PAML, currently in version 4, is a package of programs for phylogenetic analyses of DNA and protein sequences using maximum likelihood (ML). The programs may be used to compare and test phylogenetic trees, but their main strengths lie in the rich repertoire of evolutionary models implemented, which can be used to estimate parameters in models of sequence evolution and to test interesting biological hypotheses. Uses of the programs include estimation of synonymous and nonsynonymous rates (d(N) and d(S)) between two protein-coding DNA sequences, inference of positive Darwinian selection through phylogenetic comparison of protein-coding genes, reconstruction of ancestral genes and proteins for molecular restoration studies of extinct life forms, combined analysis of heterogeneous data sets from multiple gene loci, and estimation of species divergence times incorporating uncertainties in fossil calibrations. This note discusses some of the major applications of the package, which includes example data sets to demonstrate their use. The package is written in ANSI C, and runs under Windows, Mac OSX, and UNIX systems. It is available at -- (http://abacus.gene.ucl.ac.uk/software/paml.html).

/pdf/paml-4-phylogenetic-analysis-by-maximum-likelihood-2gg19rsgos.pdf

PAML 4: Phylogenetic Analysis by Maximum Likelihood

Retroviral vectors derived from lentiviruses such as HIV-1 are promising tools for human gene therapy because they mediate the in vivo delivery and long-term expression of transgenes in nondividing tissues. We describe an HIV vector system in which the virulence genes env, vif, vpr, vpu, and nef have been deleted. This multiply attenuated vector conserved the ability to transduce growth-arrested cells and monocyte-derived macrophages in culture, and could efficiently deliver genes in vivo into adult neurons. These data demonstrate the potential of lentiviral vectors in human gene therapy.

Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo.

1.1. Uncharacterized Protein Segments Are a Source of Functional Novelty
Over the past decade, we have observed a massive increase in the amount of information describing protein sequences from a variety of organisms.1,2 While this may reflect the diversity in sequence space, and possibly also in function space,3 a large proportion of the sequences lacks any useful function annotation.4,5 Often these sequences are annotated as putative or hypothetical proteins, and for the majority their functions still remain unknown.6,7 Suggestions about potential protein function, primarily molecular function, often come from computational analysis of their sequences. For instance, homology detection allows for the transfer of information from well-characterized protein segments to those with similar sequences that lack annotation of molecular function.8−10 Other aspects of function, such as the biological processes proteins participate in, may come from genetic- and disease-association studies, expression and interaction network data, and comparative genomics approaches that investigate genomic context.11−17 Characterization of unannotated and uncharacterized protein segments is expected to lead to the discovery of novel functions as well as provide important insights into existing biological processes. In addition, it is likely to shed new light on molecular mechanisms of diseases that are not yet fully understood. Thus, uncharacterized protein segments are likely to be a large source of functional novelty relevant for discovering new biology.

/pdf/classification-of-intrinsically-disordered-regions-and-2mev7glgpx.pdf

Classification of intrinsically disordered regions and proteins.

There is an increasing interest in detecting genes, or genomic regions, that have been targeted by natural selection. The interest stems from a basic desire to learn more about evolutionary processes in humans and other organisms, and from the realization that inferences regarding selection may provide important functional information. This review provides a nonmathematical description of the issues involved in detecting selection from DNA sequences and SNP data and is intended for readers who are not familiar with population genetic theory. Particular attention is placed on issues relating to the analysis of large-scale genomic data sets.

/pdf/molecular-signatures-of-natural-selection-3c4upqfngh.pdf

Molecular Signatures of Natural Selection

The imprint of natural selection on protein coding genes is often difficult to identify because selection is frequently transient or episodic, i.e. it affects only a subset of lineages. Existing computational techniques, which are designed to identify sites subject to pervasive selection, may fail to recognize sites where selection is episodic: a large proportion of positively selected sites. We present a mixed effects model of evolution (MEME) that is capable of identifying instances of both episodic and pervasive positive selection at the level of an individual site. Using empirical and simulated data, we demonstrate the superior performance of MEME over older models under a broad range of scenarios. We find that episodic selection is widespread and conclude that the number of sites experiencing positive selection may have been vastly underestimated.

/pdf/detecting-individual-sites-subject-to-episodic-diversifying-4uxpbd6t5m.pdf

Detecting individual sites subject to episodic diversifying selection.

Primate genomes encode a variety of innate immune strategies to defend themselves against retroviruses. One of these, TRIM5alpha, can restrict diverse retroviruses in a species-specific manner. Thus, whereas rhesus TRIM5alpha can strongly restrict HIV-1, human TRIM5alpha only has weak HIV-1 restriction. The biology of TRIM5alpha restriction suggests that it is locked in an antagonistic conflict with the proteins encoding the viral capsid. Such antagonistic interactions frequently result in rapid amino acid replacements at the protein-protein interface, as each genetic entity vies for evolutionary dominance. By analyzing its evolutionary history, we find strong evidence for ancient positive selection in the primate TRIM5alpha gene. This selection is strikingly variable with some of the strongest selection occurring in the human lineage. This history suggests that TRIM5alpha evolution has been driven by antagonistic interactions with a wide variety of viruses and endogenous retroviruses that predate the origin of primate lentiviruses. A 13-aa "patch" in the SPRY protein domain bears a dense concentration of positively selected residues, potentially implicating it as an antiviral interface. By using functional studies of chimeric TRIM5alpha genes, we show that this patch is generally essential for retroviral restriction and is responsible for most of the species-specific antiretroviral restriction activity. Our study highlights the power of evolutionary analyses, in which positive selection identifies not only the age of genetic conflict but also the interaction interface where this conflict plays out.

/pdf/positive-selection-of-primate-trim5a-identifies-a-critical-1yal39secn.pdf

Positive selection of primate TRIM5α identifies a critical species-specific retroviral restriction domain

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that can cause extensive cytopathicity in T cells. However, long-term productive infection of T-cell lines has been described. Here we show that although Vpr has no effect on the initial cytopathic effect of HIV-1, viruses that contain an intact vpr gene are unable to establish a chronic infection of T cells. However, virus with a mutated vpr gene can readily establish such long-term cultures. The effect of Vpr is independent of the env gene and the nef gene. Furthermore, expression of Vpr alone affects the progression of cells in the cell cycle. These results suggest that HIV-1 has evolved a viral gene to prevent chronic infection of T cells.

The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection.

http://www.lifesci.utexas.edu/faculty/ohalloran/webpage/Mol190%20papers/MOLC.7.1025.01.pdf

HIV-1 infection requires a functional integrase NLS.

Indicator Cell Lines for Detection of Primary Strains of Human and Simian Immunodeficiency Viruses

On January 26 2020, the first Coronavirus Disease 2019 (COVID-19) case was reported in Arizona (3rd case in the US) (1).…

Lily I. Wu

Papers

Positive selection of primate TRIM5α identifies a critical species-specific retroviral restriction domain

The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection.

HIV-1 infection requires a functional integrase NLS.

Indicator Cell Lines for Detection of Primary Strains of Human and Simian Immunodeficiency Viruses

An 81-Nucleotide Deletion in SARS-CoV-2 ORF7a Identified from Sentinel Surveillance in Arizona (January to March 2020).