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Biomedical subjects

W H Li

Publications and source records attributed to W H Li.

At least 109 records · Page 6Linked to original sources
PubMed1994

A model for the correlation of mutation rate with GC content and the origin of GC-rich isochores.

Based on the biochemical kinetics of DNA replication and mutagenesis, including misincorporation and correction, a model has been developed for studying the relationships among the mutation rate (u), the G+C content of the sequence (f), and the G+C proportion in the nucleotide precursor pool (N). Also a measure for the next-nucleotide effect, called the maximum capacity of the next-nucleotide effect (MC), has been proposed. Under the normal physiological conditions of mammalian germ cells, our results indicate: (1) the equilibrium G+C content in a sequence is approximately equal to the G+C proportion in the nucleotide precursor pool, i.e., f approximately N, which is independent of the next-nucleotide effect; (2) an inverted-V-shaped distribution of mutation rates with respect to G+C contents is predicted, when the next-nucleotide effect is week, i.e., MC approximately 1; (3) the distribution becomes flatter (i.e., inverted-U-shaped) as MC increases, but the peak at 50% GC is still observed when MC < 2; and (4) the peak disappears when MC > 2.8, that is, when the next-nucleotide effect becomes strong. Our results suggest that changes in the relative concentrations of nucleotide precursors can cause variations among genes both in mutation rate and in G+C content and that compositional isochores (DNA segments with a homogeneous G+C content) can arise in a genome due to differences in replication times of DNA segments.

Base Composition↗
PubMed1994

Intronic gene conversion in the evolution of human X-linked color vision genes.

Human red and green visual pigment genes are X-linked duplicate genes. To study their evolutionary history, introns 2 and 4 (1,987 and 1,552 bp, respectively) of human red and green pigment genes were sequenced. Surprisingly, we found that intron 4 sequences of these two genes are identical and that the intron 2 sequences differ by only 0.3%. The low divergences are unexpected because the duplication event producing the two genes is believed to have occurred before the separation of the human and Old World monkey (OWM) lineages. Indeed, the divergences in the two introns are significantly lower than both the synonymous divergence (3.2% +/- 1.1%) and the nonsynonymous divergence (2.0% +/- 0.5%) in the coding sequences (exons 1-6). A comparison of partial sequences of exons 4 and 5 of human and OWM red and green pigment genes supports the hypothesis that the gene duplication occurred before the human-OWM split. In conclusion, the high similarities in the two intron sequences might be due to very recent gene conversion, probably during evolution of the human lineage.

Animals↗
PubMed1994

Evolution of base composition in the insulin and insulin-like growth factor genes.

The genomes of homeothermic (warm-blooded) vertebrates are mosaic interspersions of homogeneously GC-rich and GC-poor regions (isochores). Evolution of genome compartmentalization and GC-rich isochores is hypothesized to reflect either selective advantages of an elevated GC content or chromosome location and mutational pressure associated with the timing of DNA replication in germ cells. To address the present controversy regarding the origins and maintenance of isochores in homeothermic vertebrates, newly obtained as well as published nucleotide sequences of the insulin and insulin-like growth factor (IGF) genes, members of a well-characterized gene family believed to have evolved by repeated duplication and divergence, were utilized to examine the evolution of base composition in nonconstrained (flanking) and weakly constrained (introns and fourfold degenerate sites) regions. A phylogeny derived from amino acid sequences supports a common evolutionary history for the insulin/IGF family genes. In cold-blooded vertebrates, insulin and the IGFs were similar in base composition. In contrast, insulin and IGF-II demonstrate dramatic increases in GC richness in mammals, but no such trend occurred in IGF-I. Base composition of the coding portions of the insulin and IGF genes across vertebrates correlated (r = 0.90) with that of the introns and flanking regions. The GC content of homologous introns differed dramatically between insulin/IGF-II and IGF-I genes in mammals but was similar to the GC level of noncoding regions in neighboring genes. Our findings suggest that the base composition of introns and flanking regions is determined by chromosomal location and the mutational pressure of the isochore in which the sequences are embedded. An elevated GC content at codon third positions in the insulin and the IGF genes may reflect selective constraints on the usage of synonymous codons.

Animals↗
PubMed1994

[Effects of sodium diethyldithiocarbamate on ischemia-reperfusion-induced brain injury in Mongolian gerbil].

