Multi-Organ, Multi-Lineage Engraftment by a Single Bone Marrow-Derived Stem Cell

The first wave of information from the analysis of the human genome revealed SNPs to be the main source of genetic and phenotypic human variation. However, the advent of genome-scanning technologies has now uncovered an unexpectedly large extent of what we term 'structural variation' in the human genome. This comprises microscopic and, more commonly, submicroscopic variants, which include deletions, duplications and large-scale copy-number variants - collectively termed copy-number variants or copy-number polymorphisms - as well as insertions, inversions and translocations. Rapidly accumulating evidence indicates that structural variants can comprise millions of nucleotides of heterogeneity within every genome, and are likely to make an important contribution to human diversity and disease susceptibility.

Structural variation in the human genome

A large case-control study of malaria in West African children shows that a human leucocyte class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501), common in West Africans but rare in other racial groups, are independently associated with protection from severe malaria. In this population they account for as great a reduction in disease incidence as the sickle-cell haemoglobin variant. These data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.

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Common West African HLA antigens are associated with protection from severe malaria

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1053/jhep.2000.9124

Liver from bone marrow in humans.

Publisher Summary Glutathione (GSH) is the most important nonprotein thiol in living systems and is of widespread occurrence in the intracellular milieu of animals, plants, and microorganisms GSH was isolated and named by the English biochemist Frederick Gowland Hopkins This chapter discusses GSH status, the biologically relevant chemistry of GSH, the forms in which GSH can be present within the cell, along with the GSH content of cells and the methods for analysis of this substance GSH-related biochemical reactions and the biological roles of GSH are discussed in the chapter The use of perturbations in GSH status as a means for investigating GSH-related phenomena and an analysis of the consequences of perturbation are presented A short summary of genetic lesions related to GSH is also included Like chemically induced perturbations in GSH status, genetic lesions provide valuable insights into the role of GSH in normal functions and processes in cells The chapter concludes with some brief comments about the future of the relationship of GSH status to cellular processes

The Glutathione Status of Cells

The authors report data on the genetic distribution of thalassaemia and of glucose-6-phosphate dehydrogenase deficiency in the populations of certain Sardinian villages, many of which are not only of great antiquity but have maintained isolation for very long periods and therefore possess the following three requirements for suitability for investigation of the possible interrelationships among malaria, thalassaemia and G-6-PD deficiency: a reasonable degree of ethnic homogeneity, availability of reliable demographic data, and availability of malaria-free populations of adequate size and of ethnic background and genetic isolation similar to those of the malarial populations.Investigations including more than 6000 observations in 52 villages demonstrated a positive correlation between the incidences of thalassaemia and G-6-PD deficiency. It is suggested that the genotype that carries thalassaemia and/or the enzyme deficiency may have a high adaptive value in a malarial environment.It is concluded that there is a need further to investigate human genetic structure and the biological fitness of the principal genotype combinations in both existing environments and those that will result from continued cultural evolution.

Population genetics of haemoglobin variants, thalassaemia and glucose-6-phosphate dehydrogenase deficiency, with particular reference to the malaria hypothesis

The analysis of polymerase chain reaction (PCR)-amplified beta-globin DNA with allele-specific oligonucleotide (ASO) probes reveals a very heterogeneous spectrum of beta-thalassaemia in the Netherlands. However about 20% of the beta-thalassemia mutations cannot be identified with this approach. The combination of specific amplification of certain regions of the beta-globin gene with denaturing gradient gel electrophoresis (DGGE) allowed us to rapidly localize several of these mutations to specific regions of the gene, which were again amplified and directly sequenced. We believe that the combination of DGGE and the direct sequence determination of PCR amplified genomic DNA represents a valid alternative to the 'ASO probes' approach, especially in countries where a very heterogeneous spectrum of beta-thalassaemia mutations occurs.

Denaturing gradient gel electrophoresis and direct sequencing of PCR amplified genomic DNA: a rapid and reliable diagnostic approach to beta thalassaemia.

Summary

Descendants of Dutch colonists, who emigrated to Surinam in the last century and survived epidemics of typhoid and yellow fever with a total mortality of about 60%, were tested for twenty-six polymorphisms. The gene frequencies were compared with those of a large Dutch control sample. An analysis of drift indicated that the variations in gene frequencies observed for C3, Gm, HLA-B, and GLO were unlikely to be due to drift. Therefore these data might indicate selection through genetic control of survival in these epidemics.

Genetic control of survival in epidemics.

A new type of hemoglobin F, in which isoleucine in position 75 (E 19) of the γ chain is replaced by a threonine residue, has been found in 29 out of 32 homozygotes for β thalassemia. The amount of this hemoglobin ranges from traces to 40% of the total Hb F. The same γ75 Thr chain is also present in the Hb F of 40% of normal newborns and premature infants examined, of one 14-week-old fetus and in one out of 3 patients with aplastic anemia and raised levels of Hb F. Our results strongly suggest that the synthesis of this new chain is under the control of a γ gene nonallelic with those coding for Aγ and Gγ chains.

Significance of a new type of human fetal hemoglobin carrying a replacement isoleucine → threonine at position 75 (E 19) of the γ chain

In a family of Indian origin we have identified a deletion of two bases at the polyadenylation signal sequence of the alpha 2-globin gene (AATAAA-->AATA). Three individuals heterozygous for this mutation display an alpha o-thalassaemia-like phenotype. Single-stranded conformation analysis and automatic sequencing showed no additional mutations in either alpha 1- or alpha 2-globin genes. A previously described polyadenylation sequence mutation (AATAAA-->AATAAG), alpha TSaudi alpha, causes HbH disease in homozygotes. In this study the patients heterozygous for the AATA(-AA) mutation show a similar phenotype observed in the alpha TSaudi alpha heterozygotes. This confirms the observation that the inefficient transcriptional termination due to mutations of the polyadenylation sequence of the alpha 2-gene might interfere with the alpha 1-gene expression.

Luigi F. Bernini

Papers

Population genetics of haemoglobin variants, thalassaemia and glucose-6-phosphate dehydrogenase deficiency, with particular reference to the malaria hypothesis

Denaturing gradient gel electrophoresis and direct sequencing of PCR amplified genomic DNA: a rapid and reliable diagnostic approach to beta thalassaemia.

Genetic control of survival in epidemics.

Significance of a new type of human fetal hemoglobin carrying a replacement isoleucine → threonine at position 75 (E 19) of the γ chain

A novel polyadenylation signal mutation in the α2‐globin gene causing α thalassaemia