A Tool Used by Scientists to Study Genetics in a Family

Alcohol Health Res World. 1995; xix(3): 190–195.

The Homo Genome Projection

Abstract

The Human Genome Project is an ambitious enquiry endeavour aimed at deciphering the chemical makeup of the unabridged human genetic code (i.due east., the genome). The main work of the project is to develop three research tools that will allow scientists to identify genes involved in both rare and mutual diseases. Another project priority is to examine the ethical, legal, and social implications of new genetic technologies and to educate the public virtually these issues. Although it has been in beingness for less than 6 years, the Human Genome Project already has produced results that are permeating basic biological research and clinical medicine. For example, researchers accept successfully mapped the mouse genome, and work is well under way to develop a genetic map of the rat, a useful model for studying circuitous disorders such as hypertension, diabetes, and alcoholism.

Keywords: genome, genetic mapping, DNA, practical inquiry, molecular genetics

The Homo Genome Project is an international research project whose primary mission is to decipher the chemic sequence of the complete human being genetic fabric (i.east., the entire genome), identify all 50,000 to 100,000 genes independent within the genome, and provide inquiry tools to analyze all this genetic information. This ambitious project is based on the fact that the isolation and analysis of the genetic material independent in the Dna¹ (figure 1) tin can provide scientists with powerful new approaches to understanding the evolution of diseases and to creating new strategies for their prevention and treatment. Well-nigh all human medical conditions, except physical injuries, are related to changes (i.due east., mutations) in the structure and function of Dna. These disorders include the 4,000 or so heritable "Mendelian" diseases that result from mutations in a unmarried gene; complex and common disorders that arise from heritable alterations in multiple genes; and disorders, such as many cancers, that result from Deoxyribonucleic acid mutations caused during a person'south lifetime. (For more data on the genetics of alcoholism, come across the manufactures past Goate, pp. 217–220, and Grisel and Crabbe, pp. 220–227.)

Artist's rendering of the Dna molecule from a single cell.

Although scientists have performed many of these tasks and experiments for decades, the Human Genome Project is unique and remarkable for the enormity of its endeavour. The human genome contains 3 billion DNA building blocks (i.e., nucleotides), enough to fill approximately yard 1,000-folio telephone books if each nucleotide is represented by one letter. Given the size of the human genome, researchers must develop new methods for DNA analysis that can process large amounts of information quickly, cost-effectively, and accurately. These techniques will narrate DNA for family unit studies of illness, create genomic maps, determine the nucleotide sequence of genes and other big Deoxyribonucleic acid fragments, identify genes, and enable extensive computer manipulations of genetic data.

Focus of the Human Genome Project

The primary work of the Man Genome Projection has been to produce iii master research tools that will allow investigators to identify genes involved in normal biological science equally well as in both rare and common diseases. These tools are known as positional cloning (Collins 1992). These avant-garde techniques enable researchers to search for disease-linked genes directly in the genome without first having to identify the factor's poly peptide production or function. (See the commodity by Goate, pp. 217–220.) Since 1986, when researchers first found the gene for chronic granulomatous disease² through positional cloning, this technique has led to the isolation of considerably more 40 disease-linked genes and will allow the identification of many more genes in the time to come (tabular array 1).

Table 1

Disease Genes Identifed Using Positional Cloning

Year	Affliction
1986	Chronic Granulomatous Disease Duchenne's Muscular Dystrophy Retinoblastoma
1989	Cystic Fibrosis
1990	Wilms' Tumor Neurofibromatosis Blazon 1 Testis Determining Cistron Choroideremia
1991	Delicate Ten Syndrome Familial Polyposis Coli Kallmann's Syndrome Aniridia
1992	Myotonic Dystrophy Lowe's Syndrome Norris's Syndrome
1993	Menkes' Affliction 10-Linked A gammaglobulinemia Glycerol Kinase Deficiency Adrenoleukodystrophy Neurofibromatosis Type two Huntington's Illness von Hippel-Lindau Disease Spinocerebellar Clutter I Lissencephaly Wilson's Affliction Tuberous Sclerosis
1994	MacLeod's Syndrome Polycystic Kidney Illness Dentatorubral Pallidoluysian Cloudburst Frail 10 "East" Achondroplasia Wiskott Aldrich Syndrome Early Onset Breast/Ovarian Cancer (BRCA one) Diastrophic Dysplasia Aarskog-Scott Syndrome Built Adrenal Hypoplasia Emery-Dreifuss Muscular Dystrophy Machado-Joseph Disease
1995	Spinal Muscular Atrophy Chondrodysplasia Punctate Limb-Girdle Muscular Dystrophy Ocular Albinism Ataxia Telangiectasia Alzheimer's Disease Hypophosphatemic Rickets Hereditary Multiple Exostoses Flower Syndrome Early Onset Breast Cancer (BRCA two)

