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PubMed1998

Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase.

Allelic variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase gene (LPL) was scored in 71 healthy individuals (142 chromosomes) from three populations: African Americans (24) from Jackson, MS; Finns (24) from North Karelia, Finland; and non-Hispanic Whites (23) from Rochester, MN. The sequences had a total of 88 variable sites, with a nucleotide diversity (site-specific heterozygosity) of .002+/-.001 across this 9.7-kb region. The frequency spectrum of nucleotide variation exhibited a slight excess of heterozygosity, but, in general, the data fit expectations of the infinite-sites model of mutation and genetic drift. Allele-specific PCR helped resolve linkage phases, and a total of 88 distinct haplotypes were identified. For 1,410 (64%) of the 2,211 site pairs, all four possible gametes were present in these haplotypes, reflecting a rich history of past recombination. Despite the strong evidence for recombination, extensive linkage disequilibrium was observed. The number of haplotypes generally is much greater than the number expected under the infinite-sites model, but there was sufficient multisite linkage disequilibrium to reveal two major clades, which appear to be very old. Variation in this region of LPL may depart from the variation expected under a simple, neutral model, owing to complex historical patterns of population founding, drift, selection, and recombination. These data suggest that the design and interpretation of disease-association studies may not be as straightforward as often is assumed.

Animals↗
PubMed2000

Apparent founder effect during the early years of the San Francisco HIV type 1 epidemic (1978-1979).

HIV-1 envelope sequence variants were RT-PCR amplified from serum samples cryopreserved in San Francisco in 1978-1979. The HIV-1 subtype B env V3-V5 sequences from four homosexual men clustered phylogenetically, with a median nucleotide distance of 2.8%, reflecting a recent common origin. These early U.S. HIV-1 env variants mapped close to the phylogenetic root of the subtype B tree while env variants collected in the United States throughout the 1980s and 1990s showed, on average, increasing genetic diversity and divergence from the subtype B consensus sequence. These results indicate that the majority of HIV-1 currently circulating in the United States may be descended from an initial introduction and rapid spread during the mid- to late 1970s of subtype B viruses with limited variability (i.e., a founder effect). As expected from the starburst-shaped phylogeny of HIV-1 subtype B, contemporary U.S. strains were, on average, more closely related at the nucleic acid and amino acid levels to the earlier 1978-1979 env variants than to each other. The growing levels of HIV-1 genetic diversity, one of multiple obstacles in designing a protective vaccine, may therefore be mitigated by using epidemic founding variants as antigenic strains for protection against contemporary strains.

AIDS Vaccines↗
PubMed2003

Following the LINEs: an analysis of primate genomic variation at human-specific LINE-1 insertion sites.

The L1 Ta subfamily of long interspersed elements (LINEs) consists exclusively of human-specific L1 elements. Polymerase chain reaction-based screening in nonhuman primate genomes of the orthologous sites for 249 human L1 Ta elements resulted in the recovery of various types of sequence variants for approximately 12% of these loci. Sequence analysis was employed to capture the nature of the observed variation and to determine the levels of gene conversion and insertion site homoplasy associated with LINE elements. Half of the orthologous loci differed from the predicted sizes due to localized sequence variants that occurred as a result of common mutational processes in ancestral sequences, often including regions containing simple sequence repeats. Additional sequence variation included genomic deletions that occurred upon L1 insertion, as well as successive mobile element insertions that accumulated within a single locus over evolutionary time. Parallel independent mobile element insertions at orthologous loci in distinct species may introduce homoplasy into retroelement-based phylogenetic and population genetic data. We estimate the overall frequency of parallel independent insertion events at L1 insertion sites in seven different primate species to be very low (0.52%). In addition, no cases of insertion site homoplasy involved the integration of a second L1 element at any of the loci, but rather largely involved secondary insertions of Alu elements. No independent mobile element insertion events were found at orthologous loci in the human and chimpanzee genomes. Therefore, L1 insertion polymorphisms appear to be essentially homoplasy free characters well suited for the study of population genetics and phylogenetic relationships within closely related species.

