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Non-insulin dependent diabetes mellitus (NIDDM) affects more than 100 million people worldwide and is associated with severe metabolic defects, including peripheral insulin resistance, elevated hepatic glucose production, and inappropriate insulin secretion. Family studies point to a major genetic component, but specific susceptibility genes have not yet been identified-except for rare early-onset forms with monogenic or mitochondrial inheritance. We have screened over 4,000 individuals from a population isolate in western Finland, identified 26 families (comprising 217 individuals) enriched for NIDDM and performed a genome-wide scan using non-parametric linkage analysis. We found no significant evidence for linkage when the families were analysed together, but strong evidence for linkage when families were classified according to mean insulin levels in affecteds (in oral glucose tolerance tests). Specifically, families with the lowest insulin levels showed linkage (P = 2 x 10(-6)) to chromosome 12 near D12S1349. Interestingly, this region contains the gene causing the rare, dominant, early-onset form of diabetes MODY3. Unlike MODY3 families, the Finnish families with low insulin have an age-of-onset typical for NIDDM (mean = 58 years). We infer the existence of a gene NIDDM2 causing NIDDM associated with low insulin secretion, and suggest that NIDDM2 and MODY3 may represent different alleles of the same gene.

Maturity-onset diabetes of the young (MODY) type 3 is a dominantly inherited form of diabetes, which is often misdiagnosed as non-insulin-dependent diabetes mellitus (NIDDM) or insulin-dependent diabetes mellitus (IDDM). Phenotypic analysis of members from four large Finnish MODY3 kindreds (linked to chromosome 12q with a maximum lod score of 15) revealed a severe impairment in insulin secretion, which was present also in those normoglycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with IDDM by lack of glutamic acid decarboxylase antibodies (GAD-Ab). Taken

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Classical genetic studies in Drosophila and yeast have shown that chromosome centromeres have a cis-acting ability to repress meiotic exchange in adjacent DNA. To determine whether a similar phenomenon exists at human centromeres, we measured the rate of meiotic recombination across the centromere of the human X chromosome. We have constructed a long-range physical map of centromeric ␣-satellite DNA (DXZ1) by pulsed-field gel analysis, as well as detailed meiotic maps of the pericentromeric region of the X chromosome in the CEPH family panel. By comparing these two maps, we determined that, in the proximal region of the X chromosome, a genetic distance of 0.57 cM exists between markers that span the centromere and are separated by at least the average 3600 kb physical distance mapped across the DXZ1 array. Therefore, the rate of meiotic exchange across the X chromosome centromere is <1 cM/6300 kb (and perhaps as low as 1 cM/17,000 kb on the basis of other physical mapping data), at least eightfold lower than the average rate of female recombination on the X chromosome and one of the lowest rates of exchange yet observed in the human genome.Meiotic exchange is not distributed randomly along the length of eukaryotic chromosomes; indeed, much regional variation in recombination frequency has been observed. Perhaps the most conspicuous departure from uniformity is the dramatic repression of exchange found near eukaryotic chromosome centromeres and some telomeres (Mather 1936(Mather , 1939. Repression of meiotic recombination adjacent to the centromere (the centromere effect) is most obvious on the Drosophila X chromosome in which the centric heterochromatin, comprising half of the chromosome's cytogenetic length, barely contributes to its genetic length (Mather 1939;Roberts 1965); a similar centromere-associated repression of recombination is found on the autosomes of Drosophila (Beadle 1932;Painter 1935;Thompson 1963). Some of this repression of exchange is caused by the large blocks of heterochromatin present at the centromeres of higher eukaryotes (Willard 1990;Murphy and Karpen 1995), because heterochromatin, at least in Drosophila, is a poor substrate for recombination regardless of chromosomal location (Baker 1958). Because deletions of centric heterochromatin result in lowered levels of meiotic exchange in centromere-adjacent euchromatin (Yamamoto and Miklos 1978), the presence alone of heterochromatin at Drosophila centromeres does not fully explain the centromere effect. Rather, the centromere seems to exert a suppression of recombination that spreads to adjacent DNA.Studies in yeast support a similar centromeric suppression of meiotic exchange in proximal chromosome regions, although this effect may be less pronounced. In both Saccharomyces cerevisiae and Schizosaccharomyces pombe, mitotic recombination is relatively more frequent than meiotic recombination in the proximity of centromeres (Malone et al. 1980;Minet et al. 1980). Direct evidence for the centromere effect in yeast has come from studies of c...