Elevated gene expression levels distinguish human from non-human primate brains

Cáceres, Mario; Lachuer, Joël; Zapala, Matthew A.; Redmond, John C.; Kudo, Lili C.; Geschwind, Daniel H.; Lockhart, David J.; Preuss, Todd M.; Barlow, Carrolee

doi:10.1073/pnas.2135499100

Cited by 459 publications

(458 citation statements)

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“…An alternate, albeit related, explanation would be that regions with low genetic variance have greater functional constraints on their determinants of cortical thickness, such that genetic mutations influencing these regions will typically be eliminated quickly from the population through purifying selection. Comparative genomic experiments have shown that a subset of neurally-expressed genes have evolved more rapidly in humans than in other primates [Chimpanzee Sequencing and Analysis Consortium, 2005;Dorus et al, 2004;Khaitovich et al, 2005]; both gene expression changes and protein sequence modification have accelerated in humans relative to nonhuman primates [Caceres et al, 2003;Enard et al, 2002;Gu and Gu, 2003;Hsieh et al, 2003;Uddin et al, 2004]. The findings of increased genetic variance in evolutionarily recent structures may represent a remnant of these rapid neurogenetic changes that accompanied our divergence from other primates.…”

Section: Discussionmentioning

confidence: 99%

Differences in genetic and environmental influences on the human cerebral cortex associated with development during childhood and adolescence

Lenroot

Schmitt

Ordaz

et al. 2007

Human Brain Mapping

308

260

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In this report, we present the first regional quantitative analysis of age-related differences in the heritability of cortical thickness using anatomic MRI with a large pediatric sample of twins, twin siblings, and singletons (n 5 600, mean age 11.1 years, range 5-19). Regions of primary sensory and motor cortex, which develop earlier, both phylogenetically and ontologically, show relatively greater genetic effects earlier in childhood. Later developing regions within the dorsal prefrontal cortex and temporal lobes conversely show increasingly prominent genetic effects with maturation. The observation that regions associated with complex cognitive processes such as language, tool use, and executive function are more heritable in adolescents than children is consistent with previous studies showing that IQ becomes increasingly heritable with maturity(Plomin et al. [1997]: Psychol Sci 8:442-447). These results suggest that both the specific cortical region and the age of the population should be taken into account when using cortical thickness as an intermediate phenotype to link genes, environment, and behavior. Hum Brain Mapp 30: [163][164][165][166][167][168][169][170][171][172][173][174] 2009. V V C 2007 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Differences in genetic and environmental influences on the human cerebral cortex associated with development during childhood and adolescence

Lenroot

Schmitt

Ordaz

et al. 2007

Human Brain Mapping

308

260

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“…The aim has been to characterize general trends in the evolution of gene expression rather than to identify specific genes of interest. To date, conclusions about the selection pressures acting on gene expression have been conflicting 2,3,6,[11][12][13] .These studies have all relied on data collected from arrays using gene probes that were designed on the basis of human sequences only. However, sequence mismatches affect hybridization intensity and can therefore bias estimates of gene expression differences between species 14 .…”

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confidence: 99%

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confidence: 99%

Expression profiling in primates reveals a rapid evolution of human transcription factors

Gilad

Oshlack

Smyth

et al. 2006

Nature

285

253

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Although it has been hypothesized for thirty years that many human adaptations are likely to be due to changes in gene regulation 1 , almost nothing is known about the modes of natural selection acting on regulation in primates. Here we identify a set of genes for which expression is evolving under natural selection. We use a new multi-species complementary DNA array to compare steady-state messenger RNA levels in liver tissues within and between humans, chimpanzees, orangutans and rhesus macaques. Using estimates from a linear mixed model, we identify a set of genes for which expression levels have remained constant across the entire phylogeny (,70 million years), and are therefore likely to be under stabilizing selection. Among the top candidates are five genes with expression levels that have previously been shown to be altered in liver carcinoma. We also find a number of genes with similar expression levels among non-human primates but significantly elevated or reduced expression in the human lineage, features that point to the action of directional selection. Among the gene set with a human-specific increase in expression, there is an excess of transcription factors; the same is not true for genes with increased expression in chimpanzee.A number of recent studies have used DNA microarrays to compare patterns of gene expression between closely related species 2-9 . Within primates, the focus has been primarily on human-chimpanzee comparisons, estimating gene expression profiles for a number of tissues, including liver, brain and heart 2,6,7,10 . The aim has been to characterize general trends in the evolution of gene expression rather than to identify specific genes of interest. To date, conclusions about the selection pressures acting on gene expression have been conflicting 2,3,6,[11][12][13] .These studies have all relied on data collected from arrays using gene probes that were designed on the basis of human sequences only. However, sequence mismatches affect hybridization intensity and can therefore bias estimates of gene expression differences between species 14 . This limitation of single-species arrays is especially problematic when the goal is to study how expression changes over evolutionary time. To make comparisons between more distantly related primate species, we generated a multi-species cDNA array that allows comparison of gene expression between species without the confounding effects of sequence divergence 14 . This cDNA array contains probes for 1,056 orthologous genes from four species (see Supplementary Methods) 14 .We used this array to compare gene expression profiles in the livers of humans, chimpanzees (Pan troglodytes), orangutans (Pongo pygmaeus) and rhesus macaques (Macaca mulatta), the phylogeny of which represents approximately 70 million years (Myr) of evolution. By assigning expression changes in the liver to particular lineages, we were able to identify the first set of genes for which regulation seems to be under lineage-specific selection pressures. In order to measure gene...

