Papers by philipp khaitovich
<p>(A) Transcriptional similarity among autism and control cases during PFC development, vi... more <p>(A) Transcriptional similarity among autism and control cases during PFC development, visualized using multidimensional scaling (MDS) with expression correlation as distance (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002558#pbio.1002558.s002" target="_blank">S2 Data</a>). Each circle represents an individual. The size of the circles is proportional to the individuals’ age (smaller circles correspond to younger individuals). The border colors represent different groups (black: autism cases, red: controls). The filled colors with different shades indicate the levels of cognitive decline for autistic individuals (darker purple correspond to more severe cases). The first dimension correlates with levels of cognitive decline (Pearson correlation, <i>r</i> = 0.42, <i>p</i> < 0.001) and the second with age (Pearson correlation, <i>r</i> = 0.73, <i>p</i> < 0.001). (B) Proportions of the total expression variation explained by disease status, age, sex, RNA quality, and sample batch across all 12,557 genes expressed in autism and control cases. (C) Distance between the expression trajectory of control group and autism cases with different levels of Autism Diagnostic Interview-Revised (ADI-R) scores. Darker shade of purple corresponds to higher ADI-R scores.</p
<p>(A) Hierarchical clustering of 1,775 genes differently expressed between autism cases an... more <p>(A) Hierarchical clustering of 1,775 genes differently expressed between autism cases and unaffected controls (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002558#pbio.1002558.s003" target="_blank">S3 Data</a>). (B) Expression patterns of the six major gene clusters. The <i>x</i>-axis shows the age information on the (age)<sup>1/4</sup> scale; the <i>y</i>-axis shows the expression levels standardized to mean = 0 and standard deviation = 1 before plotting. The points represent mean expression levels in each individual (red: controls; black: autism cases); the lines show cubic spline curves fitted to the individual data; the shaded areas show the standard deviation of the spline curves within a cluster. The cluster number and the number of genes within the cluster are shown on top of the panels. (C) Summary of functional pathways enriched in each cluster (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002558#pbio.1002558.s028" target="_blank">S3 Table</a>). (D) Overlap between genes with 1–4 scores in SFARI AutDB linked to autism by genetic association studies and six major clusters of expression changes in autism (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002558#pbio.1002558.s004" target="_blank">S4 Data</a>). The red bars show the numbers of overlapping genes; the streaked bars show the mean numbers of overlapping genes expected by chance, estimated by 1,000 permutations of cluster labels. The symbols above the bars show the significance based on 1,000 permutations of cluster labels (**: <i>p</i> < 0.01).</p
Nature, 2019
R performed RNA-seq experiments. B.V. and W.H. contributed to analyses on trajectory changes. S.O... more R performed RNA-seq experiments. B.V. and W.H. contributed to analyses on trajectory changes. S.O., S.Anders and P.V.M. contributed to analyses on developmental correspondences. C.C., Y.S. and Y.E.Z. contributed to analyses on transcriptome age. M.M. and D.N.C. contributed to data interpretation. I.X. organized high-performance computational resources. K.H. organized high-throughput sequencing. Data availability Raw and processed RNA-seq data have been deposited in ArrayExpress with the accession codes: E-MTAB-6769 (chicken), E-MTAB-6782 (rabbit) E-MTAB-6798 (mouse), E-MTAB-6811 (rat), E-MTAB-6813 (rhesus), E-MTAB-6814 (human) and E-MTAB-6833 (opossum) (https://www.ebi.ac.uk/arrayexpress/). The temporal profiles of individual genes across organs and species can be visualized and downloaded using the web-based application: http://evodevoapp.kaessmannlab.org.
Complex Psychiatry, 2016
Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder. Several studies have at... more Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder. Several studies have attempted to characterize molecular alterations associated with PTSD, but most findings were limited to the investigation of specific cellular markers in the periphery or defined brain regions. In the current study, we aimed to unravel affected molecular pathways/mechanisms in the fear circuitry associated with PTSD. We interrogated a foot shock-induced PTSD mouse model by integrating proteomics and metabolomics profiling data. Alterations at the proteome level were analyzed using in vivo 15N metabolic labeling combined with mass spectrometry in the prelimbic cortex (PrL), anterior cingulate cortex (ACC), basolateral amygdala, central nucleus of the amygdala and CA1 of the hippocampus between shocked and nonshocked (control) mice, with and without fluoxetine treatment. In silico pathway analyses revealed an upregulation of the citric acid cycle pathway in PrL, and downregulation in ACC and...
