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1.  Differential immunoglobulin class-mediated responses to components of the U1 small nuclear ribonucleoprotein in Systemic Lupus Erythematosus and Mixed Connective Tissue Disease 
Lupus  2013;22(13):10.1177/0961203313508444.
Summary
Objective
To determine whether patients with Systemic Lupus Erythematosus (SLE) and Mixed Connective Tissue Disease (MCTD) possess differential IgM-and IgG-specific reactivity against peptides from the U1 small nuclear ribonucleoprotein particle (U1 snRNP).
Methods
The IgM- and IgG-mediated responses against 15 peptides from subunits of the U1 snRNP were assessed by indirect ELISAs in sera from patients with SLE and MCTD and healthy individuals (n = 81, 41 and 31, respectively). Additionally, 42 laboratory tests and 40 clinical symptoms were evaluated to uncover potential differences. Binomial logistic regression analyses (BLR) were performed to construct models to support the independent nature of SLE and MCTD. Receiver Operating Characteristic (ROC) curves corroborated the classification power of the models.
Results
We analyzed IgM and IgG anti-U1 snRNP titers to classify SLE and MCTD patients. IgG anti-U1 snRNP reactivity segregates SLE and MCTD from non-disease controls with an accuracy of 94.1% while IgM-specific anti-U1 snRNP responses distinguish SLE from MCTD patients with an accuracy of 71.3%. Comparison of the IgG and IgM anti-U1 snRNP approach with clinical tests used for diagnosing SLE and MCTD revealed that our method is the best classification tool of those analyzed (p ≤ 0.0001).
Conclusions
Our IgM anti-U1 snRNP system along with lab tests and symptoms provide additional molecular and clinical evidence to support the hypothesis that SLE and MCTD may be distinct syndromes.
doi:10.1177/0961203313508444
PMCID: PMC3875166  PMID: 24158973
Systemic Lupus Erythematosus (SLE); Mixed Connective Tissue Disease (MCTD); immunoglobulin M (IgM); U1 small nuclear ribonucleoprotein particle (U1 snRNP); auto-immune disorders; classification criteria
2.  Afghanistan from a Y-chromosome perspective 
European Journal of Human Genetics  2012;20(10):1063-1070.
Central Asia has served as a corridor for human migrations providing trading routes since ancient times. It has functioned as a conduit connecting Europe and the Middle East with South Asia and far Eastern civilizations. Therefore, the study of populations in this region is essential for a comprehensive understanding of early human dispersal on the Eurasian continent. Although Y- chromosome distributions in Central Asia have been widely surveyed, present-day Afghanistan remains poorly characterized genetically. The present study addresses this lacuna by analyzing 190 Pathan males from Afghanistan using high-resolution Y-chromosome binary markers. In addition, haplotype diversity for its most common lineages (haplogroups R1a1a*-M198 and L3-M357) was estimated using a set of 15 Y-specific STR loci. The observed haplogroup distribution suggests some degree of genetic isolation of the northern population, likely due to the Hindu Kush mountain range separating it from the southern Afghans who have had greater contact with neighboring Pathans from Pakistan and migrations from the Indian subcontinent. Our study demonstrates genetic similarities between Pathans from Afghanistan and Pakistan, both of which are characterized by the predominance of haplogroup R1a1a*-M198 (>50%) and the sharing of the same modal haplotype. Furthermore, the high frequencies of R1a1a-M198 and the presence of G2c-M377 chromosomes in Pathans might represent phylogenetic signals from Khazars, a common link between Pathans and Ashkenazi groups, whereas the absence of E1b1b1a2-V13 lineage does not support their professed Greek ancestry.
doi:10.1038/ejhg.2012.59
PMCID: PMC3449065  PMID: 22510847
Afghanistan; Pathans/Pashtuns; Y-SNP; phylogenetic analyses; haplogroup; haplotype
3.  Spliceosomal Immunophilins 
FEBS letters  2008;582(16):2345-2351.
