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PubMed2004

Genetic variability and evolution of two pharmacologically important classes of genes.

We have studied the human genetic variability of single nucleotide polymorphisms (SNPs) and haplotypes in two pharmaceutically important classes of genes that might be expected to experience different evolutionary pressures: antigen presentation and processing (APP) and nuclear hormone receptor (NHR) genes. We compared the variation pattern in these two classes of genes with 5119 reference (REF) genes. We assessed this variability by sequencing and discovering SNPs in 5'-upstream, 5'-untranslated region (5'UTR), exon, intron, 3'UTR and 3'-downstream regions of all these genes in 79 unrelated humans from diverse ethnic backgrounds, one chimpanzee (Pan troglodytes) and a gorilla (Gorilla gorilla). SNP density and nucleotide diversity were higher in the APP genes than the REF genes. Relative to the REF genes, APP SNP density was significantly higher in the coding and 3'UTR regions. Higher variation in the coding region of the APP genes was due specifically to having more non-synonymous changes, which suggests that natural selection may be acting to promote change or diversity in these proteins. In contrast, the NHR genes showed lower SNP density and diversity relative to REF genes. The NHR genes consistently showed lower nucleotide diversity in all the genomic regions except in the 3'downstream region. SNP frequency data on the non-synonymous SNPs also suggested that the coding region in the NHR genes is conserved to a higher degree than the coding region in the REF genes. Significantly lower SNP density was observed in the 5'-upstream and 5'UTR regions of the NHR genes, perhaps reflecting selective conservation of these regions. Heterozygosity in the APP genes was significantly higher than in the NHR genes in each of the three species tested. Moreover, between species there were more fixed differences in the APP genes than in the NHR genes. Substantial variability exists in these two classes of genes. It is important to consider this interindividual variability pattern while developing drugs that act on such targets.

Alleles↗
PubMed2004

Ontogenetic allometry, heterochrony, and interspecific differences in the skull of African apes, using tridimensional Procrustes analysis.

Ontogenetic studies of African ape skulls lead to an analysis of morphological differences in terms of allometry, heterochrony, and sexual dimorphism. The use of geometric morphometrics allows us 1) to define size and shape variations as independent factors (an essential but seldom respected condition for heterochrony), and 2) to calculate in percentage of shape changes and to graphically represent the parts of shape variation which are related to various biological phenomena: common allometry, intraspecific allometry, and allometric and nonallometric shape discrimination. Three tridimensional Procrustes analyses and the calculation of multivariate allometries, discriminant functions, and statistical tests are used to compare the skulls of 50 Pan troglodytes, and 50 Gorilla gorilla of different dental stages. The results both complement and modify classical results obtained from similar material but with different methods. Size and Scaling in Primate Morphology, New York: Plenum, p. 175-205). As previously described by Shea, the common growth allometric pattern is very important (64% of total shape variation). It corresponds to a larger increase of facial volume than of neurocranial volume, a more obliquely oriented foramen magnum, and a noticeable reshaping of the nuchal region (higher inion). However, the heterochronic interpretation based on common allometry is rather different from Shea. Gorillas differ from chimpanzees not only with a larger magnitude of allometric change (rate peramorphosis), as is classically said, but also grow more in size than in shape (size acceleration). In other words, for a similar stage of growth, gorillas have the size and shape corresponding to older chimpanzees, and for a similar shape, gorillas have a larger size than chimpanzees. In contrast, sexual dimorphism actually corresponds to allometric changes only, as classically demonstrated (time hypermorphosis). Sexual dimorphism is here significant in adult gorillas alone, and solely in terms of allometry (size-related shape and size, given that sagittal and nuchal crests are not taken into account). The study also permits us to differentiate two different shape variations that are classically confused in ontogenetic studies: a very small part of allometric shape change which is specific to each species (1% of the total shape variation), and nonallometric species-specific traits independent of growth (8% of total shape change). When calculated in terms of intraspecific allometries (including common allometry and noncommon allometry), shape changes are more extensive in gorillas (36% of total shape change) than in chimpanzees (29% of total shape change). The allometric differences mainly concern the inion, which becomes higher; the position of the foramen magnum, more dorsally oriented; and the palate, more tilted in adult gorillas than in adult chimpanzees. In contrast, nonallometric species-specific traits in gorillas are the long and flat vault characterized by a prominent occipital region, the higher and displaced backward glabella, and the protrusive nose. Biomechanical schemes built from shape partition suggest that the increased out-of-plumb position of the head during growth is partially compensated in gorillas by a powerful nuchal musculature due to the peculiar shape of the occipital region.

