Human Genome Project
Human genetics is the discipline concerned with identifying and studying the genes carried by humans, the control and expression of traits caused by these genes, their transmission from generation to generation, and their expression in offspring. Modern human genetics properly begins with the elucidation of the structure of DNA in 1953 by James D. Watson and Francis H. Crick. This discovery led to very rapid advances in acquisition of genetic information and ultimately spawned the Human Genome Project (HGP), which was initiated in 1986 by the DOE (Department of Energy). In 1990 the DOE combined efforts with the National Institutes of Health (NIH) and private collaborators, including the Wellcome Trust of the United Kingdom, along with private companies based in Japan, France, Germany, and China. The ultimate goal of HGP was to determine the precise genetic makeup of humans as well as explore human genetic variation and human gene function. The first high-quality draft of the human genetic sequence was completed in April of 2003, thereby providing a suitable salute to the fiftieth anniversary of the discovery of DNA, which opened the modern era of human genetics.
Almost all current human genetics is directly related to the enormous mass of genetic data obtained and made available by the HGP. Some of the many themes now being explored include medical genetics, genetic bioinformatics, proteomics, toxicogenomics, the inheritance and prevention of gene-related cancers and other diseases, and policy and ethical issues related to genetic concerns of humans.
The human genome consists of genes located in chromosomes, along with a much smaller gene content, found in mitochondria, that is called mitochondrial DNA or mtDNA. About 99.7 percent of the human genome is located in the chromosomes, and another 0.3 percent consists of the mtDNA genome, which encodes for a number of enzymes involved in cellular respiration. The mtDNA is inherited almost entirely through the female line, so its genetic transmission and expression differ from that of classical Mendelian genetics. Studies of human mtDNA have revealed a number of medical pathologies associated with this unique mode of inheritance transmission. Studies have also proven useful in determining significant trends in the evolutionary development of Homo sapiens and elucidating relationships with the near-species Homo neanderthalensis (the now extinct Neanderthals).
The HGP effort decoded the genetic arrangement—the gene sequence of roughly 3 billion nucleotide base pairs of between 25,000 and 45,000 genes that collectively form the human genome. Many, but not all, of these have been sequenced and their locations on chromosomes mapped. Structurally, base-sequencing studies reveal that human genes showed great variations in size, ranging from several thousand base pairs to some genes comprising nearly half a million base pairs. The genetic functions have been determined for about half of the human genes that have been identified and sequenced. HGP provided so much information that a new field called bioinformatics was developed to handle the enormous amounts of genetic sequencing data for the human genome.
Bioinformatics
The purpose of bioinformatics is to help organize, store, and analyze genetic biological information in a rapid and precise manner, dictated by the need to be able to access genetic information quickly. In the United States the online database that provides access to these gene sequences is called GenBank, which is under the purview of the National Center for Biotechnology Information (NCBI) and has been made available on the Internet. In addition to human genome sequence records, GenBank provides genome information about plants, bacteria, and other animals.
Proteomics
Bioinformatics provides the basis for all modern studies of human genetics, including analysis of genes and gene sequences, determining gene functions, and detecting faulty genes. The study of genes and their functions is called proteomics, which involves the comparative study of protein expression. That is, exactly what is the metabolic and morphological relationship between the protein encoded within the genome and how that protein works. Geneticists are now classifying proteins into families, superfamilies, and folds according to their configuration, enzymatic activity, and sequence. Ultimately proteomics will complete the picture of the genetic structure and functioning of all human genes.
Toxicogenomics
Another newly developing field that relies on bioinformatics is the study of toxicogenomics, which is concerned with how human genes respond to toxins. Currently, this field is specifically concerned with evaluating how environmental factors negatively interact with messenger RNA (mRNA) translation, resulting in disease or dysfunction.
Medical Genetics
Almost all of current human medical genetics rests on the identification of human gene sequences that were provided by the HGP and made accessible through bioinformatics. Human medical genetics begins with recognition of defective genes that are either nonfunctioning or malfunctioning and that cause diseases or tissue malformation. Once defective genes have been identified and cataloged, patients can be screened with gene testing procedures to determine if they carry such genes. Following detection of a defective gene, several options may be explored and implemented, including genetic counseling, gene therapy, and pharmacogenetics.