The spliceosome is a dynamic, macromolecular complex, which removes non-protein-coding introns from pre-mRNA to form mature mRNA in a process known as splicing. This ribonucleoprotein assembly is comprised of five uridine-rich small nuclear RNAs (snRNAs) as well as over 300 proteins. In humans, several of the known splicing factors are members of the immunophilin superfamily. Immunophilins are peptidyl-prolyl cis-trans isomerases that catalyze the conversion of proteins from cis to trans at Xaa-Pro bonds. Our review of the data portrays a picture of this protein family as activators of spliceosomal proteins by way of folding and transport.
doi:10.1016/j.febslet.2008.06.006
PMCID: PMC2546689  PMID: 18544344
cyclophilin; FKBP; spliceosome; cyclosporin; FK506; small nuclear RNAs
4.  Neolithic patrilineal signals indicate that the Armenian plateau was repopulated by agriculturalists 
Armenia, situated between the Black and Caspian Seas, lies at the junction of Turkey, Iran, Georgia, Azerbaijan and former Mesopotamia. This geographic position made it a potential contact zone between Eastern and Western civilizations. In this investigation, we assess Y-chromosomal diversity in four geographically distinct populations that represent the extent of historical Armenia. We find a striking prominence of haplogroups previously implicated with the Agricultural Revolution in the Near East, including the J2a-M410-, R1b1b1*-L23-, G2a-P15- and J1-M267-derived lineages. Given that the Last Glacial Maximum event in the Armenian plateau occured a few millennia before the Neolithic era, we envision a scenario in which its repopulation was achieved mainly by the arrival of farmers from the Fertile Crescent temporally coincident with the initial inception of farming in Greece. However, we detect very restricted genetic affinities with Europe that suggest any later cultural diffusions from Armenia to Europe were not associated with substantial amounts of paternal gene flow, despite the presence of closely related Indo-European languages in both Armenia and Southeast Europe.
doi:10.1038/ejhg.2011.192
PMCID: PMC3286660  PMID: 22085901
Armenia; phylogenetics; Y-chromosome; SNPs; neolithic
6.  The emergence of Y-chromosome haplogroup J1e among Arabic-speaking populations 
Haplogroup J1 is a prevalent Y-chromosome lineage within the Near East. We report the frequency and YSTR diversity data for its major sub-clade (J1e). The overall expansion time estimated from 453 chromosomes is 10 000 years. Moreover, the previously described J1 (DYS388=13) chromosomes, frequently found in the Caucasus and eastern Anatolian populations, were ancestral to J1e and displayed an expansion time of 9000 years. For J1e, the Zagros/Taurus mountain region displays the highest haplotype diversity, although the J1e frequency increases toward the peripheral Arabian Peninsula. The southerly pattern of decreasing expansion time estimates is consistent with the serial drift and founder effect processes. The first such migration is predicted to have occurred at the onset of the Neolithic, and accordingly J1e parallels the establishment of rain-fed agriculture and semi-nomadic herders throughout the Fertile Crescent. Subsequently, J1e lineages might have been involved in episodes of the expansion of pastoralists into arid habitats coinciding with the spread of Arabic and other Semitic-speaking populations.
doi:10.1038/ejhg.2009.166
PMCID: PMC2987219  PMID: 19826455
Y-chromosome haplogroup J1e; Neolithic; Arabic languages; pastoralism
8.  Y-Chromosome distribution within the geo-linguistic landscape of northwestern Russia 
European Journal of Human Genetics  2009;17(10):1260-1273.