Africa↗
PubMed1992

Mhc-DRB diversity of the chimpanzee (Pan troglodytes).

Fifty-four chimpanzee Patr-DRB and five human HLA-DRB second exons were cloned and sequenced from thirty-five chimpanzees and four human B-cell lines and compared with known Mhc-DRB sequences of these two species. Equivalents of the HLA-DRB1*02, -DRB1*03, -DRB1*07 allelic lineages and the HLA-DRB3, -DRB4, -DRB5, -DRB6, and -DRB7 loci were all found in the chimpanzee. In addition, two chimpanzee Patr-DRB lineages (Patr-DRBX and -DRBY) were found for which no human counterparts have been described. None of the Patr-DRB sequences is identical to known HLA-DRB sequences. The Patr-DRB1*0702 and HLA-DRB1*0701 alleles are the most similar sequences in a comparison between the two species and differ by only two nucleotides out of 246 sequenced. Equivalents of the HLA-DRB1*01, -DRB1*04, and -DRB1*09 alleles were not found in our sample of chimpanzees. A per locus comparison of the number of Patr-DRB alleles with the HLA-DRB alleles shows that the Patr-DRB3, -DRB4, -DRB5, and -DRB6 locus are, thus far, more polymorphic than their human homologs. The polymorphism of the Patr-DRB1 locus seems to be less extensive than that reported for the HLA-DRB1 locus. Nevertheless, the Patr-DRB1 locus seems to be the most polymorphic of the Patr-DRB loci. Phylogenetic analyses indicate that the HLA-DRB1*09 allele may have originated from a recombination between a Mhc-DRB5 allele and the DRB1 allele of a Mhc-DR7 haplotype. Although recombination seems to increase the diversity of the Patr-DRB alleles, its contribution to the generation of Patr-DRB variation is probably low. Hence, most Patr-DRB diversity presumably accumulated via recurrent point mutations. Finally, two distinct Patr-DRB haplotypes are deduced, one of which (the chimpanzee equivalent of the HLA-DR7 haplotype) is probably older than 6-8 million years.

Amino Acid Sequence↗
PubMed2001

Genetic variation of the nucleocapsid genes of waterfowl parvovirus.

Duck parvovirus (DPV) and Goose parvovirus (GPV) isolated from infected waterfowls with Derzsy's disease in the year 1999 were identified by polymerase chain reaction and sequencing. The nucleotide sequences of their viral capsid proteins (VPs) show that they share 77% similarity at the DNA, and 84.6% at the protein level. The most variable region between DPV and GPV resides in the N-terminal of VP2 before the initiation codon of VP3 with 35% (19/54) amino acids divergence. Viral capsid protein sequences diverge 4.1 to 4.4% among 1990-99 isolated strains. Variant amino acids cluster in the common regions of VP3 at residues 203-266 and 482-534 which overlaps with the regions proposed to expose on the outer surfaces of parvoviral particles, implying that selective pressure from host immune system might play a part. These data provide useful information for antigenic epitope prediction. This study also reveal the presence of conserved strain-specific residues in VPs and these residues seldom vary among different viral isolates, suggesting that they might be functionally important and worth further investigation.

Amino Acid Sequence↗
PubMed1989

Influence of ejaculation frequency on semen characteristics in chimpanzees (Pan troglodytes).

Semen samples were obtained by masturbation from 6 chimpanzees and the spontaneously liquefied fraction and the remaining coagulum were studied separately. When semen was collected once or twice a week, large intra-individual variations were observed for all measures. The liquefied fraction represented 26.5 +/- 3.2% (weighted mean +/- s.d.) of the total ejaculate but contained 51.3 +/- 3.8% of all emitted spermatozoa. Fructose concentration was higher in the coagulum than in the liquefied fraction (29.3 +/- 3.0 mumol/ml vs 12.0 +/- 2.7 mumol/ml, P less than 0.001) whereas acid phosphatase was less concentrated in the coagulum than in the liquefied fraction (3.5 +/- 0.3 x 10(3) IU/ml vs 13.0 +/- 0.9 x 10(3) IU/ml, P less than 0.001). L-Carnitine and citrate concentrations did not differ between the two fractions of the ejaculate. When semen collection was repeated every hour for 5 h, the ejaculate volume increased from 2.6 +/- 0.7 to 4.7 +/- 0.6 ml (P less than 0.001), whereas total sperm count decreased from 1278 +/- 872 x 10(6) to 587 +/- 329 x 10(6) (P less than 0.05) between the 1st and the 6th ejaculate. In the spontaneously liquefied fraction, the sperm count decreased from 984 to 369 x 10(6). The 6 successive ejaculates gave a total of 20.2 +/- 7.6 ml and 4278 +/- 2884 x 10(6) spermatozoa. The increase of the ejaculate volume was essentially due to an increase of the volume of the coagulum which closely correlated with total amount of fructose (from seminal vesicles) (r = 0.913, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

