癌症相关的DNA甲基化连锁区域

DNA甲基化是重要的表观遗传标记之一,在转录调控中起直接作用。DNA甲基化的异常与癌症的发生发展密切相关。高通量测序使得在单碱基分辨率下检测全基因组的DNA甲基化水平成为可能。本文基于临近CpGs位点甲基化水平的相关性挖掘DNA甲基化连锁区域。结果发现DNA甲基化连锁区域的甲基化水平和模式在癌症中存在异常,而且显著富集到分化/发育相关的生物学功能。DNA甲基化连锁区域的挖掘有助于对具有生物学功能的表观遗传标记的进一步理解,有助于对癌症诊断的表观遗传标记的挖掘。     

Hybrid zone dynamics and species replacement between Orconectes crayfishes in a northern Wisconsin lake

Hybrid zones that result in the genetic assimilation (replacement) of one species by another are underrepresented in the animal literature, most likely due to their transient nature. One such zone involves the rusty crayfish, Orconectes rusticus, and its congener O. propinquus. Orconectes rusticus was recently introduced into northern Wisconsin and Michigan lakes and streams, where it is hybridizing with and displacing resident O. propinquus. Here we report on a study investigating the dynamics of a hybrid zone between the two crayfish in Trout Lake, Wisconsin, where both the time (circa 1979) and location of the initial introduction are known. Our prediction was that hybridization should hasten the demise of O. propinquus because we expected that male O. rusticus (which are larger than congeners) would outcompete male O. propinquus for mates of both species. If hybrid progeny are unfit, then the result would be decreased reproductive output of O. propinquus females. However, we found a pattern of cytonuclear disequilibrium between allozymes and mtDNA suggesting that a majority (94.5%) of F1 hybrids resulted from matings between O. rusticus females and O. propinquus males. Also contrary to expectations, fecundity (O. rusticus and O. propinquus) and early hybrid survivorship did not differ significantly from nonhybrids. Moreover, adults of mixed ancestry were superior to both O. rusticus and O. propinquus in competition for a limiting food resource. Using a single-locus model, we estimated that hybridization increases the advance of O. rusticus genes in Trout Lake between 4.8% and 36.3% above that due to the previously documented ecological interactions. Consequently, whereas hybridization may be hastening the elimination of genetically pure O. propinquus, introgression is nevertheless slowing the loss of O. propinquus nuclear genes. Although our results suggest that O. rusticus and O. propinquus may not be true species under the biological concept, their ecological differences are of great conservation importance.     

Gene mapping by linkage and association analysis

Genetic analysis is used to map genes, including disease loci, to positions within the human genome. Linkage analysis depends on the co-segregation of a gene (locus) and a phenotype through a pedigree, while association analysis, or linkage disequilibrium mapping, depends on measuring deviation from the random occurrence of alleles in a haplotype in unrelated individuals or nuclear families. Complex computer programs may be used in both forms of analysis. In recent years most interest has focused on identifying genes involved in common, multifactorial diseases. Here I review some current and developing techniques of genetic analysis and give references to where further information can be obtained.     

Suggestive evidence of association of C-159T functional polymorphism of the <Emphasis Type="Italic">CD14</Emphasis> gene with atopic asthma in northern and northwestern Indian populations

CD14 is a lipopolysaccharide receptor known to be an important modulator of Th1–Th2 response during early childhood. Genetic association studies of the CD14 gene with asthma and atopic disorders have shown positive as well as negative results in different ethnic populations. The aim of this study was to test for association of C-159T functional promoter polymorphism with atopic asthma and serum IgE levels in northern and northwestern Indian populations. DNA was assayed for the CD14 C-159T polymorphism in a case-control study involving atopic asthmatics (n=187) and healthy normal controls (n=227), and in a family-based association study of 106 trios. The case-control study showed an association at the genotypic (P=0.0146) as well as the allelic level (P=0.0048). Moreover, we observed a deviation of allelic transmission from random proportions (P=0.024) in the transmission disequilibrium test analysis. When we analyzed our results for serum total IgE levels, against this polymorphism, we observed a difference at the genotypic (P=0.0026) as well as at the allelic level (P=0.0016) in a case-control study, whereas no association in the quantitative transmission disequilibrium test analysis was obtained. These findings provide suggestive evidence of association of the CD14 gene locus with atopic asthma in northern and northwestern Indian populations.     

