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Austin L Hughes

Publications and source records attributed to Austin L Hughes.

At least 37 records · Page 2Linked to original sources
PubMed2005

Unusually high frequency MHC class I alleles in Mauritian origin cynomolgus macaques.

Acute shortages of Indian origin Rhesus macaques significantly hinder HIV/AIDS research. Cellular immune responses are particularly difficult to study because only a subset of animals possess MHC class I (MHC I) alleles with defined peptide-binding specificities. To expand the pool of nonhuman primates suitable for studies of cellular immunity, we defined 66 MHC I alleles in Cynomolgus macaques (Macaca fascicularis) of Chinese, Vietnamese, and Mauritian origin. Most MHC I alleles were found only in animals from a single geographic origin, suggesting that Cynomolgus macaques from different origins are not interchangeable in studies of cellular immunity. Animals from Mauritius may be particularly valuable because >50% of these Cynomolgus macaques share the MHC class I allele combination Mafa-B*430101, Mafa-B*440101, and Mafa-B*460101. The increased MHC I allele sharing of Mauritian origin Cynomolgus macaques may dramatically reduce the overall number of animals needed to study cellular immune responses in nonhuman primates while simultaneously reducing the confounding effects of genetic heterogeneity in HIV/AIDS research.

Alleles↗
PubMed2005

Patterns of sequence evolution at epitopes for host antibodies and cytotoxic T-lymphocytes in human immunodeficiency virus type 1.

Analysis of published sequence data from the nine protein-coding genes of human immunodeficiency virus type 1 (HIV-1) showed striking differences in evolutionary pattern between epitopes for host neutralizing antibodies (Ab) and epitopes for cytotoxic T cells (CTL). In all sequences analyzed, the greatest median amino acid residue diversity was seen at sites that formed part of Ab epitopes, but not of CTL epitopes. By contrast, sites belonging to CTL epitopes but not to Ab epitopes showed reduced median amino acid sequence diversity not only in comparison to sites in Ab epitopes but also in comparison to non-epitope sites. Ab epitopes that did not overlap CTL epitopes showed the highest frequency of comparisons in which the rate of nonsynonymous (amino acid-altering) nucleotide substitution exceeded that of synonymous nucleotide substitution, supporting the hypothesis that much of the diversity at Ab epitopes results from positive selection exerted by the host immune system. Though less frequent than that at Ab epitopes, there was evidence of such selection at certain CTL epitopes as well; and amino acid differences between sister pairs of sequences in CTL epitopes were more likely to be convergent than those in Ab epitopes. The pattern seen at CTL epitopes may represent the result of conflicting pressures favoring conservation of the amino acid sequence for functional reasons and amino acid replacements for reasons of CTL escape.

Amino Acid Substitution↗
PubMed2005

Effects of natural selection on interpopulation divergence at polymorphic sites in human protein-coding Loci.

To develop new strategies for searching for genetic associations with complex human diseases, we analyzed 2784 single-nucleotide polymorphisms (SNPs) in 396 protein-coding genes involved in biological processes relevant to cancer and other complex diseases, with respect to gene diversity within samples of individuals representing the three major historic human populations (African, European, and Asian) and with respect to interpopulation genetic distance. Reduced levels of both intrapopulation gene diversity and interpopulation genetic distance were seen in the case of SNPs located within the 5'-UTR and at nonsynonymous SNPs, causing radical changes to protein structure. Reduction of gene diversity at SNP loci in these categories was evidence of purifying selection acting at these sites, which in turn causes a reduction in interpopulation divergence. By contrast, a small number of SNP sites in these categories revealed unusually high genetic distances between the two most diverged populations (African and Asian); these loci may have historically been subject to divergent selection pressures.

Databases, Genetic↗
PubMed2005

Mitochondrial genome sequences support ancient population expansion in Plasmodium vivax.

Examination of nucleotide diversity in 106 mitochondrial genomes of the most geographically widespread human malaria parasite, Plasmodium vivax, revealed a level of diversity similar to, but slightly higher than, that seen in the virulent human malaria parasite Plasmodium falciparum. The pairwise distribution of nucleotide differences among mitochondrial genome sequences supported the hypothesis that both these parasites underwent ancient population expansions. We estimated the age of the most recent common ancestor (MRCA) of the mitochondrial genomes of both P. vivax and P. falciparum at around 200,000-300,000 years ago. This is close to the previous estimates of the time of the human mitochondrial MRCA and the origin of modern Homo sapiens, consistent with the hypothesis that both these Plasmodium species were parasites of the hominid lineage before the origin of modern H. sapiens and that their population expansion coincided with the population expansion of their host.

