Genealogy), including evolutionary origin information such as neanderthal content. [56]

The 1997 science fiction film GATTACA presents a near-future society where personal genomics is readily available to anyone, and explores its societal impact. Perfect DNA [57] is a novel that uses Dr Manuel Corpas' own experiences and expertise as genome scientist to begin exploring some of these tremendously challenging issues.

Other uses

In 2018, police arrested Joseph James DeAngelo, the prime suspect for the Golden State Killer or East Area Rapist, [58] and William Earl Talbott II, the prime suspect in the murders of Jay Cook and Tanya Van Cuylenborg in 1987. [59] These arrests were based on the personal genomics uploaded to an open-source database, GEDmatch, which allowed investigators to compare DNA recovered from crime scenes to the DNA uploaded to the database by relatives of the suspect. [60] [58] In December 2018, FamilyTreeDNA changed its terms of service to allow law enforcement to use their service to identify suspects of "a violent crime" or identify the remains of victims. The company confirmed it was working with the FBI on at least a handful of cases. [61] Since then, nearly 50 suspects in crimes of assault, rape or murder have been arrested using the same method. [62]

Personal genomics have also allowed investigators to identify previously unknown bodies using GEDmatch (the Buckskin Girl, [63] Lyle Stevik [64] and Joseph Newton Chandler III). [65]

See also

Related Research Articles

<span class="mw-page-title-main">Human genome</span> Complete set of nucleic acid sequences for humans

The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. These are usually treated separately as the nuclear genome and the mitochondrial genome. Human genomes include both protein-coding DNA sequences and various types of DNA that does not encode proteins. The latter is a diverse category that includes DNA coding for non-translated RNA, such as that for ribosomal RNA, transfer RNA, ribozymes, small nuclear RNAs, and several types of regulatory RNAs. It also includes promoters and their associated gene-regulatory elements, DNA playing structural and replicatory roles, such as scaffolding regions, telomeres, centromeres, and origins of replication, plus large numbers of transposable elements, inserted viral DNA, non-functional pseudogenes and simple, highly repetitive sequences. Introns make up a large percentage of non-coding DNA. Some of this non-coding DNA is non-functional junk DNA, such as pseudogenes, but there is no firm consensus on the total amount of junk DNA.

<span class="mw-page-title-main">Genetic testing</span> Medical test

Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or through biochemical analysis to measure specific protein output. In a medical setting, genetic testing can be used to diagnose or rule out suspected genetic disorders, predict risks for specific conditions, or gain information that can be used to customize medical treatments based on an individual's genetic makeup. Genetic testing can also be used to determine biological relatives, such as a child's biological parentage through DNA paternity testing, or be used to broadly predict an individual's ancestry. Genetic testing of plants and animals can be used for similar reasons as in humans, to gain information used for selective breeding, or for efforts to boost genetic diversity in endangered populations.

<span class="mw-page-title-main">Pharmacogenomics</span> Study of the role of the genome in drug response

Pharmacogenomics, often abbreviated "PGx," is the study of the role of the genome in drug response. Its name reflects its combining of pharmacology and genomics. Pharmacogenomics analyzes how the genetic makeup of a patient affects their response to drugs. It deals with the influence of acquired and inherited genetic variation on drug response, by correlating DNA mutations with pharmacokinetic, pharmacodynamic, and/or immunogenic endpoints.

<span class="mw-page-title-main">Personalized medicine</span> Medical model that tailors medical practices to the individual patient

Personalized medicine, also referred to as precision medicine, is a medical model that separates people into different groups—with medical decisions, practices, interventions and/or products being tailored to the individual patient based on their predicted response or risk of disease. The terms personalized medicine, precision medicine, stratified medicine and P4 medicine are used interchangeably to describe this concept, though some authors and organizations differentiate between these expressions based on particular nuances. P4 is short for "predictive, preventive, personalized and participatory".