T lymphocytes expressing HECA-452 epitope are present in cutaneous acute graft-versus-host disease and erythema multiforme, but not in acute graft-versus-host disease in gut organs.

Lymphocytes in formalin-fixed skin biopsies from patients with cutaneous acute graft-versus-host disease (aGVHD) were studied with HECA-452 (an antibody recognizing lymphocytes with skin-homing properties) and a panel of antibodies recognizing pan-B (L26 [CD20]), pan-T (L60 [CD43] and A6 [CD45RA]), and T-helper subset (OPD4) antigens in paraffin sections. Biopsies from patients with erythema multiforme (EM) were similarly studied for comparison. In both conditions, T lymphocytes stained by OPD4 were predominantly confined to the dermis, whereas those stained by HECA-452 were concentrated in the epidermis; however, there was considerable variation between cases, and overlap between findings in the dermis and epidermis. Lymphocytes similarly studied in paraffin sections of liver, salivary gland, and gut affected by aGVHD were essentially unreactive with HECA-452, although they were largely stained by pan-T markers and showed some comparable reactivity with OPD4. The findings suggest that aGVHD of the skin is mediated by a different set of lymphocytes than in gut organs, and may have a similar immunologic mechanism to EM.

Acute Disease↗
PubMed2025

The landscape of structural variation in pediatric cancer.

Structural variants (SVs) account for over 60% of the driver variants in pediatric cancer, and in many cases act as the cancer initiating event. To study SVs from a pan-cancer perspective, we analyzed 1,616 pediatric cancer genomes in 16 major cancer types of hematological malignancies (n = 908), brain tumors (n = 183), and solid tumors (n = 525) and compared their profiles to those of 2,203 adult cancers. The SV burden varied ~100-fold across pediatric cancer types and demonstrated an 8- to 16-fold reduction compared to adult brain and solid tumors but was comparable in pediatric versus adult hematological malignancies. Recurrent SV hotspots occurred uniquely in pediatric acute lymphoblastic leukemias (ALLs) in proximity to RAG-mediated recombination signal sequences (RSS) and disrupted multiple immune-related loci as well as 69 genes, which often involved cryptic RSS sites. By contrast, such hotspots affected only immune-related loci but not driver genes in adult lymphoid cancers. Eight SV signatures extracted from the cohort had varying distributions across cancer types, with clustered translocations reflecting templated insertions in osteosarcoma, and medium-sized deletions (10 kb to 1 Mb) enriched in cancers with RAG-mediated deletions. Intra-patient evolutionary analysis in 13 patients with multiple spatiotemporally distinct samples revealed that RAG-mediated recombination in leukemia and complex rearrangements in solid tumors occurred both early in disease initiation and continuously during later diversification, contributing to clonal heterogeneity. Finally, we found that both driver genes and fragile sites were the two genomic regions most frequently disrupted by SVs. The unique and diverse SV landscapes that emerged from this comprehensive analysis expand the scope of RSS-mediated mutagenesis in pediatric ALL and will be a valuable resource for guiding future functional studies and the design of clinical genomic testing in pediatric cancer.

Journal Article↗
PubMed2006

Sex and handedness effects on corpus callosum morphology in chimpanzees (Pan troglodytes).

Findings suggest that in humans, sex and hand preference may be associated with the size of the corpus callosum (CC). The authors measured CC morphology from MRIs in 67 chimpanzees (Pan troglodytes) to see whether similar effects were present in this species. Hand preference was assessed by performance on 4 tasks, and chimpanzees were classified as left-handed, right-handed, or ambidextrous. In a subsequent analysis, the chimpanzees were reclassified into 2 groups: right-handed and left-handed. The results revealed no sex difference in CC area, but significant effects of hand preference were found for several CC regions (rostrum body, anterior midbody, posterior midbody, isthmus, and splenium) and for overall CC size, with left-handed chimpanzees exhibiting significantly smaller CC measurements than right-handed chimpanzees. The results indicate that lateralized hand use in chimpanzees, as in humans, is associated with variation in CC size.