Each of the 3 tools existence developed past the Human Genome Project helps bring the specific gene being sought into better focus (see sidebar, pp. 192–193). The first of these tools, the genetic map, consists of thousands of landmarks—short, distinctive pieces of DNA—more or less evenly spaced along the chromosomes. With this tool, researchers can narrow the location of a gene to a region of the chromosome. Once this region has been identified, investigators plough to a 2nd tool, the physical map, to farther pinpoint the specific cistron. Concrete maps are sets of overlapping DNA that may span an unabridged chromosome. These sets are cloned and frozen for future research. Once the physical map is complete, investigators will simply exist able to go to the freezer and option out the actual piece of DNA needed, rather than search through the chromosomes all over once again. The final tool will be the cosmos of a complete sequence map of the Dna nucleotides, which will contain the exact sequence of all the Dna that makes upwards the human genome.

Genetic Maps Provide Blueprint for Human Genome

A principal focus of the Man Genome Project is to develop tools that will enable investigators to clarify large amounts of hereditary material quickly and efficiently. The success of this projection hinges on the accurate mapping of each chromosome. The Human Genome Project is using primarily three levels of maps, each of which helps to increase agreement not just of the construction of individual genes only as well of their relation to each other and to the entire chromosomal structure.

Genetic Mapping

Genetic mapping, likewise called linkage mapping, provides the first evidence that a disease or trait (i.eastward., a characteristic) is linked to the cistron(south) inherited from one'southward parents. Through genetic mapping, researchers tin can approximate the location of a gene to a specific region on a specific chromosome; the procedure is like establishing towns on a road map (figure 1). For example, Interstate 10 runs from Florida to California. It would be difficult to find a landmark along that highway if the only cities mapped were Jacksonville and Los Angeles. It would be much easier, however, to pinpoint the landmark if i knew that it was located between markers that are closer together (e.g., El Paso and San Antonio).

Genetic mapping begins with the collection of blood or tissue samples from families in which a affliction or trait is prevalent. Afterwards extracting the DNA from the samples, researchers runway linearly the frequency of a recurring gear up of nucleotides (represented, for example, past the messages "CACACA") forth a region of a chromosome. If this sequence is shared amid family members who have the disease, the scientists may accept identified a marking for the disease-linked gene. Mapping additional Deoxyribonucleic acid samples from other people with and without the affliction allows researchers to determine the statistical probability that the marker is linked to the development of the disease.

Figure 1

Genetic Map. But every bit locating a landmark on a detail highway is easier if one can narrow the expanse of the search to between two nearby points, or markers (e.g., El Paso and San Antonio on Interstate 10), researchers get-go try to narrow their search for particular genes to a segment of chromosome denoted past a specific sequence of nucleotides (e.yard., CACACA).

Concrete Mapping

Physical mapping generates sets of overlapping DNA fragments that span regions of—or fifty-fifty whole—chromosomes. These Dna fragments, which can be isolated and stored for hereafter assay (figure 2), serve as a resource for investigators who want to isolate a gene later they have mapped it to a item chromosome or chromosomal region. The physical map allows scientists to limit the cistron search to a item subregion of a chromosome and thus aught in on their target more quickly.

1 early goal of the concrete mapping component of the Human Genome Projection was to isolate contiguous Deoxyribonucleic acid fragments that spanned at least 2 million nucleotides. Considerable progress has been made in this area, with sets of contiguous Deoxyribonucleic acid fragments ("contigs") now frequently ranging from 20 to 50 one thousand thousand nucleotides in length. Because the club of DNA fragments in a physical map should reflect their actual lodge on a chromosome, correct alignment of contigs also requires a set of markers to serve as mileposts, similar to those of an interstate highway. Genome scientists have adult a concrete map that currently contains about 23,000 markers, called sequence tagged sites (STS's). Scientists likely volition meet their ultimate goal of establishing 30,000 STS markers on the physical map—one every 100,000 nucleotides—inside the adjacent year or two. This detailed STS map will allow researchers to pinpoint the exact location of whatever gene inside 50,000 nucleotides of an STS marker.

