Biomedical subjects

Jane Gibson

Publications and source records attributed to Jane Gibson.

7 recordsLinked to original sources

PubMed2006

Extended tracts of homozygosity in outbred human populations.

Long tracts of consecutive homozygous single nucleotide polymorphisms (SNPs) can arise in the genome through a number of mechanisms. These include inbreeding in which an individual inherits chromosomal segments that are identical by descent from each parent. However, recombination and other processes break up chromosomal segments over generations. The longest tracts are therefore to be expected in populations with an appreciable degree of inbreeding. We examined the length, number and distribution of long tracts of homozygosity in the apparently outbred HapMap populations. We observed 1393 tracts exceeding 1 Mb in length among the 209 unrelated HapMap individuals. The longest was an uninterrupted run of 3922 homozygous SNPs spanning 17.9 Mb in a Japanese individual. We find that homozygous tracts are significantly more common in regions with high linkage disequilibrium and low recombination, and the location of tracts is similar across all populations. The Yoruba sample has the fewest long tracts per individual, consistent with a larger number of generations (and hence amount of recombination) since the founding of that population. Our results suggest that multiple-megabase-scale ancestral haplotypes persist in outbred human populations in broad genomic regions which have lower than average recombination rates. We observed three outlying individuals who have exceptionally long and numerous homozygous tracts that are not associated with recombination suppressed areas of the genome. We consider that this reflects a high level of relatedness in their ancestry which is too recent to have been influenced by the local recombination intensity. Possible alternative mechanisms and the implications of long homozygous tracts in the genome are discussed.

Asian People↗

PubMed2005

Cosmopolitan linkage disequilibrium maps.

Linkage maps have been invaluable for the positional cloning of many genes involved in severe human diseases. Standard genetic linkage maps have been constructed for this purpose from the Centre d'Etude du Polymorphisme Humain and other panels, and have been widely used. Now that attention has shifted towards identifying genes predisposing to common disorders using linkage disequilibrium (LD) and maps of single nucleotide polymorphisms (SNPs), it is of interest to consider a standard LD map which is somewhat analogous to the corresponding map for linkage. We have constructed and evaluated a cosmopolitan LD map by combining samples from a small number of populations using published data from a 10-megabase region on chromosome 20. In support of a pilot study, which examined a number of small genomic regions with a lower density of markers, we have found that a cosmopolitan map, which serves all populations when appropriately scaled, recovers 91 to 95 per cent of the information within population-specific maps. Recombination hot spots appear to have a dominant role in shaping patterns of LD. The success of the cosmopolitan map might be attributed to the co-localisation of hot spots in all populations. Although there must be finer scale differences between populations due to other processes (mutation, drift, selection), the results suggest that a whole-genome standard LD map would indeed be a useful resource for disease gene mapping.

Chromosome Mapping↗

PubMed2004

Impact of population structure, effective bottleneck time, and allele frequency on linkage disequilibrium maps.

Genetic maps in linkage disequilibrium (LD) units play the same role for association mapping as maps in centimorgans provide at much lower resolution for linkage mapping. Association mapping of genes determining disease susceptibility and other phenotypes is based on the theory of LD, here applied to relations with three phenomena. To test the theory, markers at high density along a 10-Mb continuous segment of chromosome 20q were studied in African-American, Asian, and Caucasian samples. Population structure, whether created by pooling samples from divergent populations or by the mating pattern in a mixed population, is accurately bioassayed from genotype frequencies. The effective bottleneck time for Eurasians is substantially less than for migration out of Africa, reflecting later bottlenecks. The classical dependence of allele frequency on mutation age does not hold for the generally shorter time span of inbreeding and LD. Limitation of the classical theory to mutation age justifies the assumption of constant time in a LD map, except for alleles that were rare at the effective bottleneck time or have arisen since. This assumption is derived from the Malecot model and verified in all samples. Tested measures of relative efficiency, support intervals, and localization error determine the operating characteristics of LD maps that are applicable to every sexually reproducing species, with implications for association mapping, high-resolution linkage maps, evolutionary inference, and identification of recombinogenic sequences.

Alleles↗

PubMed2004

Positional cloning by linkage disequilibrium.

