No abstract

In this paper the functional relevance of a TNFA promoter polymorphism, a G/A polymorphic sequence at position -238, was tested by analysing its influence on TNF alpha production upon in vitro stimulation of monocytes from 78 healthy, unrelated individuals by lipopolysaccharide (LPS) or after allogenic stimulation in a panel of 32 healthy individuals. All TNFA-A positive individuals were either DR3 or DR7 positive, confirming the previously reported strong linkage disequilibrium of the TNFA-A allele with the two extended haplotypes (B18, F1C30, DR3) and (B57, SC61, DR7). No individuals homozygous for the TNFA-A allele were present in the panel. The mean level of TNF alpha production was not significantly different in TNFA-G/G homozygous and in TNFA-A/G heterozygous individuals after LPS stimulation of monocytes (P = 0.35) or after allogenic stimulation (P = 0.7). After LPS and allogenic stimulation DR3 positive individuals had a higher mean TNF production. This could not be further differentiated by typing for TNF -283.

The human growth hormone gene (GH-N) is located in a cluster of five highly homologous genes that are coordinately expressed in pituitary (GH-N) and in placental tissues (the chorionic-somatomammotropin-like gene, the GH-variant gene and the two chorionic somatomammotropin genes). Sequence analysis from position -162 to position +100 of the GH-N gene has revealed eight nucleotide polymorphisms with no significant difference in frequency between patients affected by isolated growth hormone deficiency and controls. Remarkably, all these variations are located at positions where the GH-N differs from at least one of the other four homologous genes. The analysis of the twelve GH-N haplotypes originating from the combinations of the eight polymorphisms has revealed that not only single variations, but also nucleotide combinations are identical to those of the other placental genes. These findings suggest that whole stretches of the GH-N gene promoter have been replaced by homologous DNA stretches copied from one of the other four loci by repeated gene-conversion-like events, where the GH-N gene has acted as the recipient and the placental genes as donors of the converted sequences. The presence of a Chi-like element also indicates that the GH-N promoter represents a hot spot of gene conversion. Three of these variations cause, in addition, an amino-acid substitution in the GH-gene-derived transcriptional activator gene whose coding sequence overlaps the GH-N promoter. Thus, a DNA region that serves two distintic functions representing the proximal promoter of a gene and the 5' coding region of another gene displays an unusually high degree of polymorphism that has probably arisen because of gene conversion.

Data on microgeographic population structure on four neighbouring villages of Sardinia island (Italy) are presented and discussed. Two villages are located in the lowlands where malaria from Plasmodium falciparum was endemic until the eradication of paludism. The other two villages are located in the highlands and they were malaria-free because of the altitude. Census data, inbreeding, migration matrices and surname distributions have been collected. The genetic differentiation of the four villages, tested for 31 genetic polymorphisms (106 alleles), is only in part compatible with migration rates inferred from demographic data. The possible adaptive nature of some genetic markers with respect to malarial resistance is discussed. Ambiguous results from population genetics quantitative methods do not support definite answers.