Figure 2

Physical Map. Using diverse methods, A) whole chromosomes are B) snipped into large fragments of Dna (i.due east., sequences of nucleotides) and and then cloned. C) These cloned DNA pieces then are realigned in the order in which they originally occurred in the chromosomes and stored. The stored pieces can be used for further studies such as D) finding specific genes.

Effigy 3

Part of the Dna sequence map of a virus containing 10,000 nucleotide bases. For comparison, the human genome contains approximately 3 billion nucleotide bases.

Researchers also are attempting to employ fragments of expressed genes known equally expressed sequence tags (EST's), which are made from complimentary DNA, as markers on the physical genome map. By using EST'due south, they hope to increment the power of maps for finding specific genes. A recent collaboration between Merck and Co. (a major pharmaceutical corporation) and researchers at Washington University in St. Louis, Missouri, will provide a resource for placing tens of thousands of such markers derived from actual genes on the physical map.

Marking development to be used in creating both the linkage and the physical maps also takes into account the need for connectivity betwixt these ii types of maps. Information learned from one stage of the gene-finding procedure must be easily translatable to the next.

The DNA Sequence Map

The Human Genome Project's nigh challenging goal is to determine the order (i.east., sequence), unit by unit, of all iii billion nucleotides that brand up the human genome. In one case the genetic and physical maps are completed, a sequence map can exist constructed, which will allow scientists to discover genes, narrate Deoxyribonucleic acid regions that command cistron action, and link DNA structure to its office.

To engagement, the technology for this work has been adult and implemented primarily in model organisms. For instance, researchers now take sequenced 25 million Deoxyribonucleic acid nucleotides from the roundworm—almost 25 percent of the animal's genome—and, in the procedure, have increased their almanac sequencing rate to eleven million nucleotide bases (figure three). The investigators expect to finish sequencing the roundworm genome past the terminate of 1998. The complete Dna sequence of yeast and E. coli genomes volition be determined even sooner.

—Francis Due south. Collins and Leslie Fink

To make all this information available to researchers worldwide, the projection has the additional goal of developing estimator methods for easy storage, retrieval, and manipulation of data. Moreover, because researchers often can obtain valuable information nearly man genes and their functions by comparing them with the respective genes of other species, the project has set goals for mapping and sequencing the genomes of several of import model organisms, such as the mouse, rat, fruit wing, roundworm, yeast, and the common intestinal bacterium Eastward. coli.

Technological Advances in Genomic Research

The need for large-calibration approaches to DNA sequencing has pushed applied science toward both increasing chapters and decreasing instrument size. This demand has led, for example, to the development of automated machines that reduce the time and cost of the biochemical processes involved in sequencing, amend the analysis of these reactions, and facilitate entering the data obtained into databases. Robotic instruments also have been developed that expedite repetitive tasks inherent in big-scale inquiry and reduce the take chances for fault in several sequencing and mapping steps.

Miniaturization engineering science is facilitating the sequencing of more—and longer—DNA fragments in less time and increasing the portability of sequencing processes, a adequacy that is particularly of import in clinical or field work. In 1994, for case, the National Institutes of Wellness (NIH), through its National Eye for Human being Genome Enquiry (NCHGR), began a new initiative for the evolution of microtechnologies to reduce the size of sequencing instrumentation and thereby increase the speed of the sequencing procedure. NCHGR also is exploring new strategies for minimizing time-consuming sequencing bottlenecks by developing integrated, matched components that volition help ensure that each step in the sequencing process gain as efficiently every bit possible. The overall sequencing rate is only as fast as its slowest step.

Other developments in DNA sequencing have aimed to reduce the costs associated with the applied science. Through refinements in current sequencing methods, the cost has been lowered to about $0.50 per nucleotide. Inquiry on new Dna sequencing techniques is addressing the need for rapid, inexpensive, large-calibration sequencing processes for comparison of complex genomes and clinical applications. Further improvements in the efficiency of current processes, along with the development of entirely new approaches, will enable researchers to make up one's mind the consummate sequence of the human genome perhaps before the yr 2005.