Recently, metric linkage disequilibrium (LD) maps that assign an LD unit (LDU) location for each marker have been developed (Maniatis et al. 2002). Here we present a multiple pairwise method for positional cloning by LD within a composite likelihood framework and investigate the operating characteristics of maps in physical units (kb) and LDU for two bodies of data (Daly et al. 2001; Jeffreys et al. 2001) on which current ideas of blocks are based. False-negative indications of a disease locus (type II error) were examined by selecting one single-nucleotide polymorphism (SNP) at a time as causal and taking its allelic count (0, 1, or 2, for the three genotypes) as a pseudophenotype, Y. By use of regression and correlation, association between every pseudophenotype and the allelic count of each SNP locus (X) was based on an adaptation of the Malecot model, which includes a parameter for location of the putative gene. By expressing locations in kb or LDU, greater power for localization was observed when the LDU map was fitted. The efficiency of the kb map, relative to the LDU map, to describe LD varied from a maximum of 0.87 to a minimum of 0.36, with a mean of 0.62. False-positive indications of a disease locus (type I error) were examined by simulating an unlinked causal SNP and the allele count was used as a pseudophenotype. The type I error was in good agreement with Wald's likelihood theorem for both metrics and all models that were tested. Unlike tests that select only the most significant marker, haplotype, or haploset, these methods are robust to large numbers of markers in a candidate region. Contrary to predictions from tagging SNPs that retain haplotype diversity, the sample with smaller size but greater SNP density gave less error. The locations of causal SNPs were estimated with the same precision in blocks and steps, suggesting that block definition may be less useful than anticipated for mapping a causal SNP. These results provide a guide to efficient positional cloning by SNPs and a benchmark against which the power of positional cloning by haplotype-based alternatives may be measured.

Alleles↗

PubMed2003

Complete genome sequence of the metabolically versatile photosynthetic bacterium Rhodopseudomonas palustris.

Rhodopseudomonas palustris is among the most metabolically versatile bacteria known. It uses light, inorganic compounds, or organic compounds, for energy. It acquires carbon from many types of green plant-derived compounds or by carbon dioxide fixation, and it fixes nitrogen. Here we describe the genome sequence of R. palustris, which consists of a 5,459,213-base-pair (bp) circular chromosome with 4,836 predicted genes and a plasmid of 8,427 bp. The sequence reveals genes that confer a remarkably large number of options within a given type of metabolism, including three nitrogenases, five benzene ring cleavage pathways and four light harvesting 2 systems. R. palustris encodes 63 signal transduction histidine kinases and 79 response regulator receiver domains. Almost 15% of the genome is devoted to transport. This genome sequence is a starting point to use R. palustris as a model to explore how organisms integrate metabolic modules in response to environmental perturbations.

Biological Transport↗

PubMed2002

Metabolic diversity in aromatic compound utilization by anaerobic microbes.

A vast array of structurally diverse aromatic compounds is continually released into the environment due to the decomposition of green plants and as a consequence of human industrial activities. Increasing numbers of bacteria that utilize aromatic compounds in the absence of oxygen have been brought into pure culture in recent years. These include most major metabolic types of anaerobic heterotrophs and acetogenic bacteria. Diverse microbes utilize aromatic compounds for diverse purposes. Chlorinated aromatic compounds can serve as electron acceptors in dehalorespiration. Humic substances serve as electron shuttles to enable the use of inorganic electron acceptors, such as insoluble iron oxides, that are not always easily reduced by microbes. Substituents that are attached to aromatic rings may serve as carbon or energy sources for microbes. Examples include acyl side chains and methyl groups. Finally, aromatic compounds can be completely degraded to serve as carbon and energy sources. Routes by which various types of aromatic compounds, including toluene, ethylbenzene, phenol, benzoate, and dihydroxylated compounds, are degraded have been elucidated in recent years. Biochemical strategies employed by microbes to destabilize the aromatic ring in preparation for degradation have become apparent from this work.

Anaerobiosis↗

PubMed2002

Profiling of differential expression of messenger RNA in normal, benign, and metastatic prostate cell lines.

To understand the phenotypic changes associated with prostate cancer development and metastasis, we investigated differential gene expression in primary and established prostate cell lines used as models. We have used a differential display of messenger RNA (DDRT-PCR) technique using 168 primer combinations and total RNA from BPH-1, LNCaP, and PC3 cells to identify filter-based cDNA microarrays containing 18,376 nonredundant clones of genes and expressed sequence tags (EST) using mRNA from PrEC and MDAPCa2a cells to identify genes that are differentially expressed in normal, benign, and cancerous prostate cell lines. Twenty-five cDNA with a significant difference in expression of 76 candidate cDNA, as identified by DDRT-PCR and confirmed by slot-blot analysis, were selected for sequence analysis. Of these, 14 cDNA were further confirmed by Northern blot analysis. Analysis of the cDNA microarray data showed that a variety of genes/EST were up- or down-regulated in the metastatic prostate tumor cells and a majority of these genes encode cytoskeletal proteins and proteins with regulatory function. Expression profile of two EST was confirmed by reverse transcription polymerase chain reaction. We also have identified a number of genes exhibiting differential expression in prostate cancer cells, which were not known earlier to be involved in prostate cancer. This report provides a comparative analysis of differential gene expression between normal prostatic epithelial cells and prostate cancer cells, and a foundation to facilitate in-depth studies on the mechanism of prostate cancer development and metastasis.

Adenocarcinoma↗