At least four thousand diseases of humans are known to have a genetic basis and can be passed from generation to generation. In addition to many kinds of human cancers, all of which have a genetic basis, human genetic disorders include diabetes, heart disease, and cystic fibrosis. Other diseases and disorders that have been directly linked to human genetic anomalies include predispositions for colon cancer, Alzheimer’s disease, and breast cancer.
Gene Testing
In a gene-testing protocol, a sample of blood or body fluids is examined to detect a genetic anomaly such as the transposition of part of a chromosome or an altered sequence of the bases that comprise a specific gene, either of which can lead to a genetically based disorder or disease. Currently more than six hundred tests are available to detect malfunctioning or nonfunctioning genes. Most gene tests have focused on various types of human cancers, but other tests are being developed to detect genetic deficiencies that cause or exacerbate infectious and vascular diseases.
The emphasis on the relationship between genetics and cancer lies in the fact that all human cancers are genetically triggered by genes or have a genetic basis. Some cancers are inherited as mutations, but most result from random genetic mutations that occur in specific cells, often precipitated by viral infections or environmental factors not yet well understood.
At least four types of genetic problems have been identified in human cancers. The normal function of oncogenes, for example, is to signal the start of cell division. However, when mutations occur or oncogenes are overexpressed, the cells keep on dividing, leading to rapid growth of cell masses. The genetic inheritance of certain kinds of breast cancers and ovarian cancers results from the nonfunctioning tumor-suppressor genes
that normally stop cell division. When genetically altered tumor-suppressor genes are unable to stop cell division, cancer results. Conversely, the genes that cause inheritance of colon cancer result from the failure of DNA repair genes to correct mutations properly. The accumulation of mutations in these “proofreading” genes makes them inefficient or less efficient, and cells continue to replicate, producing a tumor mass.
If a gene screening reveals a genetic problem several options may be available, including gene therapy and genetic counseling. If the detected genetic anomaly results in disease, then pharmacogenomics holds promise of patient-specific drug treatment.
Gene Therapy
The science of gene therapy uses recombinant DNA technology to cure diseases or disorders that have a genetic basis. Still in its experimental stages, gene therapy may include procedures to replace a defective gene, repair a defective gene, or introduce healthy genes to supplement, complement, or augment the function of nonfunctional or malfunctioning genes. Several hundred protocols are being used in gene therapy trials, and many more are under development. Current trials focus on two major types of gene therapy, somatic gene therapy and germ-line gene therapy.
Somatic gene therapy focuses on altering a defective gene or genes in human body cells in an attempt to prevent or lessen the debilitating impact of a disease or other genetic disorder. Some examples of somatic cell gene therapy protocols now being tested include ones for adenosine deaminase (ADA) deficiency, cystic fibrosis, lung cancer, brain tumors, ovarian cancer, and AIDS.
In somatic gene therapy a sample of the patient’s cells may be removed and treated, and then reintegrated into body tissue carrying the corrected gene. An alternative somatic cell therapy is called gene replacement, which typically involves insertion of a normally functioning gene. Some experimental delivery methods for gene insertion include use of retroviral vectors and adenovirus vectors. These viral vectors are used because they are readily able to insert their genomes into host cells. Hence, adding the needed (or corrective) gene segment to the viral genome guarantees delivery into the cell’s nuclear interior. Nonviral delivery vectors that are being investigated for gene replacement include liposome fat bodies, human artificial chromosomes, and naked DNA (free DNA, or DNA that is not enclosed in a viral particle or any other “package”).
Another type of somatic gene therapy involves blocking gene activity, whereby potentially harmful genes such as those that cause Marfan syndrome and Huntington’s disease are disabled or destroyed. Two types of gene-blocking therapies now being investigated include the use of antisense molecules that target and bind to the messenger RNA (mRNA) produced by the gene, thereby preventing its translation, and the use of specially developed ribozymes that can target and cleave gene sequences that contain the unwanted mutation.
