David Gurwitz

The genome-wide structure of the Jewish people

Contemporary Jews comprise an aggregate of ethno-religious communities whose worldwide members identify with each other through various shared religious, historical and cultural traditions. Historical evidence suggests common origins in the Middle East, followed by migrations leading to the establishment of communities of Jews in Europe, Africa and Asia, in what is termed the Jewish Diaspora. This complex demographic history imposes special challenges in attempting to address the genetic structure of the Jewish people. Although many genetic studies have shed light on Jewish origins and on diseases prevalent among Jewish communities, including studies focusing on uniparentally and biparentally inherited markers, genome-wide patterns of variation across the vast geographic span of Jewish Diaspora communities and their respective neighbours have yet to be addressed. Here we use high-density bead arrays to genotype individuals from 14 Jewish Diaspora communities and compare these patterns of genome-wide diversity with those from 69 Old World non-Jewish populations, of which 25 have not previously been reported. These samples were carefully chosen to provide comprehensive comparisons between Jewish and non-Jewish populations in the Diaspora, as well as with non-Jewish populations from the Middle East and north Africa. Principal component and structure-like analyses identify previously unrecognized genetic substructure within the Middle East. Most Jewish samples form a remarkably tight subcluster that overlies Druze and Cypriot samples but not samples from other Levantine populations or paired Diaspora host populations. In contrast, Ethiopian Jews (Beta Israel) and Indian Jews (Bene Israel and Cochini) cluster with neighbouring autochthonous populations in Ethiopia and western India, respectively, despite a clear paternal link between the Bene Israel and the Levant. These results cast light on the variegated genetic architecture of the Middle East, and trace the origins of most Jewish Diaspora communities to the Levant.

The Matrilineal Ancestry of Ashkenazi Jewry: Portrait of a Recent Founder Event

Both the extent and location of the maternal ancestral deme from which the Ashkenazi Jewry arose remain obscure. Here, using complete sequences of the maternally inherited mitochondrial DNA (mtDNA), we show that close to one-half of Ashkenazi Jews, estimated at 8,000,000 people, can be traced back to only 4 women carrying distinct mtDNAs that are virtually absent in other populations, with the important exception of low frequencies among non-Ashkenazi Jews. We conclude that four founding mtDNAs, likely of Near Eastern ancestry, underwent major expansion(s) in Europe within the past millennium.

Activation of m1 Muscarinic Acetylcholine Receptor Regulates τ Phosphorylation in Transfected PC12 Cells

Abstract: Hyperphosphorylated τ proteins are the principal fibrous component of the neurofibrillary tangle pathology in Alzheimers disease. The possibility that τ phosphorylation is controlled by cell surface neurotransmitter receptors was examined in PC12 cells transfected with the gene for the rat m1 muscarinic acetylcholine receptor. Stimulation of m1 receptor in these cells with two acetylcholine agonists, carbachol and AF102B, decreased τ phosphorylation, as indicated by specific τ monoclonal antibodies that recognize phosphorylation‐dependent epitopes and by alkaline phosphatase treatment. The muscarinic effect was both time and dose dependent. In addition, a synergistic effect on τ phosphorylation was found between treatments with muscarinic agonists and nerve growth factor. These studies provide the first evidence for a link between the cholinergic signal transduction system and the neuronal cytoskeleton that can be mediated by regulated phosphorylation of τ microtubule‐associated protein.

Inhibition of glycogen synthase kinase-3β by bivalent zinc ions: insight into the insulin-mimetic action of zinc

Zinc is an important trace element found in most body tissues as bivalent cations and has essential roles in human health. The insulin-like effect of zinc cations raises the possibility that they inhibit glycogen synthase kinase-3beta (GSK-3beta), a serine/threonine protein kinase linked with insulin resistance and type 2 diabetes. Here we show that physiological concentrations of zinc ions directly inhibit GSK-3beta in vitro in an uncompetitive manner. Treatment of HEK-293 cells with zinc enhanced glycogen synthase activity and increased the intracellular levels of beta-catenin, providing evidence for inhibition of endogenous GSK-3beta by zinc. Moreover, zinc ions enhanced glucose uptake 3-fold in isolated mouse adipocytes, an increase similar to activation with saturated concentrations of insulin. We propose that the in vivo insulin-mimetic actions of zinc are mediated via direct inhibition of endogenous GSK-3beta.