Populations of northeastern Europe and the Uralic mountain range are found in close geographic proximity, but they have been subject to different demographic histories. The current study attempts to better understand the genetic paternal relationships of ethnic groups residing in these regions. We have performed high-resolution haplotyping of 236 Y-chromosomes from populations in northwestern Russia and the Uralic mountains, and compared them to relevant previously published data. Haplotype variation and age estimation analyses using 15 Y-STR loci were conducted for samples within the N1b, N1c1 and R1a1 single-nucleotide polymorphism backgrounds. Our results suggest that although most genetic relationships throughout Eurasia are dependent on geographic proximity, members of the Uralic and Slavic linguistic families and subfamilies, yield significant correlations at both levels of comparison making it difficult to denote either linguistics or geographic proximity as the basis for their genetic substrata. Expansion times for haplogroup R1a1 date approximately to 18 000 YBP, and age estimates along with Network topology of populations found at opposite poles of its range (Eastern Europe and South Asia) indicate that two separate haplotypic foci exist within this haplogroup. Data based on haplogroup N1b challenge earlier findings and suggest that the mutation may have occurred in the Uralic range rather than in Siberia and much earlier than has been proposed (12.9±4.1 instead of 5.2±2.7 kya). In addition, age and variance estimates for haplogroup N1c1 suggest that populations from the western Urals may have been genetically influenced by a dispersal from northeastern Europe (eg, eastern Slavs) rather than the converse.
doi:10.1038/ejhg.2009.6
PMCID: PMC2986641  PMID: 19259129
Y-chromosome; Y-STRs; northeastern Europe; phylogenetics
9.  Y-Chromosomal Diversity in Lebanon Is Structured by Recent Historical Events 
Lebanon is an eastern Mediterranean country inhabited by approximately four million people with a wide variety of ethnicities and religions, including Muslim, Christian, and Druze. In the present study, 926 Lebanese men were typed with Y-chromosomal SNP and STR markers, and unusually, male genetic variation within Lebanon was found to be more strongly structured by religious affiliation than by geography. We therefore tested the hypothesis that migrations within historical times could have contributed to this situation. Y-haplogroup J∗(xJ2) was more frequent in the putative Muslim source region (the Arabian Peninsula) than in Lebanon, and it was also more frequent in Lebanese Muslims than in Lebanese non-Muslims. Conversely, haplogroup R1b was more frequent in the putative Christian source region (western Europe) than in Lebanon and was also more frequent in Lebanese Christians than in Lebanese non-Christians. The most common R1b STR-haplotype in Lebanese Christians was otherwise highly specific for western Europe and was unlikely to have reached its current frequency in Lebanese Christians without admixture. We therefore suggest that the Islamic expansion from the Arabian Peninsula beginning in the seventh century CE introduced lineages typical of this area into those who subsequently became Lebanese Muslims, whereas the Crusader activity in the 11th–13th centuries CE introduced western European lineages into Lebanese Christians.
doi:10.1016/j.ajhg.2008.01.020
PMCID: PMC2427286  PMID: 18374297
10.  Y-Chromosomal Diversity in Lebanon Is Structured by Recent Historical Events 
Lebanon is an eastern Mediterranean country inhabited by approximately four million people with a wide variety of ethnicities and religions, including Muslim, Christian, and Druze. In the present study, 926 Lebanese men were typed with Y-chromosomal SNP and STR markers, and unusually, male genetic variation within Lebanon was found to be more strongly structured by religious affiliation than by geography. We therefore tested the hypothesis that migrations within historical times could have contributed to this situation. Y-haplogroup J∗(xJ2) was more frequent in the putative Muslim source region (the Arabian Peninsula) than in Lebanon, and it was also more frequent in Lebanese Muslims than in Lebanese non-Muslims. Conversely, haplogroup R1b was more frequent in the putative Christian source region (western Europe) than in Lebanon and was also more frequent in Lebanese Christians than in Lebanese non-Christians. The most common R1b STR-haplotype in Lebanese Christians was otherwise highly specific for western Europe and was unlikely to have reached its current frequency in Lebanese Christians without admixture. We therefore suggest that the Islamic expansion from the Arabian Peninsula beginning in the seventh century CE introduced lineages typical of this area into those who subsequently became Lebanese Muslims, whereas the Crusader activity in the 11th–13th centuries CE introduced western European lineages into Lebanese Christians.
doi:10.1016/j.ajhg.2008.01.020
PMCID: PMC2427286  PMID: 18374297
11.  Distinguishing the co-ancestries of haplogroup G Y-chromosomes in the populations of Europe and the Caucasus 
European Journal of Human Genetics  2012;20(12):1275-1282.