Germ-line therapy is concerned with altering the genetics of male and female reproductive cells, the gametes, as well as other body cells. Because germ-line therapy will alter the individual’s genes as well as those of his or her offspring, both concepts and protocols are still very controversial. Some aspects of germ-line therapy now being explored include human cloning and genetic enhancement.
The next steps in human genetic therapy involve determining the underlying mechanisms by which genes are transcribed, translated, and expressed, which is called proteomics.
Clinical Genetics
Clinical genetics is that branch of medical genetics involved in the direct clinical care of people afflicted with diseases caused by genetic disorders. Clinical genetics involves diagnosis, counseling, management, and support. Genetic counseling is a part of clinical genetics directly concerned with medical management, risk determination and options, and decisions regarding reproduction of afflicted individuals. Support services are an integral feature of all genetic counseling themes.
Clinical genetics begins with an accurate diagnosis that recognizes a specific, underlying genetic cause of a physical or biochemical defect following guidelines outlined by the NIH Counseling Development Conference. Clinical practice includes several hundred genetic tests that are able to detect mutations such as those associated with breast and colon cancers, muscular dystrophies, cystic fibrosis, sickle-cell disease, and Huntington’s disease.
Genetic counseling follows clinical diagnosis and focuses initially on explaining the risk factors and human problems associated with the genetic disorder. Both the afflicted individual and family members are involved in all counseling procedures. Important components include a frank discussion of risks, of options such as preventive operations, and of options involved in reproduction. All reproductive options are described along with their potential consequences, but genetic counseling is a support service rather than a directive mode. That is, it does not include recommendations. Instead, its ultimate mission is to help both the afflicted individuals and their families recognize and cope with the immediate and future implications of the genetic disorder.
Pharmacogenomics
That branch of human medical genetics dealing with the correlation of specific drugs to fit specific diseases in individuals is called pharmacogenomics. This field recognizes that different individuals may metabolically respond differentially to therapeutic medicines based on their genetic makeup. It is anticipated that testing human genome data will greatly speed the development of new drugs that not only target specific diseases but also will be tailored to the specific genetics of patients.
Policy and Ethical Concerns and Issues in Human Genetics
The “new genetics” of humans has raised a number of critical concerns that are currently being addressed on a number of levels. Some of these concerns are related to the ownership of genetic information obtained by the Human Genome Project, privacy issues, and use of genetic information in risk assessment and decision making.
Privacy issues have focused on psychological impact, possible discrimination, and stigmatization associated with identifying personal genetic disorders. For example, policy guarantees must be established to protect the privacy of persons with genetic disorders to prevent overt or covert societal discrimination against the affected individual. Another question arising from this is exactly who has the right to the genetic information of persons.
Use of information obtained by the Human Genome Project has provided entrepreneurial opportunities that will undoubtedly prove economically profitable. That is, the limits of commercialization of products, patents, copyrights, trade secrets, and trade agreements have to be determined. If patents of DNA sequences are permitted, will they limit accessibility and free scientific interchange among and between peoples of the world? This question becomes critical when it is recognized that the human genome is properly the property of all humans.
Noncoding “Junk” DNA
Like that of other organisms, the human genome consists of long segments of DNA that contain noncoding sequences called introns (intervening sequences). These vary from a few hundred to several thousand base pairs in length and often consist of repetitive DNA elements with no known function; that is, they do not code for proteins. Because they appear functionless but take up valuable chromosomal space, these noncoding sequences have been considered useless and have been termed junk DNA or selfish DNA.
Some studies, however, lend strong support to the possibility that the seemingly useless repetitive DNA may actually play a number of important genetic roles, from providing a substrate on which new genes can evolve to maintaining chromosome structure and participating in some sort of genetic control. Consequently, it is now out of fashion among geneticists to refer to these parts of the genome as junk DNA, but rather as DNA of unknown function.
