USH3A transcripts encode clarin-1, a four-transmembrane-domain protein with a possible role in sensory synapses

[EN] Usher syndrome type 3 (USH3) is an autosomal recessive disorder characterised by the association of post-lingual progressive hearing loss, progressive visual loss due to retinitis pigmentosa and variable presence of vestibular dysfunction. Because the previously defined transcripts do not account for all USH3 cases, we performed further analysis and revealed the presence of additional exons embedded in longer human and mouse USH3A transcripts and three novel USH3A mutations. Expression of Ush3a transcripts was localised by whole mount in situ hybridisation to cochlear hair cells and spiral ganglion cells. The full length USH3A transcript encodes clarin-1, a four-transmembrane-domain protein, which defines a novel vertebrate-specific family of three paralogues. Limited sequence homology to stargazin, a cerebellar synapse four-transmembrane-domain protein, suggests a role for clarin-1 in hair cell and photoreceptor cell synapses, as well as a common pathophysiological pathway for different Usher syndromes.We are grateful to all patients and their family members who participated in this study. We would also like to thank Ronna Hertzano for the preparation of the mouse inner ear cDNA. This work was funded by an Infrastructure grant of the Israeli Ministry of Science Culture and Sports, the Crown Human Genome Center at The Weizmann Institute of Science, the Alfried Krupp Foundation and by the Finnish Eye and Tissue Bank Foundation, the Finnish Eye Foundation, the Maud Kuistila Memorial Foundation, the Oskar Oflund Foundation, Finnish State grant TYH9235, the European Commission (QLG2-CT-1999-00988) (KB Araham) and by the Foundation Fighting Blindness. JS Beckman holds the, Hermann Mayer professorial chair and D Lancet holds the Ralf and Lois Silver professorial chair.Adato, A.; Vreugde, S.; Joensuu, T.; Avidan, N.; Hamalainen, R.; Belenkiy, O.; Olender, T.... (2002). USH3A transcripts encode clarin-1, a four-transmembrane-domain protein with a possible role in sensory synapses. European Journal of Human Genetics. 10(6):339-350. https://doi.org/10.1038/sj.ejhg.520083133935010

Counting the Founders: The Matrilineal Genetic Ancestry of the Jewish Diaspora

The history of the Jewish Diaspora dates back to the Assyrian and Babylonian conquests in the Levant, followed by complex demographic and migratory trajectories over the ensuing millennia which pose a serious challenge to unraveling population genetic patterns. Here we ask whether phylogenetic analysis, based on highly resolved mitochondrial DNA (mtDNA) phylogenies can discern among maternal ancestries of the Diaspora. Accordingly, 1,142 samples from 14 different non-Ashkenazi Jewish communities were analyzed. A list of complete mtDNA sequences was established for all variants present at high frequency in the communities studied, along with high-resolution genotyping of all samples. Unlike the previously reported pattern observed among Ashkenazi Jews, the numerically major portion of the non-Ashkenazi Jews, currently estimated at 5 million people and comprised of the Moroccan, Iraqi, Iranian and Iberian Exile Jewish communities showed no evidence for a narrow founder effect, which did however characterize the smaller and more remote Belmonte, Indian and the two Caucasus communities. The Indian and Ethiopian Jewish sample sets suggested local female introgression, while mtDNAs in all other communities studied belong to a well-characterized West Eurasian pool of maternal lineages. Absence of sub-Saharan African mtDNA lineages among the North African Jewish communities suggests negligible or low level of admixture with females of the host populations among whom the African haplogroup (Hg) L0-L3 sub-clades variants are common. In contrast, the North African and Iberian Exile Jewish communities show influence of putative Iberian admixture as documented by mtDNA Hg HV0 variants. These findings highlight striking differences in the demographic history of the widespread Jewish Diaspora