Refined Geographic Distribution of the Oriental ALDH2*504Lys (nee 487Lys) Variant

Mitochondrial aldehyde dehydrogenase (ALDH2) is one of the most important enzymes in human alcohol metabolism. The oriental ALDH2*504Lys variant functions as a dominant negative, greatly reducing activity in heterozygotes and abolishing activity in homozygotes. This allele is associated with serious disorders such as alcohol liver disease, late onset Alzheimer disease, colorectal cancer, and esophageal cancer, and is best known for protection against alcoholism. Many hundreds of papers in various languages have been published on this variant, providing allele frequency data for many different populations. To develop a highly refined global geographic distribution of ALDH2*504Lys, we have collected new data on 4,091 individuals from 86 population samples and assembled published data on a total of 80,691 individuals from 366 population samples. The allele is essentially absent in all parts of the world except East Asia. The ALDH2*504Lys allele has its highest frequency in Southeast China, and occurs in most areas of China, Japan, Korea, Mongolia, and Indochina with frequencies gradually declining radially from Southeast China. As the indigenous populations in South China have much lower frequencies than the southern Han migrants from Central China, we conclude that ALDH2*504Lys was carried by Han Chinese as they spread throughout East Asia. Esophageal cancer, with its highest incidence in East Asia, may be associated with ALDH2*504Lys because of a toxic effect of increased acetaldehyde in the tissue where ingested ethanol has its highest concentration. While the distributions of esophageal cancer and ALDH2*504Lys do not precisely correlate, that does not disprove the hypothesis. In general the study of fine scale geographic distributions of ALDH2*504Lys and diseases may help in understanding the multiple relationships among genes, diseases, environments, and cultures.

From pharmacogenetics to personalized medicine: a vital need for educating health professionals and the community

The field of pharmacogenetics will soon celebrate its 50th anniversary. Although science has delivered an impressive amount of information in these 50 years, pharmacogenetics has suffered from lack of integration into clinical practice. There are several reasons for this, including the unmet need for education at medical schools and the lack of awareness about the impact of genetic medicine on healthcare in the community. Recently, the FDA announced that it considers pharmacogenomics one of three major opportunities on the critical path to new medical products. This notion by the FDA is filling the regulatory void that existed between drug developers and drug users. However, in order to bring pharmacogenetic testing to the prescription pad successfully, healthcare professionals and policy makers, as well as patients, need to have the necessary background knowledge for making educated treatment decisions. To effectively move pharmacogenetics into everyday medicine, it is therefore imperative for scientists and teachers in the field to take on the challenge of disseminating pharmacogenetic insights to a broader audience.

Education: Teaching pharmacogenomics to prepare future physicians and researchers for personalized medicine

The vision of personalized medicine, the practice of medicine where each patient receives the most appropriate medical treatments and the most fitting dosage and combination of drugs based on his or her genetic make-up, seems to become more realistic as our knowledge about the human genome rapidly expands. We already know the reason for many types of adverse drug reactions, which are often related to polymorphic gene alleles of drug metabolizing enzymes. Moreover, insight into reasons for poor drug efficacy, often related to single nucleotide polymorphisms or larger polymorphisms in genes encoding drug target proteins, has been gained. There is a growing need to incorporate this increasingly complex body of knowledge to the standard curriculum of medical schools, so that the forthcoming generation of clinicians and researchers will be familiar with the latest developments in pharmacogenomics and medical bioinformatics, and will be capable of providing patients with the expected benefits of personalized medicine.

Pharmacogenomics education: International Society of Pharmacogenomics recommendations for medical, pharmaceutical, and health schools deans of education.

