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Y X Fu

Publications and source records attributed to Y X Fu.

At least 55 records · Page 3Linked to original sources
PubMed1998

Simultaneous estimation of all the parameters of a stepwise mutation model.

Minisatellite and microsatellite are short tandemly repetitive sequences dispersed in eukaryotic genomes, many of which are highly polymorphic due to copy number variation of the repeats. Because mutation changes copy numbers of the repeat sequences in a generalized stepwise fashion, stepwise mutation models are widely used for studying the dynamics of these loci. We propose a minimum chi-square (MCS) method for simultaneous estimation of all the parameters in a stepwise mutation model and the ancestral allelic type of a sample. The MCS estimator requires knowing the mean number of alleles of a certain size in a sample, which can be estimated using Monte Carlo samples generated by a coalescent algorithm. The method is applied to samples of seven (CA)n repeat loci from eight human populations and one chimpanzee population. The estimated values of parameters suggest that there is a general tendency for microsatellite alleles to expand in size, because (1) each mutation has a slight tendency to cause size increase and (2) the mean size increase is larger than the mean size decrease for a mutation. Our estimates also suggest that most of these CA-repeat loci evolve according to multistep mutation models rather than single-step mutation models. We also introduced several quantities for measuring the quality of the estimation of ancestral allelic type, and it appears that the majority of the estimated ancestral allelic types are reasonably accurate. Implications of our analysis and potential extensions of the method are discussed. SINCE the discovery that a large number of loci with tandemly repeated sequences in human and many eukaryote species are highly polymorphic because of copy number variation of the repeats in different individuals (Jeffreys 1985; Litt and Luty 1989; Weber and May 1989), allele size data from such loci are rapidly becoming the dominant source of genetic markers for genome mapping, forensic testing, and population studies. Loci with repeat sequences longer than 5 bp are generally referred to as minisatellite or variable number tandem repeat loci, and those with repeat sequences between 2 to 5 bp are referred to as microsatellite or short tandem repeat loci (Tautz 1993). Because mutations change the copy number of such loci in a stepwise fashion, rapid accumulation of population samples from minisatellite and microsatellite loci has resurrected the interest of the stepwise mutation model (SMM), which was popular in the 1970s.

Chi-Square Distribution↗
PubMed1998

Sequence variation in ZFX introns in human populations.

DNA variation in human populations was studied by examining the last intron of the ZFX gene (about 1, 151 bp) with a worldwide sample of 29 individuals. Only one polymorphic site was found, which is located in an Alu sequence. This polymorphism is present at an intermediate frequency in all populations studied, and could be a shared polymorphism or due to migration among populations in Asia, Europe, and Africa. The nucleotide diversity is 0.04%, supporting the view that the level of nucleotide variation in nuclear DNA is very low in humans. From the sequence data, the age (T) of the most recent common ancestor of the sampled sequences is estimated: the mode of T is about 306,000 years, and the 95% confidence interval of T is 162,000-952,000 years. This mode estimate is considerably older than the estimates from Y-linked sequences.

Animals↗
PubMed1998

Inferring the major genomic mode of dominance and overdominance.

The mode of within-locus gene action in most genomic regions is termed as the major genomic mode, i.e., it is the within-locus allelic effects in most regions of the genome. Determining whether dominance or overdominance is the major genomic mode is important for two long-standing evolutionary genetics issues: 1. How is the genetic variation in most genomic regions maintained? 2. What is the major mechanism for heterosis? Many efforts have been made, but almost all of them suffer some explanational difficulties. Here we propose an alternative inference approach. It is based on the existent theoretical results on the correlation of the recombination rate and the level of neutral variation in different genomic regions. Positive and negative correlation suggest dominance and overdominance, respectively, as the major genomic mode. Zero correlations imply either few selected sites or about equal composition and distribution of dominant and overdominant regions in the genome, depending on the data distribution. This approach not only avoids all the problems associated with earlier approaches, but it is also particularly useful in organisms where controlled breeding is difficult. Well-corroborated data in Drosophila and recently emerging data in mice and humans all suggest dominance as the major genomic mode.

Animals↗
PubMed1997

Distinct roles of lymphotoxin alpha and the type I tumor necrosis factor (TNF) receptor in the establishment of follicular dendritic cells from non-bone marrow-derived cells.