A genetic view of the Samaritan isolate

Thesis (Ph.D.)--Boston UniversityPLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at [email protected]. Thank you.The Samaritan community in the Middle East is the solitary heir of a continuous religious and cultural tradition, probably going back to an early stage in Biblical history. From a national unit of several thousand souls they have gradually become a small sect of only a few hundred individuals. There are today a total of about 381 Samaritans divided into two groups that live under different political allegancies, Jordan and Israel, but in the same geographical area that they have never left for a period of more than 2000 years. There are about 225 Samaritans residing in Nablus, Jordan, and 156 in Cholon (near Tel-Aviv) Israel. Once a year, at their Passover, all the members of the two communities join in a pilgrimage to Mt. Gerizim, near the city of Nablus. A genetic and anthropological survey of the Samaritan community in Israel carried out in the autumn of 1963 included tests for about 30 blood group antigens, several serum proteins, hemoglobin variants, Glucose-6-Phosphate Dehydrogenase activity, secretor status, color-blindness and some 18 anthropometric measurements and 18 morphological observations. About 90% of the total group were studied. All typings of red cell antigens, G6PD and hemoglobin variants were performed by conventional methods at the Tel Hashomer Hospital in Israel. Sera specimens were frozen and shipped to the U.S.A. and were tested for the following plasma components: 1. Haptoglobins and transferrins (by starch-gel electrophoresis) 2. Groups Specific Component (Gc types, by immunoelectrophoresis) 3. Lipoproteins (by the Ouchterlony procedure) 4. Gamma Globulins and Inv (a) factors by the methods used in Steinberg's Laboratory at Western Reserve University, Cleveland, Ohio. The tests for PTC taste sensitivity followed the sorting technique of Harris and Kalmus, and deficiency in color-vision was detected by the Ishihara charts and the Pickford-Nicolson anomaloscope. The anthropometry procedures followed the standard techniques of Martin. The results obtained show that the Samaritans possess a characteristic gene frequency picture which does not resemble that of any other community in the same region; in blood groups they have the highest 0 frequency in the Middle East; A2 is more common than A1 and the N gene is more frequent than M. Not a single case of G6PD deficiency was found. The incidence of color-blindness is very high (27%). There is heterogeneity in physical type and large variations between individuals are also manifested in hair and eye-color distribution. Comparison of gene frequencies within the isolate as observed in 1933 and in 1963 as well as in an age-group analysis shows that the differences between generations are very small and below magnitude that might be expected on the basis of random genetic drift. The genetic diversity of the community suggests that is spite of their being genetically isolated for a very long time no genes have been "fixed" or "lost" although the statistical probability for such an occurrence is high. This fact, and the apparent state of equilibrium in most of their genetic systems suggests that compensating selecting forces are acting to stabilize the gene frequencies. It seems likely that the isolate has developed its own unique integrated polygenic system, one that tends to persist. Examination of the degree of consanguinity in the population indicates that in 84% of the matings the partners are first cousins or second cousins. The mean coefficient of inbreeding (as computed by an IBM 1620 computer) for the present generation is 0.069: the highest value recorded for any human community. The inbred nature of this small isolate, however, is not reflected in an excess of homozygotes nor in a high incidence of congenital malformations and abnormalities. Also, sterility, abortions and infant mortality were not proportional to the degree of inbreeding. Lack of evidence for specific deleterious effects in the Samaritans leads to the suggestion that inbreeding has been practiced in this isolate for such a long time that the population has "purged" itself of many of its detrimental genes.2031-01-0

A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity.

Variants of different Class I alcohol dehydrogenase (ADH) genes have been shown to be associated with an effect that is protective against alcoholism. Previous work from our laboratory has shown that the two sites showing the association are in linkage disequilibrium and has identified the ADH1B Arg47His site as causative, with the ADH1C Ile349Val site showing association only because of the disequilibrium. Here, we describe an initial study of the nature of linkage disequilibrium and genetic variation, in population samples from different regions of the world, in a larger segment of the ADH cluster (including the three Class I ADH genes and ADH7). Linkage disequilibrium across ∼40 kb of the Class I ADH cluster is moderate to strong in all population samples that we studied. We observed nominally significant pairwise linkage disequilibrium, in some populations, between the ADH7 site and some Class I ADH sites, at moderate values and at a molecular distance as great as 100 kb. Our data indicate (1) that most ADH-alcoholism association studies have failed to consider many sites in the ADH cluster that may harbor etiologically significant alleles and (2) that the relevance of the various ADH sites will be population dependent. Some individual sites in the Class I ADH cluster show values that are among F st the highest seen among several dozen unlinked sites that were studied in the same subset of populations. The high values can be attributed to the discrepant frequencies of specific alleles in eastern Asia relative to those F st in other regions of the world. These alleles are part of a single haplotype that exists at high (165%) frequency only in the eastern-Asian samples. It seems unlikely that this haplotype, which is rare or unobserved in other populations, reached such high frequency because of random genetic drift alone

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