Fragile X and X-linked intellectual disability: four decades of discovery.

X-Linked intellectual disability (XLID) accounts for 5%-10% of intellectual disability in males. Over 150 syndromes, the most common of which is the fragile X syndrome, have been described. A large number of families with nonsyndromal XLID, 95 of which have been regionally mapped, have been described as well. Mutations in 102 X-linked genes have been associated with 81 of these XLID syndromes and with 35 of the regionally mapped families with nonsyndromal XLID. Identification of these genes has enabled considerable reclassification and better understanding of the biological basis of XLID. At the same time, it has improved the clinical diagnosis of XLID and allowed for carrier detection and prevention strategies through gamete donation, prenatal diagnosis, and genetic counseling. Progress in delineating XLID has far outpaced the efforts to understand the genetic basis for autosomal intellectual disability. In large measure, this has been because of the relative ease of identifying families with XLID and finding the responsible mutations, as well as the determined and interactive efforts of a small group of researchers worldwide.

The birth of classical genetics as the junction of two disciplines: conceptual change as representational change.

The birth of classical genetics in the 1910's was the result of the junction of two modes of analysis, corresponding to two disciplines: Mendelism and cytology. The goal of this paper is to shed some light on the change undergone by the science of heredity at the time, and to emphasize the subtlety of the conceptual articulation of Mendelian and cytological hypotheses within classical genetics. As a way to contribute to understanding how the junction of the two disciplines at play gave birth to a new way of studying heredity, my focus will be on the forms of representation used in genetics research at the time. More particularly, I will study the design and development, by Thomas H. Morgan's group, of the technique of linkage mapping, which embodies the integration of the Mendelian and cytological forms of representation. I will show that the design of this technique resulted in a genuine conceptual change, which should be described as a representational change, rather than merely as the introduction of new hypotheses into genetics.

A brief history of Drosophila's contributions to genome research.

The sequence of the Drosophila melanogaster genome presented in this issue of Science is the latest milestone in nine decades of research on this organism. Genetic and physical mapping, whole-genome mutational screens, and functional alteration of the genome by gene transfer were pioneered in metazoans with the use of this small fruit fly. Here we look at some of the instances in which work on Drosophila has led to major conceptual or technical breakthroughs in our understanding of animal genomes.

Mapping Genes Is Good for You.

I abandoned my original career choice of high school teaching to pursue dentistry and soon abandoned that path for genetics. The latter decision was due to a challenge by a professor that led to me reading Nobel speeches by pioneer geneticists before I had formal exposure to the subject. Even then, I was 15 years into my career before my interest in rodent genomes gave way to mapping cattle genes. Events behind these twists and turns in my career path comprise the first part of this review. The remainder is a review of the development of the field of bovine genomics from my personal perspective. I have had the pleasure of working with outstanding graduate students, postdocs, and colleagues to contribute my small part to a discipline that has evolved from a few individuals mapping an orphan genome to a discipline underlying a revolution in animal breeding.

Restriction enzymes and their use in molecular biology: An overview.

Restriction enzymes have been identified in the early 1950s of the past century and have quickly become key players in the molecular biology of DNA. Forty years ago, the scientists whose pioneering work had explored the activity and sequence specificity of these enzymes, contributing to the definition of their enormous potential as tools for DNA characterization, mapping and manipulation, were awarded the Nobel Prize. In this short review, we celebrate the history of these enzymes in the light of their many different uses, as these proteins have accompanied the history of DNA for over 50 years representing active witnesses of major steps in the field.

Veterinary cytogenetics: past and perspective.

Cytogenetics was conceived in the late 1800s and nurtured through the early 1900s by discoveries pointing to the chromosomal basis of inheritance. The relevance of chromosomes to human health and disease was realized more than half a century later when improvements in techniques facilitated unequivocal chromosome delineation. Veterinary cytogenetics has benefited from the information generated in human cytogenetics which, in turn, owes its theoretical and technical advancement to data gathered from plants, insects and laboratory mammals. The scope of this science has moved from the structure and number of chromosomes to molecular cytogenetics for use in research or for diagnostic and prognostic purposes including comparative genomic hybridization arrays, single nucleotide polymorphism array-based karyotyping and automated systems for counting the results of standard FISH preparations. Even though the counterparts to a variety of human diseases and disorders are seen in domestic animals, clinical applications of veterinary cytogenetics will be less well exploited mainly because of the cost-driven nature of demand on diagnosis and treatment which often out-weigh emotional and sentimental attachments. An area where the potential of veterinary cytogenetics will be fully exploited is reproduction since an inherited aberration that impacts on reproductive efficiency can compromise the success achieved over the years in animal breeding. It is gratifying to note that such aberrations can now be tracked and tackled using sophisticated cytogenetic tools already commercially available for RNA expression analysis, chromatin immunoprecipitation, or comparative genomic hybridization using custom-made microarray platforms that allow the construction of microarrays that match veterinary cytogenetic needs, be it for research or for clinical applications. Judging from the technical refinements already accomplished in veterinary cytogenetics since the 1960s, it is clear that the importance of the achievements to date are bound to be matched or out-weighed by what awaits to be accomplished in the not-too-far future.

