Showing papers by "Bartha Maria Knoppers published in 2007"

A second generation human haplotype map of over 3.1 million SNPs

Abstract: We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.

Genome-wide detection and characterization of positive selection in human populations

Abstract: With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

Trends in ethical and legal frameworks for the use of human biobanks.

Abstract: Numerous studies of genetic epidemiology and post-genomics in respiratory diseases rely on the use of biobanks, defined as organised biological sample collections with associated personal and clinical data. The use of biobanks is increasing and raises several ethical issues. What are the ethical trends and legal frameworks in the post-genomic era? Are there new issues in relation to the developments of techniques and new study designs? How does this affect the clinician's attitudes and relationship with the patients? The main ethical issues encountered are: informed consent; confidentiality; secondary use of samples and data over time; return of results; and data sharing. Different levels and modalities of dealing with such issues are identified and vary from legally binding measures to "soft" regulations, such as ethical recommendations by various committees or professional organisations. A further level of complexity appears with the increasing international dimension of such activities in a context in which national positions vary on those topics. There is a tension between a necessary level of diversity in ethical positions and an indispensable common pedestal of principles and procedures to manage these issues in order to foster research. Current legal and ethical trends favour the facilitation of secondary use of samples, more biobank openness, balanced with a growing attention to dialogue and public/stakeholder consultation, an increased role for research ethics committees and more sophisticated data protection and governance structures.

Genomic Databases and International Collaboration

Abstract: Recent years have witnessed a key development within biomedicine—namely, the move from genetic to genomic research. Genomic research, which operates at the level of the whole genome rather than individual genes, requires a powerful new set of research tools, resources and supporting technologies. Having moved from DNA sequence mapping to the use of haplotypes, the next advances in our understanding of disease risk and health may well be achieved through the study of “normal” genomic variation across whole populations. Such studies require not only samples and data, but also highly sophisticated, substantial database infrastructures to support them. Longitudinal and largely epidemiological in nature, these population-scale genomic database resources are designed to serve a multiplicity of specific research projects at both national and international levels. Current ethical guidance in the area of genetic research promotes the need for international collaboration. Yet, is international genomic research coll...

Beyond the rhetoric: population genetics and benefit-sharing.

Abstract: 1. Background Information derived from the Human Genome Project (HGP) promises to inspire an array of future innovations with profound societal benefits. (1) Population genetic research is now viewed as a necessary next step in the evolution of research based on the human genome. (2) It is anticipated that projects will be developed in which the DNA from thousands of research subjects will be linked to medical records and to genealogical data; these complex databases will provide much needed insight into the etiology and prevention of many complex human diseases. Analyses of data procured in large-scale population genetic studies will enable researchers to gain a better understanding of the gene-environment interactions that are now implicated in cardiovascular diseases, metabolic disorders, musculoskeletal diseases, neuropsychiatric diseases and cancer. The completion of the sequencing phase of the HGP provides researchers: with an unparalleled opportunity to advance our understanding of the role of genetic factors in human health and disease, to allow more precise definition of the non-genetic factors involved, and to apply this insight rapidly into the prevention, diagnosis and treatment of disease.... [T]he time is right to develop and apply large-scale genomic strategies to empower improvements in human health, while anticipating and avoiding potential harm. (3) The challenge remains to justly translate the potential of the HGP into improved human health and well-being. (4) To facilitate the understanding of gene-environment interactions, numerous large-scale population genetic research studies have been commenced or are in the process of being developed. (5) Prospectively gathered and appropriately stored biological materials coupled with comprehensive measures of environmental exposure, phenotype and genotype will help researchers to confirm or refute existing assumptions about the interrelatedness of these factors. It is hoped that such new knowledge will facilitate the planning of health promotion and disease prevention at the level of populations as well as render adverse drug reactions predictable and avoidable based on an individual's genotype. (6) 1(a) The general concerns However, with this optimism about the long-term potential of population genetic research come numerous ethical, legal and social issues; concerns regarding individual and group consent, (7) ownership of human biologic materials (8), privacy and confidentiality, (9) genetic discrimination and stigmatization (10) and eugenics (11) have been repeatedly raised. Academic researchers focussing on the "ethical, legal and social issues" (ELSI) of the HGP have initiated much debate on these topics. It has been noted that failure to apply the highest ethical standards to population genetic studies could undermine public trust and confidence in scientific development and the products of medical research. (12) Moreover, the increased involvement of the private sector in human genetic and genomic research may promote secrecy amongst researchers, inhibit academic freedom, diminish the collaborative will of researchers and inappropriately shift the focus of research from basic discovery to commercializable end products. (13) 1(b) The particular problem of property Concepts of ownership, values, rights and sharing of knowledge vary from one culture to another, between political systems and between legal systems. These differences have particular relevance to the collection and banking of human biological samples: should they be characterized "person", "property", "sui-generis"--or not at all; should human genes be patentable; what is the legal status of linked and linkable databases? These questions have been imperfectly addressed. For example, no consensus exists as to who owns donated DNA samples. In the present age of globalization, it is important that these fundamental conceptual differences not be ignored. …