Animals↗
PubMed1999

Geographic variation in the calls of wild chimpanzees: a reassessment.

Male chimpanzees produce a species-typical call, the pant hoot, to communicate to conspecifics over long-distances. Calls given by males from the well-known Gombe and Mahale populations typically consist of four different phases: an introduction, build-up, climax, and let-down. Recent observations suggest that chimpanzees living in the Kibale National Park, Uganda, consistently give calls that lack a build-up and are thus qualitatively distinguishable acoustically from those made by other East African conspecifics. We analyzed additional recordings from Mahale and Kibale to re-examine geographic variation in chimpanzee calls. Results indicate that males from both sites produce pant hoots containing all four parts of the call. Calls made by chimpanzees from the two populations, however, differ in quantitative acoustic measures. Specifically, males at Kibale initiate their calls with significantly longer elements and build-up over briefer periods at slower rates than individuals from Mahale. Kibale males also deliver acoustically less variable calls than chimpanzees at Mahale. Although climax elements do not differ between populations in any single acoustic feature, discriminant function analysis reveals that acoustic variables can be used in combination to assign calls to the correct population at rates higher than that expected by chance. Ecological factors related to differences in habitat acoustics, the sound environment of the local biota, and body size are likely to account for these observed macrogeographic variations in chimpanzee calls.

Animals↗
PubMed2004

Geometric morphometric analysis of allometric variation in the mandibular morphology of the hominids of Atapuerca, Sima de los Huesos site.

Allometry is an important factor of morphological integration that contributes to the organization of the phenotype and its variation. Variation in the allometric shape of the mandible is particularly important in hominid evolution because the mandible carries important taxonomic traits. Some of these traits are known to covary with size, particularly the retromolar space, symphyseal curvature, and position of the mental foramen. The mandible is a well studied system in the context of the evolutionary development of complex morphological structures because it is composed of different developmental units that are integrated within a single bone. In the present study, we investigated the allometric variation of two important developmental units that are separated by the inferior nerve (a branch of CN V3). We tested the null hypothesis that there would be no difference in allometric variation between the two components. Procrustes-based geometric morphometrics of 20 two-dimensional (2D) landmarks were analyzed by multivariate regressions of shape on size in samples from 121 humans, 48 chimpanzees, and 50 gorillas (all recent specimens), eight fossil hominids from Atapuerca, Sima de los Huesos (AT-SH), and 17 Neandertals. The findings show that in all of the examined species, there was significantly greater allometric variation in the supra-nerve unit than in the infra-nerve unit. The formation of the retromolar space exhibited an allometric relationship with the supra-nerve unit in all of the species studied. The formation of the chin-like morphology is an "apodynamic" feature of the infra-nerve unit in the AT-SH hominids. The results of this study support the hypothesis that allometry contributes to the organization of variation in complex morphological structures.

Animals↗
PubMed2005

Validation of a cotton-specific gene, Sad1, used as an endogenous reference gene in qualitative and real-time quantitative PCR detection of transgenic cottons.

Genetically modified (GM) cotton lines have been approved for commercialization and widely cultivated in many countries, especially in China. As a step towards the development of reliable qualitative and quantitative PCR methods for detecting GM cottons, we report here the validation of the cotton (Gossypium hirsutum) endogenous reference control gene, Sad1, using conventional and real-time (RT)-PCR methods. Both methods were tested on 15 different G. hirsutum cultivars, and identical amplicons were obtained with all of them. No amplicons were observed when DNA samples from three species of genus Gossypium, Arabidopsis thaliana, maize, and soybean and others were used as amplified templates, demonstrating that these two systems are specific for the identification and quantification of G. hirsutum. The results of Southern blot analysis also showed that the Sad1 gene was two copies in these 15 different G. hirsutum cultivars. Furthermore, one multiplex RT-quantitative PCR employing this gene as an endogenous reference gene was designed to quantify the Cry1A(c) gene modified from Bacillus thuringiensis (Bt) in the insect-resistant cottons, such as Mon531 and GK19. The quantification detection limit of the Cry1A(c) and Sad1 genes was as low as 10 pg of genomic DNA. These results indicate that the Sad1 gene can be used as an endogenous reference gene for both qualitative and quantitative PCR detection of GM cottons.