Applications of the Human Genome Project

The detailed genetic, physical, and sequence maps adult past the Human Genome Project as well volition be critical to understanding the biological basis of complex disorders resulting from the coaction of multiple genetic and ecology influences, such as diabetes; eye disease; cancer; and psychiatric illnesses, including alcoholism. In 1994, for instance, researchers used genetic maps to discover at least five unlike chromosome regions that appear to play a part in insulin-dependent (i.e., blazon 1) diabetes (Davies et al. 1994). Analyses to identify the genetic components of these complex diseases crave high-resolution genetic maps and must be conducted on a scale much larger than was previously possible. Automatic microsatellite marker technology³ now makes it possible to decide the genetic makeup (i.e., the genotype) of plenty subjects and then that genes for common diseases tin can exist mapped reliably in a reasonable amount of time. NCHGR is planning a technologically avant-garde genotyping facility to assist investigators in designing enquiry studies; performing genetic analyses; and developing new techniques for analyzing common, multigene diseases.

Molecular Medicine

Efforts to sympathise and treat affliction processes at the Deoxyribonucleic acid level are condign the basis for a new molecular medicine. The discovery of disease-associated genes provides scientists with the foundation for understanding the form of affliction, treating disorders with synthetic Deoxyribonucleic acid or gene products, and assessing the gamble for futurity illness. Thus, past going direct to the genetic source of human illness, molecular medicine strategies will offer a more than customized health management based on the unique genetic constitution of each person. Molecular medicine besides will increase clinicians' focus on prevention by enabling them to predict a person's risk for future disease and offer prevention or early treatment strategies. This approach will utilize non but to classical, single-gene hereditary disorders but too to more common, multi-gene disorders, such equally alcoholism.

During the by three years, positional cloning has led to the isolation of more than than xxx disease-associated genes. Although this number has increased dramatically, compared with the years predating the Human being Genome Projection, it is nonetheless a small fraction of the fifty,000 to 100,000 genes that await discovery in the entire genome. NCHGR has helped develop efficient biological and estimator techniques to identify all the genes in large regions of the genome. One technique was used successfully terminal twelvemonth to isolate BRCA1, the first major gene linked to inherited breast cancer. The location of BRCA1 beginning was narrowed to a DNA fragment of several hundred grand nucleotides containing many genes. A process that isolates the poly peptide-coding sequences of a cistron (i.e., exon trapping) allowed researchers to identify and examine not but the correct BRCA1 gene in that region just also several new genes that at present serve equally disease-cistron candidates for future investigations.

Diagnostics

Clinical tests that discover disease-causing mutations in Dna are the most immediate commercial awarding of gene discovery. These tests may positively identify the genetic origin of an agile disease, foreshadow the development of a disease afterward in life, or place healthy carriers of recessive diseases such as cystic fibrosis.^iv Genetic tests can be performed at any phase of the human life cycle with increasingly less invasive sampling procedures. Although DNA testing offers a powerful new tool for identifying and managing disease, information technology also poses several medical and technical challenges. The number and type of mutations for a detail disease may exist few, as in the case of achondroplasia,^v or many, as in the case of cystic fibrosis and hereditary breast cancer. Thus, information technology is essential to constitute for each potential Deoxyribonucleic acid test how often it detects disease-linked mutations and how frequently and to what caste detection of mutations correlates with the development of affliction.

Therapeutics

Factor discovery too provides opportunities for developing gene-based treatment for hereditary and caused diseases. These handling approaches range from the mass production of natural substances (e.g., blood-clotting factors, growth factors and hormones, and interleukins and interferons⁶) that are constructive in treating certain diseases to cistron-therapy strategies. Gene therapy is designed to deliver Dna carrying a functional gene to a patient'due south cells or tissues and thereby correct a genetic alteration.

Currently, more than than 100 companies conduct human clinical trials on Dna-based therapies (Pharmaceutical Enquiry and Manufacturers of America [PRMA] 1995). The top U.S. public biotechnology companies take an estimated 2,000 drugs in early evolution stages (Ernst and Young 1993). Since 1988, NIH'south Recombinant Deoxyribonucleic acid Advisory Committee has approved more than 100 man gene-therapy or gene-transfer protocols (Role of Recombinant Dna Activities, NIH, personal communication, April 1995). Seventeen gene-therapy products are now in commercial development for hereditary disorders, cancer, and AIDS (PRMA 1995).

Ethical, Legal, and Social Concerns of the Human Genome Project

Implications for Illness Detection

The translation of human being genome technologies into patient care brings with it special concerns about how these tools volition be practical. A principal arena in which psychosocial issues related to these technologies are existence raised is the testing of people who may be at risk for a genetically transmitted illness merely who do not yet prove the illness'south symptoms (i.e., are asymptomatic). These concerns stem largely from the delay between scientists' technical ability to develop Deoxyribonucleic acid-based diagnostic tests that can identify a person'due south chance for future disease and their ability to develop effective prevention or treatment strategies for the disorders those tests portend. In the meantime, people who undergo genetic tests run the chance of discrimination in health insurance and may have difficulty adapting to test results—particularly in families in which hereditary affliction is common—regardless of whether a exam indicates future illness. When no treatment is available and when no other medical course of action tin be taken on the basis of such tests, the negative social, economical, and psychological consequences of knowing one'south medical fate must be advisedly evaluated in light of the meager medical benefits of such knowledge.