Stem Cell Research Ethics: Consensus Statement on Emerging Issues

Abstract: This article is a consensus statement by an international interdisciplinary group of academic experts and Canadian policy-makers on emerging ethical, legal and social issues in human embryonic stem cells (hESC) research in Canada. The process of researching consensus included consultations with key stakeholders in hESC research (regulations, stem cell researchers, and research ethics experts), preparation and distribution of background papers, and an international workshop held in Montreal in February 2007 to discuss the papers and debate recommendations. The recommendations provided in the consensus statement focus on issues of immediate relevance to Canadian policy-makers, including informed consent to hESC research, the use of fresh embryos in research, management of conflicts of interest, and the relevance of public opinion research to policy-making.

Understanding umbilical cord blood banking: what women need to know before deciding.

Abstract: U p b nformation about umbilical cord blood (UCB) banking is surfacing at a very rapid pace. The messages, argely targeted toward women, encourage motherso-be to bank their child’s UCB. Indeed, an everrowing number of Internet sites and magazine adertisements are cautioning women that storing a ewborn’s UCB is a once-in-a-lifetime opportunity nd a worthwhile investment that can save their child f it were to ever become necessary. Previously conidered as waste and discarded without second hought, the umbilical cord is now actively being ought for hematopoietic stem cell transplantation. tem cells harvested from UCB have successfully been sed to substitute for bone marrow as a source of ematopoietic stem cells for transplants in the treatent of genetic disease, blood malignancies, and mmune deficiencies. The promise of private banking, oupled with pleas from public banks asking mothers o donate UCB for altruistic purposes, can become uzzling for pregnant women. To allow them to make n informed choice about UCB banking, it is imporant that women receive complete and accurate inforation from their obstetrical care providers. The purose of this editorial is to raise awareness about UCB anking. Most important, it focuses on the importance f knowledge in the decision-making process. Women ho know more about UCB banking are more likely o make appropriate choices for both themselves and heir families.

Legal aspects of animal-human combinations in Canada

Abstract: This article examines the current legal regime applicable to animal-human combinations under the Assisted Human Reproduction Act (Canada). The Act prohibits as criminal offences the use of non-human reproductive material in humans, the use in humans of human reproductive material previously transplanted into a non-human life form, the creation of chimeras made from human embryos, and the creation for reproductive purposes of human/non-human hybrids. Additional animal-human combinations, such as transgenic life forms, may be regulated pursuant to section 11 of the Act in the future. The underlying concerns of the Act in establishing this regime appear to be the protection of human health and safety, human dignity and individuality, and the human genome. The Act seems calibrated to prohibit the creation of animal-human combinations that are currently unsafe and scientifically and ethically problematic, while leaving open the possibility of regulating other such combinations with more immediate scientific potential, although these also raise ethical questions. Currently, certain differences subsist in Canada between what is permissible for researchers and institutions funded by federal agencies and those in privately funded research. The development of the regulatory framework under the Act will reveal how freedom of research will be balanced against the need for scientifically valid and ethically justifiable research, and whether these differences will continue to apply.