Animals↗
PubMed2005

Amino acid sequence constraint and gene expression pattern across the life history in the malaria parasite Plasmodium falciparum.

The relationship between gene expression across the life cycle and protein conservation in Plasmodium falciparum was examined by comparing gene expression data for six life-history stages with the number of nonsynonymous substitutions per site dN between 901 orthologous gene pairs of P. falciparum and Plasmodium yoelii. A high level of expression across the life history was associated with decreased dN and thus with protein conservation. By contrast, differential expression in the sporozoite and merozoite stages was associated with increased dN. At least some sporozoite- and merozoite-expressed genes with high dN have probably been subject to positive selection arising from parasite-host coevolution. A high level of expression across the life history was associated with higher than average G+C content at the first and second codon positions, whereas a high level of expression in the sporozoite and merozoite was associated with reduced G+C content at the first and second codon positions, the latter pattern evidently reflecting the relaxation of constraint on the amino acid sequence.

Amino Acid Sequence↗
PubMed2005

Variation in the pattern of synonymous and nonsynonymous difference between two fungal genomes.

The proportion of synonymous nucleotide differences per synonymous site (p(S)) and the proportion of nonsynonymous differences per nonsynonymous site (p(N)) were computed at 1,993,217 individual codons in 4,133 protein-coding genes between the two yeast species Saccharomyces cerevisiae and Saccharomyces paradoxus. When the modified Nei-Gojobori method was used, significantly more codons with p(N) > p(S) were observed than expected, based on random pairing of observed p(S) and p(N) values. However, this finding was most likely explained by the presence of a strong negative correlation between the number of synonymous differences and the number of nonsynonymous differences at codons with at least one difference. As a result of this correlation, codons with p(N) > p(S) were characterized not only by unusually high p(N) but also by unusually low p(S). On the other hand, the number of codons with p(N)>p(S) (where p(S) is the mean p(S) for all codons) was very similar to the random expectation, and the observed number of 30-codon windows with p(N) > p(S) was significantly lower than the random expectation. These results imply that the occurrence of a certain number of codons or codon windows with p(N) > p(S) is expected given the nature of nucleotide substitution and need not imply the action of positive Darwinian selection.

Codon↗
PubMed2005

The pattern of nucleotide difference at individual codons among mouse, rat, and human.

The patterns of nucleotide difference were compared at 3,473,111 codons from 9,390 aligned orthologous genes of mouse (Mus musculus), rat (Rattus norvegicus), and human (Homo sapiens). The results showed evidence of a higher frequency of both synonymous and nonsynonymous differences from human in the rat than in the mouse. However, contrary to a previous report, there was no evidence of a greater frequency of codons with multiple nonsynonymous substitutions between the two rodent species than expected under random substitution.

Animals↗
PubMed2005

DNA repeat arrays in chicken and human genomes and the adaptive evolution of avian genome size.

BACKGROUND: Birds have smaller average genome sizes than other tetrapod classes, and it has been proposed that a relatively low frequency of repeating DNA is one factor in reduction of avian genome sizes. RESULTS: DNA repeat arrays in the sequenced portion of the chicken (Gallus gallus) autosomes were quantified and compared with those in human autosomes. In the chicken 10.3% of the genome was occupied by DNA repeats, in contrast to 44.9% in human. In the chicken, the percentage of a chromosome occupied by repeats was positively correlated with chromosome length, but even the largest chicken chromosomes had repeat densities much lower than those in human, indicating that avoidance of repeats in the chicken is not confined to minichromosomes. When 294 simple sequence repeat types shared between chicken and human genomes were compared, mean repeat array length and maximum repeat array length were significantly lower in the chicken than in human. CONCLUSIONS: The fact that the chicken simple sequence repeat arrays were consistently smaller than arrays of the same type in human is evidence that the reduction in repeat array length in the chicken has involved numerous independent evolutionary events. This implies that reduction of DNA repeats in birds is the result of adaptive evolution. Reduction of DNA repeats on minichromosomes may be an adaptation to permit chiasma formation and alignment of small chromosomes. However, the fact that repeat array lengths are consistently reduced on the largest chicken chromosomes supports the hypothesis that other selective factors are at work, presumably related to the reduction of cell size and consequent advantages for the energetic demands of flight.

Animals↗
PubMed2005

Poxvirus genome evolution by gene gain and loss.

