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High spatial resolution proteomic comparison of the brain in humans and chimpanzees.
Bauernfeind AL, Reyzer ML, Caprioli RM, Ely JJ, Babbitt CC, Wray GA, Hof PR, Sherwood CC
(2015) J Comp Neurol 523: 2043-61
MeSH Terms: Adult, Animals, Brain, Cluster Analysis, Female, High-Throughput Screening Assays, Humans, Male, Mass Spectrometry, Middle Aged, Neurons, Pan troglodytes, Principal Component Analysis, Proteomics, Species Specificity
Show Abstract · Added October 15, 2015
We performed high-throughput mass spectrometry at high spatial resolution from individual regions (anterior cingulate and primary motor, somatosensory, and visual cortices) and layers of the neocortex (layers III, IV, and V) and cerebellum (granule cell layer), as well as the caudate nucleus in humans and chimpanzees. A total of 39 mass spectrometry peaks were matched with probable protein identifications in both species, allowing for comparison in expression. We explored how the pattern of protein expression varies across regions and cortical layers to provide insights into the differences in molecular phenotype of these neural structures between species. The expression of proteins differed principally in a region- and layer-specific pattern, with more subtle differences between species. Specifically, human and chimpanzee brains were similar in their distribution of proteins related to the regulation of transcription and enzyme activity but differed in their expression of proteins supporting aerobic metabolism. Whereas most work assessing molecular expression differences in the brains of primates has been performed on gene transcripts, this dataset extends current understanding of the differential molecular expression that may underlie human cognitive specializations.
© 2015 Wiley Periodicals, Inc.
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15 MeSH Terms
Many human accelerated regions are developmental enhancers.
Capra JA, Erwin GD, McKinsey G, Rubenstein JL, Pollard KS
(2013) Philos Trans R Soc Lond B Biol Sci 368: 20130025
MeSH Terms: Animals, Base Sequence, Binding Sites, Enhancer Elements, Genetic, Evolution, Molecular, Gene Expression Regulation, Developmental, Genomics, Humans, Mice, Mice, Transgenic, Molecular Sequence Data, Pan troglodytes, Sequence Analysis, DNA, Species Specificity
Show Abstract · Added April 18, 2017
The genetic changes underlying the dramatic differences in form and function between humans and other primates are largely unknown, although it is clear that gene regulatory changes play an important role. To identify regulatory sequences with potentially human-specific functions, we and others used comparative genomics to find non-coding regions conserved across mammals that have acquired many sequence changes in humans since divergence from chimpanzees. These regions are good candidates for performing human-specific regulatory functions. Here, we analysed the DNA sequence, evolutionary history, histone modifications, chromatin state and transcription factor (TF) binding sites of a combined set of 2649 non-coding human accelerated regions (ncHARs) and predicted that at least 30% of them function as developmental enhancers. We prioritized the predicted ncHAR enhancers using analysis of TF binding site gain and loss, along with the functional annotations and expression patterns of nearby genes. We then tested both the human and chimpanzee sequence for 29 ncHARs in transgenic mice, and found 24 novel developmental enhancers active in both species, 17 of which had very consistent patterns of activity in specific embryonic tissues. Of these ncHAR enhancers, five drove expression patterns suggestive of different activity for the human and chimpanzee sequence at embryonic day 11.5. The changes to human non-coding DNA in these ncHAR enhancers may modify the complex patterns of gene expression necessary for proper development in a human-specific manner and are thus promising candidates for understanding the genetic basis of human-specific biology.
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14 MeSH Terms
A model-based analysis of GC-biased gene conversion in the human and chimpanzee genomes.
