North African Jewish and non-Jewish populations form distinctive, orthogonal clusters

Campbell, Christopher L. et al.North African Jews constitute the second largest Jewish Diaspora group. However, their relatedness to each other; to European, Middle Eastern, and other Jewish Diaspora groups; and to their former North African non-Jewish neighbors has not been well defined. Here, genome-wide analysis of five North African Jewish groups (Moroccan, Algerian, Tunisian, Djerban, and Libyan) and comparison with other Jewish and non-Jewish groups demonstrated distinctive North African Jewish population clusters with proximity to other Jewish populations and variable degrees of Middle Eastern, European, and North African admixture. Two major subgroups were identified by principal component, neighbor joining tree, and identity-by-descent analysis - Moroccan/ Algerian and Djerban/Libyan - that varied in their degree of European admixture. These populations showed a high degree of endogamy and were part of a larger Ashkenazi and Sephardic Jewish group. By principal component analysis, these North African groups were orthogonal to contemporary populations from North and South Morocco, Western Sahara, Tunisia, Libya, and Egypt. Thus, this study is compatible with the history of North African Jews - founding during Classical Antiquity with proselytism of local populations, followed by genetic isolation with the rise of Christianity and then Islam, and admixture following the emigration of Sephardic Jews during the Inquisition.This work was supported in part by the Lewis and Rachel Rudin Foundation, the Iranian-American Jewish Federation of New York, the US–Israel Binational Science Foundation, National Institutes of Health Grant 5 U54 CA121852, and Ruth and Sidney Lapidus. L.R.B. and D.C. were supported by Ministerio de Ciencia e Innovación Grant CGL2010-14944/BOS.Peer Reviewe

The Missing Link of Jewish European Ancestry: Contrasting the Rhineland and the Khazarian Hypotheses

The question of Jewish ancestry has been the subject of controversy for over two centuries and has yet to be resolved. The "Rhineland Hypothesis" proposes that Eastern European Jews emerged from a small group of German Jews who migrated eastward and expanded rapidly. Alternatively, the "Khazarian Hypothesis" suggests that Eastern European descended from Judean tribes who joined the Khazars, an amalgam of Turkic clans that settled the Caucasus in the early centuries CE and converted to Judaism in the 8th century. The Judaized Empire was continuously reinforced with Mesopotamian and Greco-Roman Jews until the 13th century. Following the collapse of their empire, the Judeo-Khazars fled to Eastern Europe. The rise of European Jewry is therefore explained by the contribution of the Judeo-Khazars. Thus far, however, their contribution has been estimated only empirically; the absence of genome-wide data from Caucasus populations precluded testing the Khazarian Hypothesis. Recent sequencing of modern Caucasus populations prompted us to revisit the Khazarian Hypothesis and compare it with the Rhineland Hypothesis. We applied a wide range of population genetic analyses - including principal component, biogeographical origin, admixture, identity by descent, allele sharing distance, and uniparental analyses - to compare these two hypotheses. Our findings support the Khazarian Hypothesis and portray the European Jewish genome as a mosaic of Caucasus, European, and Semitic ancestries, thereby consolidating previous contradictory reports of Jewish ancestry.Comment: 21 pages, 7 figures, 1 table, 7 supplementary figures, 7 supplementary table

Mutations in MAP3K1 tilt the balance from SOX9/FGF9 to WNT/β-catenin signaling

In-frame missense and splicing mutations (resulting in a 2 amino acid insertion or a 34 amino acid deletion) dispersed through the MAP3K1 gene tilt the balance from the male to female sex-determining pathway, resulting in 46,XY disorder of sex development. These MAP3K1 mutations mediate this balance by enhancing WNT/β-catenin/FOXL2 expression and β-catenin activity and by reducing SOX9/FGF9/FGFR2/SRY expression. These effects are mediated at multiple levels involving MAP3K1 interaction with protein co-fact

Three synchronous primary carcinomas in a patient with HNPCC associated with a novel germline mutation in MLH1: Case report

<p>Abstract</p> <p>Background</p> <p><it>MLH1 </it>is one of six known genes responsible for DNA mismatch repair (MMR), whose inactivation leads to HNPCC. It is important to develop genotype-phenotype correlations for HNPCC, as is being done for other hereditary cancer syndromes, in order to guide surveillance and treatment strategies in the future.</p> <p>Case presentation</p> <p>We report a 47 year-old male with hereditary nonpolyposis colorectal cancer (HNPCC) associated with a novel germline mutation in <it>MLH1</it>. This patient expressed a rare and severe phenotype characterized by three synchronous primary carcinomas: ascending and splenic flexure colon adenocarcinomas, and ureteral carcinoma. Ureteral neoplasms in HNPCC are most often associated with mutations in <it>MSH2 </it>and rarely with mutations in <it>MLH1</it>. The reported mutation is a two base pair insertion into exon 10 (c.866_867insCA), which results in a premature stop codon.</p> <p>Conclusion</p> <p>Our case demonstrates that HNPCC patients with <it>MLH1 </it>mutations are also at risk for ureteral neoplasms, and therefore urological surveillance is essential. This case adds to the growing list of disease-causing MMR mutations, and contributes to the development of genotype-phenotype correlations essential for assessing individual cancer risk and tailoring of optimal surveillance strategies. Additionally, our case draws attention to limitations of the Amsterdam Criteria and the need to maintain a high index of suspicion when newly diagnosed colorectal cancer meets the Bethesda Criteria. Establishment of the diagnosis is the crucial first step in initiating appropriate surveillance for colorectal cancer and other HNPCC-associated tumors in at-risk individuals.</p

