Transcriptional neoteny in the human brain

Somel, Mehmet; Franz, Henriette; Zheng, Yanyan; Lorenc, Anna; Guo, Songlin; Giger, Thomas; Kelso, Janet; Nickel, Birgit; Dannemann, Michael; Bahn, Sabine; Webster, Maree J.; Weickert, Cynthia Shannon; Lachmann, Michael; Pääbo, Svante; Khaitovich, Philipp

doi:10.1073/pnas.0900544106

Cited by 352 publications

(349 citation statements)

References 34 publications

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“…Interestingly, the GO categories that exhibit the highest rates of evolution include "regulation of transcription, DNA-dependent," "negative regulation of transcription from RNA polymerase II promoter," and "multicellular organismal development." This squares nicely with previous reports arguing that many of the extant differences between modern humans and chimpanzees involve changes in gene regulations and neoteny (36).…”

Section: Discussionsupporting

confidence: 51%

Extensive X-linked adaptive evolution in central chimpanzees

Hvilsom

Qian

Bataillon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Surveying genome-wide coding variation within and among species gives unprecedented power to study the genetics of adaptation, in particular the proportion of amino acid substitutions fixed by positive selection. Additionally, contrasting the autosomes and the X chromosome holds information on the dominance of beneficial (adaptive) and deleterious mutations. Here we capture and sequence the complete exomes of 12 chimpanzees and present the largest set of protein-coding polymorphism to date. We report extensive adaptive evolution specifically targeting the X chromosome of chimpanzees with as much as 30% of all amino acid replacements being adaptive. Adaptive evolution is barely detectable on the autosomes except for a few striking cases of recent selective sweeps associated with immunity gene clusters. We also find much stronger purifying selection than observed in humans, and in contrast to humans, we find that purifying selection is stronger on the X chromosome than on the autosomes in chimpanzees. We therefore conclude that most adaptive mutations are recessive. We also document dramatically reduced synonymous diversity in the chimpanzee X chromosome relative to autosomes and stronger purifying selection than for the human X chromosome. If similar processes were operating in the human-chimpanzee ancestor as in central chimpanzees today, our results therefore provide an explanation for the much-discussed reduction in the human-chimpanzee divergence at the X chromosome.Pan troglodytes troglodytes | SNP | site frequency spectrum | distribution of fitness effects | faster X Q uantifying the relative importance of purifying, neutral, and positive selection in shaping divergence between species remains a challenge in evolutionary biology. Beneficial mutations are central for understanding evolution by natural selection. However, the rarity of beneficial mutations has frustrated attempts to characterize their most basic genetic properties in higher organisms (1). One way forward is to combine genome-wide surveys of polymorphism within species and between species divergence to estimate the fraction, α, of mutations that have been fixed by positive selection. Empirical studies, particularly in the Drosophila genus show that mutations fixed by positive selection can make up a sizable fraction (>50%) of the divergence between species in gene coding regions (2) but whether these results are general for mammals, for example, remains unclear. Furthermore we still know very little about the distribution of fitness effects (DFE) of these mutations and even less about their dominance in diploid organisms. Theory predicts and recent empirical studies emphasize that the demographic history as well as variation in mutation and recombination rates can blur footprints of molecular adaptation by Darwinian selection (3, 4). This in turn can complicate the inference of DFE and α (5, 6).In that context, contrasting the DFE and rates of adaptation in autosomes versus sex chromosomes is an elegant strategy to infer the genetic properties...

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Section: Discussionsupporting

confidence: 51%

Extensive X-linked adaptive evolution in central chimpanzees

Hvilsom

Qian

Bataillon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…cortices show a protracted postnatal developmental course relative to other regions (26)(27)(28). Because many of the frontotemporal regions where SA appears to be most sensitive to BW variation within MZ twins have been separately implicated in multiple common psychiatric disorders (42,43), our data also propose a potential neurodevelopmental mechanism for the observed association between normative BW variation in fullterm pregnancies and later risk for psychopathology (7).…”