Forensic Genetics
Law enforcement agencies are increasingly relying on a branch of human genetics called forensic genetics. The aims of forensic genetics typically are to determine the identity or nonidentity of suspects in crimes, based on an analysis of DNA found in hair, blood, and other body substances retrieved from the scene of the crime in comparison with that of suspects. Popularly called DNA fingerprinting,
forensic genetics relies on the fact that the DNA of every human carries unique tandem repeats of 20 or more kilobase pairs that can be compared and identified using radioactive probes. Thus, comparisons can establish identity or nonidentity to a very high level of probability. DNA fingerprinting is also used in recognizing genetic parentage of children, identifying victims—sometimes from fragments of bodies—and identifying relationships of missing children.
Phylogeny and Evolution
Another rapidly developing field in human genetics is the use of human gene sequences in both nuclear and mitochondrial DNA (mtDNA) to explore questions of human origins, evolution, phylogeny, bioarchaeology, and past human migration patterns.
Much of the analytical work has involved mtDNA to study relationships. Because it is inherited strictly through the egg line or female component, mtDNA is somewhat more useful, but comparisons of DNA sequences along the Y chromosome of human populations have also yielded valuable information regarding human origins and evolution.
One of the more interesting of these studies involves comparing mtDNA over a broad spectrum of global human populations. Comparisons of DNA sequencing of these populations has revealed differences in DNA sequences of about 0.33 percent, which is considerably less than seen in other primate species. These minor differences strongly suggest that all members of the human species, Homo sapiens, are far more closely related to one another than are members of many other vertebrate species.
A separate study compared human gene sequences among different human populations across the globe. This study revealed that the highest variations in DNA sequences are found among the human populations of Africa. Since populations that exhibit the highest genome variations are thought to be the oldest populations (because chance mutations have a longer time to accumulate in older populations as opposed to younger populations), these results strongly suggest that humans originated in Africa and subsequently dispersed into other regions of the world. This “out of Africa” theory has received compelling support from the DNA evidence, and the theory also explains why all other human populations are so remarkably similar. Since all other global human populations show minimal DNA sequence differences, it is hypothesized that a small group of humans emigrated from Africa to spread across and eventually colonize the other continents. Tests of gene sequences along Y chromosomes show similar patterns, leading to the proposal that all humans came from a
mitochondrial Eve and a Y chromosome Adam who lived between 160,000 and 200,000 years ago.
DNA-based phylogeny studies are also shedding light on the relationship between the Neanderthals (Homo neanderthalensis), a species that disappeared between 30,000 and 60,000 years ago, and the more modern Cro-Magnon humans (Homo sapiens) that replaced them. Comparisons of mtDNA between the two Homo species indicate that Neanderthals began diverging from modern humans half a million years ago and were significantly different in genomic content to be placed in a separate species. These findings also support the suggestion that Neanderthals were ecologically replaced by modern humans rather than genetically amalgamated into present human populations, as was once proposed. Although such arguments are not universally accepted, many more geneticists, paleoanthropologists, and forensic scientists are now using comparative analysis of DNA sequences among and between human populations to study questions of human evolutionary history.
Key terms
bioinformatics
:
The science of compiling and managing genetic and other biology data using computers, requisite in human genome research
dysmorphology
:
Abnormal physical development resulting from genetic disorder
forensic genetics
:
the application of genetics, particularly DNA technology, to the analysis of evidence used in civil cases, criminal cases, and paternity testing
gene therapy
:
the use of a viral or other vector to incorporate new DNA into a person’s cells with the objective of alleviating or treating the symptoms of a disease or condition
gene transfer
:
Using a viral or other vector to incorporate new DNA into a person’s cells. Gene transfer is used in gene therapy
genetic screening
:
the use of the techniques of genetics research to determine a person’s risk of developing, or his or her status as a carrier of, a disease or other disorder
genetic testing
:
the process of investigating a specific individual or population of people to detect the presence of genetic defects
genomics
:
the branch of genetics dealing with the study of the genetic sequences of organisms, including the human being
pharmacogenomics
:
The branch of human medical genetics that evaluates how an individual’s genetic makeup influences his or her response to drugs
proteomics
:
the study of how proteins are expressed in different types of cells, tissues, and organs
toxicogenomics
:
evaluating ways in which genomes respond to chemical and other pollutants in the environment
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