The poxviruses (Poxviridae) are a family of viruses with double-stranded DNA genomes and substantial numbers (often >200) of genes per genome. We studied the patterns of gene gain and loss over the evolutionary history of 17 poxvirus complete genomes. A phylogeny based on gene family presence/absence showed good agreement with families based on concatenated amino acid sequences of conserved single-copy genes. Gene duplications in poxviruses were often lineage specific, and the most extensively duplicated viral gene families were found in only a few of the genomes analyzed. A total of 34 gene families were found to include a member in at least one of the poxvirus genomes analyzed and at least one animal genome; in 16 (47%) of these families, there was evidence of recent horizontal gene transfer (HGT) from host to virus. Gene families with evidence of HGT included several involved in host immune defense mechanisms (the MHC class I, interleukin-10, interleukin-24, interleukin-18, the interferon gamma receptor, and tumor necrosis factor receptor II) and others (glutaredoxin and glutathione peroxidase) involved in resistance of cells to oxidative stress. Thus "capture" of host genes by HGT has been a recurrent feature of poxvirus evolution and has played an important role in adapting the virus to survive host antiviral defense mechanisms.

Evolution, Molecular↗
PubMed2005

Expression patterns of duplicate genes in the developing root in Arabidopsis thaliana.

Data on gene expression in the development of the root in Arabidopsis thaliana were used to test for expression profile differences among multi-gene families and to examine the extent to which expression differences accompanied coding sequences divergence within families. Significant differences among families were observed on two principal axes, accounting for over 80% of the variance in the expression data. The number of synonymous nucleotide substitutions per synonymous site (d(S)) and the number of nonsynonymous nucleotide substitutions per nonsynonymous site (d(N)) were estimated between the members of two-member families (N = 428) and between phylogenetically independent sister pairs (N = 190) of sequences within larger families. Ribosomal proteins and a few other proteins were exceptional in showing highly divergent expression patterns in spite of very low levels of amino acid sequence divergence, as indicated by the low d(N) relative to d(S). However, the majority of gene duplicates showed relatively high levels of amino acid sequence divergence without appreciable change in expression pattern in the cell types analyzed.

Arabidopsis↗
PubMed2005

Environmental kinetoplastid-like 18S rRNA sequences and phylogenetic relationships among Trypanosomatidae: paraphyly of the genus Trypanosoma.

Using kinetoplastid-like sequences from deep-sea environmental samples as an outgroup, we applied phylogenetic analysis to 18S rRNA sequences of the families Trypanosomatidae and Bodonidae (Eugelenozoa: Kinetoplastida). The monophyly of the genus Trypanosoma was not supported by a number of different methods. Rather, the results indicate that the American and African trypanosomes constitute distinct clades, therefore, implying that the major human disease agents T. cruzi (cause of Chagas' disease) and T. brucei (cause of African sleeping sickness) are not as closely related to each other as they were previously thought to be. Likewise, the results did not support monophyly of the genera Leishmania, Leptomonas, Bodo and Cryptobia.

Animals↗
PubMed2005

Towards a new conceptual approach to "parasitoproteomics".

Many parasitologists are betting heavily on proteomic studies to explain biochemical host-parasite interactions and, thus, to contribute to disease control. However, many "parasitoproteomic" studies are performed with powerful techniques but without a conceptual approach to determine whether the host genomic responses during a parasite infection represent a nonspecific response that might be induced by any parasite or any other stress. In this article, a new conceptual approach, based on evolutionary concepts of immune responses of a host to a parasite, is suggested for parasitologists to study the host proteome reaction after parasite invasion. Also, this new conceptual approach can be used to study other host-parasite interactions such as behavioral manipulation.

Animals↗
PubMed2005

Patterns of nucleotide difference in overlapping and non-overlapping reading frames of papillomavirus genomes.

On the basis of a phylogenetic analysis of papillomavirus complete genomes, 30 pairs of closely related genomes were chosen for examination of the pattern of synonymous and non-synonymous nucleotide difference in overlapping and non-overlapping reading frames. The proportion of synonymous differences per synonymous site (pS) was generally reduced in overlapping regions in comparison to non-overlapping regions. This reduction in pS appears to result from purifying selection acting on the overlapping reading frame because of functional constraint on the amino acid sequence that it encodes. As a consequence of such purifying selection, a trade-off was observed between synonymous substitution in one reading frame and non-synonymous substitution in the other; this pattern was particularly evident in the overlap between the E2 and E1 reading frames, which encodes a highly conserved portion of the E2 protein. Fifty-three sequences of the hinge region of the HPV16 E2 protein (where the E2 and E4 reading frames overlap) showed an elevated level of non-synonymous nucleotide substitution in the E2 reading frame, particularly in a region believed to be involved in immune recognition. Non-synonymous substitutions in this region occurred disproportionately in such a way as to cause synonymous substitutions in the E4 reading frame. Thus, positive diversifying selection on the E2 hinge region appears to coexist with purifying selection on the overlapping region of E4.