In mice deficient in either lymphotoxin alpha (LT-alpha) or type I tumor necrosis factor receptor (TNFR-I), organized clusters of follicular dendritic cells (FDC) and germinal centers (GC) are absent from the spleen. We investigated the role of LT-alpha and TNFR-I in the establishment of spleen FDC and GC structure by using reciprocal bone marrow (BM) transfer. When LT-alpha-deficient mice were reconstituted with wild-type BM, FDC organization and the ability to form GC were restored, indicating that the LT-alpha-expressing cells required to establish organized FDC are derived from BM. The role of LT-alpha in establishing organized FDC structure was further investigated by the transfer of complement receptor 1 and 2 (CR1/2)-deficient BM cells into LT-alpha-deficient mice. Organized FDC were identified with both the FDC-M1 and anti-CR1 monoclonal antibodies in these BM-chimeric mice, indicating that these cells were derived from the LT-alpha-deficient recipient. Thus, expression of LT-alpha in the BM-derived cells, but not in the non-BM-derived cells, is required for the maturation of FDC from non-BM precursor cells. In contrast, when TNFR-I-deficient mice were reconstituted with wild-type BM, they showed no detectable FDC clusters or GC formation. This indicates that TNFR-I expression on non-BM-derived cellular components is necessary for the establishment of these lymphoid structures. TNFR-I-deficient BM was able to restore FDC organization and GC formation in LT-alpha-deficient mice, indicating that formation of these structures does not require TNFR-I expression on BM-derived cells. The data in this study demonstrate that FDC organization and GC formation are controlled by both LT-alpha-expressing BM-derived cells and by TNFR-I-expressing non-BM-derived cells.

Animals↗
PubMed1997

Lymphotoxin-alpha (LTalpha) supports development of splenic follicular structure that is required for IgG responses.

LTalpha-deficient (LTalpha-/-) mice show altered splenic microarchitecture. This includes loss of normal B cell-T cell compartmentalization, of follicular dendritic cell (FDC) clusters, and of ability to form germinal centers (GC). LTalpha-/- mice immunized with sheep red blood cells (SRBC) produced high levels of antigen-specific IgM but no IgG in either primary or secondary responses, demonstrating failure of Ig class switching. This inability to switch to IgG could have been due to the altered splenic microarchitecture in these mice. Alternatively, it could have been due directly to a requirement for LTalpha expression by lymphocytes cooperating in the antibody response. To investigate this, we performed reciprocal spleen cell transfers. When irradiated LTalpha-/- mice were reconstituted with wild-type splenocytes and immunized immediately with SRBC, splenic microarchitecture remained disturbed and there was no IgG response. In contrast, when irradiated wild-type animals received splenocytes from LTalpha-/- mice, follicle structure and a strong IgG response were retained. These data indicate that LTalpha-deficient B cells and T cells have no intrinsic defect in ability to generate an IgG response. Rather, the altered microenvironment characteristic of LTalpha-/- mice appears to result in impaired ability to switch to a productive IgG response. To investigate whether prolonged expression of LTalpha could alter the structure and function of spleen follicles, reciprocal bone marrow (BM) transplantation was performed. Six weeks after reconstitution of LTalpha-/- mice with wild-type BM, spleen follicle structure was partially restored, with return of FDC clusters and GC. B cell/T cell compartmentalization remained abnormal and white pulp zones were small. This was accompanied by restoration of IgG response to SRBC. Reconstitution of wild-type mice with LTalpha-/- BM resulted in loss of FDC clusters and GC, and loss of the IgG response, although compartmentalized B cell and T cell zones were largely retained. Thus, defective IgG production is not absolutely associated with abnormal B cell and T cell compartmentalization. Rather, expression of LTalpha supports the maturation of spleen follicle structure, including the development and maintenance of FDC clusters, which supports Ig class switching and an effective IgG response.

Animals↗
PubMed1997

Independent signals regulate development of primary and secondary follicle structure in spleen and mesenteric lymph node.