DNA, Plant↗
PubMed2000

Evolution of the X-linked zinc finger gene and the Y-linked zinc finger gene in primates.

We have sequenced the partial exon of the zinc finger genes (ZFX and ZFY) in 5 hominoids, 2 Old World monkeys, 1 New World monkey, and 1 prosimian. Among these primate species, the percentage similarities of the nucleotide sequence of the ZFX gene were 96-100% and 91.2-99.7% for the ZFY gene. Of 397 sites in the ZFX and ZFY gene sequences, 20 for ZFX gene and 42 for ZFY gene were found to be variable. Substitution causes 1 amino acid change in ZFX, and 5 in ZFY, among 132 amino acids. The numbers of synonymous substitutions per site (Ks) between human and the chimpanzee, gorilla and orangutan for ZFY gene were 0.026, 0.033, and 0.085, respectively. In contrast, the Ks value between human and hominoid primates for the ZFX gene was 0.008 for each comparison. Comparison of the ZFX and ZFY genes revealed that the synonymous substitution levels were higher in hominoids than in other primates. The rates of synonymous substitution per site per year were higher in the ZFY exon than in the SRY exon, and higher in the ZFY exon than in the ZFY intron, in hominoid primates.

Animals↗
PubMed1988

Sequence analysis and in vitro expression of a cDNA clone of genome segment 5 from bluetongue virus, serotype 1 from South Africa.

A full length copy of genome segment 5 of bluetongue virus serotype 1 from South Africa (BTV-1SA) was assembled from two incomplete cDNA clones. The complete nucleotide sequence was determined (1635 nucleotides in length) and an open reading frame coding for 527 amino acids was found, which was flanked by a 5' non-coding region of 25 nucleotides and a 3' non-coding region of 29 nucleotides. The cDNA clone was transferred to an Sp6 expression vector from which an RNA transcript was obtained. This transcript, when translated in vitro in a reticulocyte lysate system, produced a protein that co-migrated during electrophoresis with both protein VP5 from disrupted virus particles and VP5 translated from denatured viral dsRNA. The protein synthesized from the cDNA clone was precipitable with antisera raised against BTV-1SA virus particles and with antisera raised against a synthetic peptide, the sequence of which was obtained from the predicted amino acid sequence of BTV-1SA protein VP5. These antisera also precipitated protein VP5 translated from denatured viral dsRNA. Collectively these data indicate that the cDNA clone encodes an authentic VP5 protein product. The amino acid sequence of BTV-1SA VP5, when compared to other published sequences for VP5, contained highly conserved regions interrupted by variable domains. If two isolates of the same serotype are compared, (BTV-1SA and BTV-1AUS) only two variable regions are apparent. However, if the amino acid sequences of VP5 from two different serotypes are compared, (BTV-1SA and BTV-10), eight variable regions are detectable (two of which are in the same position as the variable regions within a serotype). The implications of these variations in the outer coat protein, VP5, are discussed.

Amino Acid Sequence↗
PubMed2004

Craniofacial sexual dimorphism patterns and allometry among extant hominids.

Craniofacial sexual dimorphism in primates varies in both magnitude and pattern among species. In the past two decades, there has been an increasing emphasis in exploring the correlations of these patterns with taxonomy and the variation in patterns within and among the craniofacial regions. Scrutinising these relationships for hominids, we decompose the craniofacial morphology in five taxa: Homo sapiens, Pan paniscus, Pan troglodytes, Gorilla gorilla and Pongo pygmaeus. 3D coordinates of 35 traditional landmarks and 61 semilandmarks, covering five ridge curves, are measured for each of 268 adult and sub-adult specimens and analysed using geometric morphometric methods. A multivariate analysis in size-shape space shows that ontogenetic scaling contributes to the development of sexual dimorphism in all five taxa, but to a varying extent. In absolute as well as in relative terms P. pygmaeus shows the greatest allometric component, followed by G. gorilla. Homo is intermediate, while in Pan the non-allometric constituent part contributes a large fraction to the actual sexual dimorphism, most markedly in the pygmy chimpanzee. An eigendecomposition of the five vectors of sexual dimorphism reveals two dimensions independent of allometry. One separates orang-utan sexual dimorphism from the African apes and Homo, and the other differentiates between the great apes and Homo with Pan mediating. We discuss these patterns and speculate on their use as characters for taxonomic analysis in the fossil record.