Base Sequence↗
PubMed2005

Gene family content-based phylogeny of prokaryotes: the effect of criteria for inferring homology.

A number of recent papers have suggested that gene family content can be used to resolve phylogenies, particularly in the case of prokaryotes, in which extensive horizontal gene transfer means that individual gene phylogenies may not mirror the organismal phylogeny. However, no study has yet examined how sensitive such analyses are to the criterion of homology assessment used to assemble multigene families. Using data from 99 completely sequenced prokaryotic genomes, we examined the effect of homology criteria in phylogenetic analyses wherein presence or absence of each family in the genome was used as a cladistic character. Different criteria resulted in evidence for contradictory tree topologies, sometimes with high bootstrap support. A moderately strict criterion seemed best for assembling multigene families in a biologically meaningful way, but it was not necessarily preferable for phylogenetic analysis. Instead, a very strict criterion, which broke up gene families into smaller subfamilies, seemed to have advantages for phylogenetic purposes. The poor performance of gene family content-based phylogenetic analysis in the case of prokaryotes appears to reflect high levels of homoplasy resulting not only from horizontal gene transfer but also, more importantly, from extensive parallel loss of gene families in certain bacteria genomes.

Archaea↗
PubMed2005

Nucleotide substitution and recombination at orthologous loci in Staphylococcus aureus.

The pattern of nucleotide substitution was examined at 2,129 orthologous loci among five genomes of Staphylococcus aureus, which included two sister pairs of closely related genomes (MW2/MSSA476 and Mu50/N315) and the more distantly related MRSA252. A total of 108 loci were unusual in lacking any synonymous differences among the five genomes; most of these were short genes encoding proteins highly conserved at the amino acid sequence level (including many ribosomal proteins) or unknown predicted genes. In contrast, 45 genes were identified that showed anomalously high divergence at synonymous sites. The latter genes were evidently introduced by homologous recombination from distantly related genomes, and in many cases, the pattern of nucleotide substitution made it possible to reconstruct the most probable recombination event involved. These recombination events introduced genes encoding proteins that differed in amino acid sequence and thus potentially in function. Several of the proteins are known or likely to be involved in pathogenesis (e.g., staphylocoagulase, exotoxin, Ser-Asp fibrinogen-binding bone sialoprotein-binding protein, fibrinogen and keratin-10 binding surface-anchored protein, fibrinogen-binding protein ClfA, and enterotoxin P). Therefore, the results support the hypothesis that exchange of homologous genes among S. aureus genomes can play a role in the evolution of pathogenesis in this species.

Codon↗
PubMed2004

Evidence for abundant slightly deleterious polymorphisms in bacterial populations.

The nearly neutral theory of molecular evolution predicts that slightly deleterious mutations subject to purifying selection are widespread in natural populations, particularly those of large effective population size. To test this hypothesis, the standardized difference between pairwise nucleotide difference and number of segregation sites (corrected for number of sequences) was estimated for 149 population data sets from 84 species of bacteria. This quantity (Tajima's D-statistic) was estimated separately for synonymous (D(syn)) and nonsynonymous (D(non)) polymorphisms. D(syn) was positive in 70% of data sets, and the overall median D(syn) (0.873) was positive. By contrast D(non) was negative in 68% of data sets, and the overall median D(non) (-0.656) was negative. The preponderance of negative values of D(non) is evidence that there are widespread rare nonsynonymous polymorphisms in the process of being eliminated by purifying selection, as predicted to occur in populations with large effective size by the nearly neutral theory. The major exceptions to this trend were seen among surface proteins, particularly those of bacteria parasitic on vertebrates, which included a number of cases of polymorphisms apparently maintained by balancing selection.

Bacteria↗
PubMed2004

Codon volatility as an indicator of positive selection: data from eukaryotic genome comparisons.

It has been suggested that codon volatility (the proportion of the point-mutation neighbors of a codon that encode different amino acids) can be used as an index of past positive selection. We compared codon volatility with patterns of synonymous and nonsynonymous nucleotide substitution in genome-wide comparisons of orthologous genes between three pairs of related genomes: (1) the protists Plasmodium falciparum and P. yoelii, (2) the fungi Saccharomyces cerevisiae and S. paradoxus, and (3) the mammals mouse and rat. Codon volatility was not consistently associated with an elevated rate of nonsynonymous substitution, as would be expected under positive selection. Rather, the most consistent and powerful correlate of elevated codon volatility was nucleotide content at the second codon position, as expected, given the nature of the genetic code.

Animals↗