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Introduction and Background

Genetic variation is the material basis of evolution, and its origin and maintenance have long been the focus of population genetics and evolutionary biology. Charles Darwin (1859) recognized the importance of variation in the origin of species long before modern genetics began to emerge, and numerous other early investigators noted that human groups differ in skin color, hair form, body size, and other physical characteristics. However, it was the Hirschfelds, in a series of seminal publications shortly after World War I (see, for example, Hirschfeld and Hirschfeld 1919), who first established that human populations differ substantially in the frequency of specific, simply inherited genetic traits, namely, the ABO blood types. Later work has shown that such variation can be measured at cellular and molecular levels, as in the red-cell and white-cell antigens, serum proteins, leukocyte enzymes, mitochondrial DNA, and genomic DNA itself (for compilations of the observed variability, see Cavalli-Sforza and others 1994; Mourant and others 1976; Roychoudury and Nei 1988). The variation has been used to explore the history of human groups, to study the evolutionary relationships among existing nonhuman primates and humans, to estimate the importance of selection and genetic drift in the shaping of the genetic structure of populations, and to determine the time of origin and the spread of specific mutations.

An enormous body of data has accumulated on the extent of genetic variation among human beings, but most of the information has arisen opportunistically, having been driven by individual investigator initiatives and collected under widely differing conditions. Moreover, the information and samples that have been collected are dispersed in laboratories around the world, and access to them



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Evaluating Human Genetic Diversity 1 Introduction and Background Genetic variation is the material basis of evolution, and its origin and maintenance have long been the focus of population genetics and evolutionary biology. Charles Darwin (1859) recognized the importance of variation in the origin of species long before modern genetics began to emerge, and numerous other early investigators noted that human groups differ in skin color, hair form, body size, and other physical characteristics. However, it was the Hirschfelds, in a series of seminal publications shortly after World War I (see, for example, Hirschfeld and Hirschfeld 1919), who first established that human populations differ substantially in the frequency of specific, simply inherited genetic traits, namely, the ABO blood types. Later work has shown that such variation can be measured at cellular and molecular levels, as in the red-cell and white-cell antigens, serum proteins, leukocyte enzymes, mitochondrial DNA, and genomic DNA itself (for compilations of the observed variability, see Cavalli-Sforza and others 1994; Mourant and others 1976; Roychoudury and Nei 1988). The variation has been used to explore the history of human groups, to study the evolutionary relationships among existing nonhuman primates and humans, to estimate the importance of selection and genetic drift in the shaping of the genetic structure of populations, and to determine the time of origin and the spread of specific mutations. An enormous body of data has accumulated on the extent of genetic variation among human beings, but most of the information has arisen opportunistically, having been driven by individual investigator initiatives and collected under widely differing conditions. Moreover, the information and samples that have been collected are dispersed in laboratories around the world, and access to them

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Evaluating Human Genetic Diversity is often limited. Therefore it has proved difficult to compare results from different studies and this difficulty has limited the value of the information and samples for the study of many problems of current evolutionary and biomedical interest. To remedy those shortcomings, support has been growing in the international scientific community for a worldwide, geographically comprehensive survey of variation in the human genome. The most well-developed and widely recognized proposal for conducting such a survey is known as the Human Genome Diversity Project (HGDP). THE COMMITTEE, ITS CHARGE, AND ITS ACTIVITIES The Committee on Human Genome Diversity of the Board on Biology of the National Research Council's Commission on Life Sciences came into being as a result of a request from the National Science Foundation (NSF) and the National Institutes of Health (NIH) for the Research Council to assess the scientific value, technical aspects, and organizational requirements of a systematic worldwide survey of human genetic variability—and the ethical, legal and social issues that would be raised by it—before the commitment of any substantial funds to any such survey. The committee was organized in early 1996 and was structured to include members with expertise in all the major fields relevant to the project: population, human, and molecular genetics; evolutionary biology; anthropology (cultural and biologic); biostatistics; informatics; ethics; and law. The committee's charge, as defined in the agreement between the Research Council and the sponsors, was to evaluate the proposal to establish the HGDP. The evaluation was to include examination of the scope and objectives of the project; the technical and logistical problems that it poses, including data and specimen collection and management; the ethical, legal, and social issues that it raises; the nature of the organizational structure that it requires; the relationship of this project to other endeavors, such as the Human Genome Project (HGP); and, if possible, matters of cost, duration, and management. The committee met on 4 occasions: on April 22-23, 1996, in Washington, DC; on July 24-26, 1996, at the National Academy of Sciences Beckman Center at Irvine, California; on September 16-18, 1996, in Washington, DC; and on November 20-22, 1996, in Irvine. In addition, to elicit as wide a spectrum of opinions on the merits of the proposed survey as practical, the committee circulated a questionnaire encouraging those who could not attend the public sessions held as part of the committee's second and third meetings to submit their opinions in writing. Their comments were tabulated and taken into account in the committee's deliberations. At its first meeting, the committee was briefed by representatives of NSF and NIH, specifically, Mary Clutter, assistant director of NSF, and Judith Greenberg, director of the Division of Genetics and Developmental Biology of the National Institute of General Medical Sciences (NIGMS). The committee then discussed