Section: Modeling Prenatal Environmental Influences On Brain Developmentmentioning

confidence: 55%

“…Environmentally determined disturbances of such early processes could well have behaviorally relevant consequences for cortical development throughout the lifespan (25), which may be accompanied by neuroanatomical alterations detectable by in vivo neuroimaging. Prefrontal cortices are particularly salient in this regard given their protracted maturational course (26)(27)(28) and involvement in multiple domains of higher cognition. To provide a detailed picture of the relationship between BW variation and postnatal cortical development, we used "surface-based morphometry," to measure three distinct morphometric properties of the cortical sheet from sMRI: cortical volume (CV) and its two sole determinants [mean cortical thickness (CT) and total cortical surface area (SA)].…”

mentioning

confidence: 99%

Prenatal growth in humans and postnatal brain maturation into late adolescence

Raznahan

Greenstein²,

Lee³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

180

179

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Prenatal life encompasses a critical phase of human brain development, but neurodevelopmental consequences of normative differences in prenatal growth among full-term pregnancies remain largely uncharted. Here, we combine the power of a withinmonozygotic twin study design with longitudinal neuroimaging methods that parse dissociable components of structural brain development between ages 3 and 30 y, to show that subtle variations of the in utero environment, as indexed by mild birth weight (BW) variation within monozygotic pairs, are accompanied by statistically significant (i) differences in postnatal intelligence quotient (IQ) and (ii) alterations of brain anatomy that persist at least into late adolescence. Greater BW within the normal range confers a sustained and generalized increase in brain volume, which in the cortical sheet, is specifically driven by altered surface area rather than cortical thickness. Surface area is maximally sensitive to BW variation within cortical regions implicated in the biology of several mental disorders, the risk for which is modified by normative BW variation. We complement this near-experimental test of prenatal environmental influences on human brain development by replicating anatomical findings in dizygotic twins and unrelated singletons. Thus, using over 1,000 brain scans, across three independent samples, we link subtle differences in prenatal growth, within ranges seen among the majority of human pregnancies, to protracted surface area alterations, that preferentially impact later-maturing associative cortices important for higher cognition. By mapping the sensitivity of postnatal human brain development to prenatal influences, our findings underline the potency of in utero life in shaping postnatal outcomes of neuroscientific and public health importance.P renatal life encompasses a foundational and universally critical phase of human brain development. Consequently, research aimed at understanding how prenatal influences play out in later life cannot only illuminate mechanisms of fundamental importance to basic developmental neuroscience, but may also have public health implications.Exquisite sensitivity of the developing brain to prenatal environmental insults has been well established through experimental animal models (1). In humans, where experimental approaches are not feasible, numerous observational studies have linked frank insults during prenatal life [as indexed by premature delivery (2); abnormally low birth weight for gestational age (3); and maternal exposure to radiation (4) or starvation (5)], to altered postnatal brain development. However, by virtue of their relative rarity, such frank prenatal insults may be less impactful at the population level than more subtle variations of the in utero environment occurring among the uncomplicated pregnancies from which most people are born (6). Evidence that subtle alterations of the prenatal environment may have meaningful consequences for postnatal development in humans can be found in large-scale epidemiolog...

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“…In support of this hypothesis, it was recently shown that some, but not all, gene expression changes taking place during human postnatal prefrontal cortex (PFC) development showed timing differences relative to chimpanzees and macaques (Somel et al 2009). Although no specific mechanism associated with cognitive development was identified in that study, it reported that genes showing human-specific delays tended to be neuron-associated.…”

mentioning

confidence: 92%

Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques

Liu¹,

Somel²,

Tang³

et al. 2012

Genome Res.

Self Cite

218

216

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Over the course of ontogenesis, the human brain and human cognitive abilities develop in parallel, resulting in a phenotype strikingly distinct from that of other primates. Here, we used microarrays and RNA-sequencing to examine human-specific gene expression changes taking place during postnatal brain development in the prefrontal cortex and cerebellum of humans, chimpanzees, and rhesus macaques. We show that the most prominent human-specific expression change affects genes associated with synaptic functions and represents an extreme shift in the timing of synaptic development in the prefrontal cortex, but not the cerebellum. Consequently, peak expression of synaptic genes in the prefrontal cortex is shifted from <1 yr in chimpanzees and macaques to 5 yr in humans. This result was supported by protein expression profiles of synaptic density markers and by direct observation of synaptic density by electron microscopy. Mechanistically, the human-specific change in timing of synaptic development involves the MEF2A-mediated activity-dependent regulatory pathway. Evolutionarily, this change may have taken place after the split of the human and the Neanderthal lineages.

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Transcriptional neoteny in the human brain

Cited by 352 publications

References 34 publications

Extensive X-linked adaptive evolution in central chimpanzees

Extensive X-linked adaptive evolution in central chimpanzees

Prenatal growth in humans and postnatal brain maturation into late adolescence

Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques

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