How the worm was won. The C. elegans genome sequencing project.

The genome sequence of the free-living nematode Caenorhabditis elegans is nearly complete, with resolution of the final difficult regions expected over the next few months. This will represent the first genome of a multicellular organism to be sequenced to completion. The genome is approximately 97 Mb in total, and encodes more than 19,099 proteins, considerably more than expected before sequencing began. The sequencing project--a collaboration between the Genome Sequencing Center in St Louis and the Sanger Centre in Hinxton--has lasted eight years, with the majority of the sequence generated in the past four years. Analysis of the genome sequence is just beginning and represents an effort that will undoubtedly last more than another decade. However, some interesting findings are already apparent, indicating that the scope of the project, the approach taken, and the usefulness of having the genetic blueprint for this small organism have been well worth the effort.

A history of association mapping.

The current exciting developments in association mapping are founded on theory, which has been developed since the beginning of the last century. I hereby review these developments in their historical context.

Arabidopsis, the botanical Drosophila: from mouse cress to model organism.

The small flowering plant Arabidopsis thaliana is the best-studied model organism in plant biology. More resources are allocated to research on this little weed than to the study of well-known favourites such as worms, fruit flies and mice. Yet, up to the early 1980s plant biologists had every good reason to ignore Arabidopsis: neither did it seem to possess the characteristics of a good model organism, nor did it have any agricultural promise. The sudden prestige acquired by Arabidopsis research thus constitutes a remarkable historical puzzle. What made the mouse cress into the most successful model organism to date?

Mapping and sequencing information: the social context for the genomics revolution.

In 1983, after devoting some eight years of his life to the description of how a nematode worm develops from an embryo into an adult, molecular biologist John Sulston embarked on a remarkably different project: he decided to map the worm's genome. Sulston's impulsive desire to characterise this creature's DNA from start to finish offers only a partial explanation for this transition. Instead, a close examination of the wider social context for this 'moment' in molecular biology gives a more rewarding explanation of Sulston's intellectual leap. This reveals a world in which biotechnology gradually adapted to and integrated into an 'information society' increasingly dependent on the creation, distribution and manipulation of information. The application of computing to DNA during the first half of the 1980s was crucial for this integration, fostering the emergence of genomics and ultimately the Human Genome Project.

The human genome project: a historical perspective.

Efforts in genomics over the last decade have created a stream of opportunities for drug discovery. High-throughput DNA sequencing has forced a re-definition of the paradigm for identification and validation of targets for drug development. One purpose of this review is to delineate the different approaches to sequence data generation and to establish their various uses for the definition of gene function. There still remain crucial dilemmas for the pharmaceutical industry. The multitude of potential targets can each absorb enormous validation costs and the vast majority are likely to prove academically interesting but useless for drug development. An additional dimension arises from the importance of sequence variation between different individuals. These differences can determine response to therapy and must inform both the drug development process and healthcare delivery. This presents great challenges and opportunities for drug companies, their customers and society as a whole. I will review the technological aspects in some detail and give my view of the legal and social aspects. The field of bioinformatics is at the core of functional and pharmacogenomics and advances will depend on the continuing evolution of tools to interpret data. For the most part this evolution is reviewed in the context of specific application areas rather than as a discrete field, in recognition of its all-pervasive effects.

[Development of mammalian somatic cell genetics]. / Stanovlenie genetiki somaticheskikh kletok mlekopitaiushchikh.

The history of somatic cell genetics from the late 1950s to the present day is considered. Studies in this field provided for the elucidation of numerous fundamental and applied problems, including spontaneous mutagenesis, gene mapping with somatic cell hybrids, and genetic mechanisms of carcinogenesis (e.g., cell protooncogenes, oncogenes, and tumor suppressor genes were revealed). The knocking-out technique allowed the effects of various genes to be analyzed.

Sequencing the genome from nematode to human: changing methods, changing science.

The history of science tends to be recounted as a story of progress from early goals and discoveries to a unified outcome, in some sense implicit from the beginning, and often due to technological advances. The sequencing of the human genome is no exception. As a crucial part of the Human Genome Project, the history of genomic sequencing is typically presented as a direct result of the discoveries of the structure of DNA and its coding function, together with practical factors such as the development of techniques which made large-scale sequencing possible. However, the history of sequencing is inevitably a more complicated story, not only about molecular biology, but also about the evolving culture of scientific practice at the end of the 20th century.