Animals↗
PubMed2006

Contrasting histories of G6PD molecular evolution and malarial resistance in humans and chimpanzees.

Although mutations in the glucose-6-phosphate dehydrogenase (G6PD) gene result in several blood-related diseases in humans, they also confer resistance to malarial infection. This association between G6PD and malaria was supported by population genetic analyses of the G6PD locus, which indicated that these mutations may have recently risen in frequency in certain geographic regions as a result of positive selection. Here we characterize nucleotide sequence variation in a 5.2-kb region of the G6PD locus in a population sample of 56 chimpanzees, as well as among 7 other nonhuman primates, to compare with that in humans in determining whether other primates that are impacted by malaria also exhibit patterns of G6PD polymorphism or divergence consistent with positive selection. We find that chimpanzees have several amino acid variants but that the overall pattern at G6PD in chimpanzees, as well as in Old and New World primates in general, can be explained by recent purifying selection as well as strong functional constraint dating back to at least 30-40 MYA. These comparative analyses suggest that the recent signature of positive selection at G6PD in humans is unique.

Animals↗
PubMed2003

Large-scale variation among human and great ape genomes determined by array comparative genomic hybridization.

Large-scale genomic rearrangements are a major force of evolutionary change and the ascertainment of such events between the human and great ape genomes is fundamental to a complete understanding of the genetic history and evolution of our species. Here, we present the results of an evolutionary analysis utilizing array comparative genomic hybridization (array CGH), measuring copy-number gains and losses among these species. Using an array of 2460 human bacterial artificial chromosomes (BACs) (12% of the genome), we identified a total of 63 sites of putative DNA copy-number variation between humans and the great apes (chimpanzee, bonobo, gorilla, and orangutan). Detailed molecular characterization of a subset of these sites confirmed rearrangements ranging from 40 to at least 175 kb in size. Surprisingly, the majority of variant sites differentiating great ape and human genomes were found within interstitial euchromatin. These data suggest that such large-scale events are not restricted solely to subtelomeric or pericentromeric regions, but also occur within genic regions. In addition, 5/9 of the verified variant sites localized to areas of intrachromosomal segmental duplication within the human genome. On the basis of the frequency of duplication in humans, this represents a 14-fold positional bias. In contrast to previous cytogenetic and comparative mapping studies, these results indicate extensive local repatterning of hominoid chromosomes in euchromatic regions through a duplication-driven mechanism of genome evolution.

Animals↗
PubMed1998

Allelic diversity at the primate MHC-DMB locus: presence of a conserved tyrosine inhibitory motif in the cytoplasmic tail.

Ten new primate Mhc-DMB complete cDNA sequences have been obtained in chimpanzee (n=four), gorilla (n=three) and orangutan (n=three); this gene has not been previously studied in these species. Exonic allelism has been recorded all along the molecule domains and also in the leader peptide, but not in the transmembrane segment. An analysis of the residues critical in the conformation of the Mhc-DR peptide-binding site was done in order to look for a Mhc-DR homologue site; synonymous substitutions are favoured in this homologous HLA-DM region. This is another finding that supports the possibility that DM could not be typically presenting molecules. The immunoreceptor inhibition motif Tyr 230-Thr/Ser 231-Pro 232-Leu 233 (ITIM) is invariantly present in apes for at least 15 million years, and may have a double function: 1) To direct DMB-DMA molecules from the endoplasmic reticulum or cell surface towards the endosomal/lysosomal class II compartment and 2) to send an inhibitory signal to the cell in order to stop synthesis of unnecessary HLA-DR molecules, once all available antigenic peptides are loaded. Other molecules, like NK-cell receptors and Fc receptors, bear this type of tyrosine-based inhibitory motifs in order to switch off specific cell functions. DMB molecules (as previously shown in C4d molecules) do not present species-specific motifs in common chimpanzee, suggesting that this species is very close to gorilla or man; also, DMB, like C4d molecules, do not show a trans-species evolution pattern, suggesting the existence of extensive homogenization of DMB genes within each species or a recent generation of alleles. Finally, a clade grouping human and gorilla DMB cDNA sequences is obtained using a dendrogram (as for C4d trees); this is in contrast to others' results that obtain a human/chimpanzee clade using different DNA sequences.