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Evaluating Human Genetic Diversity its charge and how best to respond to it. It also examined its own composition to ensure that all the relevant scientific disciplines were represented and that no serious conflicts of interest existed. Because no document can be construed as the official proposal for the HGDP, the committee wrestled with the questions of what the HGDP is and who speaks on its behalf. To address the first of those questions the committee invited Luca Cavalli-Sforza, who has been an active supporter of the project, to describe the proposed survey, its aims, and the scientific issues that it addresses as he saw them. The committee then undertook the tasks of identifying persons whose experiences or known positions relative to the project were pertinent to the committee's charge, of examining the structure of the committee's final report, and of identifying subjects on which the committee would need to seek more information. At its second and third meetings, the committee continued its fact-finding and discussions. Various spokespersons were invited to present their views of the project. Both meetings also included sessions at which members of the public and spokespersons acting on the public's behalf were invited to discuss the issues with the committee. The fourth meeting was devoted to the completion of the report that follows. THE PROPOSED HUMAN GENOME DIVERSITY PROJECT In its fact-finding, it became apparent to the committee that the precise nature of the proposed survey was more elusive than the committee had initially envisioned; different participants in the formulation of its consensus document had quite different perceptions of the intent of the project and even of its organizational structure. The committee reviewed the ''consensus document" for the proposed Human Genome Diversity Project and was briefed by different participants involved in formulating the consensus document. It found there clearly was no sharply defined proposal that the committee could evaluate. However, because the consensus document addresses many of the issues—scientific, ethical, legal, and managerial—that any specific proposal must address, the committee sets out briefly the positions adopted in the consensus document and their rationale. The specifics of the HGDP grew out of 3 major workshops that were convened to examine the need for a global effort to characterize human variability and to plan the enterprise. The first—supported by NSF, NIGMS, the National Center for Human Genome Research, and the Department of Energy—took place at Stanford University in July 1992 and focused on the statistical issues associated with population sampling. The second, supported by the same agencies, took place at Pennsylvania State University in November 1992 and dealt exclusively with anthropologic issues. The last workshop—supported by the Porto Conte Research and Training Foundation, the European Commission, the Soros Foundation, and the Human Genome Organization Europe, in addition to the

