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Knowledge about the variability spectra of neutrally evolving sequences in a population is a prerequisite for the identification of genes, which may have been under positive selection during recent human evolution. Here, we report the results of a re-sequencing project of a presumably neutrally evolving chromosome 22 locus with a severely reduced recombination frequency in a group of 24 individuals of German origin. The comparison of these data with the results of a similar analysis of a chromosome 17 locus revealed striking differences, although the same group of individuals was used. For the chromosome 17 locus two well-separated groups of sequences, a positive value of Tajima's D and a TMRCA of 700 000 years were observed. In contrast, the sequences from the chromosome 22 locus were found to be relatively homogeneous, with no deep splits between subgroups; the obtained value for Tajima's D was negative and the TMRCA was only 260 000 years. These discrepancies may be explained by selection or demographic processes. Regarding demography, the most plausible explanation is the assumption of a severe bottleneck in the history of the European population: in the case of the chromosome 17 locus two ancient lineages passed this bottleneck; for the chromosome 22 locus it was only one ancient lineage. [ABSTRACT FROM AUTHOR]

The mammalian genome is not a random sequence but shows a specific, evolutionarily conserved structure that becomes manifest in its isochore pattern. Isochores, i.e. stretches of DNA with a distinct sequence composition and thus a specific GC content, cause the chromosomal banding pattern. This fundamental level of genome organization is related to several functional features like the replication timing of a DNA sequence. GC richness of genomic regions generally corresponds to an early replication time during S phase. Recently, we demonstrated this interdependency on a molecular level for an abrupt transition from a GC-poor isochore to a GC-rich one in the NF1 gene region; this isochore boundary also separates late from early replicating chromatin. Now, we analyzed another genomic region containing four isochores separated by three sharp isochore transitions. Again, the GC-rich isochores were found to be replicating early, the GC-poor isochores late in S phase; one of the replication time zones was discovered to consist of one single replicon. At the boundaries between isochores, that all show no special sequence elements, the replication machinery stopped for several hours. Thus, our results emphasize the importance of isochores as functional genomic units, and of isochore transitions as genomic landmarks with a key function for chromosome organization and basic biological properties. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The centromeric heterochromatin of all human chromosomes is composed of tandemly repeated alpha satellite DNA. Here we describe another alphoid subfamily that maps to human chromosome 22 as determined by FISH. The alphoid sequences were isolated from three YAC-clones carrying DNA from the pericentromeric region of the short arm of human chromosome 22 and limited amounts of alphoid DNA. This property enabled us to map the members of the subfamily to the border of the centromeric region and the short arm of the chromosome. The new alphoid subfamily may contribute to the closure of the gap remaining between the centromeric and short-arm maps of human chromosome 22. [ABSTRACT FROM AUTHOR]

Cell cultures were derived from angiofibromas of three patients with tuberous sclerosis (TSC), from the unaffected skin of these patients, and from the skin of five healthy donors. The length distributions of the small polydisperse circular DNA (spcDNA) fraction of these cell cultures were then analyzed. Nearly half the spcDNA molecules from the angiofibroma cultures were longer than 0.4 μm, whereas only about 7% exceeded this threshold in the spcDNA preparations from the skin fibroblast cultures. The percentage of the larger size class of spcDNA showed an increase at higher numbers of in vitro passages in all three types of cultures, but this effect was much more conspicuous in the angiofibroma-derived cultures than in those from the skin fibroblasts. An age-dependent increase in the overall amount of spcDNA was only seen in the angiofibroma-derived cultures. Our earlier finding of elevated amounts of spcDNA in angiofibroma cultures was confirmed in cultures from an additional TSC patient. [ABSTRACT FROM AUTHOR]

Much greater amounts of small polydisperse circular DNA (spcDNA) have been detected, in cell cultures derived from angiofibromas of six patients with tuberous sclerosis (TS) than in those from the skin of these patients or from the skin of 11 healthy donors. This observation could be confirmed by spreading the DNA of appropriate fractions from CsCl density gradients. The findings suggest the existence of a relationship between the chromosomal instability observed in angiofibroma cultures and the mobilization of spcDNA. [ABSTRACT FROM AUTHOR]

DNA restriction, molecular cloning, and sequencing methods have been used to characterize the mutation leading to the methemoglobinemia HbM Iwate. It could be demonstrated that the HbM Iwate defect is caused by a point mutation involving a transition from C to T in the first position of codon 87 of the α-globin gene. Furthermore, the HbM Iwate mutation can directly be identified upon RsaI digestion. This direct detection of the mutation on the gene level is of significant advantage for differential diagnostic purposes. [ABSTRACT FROM AUTHOR]

A mutant RsaI restriction endonuclease site of high frequency has been identified in individuals of German, Greek, Italian, and Turkish origin. The mutation was found within the α-globin gene complex and is located 0.7 kb 5′ to the α-globin gene. In individuals of central European origin 34 out of 58 chromosomes exhibited the α-gene linkage to the presence of the polymorphic site, and thus a preliminary estimate of the gene frequency for this allele would be 0.59. DNA analysis data of individuals derived from Mediterranean populations indicate a distribution of this polymorphic marker in similar frequencies. [ABSTRACT FROM AUTHOR]