Alleles↗
PubMed1997

Equally high prevalences of infection with cagA-positive Helicobacter pylori in Chinese patients with peptic ulcer disease and those with chronic gastritis-associated dyspepsia.

Approximately 60% of Helicobacter pylori isolates in the Western world possess the cytotoxin-associated gene A (cagA). cagA-positive H. pylori is found to be associated with peptic ulcer disease (PUD) and gastric adenocarcinoma. To investigate the cagA status of H. pylori isolates from Chinese patients with PUD and chronic gastritis (CG), H. pylori populations from 83 patients, 48 with PUD and 35 with CG, were assessed by two different cagA-specific PCRs, Southern blotting, and colony hybridization. The combined results from PCR, Southern blotting, and colony hybridization indicate a prevalence of cagA-positive H. pylori isolates of 98% (47 of 48) among Chinese PUD patients and 100% (35 of 35) among Chinese CG patients. Amplification with primer sets 1 and 2 yielded 52 and 95% of the 82 cagA-positive Chinese H. pylori, respectively. In contrast, the sensitivity of cagA-specific PCR for cagA-positive H. pylori isolates from Dutch patients with primer set 1 was 92% (112 of 122) and that with primer set 2 was 91% (50 of 55). The prevalence of cagA-positive H. pylori populations in Chinese patients with PUD and CG is almost universally high. Therefore, cagA cannot be used as a marker for the presence of PUD in Chinese patients. Our data further suggest that allelic variation in cagA may exist and that distinct H. pylori genotypes may circulate in China and Western Europe.

Adult↗
PubMedDate not supplied

Mismatch negativity and personality traits in chronic primary insomniacs.

The thalamo-(fronto)cortical circuit is involved in sleep regulation, and its dysfunction might contribute to the pathophysiology of chronic primary insomnia. To obtain more evidence of the involvement of the circuit, we studied 23 patients with chronic primary insomnia and 28 healthy volunteers via the assessment of mismatch negativity (MMN) elicited by tone intensity deviance, and of personality traits measured by Zuckerman's Sensation Seeking Scales, and Zuckerman-Kuhlman's Personality Questionnaire. In insomniacs, MMN amplitude at Fz was significantly larger; Depression, which was measured by Plutchik-van Praag's Depression Inventory, and Neuroticism-anxiety and Impulsivity scores were higher, while the Thrill and adventure seeking score was lower; MMN amplitude was positively correlated with Depression and with Impulsivity. In healthy subjects, MMN amplitude at Fz was positively correlated with Neuroticism-anxiety, but negatively with Experience seeking. The larger MMN and distinct personality traits suggest a hyperactivity in the thalamo-(fronto)cortical neuronal circuit in insomniacs, which is probably the result of weak thalamic gating mechanisms, or an imbalance of several neurotransmitter systems.

Adult↗
PubMed2001

Comparison of official coders versus physician panel in assignment of underlying cause of death.

