Genetic encapsulation among Near Eastern populations.

This report aims to genetically characterize the relationships between geographically targeted human populations covering an expanse from east sub-Saharan Africa northeastward into northern India with an emphasis on the Near East. A number of parameters of population genetics interest were examined based on allele frequencies from 15 forensic autosomal STR markers [D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, and FGA]. The phylogenetic analyses generated from genetic profiles of 885 individuals indicate that populations west of and including Iran have experienced substantial gene flow. Accordingly, our findings delineate a region of genetic homogeneity concentrated within the Near East with increasing genetic differentiation moving south into Africa and further east into Asia. We suggest that the Saharan desert, the Hindu Kush mountain range and perhaps to a lesser extent, the deserts of Iran may have acted as southern, eastern and northern geographical barriers, respectively, forming a genetic enclosure that allows limited gene flow outside the Near East. The biparental genetic landscape supports a picture of close contact between the Arab and Persian populations, perhaps beginning during the initial settlement of Asia from Africa extending to recent times.

Differential regulation of MDR1 transcription by the p53 family members. Role of the DNA binding domain.

Although the p53 family members share a similar structure and function, it has become clear that they differ with respect to their role in development and tumor progression. Because of the high degree of homology in their DNA binding domains (DBDs), it is not surprising that both p63 and p73 activate the majority of p53 target genes. However, recent studies have revealed some differences in a subset of the target genes affected, and the mechanism underlying this diversity has only recently come under investigation. Our laboratory has demonstrated previously that p53 represses transcription of the P-glycoprotein-encoding MDR1 gene via direct DNA binding through a novel p53 DNA-binding site (the HT site). By transient transfection analyses, we now show that p63 and p73 activate rather than repress MDR1 transcription, and they do so through an upstream promoter element (the alternative p63/p73 element (APE)) independent of the HT site. This activation is dependent on an intact DNA binding domain, because mutations within the p63DBD or p73DBD are sufficient to prevent APE-mediated activation. However, neither p63 nor p73 directly interact with the APE, suggesting an indirect mechanism of activation through this site. Most interestingly, when the p53DBD is replaced by the p63DBD, p53 is converted from a repressor working through the HT site to an activator working through the APE. Taken together, these data indicate that, despite considerable homology, the DBD of the p53 family members have unique properties and can differentially regulate gene targeting and transcriptional output by both DNA binding-dependent and -independent mechanisms.

The calicheamicin gene cluster and its iterative type I enediyne PKS.

The enediynes exemplify nature's ingenuity. We have cloned and characterized the biosynthetic locus coding for perhaps the most notorious member of the nonchromoprotein enediyne family, calicheamicin. This gene cluster contains an unusual polyketide synthase (PKS) that is demonstrated to be essential for enediyne biosynthesis. Comparison of the calicheamicin locus with the locus encoding the chromoprotein enediyne C-1027 reveals that the enediyne PKS is highly conserved among these distinct enediyne families. Contrary to previous hypotheses, this suggests that the chromoprotein and nonchromoprotein enediynes are generated by similar biosynthetic pathways.