Biomedical subjects

Robert Friedman

Publications and source records attributed to Robert Friedman.

At least 19 recordsLinked to original sources

PubMed2006

Variable intensity of purifying selection on cytotoxic T-lymphocyte epitopes in hepatitis C virus.

In an analysis of the patterns of nucleotide diversity in 26 datasets providing population-level data on different genomic regions of different hepatitis C virus (HCV) subtypes, known cytotoxic T-lymphocyte (CTL) epitope regions in most cases showed evidence of the occurrence of purifying selection. Two main factors were found to be associated with the strength of purifying selection: (1) purifying selection was stronger in CTL epitopes in non-envelope proteins than in envelope proteins and (2) purifying selection was stronger when the epitope was "matched", i.e., when the described or "canonical" epitope sequence was present unaltered in at least one sequence in the dataset. Of all polymorphic sites, non-synonymous sites in matched CTL epitopes in non-envelope proteins had the lowest gene diversities, implying that these variants are subject to ongoing purifying selection. This in turn suggests that the population frequency of such variants may of be the result of a balance between opposing forces: on the one hand, positive selection favoring escape mutants in hosts that express the presenting MHC molecule and, on the other hand, purifying selection acting, in the absence of the presenting MHC molecule, to reduce the frequency of slightly deleterious variants.

Epitopes, T-Lymphocyte↗

PubMed2006

Sharing of transcription factors after gene duplication in the yeast Saccharomyces cerevisiae.

In a set of 190 duplicate gene pairs in yeast Saccharomyces cerevisiae, the sharing of transcription factors tended to decrease with increased divergence in coding sequence, at both synonymous and nonsynonymous sites. Our results showed a significantly higher sharing of transcription factors by duplicated gene pairs falling within duplicated genomic blocks than in other duplicated gene pairs; and genes in duplicated blocks also showed significantly greater conservation at the coding sequence level. In spite of the overall trends, there were certain gene pairs, both in duplicated blocks and in other genomic regions, which were highly divergent in coding sequence and yet had identical patterns of transcription factor binding. These results suggest that functional differentiation of genes after duplication is a multi-dimensional process, with different duplicate pairs differentiating in different ways.

Base Sequence↗

PubMed2006

Likelihood-ratio tests for positive selection of human and mouse duplicate genes reveal nonconservative and anomalous properties of widely used methods.

Two commonly used methods based on likelihood-ratio tests (LRTs) for detecting positive Darwinian selection at the molecular level were applied to a data set of 604 gene families containing two members in the human genome and two members in the mouse genome. These methods detected positive selection in a very high proportion of families; in over 50% of families, there was significant evidence of positive selection by one or both methods. However, less than a third of families showing evidence for positive selection by at least one of the methods showed evidence of positive selection by both methods. The outcome of these tests was predicted better by sequence length, G+C content at third-codon positions, and the level of synonymous substitution than by the level of nonsynonymous substitution or the ratio of nonsynonymous to synonymous substitution. These results suggested that LRT-based tests for positive selection may be sensitive to certain factors that make it difficult to reconstruct the true pattern of nucleotide substitution.

Animals↗

PubMed2006

A Sanger/pyrosequencing hybrid approach for the generation of high-quality draft assemblies of marine microbial genomes.

Since its introduction a decade ago, whole-genome shotgun sequencing (WGS) has been the main approach for producing cost-effective and high-quality genome sequence data. Until now, the Sanger sequencing technology that has served as a platform for WGS has not been truly challenged by emerging technologies. The recent introduction of the pyrosequencing-based 454 sequencing platform (454 Life Sciences, Branford, CT) offers a very promising sequencing technology alternative for incorporation in WGS. In this study, we evaluated the utility and cost-effectiveness of a hybrid sequencing approach using 3730xl Sanger data and 454 data to generate higher-quality lower-cost assemblies of microbial genomes compared to current Sanger sequencing strategies alone.

Biotechnology↗

PubMed2006

Across-tissue expression and evolution of genes controlled by the Aire transcription factor.

Aire (autoimmune regulatory protein) enhances expression of certain genes in thymic medullary epithelial cells (MECs). Using publicly available data, we examined expression patterns, across 82 distinct tissue types, of genes previously identified as Aire-activated, Aire-repressed, and Aire-independent. Consistent with the hypothesis that the effect of Aire in MECs is to increase expression of tissue-specific genes, Aire-activated genes had a low overall level of expression but a large range between the lowest and the highest levels of expression in different tissues. By contrast, Aire-repressed genes tended to have a high overall level of expression and less marked differences between the highest and the lowest levels of expression. Nonetheless, the expression scores of Aire-repressed genes showed broader ranges of values than those of Aire-independent genes. Phylogenetic analyses of members of two gene families that included two Aire-activated genes illustrated two contrasting patterns of the relationship of Aire-activated genes within the same family. The two Aire-activated members of the major urinary protein family arose through a recent gene duplication (after the rat-mouse divergence), whereas the most recent common ancestor of the two Aire-activated members of cytochrome p450 family 2 duplicated prior to the radiation of the eutherian orders. In the latter family, the Aire-activated Cyp2a4 gene and the Aire-independent Cyp2a5 gene arose through a recent duplication, after the rat-mouse divergence. Thus the set of Aire-activated genes is subject to change over evolutionary time and includes genes of recent origin.

Animals↗

PubMed2006

Analysis of core housekeeping and virulence genes reveals cryptic lineages of Clostridium perfringens that are associated with distinct disease presentations.