BMC genomics, Jan 10, 2014
Comprehensive annotation of transcripts expressed in a given tissue is a critical step towards th... more Comprehensive annotation of transcripts expressed in a given tissue is a critical step towards the understanding of regulatory and functional pathways that shape the transcriptome. Here, we reconstructed a cumulative transcriptome of the human prefrontal cortex (PFC) based on approximately 300 million strand-specific RNA sequence (RNA-seq) reads collected at different stages of postnatal development. We find that more than 50% of reconstructed transcripts represent novel transcriptome elements, including 8,343 novel exons and exon extensions of annotated coding genes, 11,217 novel antisense transcripts and 29,541 novel intergenic transcripts or their fragments showing canonical features of long non-coding RNAs (lncRNAs). Our analysis further led to a surprising discovery of a novel class of bidirectional promoters (NBiPs) driving divergent transcription of mRNA and novel lncRNA pairs and displaying a distinct set of sequence and epigenetic features. In contrast to known bidirectiona...
RNA (New York, N.Y.), 2014
The current annotation of the human genome includes more than 12,000 long intergenic noncoding RN... more The current annotation of the human genome includes more than 12,000 long intergenic noncoding RNAs (lincRNA). While a handful of lincRNA have been shown to play important regulatory roles, the functionality of most remains unclear. Here, we examined the expression conservation and putative functionality of lincRNA in human and macaque prefrontal cortex (PFC) development and maturation. We analyzed transcriptome sequence (RNA-seq) data from 38 human and 40 macaque individuals covering the entire postnatal development interval. Using the human data set, we detected the expression of 5835 lincRNA annotated in GENCODE and further identified 1888 novel lincRNA. Most of these lincRNA show low DNA sequence conservation, as well as low expression levels. Remarkably, developmental expression patterns of these lincRNA were as conserved between humans and macaques as those of protein-coding genes. Transfection of development-associated lincRNA into human SH-SY5Y cells affected gene expression...
Primatology Monographs, 2011
ABSTRACT Humans are separated from their closest living relatives, the chimpanzees, by 6–7 millio... more ABSTRACT Humans are separated from their closest living relatives, the chimpanzees, by 6–7 million years of evolution. This is a short period in evolutionary terms: genetically, the two species are as much as 99% identical. Within this short time, however, human ancestors evolved a unique set of cognitive abilities distinguishing humans from other species. This raises the question: how, mechanistically, could human cognitive abilities evolve in such a short time interval? More than 30 years ago M.C. King and A. Wilson had already proposed that identifying differences in the timing of gene expression during brain development between humans and apes would be crucial for understanding human evolution. Indeed, change in timing and rate of ontogenetic changes, or heterochrony, has long been known as a potent mechanism of creating evolutionary novelties. If true, this mechanism offers a solution to the conundrum of human evolution, by allowing novel human cognitive abilities to develop on the basis of preexisting cognitive machinery. Comparison of human and chimpanzee ontogenetic changes on the molecular level, however, has visibly lagged behind those in model organisms. Here, we describe recent advances in this field, which imply a molecular link between the evolution of two seemingly independent human-specific features: cognitive abilities and longevity.
PLoS ONE, 2007
Even though mRNA expression levels are commonly used as a proxy for estimating functional differe... more Even though mRNA expression levels are commonly used as a proxy for estimating functional differences that occur at the protein level, the relation between mRNA and protein expression is not well established. Further, no study to date has tested whether the evolutionary differences in mRNA expression observed between species reflect those observed in protein expression. Since a large proportion of mRNA expression differences observed between mammalian species appears to have no functional consequences for the phenotype, it is conceivable that many or most mRNA expression differences are not reflected at the protein level. If this is true, then differences in protein expression may largely reflect functional adaptations observed in species phenotypes. In this paper, we present the first direct comparison of mRNA and protein expression differences seen between humans and chimpanzees. We reproducibly find a significant positive correlation between mRNA expression and protein expression differences. This correlation is comparable in magnitude to that found between mRNA and protein expression changes at different developmental stages or in different physiological conditions within one species. Noticeably, this correlation is mainly due to genes with large expression differences between species. Our study opens the door to a new level of understanding of regulatory evolution and poses many new questions that remain to be answered.
