Abstract: Background Nonsynonymous mutations in the coding regions of human genes are responsible for phenotypic differences between humans and for susceptibility to genetic disease. Computational methods were recently used to predict deleterious effects of nonsynonymous human mutations and polymorphisms. Here we focus on understanding the amino-acid mutation spectrum of human genetic disease. We compare the disease spectrum to the spectra of mutual amino-acid mutation frequencies, non-disease polymorphisms in human genes, and substitutions fixed between species.

Abstract: Preface Lemonade The Cell DNA & the Genetic Code Epigenesis & Genetic Regulation Mendelian Traits & Behavior DCG: Disorders with Complex Genetics The New Genetics: Techniques for DNA Analysis Chromosomes & Chromosomal Anomalies Mendel Morgan & Linkage The Association Study Introduction to Module 2: Evolution The Five Forces Behind Human Evolution Human Evolution Introduction to Evolutionary Psychology Principles of Evolutionary Psychology Introduction to Module 3: Individual Differences Quantitative Genetics I: Important Concepts Quantitative II: Estimation & Testing Genes, IQ Scores, & Social Status: I. The Phenotype of IQ Genes, IQ Scores, & Social Status: II. Genetic Epidemiology Personality Schizophrenia Antisocial Behavior & Violence

Abstract: The renin-angiotensin system plays a central role in the pathogenesis of cardiovascular disease. At the molecular and cellular levels, angiotensin II, the main effector peptide of the system, stimulates key components of atherosclerosis. Trials in animals and humans indicate that blocking renin-angiotensin system pathways decreases atherosclerotic plaque progression and ischemic events. This review provides a broad overview of the entire role of the renin-angiotensin system in atherothrombotic disease, ranging from molecular pathways to human genetics to the latest clinical trials.

Abstract: Truly 'personalized' medicine remains a distant goal. But researchers are now thinking about how to use genomic data to avoid prescribing drugs that may kill, or won't work. Alison Abbott reports.

Abstract: Sirs, Parkinson’s disease (PD) is a neurodegenerative disorder, clinically characterized by a triad of rigidity, resting tremor, and bradykinesia. To date, mutations in four separate PD genes have been identified: the genes for alpha-synuclein and for ubiquitin C-terminal hydrolase L1 both cause autosomal dominant forms of PD, whereas mutations in the parkin gene and DJ-1 are associated with early onset recessive parkinsonism [1, 2]. Recently, two variants (-245T!G and 291Tdel) in exon1 of the NR4A2 gene were identified in 2 and 8 patients, respectively of 107 patients with familial PD [3]. Neither of these two variants was found in 94 sporadic PD patients or age-matched controls (n=221). NR4A2 is a member of the superfamily of “zinc finger” transcription factors and has been shown to be an absolute requirement for the development of dopaminergic neurons [4]. Although both described variants are located in the 5́UTR of exon 1 and do not change the amino acid composition of the protein, they resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals. We aimed to replicate this study by sequencing exon 1 of 44 cases of familial PD. All index patients of Caucasian ethnicity were diagnosed with PD according to United Kingdom brain bank criteria. The mean age at onset was 58€9.3 years (range 35–73 years). Family history was regarded positive in all cases, since levodopa-responsive rest tremor and/or hyopkinetic symptoms were reported in at least one first-degree relative (sibling or parent). Of 44 cases (32 male, 12 female), 14 had one or more affected siblings and 30 showed a parent-child transmission. All patients were parkin negative. A 269-bp PCR fragment of NR4A2 exon 1 was generated and directly sequenced using genomic DNA (NR4A2Ex1F: cgc aag cca cat aaa caa ag and Nurrex1R: act gca tgg gct gca tct act). Neither the 291Tdel nor the 245T!G mutation occurred in any of our PD patients. No other sequence variants relative to the published sequence in the exon 1 region were identified. The mutations found by Le et al. [3] were present in a heterozygous state, suggesting an autosomal dominant transmission. Therefore the most-significant result in our study was that no mutations were found in the 30 families with known parent-child transmission. The 14 affected siblings might either be associated with recessive mutations or with a dominant inheritance with reduced penetrance. Our findings show that sequence alterations in exon 1 of the NR4A2 gene are not a major cause of familial PD in central Europe. The NR4A2 mutations associated with familial PD reported by Le et al. [3] are apparently caused by strong A. Zimprich · F. Asmus · P. Leitner · T. Gasser ()) Center of Neurology, University of Tuebingen, Department of Neurology and Hertie-Institute of Clinical Brain Research, Section for Neurodegenerative Diseases, Hoppe-Seyler Strasse 3, 72076 Tuebingen, Germany e-mail: Thomas.Gasser@med.uni-tuebingen.de Tel.: +49-7071-2986529 Fax: +49-7071-294839

