Viruses, Genes and Cancer

Cancer takes many forms and has many causes. But it is possibleto unite these many forms and causes with a single hypothesis:that cancer may be a malady of genes, that abnormalities ofgenes usually lie at the heart of the disease. Recent researchhas uncovered evidence that this hypothesis may be correct.Many human tumors contain genetic damage that can account forcancerous growth. The damage affects genes that are normallyvital to normal growth and development, but that have run amokin cancer cells. The prevention and treatment of cancer hasuntil now been based on trial and error. The identificationand characterization of damaged genes in human tumors pointsthe way to new and more rational strategies for the diagnosis,prognosis and therapy of cancer.     

Gene Conversion, Linkage, and the Evolution of Repeated Genes Dispersed among Multiple Chromosomes

The evolution of the probabilities of genetic identity within and between the loci of a multigene family dispersed among multiple chromosomes is investigated. Unbiased gene conversion, equal crossing over, random genetic drift, and mutation to new alleles are incorporated. Generations are discrete and nonoverlapping; the diploid, monoecious population mates at random. The linkage map is arbitrary, but the same for every chromosome; the dependence of the probabilities of identity on the location on each chromosome is formulated exactly. The greatest of the rates of gene conversion, random drift, and mutation is epsilon much less than 1. Under the assumption of loose linkage (i.e., all the crossover rates greatly exceed epsilon, though they may still be much less than 1/2), explicit approximations are obtained for the equilibrium values of the probabilities of identity and of the linkage of disequilibria. The probabilities of identity are of order one [i.e., O(1)] and do not depend on location; the linkage disequilibria are of O(epsilon) and, within each chromosome, depend on location through the crossover rates. It is demonstrated also that the ultimate rate and pattern of convergence to equilibrium are close to that of a much simpler, location-independent model. If intrachromosomal conversion is absent, the above results hold even without the assumption of loose linkage. In all cases, the relative errors are of O(epsilon). Even if the conversion rate between genes on nonhomologous chromosomes is considerably less than between genes on the same chromosome or homologous chromosomes, the probabilities of identity between the former genes are still almost as high as those between the latter, and the rate of convergence is still not much less than with equal conversion rates. If the crossover rates are much less than 1/2, then most of the linkage disequilibrium is due to intrachromosomal conversion. If linkage is loose, the reduction of the linkage disequilibria to O(epsilon) requires only O(-ln epsilon) generations.     

Why Genes Evolve Faster on Secondary Chromosomes in Bacteria

In bacterial genomes composed of more than one chromosome, one replicon is typically larger, harbors more essential genes than the others, and is considered primary. The greater variability of secondary chromosomes among related taxa has led to the theory that they serve as an accessory genome for specific niches or conditions. By this rationale, purifying selection should be weaker on genes on secondary chromosomes because of their reduced necessity or usage. To test this hypothesis we selected bacterial genomes composed of multiple chromosomes from two genera, Burkholderia and Vibrio, and quantified the evolutionary rates (dN and dS) of all orthologs within each genus. Both evolutionary rate parameters were faster among orthologs found on secondary chromosomes than those on the primary chromosome. Further, in every bacterial genome with multiple chromosomes that we studied, genes on secondary chromosomes exhibited significantly weaker codon usage bias than those on primary chromosomes. Faster evolution and reduced codon bias could in turn result from global effects of chromosome position, as genes on secondary chromosomes experience reduced dosage and expression due to their delayed replication, or selection on specific gene attributes. These alternatives were evaluated using orthologs common to genomes with multiple chromosomes and genomes with single chromosomes. Analysis of these ortholog sets suggested that inherently fast-evolving genes tend to be sorted to secondary chromosomes when they arise; however, prolonged evolution on a secondary chromosome further accelerated substitution rates. In summary, secondary chromosomes in bacteria are evolutionary test beds where genes are weakly preserved and evolve more rapidly, likely because they are used less frequently.     

应用显微操作和PCR技术进行基因的染色体定位

介绍了一种将染色体显微操作和ＰＣＲ技术结合起来进行基因染色体定位的方法,具有简便易行,特异性和敏感性很高等特点。分析了这种定位方法的技术特点,以及ＳＳＣＰ和ＤＮＡ序列分析等方法在排除错误结果中的运用。     

Genes on Rat Chromosomes 3, 5, 10, and 16 Are Linked With Facets of Metabolic Syndrome

WOKW (Wistar Ottawa Karlsburg W) rats develop metabolic syndrome closely resembling human disorder. In crossing studies between disease‐prone WOKW and disease‐resistant DA (Dark Agouti) rats, several quantitative trait loci (QTLs) were mapped. To prove the in vivo relevance of QTLs, congenic DA.WOKW rats, briefly termed DA.3aW, DA.3bW, DA.5W, DA.10W, and DA.16W, were generated by transferring chromosomal regions of WOKW chromosomes 3, 5, 10, and 16 onto DA genetic background. Male (n = 12) and female (n = 12) rats of each congenic strain and their parental strain DA were characterized for adiposity index (AI), serum leptin, and serum insulin as well as serum cholesterol and serum triglycerides as single facets of metabolic syndrome at the age of 30 weeks. The data showed a significant higher AI for male and female DA.3aW and female DA.16W compared with DA. Serum leptin was significantly elevated in male and female DA.3aW, DA.10W, and DA.16W rats in comparison with DA. Rats of both sexes of DA.10W and female DA.16W showed significantly elevated serum insulin in comparison to DA. Female rats of all congenics had significantly higher serum cholesterol compared with DA, while males did not differ. Finally, triglycerides were only elevated in male DA.16W. The results demonstrate an involvement of WOKW chromosomes 3, 5, 10, and 16 in developing facets of the metabolic syndrome.     