Capra JA, Hubisz MJ, Kostka D, Pollard KS, Siepel A
(2013) PLoS Genet 9: e1003684
MeSH Terms: Animals, Base Sequence, Chromosome Mapping, Evolution, Molecular, Gene Conversion, Genome, Humans, Mammals, Models, Theoretical, Pan troglodytes, Phylogeny, Recombination, Genetic, Selection, Genetic, Sequence Alignment
Show Abstract · Added April 18, 2017
GC-biased gene conversion (gBGC) is a recombination-associated process that favors the fixation of G/C alleles over A/T alleles. In mammals, gBGC is hypothesized to contribute to variation in GC content, rapidly evolving sequences, and the fixation of deleterious mutations, but its prevalence and general functional consequences remain poorly understood. gBGC is difficult to incorporate into models of molecular evolution and so far has primarily been studied using summary statistics from genomic comparisons. Here, we introduce a new probabilistic model that captures the joint effects of natural selection and gBGC on nucleotide substitution patterns, while allowing for correlations along the genome in these effects. We implemented our model in a computer program, called phastBias, that can accurately detect gBGC tracts about 1 kilobase or longer in simulated sequence alignments. When applied to real primate genome sequences, phastBias predicts gBGC tracts that cover roughly 0.3% of the human and chimpanzee genomes and account for 1.2% of human-chimpanzee nucleotide differences. These tracts fall in clusters, particularly in subtelomeric regions; they are enriched for recombination hotspots and fast-evolving sequences; and they display an ongoing fixation preference for G and C alleles. They are also significantly enriched for disease-associated polymorphisms, suggesting that they contribute to the fixation of deleterious alleles. The gBGC tracts provide a unique window into historical recombination processes along the human and chimpanzee lineages. They supply additional evidence of long-term conservation of megabase-scale recombination rates accompanied by rapid turnover of hotspots. Together, these findings shed new light on the evolutionary, functional, and disease implications of gBGC. The phastBias program and our predicted tracts are freely available.
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14 MeSH Terms
De novo DNA demethylation and noncoding transcription define active intergenic regulatory elements.
Schlesinger F, Smith AD, Gingeras TR, Hannon GJ, Hodges E
(2013) Genome Res 23: 1601-14
MeSH Terms: Animals, B-Lymphocytes, Cell Differentiation, Cell Line, Chromatin, CpG Islands, DNA Methylation, DNA, Intergenic, Enhancer Elements, Genetic, Evolution, Molecular, Female, Gene Expression Profiling, Hematopoietic Stem Cells, High-Throughput Nucleotide Sequencing, Humans, Lymphopoiesis, Pan troglodytes, Phylogeny, Promoter Regions, Genetic, RNA, Untranslated, Regulatory Elements, Transcriptional, Sequence Analysis, DNA, Transcription Initiation, Genetic
Show Abstract · Added February 15, 2016
Deep sequencing of mammalian DNA methylomes has uncovered a previously unpredicted number of discrete hypomethylated regions in intergenic space (iHMRs). Here, we combined whole-genome bisulfite sequencing data with extensive gene expression and chromatin-state data to define functional classes of iHMRs, and to reconstruct the dynamics of their establishment in a developmental setting. Comparing HMR profiles in embryonic stem and primary blood cells, we show that iHMRs mark an exclusive subset of active DNase hypersensitive sites (DHS), and that both developmentally constitutive and cell-type-specific iHMRs display chromatin states typical of distinct regulatory elements. We also observe that iHMR changes are more predictive of nearby gene activity than the promoter HMR itself, and that expression of noncoding RNAs within the iHMR accompanies full activation and complete demethylation of mature B cell enhancers. Conserved sequence features corresponding to iHMR transcript start sites, including a discernible TATA motif, suggest a conserved, functional role for transcription in these regions. Similarly, we explored both primate-specific and human population variation at iHMRs, finding that while enhancer iHMRs are more variable in sequence and methylation status than any other functional class, conservation of the TATA box is highly predictive of iHMR maintenance, reflecting the impact of sequence plasticity and transcriptional signals on iHMR establishment. Overall, our analysis allowed us to construct a three-step timeline in which (1) intergenic DHS are pre-established in the stem cell, (2) partial demethylation of blood-specific intergenic DHSs occurs in blood progenitors, and (3) complete iHMR formation and transcription coincide with enhancer activation in lymphoid-specified cells.
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23 MeSH Terms
Sperm methylation profiles reveal features of epigenetic inheritance and evolution in primates.