Pharmacogenomics would be instrumental for the realization of personalized medicine in coming decades. Efforts are evident to clarify the potential bioethical, societal, and legal implications of key pharmacogenomics-based technologies projected to be soon introduced into the core practice of medicine. In sharp contrast, a lack of sufficient attention to educational aspects of pharmacogenomics, both for professionals and for society at large, is evident. In order to contribute to this discussion, a ‘Pharmacogenomics Education Forum’ was held on October 2, 2004 during the 3rd Annual Meeting of the International Society of Pharmacogenomics (ISP) at Santorini, Greece. The participants, members of the ISP Pharmacogenomics Education Forum, after deliberate discussions, proposed a document of ‘Background Statement’ and ‘Recommendations and Call for Action’ addressed to Deans of Education at Medical, Pharmaceutical, and Health Schools globally. This document has been considered by the education committee of the International Society of Pharmacogenomics and the result is presented here. We hope that this call would be listened to, and soon followed by beneficial action, ultimately leading to enhanced implementation of personalized medicine into core medical education and practice.

Head circumference and incident Alzheimer’s disease Modification by apolipoprotein E

Background: The clinical expression of AD likely occurs when the accumulation of degeneration in specific brain regions leads to the descent below a critical threshold of “brain reserve” beyond which normal cognitive function cannot be maintained. The association between head circumference (HC), a measure of brain reserve, and the incidence of probable AD was examined in a large nondemented cohort that has been followed since 1992 and its modification by APOE ε4 genotype. Methods: Fifty-nine incident cases of probable AD were identified from 1,869 initially nondemented individuals seen at the baseline examination (1992 to 1994) and followed for a mean of 3.8 years. Variables measured at baseline included age, education, gender, HC, height, weight, and score on the National Adult Reading Test–Revised. APOE was genotyped at the time of the first biennial examination (1994 to 1996) and was available for 1,111 individuals in the cohort. Cox proportional hazard regression was performed to estimate hazard ratios (HR) for probable AD for HC and other covariates. Results: Incident cases were significantly older, less educated, shorter, and lighter, had lower estimated verbal IQ scores, and were more likely to have at least one APOE ε4 allele than unaffected individuals. The HR associated with the lowest tertile of HC (<21.4 inches) adjusted for education, gender, and APOE ε4 was 2.3 (95% CI 0.7 to 6.9, p = 0.16). The HR for one or two APOE ε4 alleles was significant (HR = 4.8, 95% CI 1.8 to 12.9, p = 0.002). The combination of low HC and APOE ε4 strongly predicted earlier onset of AD with HR = 14.1 (95% CI 3.0 to 65, p = 0.0007). Conclusions: Smaller HC, in the presence of the APOE ε4 allele, hastens the age at onset of AD. These results support the brain reserve hypothesis and its importance in precipitating the clinical expression of AD among genetically predisposed individuals.

MtDNA evidence for a genetic bottleneck in the early history of the Ashkenazi Jewish population

The relative roles of natural selection and accentuated genetic drift as explanations for the high frequency of more than 20 Ashkenazi Jewish disease alleles remain controversial. To test for the effects of a maternal bottleneck on the Ashkenazi Jewish population, we performed an extensive analysis of mitochondrial DNA (mtDNA) hypervariable segment 1 (HVS-1) sequence and restriction site polymorphisms in 565 Ashkenazi Jews from different parts of Europe. These patterns of variation were compared with those of five Near Eastern (n=327) and 10 host European (n=849) non-Jewish populations. Only four mtDNA haplogroups (Hgs) (defined on the basis of diagnostic coding region RFLPs and HVS-1 sequence variants) account for ∼70% of Ashkenazi mtDNA variation. While several Ashkenazi Jewish mtDNA Hgs appear to derive from the Near East, there is also evidence for a low level of introgression from host European non-Jewish populations. HVS-1 sequence analysis revealed increased frequencies of Ashkenazi Jewish haplotypes that are rare or absent in other populations, and a reduced number of singletons in the Ashkenazi Jewish sample. These diversity patterns provide evidence for a prolonged period of low effective size in the history of the Ashkenazi population. The data best fit a model of an early bottleneck (∼100 generations ago), perhaps corresponding to initial migrations of ancestral Ashkenazim in the Near East or to Europe. A genetic bottleneck followed by the recent phenomenon of rapid population growth are likely to have produced the conditions that led to the high frequency of many genetic disease alleles in the Ashkenazi population.