Effects of natural selection and gene conversion on the evolution of human glycophorins coding for MNS blood polymorphisms in malaria-endemic African populations.

Malaria has been a very strong selection pressure in recent human evolution, particularly in Africa. Of the one million deaths per year due to malaria, more than 90% are in sub-Saharan Africa, a region with high levels of genetic variation and population substructure. However, there have been few studies of nucleotide variation at genetic loci that are relevant to malaria susceptibility across geographically and genetically diverse ethnic groups in Africa. Invasion of erythrocytes by Plasmodium falciparum parasites is central to the pathology of malaria. Glycophorin A (GYPA) and B (GYPB), which determine MN and Ss blood types, are two major receptors that are expressed on erythrocyte surfaces and interact with parasite ligands. We analyzed nucleotide diversity of the glycophorin gene family in 15 African populations with different levels of malaria exposure. High levels of nucleotide diversity and gene conversion were found at these genes. We observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. Specifically, we identified fixed adaptive changes at exons 3-4 of GYPA. By contrast, we observed an allele frequency spectrum skewed toward a significant excess of intermediate-frequency alleles at GYPA exon 2 in many populations; the degree of spectrum distortion is correlated with malaria exposure, possibly because of the joint effects of gene conversion and balancing selection. We also identified a haplotype causing three amino acid changes in the extracellular domain of glycophorin B. This haplotype might have evolved adaptively in five populations with high exposure to malaria.

Systematic classification of alleles of the glycophorin A (MN blood group) gene.

Ten alleles (five M and five N alleles) of the MN blood group system with normal antigenicity were found by sequencing the glycophorin A (GPA) gene. This study demonstrates the systematic classification of these alleles to major or minor variations of the standard alleles. GPA-specific fragments ranging from 150 to 3.8 kb in length were amplified from the templates, and exons 1-7 and introns 1-6 were sequenced. The data were analyzed phylogenetically to classify these alleles into major groups or clusters. The ten alleles were grouped into four major clusters M10X (M101-M103), M20X (M201 and M202), N10X (N101-N104) and N20X (N201), where 'X' represents a digit indicating minor variations. This grouping was supported by phylogenetic analysis. The cluster system of GPA alleles is highly informative for genetic screening.

Five types of glycophorin variants found in southern China.

PURPOSE: To summarize the results of gene analysis for five types of glycophorin (GP) variants found in a screening survey conducted in several regions of Southern China. DATA SOURCES: Papers cited in Chinese biochemical and biomedical literatures with a bibliographic review of articles relevant to hematology and biochemistry. STUDY SELECTION: All GP variant reports of our research group published during 1991-1997 were included. DATA EXTRACTION: Data concerning 5 types of GP variants found in Southern China were briefly abstracted. GP variant frequencies with their phenotypes among 3 districts and those among Han, Li, Buyi and Yao ethnic groups were calculated. RESULTS: Five phenotypes of GP variants [Sta, Mi III, Mi V (J.L.), Mi VI and a novel case] were identified from 180 unrelated healthy individuals (Hunan, Hainan) and 222 residents of a tertian malaria hyperendemic area (Guizhou), using immunoblotting techniques, Southen hybridization and PCR-direct sequencing. CONCLUSIONS: These five types of GP variants were first reported in China. There were some differences in the geographical distribution of GP variants among Hunan, Hainan and Guizhou districts. Mi III GP was commonly found in national minorities of Li and Buyi, while the frequency of Sta GP occurrence was considerably higher in Han ethnic group. The frequency of GP variants in a malaria hyperendemic area of Guizhou Province does not depend upon the severity of tertian malaria morbidity.

Gerbich blood groups and minor glycophorins of human erythrocytes.