Lymphotoxin-alpha-deficient (LT-alpha-/-) mice manifest congenital absence of lymph nodes (LNs) and Peyer's patches and disturbed spleen follicle structure. The splenic white pulp areas show loss of discrete T and B lymphocyte zones, of follicular dendritic cell (FDC) clusters, and of germinal centers (GCs). Tumor necrosis factor receptor I-deficient (TNFR-I-/-) mice show similar absence of FDC clusters and GCs but retain segregation of T and B cell zones. Rarely are mesenteric LNs found in LT-alpha-/- mice. These mesenteric LNs show segregation of T and B cell zones similar to wild-type mice. In contrast, mesenteric LNs in TNFR-I-/- mice manifest grossly disturbed organization of T and B cells. Both LT-alpha-/- and TNFR-I-/- mice lacked FDC clusters in LNs and spleen. Interestingly, although both LT-alpha-/- and TNFR-I-/- mice that had been immunized with sheep red blood cells failed to form GCs in the spleen, they both developed GC-like clusters of peanut agglutinin-positive (PNA+) cells in their LNs. Furthermore, when lethally irradiated recombination activating gene (RAG)-1-deficient (RAG-1(-/-)) mice that had received spleen cells from LT-alpha-/- mice were immunized with sheep red blood cells, they failed to generate PNA+ clusters in the reconstituted spleen but showed robust PNA+ clusters in the reconstituted LNs. These data demonstrate that the signals that regulate the development of distinct T and B cell zones as well as the signals that regulate B cell activation to produce clusters of PNA+ cells differ between the spleen and LNs.

Animals↗
PubMed1997

Coalescent theory for a partially selfing population.

A coalescent theory for a sample of DNA sequences from a partially selfing diploid population and an algorithm for simulating such samples are developed in this article. Approximate formulas are given for the expectation and the variance of the number of segregating sites in a sample of k sequences from n individuals. Several new estimators of the important parameters theta = 4N mu and the selfing rate s, where N and mu are, respectively, the effective population size and the mutation rate per sequence per generation, are proposed and their sampling properties are studied.

Algorithms↗
PubMed1997

Statistical tests of neutrality of mutations against population growth, hitchhiking and background selection.

The main purpose of this article is to present several new statistical tests of neutrality of mutations against a class of alternative models, under which DNA polymorphisms tend to exhibit excesses of rare alleles or young mutations. Another purpose is to study the powers of existing and newly developed tests and to examine the detailed pattern of polymorphisms under population growth, genetic hitchhiking and background selection. It is found that the polymorphic patterns in a DNA sample under logistic population growth and genetic hitchhiking are very similar and that one of the newly developed tests, Fs, is considerably more powerful than existing tests for rejecting the hypothesis of neutrality of mutations. Background selection gives rise to quite different polymorphic patterns than does logistic population growth or genetic hitchhiking, although all of them show excesses of rare alleles or young mutations. We show that Fu and Li's tests are among the most powerful tests against background selection. Implications of these results are discussed.

Models, Genetic↗
PubMed1997

Estimating the age of the common ancestor of a sample of DNA sequences.

We present a simple Monte Carlo method for estimating the age of the most recent common ancestor (MRCA) of a sample of DNA sequences. We show that Templeton's (1993) estimator of the age of the MRCA based on the maximum number of nucleotide differences between two sequences in a sample is inaccurate, and we demonstrate the new method by reanalyzing a sample of DNA sequences from human Y chromosomes and a sample of human Alu sequences.

Animals↗
PubMed1997

Lymphotoxin-alpha-deficient and TNF receptor-I-deficient mice define developmental and functional characteristics of germinal centers.

Mice deficient in LT alpha (LT alpha-/-) lack lymph nodes and Peyer's patches. This action of LT alpha in lymph node organogenesis appears to be mediated by the membrane form of LT using a mechanism independent of TNF receptor I (TNFR-I) or II (TNFR-II). In contrast, normal Peyer's patch development appears to require both LT alpha and TNFR-I, with TNFR-I-/- mice showing hypoplastic Peyer's patch structures. LT alpha-/- mice also fail to support the normal segregation of T-cell and B-cell zones within the splenic white pulp. Again, this occurs via a mechanism independent of TNFR-I or TNFR-II. Additionally, follicular dendritic cell (FDC) clusters or germinal centers fail to develop in the spleen of LT alpha-/- animals. Mice deficient in either TNF alpha or TNFR-I also fail to develop splenic FDC clusters and germinal centers, indicating that signaling by both LT alpha and TNF alpha is required for development of these specialized lymphoid tissue structures. Finally, the splenic white pulp areas in LT alpha-/- mice lack the marginal zone of monoclonal antibody MOMA-1-staining metallophilic macrophages, whereas TNFR-I-deficient mice have preserved MOMA-1 staining. Thus, certain actions of LT alpha to regulate spleen white pulp architecture are mediated by receptors other than TNFR-I, most likely by the LT beta R or a closely related receptor. We tested whether germinal centers are essential for maturation of T-cell-dependent antibody responses. When LT alpha-/- mice were immunized with low doses of NP-ovalbumin (NP-OVA) adsorbed to alum, there was dramatically impaired production of high affinity anti NP IgG; however, after immunization with high doses of NP-OVA adsorbed to alum, LT alpha-/- mice mounted a high affinity NP-specific serum IgG response similar to wild-type mice, all in the absence of germinal centers or clustered FDC. Thus, although germinal centers enhance the processes required for maturation of the humoral immune response, the mechanisms responsible for affinity maturation are not absolutely dependent on the presence of germinal centers.

