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PubMed2005

Comparative genomic analysis of human and chimpanzee proteases.

Proteolytic enzymes are implicated in multiple physiological and pathological processes. The availability of the sequence of the chimpanzee genome has allowed us to determine that the chimpanzee degradome-the repertoire of protease genes from this organism-is composed of at least 559 protease and protease-like genes and is virtually identical to that of human, containing 561 genes. Despite the high degree of conservation between both genomes, we have identified important differences that vary from deletion of whole genes to small insertion/deletion events or single nucleotide changes that lead to the specific gene inactivation in one species, mostly affecting immune system genes. For example, the genes encoding PRSS33/EOS, a macrophage serine protease conserved in most mammals, and GGTLA1 are absent in chimpanzee, while the gene for metalloprotease MMP23A, located in chromosome 1p36, has been specifically duplicated in the human genome together with its neighbor gene CDC2L1. Other differences arise from single nucleotide changes in protease genes, such as NAPSB and CASP12, resulting in the presence of functional genes in chimpanzee and pseudogenes in human. Finally, we have confirmed that the Trypanosoma lytic factor HPR is inactive in chimpanzee, likely contributing to the susceptibility of chimpanzees to T. brucei infection. This study provides the first analysis of the chimpanzee degradome and might contribute to the understanding of the molecular bases underlying variations in host defense mechanisms between human and chimpanzee.

Amino Acid Sequence↗
PubMed2000

Adaptive evolution of the tumour suppressor BRCA1 in humans and chimpanzees. Australian Breast Cancer Family Study.

Mutations in BRCA1 (ref. 1) confer an increased risk of female breast cancer. In a genome-wide scan of linkage disequilibrium (LD), a high level of LD was detected among microsatellite markers flanking BRCA1 (ref. 3), raising the prospect that positive natural selection may have acted on this gene. We have used the predictions of evolutionary genetic theory to investigate this further. Using phylogeny-based maximum likelihood analysis of the BRCA1 sequences from primates and other mammals, we found that the ratios of replacement to silent nucleotide substitutions on the human and chimpanzee lineages were not different from one another (P=0.8), were different from those of other primate lineages (P=0.004) and were greater than 1 (P=0.04). This is consistent with the historic occurrence of positive darwinian selection pressure on the BRCA1 protein in the human and chimpanzee lineages. Analysis of genetic variation in a sample of female Australians of Northern European origin showed evidence for Hardy-Weinberg (HW) disequilibrium at polymorphic sites in BRCA1, consistent with the possibility that natural selection is affecting genotype frequencies in modern Europeans. The clustering of between-species variation in the region of the gene encoding the RAD51-interaction domain of BRCA1 suggests the maintenance of genomic integrity as a possible target of selection.

Adaptation, Biological↗
PubMed2005

Placing confidence limits on the molecular age of the human-chimpanzee divergence.

Molecular clocks have been used to date the divergence of humans and chimpanzees for nearly four decades. Nonetheless, this date and its confidence interval remain to be firmly established. In an effort to generate a genomic view of the human-chimpanzee divergence, we have analyzed 167 nuclear protein-coding genes and built a reliable confidence interval around the calculated time by applying a multifactor bootstrap-resampling approach. Bayesian and maximum likelihood analyses of neutral DNA substitutions show that the human-chimpanzee divergence is close to 20% of the ape-Old World monkey (OWM) divergence. Therefore, the generally accepted range of 23.8-35 millions of years ago for the ape-OWM divergence yields a range of 4.98-7.02 millions of years ago for human-chimpanzee divergence. Thus, the older time estimates for the human-chimpanzee divergence, from molecular and paleontological studies, are unlikely to be correct. For a given the ape-OWM divergence time, the 95% confidence interval of the human-chimpanzee divergence ranges from -12% to 19% of the estimated time. Computer simulations suggest that the 95% confidence intervals obtained by using a multifactor bootstrap-resampling approach contain the true value with >95% probability, whether deviations from the molecular clock are random or correlated among lineages. Analyses revealed that the use of amino acid sequence differences is not optimal for dating human-chimpanzee divergence and that the inclusion of additional genes is unlikely to narrow the confidence interval significantly. We conclude that tests of hypotheses about the timing of human-chimpanzee divergence demand more precise fossil-based calibrations.

Animals↗
PubMed1997

Purification and characterization of manganese superoxide dismutase from Ganoderma microsporum.