Brain injury in Mongolian gerbil (Merisones unguiculatus) was induced by occluding bilateral common carotid arteries for 60 min followed by reperfusion for 5 or 30 min. Oxygen free radicals in brain tissue were measured by electron spin resonance (ESR) technique, malondialdehyde (MDA) was measured by fluorescence spectrometry, and superoxide dismutase (SOD) was measured by nitrite kit. Oxygen free radicals and MDA were not significantly increased, but activities of T-SOD and Mn-SOD were decreased after 60 min of cerebral ischemia. The free radicals were increased at 5-min reperfusion, and then reduced to the level of ischemia group after 30-min reperfusion. MDA was increased remarkably after reperfusion of 30 min, whereas the activity of SOD continued to decrease. Sodium diethyldithiocarbamate (DTC), i.v. 5-100 mg.kg-1 15 min before occlusion, decreased the production of MDA and increased the activities of T-SOD and Mn-SOD. The formation of oxygen free radicals was depressed by i.v. DTC 50 mg.kg-1. The result suggested that the protective effects of DTC on ischemia-reperfusion-induced brain injury might be induced by scavenging the oxygen free radicals, increasing the Mn-SOD activity and decreasing the production of MDA.

Animals↗
PubMed1994

[A benign neuroendocrine tumor of the lung: study on the origin of the so-called sclerosing hemangioma of the lung].

31 cases of the so-called sclerosing hemangiomas of the lung were studied by light microscope, immunohistochemical and electron microscopy. This tumor is benign and has 3 histologic patterns: papillary, hemangioma-like and solid type. Characteristic morphology being uniform round tumor cells, lying within the stroma in different patterns and regarded as the major component of sclerosing hemangioma, expressing neuroendocrine markers which include chromagranin A, neuron-specific enolase, ACTH, growth hormone, calcitonin and gastrin. Only a few tumor cells were positive for epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA), all the tumor cells were negative for keratin (Polyclonal, Z622) stain. However, in contrast to the round tumor cells, the cells lining papillary projections or cystic spaces, which presented as normal or hyperplastic alveolar cells, stained positive for keratin, EMA and CEA but negative for neuroendocrine markers. Both the surface cells and tumor cells were negative for Factor VIII-related antigen and alpha 1-AT. Therefore, pulmonary sclerosing hemangioma was regarded to be a benign tumor originating from the neuroendocrine cells of the lung and we suggest that it be renamed as benign neuroendocrine tumor of the lung (LBNET). This viewpoint has not been previously reported in the literature.

Adenoma↗
PubMed1993

Male-driven evolution of DNA sequences.

It is commonly believed that the mutation rate is much higher in the human male germ line than in the female germ line because the number of germ-cell divisions per generation is much larger in males than in females. But direct estimation of mutation rates is difficult, relying mainly on sex-linked genetic diseases, so the ratio (alpha m) of male to female mutation rates is not clear. It has been noted that if alpha m is very large, then the rate of synonymous substitution in X-linked genes should be only 2/3 of that in autosomal genes, and comparison of human and rodent genes supported this prediction. As the number of X-linked genes used in the study was small and the X-linked and autosomal sequences were non-homologous, and given that the synonymous rate varies among genes, we sequenced the last intron (approximately 1 kb) of the Y-linked and X-linked zinc-finger-protein genes (ZFY and ZFX) in humans, orang-utans, baboons and squirrel monkeys. The ratio Y/X of the substitution rate in the Y-linked intron to that in the X-linked intron is approximately 2.3, which is close to that estimated from synonymous rates in the ZFY and ZFX genes and implies alpha m approximately 6. This estimate of alpha m supports the view that the evolution of DNA sequences in higher primates is male-driven. It is, however, much lower than the previous estimate and therefore raises a number of issues.

Animals↗
PubMed1993

Insulin-like growth factor II intron sequences support the hominoid rate-slowdown hypothesis.

Nucleotide sequences were obtained from the approximately 1.7 kb intron 7 of the insulin-like growth factor II gene in human and representatives of both Old World and New World monkeys and analyzed with additional published noncoding regions (both introns and flanking regions) that differ substantially in base composition (GC content). Relative rate tests, utilized to examine differential rates of molecular evolution between humans and Old World monkeys, support the hypothesis that the rate of nucleotide substitution is slower in humans than in Old World monkeys. Comparisons of approximately 4,300 nucleotide positions revealed a significantly higher evolutionary rate in the Old World monkey lineage than in the human lineage for both intron sequences and flanking regions. The data indicate that the molecular clock hypothesis is not applicable to the human and Old World monkey lineages and that the hominoid rate slowdown is a general phenomenon--it is not unique to a particular gene region and is not influenced by regional differences in base composition.

Animals↗
PubMed1993

Structure and evolution of opossum, guinea pig, and porcupine cytochrome b genes.