Animals↗
PubMed1997

A novel transcript encoding an N-terminally truncated AML1/PEBP2 alphaB protein interferes with transactivation and blocks granulocytic differentiation of 32Dcl3 myeloid cells.

The gene AML1/PEBP2 alphaB encodes the alpha subunit of transcription factor PEBP2/CBF and is essential for the establishment of fetal liver hematopoiesis. Rearrangements of AML1 are frequently associated with several types of human leukemia. Three types of AML1 cDNA isoforms have been described to date; they have been designated AML1a, AML1b, and AML1c. All of these isoforms encode the conserved-Runt domain, which harbors the DNA binding and heterodimerization activities. We have identified a new isoform of the AML1 transcript, termed AML1 deltaN, in which exon 1 is directly connected to exon 4 by alternative splicing. The AML1 deltaN transcript was detected in various hematopoietic cell lines of lymphoid to myeloid cell origin, as revealed by RNase protection and reverse transcriptase PCR analyses. The protein product of AML1 deltaN lacks the N-terminal region of AML1, including half of the Runt domain, and neither binds to DNA nor heterodimerizes with the beta subunit. However, AML1 deltaN was found to interfere with the transactivation activity of PEBP2, and the molecular region responsible for this activity was identified. Stable expression of AML1 deltaN in 32Dcl3 myeloid cells blocked granulocytic differentiation in response to granulocyte colony-stimulating factor. These results suggest that AML1 deltaN acts as a modulator of AML1 function and serves as a useful tool to dissect the functional domains in the C-terminal region of AML1.

Amino Acid Sequence↗
PubMed1997

[Comparison on treatment of falciparum malaria with different courses of artesunate tablet].

OBJECTIVE: To assess the efficacy of Artesunate on falciparum malaria. METHODS: A randomized controlled study on the treatment of 90 uncomplicated falciparum malaria patients was carried out with 400 mg of artesunate tablet as a total dose over 3 days, 600 mg over 5 days and 800 mg over 7 days. RESULTS: All patients were cured. Fever clearance time (FCT) and parasite clearance time(PCT) among the three groups were similar. Parasite recrudescence rate within 28 days was 39.3% (11/ 28) in 3 day group, 6.9% (2/29) in 5 day group and 3.4% (1/29) in 7 day group (comparing 5 day group with 3 day group, P < 0.005, comparing 7 day group with 3 day group, P < 0.005). CONCLUSION: It indicated that parasite recrudescence rate may be effectively decreased by prolonging treatment courses.

Adolescent↗
PubMed1996

Multimodality therapy of an acquired factor V inhibitor.

Acquired inhibitors of factor V are rare causes of clinical bleeding, whose severity ranges from mild to life-threatening. Optimal treatment of patients with factor V inhibitors is uncertain. We report on our successful treatment approach in a patient with spontaneous, life-threatening intracranial bleeding caused by a factor V inhibitor. The patient deteriorated after initial treatment with fresh-frozen plasma and platelet transfusions. He was subsequently treated with a combination of plasma exchange and chemotherapy, which led to complete recovery. Our experience suggests that plasma exchange may be life-saving in cases of severe bleeding caused by factor V inhibitors. The use of plasmapheresis in conjunction with chemotherapy is an efficacious and well-tolerated treatment and should be considered in patients with factor V inhibitors.

Aged↗
PubMed1996

New statistical tests of neutrality for DNA samples from a population.