Haplogroup G, together with J2 clades, has been associated with the spread of agriculture, especially in the European context. However, interpretations based on simple haplogroup frequency clines do not recognize underlying patterns of genetic diversification. Although progress has been recently made in resolving the haplogroup G phylogeny, a comprehensive survey of the geographic distribution patterns of the significant sub-clades of this haplogroup has not been conducted yet. Here we present the haplogroup frequency distribution and STR variation of 16 informative G sub-clades by evaluating 1472 haplogroup G chromosomes belonging to 98 populations ranging from Europe to Pakistan. Although no basal G-M201* chromosomes were detected in our data set, the homeland of this haplogroup has been estimated to be somewhere nearby eastern Anatolia, Armenia or western Iran, the only areas characterized by the co-presence of deep basal branches as well as the occurrence of high sub-haplogroup diversity. The P303 SNP defines the most frequent and widespread G sub-haplogroup. However, its sub-clades have more localized distribution with the U1-defined branch largely restricted to Near/Middle Eastern and the Caucasus, whereas L497 lineages essentially occur in Europe where they likely originated. In contrast, the only U1 representative in Europe is the G-M527 lineage whose distribution pattern is consistent with regions of Greek colonization. No clinal patterns were detected suggesting that the distributions are rather indicative of isolation by distance and demographic complexities.
doi:10.1038/ejhg.2012.86
PMCID: PMC3499744  PMID: 22588667
Y-chromosome; haplogroup G; human evolution; population genetics
12.  The Expanded mtDNA Phylogeny of the Franco-Cantabrian Region Upholds the Pre-Neolithic Genetic Substrate of Basques 
PLoS ONE  2013;8(7):e67835.
The European genetic landscape has been shaped by several human migrations occurred since Paleolithic times. The accumulation of archaeological records and the concordance of different lines of genetic evidence during the last two decades have triggered an interesting debate concerning the role of ancient settlers from the Franco-Cantabrian region in the postglacial resettlement of Europe. Among the Franco-Cantabrian populations, Basques are regarded as one of the oldest and more intriguing human groups of Europe. Recent data on complete mitochondrial DNA genomes focused on macrohaplogroup R0 revealed that Basques harbor some autochthonous lineages, suggesting a genetic continuity since pre-Neolithic times. However, excluding haplogroup H, the most representative lineage of macrohaplogroup R0, the majority of maternal lineages of this area remains virtually unexplored, so that further refinement of the mtDNA phylogeny based on analyses at the highest level of resolution is crucial for a better understanding of the European prehistory. We thus explored the maternal ancestry of 548 autochthonous individuals from various Franco-Cantabrian populations and sequenced 76 mitogenomes of the most representative lineages. Interestingly, we identified three mtDNA haplogroups, U5b1f, J1c5c1 and V22, that proved to be representative of Franco-Cantabria, notably of the Basque population. The seclusion and diversity of these female genetic lineages support a local origin in the Franco-Cantabrian area during the Mesolithic of southwestern Europe, ∼10,000 years before present (YBP), with signals of expansions at ∼3,500 YBP. These findings provide robust evidence of a partial genetic continuity between contemporary autochthonous populations from the Franco-Cantabrian region, specifically the Basques, and Paleolithic/Mesolithic hunter-gatherer groups. Furthermore, our results raise the current proportion (≈15%) of the Franco-Cantabrian maternal gene pool with a putative pre-Neolithic origin to ≈35%, further supporting the notion of a predominant Paleolithic genetic substrate in extant European populations.