Animals↗
PubMed1999

The RAG1/RAG2 complex constitutes a 3' flap endonuclease: implications for junctional diversity in V(D)J and transpositional recombination.

During V(D)J recombination, processing of branched coding end intermediates is essential for generating junctional diversity. Here, we report that the RAG1/ RAG2 recombinase is a 3' flap endonuclease. Substrates of this nuclease activity include various coding end intermediates, suggesting a direct role for RAG1/ RAG2 in generating junctional diversity during V(D)J recombination. Evidence is also provided indicating that site-specific RSS nicking involves RAG1/RAG2-mediated processing of a localized flap-like structure, implying 3' flap nicking in multiple DNA processing reactions. We have also demonstrated that the bacterial transposase Tn10 contains a 3' flap endonuclease activity, suggesting a mechanistic parallel between RAG1/RAG2 and other transposases. Based on these data, we propose that numerous transposases may facilitate genomic evolution by removing single-stranded extensions during the processing of excision site junctions.

Animals↗
PubMed2002

Evidence for positive selection and population structure at the human MAO-A gene.

We report the analysis of human nucleotide diversity at a genetic locus known to be involved in a behavioral phenotype, the monoamine oxidase A gene. Sequencing of five regions totaling 18.8 kb and spanning 90 kb of the monoamine oxidase A gene was carried out in 56 male individuals from seven different ethnogeographic groups. We uncovered 41 segregating sites, which formed 46 distinct haplotypes. A permutation test detected substantial population structure in these samples. Consistent with differentiation between populations, linkage disequilibrium is higher than expected under panmixia, with no evidence of a decay with distance. The extent of linkage disequilibrium is not typical of nuclear loci and suggests that the underlying population structure may have been accentuated by a selective sweep that fixed different haplotypes in different populations, or by local adaptation. In support of this suggestion, we find both a reduction in levels of diversity (as measured by a Hudson-Kreitman-Aguade test with the DMD44 locus) and an excess of high frequency-derived variants, as expected after a recent episode of positive selection.

Animals↗
PubMed2003

Modified nonparametric approaches to detecting differentially expressed genes in replicated microarray experiments.

MOTIVATION: An important goal 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. Various parametric tests, such as the two-sample t-test, have been used, but their possibly too strong parametric assumptions or large sample justifications may not hold in practice. As alternatives, a class of three nonparametric statistical methods, including the empirical Bayes method of Efron et al. (2001), the significance analysis of microarray (SAM) method of Tusher et al. (2001) and the mixture model method (MMM) of Pan et al. (2001), have been proposed. All the three methods depend on constructing a test statistic and a so-called null statistic such that the null statistic's distribution can be used to approximate the null distribution of the test statistic. However, relatively little effort has been directed toward assessment of the performance or the underlying assumptions of the methods in constructing such test and null statistics. RESULTS: We point out a problem of a current method to construct the test and null statistics, which may lead to largely inflated Type I errors (i.e. false positives). We also propose two modifications that overcome the problem. In the context of MMM, the improved performance of the modified methods is demonstrated using simulated data. In addition, our numerical results also provide evidence to support the utility and effectiveness of MMM.

Algorithms↗
PubMed2003

On the use of permutation in and the performance of a class of nonparametric methods to detect differential gene expression.

MOTIVATION: Recently a class of nonparametric statistical methods, including the empirical Bayes (EB) method, the significance analysis of microarray (SAM) method and the mixture model method (MMM), have been proposed to detect differential gene expression for replicated microarray experiments conducted under two conditions. All the methods depend on constructing a test statistic Z and a so-called null statistic z. The null statistic z is used to provide some reference distribution for Z such that statistical inference can be accomplished. A common way of constructing z is to apply Z to randomly permuted data. Here we point our that the distribution of z may not approximate the null distribution of Z well, leading to possibly too conservative inference. This observation may apply to other permutation-based nonparametric methods. We propose a new method of constructing a null statistic that aims to estimate the null distribution of a test statistic directly. RESULTS: Using simulated data and real data, we assess and compare the performance of the existing method and our new method when applied in EB, SAM and MMM. Some interesting findings on operating characteristics of EB, SAM and MMM are also reported. Finally, by combining the idea of SAM and MMM, we outline a simple nonparametric method based on the direct use of a test statistic and a null statistic.

Algorithms↗