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Many questions can be explored thanks to whole-genome data. The aim of this study was to overcome their main limits, software availability and database accuracy, and estimate the feasibility of red blood cell (RBC) antigen typing from whole-genome sequencing (WGS) data. We analyzed whole-genome data from 79 individuals for HLA-DRB1 and 9 RBC antigens. Whole-genome sequencing data was analyzed with software allowing phasing of variable positions to define alleles or haplotypes and validated for HLA typing from next-generation sequencing data. A dedicated database was set up with 1648 variable positions analyzed in KEL (KEL), ACKR1 (FY), SLC14A1 (JK), ACHE (YT), ART4 (DO), AQP1 (CO), CD44 (IN), SLC4A1 (DI) and ICAM4 (LW). Whole-genome sequencing typing was compared to that previously obtained by amplicon-based monoallelic sequencing and by SNaPshot analysis. Whole-genome sequencing data were also explored for other alleles. Our results showed 93% of concordance for blood group polymorphisms and 91% for HLA-DRB1. Incorrect typing and unresolved results confirm that WGS should be considered reliable with read depths strictly above 15x. Our results supported that RBC antigen typing from WGS is feasible but requires improvements in read depth for SNV polymorphisms typing accuracy. We also showed the potential for WGS in screening donors with rare blood antigens, such as weak JK alleles. The development of WGS analysis in immunogenetics laboratories would offer personalized care in the management of RBC disorders. [ABSTRACT FROM AUTHOR]

We studied a cohort of 367 healthy related donors who volunteered to donate their hematopoietic stem cells for allogeneic transplantation. All donors were homogeneously cared for at a single institution, and received rhG-CSF as a mobilization treatment prior to undergoing apheresis. Peripheral blood CD34+ cell counts were used as the main surrogate marker for rhG-CSF induced mobilization. We searched whether inter-individual variations in known genetic polymorphisms located in genes whose products are functionally important for mobilization, could affect the extent of CD34+ mobilization, either individually or in combination. We found little or no influence of individual SNPs or haplotypes for the SDF1, CXCR4, VCAM and VLA4 genes, whether using CD34+ cell counts as a continuous or a categorical variable. Simple clinical characteristics describing donors such as body mass index, age and possibly sex are more potent predictors of stem cell mobilization. The size of our cohort remains relatively small for genetic analyses, however compares favorably with cohorts analyzed in previously published reports suggesting associations of genetic traits to response to rhG-CSF; notwithstanding this limitation, our data do not support the use of genetic analyses when the choice exists of several potential donors for a given patient. [ABSTRACT FROM AUTHOR]

African populations are characterized by high degree of genetic diversity. This high genetic diversity could result from the natural selection pressure. Several studies have described an association between some genetic diversities and difference of susceptibility to infectious diseases like malaria. It seems therefore important to consider genetic diversity impact when interpreting results of clinical trials in malaria endemic areas. This study aimed to determine the genetic polymorphism with erythrocyte traits in different populations of malaria endemic area in Mali. The cross-sectional surveys were carried out in different ethnic groups living in malaria endemic areas in Mali. Six milliliters of whole blood were collected in EDTA vials from each participant after informed consent has been obtained. The ABO, RH, Kell, MNSs, Kidd and Duffy systems phenotypes were assessed by the technique of gel filtration. A total of 231 subjects were included from six villages. The blood groups phenotypes O (40.7%) and A (31.2%) were more frequent with respective allele frequencies of 0.65 and 0.21. In the RH system the haplotypes R0 (0.55), r (0.20) and R1 (0.13) were the most frequent. Seven percent (7%) of Duffy positive and 4% of Glycophorin B deficiency (S-s-) were observed among participants. All participants were Kell negative. ABO and RH systems were polymorphic in these ethnic groups in Mali. Their implication in susceptibility to malaria should be taken into account in clinical trials interpretation, and for prevention of blood transfusion risks during anemia frequently caused by malaria in children. [ABSTRACT FROM AUTHOR]

Defining worldwide human genetic variation is a critical step to reveal how genome plasticity contributes to disease. Yet, there is currently no metric to assess the representativeness and completeness of current and widely used data on genetic variation. We show here that Human Leukocyte Antigen (HLA) genes can serve as such metric as they are both the most polymorphic and the most studied genetic system. As a test case, we investigated the 1,000 Genomes Project panel. Using high-accuracy in silico HLA typing, we find that over 20% of the common HLA variants and over 70% of the rare HLA variants are missing in this reference panel for worldwide genetic variation, due to undersampling and incomplete geographical coverage, in particular in Oceania and West Asia. Because common and rare variants both contribute to disease, this study thus illustrates how HLA diversity can detect and help fix incomplete sampling and hence accelerate efforts to draw a comprehensive overview of the genetic variation that is relevant to health and disease. [ABSTRACT FROM AUTHOR]