Abstract: It is estimated that between 10-20% of amyotrophic lateral sclerosis (ALS) is familial and these cases encompass recessive and dominant modes of inheritance. So far, mutations in three genes, superoxide dismutase 1 (SOD1), the p150 subunit of dynactin (DCTN1), and alsin have been shown to be directly causal for motor neuron degeneration in humans. However, clearly the disorder is genetically heterogeneous and other causal genes remain to be found that explain the vast majority of familial ALS cases. Human genetics can be problematical in that it is difficult to detect linkage in disorders in which multiple loci give similar phenotypes and where families are often small. In addition, the vertical collection of generations is often not possible with late onset disorders. An excellent genetic model of humans is provided by the mouse. We can use mouse models of neurodegeneration to find new genes in the human population. These models are not exact replicas of the human condition, but are the mouse equivalent and are incredibly valuable resources for highlighting genes and biochemical pathways disrupted in ALS and other diseases. In addition mouse models give us access to both control and affected tissues, at all stages of development and disease, thus greatly facilitating our understanding of pathogenesis. They also provide us with model systems for testing new therapies. Here we describe the approach taken to the characterization of new models of motor neuron disease and illustrate this with examples, including a recently characterized mouse model, Legs at odd angles (Loa).

Abstract: Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons characterized by progressive paralysis leading to death, usually within 3–5 years. About 10% of cases are familial and autosomal dominant. Until recently, only one gene (Cu/Zn superoxide dismutase or SOD1) was known to be mutated in ALS, with mutations accounting for 20% of familial cases [1]. For sporadic cases, various studies have shown between 2% and 7% have mutations in SOD1 [2, 3]. A recessive form of the disease with onset usually by the early teens, prominent corticobulbar and corticospinal involvement, and slow progression was recently associated with mutations in a novel ALS2 gene on chromosome 2 [4, 5]. Seven mutations have been reported so far, initially in inbred families, but more recently also from families with no apparent consanguinuity. This, coupled with the knowledge that SOD1 mutations may be a cause of sporadic disease, has led to speculation that compound heterozygosity for ALS2 mutant alleles is also a cryptic cause of sporadic ALS. If ALS2 mutant alleles had a frequency as low as 0.001 (q) in the general population, individuals homozygous for ALS2 mutations would still comprise 1 per million people (q2), potentially accounting for about 10% of sporadic ALS. We have tested this hypothesis by direct sequencing of individuals with a phenotype sharing some features with the original ALS2 families and by searching for variants associated with increased risk in an allelic association study using DNA pooling [6] in a sporadic ALS population. We sequenced 6 cases from the United Kingdom and 6 from the United States for all 34 exons of the ALS2 gene. Mean age of onset was 29 years. One person had a very young age of onset of 7 years. One patient had died after 4 years; the rest were alive with a median disease duration of 8 years. Three people had disease confined to the upper motor neurons (primary lateral sclerosis variant of motor neuron disease). We identified 21 variants in the ALS2 gene. These include 18 different single nucleotide polymorphisms (SNPs), of which 5 were exonic and 13 intronic, as well as 3 variants that were not SNPs (Table 1). All but one were conservative (1102 g>a, V368 M in exon 4, within blade 4 of the RCC1 propeller, previously reported and representing a conservative amino acid substitution [4, 5]). Eleven variants that were rare or uninformative were eliminated. The remaining 10 variants were analyzed for co-association using the program EH Plus [7]. This revealed a core set of 4 variants that were strongly coassociated (P<0.0001), extending from intron 10 to the end of intron 25 (33 kilobases). For DNA pooling, there were 300 ALS cases and 300 exactly ageand sex-matched controls. The sample was typical of sporadic ALS, with a mean age of onset of 56.3 years (range 26.4–80.9 years, SD 12.6), a 3:2 ratio of A. Al-Chalabi · J. Xi · B. A. Hosler · D. McKenna-Yasek · R. H. Brown Jr Cecil B. Day Laboratory for Neuromuscular Research, Massachusetts General Hospital, MGH East, Building 114, 16th Street, Charlestown, MA 02129, USA