We have sequenced the mitochondrial cytochrome b gene from the guinea pig, the African porcupine, and a South American opossum. A phylogenetic analysis, which includes 22 eutherian and four other vertebrate cytochrome b sequences, indicates that the guinea pig and the porcupine constitute a natural clade (Hystricomorpha) that is not a sister group to the clade of mice and rats (Myomorpha). Therefore, the hypothesis that the Rodentia is paraphyletic receives additional support. The artiodactyls, the perissodactyls, and the cetaceans form a group that is separated from the primates and the rodents. The 26 sequences are used to study the structure/function relationships in cytochrome b, whose function is electron transport. Most of the amino acid residues involved in the two reaction centers are well conserved in evolution. The four histidines that are believed to ligate the two hemes are invariant among the 26 sequences, but their nearby residues are not well conserved in evolution. The eight transmembrane domains represent some of the most divergent regions in the cytochrome b sequence. The rate of nonsynonymous substitution is considerably faster in the human and elephant lineages than in other eutherian lineages; the faster rate might be due to coevolution between cytochrome b and cytochrome c.

Amino Acid Sequence↗
PubMed1993

The phylogenetic position of Taxaceae based on 18S rRNA sequences.

The evolutionary position of the yew family, Taxaceae, has been very controversial. Some plant taxonomists strongly advocate excluding Taxaceae from the conifer order and raising its taxonomic status to a new order or even class because of its absence of seed cones, contrary to the case in the majority of conifers. However, other authors believe that the Taxaceae are not fundamentally different from the rest of the conifers except in that they possess the most reduced solitary-ovule cones. To resolve the controversy, we have sequenced the 18S rRNA genes from representative gymnosperms: Taxus mairei (Taxaceae), Podocarpus nakaii (Podocarpaceae), Pinus luchuensis (Pinaceae), and Ginkgo biloba (Ginkgoales). Our phylogenetic analysis of the new sequence data with the published 18S rRNA sequence of Zamia pumila (a.cycad) as an outgroup strongly indicates that Taxus, Pinus, and Podocarpus form a monophyletic group with the exclusion of Ginkgo and that Taxus is more closely related to Pinus than to Podocarpus. Therefore, Taxaceae should be classified as a family of Coniferales. Our finding that Taxaceae, Pinaceae, and Podocarpaceae form a clade contradicts both the view that the uniovulate seed of Taxaceae is a primitive character and the view that the Taxaceae are descendants of the Podocarpaceae. Rather, the uniovulate seed of Taxaceae and that of some species of Podocarpus appear to have different origins, probably all reduced from multiovulate cones.

Base Sequence↗
PubMed1993

Primary structure of Beijing duck apolipoprotein A-1.

The primary structure of Beijing duck apolipoprotein A-1 was determined by sequencing peptide fragments derived from tryptic and endoproteinase Asp-N digestion of the protein, and alignment with homologous chicken apo A-1. All of the peptide fragments were isolated by high-pressure liquid chromatography (HPLC) with a Vydac C18 column using a trifluoroacetic acid (TFA) buffer system. The N-terminus of the protein was determined to be aspartic acid by directly sequencing 52 residues of the intact protein. The C-terminus was alanine. The protein contains 240 amino acid residues. By analysis of the whole protein and its tryptic peptides, a six amino acid (Arg-Tyr-Phe-Trp-Gln-His) prosegment was determined. No cross-reactivity between duck and human apo A-1 with a goat antiserum against human apo A-1 was found. Sequence analysis of apo A-1 of other species indicates that amino acid substitutions in rat are more extensive than in other mammals. Isoleucine residues in apo A-1 are inversely correlated to the homology of human to other species, except dog.

Amino Acid Sequence↗
PubMed1993

Unbiased estimation of the rates of synonymous and nonsynonymous substitution.

The current convention in estimating the number of substitutions per synonymous site (KS) and per nonsynonymous site (KA) between two protein-coding genes is to count each twofold degenerate site as one-third synonymous and two-thirds nonsynonymous because one of the three possible changes at such a site is synonymous and the other two are nonsynonymous. This counting rule can considerably overestimate the KS value because transitional mutations tend to occur more often than transversional mutations and because most transitional mutations at twofold degenerate sites are synonymous. A new method that gives unbiased estimates is proposed. An application of the new and the old method to 14 pairs of mouse and rat genes shows that the new method gives a KS value very close to the number of substitutions per four-fold degenerate site whereas the old method gives a value 30% higher. Both methods give a KA value close to the number of substitutions per nondegenerate site.

Animals↗
PubMed1993

Potential problems in estimating the male-to-female mutation rate ratio from DNA sequence data.