Genetic discrimination occurs when people treat others differently because they have or are perceived to have a gene mutation(s) that causes or increases the risk of an inherited disorder. It may also refer to any and all discrimination based on the genotype of a person rather than their individual merits, including that related to race, although the latter would be more appropriately included under racial discrimination. Some legal scholars have argued for a more precise and broader definition of genetic discrimination: "Genetic discrimination should be defined as when an individual is subjected to negative treatment, not as a result of the individual's physical manifestation of disease or disability, but solely because of the individual's genetic composition." Genetic Discrimination is considered to have its foundations in genetic determinism and genetic essentialism, and is based on the concept of genism, i.e. distinctive human characteristics and capacities are determined by genes.

Public health genomics is the use of genomics information to benefit public health. This is visualized as more effective preventive care and disease treatments with better specificity, tailored to the genetic makeup of each patient. According to the Centers for Disease Control and Prevention (U.S.), Public Health genomics is an emerging field of study that assesses the impact of genes and their interaction with behavior, diet and the environment on the population's health.

<span class="mw-page-title-main">Whole genome sequencing</span> Determining nearly the entirety of the DNA sequence of an organisms genome at a single time

Whole genome sequencing (WGS) is the process of determining the entirety, or nearly the entirety, of the DNA sequence of an organism's genome at a single time. This entails sequencing all of an organism's chromosomal DNA as well as DNA contained in the mitochondria and, for plants, in the chloroplast.

Genomic counseling is the process by which a person gets informed about his or her genome often in the setting of elective genetic and genomic testing. In contrast to genetic counseling, which focuses on Mendelian diseases and typically involves person-to-person communication with a genetic counselor or other medical genetics expert, genomic counseling is not limited to currently clinically relevant information. It is often based on genomic information that is of interest for the informed person, such as increased risk for common complex disease that has actionable components, genetically determined non-disease related traits, or recreational forms of information and genetic genealogy data. An individual's response to certain medications/drugs based on their pharmacogenomic profile may be provided.

<span class="mw-page-title-main">Exome sequencing</span> Sequencing of all the exons of a genome

Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome. It consists of two steps: the first step is to select only the subset of DNA that encodes proteins. These regions are known as exons—humans have about 180,000 exons, constituting about 1% of the human genome, or approximately 30 million base pairs. The second step is to sequence the exonic DNA using any high-throughput DNA sequencing technology.

Brandon Ross Colby is an American medical geneticist in Beverly Hills, California and physician specializing in predictive medicine and genetic testing. He is author of Outsmart Your Genes, a book about genetics published in 2011, and he is the founder and CEO of direct-to-consumer genetic testing service Sequencing.

<span class="mw-page-title-main">Robert C. Green</span> American geneticist

Robert C. Green is an American medical geneticist, physician, and public health researcher. He directs the Genomes2People Research Program in translational genomics and health outcomes in the Division of Genetics at Brigham and Women's Hospital and the Broad Institute, and is Director of the Preventive Genomics Clinic at Brigham and Women's Hospital. Research led by Green includes clinical and research aspects of genomic and precision medicine, including the development and disclosure of Alzheimer's disease risk estimates and one of the first prospective studies of direct-to-consumer genetic testing services. He has studied the implementation of medical sequencing in healthy adults, newborns, and active duty military personnel. As of 2020, he is leading the first research collaboration to explore return of genomic results and better understand penetrance in a population-based cohort of underrepresented minorities. He has led the Preventive Genomics Clinic at Brigham and Women's Hospital since its creation in 2019.

Dr Vinod Scaria FRSB, FRSPH is an Indian biologist, medical researcher pioneering in Precision Medicine and Clinical Genomics in India. He is best known for sequencing the first Indian genome. He was also instrumental in the sequencing of The first Sri Lankan Genome, analysis of the first Malaysian Genome sequencing and analysis of the Wild-type strain of Zebrafish and the IndiGen programme on Genomics for Public Health in India.

Personalized medicine involves medical treatments based on the characteristics of individual patients, including their medical history, family history, and genetics. Although personal genetic information is becoming increasingly important in healthcare, there is a lack of sufficient education in medical genetics among physicians and the general public. For example, pharmacogenomics is practiced worldwide by only a limited number of pharmacists, although most pharmacy colleges in the United States now include it in their curriculum. It is also increasingly common for genetic testing to be offered directly to consumers, who subsequently seek out educational materials and bring their results to their doctors. Issues involving genetic testing also invariably lead to ethical and legal concerns, such as the potential for inadvertent effects on family members, increased insurance rates, or increased psychological stress.