Abstract: The advances in reproductive biology that have made it possible to produce human preembryos in vitro have been among the most significant scientific achievements of the past 25 years. For many couples who were previously considered sterile, the emergence of these new techniques to alleviate infertility has offered new opportunities to conceive. Moreover, although there is a wide variation in standards, patient selection criteria, and treatment protocols, assisted reproduction technology (ART) has become a routine tool in the treatment of infertile couples. After the initial enthusiasm, however, in many countries, society realized that, concomitant with the great advances, limitations had to be established on this new technology of human reproduction (1). Alongside the scientific achievement, a public debate has been held in many countries concerning questions such as the setting up of regulation or legislation, the right to ART treatment, the cost of assisted conception, resource availability, who should control the quality of ART practice and how, and whether donation of genetic material should be practiced. The development of new methods of ART, including micromanipulation, preimplantation diagnosis, genetic manipulation, therapeutic cloning, and stem cell research, continues to provide major breakthroughs not only in the treatment of infertile couples but also in future medical practice. Since we are deal-

Abstract: The ability to predict the genetic consequences for humans of exposure to ionising radiation has certainly been one of the most important goals of human genetics in the past fifty years. However, despite numerous experimental studies, little is known about the effects of radiation exposure on germline mutation in humans. For example, data collected in Hiroshima and Nagasaki during the past 40 years on children of atomic bomb survivors using standard monitoring systems have not provided evidence of any statistically signifycant differences in mutation rate between exposed and control families (Neel at al., 1990). Similarly, a survey of survivors treated with radiotherapy showed that the occurrence of genetic diseases in their offspring was similar to that in control families (Byrne et al, 1998). For this reason, germline mutation induction in mice still remains the main source of experimental data used to evaluate the genetic risk of human exposure to ionising radiation (UNCEAR, 1993; Sankaranarayanan and Chakraborty, 2000).

Abstract: with being a committed social activist, and even fewer are able to do this successfully. Jon Beckwith is one of these very few and this makes the account of his life both fascinating and important. Beckwith traces the different strands of his life and career step by step, coinciding with and making contributions to the formative years of basic molecular genetics and their later applications in human genetics. Reassuringly, he does not emerge as someone with clear goals or inspiration from the beginning, but as hesitant, with major steps in his career often dependent on chance, and at times torn between science and other careers as a result of his broad interests. With his career in bacterial genetics well established after becoming the first person to isolate a gene, the conflicts caused by his growing awareness and involvement in radical social issues are vividly and honestly described, requiring a continual and not always successful balancing act to keep both parts of his life in harmony, and considerable courage in the face of opposition from the scientific establishment. Although Beckwith has never worked directly in human molecular genetics, he has played a key role in creating awareness of its implications for wider society and it is here that the value of this book lies for those of us in the field, whether scientists or clinicians. Repeatedly, he has seen the potential for future misuse of new advances at a time when most scientists were denying the possibility of this, frequently coming under criticism for obstructing scientific progress. He has equally taken the lead in opposing applications or views that have over-promoted the contribution of genetics, notably in relation to behaviour genetics and “sociobiology”, showing how frequently politicians and others have built social abuses on these false or flimsy scientific foundations, and how these fields have often reflected the personal prejudices of their proponents. All this makes fascinating reading but the real importance of Beckwith’s book is that the same problems are still happening today – the same sweeping claims based on inadequate foundations, the same prejudices of scientists and the same distortions by politicians and others. Yet, most workers in genetics still prefer to keep their heads down and hope that the issues will go away. I would put this book, along with Benno Muller-Hill’s “Murderous Science”, as obligatory reading for anyone planning a career in science. Most of us will not have Beckwith’s ability, nor his determination and courage, to make a successful long-term combination of research and social commitment but his book has almost certainly helped to guard our society from abuses of science, whether from genetics or elsewhere, by opening the eyes of many who would otherwise have remained unaware or silent; people like him will be needed in the future as much as, or even more than, in the past. Peter S. Harper