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“…Large-scale gene expression studies showed that an overall upregulation of genes involved in synaptic transmission and metabolic processes that support it has occurred on the human lineage (e.g., ref. 14), suggesting that higher neuronal activity may have coevolved with greater brain size and other changes.…”

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confidence: 99%

Birth and adaptive evolution of a hominoid gene that supports high neurotransmitter flux

2004

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The enzyme glutamate dehydrogenase (GDH) is important for recycling the chief excitatory neurotransmitter, glutamate, during neurotransmission. Human GDH exists in housekeeping and brain-specific isotypes encoded by the genes GLUD1 and GLUD2, respectively. Here we show that GLUD2 originated by retroposition from GLUD1 in the hominoid ancestor less than 23 million years ago. The amino acid changes responsible for the unique brain-specific properties of the enzyme derived from GLUD2 occurred during a period of positive selection after the duplication event.Astrocytes are glial cells that surround neurons and have a pivotal role in regulating the flux of glutamate 1 . After neuron firing, this neurotransmitter is inactivated by its uptake into astrocytes, where it is metabolized by several key enzymes 1,2 . One of these enzymes, GDH, catalyzes the oxidative deamination of glutamate to ammonia and a-ketoglutarate (generating ATP through the Krebs cycle 3 ), a reaction that fuels recycling of glutamate by glutamine synthetase 2 . In addition, degradation by GDH seems to be important for the detoxification of glutamate at high concentrations after neuron firing 4 . Altered activity of this enzyme is implicated in human neurodegenerative disorders 3 and potentially in other neurological deficiencies 5,6 .In the human brain, GDH exists in two isotypes encoded by GLUD1 and GLUD2 (ref. 4). GLUD1 is an important housekeeping gene expressed in many tissues 4 , whereas GLUD2 is specifically expressed in nerve tissues (brain and retina) and in testis 7 . Unlike GLUD1, the enzyme derived from GLUD2 is highly adapted to functioning in the brain 4 : it is highly functional in spite of the high GTP levels in the brain; its activity is up to 25 times higher than the basal level, depending on the concentrations of the allosteric activators ADP and L-leucine; and it can function at relatively low pH levels 3,4 . These properties permit instant activation of the enzyme in the brain under high-frequency firing of the neurons.GLUD2 is an X-linked intronless gene 7 that probably originated by retroposition of a spliced mRNA derived from the intron-containing gene GLUD1 on chromosome 10. We could identify only single functional GLUD genes orthologous to human GLUD1 when screening available genome sequences (Supplementary Methods online). Because a primate burst of retroposition, which began B40-50 million years ago 8 , has generated a large number of retrocopies of genes on the primate lineage, we hypothesized that GLUD2 might be a young primate retrogene that originated recently by retroduplication of GLUD1 and then adopted its brain-specific function.To test this hypothesis, we first gauged the age of GLUD2 by screening for the presence or absence of GLUD2 in primates using PCR with primers flanking the retrogene insertion site. We found that GLUD2 was present only in humans and apes and that the sequence of the insertion site in Old World monkeys (OWMs) reflects the ancestral state, before the GLUD2 insertion ( Supplementary Fig. 1 on...

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Elevated gene expression levels distinguish human from non-human primate brains

Cited by 459 publications

References 42 publications

Differences in genetic and environmental influences on the human cerebral cortex associated with development during childhood and adolescence

Differences in genetic and environmental influences on the human cerebral cortex associated with development during childhood and adolescence

Expression profiling in primates reveals a rapid evolution of human transcription factors

Birth and adaptive evolution of a hominoid gene that supports high neurotransmitter flux

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