<span class="mw-page-title-main">Variant of uncertain significance</span>

A variant of uncertainsignificance (VUS) is a genetic variant that has been identified through genetic testing but whose significance to the function or health of an organism is not known. Two related terms are "gene of uncertain significance" (GUS), which refers to a gene that has been identified through genome sequencing but whose connection to a human disease has not been established, and "insignificant mutation", referring to a gene variant that has no impact on the health or function of an organism. The term "variant' is favored in clinical practice over "mutation" because it can be used to describe an allele more precisely. When the variant has no impact on health, it is called a "benign variant". When it is associated with a disease, it is called a "pathogenic variant". A "pharmacogenomic variant" has an effect only when an individual takes a particular drug and therefore is neither benign nor pathogenic.

Clinicogenomics, also referred to as clinical genomics, is the study of clinical outcomes with genomic data. Genomic factors have a causal effect on clinical data. Clinicogenomics uses the entire genome of a patient in order to diagnose diseases or adjust medications exclusively for that patient. Whole genome testing can detect more mutations and structural anomalies than targeted gene testing. Furthermore, targeted gene testing can only test for the diseases for which the doctor screens, whereas testing the whole genome screens for all diseases with known markers at once.

Genetic privacy involves the concept of personal privacy concerning the storing, repurposing, provision to third parties, and displaying of information pertaining to one's genetic information. This concept also encompasses privacy regarding the ability to identify specific individuals by their genetic sequence, and the potential to gain information on specific characteristics about that person via portions of their genetic information, such as their propensity for specific diseases or their immediate or distant ancestry.

Elective genetic and genomic testing are DNA tests performed for an individual who does not have an indication for testing. An elective genetic test analyzes selected sites in the human genome while an elective genomic test analyzes the entire human genome. Some elective genetic and genomic tests require a physician to order the test to ensure that individuals understand the risks and benefits of testing as well as the results. Other DNA-based tests, such as a genealogical DNA test do not require a physician's order. Elective testing is generally not paid for by health insurance companies. With the advent of personalized medicine, also called precision medicine, an increasing number of individuals are undertaking elective genetic and genomic testing.

DNA encryption is the process of hiding or perplexing genetic information by a computational method in order to improve genetic privacy in DNA sequencing processes. The human genome is complex and long, but it is very possible to interpret important, and identifying, information from smaller variabilities, rather than reading the entire genome. A whole human genome is a string of 3.2 billion base paired nucleotides, the building blocks of life, but between individuals the genetic variation differs only by 0.5%, an important 0.5% that accounts for all of human diversity, the pathology of different diseases, and ancestral story. Emerging strategies incorporate different methods, such as randomization algorithms and cryptographic approaches, to de-identify the genetic sequence from the individual, and fundamentally, isolate only the necessary information while protecting the rest of the genome from unnecessary inquiry. The priority now is to ascertain which methods are robust, and how policy should ensure the ongoing protection of genetic privacy.

Personalized onco-genomics (POG) is the field of oncology and genomics that is focused on using whole genome analysis to make personalized clinical treatment decisions. The program was devised at British Columbia's BC Cancer Agency and is currently being led by Marco Marra and Janessa Laskin. Genome instability has been identified as one of the underlying hallmarks of cancer. The genetic diversity of cancer cells promotes multiple other cancer hallmark functions that help them survive in their microenvironment and eventually metastasise. The pronounced genomic heterogeneity of tumours has led researchers to develop an approach that assesses each individual's cancer to identify targeted therapies that can halt cancer growth. Identification of these "drivers" and corresponding medications used to possibly halt these pathways are important in cancer treatment.

Personalized genomics is the human genetics-derived study of analyzing and interpreting individualized genetic information by genome sequencing to identify genetic variations compared to the library of known sequences. International genetics communities have spared no effort from the past and have gradually cooperated to prosecute research projects to determine DNA sequences of the human genome using DNA sequencing techniques. The methods that are the most commonly used are whole exome sequencing and whole genome sequencing. Both approaches are used to identify genetic variations. Genome sequencing became more cost-effective over time, and made it applicable in the medical field, allowing scientists to understand which genes are attributed to specific diseases.

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