Clostridium perfringens is an important human and animal pathogen that causes a number of diseases that vary in their etiology and severity. Differences between strains regarding toxin gene composition and toxin production partly explain why some strains cause radically different diseases than others. However, they do not provide a complete explanation. The purpose of this study was to determine if there is a phylogenetic component that explains the variance in C. perfringens strain virulence by assessing patterns of genetic polymorphism in genes (colA gyrA, plc, pfoS, and rplL) that form part of the core genome in 248 type A strains. We found that purifying selection plays a central role in shaping the patterns of nucleotide substitution and polymorphism in both housekeeping and virulence genes. In contrast, recombination was found to be a significant factor only for the virulence genes plc and colA and the housekeeping gene gyrA. Finally, we found that the strains grouped into five distinct evolutionary lineages that show evidence of host adaptation and the early stages of speciation. The discovery of these previously unknown lineages and their association with distinct disease presentations carries important implications for human and veterinary clostridial disease epidemiology and provides important insights into the pathways through which virulence has evolved in C. perfringens.

Animals↗

PubMed2006

Pattern of gene duplication in the Cotesia congregata Bracovirus.

Polydnaviruses (PDVs) are a family of double-stranded DNA viruses genetically linked to their wasp hosts. These viruses utilize the transcriptional machinery of the wasp cells to manufacture viral particles which contain circular segments of DNA. The female wasp, hosting the polydnavirus, lays its eggs along with the viral particles inside a caterpillar. Because no replication of the virus occurs while inside the caterpillar, fixed genetic changes occur solely inside the female wasp, as an integrated portion of its genome. Therefore, evolution of the polydnavirus is expected to parallel that of the wasp. Phylogenetic analysis of the polydnavirus genome showed a pattern of gene duplication consistent with the "birth-and-death" process frequently observed in eukaryotic genomes. Phylogenies provided no unequivocal evidence of horizontal gene transfer between the wasp host and the polydnavirus, but in some cases there were suggestions of such gene transfer.

Animals↗

PubMed2005

Gene duplication and the properties of biological networks.

Patterns of network connection of members of multigene families were examined for two biological networks: a genetic network from the yeast Saccharomyces cerevisiae and a protein-protein interaction network from Caenorhabditis elegans. In both networks, genes belonging to gene families represented by a single member in the genome ("singletons") were disproportionately represented among the nodes having large numbers of connections. Of 68 single-member yeast families with 25 or more network connections, 28 (44.4%) were located in duplicated genomic segments believed to have originated from an ancient polyploidization event; thus, each of these 28 loci was thus presumably duplicated along with the genomic segment to which it belongs, but one of the two duplicates has subsequently been deleted. Nodes connected to major "hubs" with a large number of connections, tended to be relatively sparsely interconnected among themselves. Furthermore, duplicated genes, even those arising from recent duplication, rarely shared many network connections, suggesting that network connections are remarkably labile over evolutionary time. These factors serve to explain well-known general properties of biological networks, including their scale-free and modular nature.

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

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

Transforming mental health care for children and their families.

In April 2002, the President's New Freedom Commission on Mental Health was created by executive order to study the mental health care delivery system in our nation and to make recommendations for improvements so that individuals with serious mental disorders can live, work, learn, and fully participate in their homes and communities. In its report, "Achieving the Promise: Transforming Mental Health Care in America," the commission provided strategies to address critical infrastructure, practice, and research issues. This article focuses on the work of the commission's Subcommittee on Children and Families, describing its vision for mental health service delivery for children and providing suggestions for strengthening community-based care for youths with or at risk of behavioral health disorders. Training, research, practice, and policy implications for psychologists are discussed.

Adolescent↗

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

Maxillary sinus augmentation using a peptide-modified graft material in three mixtures: a prospective human case series of histologic and histomorphometric results.

This prospective study assessed vital bone quality and quantity after grafting maxillary sinuses with anorganic bone mineral containing a cell binding peptide (ABM/P-15) in combination with DFDBA (Mix I), hydrogel/ABM/P-15 (Mix II), or PRP (Mix III). Fifteen maxillary sinuses in 12 patients were grafted with the ABM/P-15 mixtures and after 4 to 5 months, cores were taken and analyzed histologically and histomorphometrically. Fifty-nine screw-type implants were placed. Mixes containing a spacer material (Mix I and II) produced greater average vital bone, more mature bone, and more interconnected bone bridges from the cortical (oral) end to the most apical portion, compared to a mix that lacked a spacer material (Mix III). None of the 59 implants failed with any graft material up to 5 months following implant placement. The study demonstrates that new trabecular bone is formed after grafting ABM/P-15 in the sinus floor; that more vital bone is formed when ABM/P-15 is mixed with a spacer material than without; and that implants can be successfully placed.

Adult↗

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

Telephone-linked care for physical activity: a qualitative evaluation of the use patterns of an information technology program for patients.

Automated health behavior interventions that involve discretionary use by patients or consumers over extended periods of time are becoming more common and it is generally assumed that adherence to the recommended schedule is related to the impact of the system on users. Yet reasons for use or non-use of such systems have not been carefully explored. An understanding of factors that influence people to use, not use, or underutilize these automated behavioral change and self-care management systems can help in designing systems that are more effective and acceptable to users. Using qualitative research methods, this study explored the experiences of 45 users of a multiple-contact health promotion application with the goal of understanding the major factors that affect patterns of use (frequency of and duration of contact). The in-depth exploration of users' perceptions and views made possible by the qualitative research methods revealed a number of important themes. Reported reasons for underutilization or non-use were found to be both user-related and system-related. User-related reasons encompassed personal and individual events that prevented or impeded system utilization. System-related reasons included those that related to the medium itself as well as the content of the application. The qualitative methods employed in this study created a forum through which users' feedback could be fully explored and then synthesized to assist in the improvement of this and other automated health behavior interventions.

Adult↗