Molaro A, Hodges E, Fang F, Song Q, McCombie WR, Hannon GJ, Smith AD
(2011) Cell 146: 1029-41
MeSH Terms: Animals, Centromere, DNA Methylation, Embryonic Stem Cells, Epigenesis, Genetic, Genomics, Humans, Male, Pan troglodytes, Primates, Promoter Regions, Genetic, Spermatozoa
Show Abstract · Added February 15, 2016
During germ cell and preimplantation development, mammalian cells undergo nearly complete reprogramming of DNA methylation patterns. We profiled the methylomes of human and chimp sperm as a basis for comparison to methylation patterns of ESCs. Although the majority of promoters escape methylation in both ESCs and sperm, the corresponding hypomethylated regions show substantial structural differences. Repeat elements are heavily methylated in both germ and somatic cells; however, retrotransposons from several subfamilies evade methylation more effectively during male germ cell development, whereas other subfamilies show the opposite trend. Comparing methylomes of human and chimp sperm revealed a subset of differentially methylated promoters and strikingly divergent methylation in retrotransposon subfamilies, with an evolutionary impact that is apparent in the underlying genomic sequence. Thus, the features that determine DNA methylation patterns differ between male germ cells and somatic cells, and elements of these features have diverged between humans and chimpanzees.
Copyright © 2011 Elsevier Inc. All rights reserved.
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12 MeSH Terms
Features of recent codon evolution: a comparative polymorphism-fixation study.
Zhao Z, Jiang C
(2010) J Biomed Biotechnol 2010: 202918
MeSH Terms: Amino Acid Substitution, Animals, Base Composition, Codon, CpG Islands, Evolution, Molecular, Humans, Mice, Mutation, Pan troglodytes, Polymorphism, Genetic, Species Specificity
Show Abstract · Added March 5, 2014
Features of amino-acid and codon changes can provide us important insights on protein evolution. So far, investigators have often examined mutation patterns at either interspecies fixed substitution or intraspecies nucleotide polymorphism level, but not both. Here, we performed a unique analysis of a combined set of intra-species polymorphisms and inter-species substitutions in human codons. Strong difference in mutational pattern was found at codon positions 1, 2, and 3 between the polymorphism and fixation data. Fixation had strong bias towards increasing the rarest codons but decreasing the most frequently used codons, suggesting that codon equilibrium has not been reached yet. We detected strong CpG effect on CG-containing codons and subsequent suppression by fixation. Finally, we detected the signature of purifying selection against Amid R:U dinucleotides at synonymous dicodon boundaries. Overall, fixation process could effectively and quickly correct the volatile changes introduced by polymorphisms so that codon changes could be gradual and directional and that codon composition could be kept relatively stable during evolution.
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12 MeSH Terms
Genomics through the lens of next-generation sequencing.
Capra JA, Carbone L, Riesenfeld SJ, Wall JD
(2010) Genome Biol 11: 306
MeSH Terms: Animals, Chromosome Mapping, Evolution, Molecular, Genomics, Humans, Neoplasms, Pan troglodytes, Quantitative Trait, Heritable, Saccharomyces cerevisiae, Sequence Analysis, DNA
Show Abstract · Added April 18, 2017
A report on the 23rd annual meeting on 'The Biology of Genomes', 11-15 May 2010, Cold Spring Harbor, USA.
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10 MeSH Terms
Targeted investigation of the Neandertal genome by array-based sequence capture.
Burbano HA, Hodges E, Green RE, Briggs AW, Krause J, Meyer M, Good JM, Maricic T, Johnson PL, Xuan Z, Rooks M, Bhattacharjee A, Brizuela L, Albert FW, de la Rasilla M, Fortea J, Rosas A, Lachmann M, Hannon GJ, Pääbo S
(2010) Science 328: 723-5
MeSH Terms: Amino Acid Substitution, Animals, Fossils, Genes, Genome, Genome, Human, Hominidae, Humans, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Pan troglodytes, Proteins, Sequence Alignment, Sequence Analysis, DNA
Show Abstract · Added February 15, 2016
It is now possible to perform whole-genome shotgun sequencing as well as capture of specific genomic regions for extinct organisms. However, targeted resequencing of large parts of nuclear genomes has yet to be demonstrated for ancient DNA. Here we show that hybridization capture on microarrays can successfully recover more than a megabase of target regions from Neandertal DNA even in the presence of approximately 99.8% microbial DNA. Using this approach, we have sequenced approximately 14,000 protein-coding positions inferred to have changed on the human lineage since the last common ancestor shared with chimpanzees. By generating the sequence of one Neandertal and 50 present-day humans at these positions, we have identified 88 amino acid substitutions that have become fixed in humans since our divergence from the Neandertals.