doi:10.1371/journal.pone.0067835
PMCID: PMC3700859  PMID: 23844106
13.  A major Y-chromosome haplogroup R1b Holocene era founder effect in Central and Western Europe 
The phylogenetic relationships of numerous branches within the core Y-chromosome haplogroup R-M207 support a West Asian origin of haplogroup R1b, its initial differentiation there followed by a rapid spread of one of its sub-clades carrying the M269 mutation to Europe. Here, we present phylogeographically resolved data for 2043 M269-derived Y-chromosomes from 118 West Asian and European populations assessed for the M412 SNP that largely separates the majority of Central and West European R1b lineages from those observed in Eastern Europe, the Circum-Uralic region, the Near East, the Caucasus and Pakistan. Within the M412 dichotomy, the major S116 sub-clade shows a frequency peak in the upper Danube basin and Paris area with declining frequency toward Italy, Iberia, Southern France and British Isles. Although this frequency pattern closely approximates the spread of the Linearbandkeramik (LBK), Neolithic culture, an advent leading to a number of pre-historic cultural developments during the past ≤10 thousand years, more complex pre-Neolithic scenarios remain possible for the L23(xM412) components in Southeast Europe and elsewhere.
doi:10.1038/ejhg.2010.146
PMCID: PMC3039512  PMID: 20736979
Y-chromosome; haplogroup R1b; human evolution; population genetics
14.  Separating the post-Glacial coancestry of European and Asian Y chromosomes within haplogroup R1a 
Human Y-chromosome haplogroup structure is largely circumscribed by continental boundaries. One notable exception to this general pattern is the young haplogroup R1a that exhibits post-Glacial coalescent times and relates the paternal ancestry of more than 10% of men in a wide geographic area extending from South Asia to Central East Europe and South Siberia. Its origin and dispersal patterns are poorly understood as no marker has yet been described that would distinguish European R1a chromosomes from Asian. Here we present frequency and haplotype diversity estimates for more than 2000 R1a chromosomes assessed for several newly discovered SNP markers that introduce the onset of informative R1a subdivisions by geography. Marker M434 has a low frequency and a late origin in West Asia bearing witness to recent gene flow over the Arabian Sea. Conversely, marker M458 has a significant frequency in Europe, exceeding 30% in its core area in Eastern Europe and comprising up to 70% of all M17 chromosomes present there. The diversity and frequency profiles of M458 suggest its origin during the early Holocene and a subsequent expansion likely related to a number of prehistoric cultural developments in the region. Its primary frequency and diversity distribution correlates well with some of the major Central and East European river basins where settled farming was established before its spread further eastward. Importantly, the virtual absence of M458 chromosomes outside Europe speaks against substantial patrilineal gene flow from East Europe to Asia, including to India, at least since the mid-Holocene.
doi:10.1038/ejhg.2009.194
PMCID: PMC2987245  PMID: 19888303
Y chromosome; haplogroup R1a; human evolution; population genetics
15.  J1-M267 Y lineage marks climate-driven pre-historical human displacements 
European Journal of Human Genetics  2009;17(11):1520-1524.
The present day distribution of Y chromosomes bearing the haplogroup J1 M267*G variant has been associated with different episodes of human demographic history, the main one being the diffusion of Islam since the Early Middle Ages. To better understand the modes and timing of J1 dispersals, we reconstructed the genealogical relationships among 282 M267*G chromosomes from 29 populations typed at 20 YSTRs and 6 SNPs. Phylogenetic analyses depicted a new genetic background consistent with climate-driven demographic dynamics occurring during two key phases of human pre-history: (1) the spatial expansion of hunter gatherers in response to the end of the late Pleistocene cooling phases and (2) the displacement of groups of foragers/herders following the mid-Holocene rainfall retreats across the Sahara and Arabia. Furthermore, J1 STR motifs previously used to trace Arab or Jewish ancestries were shown unsuitable as diagnostic markers for ethnicity.
doi:10.1038/ejhg.2009.58
PMCID: PMC2986692  PMID: 19367321
Y chromosome; haplogroup J1; human population history; Holocene

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