No abstract

It is well accepted that the Americas were the last continents reached by modern humans, most likely through Beringia. However, the precise time and mode of the colonization of the New World remain hotly disputed issues. Native American populations exhibit almost exclusively five mitochondrial DNA (mtDNA) haplogroups (A-D and X). Haplogroups A-D are also frequent in Asia, suggesting a northeastern Asian origin of these lineages. However, the differential pattern of distribution and frequency of haplogroup X led some to suggest that it may represent an independent migration to the Americas. Here we show, by using 86 complete mitochondrial genomes, that all Native American haplogroups, including haplogroup X, were part of a single founding population, thereby refuting multiple-migration models. A detailed demographic history of the mtDNA sequences estimated with a Bayesian coalescent method indicates a complex model for the peopling of the Americas, in which the initial differentiation from Asian populations ended with a moderate bottleneck in Beringia during the last glacial maximum (LGM), around approximately 23,000 to approximately 19,000 years ago. Toward the end of the LGM, a strong population expansion started approximately 18,000 and finished approximately 15,000 years ago. These results support a pre-Clovis occupation of the New World, suggesting a rapid settlement of the continent along a Pacific coastal route.

Mesenchymal stem cells (MSCs) give origin to the marrow stromal environment that supports hematopoiesis. These cells present a wide range of differentiation potentials and a complex relationship with hematopoietic stem cells (HSCs) and endothelial cells. In addition to bone marrow (BM), MSCs can be obtained from other sites in the adult or the fetus. We isolate MSCs from the umbilical cord (UC) veins that are morphologically and immunophenotpically similar to MSCs obtained from the BM. In culture, these cells are capable of differentiating in vitro into adipocytes, osteoblasts, and condrocytes. The gene expression profiles of BM-MSCs and of UC-MSCs were compared by serial analysis of gene expression, then validated by reverse transcription polymerase chain reaction of selected genes. The two lineages shared almost all of the first thousand most expressed transcripts, including vimentin, galectin 1, osteonectin, collagens, transgelins, annexin A2, and MMP2. Nevertheless, a set of genes related to antimicrobial activity and to osteogenesis was more expressed in BM-MSCs, whereas higher expression in UC-MSCs was observed for genes that participate in pathways related to matrix remodeling via metalloproteinases and angiogenesis. Finally, cultured endothelial cells, CD34 + HSCs, MSCs, blood leukocytes, and bulk BM clustered together, separated from seven other normal nonhematopoietic tissues, on the basis of shared expressed genes. MSCs isolated from UC veins are functionally similar to BM-MSCs, but differentially expressed genes may reflect differences related to their sites of origin: BMMSCs would be more committed to osteogenesis, whereas UC-MSCs would be more committed to angiogenesis.

ABSTRACT

We made the hypothesis that donor and recipient gene polymorphisms that drive the host response to microorganisms could be associated with infections after bone marrow transplantation (BMT). HLAidentical BMT was performed for patients with acute (n ‫؍‬ 39) or chronic leukemia (n ‫؍‬ 68). Univariate and multivariate analyses, using death as a competing event, were performed to study risk factors. In multivariate analysis, first overall infections were increased in patients with the Fc␥RIIa R-131 genotype (hazard ratio [HR] ‫؍‬ 1.92; P ‫؍‬ .04), and severe bacterial infections were increased when the MPO donor genotype was AG or AA (HR ‫؍‬ 2.16; P ‫؍‬ .03). Viral and invasive fungal infections were not influenced by any genetic factor studied. Interestingly, we also found that (1) time to neutrophil recovery was shorter when donors were Fc␥RIIIb HNA-1a/HNA-1b (HR ‫؍‬ 1.77; P ‫؍‬ .002); (2) donor IL-1Ra (absence of IL-1RN*2) increased the risk for acute graft-versus-host disease (GVHD) (II-IV) (HR ‫؍‬ 2.17; P ‫؍‬ .017); and (3) recipient IL-10 (GG) and IL-1Ra genotypes increased the risk for chronic GVHD (P ‫؍‬ .03 and P ‫؍‬ .03, respectively). Finally, 180-day transplantation-related mortality rates were increased when donors were Fc␥RIIIb HNA-1a/HNA-1a or HNA-1b/ HNA-1b (HR ‫؍‬ 2.57; P ‫؍‬ .05) and donor MPO genotype was AA (HR ‫؍‬ 5.14; P ‫؍‬ .004). In conclusion, donor and recipient gene polymorphisms are informative genetic risk factors for selecting donor/ recipient pairs and could help in the understanding of mechanisms involved in host defenses of BM transplant recipients. (Blood. 2002;100:3908-3918)