The Global Campaign to Eliminate Leprosy

While effective drug treatments have reduced the global disease burden, there remain important challenges to fighting and controlling the disease

PCAdmix: Principal Components-Based Assignment of Ancestry along Each Chromosome in Individuals with Admixed Ancestry from Two or More Populations

Identifying ancestry along each chromosome in admixed individuals provides a wealth of information for understanding the population genetic history of admixture events and is valuable for admixture mapping and identifying recent targets of selection. We present PCAdmix (available at https://sites.google.com/site/pcadmix/home), a Principal Componentsbased algorithm for determining ancestry along each chromosome from a high-density, genome-wide set of phased single-nucleotide polymorphism (SNP) genotypes of admixed individuals. We compare our method to HAPMIX on simulated data from two ancestral populations, and we find high concordance between the methods. Our method also has better accuracy than LAMP when applied to three-population admixture, a situation as yet unaddressed by HAPMIX. Finally, we apply our method to a data set of four Latino populations with European, African, and Native American ancestry. We find evidence of assortative mating in each of the four populations, and we identify regions of shared ancestry that may be recent targets of selection and could serve as candidate regions for admixture-based association mapping

No major association between TGFBR1*6A and prostate cancer

Prostate cancer is the most commonly diagnosed cancer in men and one of the leading causes of cancer deaths. There is strong genetic evidence indicating that a large proportion of prostate cancers are caused by heritable factors but the search for prostate cancer susceptibility genes has thus far remained elusive. TGFBR1*6A, a common hypomorphic variant of the type I Transforming Growth Factor Beta receptor, is emerging as a tumor susceptibility allele that predisposes to the development of breast, colon and ovarian cancer. The association with prostate cancer has not yet been explored. A total of 907 cases and controls from New York City were genotyped to test the hypothesis that TGFBR1*6A may contribute to the development of prostate cancer. TGFBR1*6A allelic frequency among cases (0.086) was slightly higher than among controls (0.080) but the differences in TGFBR1*6A genotype distribution between cases and controls did not reach statistical significance (p = 0.67). Our data suggest that TGFBR1*6A does not contribute to the development of prostate cancer

A genetic contribution from the Far East into Ashkenazi Jews via the ancient Silk Road

Contemporary Jews retain a genetic imprint from their Near Eastern ancestry, but obtained substantial genetic components from their neighboring populations during their history. Whether they received any genetic contribution from the Far East remains unknown, but frequent communication with the Chinese has been observed since the Silk Road period. To address this issue, mitochondrial DNA (mtDNA) variation from 55,595 Eurasians are analyzed. The existence of some eastern Eurasian haplotypes in eastern Ashkenazi Jews supports an East Asian genetic contribution, likely from Chinese. Further evidence indicates that this connection can be attributed to a gene flow event that occurred less than 1.4 kilo-years ago (kya), which falls within the time frame of the Silk Road scenario and fits well with historical records and archaeological discoveries. This observed genetic contribution from Chinese to Ashkenazi Jews demonstrates that the historical exchange between Ashkenazim and the Far East was not confined to the cultural sphere but also extended to an exchange of genes

Localizing Ashkenazic Jews to Primeval Villages in the Ancient Iranian Lands of Ashkenaz

TheYiddishlanguageisover1,000yearsoldandincorporatesGerman,Slavic,andHebrewelements.TheprevalentviewclaimsYiddish hasaGermanorigin,whereastheopposingviewpositsaSlavicoriginwithstrongIranianandweakTurkicsubstrata.Oneofthemajor difficulties in deciding between these hypotheses is the unknown geographical origin of Yiddish speaking Ashkenazic Jews (AJs). An analysis of 393 Ashkenazic, Iranian, and mountain Jews and over 600 non-Jewish genomes demonstrated that Greeks, Romans, Iranians,andTurksexhibitthehighestgeneticsimilaritywithAJs.TheGeographicPopulationStructureanalysislocalizedmostAJsalong major primeval trade routes in northeastern Turkey adjacent to primeval villages with names that may be derived from “Ashkenaz.” IranianandmountainJewswerelocalizedalongtraderoutesontheTurkey’seasternborder.Lossofmaternalhaplogroupswasevident in non-Yiddish speaking AJs. Our results suggest that AJs originated from a Slavo-Iranian confederation, which the Jews call “Ashkenazic” (i.e., “Scythian”), though these Jews probably spoke Persian and/or Ossete. This is compatible with linguistic evidence suggesting that Yiddish is a Slavic language created by Irano-Turko-Slavic Jewish merchants along the Silk Roads as a cryptic trade language, spoken only by its originators to gain an advantage in trade. Later, in the 9th century, Yiddish underwent relexification by adoptinganewvocabularythatconsistsofaminorityofGermanandHebrewandamajorityofnewlycoinedGermanoidandHebroid elements that replaced most of the original Eastern Slavic and Sorbian vocabularies, while keeping the original grammars intact