The rarity of human remains makes it difficult to apprehend the first settlements in Corsica. It is admitted that initial colonization could have occurred during the Mesolithic period when glaciations would have shortened the open water travel distance from the continent. Mesolithic sites in Corsica show relatively short and irregular occupation, and suggest discontinuous settling of very mobile groups probably traveling by boat. Previous genetic studies on Corsican populations showed internal differentiation and a relatively poor genetic relationship with continental populations, despite intense historical contacts, however local Mesolithic-based genetic inheritance has never been properly estimated. The aim of this study was to explore the Corsican genetic profile of Y-chromosomes in order to trace the genetic signatures back to the first migrations to Corsica. This study included 321 samples from men throughout Corsica; samples from Provence and Tuscany were added to the cohort. All samples were typed for 92 Y-SNPs, and Y-STRs were also analyzed. Results revealed highly differentiated haplogroup patterns among Corsican populations. Haplogroup G had the highest frequency in Corsica, mostly displaying a unique Y-STR profile. When compared with Provence and Tuscany, Corsican populations displayed limited genetic proximity. Corsican populations present a remarkable Y-chromosome genetic mixture. Although the Corsican Y-chromosome profile shows similarities with both Provence and to a lesser extent Tuscany, it mainly displays its own specificity. This study confirms the high level of genetic diversity in Corsican populations and backs genetic contributions from prehistoric migrations associated with the Mesolithic, Neolithic and Metal Age eras, rather than from historical movements to Corsica, respectively attested by frequencies and TMRCA of haplogroups G2a-L91 and G2a-P15, J2a-M241 and J2-DYS445 = 6, R1b-U152 and R1b-U106. These results suggest that marine routes to reach the Corsican coast in many different points may have led to such a genetic heterogeneity. [ABSTRACT FROM AUTHOR]

The HLA-A locus is surrounded by HLA class Ib genes: HLA-E, HLA-H, HLA-G and HLA-F. HLA class Ib molecules are involved in immuno-modulation with a central role for HLA-G and HLA-E, an emerging role for HLA-F and a yet unknown function for HLA-H. Thus, the principal objective of this study was to describe the main allelic associations between HLA-A and HLA-H, -G, -F and -E. Therefore, HLA-A, -E, -G, -H and -F coding polymorphisms, as well as HLA-G UnTranslated Region haplotypes (referred to as HLA-G UTRs), were explored in 191 voluntary blood donors. Allelic frequencies, Global Linkage Disequilibrium (GLD), Linkage Disequilibrium (LD) for specific pairs of alleles and two-loci haplotype frequencies were estimated. We showed that HLA-A, HLA-H, HLA-F, HLA-G and HLA-G UTRs were all in highly significant pairwise GLD, in contrast to HLA-E. Moreover, HLA-A displayed restricted associations with HLA-G UTR and HLA-H. We also confirmed several associations that were previously found to have a negative impact on transplantation outcome. In summary, our results suggest complex functional and clinical implications of the HLA-A genetic region. [ABSTRACT FROM AUTHOR]

The HLA-G molecule plays an important role in immunomodulation. In a previous study carried out on a southern French population our team showed that HLA-G haplotypes, defined by SNPs in the coding region and specific SNPs located in 5′URR and 3′UTR regulatory regions, are associated with differential soluble HLA-G expression (sHLA-G). Furthermore, the structure of these HLA-G haplotypes appears to be conserved in geographically distant populations. The aim of our study is to confirm these expectations in a sub-Saharan African population and to explore additional factors, such as HLA-A alleles, that might influence sHLA-G expression. DNA and plasma samples were collected from 229 Malians; HLA-G and HLA-A genotyping were respectively performed by the Snap Shot® method and by Luminex™ technology. sHLA-G dosage was performed using an ELISA kit. HLA-G and HLA-A allelic and haplotypic frequencies were estimated using an EM algorithm from the Gene[Rate] program. Associations between genetic and non genetic parameters with sHLA-G were performed using a non-parametric test with GRAPH PAD Prism 5. Our results reveal a good conservation of the HLA-G UTR haplotype structure in populations with different origins and demographic histories. These UTR haplotypes appear to be involved in different sHLA-G expression patterns. Specifically, the UTR-2 haplotype was associated with low sHLA-G levels, displaying a dominant negative effect. Furthermore, an allelic effect of both HLA-G and HLA-A, as well as non genetic parameters, such as age and gender possibly linked to osteogenesis and sexual hormones, also seem to be involved in the modulation of sHLA-G. These data suggest that further investigation in larger cohorts and in populations from various ethnical backgrounds is necessary not only to detect new functional polymorphism in HLA-G regulatory regions, but also to reveal the extent of biological phenomena that influence sHLA-G secretion and this might therefore have an impact on transplantation practice. [ABSTRACT FROM AUTHOR]

Despite being located at the crossroads of Asia, genetics of the Afghanistan populations have been largely overlooked. It is currently inhabited by five major ethnic populations: Pashtun, Tajik, Hazara, Uzbek and Turkmen. Here we present autosomal from a subset of our samples, mitochondrial and Y- chromosome data from over 500 Afghan samples among these 5 ethnic groups. This Afghan data was supplemented with the same Y-chromosome analyses of samples from Iran, Kyrgyzstan, Mongolia and updated Pakistani samples (HGDP-CEPH). The data presented here was integrated into existing knowledge of pan-Eurasian genetic diversity. The pattern of genetic variation, revealed by structure-like and Principal Component analyses and Analysis of Molecular Variance indicates that the people of Afghanistan are made up of a mosaic of components representing various geographic regions of Eurasian ancestry. The absence of a major Central Asian-specific component indicates that the Hindu Kush, like the gene pool of Central Asian populations in general, is a confluence of gene flows rather than a source of distinctly autochthonous populations that have arisen in situ: a conclusion that is reinforced by the phylogeography of both haploid loci. [ABSTRACT FROM AUTHOR]