| Introduction Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. The prevalence of type 2 diabetes mellitus (T2DM) has almost tripled within last 15 years, from 1% to about 3% in China. However, the exact etiology and pathogenesis of the disease remain unclear. Thus, it is hard to cure type 2 diabetes mellitus at present. Cumulative evidence on the high prevalence of T2DM in certain ethnic groups, the high concordance rate for the disease in monozygotic twins, familial aggregation, and familial transmission patterns suggest that the genetic factors may play important roles in the development of T2DM. Over the past decades, many scientists are devoted into susceptibility genes of type 2 diabetes mellitus. Currently, there are two common approaches for identifying genetic determinants: the candidate gene approach and the genome wide scan using anonymous polymorphic markers. So far, over 250 candidate genes have been screened, but no specific gene(s) accounting for the majorityof cases of the common type of T2DM has been identified, except for a small percentage of T2DM patients or to specific populations. In the past 10 years, with the development of human genome program, a number of susceptibility loci have been located on a variety of chromosomes in pedigrees by genome-wide scan analysis. For examples, a genome scan of Hispanic-American families (330 affected sib-pairs [ASPs] found linkage to chromosome 2q37 (logarithm of odds [LOD] 4.15). The largest genome-wide scan for. *type 2 diabetes loci reported to date studied 477 Finnish families (716 ASPs) and found evidence for linkage to chromosome 20ql2-13.1 (LOD 2.06 at D20S107). A number of other genome scans in various racial groups have also identified other putative susceptibility loci. Most recently, two new candidate susceptibility loci have been reported to reside on chromosome 9 (D9S171 and D9S175) in pedigrees of Chinese population. However, very little is known about the nature of the susceptibility genes and the magnitude of their effect on type 2 diabetes.Materials and methods Analysis of nucleotide sequences in type 2 diabetes mellitus susceptibility lociMany loci predisposing to type 2 diabetes have been located on a variety of chromosomes within high-risk pedigrees. However, the type 2 diabetes susceptibility genes remain elusive. Here, we designed a novel strategy to identify the susceptibility genes in the human genome. First, we searched for the common features of the putative susceptibility genes in the reported susceptibility loci. Second, we investigated the expression level of the putative susceptibility genes in patients with type 2 diabetes and normal controls using RT-PCR. Third, we performed candidate-gene mutation screening via sequencing. We originally analyzed nucleotide sequences of the reported susceptibility loci on chromosome 9 D9S171 and D9S175 in pedigrees of Chinese population. To ourgreat surprise, an LI-like retrotransposon genome was found in these two susceptibility loci on chromosome 9p2l, proximal P16CDKN2A locus. Nucleotide sequence analysis showed that the LI-like retrotransposon on loci D9S175 is about 6kb in size and composed of 5'UTR, ORF1, ORF2 and 3'UTR elements (fig.l) . To investigate the natures of this LI-like retrotransposon, we isolated, cloned, and sequenced the entire DNA genome of this LI-like retrotrasposon. Alignment of nucleotide sequence revealed that the Ll-like retrotransposon had a 98% of nucleotide homology to that of L1.39 retrotransposon , but the deduced amino acid identities of ORF1 encoding p40 and ORF2 encoding pi50 were 96% and 94%, with that of LI.39 retrotransposon, respectively. These results indicate that the Ll-like retrotransposon may be a novel functional LI retrotransposon. To demonstrate whether the novel Ll-like retrotransposon is associated with other reported susceptibility loci, we screened the human genome for the retrotransposon-like gen... |
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