Comparative mapping between<Emphasis Type="Italic"> Medicago sativa</Emphasis> and<Emphasis Type="Italic"> Pisum sativum</Emphasis>

Comparative genome analysis has been performed between alfalfa ( Medicago sativa) and pea ( Pisum sativum), species which represent two closely related tribes of the subfamily Papilionoideae with different basic chromosome numbers. The positions of genes on the most recent linkage map of diploid alfalfa were compared to those of homologous loci on the combined genetic map of pea to analyze the degree of co-linearity between their linkage groups. In addition to using unique genes, analysis of the map positions of multicopy (homologous) genes identified syntenic homologs (characterized by similar positions on the maps) and pinpointed the positions of non-syntenic homologs. The comparison revealed extensive conservation of gene order between alfalfa and pea. However, genetic rearrangements (due to breakage and reunion) were localized which can account for the difference in chromosome number (8 for alfalfa and 7 for pea). Based on these genetic events and our increasing knowledge of the genomic structure of pea, it was concluded that the difference in genome size between the two species (the pea genome is 5- to 10-fold larger than that of alfalfa) is not a consequence of genome duplication in pea. The high degree of synteny observed between pea and Medicago loci makes further map-based cloning of pea genes based on the genome resources now available for M. truncatula a promising strategy.Electronic Supplementary Material Supplementary material is available in the online version of this article at Communicated by W. R. McCombie     

Haplotype block and superblock structures of the alpha1-adrenergic receptor genes reveal echoes from the chromosomal past

A significant proportion of the human genome is contained within haplotype blocks across which pairwise linkage disequilibrium (LD) is very high. However, LD is also often high between markers at more remote distances, and within different haplotype blocks. Here, we evaluate the origins of haplotype block structure in the three genes for alpha1 adrenergic receptors (alpha1-AR) in the human genome ( ADRA1A, ADRA1B and ADRA1D) by genotyping dense single-nucleotide polymorphism (SNP) marker maps, and show that LD signals between distant markers are due to the presence of extended haplotype superblocks in individuals with ancient chromosomes which have escaped historic recombination. ARs mediate the physiological effects of epinephrine and norepinephrine, and are targets of many therapeutic drugs. This work has identified haplotype backgrounds of alpha1-AR missense variants, haplotype block structures in US Caucasians and African Americans, and haplotype tag SNPs for each block, and we present strong evidence for ancient haplotype block superstructure at these genes which has been partially disrupted by recombination, and evidence for reinstatement of linkage disequilibrium by subsequent recombination events. ADRA1A is comprised of four haplotype blocks in US Caucasians, while in African Americans Block 1 is split. ADRA1B has four blocks in US Caucasians, but in African Americans only the first two blocks are present. ADRA1D has two blocks in US Caucasians, and the first block is replaced by two smaller blocks in African Americans. For both ADRA1A and ADRA1B, haplotype superstructures may represent a novel, higher-level hierarchy in the human genome, which may reduce redundancy of testing by further aggregation of genotype data.Electronic Supplementary Material Supplementary material is available in the online version of this article at Communicated by W. R. McCombie     

Genetic assignment methods for the direct, real-time estimation of migration rate: a simulation-based exploration of accuracy and power

Genetic assignment methods use genotype likelihoods to draw inference about where individuals were or were not born, potentially allowing direct, real-time estimates of dispersal. We used simulated data sets to test the power and accuracy of Monte Carlo resampling methods in generating statistical thresholds for identifying F0 immigrants in populations with ongoing gene flow, and hence for providing direct, real-time estimates of migration rates. The identification of accurate critical values required that resampling methods preserved the linkage disequilibrium deriving from recent generations of immigrants and reflected the sampling variance present in the data set being analysed. A novel Monte Carlo resampling method taking into account these aspects was proposed and its efficiency was evaluated. Power and error were relatively insensitive to the frequency assumed for missing alleles. Power to identify F0 immigrants was improved by using large sample size (up to about 50 individuals) and by sampling all populations from which migrants may have originated. A combination of plotting genotype likelihoods and calculating mean genotype likelihood ratios (DLR) appeared to be an effective way to predict whether F0 immigrants could be identified for a particular pair of populations using a given set of markers.     

Major histocompatibility complex variation at three class II loci in the northern elephant seal

Northern elephant seals were hunted to near extinction in the 19th century, yet have recovered remarkably and now number around 175,000. We surveyed 110 seals for single-strand conformation polymorphism (SSCP) and sequence variation at three major histocompatibility (MHC) class II loci (DQA, DQB and DRB) to evaluate the genetic consequences of the population bottleneck at these loci vs. other well-studied genes. We found very few alleles at each MHC locus, significant variation among breeding sites for the DQA locus, and linkage disequilibrium between the DQB and DRB loci. Northern elephant seals are evidently inbred, although there is as yet no evidence of correlative reductions in fitness.