Genome Biology, 2008
Human brain evolution <p>Human cognitive evolution involved genes implicated in energy metabolism... more Human brain evolution <p>Human cognitive evolution involved genes implicated in energy metabolism and energy-expensive brain functions that are also altered in schizophrenia, suggesting that human brains may have reached their metabolic limit, with schizophrenia as a costly by-product.</p>
The onset of neurogenesis in the various regions of the mammalian brain is controlled by a comple... more The onset of neurogenesis in the various regions of the mammalian brain is controlled by a complex interplay of transcriptional regulators (Guillemot, 2005; Kageyama et al., 2005). Knockout mice in the Hes genes show a premature onset of neurogenesis (Guillemot, 2005; Kageyama et al., 2005). Remarkably, in the E10.5 hindbrain of Hes5 knockout mice, a brain region in which the phenotype with regard to neurogenesis is more profound than in the E10.5 dTel (due to lesser compensation by other Hes genes) (Hatakeyama et al., 2004; Ross et al., 2003), Insm1 expression in the VZ was markedly increased (Figure S2). This increase reflected the fact that in the absence of Hes5, a much greater proportion (≈50%) of APs than normal showed Insm1 expression at this early stage of neurogenesis (Fig. 2H, Figure S2). This increased Insm1 expression may be mediated by proneural genes, as these are known to be upregulated in the Hes5 knockout (Hatakeyama et al., 2004) and drive Insm1 expression ((Castro et al., 2006); and Figures S2 and 3 below). Next, we investigated whether the expression of Insm1 in neurogenic PCs was dependent on proneural genes, which are known to induce NE PCs to become neurogenic (Gohlke et al., 2008; Guillemot, 2005). Indeed, in E10.0 Mash1 and E10.5 Ngn2 knockout mice, in which the
Science, 2005
The determination of the chimpanzee genome sequence provides a means to study both structural and... more The determination of the chimpanzee genome sequence provides a means to study both structural and functional aspects of the evolution of the human genome. Here we compare humans and chimpanzees with respect to differences in expression levels and protein-coding sequences for genes active in brain, heart, liver, kidney, and testis. We find that the patterns of differences in gene expression and gene sequences are markedly similar. In particular, there is a gradation of selective constraints among the tissues so that the brain shows the least differences between the species whereas liver shows the most. Furthermore, expression levels as well as amino acid sequences of genes active in more tissues have diverged less between the species than have genes active in fewer tissues. In general, these patterns are consistent with a model of neutral evolution with negative selection. However, for X-chromosomal genes expressed in testis, patterns suggestive of positive selection on sequence chan...
PLoS Genetics, 2011
Among other factors, changes in gene expression on the human evolutionary lineage have been sugge... more Among other factors, changes in gene expression on the human evolutionary lineage have been suggested to play an important role in the establishment of human-specific phenotypes. However, the molecular mechanisms underlying these expression changes are largely unknown. Here, we have explored the role of microRNA (miRNA) in the regulation of gene expression divergence among adult humans, chimpanzees, and rhesus macaques, in two brain regions: prefrontal cortex and cerebellum. Using a combination of high-throughput sequencing, miRNA microarrays, and Q-PCR, we have shown that up to 11% of the 325 expressed miRNA diverged significantly between humans and chimpanzees and up to 31% between humans and macaques. Measuring mRNA and protein expression in human and chimpanzee brains, we found a significant inverse relationship between the miRNA and the target genes expression divergence, explaining 2%-4% of mRNA and 4%-6% of protein expression differences. Notably, miRNA showing human-specific expression localize in neurons and target genes that are involved in neural functions. Enrichment in neural functions, as well as miRNA-driven regulation on the human evolutionary lineage, was further confirmed by experimental validation of predicted miRNA targets in two neuroblastoma cell lines. Finally, we identified a signature of positive selection in the upstream region of one of the five miRNA with human-specific expression, miR-34c-5p. This suggests that miR-34c-5p expression change took place after the split of the human and the Neanderthal lineages and had adaptive significance. Taken together these results indicate that changes in miRNA expression might have contributed to evolution of human cognitive functions.
PLoS Genetics, 2005
Although a large proportion of human transcription occurs outside the boundaries of known genes, ... more Although a large proportion of human transcription occurs outside the boundaries of known genes, the functional significance of this transcription remains unknown. We have compared the expression patterns of known genes as well as intergenic transcripts within the ENCODE regions between humans and chimpanzees in brain, heart, testis, and lymphoblastoid cell lines. We find that intergenic transcripts show patterns of tissue-specific conservation of their expression, which are comparable to exonic transcripts of known genes. This suggests that intergenic transcripts are subject to functional constraints that restrict their rate of evolutionary change as well as putative positive selection to an extent comparable to that of classical protein-coding genes. In brain and testis, we find that part of this intergenic transcription is caused by widespread use of alternative promoters. Further, we find that about half of the expression differences between humans and chimpanzees are due to intergenic transcripts.