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Evaluating Human Genetic Diversity aforementioned US agencies—was held in Porto Conte, Sardinia, in September 1993, at which time the views of some 80 participants were summarized in a consensus document that set forth the aims, rationale, value of, and guidelines for the design and scope of the proposed global survey. Briefly put, the proposed survey focuses on variation between rather than within human populations and has 2 major aims: to investigate differences in the human genome by studying samples collected from populations that represent all the world's peoples, and to create a resource for the benefit of all humanity and for the scientific community worldwide. The proposed resource would exist as a collection of samples representing the genetic variation in human populations and as an open, long-term genetic and statistical database on variation in the human species. The term "population" has many meanings; it is most often used to designate a body of persons (or other organisms) that have a common quality or characteristic, to designate a group of interbreeding organisms, or to designate a group of persons (or other organisms) that occupy a specific geographic locale. If language is used as the shared characteristic, over 5,000 human populations in the world have distinct properties and possibly distinct gene frequencies; these populations vary from tens of individuals to hundreds of millions. It is patently impractical to study all those populations, so some selection is inevitable. The planners of the proposed project recognize that any method of selection will be imperfect, is apt to be controversial, and could be divisive. Accordingly, they have focused their recommendations on the types of populations to be included in the survey rather than on the identification of specific human groups to be sampled. The types suggested are populations whose use can answer specific questions about the processes that have had a major influence on the composition of current ethnic groups, language groups, and cultures; populations that are anthropologically unique; populations that constitute linguistic isolates; populations that might be especially informative in identifying the genetic etiology of important diseases; and populations that are in danger of losing their identity as recognizably separate cultural, linguistic, or geographic groups of individuals. The planners do not specify a sampling strategy. They recognize that sampling might be opportunistic, might involve a grid approach if the population is relatively large and dispersed, might entail a stratified proportional approach, or might follow some other strategy. The primary goal, however, remains the same: to obtain a sample that represents the genetic variation in the population under study. The proponents of the proposal recognize that the number of persons sampled can vary, but they suggest that a minimum of 25 samples be obtained from each population studied, although their suggested norm is 150. Sample sizes may be even larger in some instances, particularly if the aim of the research is to study phenotype-genotype associations. The HGDP consensus document strongly recommends that all samples collected and studied be tested against a predefined core set of alleles or other

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Evaluating Human Genetic Diversity genetic markers. The planners recognize, however, that a much wider variety of other markers will eventually be studied, so they require that the choice of specimens and their method of collection provide for possible expansion of tested markers. The core set has not yet been identified at the time of this study, but the planners have examined the usefulness of classical markers, restriction fragment-length polymorphisms (RFLPs), minisatellites, Y-chromosome polymorphisms, and microsatellite loci. They recommend that emphasis be placed on polymerase chain reaction (PCR)-based systems to type polymorphic markers in as much as such systems are highly flexible, are portable, are fast, are amenable to automation, and can be conducted in a multiple-locus format. But the planners note that the choice of markers should also be contingent on other considerations, including that they are technically robust, can be determined in regional and local laboratories, and ideally can be detected with nonradioactive test components. Administratively, the implementation of the proposed project would entail the establishment and coordination of a number of regional activities and committees; some of the latter have already been constituted. However, the proposal does not make clear how centralized or dispersed the control of the database and specimen repository will be. Our committee believes that this is a potentially troublesome issue, given the number of polities and investigative groups that would be involved. Nonetheless, it clearly is important that the administrative structure be a flexible one that invites and encourages widespread participation in the project and that can adapt to new investigative groups as they develop the requisite skills and interest. The planners have noted that the proposed survey poses ethical and legal issues; to address these, the regional committees, especially the North American one, have formulated a series of model ethical protocols for collecting DNA samples. The protocols set out guidelines for finding and approaching study populations, for achieving informed consent, for providing benefits to the sample populations (including medical services), and for maintaining privacy and confidentiality of the information that is obtained. The protocols also address such matters as the ownership and control of the samples and the patenting and commercial use of specimen-derived information. Finally, the protocols strongly recommend that investigators establish partnerships with participating populations, including their involvement in planning and conducting the research and disseminating the results. THIS REPORT This report examines the scientific merits and value of research on human genetic or genomic variation and the organizational, policy, and ethical issues that such research poses in a more-general context than the proposed HGDP. Chapter 2 discusses the scientific basis and usefulness of a worldwide systematic survey of human genetic variation. Chapters 3 and 4 address technical and

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Evaluating Human Genetic Diversity logistical problems posed by such a project with respect to sampling design, obtaining and maintaining sufficient genetic material, access to research materials and information, and data handling. Chapter 5 examines ethical, legal, and social issues. Chapter 6 treats the organization of the project and research priorities.