Isochores Merit the Prefix 'Iso'

The isochore concept in human genome sequence was challenged in an analysis by the International Human Genome Sequencing Consortium (IHGSC). We argue here that a statement in IGHSC analysis concerning the existence of isochore is incorrect, because it had applied an inappropriate statistical test. To test the existence of isochores should be equivalent to a test of homogeneity of windowed GC%. The statistical test applied in the IHGSC's analysis, the binomial test, is however a test of a sequence being random on the base level. For testing the existence of isochore, or homogeneity in GC%, we propose to use another statistical test: the analysis of variance (ANOVA). It can be shown that DNA sequences that are rejected by binomial test may not be rejected by the ANOVA test.Comment: 14 pages (including 1 figure), submitte

NIH Data and Resource Sharing, Data Release and Intellectual Property Policies for Genomics Community Resource Projects

Most observers predict significant health-related gains from genomics research. Policy and legal decisions made by government institutions, the courts and legislatures have the potential to make a significant impact on both the quantity and quality of effective and innovative healthcare-related products ultimately derived from the vibrant genomics research enterprise. In particular, the careful management of the intellectual property (IP) aspects of this promising area of research will be necessary to maximise scientific progress, provide appropriate incentives for investment, and ultimately ensure optimal public benefit. It is the mission of the US National Institutes of Health (NIH), which is comprised of 27 individual institutes and is an agency of the US Department of Health and Human Services, to facilitate the translation of basic biomedical research discoveries into useful healthcare services and products. Within the NIH, the National Human Genome Research Institute (NHGRI) is the agency’s lead entity for advancing human health through genetic research.Through its stewardship of an array of infrastructure and research projects, including several innovative public-private consortia efforts, the NHGRI seeks to contribute to the genomic tools, data and knowledge bases. In general, I believe that scientific progress in this still young field will be best served by early, open and continuing access to: i) comprehensive, high-quality data sets containing basic biological and biochemical data; and ii) critical biological materials such as animal models and genes. Data such as the complete nucleotide sequence of many different organisms’ genomes, information on genetic variation within and among populations, and results on how gene expression is regulated at the cellular and molecular level are often referred to as ‘precompetitive’ information, and in my view should be made rapidly available to all, without restrictions on use. Adherence by data and resource producers and users to this simple strategy should ensure that industry and academic researchers will be able to build upon this strong foundation. At the NIH we are expected to support basic scientific discovery whilst simultaneously facilitating the appropriate commercial research and development of the results of our formidable research programs. A sizeable number of end users for these resource projects are employed with private sector companies. For this constituency the terms governing the data use, data release, the sharing and distribution of research resources and intellectual property rights of derivative inventions are of particular importance. Policies that limit companies’ ability to file patent applications or licence downstream uses could end up having an unintended inhibitory effect on the development of biomedical products. Government policies need to balance the important dual goals of continuing to rapidly place huge amounts of data in the public domain and encouraging restriction-free sharing of genomic tools, whilst also ensuring that more applied inventions, notably those closer to being an actual product, can be patented. US taxpayers, and especially patients, would like the government to appropriately foster the commercialisation of promising inventions derived from use of the data and reagents generated by these efforts. Currently, the NHGRI is actively involved in the development and vetting of policy options aimed at ensuring that genomic tools, resources and databases of genomic information are used in a manner that promotes scientific research and the practice of medicine. Relevant policies implemented by NIH-supported public private consortia efforts such the International Human Genome Sequencing Consortium (IHGSC),2 the Trans-NIH Mouse Initiative,3 the Mammalian Gene Collection (MGC)4 and the International Haplotype Map Project (HapMap)5 are specifically covered in this review

NIH Data and Resource Sharing, Data Release and Intellectual Property Policies for Genomics Community Resource Projects

Most observers predict significant health-related gains from genomics research. Policy and legal decisions made by government institutions, the courts and legislatures have the potential to make a significant impact on both the quantity and quality of effective and innovative healthcare-related products ultimately derived from the vibrant genomics research enterprise. In particular, the careful management of the intellectual property (IP) aspects of this promising area of research will be necessary to maximise scientific progress, provide appropriate incentives for investment, and ultimately ensure optimal public benefit. It is the mission of the US National Institutes of Health (NIH), which is comprised of 27 individual institutes and is an agency of the US Department of Health and Human Services, to facilitate the translation of basic biomedical research discoveries into useful healthcare services and products. Within the NIH, the National Human Genome Research Institute (NHGRI) is the agency’s lead entity for advancing human health through genetic research.Through its stewardship of an array of infrastructure and research projects, including several innovative public-private consortia efforts, the NHGRI seeks to contribute to the genomic tools, data and knowledge bases. In general, I believe that scientific progress in this still young field will be best served by early, open and continuing access to: i) comprehensive, high-quality data sets containing basic biological and biochemical data; and ii) critical biological materials such as animal models and genes. Data such as the complete nucleotide sequence of many different organisms’ genomes, information on genetic variation within and among populations, and results on how gene expression is regulated at the cellular and molecular level are often referred to as ‘precompetitive’ information, and in my view should be made rapidly available to all, without restrictions on use. Adherence by data and resource producers and users to this simple strategy should ensure that industry and academic researchers will be able to build upon this strong foundation. At the NIH we are expected to support basic scientific discovery whilst simultaneously facilitating the appropriate commercial research and development of the results of our formidable research programs. A sizeable number of end users for these resource projects are employed with private sector companies. For this constituency the terms governing the data use, data release, the sharing and distribution of research resources and intellectual property rights of derivative inventions are of particular importance. Policies that limit companies’ ability to file patent applications or licence downstream uses could end up having an unintended inhibitory effect on the development of biomedical products. Government policies need to balance the important dual goals of continuing to rapidly place huge amounts of data in the public domain and encouraging restriction-free sharing of genomic tools, whilst also ensuring that more applied inventions, notably those closer to being an actual product, can be patented. US taxpayers, and especially patients, would like the government to appropriately foster the commercialisation of promising inventions derived from use of the data and reagents generated by these efforts. Currently, the NHGRI is actively involved in the development and vetting of policy options aimed at ensuring that genomic tools, resources and databases of genomic information are used in a manner that promotes scientific research and the practice of medicine. Relevant policies implemented by NIH-supported public private consortia efforts such the International Human Genome Sequencing Consortium (IHGSC),2 the Trans-NIH Mouse Initiative,3 the Mammalian Gene Collection (MGC)4 and the International Haplotype Map Project (HapMap)5 are specifically covered in this review