PLoS Computational Biology, 2010
Transcription is the first step connecting genetic information with an organism's phenotype. Whil... more Transcription is the first step connecting genetic information with an organism's phenotype. While expression of annotated genes in the human brain has been characterized extensively, our knowledge about the scope and the conservation of transcripts located outside of the known genes' boundaries is limited. Here, we use high-throughput transcriptome sequencing (RNA-Seq) to characterize the total non-ribosomal transcriptome of human, chimpanzee, and rhesus macaque brain. In all species, only 20-28% of non-ribosomal transcripts correspond to annotated exons and 20-23% to introns. By contrast, transcripts originating within intronic and intergenic repetitive sequences constitute 40-48% of the total brain transcriptome. Notably, some repeat families show elevated transcription. In non-repetitive intergenic regions, we identify and characterize 1,093 distinct regions highly expressed in the human brain. These regions are conserved at the RNA expression level across primates studied and at the DNA sequence level across mammals. A large proportion of these transcripts (20%) represents 39UTR extensions of known genes and may play roles in alternative microRNA-directed regulation. Finally, we show that while transcriptome divergence between species increases with evolutionary time, intergenic transcripts show more expression differences among species and exons show less. Our results show that many yet uncharacterized evolutionary conserved transcripts exist in the human brain. Some of these transcripts may play roles in transcriptional regulation and contribute to evolution of human-specific phenotypic traits.
PLoS Biology, 2005
It is well established that gene expression levels in many organisms change during the aging proc... more It is well established that gene expression levels in many organisms change during the aging process, and the advent of DNA microarrays has allowed genome-wide patterns of transcriptional changes associated with aging to be studied in both model organisms and various human tissues. Understanding the effects of aging on gene expression in the human brain is of particular interest, because of its relation to both normal and pathological neurodegeneration. Here we show that human cerebral cortex, human cerebellum, and chimpanzee cortex each undergo different patterns of age-related gene expression alterations. In humans, many more genes undergo consistent expression changes in the cortex than in the cerebellum; in chimpanzees, many genes change expression with age in cortex, but the pattern of changes in expression bears almost no resemblance to that of human cortex. These results demonstrate the diversity of aging patterns present within the human brain, as well as how rapidly genome-wide patterns of aging can evolve between species; they may also have implications for the oxidative free radical theory of aging, and help to improve our understanding of human neurodegenerative diseases.
PLoS Biology, 2005
Retroviral infections of the germline have the potential to episodically alter gene function and ... more Retroviral infections of the germline have the potential to episodically alter gene function and genome structure during the course of evolution. Horizontal transmissions between species have been proposed, but little evidence exists for such events in the human/great ape lineage of evolution. Based on analysis of finished BAC chimpanzee genome sequence, we characterize a retroviral element (Pan troglodytes endogenous retrovirus 1 [PTERV1]) that has become integrated in the germline of African great ape and Old World monkey species but is absent from humans and Asian ape genomes. We unambiguously map 287 retroviral integration sites and determine that approximately 95.8% of the insertions occur at non-orthologous regions between closely related species. Phylogenetic analysis of the endogenous retrovirus reveals that the gorilla and chimpanzee elements share a monophyletic origin with a subset of the Old World monkey retroviral elements, but that the average sequence divergence exceeds neutral expectation for a strictly nuclear inherited DNA molecule. Within the chimpanzee, there is a significant integration bias against genes, with only 14 of these insertions mapping within intronic regions. Six out of ten of these genes, for which there are expression data, show significant differences in transcript expression between human and chimpanzee. Our data are consistent with a retroviral infection that bombarded the genomes of chimpanzees and gorillas independently and concurrently, 3-4 million years ago. We speculate on the potential impact of such recent events on the evolution of humans and great apes.
Nature Reviews Genetics, 2006
Negative selection Removal of genetic variants in a population that decrease the fitness of their... more Negative selection Removal of genetic variants in a population that decrease the fitness of their carrier. If negative selection acts on a phenotypic trait, this is also called stabilizing selection. Positive selection Increase in frequency of a genetic variant or a phenotypic trait because it increases the fitness of its carrier. If positive selection acts on a phenotypic trait, this is also called directional selection.
Nature, 2005
Gene and duplication structure analysis Although most (66%) of the autosomal base pairs (bp) dupl... more Gene and duplication structure analysis Although most (66%) of the autosomal base pairs (bp) duplicated in humans are shared between human and chimpanzee (Table 1), a
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Papers by philipp khaitovich