It is commonly believed that the rate of mutation is much higher in males than in females because the number of germ-cell divisions per generation is much larger in males than in females. However, the precise magnitude of the male-to-female mutation rate ratio (alpha m) remains unknown. Recently there have been efforts to estimate alpha m by using DNA sequence data from different species. We have studied the potential problems in such an approach. We found that the rate of synonymous substitution varies about fivefold among X-linked genes, as large as the variation among autosomal genes. This large variation makes the assumption of selective neutrality of synonymous changes dubious, so one should be cautious in using the synonymous rates in X-linked and autosomal genes to estimate alpha m. A similar difficulty was also observed in using nonhomologous intron sequences to estimate alpha m. Contrary to the expectation that X-linked sequences should evolve more slowly than autosomal sequences, the Alu repeat in the last intron of the X-linked zinc finger gene has evolved faster than the four autosomal Alu repeats used in this study. It appears that the best way to estimate alpha m is to use homologous sequences. However, such sequences may be involved in gene conversion events. In fact, we found evidence that the Y-linked and X-linked zinc finger genes have been involved in multiple conversion events during primate evolution. Thus, the possibility of gene conversion should be considered when using homologous sequences to estimate alpha m.

Animals↗
PubMed1993

So, what about the molecular clock hypothesis?

Recent studies have provided strong evidence for significant variation in rates of nucleotide substitution among evolutionary lineages. They have also provided evidence for germ-cell division as a major source of mutation (i.e. the generation-time effect hypothesis). Moreover, they have suggested the importance of differences in metabolic rate as a cause of rate variation.

Animals↗
PubMed1993

Statistical tests of neutrality of mutations.

Mutations in the genealogy of the sequences in a random sample from a population can be classified as external and internal. External mutations are mutations that occurred in the external branches and internal mutations are mutations that occurred in the internal branches of the genealogy. Under the assumption of selective neutrality, the expected number of external mutations is equal to theta = 4Ne mu, where Ne is the effective population size and mu is the rate of mutation per gene per generation. Interestingly, this expectation is independent of the sample size. The number of external mutations is likely to deviate from its neutral expectation when there is selection while the number of internal mutations is less affected by the presence of selection. Statistical properties of the numbers of external mutations and of internal mutations are studied and their relationships to two commonly used estimates of theta are derived. From these properties, several new statistical tests based on a random sample of DNA sequences from the population are developed for testing the hypothesis that all mutations at a locus are neutral.

Analysis of Variance↗
PubMed1993

Maximum likelihood estimation of population parameters.

One of the most important parameters in population genetics is theta = 4Ne mu where Ne is the effective population size and mu is the rate of mutation per gene per generation. We study two related problems, using the maximum likelihood method and the theory of coalescence. One problem is the potential improvement of accuracy in estimating the parameter theta over existing methods and the other is the estimation of parameter lambda which is the ratio of two theta's. The minimum variances of estimates of the parameter theta are derived under two idealized situations. These minimum variances serve as the lower bounds of the variances of all possible estimates of theta in practice. We then show that Watterson's estimate of theta based on the number of segregating sites is asymptotically an optimal estimate of theta. However, for a finite sample of sequences, substantial improvement over Watterson's estimate is possible when theta is large. The maximum likelihood estimate of lambda = theta 1/theta 2 is obtained and the properties of the estimate are discussed.

Biological Evolution↗
PubMed1993

[Carcinoma of the hilar bile duct: a clinical and pathological study].

From 1986 through 1990, 50 patients suffering from hilar bile duct carcinoma underwent exploration with the resection of the tumor in 31 (62%), and hepatic lobectomy in 16 (51.6%). There was no operative mortality. Resection of the recurrent tumor was successfully performed in 5 cases, among them 4 were still alive upon 1-4 year follow-up. The median survival period was 15 months for the resection group and late deaths were frequently caused by local recurrence. Pathological study based on 27 surgically resected specimens and 5 autopsies classified the tumors into 4 types: (1)papillary adenocarcinoma (6 cases), (2)well differentiated adenocarcinoma (21 cases), (3) poorly differentiated carcinoma (3 cases), and (4) carcinoma simplex (2 cases). The authors discussed the biological behaviour of such tumors, and stressed the need of early diagnosis of hilar bile duct carcinoma at its subclinical stage.

Adenocarcinoma↗
PubMed1993

[Morphological and immunohistochemical observations on 30 cases of neuroendocrine carcinoma of the lung].

30 cases of resected pulmonary neuroendocrine carcinoma (NEC) collected from September 1983 to February 1992 were confirmed by microscopy, electron microscopy and immunohistochemical observations. Of the 30 cases, 8 were typical carcinoid (TC), 15 atypical carcinoid (AC), 5 small cell lung carcinoma (SCLC) and 2 cases of giant cell neuroendocrine carcinoma (LCNEC), which have never been reported in the literature. This series of pulmonary NEC exhibited their specific morphology under light microscope. Electron microscopic examination found the common feature of neuroendocrine granules in the cytoplasm of carcinoma cells. Immunohistochemical studies with neuroendocrine cell markers for NEC gave positive results. The morphological features and differential diagnosis of the various NEC under light microscope and electron microscope were compared and are discussed. Complimental devise to the classification of NECs of the lung is suggested.

Adult↗