The Distributions of "New" and "Old" Alu Sequences in the Human Genome: The Solution of a "Mystery"

The distribution in the human genome of the largest family of mobile elements, the Alu sequences, has been investigated for the past 30 years, and the vast majority of Alu sequences were shown to have the highest density in GC-rich isochores. Ten years ago, it was discovered, however, that the small ''youngest'' (most recently transposed) Alu families had a strikingly different distribution compared with the ''old'' families. This raised the question as to how this change took place in evolution. We solved what was considered to be a ''mystery'' by 1) revisiting our previous results on the integration and stability of retroviral sequences, and 2) assessing the densities of acceptor sites TTTT/AA in isochore families. We could conclude 1) that the open state of chromatin structure plays a crucial role in allowing not only the initial integration of retroviral sequences but also that of the youngest Alu sequences, and 2) that the distribution of old Alus can be explained as due to Alu sequences being unstable in the GC-poor isochores but stable in the compositionally matching GC-rich isochores, again in line with what happens in the case of retroviral sequences

How is the Human Pangenome Project Like a Whole Person Psychology? (Editor’s Introduction)

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The Nobel Prize as a Reward Mechanism in the Genomics Era: Anonymous Researchers, Visible Managers and the Ethics of Excellence

The Human Genome Project (HGP) is regarded by many as one of the major scientific achievements in recent science history, a large-scale endeavour that is changing the way in which biomedical research is done and expected, moreover, to yield considerable benefit for society. Thus, since the completion of the human genome sequencing effort, a debate has emerged over the question whether this effort merits to be awarded a Nobel Prize and if so, who should be the one(s) to receive it, as (according to current procedures) no more than three individuals can be selected. In this article, the HGP is taken as a case study to consider the ethical question to what extent it is still possible, in an era of big science, of large-scale consortia and global team work, to acknowledge and reward individual contributions to important breakthroughs in biomedical fields. Is it still viable to single out individuals for their decisive contributions in order to reward them in a fair and convincing way? Whereas the concept of the Nobel prize as such seems to reflect an archetypical view of scientists as solitary researchers who, at a certain point in their careers, make their one decisive discovery, this vision has proven to be problematic from the very outset. Already during the first decade of the Nobel era, Ivan Pavlov was denied the Prize several times before finally receiving it, on the basis of the argument that he had been active as a research manager (a designer and supervisor of research projects) rather than as a researcher himself. The question then is whether, in the case of the HGP, a research effort that involved the contributions of hundreds or even thousands of researchers worldwide, it is still possible to “individualise” the Prize? The “HGP Nobel Prize problem” is regarded as an exemplary issue in current research ethics, highlighting a number of quandaries and trends involved in contemporary life science research practices more broadly

Computational comparison of human genomic sequence assemblies for a region of chromosome 4

Much of the available human genomic sequence data exist in a fragmentary draft state following the completion of the initial high-volume sequencing performed by the International Human Genome Sequencing Consortium (IHGSC) and Celera Genomics (CG). We compared six draft genome assemblies over a region of chromosome 4p (D4S394–D4S403), two consecutive releases by the IHGSC at University of California, Santa Cruz (UCSC), two consecutive releases from the National Centre for Biotechnology Information (NCBI), the public release from CG, and a hybrid assembly we have produced using IHGSC and CG sequence data. This region presents particular problems for genomic sequence assembly algorithms as it contains a large tandem repeat and is sparsely covered by draft sequences. The six assemblies differed both in terms of their relative coverage of sequence data from the region and in their estimated rates of misassembly. The CG assembly method attained the lowest level of misassembly, whereas NCBI and UCSC assemblies had the highest levels of coverage. All assemblies examined included <60% of the publicly available sequence from the region. At least 6% of the sequence data within the CG assembly for the D4S394–D4S403 region was not present in publicly available sequence data. We also show that even in a problematic region, existing software tools can be used with high-quality mapping data to produce genomic sequence contigs with a low rate of rearrangements. [All sequence accessions for the genomic sequence assemblies analyzed and the data sets used to assess coverage and rates of misassembly are available from http://www.ed.ac.uk/∼csemple.

Compositional Analysis of Homogeneous Regions in Human Genomic DNA

Due to increased production of human DNA sequence, it is now possible to explore and understand human genomic organization at the sequence level. In particular, we have studied one of the major organizational components of vertebrate genome organization previously described as isochores (Bernardi, 1993), which are compositionally homogeneous DNA segments based on G+C content. We have examined sequence data for the existence of compositionally differing regions and report that while compositionally homogeneous regions are present in the human genome, current isochore classification schemes are too brad for sequence-level data