Jacques Chiaroni

New insights into the Tyrolean Iceman's origin and phenotype as inferred by whole-genome sequencing

The Tyrolean Iceman, a 5,300-year-old Copper age individual, was discovered in 1991 on the Tisenjoch Pass in the Italian part of the Ötztal Alps. Here we report the complete genome sequence of the Iceman and show 100% concordance between the previously reported mitochondrial genome sequence and the consensus sequence generated from our genomic data. We present indications for recent common ancestry between the Iceman and present-day inhabitants of the Tyrrhenian Sea, that the Iceman probably had brown eyes, belonged to blood group O and was lactose intolerant. His genetic predisposition shows an increased risk for coronary heart disease and may have contributed to the development of previously reported vascular calcifications. Sequences corresponding to ~60% of the genome of Borrelia burgdorferi are indicative of the earliest human case of infection with the pathogen for Lyme borreliosis.

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.

Sequence family variant loss from the AZFc interval of the human Y chromosome, but not gene copy loss, is strongly associated with male infertility

Background: Complete deletion of the complete AZFc interval of the Y chromosome is the most common known genetic cause of human male infertility. Two partial AZFc deletions (gr/gr and b1/b3) that remove some copies of all AZFc genes have recently been identified in infertile and fertile populations, and an association study indicates that the resulting gene dose reduction represents a risk factor for spermatogenic failure. Methods: To determine the incidence of various partial AZFc deletions and their effect on fertility, we combined quantitative and qualitative analyses of the AZFc interval at the DAZ and CDY1 loci in 300 infertile men and 399 control men. Results: We detected 34 partial AZFc deletions (32 gr/gr deletions), arising from at least 19 independent deletion events, and found gr/gr deletion in 6% of infertile and 3.5% of control men (p>0.05). Our data provide evidence for two large AZFc inversion polymorphisms, and for relative hot and cold spots of unequal crossing over within the blocks of homology that mediate gr/gr deletion. Using SFVs (sequence family variants), we discriminate DAZ1/2, DAZ3/4, CDY1a (proximal), and CDY1b (distal) and define four types of DAZ-CDY1 gr/gr deletion. Conclusions: The only deletion type to show an association with infertility was DAZ3/4-CDY1a (p = 0.042), suggesting that most gr/gr deletions are neutral variants. We see a stronger association, however, between loss of the CDY1a SFV and infertility (p = 0.002). Thus, loss of this SFV through deletion or gene conversion could be a major risk factor for male infertility.

Y chromosome diversity, human expansion, drift, and cultural evolution

The relative importance of the roles of adaptation and chance in determining genetic diversity and evolution has received attention in the last 50 years, but our understanding is still incomplete. All statements about the relative effects of evolutionary factors, especially drift, need confirmation by strong demographic observations, some of which are easier to obtain in a species like ours. Earlier quantitative studies on a variety of data have shown that the amount of genetic differentiation in living human populations indicates that the role of positive (or directional) selection is modest. We observe geographic peculiarities with some Y chromosome mutants, most probably due to a drift-related phenomenon called the surfing effect. We also compare the overall genetic diversity in Y chromosome DNA data with that of other chromosomes and their expectations under drift and natural selection, as well as the rate of fall of diversity within populations known as the serial founder effect during the recent “Out of Africa” expansion of modern humans to the whole world. All these observations are difficult to explain without accepting a major relative role for drift in the course of human expansions. The increasing role of human creativity and the fast diffusion of inventions seem to have favored cultural solutions for many of the problems encountered in the expansion. We suggest that cultural evolution has been subrogating biologic evolution in providing natural selection advantages and reducing our dependence on genetic mutations, especially in the last phase of transition from food collection to food production.

Marseillevirus-Like Virus Recovered From Blood Donated by Asymptomatic Humans

The study of the human virome is still in its infancy, especially with regard to the viral content of the blood of people who are apparently disease free. In this study, the genome of a new giant virus that is related to the amoeba-infecting pathogen Marseillevirus was recovered from donated blood, using high-throughput sequencing. Viral antigens were identified by an immunoconversion assay. The virus was visualized with transmission electron microscopy and fluorescence in situ hybridization and was grown in human T lymphocytes. Specific antibody reactions were used to identify viral proteins in blood specimens from polymerase chain reactive-positive donors. Finally, we tested 20 blood specimens from additional donors. Three had antibodies directed against this virus, and 2 had circulating viral DNA. This study shows that giant viruses, which are missed by the use of ultrafilters, are part of the human blood virome. The putative pathogenic role of giant viruses in humans remains undefined.

HLA-DRB1 alleles and Jka immunization

BACKGROUND: In transfusion medicine, anti‐Jka has been implicated in hemolytic transfusion reactions. Development of anti‐Jka after transfusion does not always occur after Jk(a–) patients receive at least 1 unit of Jk(a+) blood unit. This study was designed to identify HLA‐DRB1 alleles associated with predisposition to Jka immunization after blood transfusion or pregnancy.

Analysis of ABO discrepancies occurring in 35 French hospitals.

BACKGROUND:  The risk of immunohemolytic reaction owing to ABO‐mismatched mistransfusion is 100 to 1000 times higher than the risk of viral infection. Like analysis of incident reports, evaluation of near‐miss events can provide useful insight into hazardous situations for mis‐matched blood transfusion. The aim of this prospective study was to assess the incidence and root causes of all ABO discrepancies, detected by a central hematology laboratory, in blood samples referred from 35 district hospitals.

DISTINGUISHING THE CO-ANCESTRIES OF HAPLOGROUP G Y-CHROMOSOMES IN THE POPULATIONS OF EUROPE AND THE CAUCASUS

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.

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.

HLA-DRB1 polymorphism is associated with Kell immunisation

K immunisation is observed in some polytransfused patients and pregnant women but does not occur in all cases of K incompatibility. This study analysed the role of genetic background in this selective response to K antigen by investigating HLA‐DRB1 alleles associated with K immunisation in a southern European population. HLA‐DRB1 genotyping was performed by polymerase chain reaction sequence‐specific oligonucleotide/sequence‐specific primer procedures in 54 K immunised patients and 200 healthy controls. The frequency of HLA‐DRB1*11 was significantly higher in K immunised patients than healthy controls: 31 of 54 (57%) vs. 56 of 200 (28%) (Pc < 0·001). In the remaining K immunised HLA‐DRB1*11‐negative patients, the frequency of HLA‐DRB1*13 was increased: 14 of 23 (61%) vs. 49 of 144 in healthy controls (34%) (P < 0·02). The combined frequency of the two HLA‐DRB1 alleles (HLA‐DRB1*11 and HLA‐DRB1*13) was 83% in K immunised patients when compared with 52% in healthy controls (Pc < 0·001). K and k differ by a single amino acid T193 (M). The DRB1*11 and DRB1*13 alleles share a HLA‐DRB1 gene sequence containing S in position 13, D in 70 and A in 74, and coding for the P4 pocket within the HLA‐DR binding groove. This feature of the HLA‐DRB1 gene could be involved in the K peptide presentation through a polymorphism ligand specific for the T193 (M) of K. In conclusion, this study demonstrated a high frequency of HLA‐DRB1*11 or HLA‐DRB1*13 alleles in K immunised patients, which could be due to specific K peptide presentation by HLA‐DR molecules.