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      Primate TNF Promoters Reveal Markers of Phylogeny and Evolution of Innate Immunity

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          Tumor necrosis factor (TNF) is a critical cytokine in the immune response whose transcriptional activation is controlled by a proximal promoter region that is highly conserved in mammals and, in particular, primates. Specific single nucleotide polymorphisms (SNPs) upstream of the proximal human TNF promoter have been identified, which are markers of human ancestry.

          Methodology/Principal findings

          Using a comparative genomics approach we show that certain fixed genetic differences in the TNF promoter serve as markers of primate speciation. We also demonstrate that distinct alleles of most human TNF promoter SNPs are identical to fixed nucleotides in primate TNF promoters. Furthermore, we identify fixed genetic differences within the proximal TNF promoters of Asian apes that do not occur in African ape or human TNF promoters. Strikingly, protein-DNA binding assays and gene reporter assays comparing these Asian ape TNF promoters to African ape and human TNF promoters demonstrate that, unlike the fixed differences that we define that are associated with primate phylogeny, these Asian ape-specific fixed differences impair transcription factor binding at an Sp1 site and decrease TNF transcription induced by bacterial stimulation of macrophages.


          Here, we have presented the broadest interspecies comparison of a regulatory region of an innate immune response gene to date. We have characterized nucleotide positions in Asian ape TNF promoters that underlie functional changes in cell type- and stimulus-specific activation of the TNF gene. We have also identified ancestral TNF promoter nucleotide states in the primate lineage that correspond to human SNP alleles. These findings may reflect evolution of Asian and African apes under a distinct set of infectious disease pressures involving the innate immune response and TNF.

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          Most cited references 113

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          CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.

          The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved for the alignment of divergent protein sequences. Firstly, individual weights are assigned to each sequence in a partial alignment in order to down-weight near-duplicate sequences and up-weight the most divergent ones. Secondly, amino acid substitution matrices are varied at different alignment stages according to the divergence of the sequences to be aligned. Thirdly, residue-specific gap penalties and locally reduced gap penalties in hydrophilic regions encourage new gaps in potential loop regions rather than regular secondary structure. Fourthly, positions in early alignments where gaps have been opened receive locally reduced gap penalties to encourage the opening up of new gaps at these positions. These modifications are incorporated into a new program, CLUSTAL W which is freely available.
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            The International HapMap Project.

            The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.
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              Initial sequence of the chimpanzee genome and comparison with the human genome.

              Here we present a draft genome sequence of the common chimpanzee (Pan troglodytes). Through comparison with the human genome, we have generated a largely complete catalogue of the genetic differences that have accumulated since the human and chimpanzee species diverged from our common ancestor, constituting approximately thirty-five million single-nucleotide changes, five million insertion/deletion events, and various chromosomal rearrangements. We use this catalogue to explore the magnitude and regional variation of mutational forces shaping these two genomes, and the strength of positive and negative selection acting on their genes. In particular, we find that the patterns of evolution in human and chimpanzee protein-coding genes are highly correlated and dominated by the fixation of neutral and slightly deleterious alleles. We also use the chimpanzee genome as an outgroup to investigate human population genetics and identify signatures of selective sweeps in recent human evolution.

                Author and article information

                Role: Academic Editor
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                18 July 2007
                : 2
                : 7
                [1 ]The CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, United States of America
                [2 ]Gibbon Conservation Center, Santa Clarita, California, United States of America
                [3 ]Laboratoire de Rétrovirologie, Institut Pasteur, Dakar, Senegal
                [4 ]Unidad de Rescate y Rehabilitación de Animales Silvestres, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional de Colombia, Bogotá, Colombia
                [5 ]Project for Explaining the Origin of Humans, Glycobiology Research and Training Center, Department of Medicine and Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, United States of America
                [6 ]Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland, United States of America
                [7 ]Conservation and Research for Endangered Species, Zoological Society of San Diego, San Diego, California, United States of America
                [8 ]Division of Biological Sciences, University of California at San Diego, La Jolla, California, United States of America
                Sanofi-Aventis, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: goldfeld@

                Conceived and designed the experiments: AG AT AB. Performed the experiments: AT FL AB. Analyzed the data: OR AG AT JF AB. Contributed reagents/materials/analysis tools: SO OR AM OD PG CB. Wrote the paper: AG JF.


                Current address: Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York, United States of America

                Baena et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Pages: 14
                Research Article
                Evolutionary Biology/Evolutionary and Comparative Genetics
                Genetics and Genomics/Functional Genomics
                Immunology/Genetics of the Immune System
                Immunology/Immunity to Infections
                Evolutionary Biology/Human Evolution



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