Abstract: A new effort to map human genetic variation should provide a shortcut for researchers trying to uncover the roots of disease. Carina Dennis profiles the 'HapMap' project.

Abstract: The autosomal gene pool of Yakuts was analyzed with a panel of polymorphic Alu insertions. The observed allele frequencies were typical for other Asian ethnic groups. Genetic differentiation of three Yakut populations was relatively high, 2%. East Siberian ethnic groups were shown to have a common gene pool and to experience no intense gene flow from other populations. Development of the Yakut gene pool was assumed to involve no substantial genetic effect of neighboring populations. The results fit both autochthonous and southern origin hypotheses.

Abstract: Mutations in ion-transport proteins can destabilize the electrical activity of the heart, causing sudden death. It now seems that mutations in a protein that anchors ion transporters to cell membranes can have the same effect.

Abstract: [The basis of Christian ethics is a balance of the doctrines of creation, sin, redemption, and fulfillment which are at the heart of all human situations. Applying these four doctrines to human genetics leads to: recognizing a creative human role that respects the inner constitution of the human creature; being alert to the human capacity to misuse God's gifts and creatures; welcoming the opportunity to extend God's healing power in history; and promoting human solidarity in the application of genetic development for the common good.]

Abstract: A solution to get the problem off, have you found it? Really? What kind of solution do you resolve the problem? From what sources? Well, there are so many questions that we utter every day. No matter how you will get the solution, it will mean better. You can take the reference from some books. And the par for the course is one book that we really recommend you to read, to get more solutions in solving this problem.

Abstract: A resumptive review of the three types of effects of new environmental factors on human heredity is presented: 1) alteration of hereditary elements (induced mutagenesis); 2) pathological manifestations of gene expression on the specific environmental factors (ecogenetic diseases, pharmacogenetics, toxicogenomics, nutrigenomics); 3) alteration of the population gene pool as a result of disturbance of genetic balance between mutation process and selection. The following thesis is proving: in spite of severity and seriousness of current problems of ecological human genetics, the decision can be made on the basis of fundamental sciences advances and technological progress.

Abstract: The new hybrid-electric cars have generated quite a buzz from the automobile industry, investors, manufacturers and even the general public as we move toward more fuel effecient vehicles. The excitement grew this past year after one car surpassed 100,000 miles on a test track — all powered by the lead-acid battery system. Researchers in Australia have developed what has been called “a lead-acid battery on steroids”: The UltraBattery.

Abstract: A report on the Sixth International Meeting of the Microarray Gene Expression Data Society ('MGED6'), Aix-en-Provence, France, 6-8 September 2003.

Abstract: Genome-wide studies of transcription in the skeletal muscle of type 2 diabetic patients have identified coordinated changes in the expression of genes involved in oxidative phosphorylation, and have underlined the central role of the oxidative-phosphorylation regulator, PCG1α. These findings help unravel the complex pathogenesis and inheritance of polygenic type 2 diabetes mellitus.

Abstract: Received November 5, 2002; accepted for publicationNovember14, 2002; electronically published January 23, 2003.Address for correspondence and reprints: Dr. Albert de la Cha-pelle, Human Cancer Genetics Program, 646 Tzagournis MedicalResearch Facility, 420 West 12th Avenue, Columbus, OH 43210.E-mail: delachapelle-1@medctr.osu.edu* Previously presented at the annual meeting of The AmericanSociety of Human Genetics, in Baltimore, on October 18, 2002.