BACKGROUND AND PURPOSE: In outcome analyses of clinical trials and mortality follow-up studies, the underlying cause of death (UCOD) is commonly assigned either by official coders or by a panel of physicians. We evaluated the validity of UCOD assigned by official coders by comparison with the assignments of a panel of physicians who reviewed the available medical records of the deceased. METHODS: The comparisons focused on deaths occurring from October 1995 through June 1998 in a series of residents in a veterans home. Because of limited resources, only the first 104 deaths that occurred during the study period were included. Agreement rate, sensitivity, specificity, and kappa statistics were calculated to assess the consistency of coder versus physician panel assignment of UCOD by selected main causes of death. For 32 of the 104 deaths, the panel concluded that the information obtained from medical records was insufficient to determine the UCOD, and the following analyses were confined to the other 72 deaths. RESULTS: For the 72 deaths considered by the panel to have sufficient information to determine UCOD, all four physicians agreed on a single UCOD in 50 (69%) cases, while three or four agreed in 66 (92%) cases. A consensus was reached in cases with disagreement. The two procedures completely agreed in 40 (56%) of the deaths. For general category UCOD, the kappa value was high for cancer (0.83) and cardiovascular disease (CVD, 0.73) but only moderate for pulmonary disease (PD, 0.60). When the UCOD assigned by the panel was used as the gold standard, official coders showed relatively low sensitivity for correct determination of UCOD in cases of CVD (0.76) compared with cancer (0.86) and PD (0.80). CONCLUSIONS: Given the high inter-physician consistency and the relatively low sensitivity of official coders in assigning CVD as the UCOD, we conclude that the use of clinical review panels would provide more accurate UCOD assignments for use in outcome analyses in mortality follow-up studies and clinical trials in Taiwan.

Aged↗
PubMed2002

The risk of coronary artery disease in population of Taiwan is associated with Cys-Ser 311 polymorphism of human paraoxonase (PON)-2 gene.

BACKGROUND: Paraoxonase (PON), a high density lipoprotein (HDL)-associated enzyme, is capable of inhibiting low density lipoprotein (LDL) oxidation by destroying the biologically active phospholipids in oxidatively modified LDL. An increased risk of coronary artery disease (CAD) has shown to associate with polymorphisms of PON gene (PON1) in different population. The risk of CAD associated with the other PON1-like gene, designated PON2, which has a similar function and is structurally related to PON1, is least discussed. A population-based case-control study was conducted to investigate the association between CAD and the polymorphisms at two common codons 148 and 311 of PON2 in the population of Taiwan. METHODS: Totally 364 unrelated, angiographically proved CAD-positive patients (338 male and 26 female) and 337 unrelated, CAD-free control subjects (249 male and 88 female) enrolled in this study. Lipids and lipoproteins profile and the association of PON2 genotypes and allele frequencies were analyzed in all study cohorts. RESULTS: The plasma levels of HDL-cholesterol and apoA-I were significantly lower in patients with CAD than in control subjects (both p = 0.0001). There was no difference in the genotype frequency distribution at codon 148 of PON2 between CAD patients and the controls. However, age-, sex- and diabetes-adjusted odds ratios for individuals with the SS genotype of the codon 311 polymorphism (Cys --> Ser, PON2*C allele --> PON2*S allele) showed a 4.6-fold higher risk of CAD (95% CI = 1.6-15.3, p = 0.006) they ran. Also, in the control subjects, PON2*C allele carriers (CC and CS genotypes) had higher plasma levels of HDL than cases with the SS genotypes (p = 0.035 and p = 0.012, respectively). CONCLUSIONS: Our data implicate that the genotypic variation at codon 311 of PON2 contributes to the susceptibility of CAD in the population of Taiwan.

Adult↗
PubMed2002

A comprehensive analysis of recently integrated human Ta L1 elements.

