A cause of aging in yeast is the accumulation of circular species of ribosomal DNA (rDNA) arising from the 100-200 tandemly repeated copies in the genome. We show here that mutation of the FOB1 gene slows the generation of these circles and thus extends life span. Fob1p is known to create a unidirectional block to replication forks in the rDNA. We show that Fob1p is a nucleolar protein, suggesting a direct involvement in the replication fork block. We propose that this block can trigger aging by causing chromosomal breaks, the repair of which results in the generation of rDNA circles. These findings may provide a novel link between metabolic rate and aging in yeast and, perhaps, higher organisms.

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Special mechanisms for stimulating recombination among the nearly identical repeat units of certain multigene families may exist in order to maintain their sequence homogeneity. We have found evidence for such a recombination-stimulating activity in the tandemly repeated ribosomal RNA genes of yeast. A fragment of the yeast ribosomal DNA (rDNA), containing the 5S gene, nontranscribed spacer DNA, and part of the 25S gene, causes a localized stimulation of recombination when inserted at novel locations in the yeast genome. The rDNA fragment stimulates both interchromosomal and intrachromosomal mitotic recombination but not meiotic recombination. To stimulate mitotic recombination, the fragment must act on both copies of the recombining gene. Furthermore, the rDNA fragment stimulates exchange only when inserted with the 5S gene proximal to, and the 25S gene distal to, the recombining alleles.

We have used a series of 30 DNA probes previously mapped to the long arm of the human Y chromosome, to screen a panel of 21 patients with structural abnormalities in Yq, by genomic blot hybridisation. The results have allowed us to construct a detailed map of interval 6 of the Y chromosome, in which 28 of the probes could be assigned to 14 sub-intervals within interval 6. Some probes detect two or more loci within this region, each of which has been localised. The same set of probes has been used to screen a panel of 19 chromosomally normal azoospermic men, two of whom have been found to carry microdeletions within this region. With the completion of this map we have been able accurately to localise these microdeletions within interval 6 and show that they do not overlap. We believe these microdeletions may disrupt the azoospermia factor (AZF) involved in spermatogenesis, and which is known to lie in this region. These results are an important step towards the localisation of the AZF locus.