Manganese superoxide dismutase (Mn-SOD) in the mycelium of Ganoderma microsporum was purified to homogeneity by heat treatment at 70 degrees C, ammonium sulfate fractionation, DEAE-52 anion-exchange chromatography, and Sephacryl SH-200 chromatography. The molecular mass of its native form was estimated to be 98 kD by size-exclusion chromatography. This enzyme is tetrameric composed of four subunits of equal size of 25 kD. The pI of this purified Mn-SOD was located at pH 6.34 and 5.06 by isoelectric focusing. Comparisons of 17 amino acids from the N-terminus of Mn-SOD subunit with the derived amino acid sequences from the reported Mn-SOD cDNA clones of other sources indicated a high degree of homology among the Ganoderma genus but the Mn-SOD from G. microsporum showed a high variation when compared with other organisms.

Amino Acid Sequence↗
PubMed2003

Low nucleotide diversity in chimpanzees and bonobos.

Comparison of the levels of nucleotide diversity in humans and apes may provide much insight into the mechanisms of maintenance of DNA polymorphism and the demographic history of these organisms. In the past, abundant mitochondrial DNA (mtDNA) polymorphism data indicated that nucleotide diversity (pi) is more than threefold higher in chimpanzees than in humans. Furthermore, it has recently been claimed, on the basis of limited data, that this is also true for nuclear DNA. In this study we sequenced 50 noncoding, nonrepetitive DNA segments randomly chosen from the nuclear genome in 9 bonobos and 17 chimpanzees. Surprisingly, the pi value for bonobos is only 0.078%, even somewhat lower than that (0.088%) for humans for the same 50 segments. The pi values are 0.092, 0.130, and 0.082% for East, Central, and West African chimpanzees, respectively, and 0.132% for all chimpanzees. These values are similar to or at most only 1.5 times higher than that for humans. The much larger difference in mtDNA diversity than in nuclear DNA diversity between humans and chimpanzees is puzzling. We speculate that it is due mainly to a reduction in effective population size (N(e)) in the human lineage after the human-chimpanzee divergence, because a reduction in N(e) has a stronger effect on mtDNA diversity than on nuclear DNA diversity. Sequence data from this article have been deposited with the GenBank Data libraries under accession nos. AY 275957-AY 277244.

Animals↗
PubMed2006

Higher intensity of purifying selection on >90% of the human genes revealed by the intrinsic replacement mutation rates.

For over 3 decades, the rate of replacement mutations has been assumed to be equal to, and estimated from, the rate of "strictly" neutral sequence divergence in noncoding regions and in silent-codon positions where mutations do not alter the amino acid encoded. This assumption is fundamental to estimating the fraction of harmful protein mutations and to identifying adaptive evolution at individual codons and proteins. We show that the assumption is not justifiable because a much larger fraction of codon positions is involved in hypermutable CpG dinucleotides as compared with the introns, leading to a higher expected replacement mutation rate per site in a vast majority of the genes. Consideration of this difference reveals a higher intensity of purifying natural selection than previously inferred in human genes. We also show that a much smaller number of genes are expected to be evolving with positive selection than that predicted using sequence divergence at intron and silent positions in the human genome. These patterns indicate the need for using new approaches for estimating rates of amino acid-altering mutations in order to find positively selected genes and codons in genomes that contain hypermutable CpG's.

Animals↗
PubMed1999

Substitution rate variation among sites in mitochondrial hypervariable region I of humans and chimpanzees.

Mitochondrial D-loop hypervariable region I (HVI) sequences are widely used in human molecular evolutionary studies, and therefore accurate assessment of rate heterogeneity among sites is essential. We used the maximum-likelihood method to estimate the gamma shape parameter alpha for variable substitution rates among sites for HVI from humans and chimpanzees to provide estimates for future studies. The complete data of 839 humans and 224 chimpanzees, as well as many subsets of these data, were analyzed to examine the effect of sequence sampling. The effects of the genealogical tree and the nucleotide substitution model were also examined. The transition/transversion rate ratio (kappa) is estimated to be about 25, although much larger and biased estimates were also obtained from small data sets at low divergences. Estimates of alpha were 0.28-0.39 for human data sets of different sizes and 0.20-0.39 for data sets including different chimpanzee subspecies. The combined data set of both species gave estimates of 0.42-0.45. While all those estimates suggest highly variable substitution rates among sites, smaller samples tend to give smaller estimates of alpha. Possible causes for this pattern were examined, such as biases in the estimation procedure and shifts in the rate distribution along certain lineages. Computer simulations suggest that the estimation procedure is quite reliable for large trees but can be biased for small samples at low divergences. Thus, an alpha of 0.4 appears suitable for both humans and chimpanzees. Estimates of alpha can be affected by the nucleotide sites included in the data, the overall tree length (the amount of sequence divergence), the number of rate classes used for the estimation, and to a lesser extent, the included sequences. The genealogical tree, the substitution model, and demographic processes such as population expansion do not have much effect.