The Ta (transcribed, subset a) subfamily of L1 LINEs (long interspersed elements) is characterized by a 3-bp ACA sequence in the 3' untranslated region and contains approximately 520 members in the human genome. Here, we have extracted 468 Ta L1Hs (L1 human specific) elements from the draft human genomic sequence and screened individual elements using polymerase-chain-reaction (PCR) assays to determine their phylogenetic origin and levels of human genomic diversity. One hundred twenty-four of the elements amenable to complete sequence analysis were full length ( approximately 6 kb) and have apparently escaped any 5' truncation. Forty-four of these full-length elements have two intact open reading frames and may be capable of retrotransposition. Sequence analysis of the Ta L1 elements showed a low level of nucleotide divergence with an estimated age of 1.99 million years, suggesting that expansion of the L1 Ta subfamily occurred after the divergence of humans and African apes. A total of 262 Ta L1 elements were screened with PCR-based assays to determine their phylogenetic origin and the level of human genomic variation associated with each element. All of the Ta L1 elements analyzed by PCR were absent from the orthologous positions in nonhuman primate genomes, except for a single element (L1HS72) that was also present in the common (Pan troglodytes) and pygmy (P. paniscus) chimpanzee genomes. Sequence analysis revealed that this single exception is the product of a gene conversion event involving an older preexisting L1 element. One hundred fifteen (45%) of the Ta L1 elements were polymorphic with respect to insertion presence or absence and will serve as identical-by-descent markers for the study of human evolution.

Animals↗
PubMed1998

Sialic acid concentration of brain gangliosides: variation among eight mammalian species.

Sialic acid is a vital component of brain gangliosides which play an essential role in the transmission and storage of information in the brain. The concentration of bound sialic acid in gangliosides and free sialic acid in the brain cortex of eight different mammals [human, chimpanzee (Pan troglodytes), rat (Rattus norvegicus), mouse (Mus musculus), rabbit (Oryctolagus cuniculus), sheep (Ovis aries), cow (Bos indicus) and pig (Sus scrofa)] were compared. Total sialic acid concentration (890+/-103 microg/g wet weight tissue, mean+/-SE, n = 6) was 2-4 times higher in the human brain compared with the other species studied (0.001 < p < 0.05). There was no significant difference between human males and females. The rank order of adult brain sialic acid after humans (in microg/g) was rat (493+/-23, n = 12), mouse (445+/-29, n = 16), rabbit (380+/-18, n = 6), sheep (323+/-43, n = 6), cow (304+/-14, n = 6) and pig (252+/-14, n = 6). Apart from the cow vs the sheep, the differences between species were statistically significant (p < 0.05). In the mouse, cow and sheep, total sialic acid concentration increased during maturation by 18-32% (p < 0.05). In a 2-year-old chimpanzee, the sialic acid concentration in the left lobe of the brain cortex was 25% higher than that of right lobe at 6 weeks of age (p < 0.05). Free sialic acid was higher in the human brain cortex (41+/-3 microg/g) than that of the rat and mouse (32+/-3 and 25+/-5 microg/g respectively) and absent from other species. Variation in brain sialic acid concentration among different animals has implications for the evolution of the brain and may affect learning ability in animals.

Aging↗
PubMed1998

Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum.

Members of the Plasmodium falciparum var gene family encode clonally variant adhesins, which play an important role in the pathogenicity of tropical malaria. Here we employ a selective panning protocol to generate isogenic P.falciparum populations with defined adhesive phenotypes for CD36, ICAM-1 and CSA, expressing single and distinct var gene variants. This technique has established the framework for examining var gene expression, its regulation and switching. It was found that var gene switching occurs in situ. Ubiquitous transcription of all var gene variants appears to occur in early ring stages. However, var gene expression is tightly regulated in trophozoites and is exerted through a silencing mechanism. Transcriptional control is mutually exclusive in parasites that express defined adhesive phenotypes. In situ var gene switching is apparently mediated at the level of transcriptional initiation, as demonstrated by nuclear run-on analyses. Our results suggest that an epigenetic mechanism(s) is involved in var gene regulation.

ADP-ribosyl Cyclase↗
PubMed1987

How closely do circulating blood glucose levels reflect feeding state in fowls?

