Publisher Summary This chapter discusses the formal genetics of mouse anemias and their significance for an analysis of patterns of mammalian gene action. It also describes normal hemopoietic development, homeostasis, and hemoglobin polymorphism. Anemias are classified into five categories—(1) anemias of maturation arrest, (2) anemias involving defects in iron utilization, (3) anemias involving greatly reduced erythrocyte life-span, (4) hemoglobinopathies, and (5) anemias almost secondary to genetically induced defects. During the total life of a mouse, including prenatal development, hemopoiesis takes place in four different sites. Although hemopoiesis continues in the liver until birth and for a brief time thereafter, hemopoiesis (largely myelopoiesis) commences in the spleen on fetal day 15 or 16 and in the marrow around the time of birth. Hematologically normal adult mice from many different inbred strains regularly produce more than one kind of hemoglobin. There is a widespread genetic polymorphism at both the Hba locus, determining the α-globin structure and the Hbb locus, determining the β-globin structure, and both the loci involve considerable genetic complexity.

Hereditary Anemias of the Mouse: A Review for Geneticists*

STUDIES of the regulation of human erythropoiesis and haemoglobin synthesis at different phases of development are hampered by the lack of a self-sustaining culture in which erythroid differentiation can be examined, and by difficulties in obtaining erythropoietic tissue in embryonic and early fetal life1. New insights into the regulation of murine erythropoiesis have been obtained by the study of established cultures of erythro-leukaemic cells (Friend cells) which can be induced to differentiate in vitro2. Recently, Andersson et al. 3,4 have reported that the K562 human cell line, obtained from a patient with an acute transformation of chronic myeloid leukaemia (CML) has properties in common with erythroid cells. In particular, cells of this line contain glycophorin and spectrin in their membranes and synthesise minute amounts of haemoglobin, detectable by radioimmunoassay. We have investigated the capacity of these cells to differentiate in vitro and report here that they are induced by haemin to synthesise large amounts of haemoglobin; preliminary analysis indicates that this is predominantly of the embryonic type.

K562 human leukaemic cells synthesise embryonic haemoglobin in response to haemin.

Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom?

The chromosomal arrangement of human alpha-like globin genes: sequence homology and alpha-globin gene deletions.

Despite considerable excitement over the potential functional significance of copy-number variants (CNVs), we still lack knowledge of the fine-scale architecture of the large majority of CNV regions in the human genome. In this study, we used a high-resolution array-based comparative genomic hybridization (aCGH) platform that targeted known CNV regions of the human genome at approximately 1 kb resolution to interrogate the genomic DNAs of 30 individuals from four HapMap populations. Our results revealed that 1020 of 1153 CNV loci (88%) were actually smaller in size than what is recorded in the Database of Genomic Variants based on previously published studies. A reduction in size of more than 50% was observed for 876 CNV regions (76%). We conclude that the total genomic content of currently known common human CNVs is likely smaller than previously thought. In addition, approximately 8% of the CNV regions observed in multiple individuals exhibited genomic architectural complexity in the form of smaller CNVs within larger ones and CNVs with interindividual variation in breakpoints. Future association studies that aim to capture the potential influences of CNVs on disease phenotypes will need to consider how to best ascertain this previously uncharacterized complexity.

/pdf/the-fine-scale-and-complex-architecture-of-human-copy-number-4tzkbsslbq.pdf

The fine-scale and complex architecture of human copy-number variation.

Two independent groups show that the absence of all or part of the globin α-chain gene is the origin of the homozygous α thalassaemia.

The severe form of alpha thalassaemia is caused by a haemoglobin gene deletion.

Summary. The haemoglobin constitution of 14 infants with the haemoglobin Bart's hydrops syndrome has been examined. Thirteen of the infants were stillborn or lived only a few minutes after delivery, but in one case an exchange transfusion was performed and the pattern of globin chain synthesis examined by an [H3]leucine incorporation experiment utilizing umbilical cord blood. These studies indicate that the syndrome results from a total deficiency of α-chain production. Furthermore, it has been possible to exclude the presence of fragments of α-chain longer than II residues in the cells of these infants.

In each infant a small quantity of haemoglobin was found which consisted of normal γ-chains in association with chains of unique constitution. A similar component was found in trace amounts in normal umbilical cord blood. This haemoglobin may be identical with haemoglobin Portland. It is suggested that the non-γ-chain of this haemoglobin is the product of a normal foetal haemoglobin locus which produces very small amounts of gene product in normal infants but which is capable of increased activity in the presence of a partial or total deficiency of α-chains.

The haemoglobin constitution of infants with the haemoglobin Bart's hydrops foetalis syndrome.

AN abnormal haemoglobin with a substitution involving a proline residue might be expected to be either unstable or functionally abnormal because of the inevitable conformational changes which occur. This has been borne out in the cases of haemoglobins Genova, Dhofar, Bibba and Santa Ana, all of which are unstable and associated with Heinz body anaemia1. Replacements involving proline residues do not, however, invariably result in these changes. Thus Hb-Chiapas2,3 is not unstable and its presence does not lead to clinical or haematological symptoms. We have recently observed two new haemoglobin variants of this type which are also not associated with marked molecular instability.

Two new haemoglobin variants involving proline substitutions.

SAMPLES of blood from 64 normal unrelated Chinese people, mostly from Singapore, were tested for the X-linked blood group antigen Xga with the following results:

Wong Hock Boon

Papers

The severe form of alpha thalassaemia is caused by a haemoglobin gene deletion.

The haemoglobin constitution of infants with the haemoglobin Bart's hydrops foetalis syndrome.

Two new haemoglobin variants involving proline substitutions.

Xg blood groups of chinese.