Genes on mouse Chromosomes 2 and 9 determine variation in ethanol consumption

Quantitative trait locus (QTL) mapping efforts in alcohol (ethanol) research are beginning to generate promising data that may ultimately lead to the identification of genes influencing alcohol addiction. Rodents have been extensively utilized to study ethanol's rewarding and aversive effects, and to demonstrate the existence of genetic influences on traits such as free-choice ethanol-consumption, ethanol-conditioned place preference and ethanol-conditioned taste aversion. The purpose of the current investigation was to verify or eliminate from further consideration putative QTLs for free-choice ethanol consumption originally identified in BXD Recombinant Inbred (RI) strains and other informative genetic crosses. B6D2F₂ mice were utilized in a verification testing strategy to evaluate the viability of putative ethanol consumption QTLs. When data were combined from BXD RI, B6D2F₂ and short-term selected line (STSL) mapping studies, verification was obtained for two QTLs, one on Chromosome (Chr) 9 (proximal-mid) and another on Chr 2 (distal), and suggestive verification was obtained for QTLs on Chrs 2 (proximal), 3, 4, 7, and 15. In addition, the possible genetic association of ethanol consumption with conditioned place preference was evaluated. Genetic correlations were estimated from BXD RI strain means, and QTL maps for these traits were compared to evaluate the possibility of a genetic association. The correlational analysis yielded a trend (r = 0.34, p = 0.09), but no statistically significant results. However, comparisons of QTL mapping results between phenotypes suggested some possible genetic overlap for these traits, both putative measures of ethanol reward. These data suggest that the determinants of these two measures are genetically diverse, but may share some common genetic elements. Received: 15 September 1998 / Accepted: 8 October 1998     

Linkage of Genes Controlling Morphological Traits with Isozyme Markers of Rye Chromosomes

Data on linkage of 12 rye genes controlling morphological traits (el, Vs, ln, w, np, ct2, Hs, Ddw, cb, mn, vi1, mp) with one or several isozyme markers of individual rye chromosomes (2R–7R) are presented. Linkage of the following gene pairs was established: chromosome 2R: Est3/5–el, el–-Glu, Sod2–el, Sod2–Vs; chromosome 3R: ln–Got4; chromosome 4R: w–Got1, np–Got1; chromosome 5R: Est4–ct2, Est6/9–ct2, ct2–Est2, ct2–Aco2, Est2–Hs, Aco2–Hs, Est2–Ddw, Aco2–Ddw; chromosome 6R:Lap2–cb, cb–Aco1, Est10–mn; chromosome 7R: Acph2/3–vi1, Got2–vi1, mp–Acph2/3. The reasons for mapping a very small number of genes in rye in spite of high intraspecific variability of this species are discussed. An approach is suggested to improve this situation by simultaneous identification and mapping of all diverse spontaneous mutations maintained in heterozygous state in various rye cultivars.     

Mismatch Repair Genes on Chromosomes 2p and 3p Account for a Major Share of Hereditary Nonpolyposis Colorectal Cancer Families Evaluable by Linkage

Two susceptibility loci for hereditary nonpolyposis colo-rectal cancer (HNPCC) have been identified, and each contains a mismatch repair gene: MSH2 on chromosome 2p and MLH1 on chromosome 3p. We studied the involvement of these loci in 13 large HNPCC kindreds originating from three different continents. Six families showed close linkage to the 2p locus, and a heritable mutation of the MSH2 gene was subsequently found in four. The 2p-linked kindreds included a family characterized by the lack of extracolonic manifestations (Lynch I syndrome), as well as two families with cutaneous manifestations typical of the Muir-Torre syndrome. Four families showed evidence for linkage to the 3p locus, and a heritable mutation of the MLH1 gene was later detected in three. One 3p-linked kindred was of Amerindian origin. Of the remaining three families studied for linkage, one showed lod scores compatible with exclusion of both MSH2 and MLH1, while lod scores obtained in the other two families suggested exclusion of one HNPCC locus (MSH2 or MLH1) but were uninformative for markers flanking the other locus. Our results suggest that mismatch repair genes on 2p and 3p account for a major share of HNPCC in kindreds that can be evaluated by linkage analysis.     

Polytenization of the Ribosomal Genes on the X and Y Chromosomes of DROSOPHILA MELANOGASTER

It has previously been shown (Endow and Glover 1979), that polytenization of the ribosomal genes in D. melanogaster Ore-R X/Y cells and in hybrid X/X cells (Endow 1980) involves replication of genes predominantly from one of the cell's two nucleolus organizers. This analysis takes advantage of strain-specific differences in X and Y chromosome rDNA hybridization patterns detected using the Southern blotting technique. In this report, I extend the previous observations by examining polytene rDNA patterns in wild-type and hybrid X/Y cells. A dominance hierarchy for the X and Y chromosomes from three strains of D. melanogaster is presented and possible mechanisms of replicative dominance are discussed.