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14 MeSH Terms
Functional characterization of chimpanzee cytomegalovirus chemokine, vCXCL-1(CCMV).
Miller-Kittrell M, Sai J, Penfold M, Richmond A, Sparer TE
(2007) Virology 364: 454-65
MeSH Terms: Amino Acid Sequence, Animals, Apoptosis, Baculoviridae, CD11b Antigen, CD11c Antigen, Calcium Signaling, Chemokines, CXC, Conserved Sequence, Cytomegalovirus, Humans, In Vitro Techniques, Molecular Sequence Data, Neutrophils, Pan troglodytes, Protein Sorting Signals, Receptors, Interleukin-8B, Sequence Homology, Amino Acid, Viral Proteins, Virulence
Show Abstract · Added May 31, 2013
Human cytomegaloviruses (HCMVs) are important pathogens in immunocompromised patients and newborns. The viral chemokine, vCXCL-1, of the Toledo (Tol) strain of HCMV has been implicated in HCMV virulence. Chimpanzee CMV (CCMV) has several genes with similarity to the vCXCL-1(Tol) gene, UL146. In order to test whether the CCMV viral chemokine, vCXCL-1(CCMV), is similar to vCXCL-1(Tol), we characterized its function in vitro. Receptor binding, activation, chemotaxis, signaling, and apoptosis in neutrophils were compared between vCXCL-1(Tol) and vCXCL-1(CCMV) and host chemokines. Although the homologues had similar activation potentials, chemotactic properties, and signaling, vCXCL-1(CCMV) had a approximately 70-fold lower affinity for CXCR2 and displayed differences in integrin upregulation and neutrophil apoptosis. These data demonstrate that in spite of extensive amino acid variability in vCXCL-1, CCMV may provide a model for assessing the role of vCXCL-1 in CMV pathogenesis in vivo.
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20 MeSH Terms
Directionality of point mutation and 5-methylcytosine deamination rates in the chimpanzee genome.
Jiang C, Zhao Z
(2006) BMC Genomics 7: 316
MeSH Terms: 5-Methylcytosine, Animals, Base Composition, CpG Islands, DNA Mutational Analysis, Databases, Nucleic Acid, Deamination, Evolution, Molecular, Exons, Genome, Genome, Human, Humans, Pan troglodytes, Point Mutation, Polymorphism, Single Nucleotide
Show Abstract · Added March 5, 2014
BACKGROUND - The pattern of point mutation is important for studying mutational mechanisms, genome evolution, and diseases. Previous studies of mutation direction were largely based on substitution data from a limited number of loci. To date, there is no genome-wide analysis of mutation direction or methylation-dependent transition rates in the chimpanzee or its categorized genomic regions.
RESULTS - In this study, we performed a detailed examination of mutation direction in the chimpanzee genome and its categorized genomic regions using 588,918 SNPs whose ancestral alleles could be inferred by mapping them to human genome sequences. The C-->T (G-->A) changes occurred most frequently in the chimpanzee genome. Each type of transition occurred approximately four times more frequently than each type of transversion. Notably, the frequency of C-->T (G-->A) was the highest in exons among the genomic categories regardless of whether we calculated directly, normalized with the nucleotide content, or removed the SNPs involved in the CpG effect. Moreover, the directionality of the point mutation in exons and CpG islands were opposite relative to their corresponding intergenic regions, indicating that different forces govern the nucleotide changes. Our analysis suggests that the GC content is not in equilibrium in the chimpanzee genome. Further quantitative analysis revealed that the 5-methylcytosine deamination rates at CpG sites were highly dependent on the local GC content and the lengths of SNP flanking sequences and varied among categorized genomic regions.
CONCLUSION - We present the first mutational spectrum, estimated by three different approaches, in the chimpanzee genome. Our results provide detailed information on recent nucleotide changes and methylation-dependent transition rates in the chimpanzee genome after its split from the human. These results have important implications for understanding genome composition evolution, mechanisms of point mutation, and other genetic factors such as selection, biased codon usage, biased gene conversion, and recombination.
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15 MeSH Terms