ABSTRACT Cytochrome c (cyt c) is a highly conserved protein among eukaryotes, mainly owing to its... more ABSTRACT Cytochrome c (cyt c) is a highly conserved protein among eukaryotes, mainly owing to its pivotal role in two crucial cellular processes: apoptosis and respiratory chain function. Despite its overall stability, previous studies have reported on the human lineage: (i) a high amino acid evolution rate of cyt c somatic isoform, (ii) absence of the testis isoform, and (iii) atypical biochemical behavior of human cyt c. In order to gain insight, we have investigated the cyt c loci and sequence evolution among primate lineages. Using cyt c sequences obtained by sequencing and from databases, genomic loci were obtained and compared using the UCSC Genome Browser. Phylogenetic statistical approaches were used to construct trees, to estimate divergence times, and to test selection models. Then potential effects of the changes were evaluated with spatial comparison and mathematical modeling. All the analyzed primate testis cyt c sequences share the same nonsense mutation, which suggests that the silencing occurred in the early primate stem. The phylogenetic analyses of somatic cyt c converged to the same tree topology recovering all major groups with maximal branch support. The evolutionary analyses show that strong positive selection occurs specifically on the anthropoid lineage root and then continued in parallel on the early catarrhini and platyrrhini stem. Spatial analysis and mathematical modeling suggest that evolution specifically focus on the respiratory chain rather than apoptosis or other cyt c functions. Supported by previous biochemical studies, our results show that the silencing of the cyt c testis isoform is correlated with the decrease of primate reproduction and that the fast evolution of the cyt c somatic isoform is correlated with the increase of primate metabolism. Finally, the parallel evolution of cyt c in the two sister anthropoid groups leads us to propose that cyt evolution may in fact have participated in the evolutionary events with which its changes are correlated.
Collection and processing of whole blood samples in a non-clinical setting offers a unique opport... more Collection and processing of whole blood samples in a non-clinical setting offers a unique opportunity to evaluate community-dwelling individuals both with and without preexisting conditions. Rapid processing of these samples is essential to avoid degradation of key cellular components. Included here are methods for simultaneous peripheral blood mononuclear cell (PBMC), DNA, RNA and serum isolation from a single blood draw performed in the homes of consenting participants across a metropolitan area, with processing initiated within 2 hr of collection. We have used these techniques to process over 1,600 blood specimens yielding consistent, high quality material, which has subsequently been used in successful DNA methylation, genotyping, gene expression and flow cytometry analyses. Some of the methods employed are standard; however, when combined in the described manner, they enable efficient processing of samples from participants of population- and/or community-based studies who would not normally be evaluated in a clinical setting. Therefore, this protocol has the potential to obtain samples (and subsequently data) that are more representative of the general population.
DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post... more DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3' un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated...
Proceedings of The National Academy of Sciences, 2004
The phytochrome (phy) family of sensory photoreceptors transduce informational light signals to s... more The phytochrome (phy) family of sensory photoreceptors transduce informational light signals to selected nuclear genes, inducing plant growth and developmental responses appropriate to the environment. Existing data suggest that one signaling pathway by which this occurs involves direct, intranuclear interaction of the photoactivated phy molecule with PIF3, a basic helix-loop-helix transcription factor. Here, we provide evidence from recently identified pif3
The human brain, and human cognitive abilities, are strikingly different from those of other grea... more The human brain, and human cognitive abilities, are strikingly different from those of other great apes despite relatively modest genome sequence divergence. However, little is presently known about the interspecies divergence in gene structure and transcription that might contribute to these phenotypic differences. To date, most comparative studies of gene structure in the brain have examined humans, chimpanzees, and macaque monkeys. To add to this body of knowledge, we analyze here the brain transcriptome of the western lowland gorilla (Gorilla gorilla gorilla), an African great ape species that is phylogenetically closely related to humans, but with a brain that is approximately one-third the size. Manual transcriptome curation from a sample of the planum temporale region of the neocortex revealed 12 protein-coding genes and one noncoding-RNA gene with exons in the gorilla unmatched by public transcriptome data from the orthologous human loci. These interspecies gene structure di...