The purpose of this paper is to develop statistical tests of the neutral model of evolution against a class of alternative models with the common characteristic of having an excess of mutations that occurred a long time ago or a reduction of recent mutations compared to the neutral model. This class of population genetics models include models for structured populations, models with decreasing effective population size and models of selection and mutation balance. Four statistical tests were proposed in this paper for DNA samples from a population. Two of these tests, one new and another a modification of an existing test, are based on EWENS' sampling formula, and the other two new tests make use of the frequencies of mutations of various classes. Using simulated samples and regression analyses, the critical values of these tests can be computed from regression equations. This approach for computing the critical values of a test was found to be appropriate and quite effective. We examined the powers of these four tests using simulated samples from structured populations, populations with linearly decreasing sizes and models of selection and mutation balance and found that they are more powerful than existing statistical tests of the neutral model of evolution.

Biological Evolution↗
PubMed1996

Estimating the age of the common ancestor of a DNA sample using the number of segregating sites.

The number of segregating sites in a sample of DNA sequences and the age of the most recent common ancestor (MRCA) of the sequences in the sample are positively correlated. The value of the former can be used to estimate the value of the latter. Using the coalescent approach, we derive in this paper the joint probability distribution of the number of segregating sites and the age of the MRCA of a sample under the neutral Wright-Fisher model. From this distribution, we are able to compute the likelihood function of the number of segregating sites and the posterior probability of the age of the MRCA of a sample. Three point estimators and one interval estimator of the age of the MRCA are developed; their relationships and properties are investigated. The estimation of the age of the MRCA of human Y chromosomes from a sample of no variation is discussed.

DNA↗
PubMed1996

The effects of variable mutation rates across sites on the phylogenetic estimation of effective population size or mutation rate of DNA sequences.

Multiple hits at some sites of human mitochondrial DNA sequences suggest that the commonly assumed infinite-sites model can be violated. Under the neutral Wright-Fisher model without recombination and population subdivision, we investigated, by computer simulations, the effect of multiple hits on the estimation of the essential parameter theta = 4Nmu by FU's UPBLUE procedure. We found that with moderate mutation rate heterogeneity, UPBLUE performs very well in terms of unbiasness and efficiency. Under extreme mutation rate heterogeneity, if sample size is reasonably large (e.g., > 60), UPBLUE is still very satisfactory; otherwise we developed a new correction equation. Given knowledge of the degree of mutation rate heterogeneity, the performance of UPBLUE with the new correction equation was tested to be fairly satisfactory: there is almost no bias and the sampling variance is only slightly higher than the theoretical minimum variance. Thus, with an appropriate correction, UPBL.UE is relatively robust to the multiple hits. In genealogies reconstructed by UPGMA, we found that the total length of branches directly linked to the tips is underestimated, and those far away tend to be overestimated, while the total length of all branches is not biased.

Computer Simulation↗
PubMed1995

Linear invariants under Jukes' and Cantor's one-parameter model.

Linear invariants are random variables with zero expectations under certain assumptions. In this paper, linear invariants under Jukes' and Cantor's one-parameter model, both with and without the assumption that nucleotide frequencies are at equilibrium, are studied using the method developed in a previous paper. Phylogenetic linear invariants (random variables that are linear invariants of some but not all trees of the same number of species) for trees with up to seven species are derived and bases of phylogenetic linear invariant spaces for unrooted trees with four, five and six species are presented. All these bases consist of invariants of simple form. The constraints that specify non-phylogenetic linear invariants (invariants shared by all trees of the same number of species) are determined. Under the assumption that nucleotide frequencies are at equilibrium, it is found that (i) each five-species tree has 17 independent phylogenetic linear invariants, and for two different trees with five species, there are at least three phylogenetic linear invariants of one tree that are not invariants of the other tree; (ii) each six-species tree has 98 independent phylogenetic linear invariants, and for two different trees of six species there are at least nine independent phylogenetic linear invariants that are not invariants of the other tree; and (iii) each seven-species tree has 482 independent phylogenetic linear invariants. It is also found that the number of independent phylogenetic linear invariants is much larger without the assumption of equilibrium than with it, but the reverse is true for the number of non-phylogenetic linear invariants. A class of random variables that are phylogenetic linear invariants with or without the equilibrium assumption is also identified.

Animals↗