To help ensure that medical benefits are maximized without jeopardizing psychosocial and economic well-beingness, the Human Genome Projection, from its beginning, has allocated a portion of its research dollars to study the ethical, legal, and social implications (ELSI) of the new genetic technologies. A diverse funding program supports inquiry in 4 priority areas: the upstanding issues surrounding the acquit of genetic research, the responsible integration of new genetic technologies into the clinic, the privacy and fair use of genetic data, and the professional and public education about these issues.

Because of the many unresolved questions surrounding Dna testing in asymptomatic patients, in 1994 NCHGR's informational body released a statement urging wellness care professionals to offer DNA testing for the predisposition to breast, ovarian, and colon cancers just within approved pilot research programs until more is known about the science, psychology, and sociology of genetic testing for some diseases (National Advisory Council for Human Genome Research 1994). The American Order of Human Genetics and the National Breast Cancer Coalition have issued similar statements. More recently, the NIH–DOE [Section of Energy] Working Grouping on ELSI launched a job strength to perform a comprehensive, 2-yr evaluation of the current state of genetic testing technologies in the United States. The task force will examine safety, accuracy, predictability, quality assurance, and counseling strategies for the responsible use of genetic tests.

In a related project, NCHGR'southward ELSI co-operative spearheaded a new group of pilot studies shortly after researchers isolated BRCA1 and several genes for colon cancer predisposition. These three-year studies are examining the psychosocial and patient-education issues related to testing salubrious members of families with high incidences of cancer for the presence of mutations that profoundly increase the run a risk of developing cancer. The results will provide a thorough base of noesis on which to build plans for introducing genetic tests for cancer predisposition into medical practice.

Implications for Circuitous Traits

Research in man genetics focuses non simply on the causes of affliction and disability just also on genes and genetic markers that announced to be associated with other homo characteristics, such as pinnacle, weight, metabolism, learning ability, sexual orientation, and various behaviors (Hamer et al. 1993; Brunner et al. 1993). Associating genes with human traits that vary widely in the population raises unique and potentially controversial social issues. Genetic studies elucidate only one component of these complex traits. The findings of these studies, yet, may be interpreted to mean that such characteristics can be reduced to the expression of particular genes, thus excluding the contributions of psychosocial or environmental factors. Genetic studies can also be interpreted in a way that narrows the range of variation considered "normal" or "healthy."

Both reducing complex human characteristics to the role of genes and restricting the definition of what is normal can take harmful—even devastating—consequences, such as the devaluation of human diversity and social discrimination based on a person'due south genetic makeup. The Human Genome Project must therefore foster a improve understanding of man genetic variation among the general public and health care professionals besides as offer enquiry policy options to foreclose genetic stigmatization, discrimination, and other misuses and misinterpretations of genetic information.

Progress on Genetic and Physical Maps

In the United States, NCHGR and DOE, through its Part of Environmental Health Enquiry, are the primary public supporters of major genome research programs. In 1990, when the fifteen-year Human Genome Projection began, NCHGR and DOE established ambitious goals to guide the research through its offset years (U.S. Department of Health and Man Services and U.S. Department of Energy 1990). Afterward virtually six years, scientists involved in the Human Genome Project have met or exceeded most of those goals—some alee of time and all nether upkeep. Because scientific advances may speedily make the latest technologies obsolete, a second v-yr plan was published in 1993 (Collins and Galas 1993) to keep ahead of the projection's progress. Already, farther technological advances make information technology likely that a new plan will be needed, perchance as early on every bit this year.

In 1994, an international consortium headed past the Genome Science and Technology Center in Iowa published a genetic map of the human being genome containing almost half-dozen,000 markers spaced less than i meg nucleotides autonomously (Cooperative Homo Linkage Center et al. 1994). This map was completed more 1 year ahead of schedule, and its density of markers is 4 to six times greater than that called for by the 1990 goals. This early achievement is largely a upshot of the discovery and evolution of micro-satellite DNA markers and of large-scale methods for marker isolation and analysis.