Animals↗
PubMed1989

A statistical test of phylogenies estimated from sequence data.

A simple approach to testing the significance of the branching order, estimated from protein or DNA sequence data, of three taxa is proposed. The branching order is inferred by the transformed-distance method, under the assumption that one or two outgroups are available, and the branch lengths are estimated by the least-squares method. The inferred branching order is considered significant if the estimated internodal distance is significantly greater than zero. To test this, a formula for the variance of the internodal distance has been developed. The statistical test proposed has been checked by computer simulation. The same test also applies to the case of four taxa with no outgroup, if one considers an unrooted tree. Formulas for the variances of internodal distances have also been developed for the case of five taxa. Conditions are given under which it is more efficient to add the sequence of a fifth taxon than to do 25% more nucleotide sequencing in each of the original four. A method is presented for combining analyses of disparate data to get a single P value. Finally, the test, applied to the human-chimpanzee-gorilla problem, shows that the issue is not yet resolved.

Animals↗
PubMed2003

A population threshold for functional polymorphisms.

We sequenced 114 genes (for DNA repair, cell cycle arrest, apoptosis, and detoxification)in a mixed human population and observed a sudden increase in the number of functional polymorphisms below a minor allele frequency of approximately 6%. Functionality is assessed by considering the ratio in the number of nonsynonymous single nucletide polymorphisms (SNPs)to the number of synonymous or intron SNPs. This ratio is steady from below 1% in frequency-that regime traditionally associated with rare Mendelian diseases-all the way up to about 6% in frequency, after which it falls precipitously. We consider possible explanations for this threshold effect. There are four candidates as follows: (1). deleterious variants that have yet to be purified from the population, (2). balancing selection, in which a selective advantage accrues to the heterozygotes, (3). population-specific functional polymorphisms, and (4). adaptive variants that are accumulating in the population as a response to the dramatic environmental changes of the last 7000 approximately 17000 years.

Animals↗
PubMed2005

Divergent V1R repertoires in five species: Amplification in rodents, decimation in primates, and a surprisingly small repertoire in dogs.

The V1R gene family comprises one of two types of putative pheromone receptors expressed in the mammalian vomeronasal organ (VNO). We searched the most recent mouse, rat, dog, chimpanzee, and human genome sequence assemblies to compile a near-complete repertoire of V1R genes for each species. Dog, human, and chimpanzee have very few intact V1Rs (8, 2, and 0, respectively) compared to more than a hundred intact V1Rs in each of the rat (106) and mouse (165) genomes. We also provide the first description of the diversity of V1R pseudogenes in these species. We identify at least 165 pseudogenes in mouse, 110 in rat, 102 in chimpanzee, 115 in human, and 54 in dog. Primate and dog pseudogenes are distributed among almost all V1R subfamilies seen in rodents, indicating that the common ancestor of these species had a diverse V1R repertoire. We find that V1R genes were subject to strikingly different fates in different species and in different subfamilies. In rodents, some subfamilies remained relatively stable or underwent roughly equivalent expansion in mouse and rat; other subfamilies expanded in one species but not the other. The small number of intact V1Rs in the dog genome is unexpected given the presumption that dogs, like rodents, have a functional VNO, and a complex system of pheromone-based behaviors. We identify an intact transient receptor potential channel 2beta in the dog genome, consistent with a functional VNO in dogs. The diminished V1R repertoire in dogs raises questions about the relative contributions of V1Rs versus other candidate pheromone receptor genes in the establishment of complex pheromone systems in mammals.

Animals↗
PubMed1992

Diversity of human anti-D monoclonal antibodies revealed by reactions with chimpanzee red blood cells.

Fifty-three human anti-D monoclonal antibodies (mAbs) revealed a striking diversity of reactions in tests with panels of chimpanzee red blood cells (RBCs) of various R-C-E-F blood group phenotypes (counterparts of the human Rh-Hr groups). The reactivities of these antibodies, which depended on the agglutination technique used, could be classified into four main types. These patterns of reactivity of anti-D mAbs with chimpanzee RBCs showed only limited correlation with types of reactions observed with human D variant RBCs. Primate red cells may, therefore, constitute an independent test system for subclassification of human monoclonal antibodies. Comparison of reactivities of human anti-D mAbs with chimpanzee and human D variant RBCs confirms the homology between the chimpanzee Rc, and the human D antigens. The chimpanzee Rc shares with human D the epitopes epD5, epD6/7 and epD8, but lacks epitopes epD1, epD2, epD3 and epD4 of the Rh mosaic, thus resembling the human D variants IVb and Vc.