Four main glycophorins which can be specifically detected by periodic-acid-Schiff (PAS) staining after separation of red cell membranes by SDS-polyacrylamide gel electrophoresis have been identified and are known under different nomenclatures. Here, the designation of glycophorins A, B and C and glycophorin D will be used. A new member designated glycophorin E (GPE) has been recently identified in the course of molecular genetic studies. These glycophorins represent about 2% of the total erythrocyte membrane protein mass and have been fully characterized both at the protein and at the DNA level. Accordingly, these molecules can be subdivided into two groups that are distinguished by distinct properties such as blood group antigenic properties, apparent M(r), copy number, attached glycans, detergent solubility, and gene structure. GPC and GPD are minor sialoglycoproteins contributing to 4 and 1% to the PAS-positive material and are present at about 2.0 and 0.5 x 10(5) copies/cell, respectively. Both carry blood group Gerbich (Ge) antigens. Protein and nucleic acid analysis indicated that GPD is a truncated form of GPC in its N-terminal region and that both proteins are produced by a unique gene which is present as a single copy on chromosome 2q14-q21. GPC and GPD are produced from the same gene through use of alternative translation initiation sites. These proteins and the GYPC gene share no homology with the GPA, GPB and GPE proteins and the GYPA gene cluster, respectively. Thus, the glycophorin name, which suggests that all these sialoglycopropteins have a common genetic origin, might be now considered as a misnomer. As a further difference between the two groups of membrane proteins, GPC and GPD are expressed both in erythroid and non erythroid tissues, but the level of transcription is much higher in erythroid than in non erythroid tissues and in addition the proteins are differently glycosylated in the two cell types. Increasing evidence suggests a significant role for GPC and GPD in the regulation of the red cell shape and the membrane mechanical properties by providing a membrane linkage site for cytoskeletal proteins, especially proteins 4.1 and p55. The total lack of GPC and GPD in the red cell membrane is associated with hereditary ellyptocytosis in the Leach phenotype and the molecular basis of these defects have been elucidated.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormal blood-group-Ss-active sialoglycoproteins in the membrane of Miltenberger class III, IV and V human erythrocytes.

1. We have studied the inherited changes occurring in the sialoglycoproteins of membranes from erythrocytes of type Miltenberger Class III (Mi.III), Miltenberger Class IV (Mi.IV) and Miltenberger Class V (Mi.V) by using sodium dodecyl sulphate/polyacrylamide gel electrophoresis and lactoperoxidase radioiodination. 2. Mi.III erythrocytes lack the normal blood-group-Ss-active sialoglycoprotein but contain an unusual s-active sialoglycoprotein of higher apparent molecular weight. A similar abnormal S-active sialoglycoprotein appears to occur in Mi.IV erythrocytes. 3. The Mi.V condition is associated with the hemizygous absence of both the normal blood-group-MN-active sialoglycoprotein and the normal Ss-active sialoglycorprotein. However, a new sialoglycoprotein component is present in these cells that has properties characteristic of both the MN-active and Ss-active sialoglycoproteins. 4. Our results suggest that the new sialoglycorportein present in Mi.V erythrocytes is a hybrid of the normal MN sialoglycoprotein and an s-active sialoglycoprotein that has properties similar to the s-active sialoglycoprotein found in Mi.III erythrocytes. We suggest that the unusual Mi.V sialoglycoprotein is derived from chromosomal misalignment with unequal crossing-over between the genes for the MN- and Ss-active sialoglycoproteins in a manner similar to that which gives rise to haemoglobin Lepore. 5. Further studies of S-s-erythrocytes confirm that these cells lack normal Ss-active sialoglycoprotein, but contain an unusual component that shows some of the properties of the normal Ss-active sialoglycoprotein. 6. Analysis of erythrocytes of type Mk/Mi.III confirms that, in addition to the known hemizygous lack of the MN-active sialoglycoprotein, the Mk condition is also associated with a loss of the Ss-active sialoglycoprotein. 7. In order to facilitate discussion of the complex changes that occur in these variant erythrocytes, a new unified nomenclature is used for the erythrocyte sialoglycoproteins.