In a related project, technology developed and so quickly that a high resolution genetic map of the mouse genome was completed in just 2 years. NCHGR is now helping to coordinate an initiative with other NIH institutes, peculiarly the National Middle, Lung, and Blood Constitute and the National Institute on Booze Abuse and Alcoholism, to develop a loftier-resolution genetic map of the rat, a useful model for studying complex disorders such every bit hypertension, diabetes, and alcoholism.

The original v-yr goal to isolate contiguous Dna fragments that span at least ii million nucleotides was met early; soon, more than than ninety percent of the human genome will be accounted for using sets of overlapping DNA fragments, each of which is at least 10 million nucleotides long. Complete physical maps now exist for human chromosomes 21, 22, and Y. Near complete maps have been developed for chromosomes iii, four, 7, 11, 12, 16, 19, and 10.^vii

As the end of the first stage of the Human Genome Projection draws almost, its bear upon already is rippling through basic biological research and clinical medicine. From deciphering information in genes, researchers have gained new knowledge near the nature of mutations and how they cause illness. Even afterward someday identifying all human genes, scientists volition face the daunting job of elucidating the genes' functions. Furthermore, new paradigms will sally equally researchers and clinicians sympathise interactions betwixt genes, the molecular basis of multigene disorders, and even tissue and organ office.

The translation of this increasing cognition into improved health intendance already is nether way; yet, the value of factor discovery to the promising new field of molecular medicine volition be fully realized just when the public is secure in the employ of genetic technologies.

Footnotes

¹For a definition of this and other technical terms used in this article, meet central glossary, pp. 182–183.

²Chronic granulomatous illness is an inherited affliction of the allowed system.

³Microsatellite markers are short DNA sequences that vary in length from person to person. The length of a particular marker is inherited from one's parents, allowing researchers to rail the markers through several generations of the same family unit.

^ivFor a recessive disease to develop, a person must inherit two contradistinct factor copies, one from each parent. People who inherit only one altered gene copy usually are healthy (i.e., they practice not show symptoms of the disease); these people are chosen asymptomatic carriers.

⁵Achondroplasia is a disorder that results in lacking skeletal development in the fetus and dwarfism. Afflicted children often dice earlier or within their first twelvemonth of life.

⁶Interleukins and interferons are substances that stimulate and regulate the allowed system.

^viiOf the 23 chromosome pairs in human cells, 22 pairs are numbered according to their size, with chromosome 1 being the largest and chromosome 22 existence the smallest chromosome. The gender-determining chromosomes are referred to as X and Y.

References

• Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Scientific discipline. 1993;261:321–327. [PubMed] [Google Scholar]
• Collins FS. Let's not call it reverse genetics. Nature Genetics. 1992;1:3–six. [PubMed] [Google Scholar]
• Collins FS, Galas D. A new five-yr program for the U.Southward. human genome project. Science. 1993;262:43–46. [PubMed] [Google Scholar]
• Cooperative Human Linkage Center (CHLC) Murray JC, Buetow KH, Weber JL, Ludwigsen S, Scherpbier-Heddema T, Manion F, Quillen J, Sheffield VC, Sunden S, Duyk GM, et al. A comprehensive human linkage map with centimorgan density. Science. 1994;265:2049–2054. [PubMed] [Google Scholar]
• Davies JL, Kawaguchi Y, Bennett ST, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SC, Jenkins SC, Palmer SM, et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature. 1994;371:130–136. [PubMed] [Google Scholar]
• Ernst, Young . The Industry Annual Study. 1993. Biotech 94: Long-term Value, Short-term Hurdles; p. 31. [Google Scholar]
• Hamer DH, Hu S, Magnuson VL, Hu N, Pattatucci AML. A linkage between Deoxyribonucleic acid markers on the X chromosome and male sexual orientation. Scientific discipline. 1993;262:578–580. [PubMed] [Google Scholar]
• National Advisory Quango for Human Genome Research. Argument on utilise of Deoxyribonucleic acid testing for presymptomatic identification of cancer risk. Journal of the American Medical Association. 1994;271(10):785. [PubMed] [Google Scholar]
• Pharmaceutical Research and Manufacturers of America. Biotechnology Medicines in Development. Mar, 1995. [Google Scholar]
• U.S. Department of Wellness and Human Services and U.South. Section of Energy. The U.S. Human Genome Projection: The First Five Years. Bethesda, MD: National Institutes of Health; 1990. Understanding Our Genetic Inheritance. NIH Publication No. ninety–1590. [Google Scholar]

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875757/

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