1. Amounts of food eaten in 30 min, by fasted-refed immature hens, were not correlated with plasma glucose levels before feeding, or with increases in glucose after feeding. 2. When previously fasted birds were given 0, 5, 10, 15 or 20 g food to eat, their plasma glucose increased by similar amounts with 10, 15 and 20 g, by slightly less with 5 g, and hardly at all with 0 g. 3. When food was removed from free-feeding birds, their plasma glucose levels declined slightly in 2 hr and then remained steady. They declined markedly further overnight, but recovered to a level higher than before deprivation when 10 g food was provided. 4. Four hours darkness during normal daytime had no effect on plasma glucose in fasted-refed birds, but sight of food and presentation of an empty food pan caused slight increases in glucose in 24-hr fasted birds. 5. It is concluded that blood glucose in fowls fluctuates around several "typical" levels, but that there is also much variation between and within birds. Direct (absorbed) and indirect (thermogenic) consequences of feeding probably both contribute to fluctuations in glucose, and these seem more likely to influence regulation of food intake in the longer-term rather than the short-term.

Animals↗
PubMed2024

SJPedPanel: A Pan-Cancer Gene Panel for Childhood Malignancies to Enhance Cancer Monitoring and Early Detection.

PURPOSE: The purpose of the study was to design a pan-cancer gene panel for childhood malignancies and validate it using clinically characterized patient samples. EXPERIMENTAL DESIGN: In addition to 5,275 coding exons, SJPedPanel also covers 297 introns for fusions/structural variations and 7,590 polymorphic sites for copy-number alterations. Capture uniformity and limit of detection are determined by targeted sequencing of cell lines using dilution experiment. We validate its coverage by in silico analysis of an established real-time clinical genomics (RTCG) cohort of 253 patients. We further validate its performance by targeted resequencing of 113 patient samples from the RTCG cohort. We demonstrate its power in analyzing low tumor burden specimens using morphologic remission and monitoring samples. RESULTS: Among the 485 pathogenic variants reported in RTCG cohort, SJPedPanel covered 86% of variants, including 82% of 90 rearrangements responsible for fusion oncoproteins. In our targeted resequencing cohort, 91% of 389 pathogenic variants are detected. The gene panel enabled us to detect &#x223c;95% of variants at allele fraction (AF) 0.5%, whereas the detection rate is &#x223c;80% at AF 0.2%. The panel detected low-frequency driver alterations from morphologic leukemia remission samples and relapse-enriched alterations from monitoring samples, demonstrating its power for cancer monitoring and early detection. CONCLUSIONS: SJPedPanel enables the cost-effective detection of clinically relevant genetic alterations including rearrangements responsible for subtype-defining fusions by targeted sequencing of &#x223c;0.15% of human genome for childhood malignancies. It will enhance the analysis of specimens with low tumor burdens for cancer monitoring and early detection.

Humans↗
PubMed2002

A comparative review of statistical methods for discovering differentially expressed genes in replicated microarray experiments.

MOTIVATION: A common task in analyzing microarray data is to determine which genes are differentially expressed across two kinds of tissue samples or samples obtained under two experimental conditions. Recently several statistical methods have been proposed to accomplish this goal when there are replicated samples under each condition. However, it may not be clear how these methods compare with each other. Our main goal here is to compare three methods, the t-test, a regression modeling approach (Thomas et al., Genome Res., 11, 1227-1236, 2001) and a mixture model approach (Pan et al., http://www.biostat.umn.edu/cgi-bin/rrs?print+2001,2001a,b) with particular attention to their different modeling assumptions. RESULTS: It is pointed out that all the three methods are based on using the two-sample t-statistic or its minor variation, but they differ in how to associate a statistical significance level to the corresponding statistic, leading to possibly large difference in the resulting significance levels and the numbers of genes detected. In particular, we give an explicit formula for the test statistic used in the regression approach. Using the leukemia data of Golub et al. (Science, 285, 531-537, 1999), we illustrate these points. We also briefly compare the results with those of several other methods, including the empirical Bayesian method of Efron et al. (J. Am. Stat. Assoc., to appear, 2001) and the Significance Analysis of Microarray (SAM) method of Tusher et al. (PROC: Natl Acad. Sci. USA, 98, 5116-5121, 2001).

Acute Disease↗