Animals↗
PubMed2006

Geometrical perturbation of an inclined wall on decay times of acoustic modes in a trapezoidal cavity with an impedance surface.

Decay times of acoustic modes of a trapezoidal cavity (TC modes) with an inclined wall are studied. Each cavity wall is successively assigned an impedance surface and the other five walls are rigid. The decay times are obtained from the coupling between rigid-walled modes of the rectangular cavity (RC modes) that bounds the trapezoidal cavity. Two coupling mechanisms are identified, namely, the damping coupling and the geometrical coupling. The former is related to the coupling of RC modes at the impedance surface, while the latter is related to the coupling of RC modes at the inclined wall. Both mechanisms include the same volume coupling where RC modes couple throughout the trapezoidal cavity. When the impedance surface is at either of the two trapezoidal walls, the grouping of TC modes with same decay times and the decay time variation with the wall inclination are determined only by the damping coupling. When the surface is at any of the other rectangular walls, both the damping and geometrical couplings are at work. This paper provides an understanding of how the inclined wall and the impedance surface location affect the TC-mode grouping, and what determines the decay time variation with the inclination.

Journal Article↗
PubMed2006

Genomic divergences among cattle, dog and human estimated from large-scale alignments of genomic sequences.

BACKGROUND: Approximately 11 Mb of finished high quality genomic sequences were sampled from cattle, dog and human to estimate genomic divergences and their regional variation among these lineages. RESULTS: Optimal three-way multi-species global sequence alignments for 84 cattle clones or loci (each >50 kb of genomic sequence) were constructed using the human and dog genome assemblies as references. Genomic divergences and substitution rates were examined for each clone and for various sequence classes under different functional constraints. Analysis of these alignments revealed that the overall genomic divergences are relatively constant (0.32-0.37 change/site) for pairwise comparisons among cattle, dog and human; however substitution rates vary across genomic regions and among different sequence classes. A neutral mutation rate (2.0-2.2 x 10(-9) change/site/year) was derived from ancestral repetitive sequences, whereas the substitution rate in coding sequences (1.1 x 10(-9) change/site/year) was approximately half of the overall rate (1.9-2.0 x 10(-9) change/site/year). Relative rate tests also indicated that cattle have a significantly faster rate of substitution as compared to dog and that this difference is about 6%. CONCLUSION: This analysis provides a large-scale and unbiased assessment of genomic divergences and regional variation of substitution rates among cattle, dog and human. It is expected that these data will serve as a baseline for future mammalian molecular evolution studies.

Animals↗
PubMed2006

Evolution of candidate transcriptional regulatory motifs since the human-chimpanzee divergence.

BACKGROUND: Despite the recent completion of the chimpanzee genome project, few functionally significant sequence differences between humans and chimpanzees have thus far been identified. Alteration in transcriptional regulatory mechanisms represents an important platform for evolutionary change, suggesting that a significant proportion of functional human-chimpanzee sequence differences may affect regulatory elements. RESULTS: To explore this hypothesis, we performed genome-wide identification of conserved candidate transcription-factor binding sites that have evolved since the divergence of humans and chimpanzees. Analysis of candidate transcription-factor binding sites conserved between mouse and chimpanzee yet absent in human indicated that loss of candidate transcription-factor binding sites in the human lineage was not random but instead correlated with the biologic functions of associated genes. CONCLUSION: Our data support the notion that changes in transcriptional regulation have contributed to the recent evolution of humans. Moreover, genes associated with mutated candidate transcription-factor binding sites highlight potential pathways underlying human-chimpanzee divergence.

Animals↗
PubMedDate not supplied

Isolation and phylogenetic characterization of Ebola viruses causing different outbreaks in Gabon.

Three outbreaks of Ebola hemorrhagic fever have recently occurred in Gabon. Virus has been isolated from clinical materials from all three outbreaks, and nucleotide sequence analysis of the glycoprotein gene of the isolates and virus present in clinical samples has been carried out. These data indicate that each of the three outbreaks should be considered an independent emergence of a different Ebola virus of the Zaire subtype. As in earlier Ebola virus outbreaks, no genetic variability was detected between virus samples taken during an individual outbreak.

Animals↗