ABSTRACT Cytochrome c (cyt c) is a highly conserved protein among eukaryotes, mainly owing to its... more ABSTRACT Cytochrome c (cyt c) is a highly conserved protein among eukaryotes, mainly owing to its pivotal role in two crucial cellular processes: apoptosis and respiratory chain function. Despite its overall stability, previous studies have reported on the human lineage: (i) a high amino acid evolution rate of cyt c somatic isoform, (ii) absence of the testis isoform, and (iii) atypical biochemical behavior of human cyt c. In order to gain insight, we have investigated the cyt c loci and sequence evolution among primate lineages. Using cyt c sequences obtained by sequencing and from databases, genomic loci were obtained and compared using the UCSC Genome Browser. Phylogenetic statistical approaches were used to construct trees, to estimate divergence times, and to test selection models. Then potential effects of the changes were evaluated with spatial comparison and mathematical modeling. All the analyzed primate testis cyt c sequences share the same nonsense mutation, which suggests that the silencing occurred in the early primate stem. The phylogenetic analyses of somatic cyt c converged to the same tree topology recovering all major groups with maximal branch support. The evolutionary analyses show that strong positive selection occurs specifically on the anthropoid lineage root and then continued in parallel on the early catarrhini and platyrrhini stem. Spatial analysis and mathematical modeling suggest that evolution specifically focus on the respiratory chain rather than apoptosis or other cyt c functions. Supported by previous biochemical studies, our results show that the silencing of the cyt c testis isoform is correlated with the decrease of primate reproduction and that the fast evolution of the cyt c somatic isoform is correlated with the increase of primate metabolism. Finally, the parallel evolution of cyt c in the two sister anthropoid groups leads us to propose that cyt evolution may in fact have participated in the evolutionary events with which its changes are correlated.
Collection and processing of whole blood samples in a non-clinical setting offers a unique opport... more Collection and processing of whole blood samples in a non-clinical setting offers a unique opportunity to evaluate community-dwelling individuals both with and without preexisting conditions. Rapid processing of these samples is essential to avoid degradation of key cellular components. Included here are methods for simultaneous peripheral blood mononuclear cell (PBMC), DNA, RNA and serum isolation from a single blood draw performed in the homes of consenting participants across a metropolitan area, with processing initiated within 2 hr of collection. We have used these techniques to process over 1,600 blood specimens yielding consistent, high quality material, which has subsequently been used in successful DNA methylation, genotyping, gene expression and flow cytometry analyses. Some of the methods employed are standard; however, when combined in the described manner, they enable efficient processing of samples from participants of population- and/or community-based studies who would not normally be evaluated in a clinical setting. Therefore, this protocol has the potential to obtain samples (and subsequently data) that are more representative of the general population.
DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post... more DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3' un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated...
Proceedings of The National Academy of Sciences, 2004
The phytochrome (phy) family of sensory photoreceptors transduce informational light signals to s... more The phytochrome (phy) family of sensory photoreceptors transduce informational light signals to selected nuclear genes, inducing plant growth and developmental responses appropriate to the environment. Existing data suggest that one signaling pathway by which this occurs involves direct, intranuclear interaction of the photoactivated phy molecule with PIF3, a basic helix-loop-helix transcription factor. Here, we provide evidence from recently identified pif3
The human brain, and human cognitive abilities, are strikingly different from those of other grea... more The human brain, and human cognitive abilities, are strikingly different from those of other great apes despite relatively modest genome sequence divergence. However, little is presently known about the interspecies divergence in gene structure and transcription that might contribute to these phenotypic differences. To date, most comparative studies of gene structure in the brain have examined humans, chimpanzees, and macaque monkeys. To add to this body of knowledge, we analyze here the brain transcriptome of the western lowland gorilla (Gorilla gorilla gorilla), an African great ape species that is phylogenetically closely related to humans, but with a brain that is approximately one-third the size. Manual transcriptome curation from a sample of the planum temporale region of the neocortex revealed 12 protein-coding genes and one noncoding-RNA gene with exons in the gorilla unmatched by public transcriptome data from the orthologous human loci. These interspecies gene structure di...
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Papers by Derek Wildman