MicroRNA-Driven Developmental Remodeling in the Brain Distinguishes Humans from Other Primates

Download
2011-12-01
Somel, Mehmet
Tang, Lin
Yan, Zheng
Hu, Haiyang
Guo, Song
Jiang, Xi
Zhang, Xiaoyu
Xu, Guohua
Xie, Gangcai
Li, Na
Hu, Yuhui
Chen, Wei
Paeaebo, Svante
Khaitovich, Philipp
While multiple studies have reported the accelerated evolution of brain gene expression in the human lineage, the mechanisms underlying such changes are unknown. Here, we address this issue from a developmental perspective, by analyzing mRNA and microRNA (miRNA) expression in two brain regions within macaques, chimpanzees, and humans throughout their lifespan. We find that constitutive gene expression divergence (species differences independent of age) is comparable between humans and chimpanzees. However, humans display a 3-5 times faster evolutionary rate in divergence of developmental patterns, compared to chimpanzees. Such accelerated evolution of human brain developmental patterns (i) cannot be explained by life-history changes among species, (ii) is twice as pronounced in the prefrontal cortex than the cerebellum, (iii) preferentially affects neuron-related genes, and (iv) unlike constitutive divergence does not depend on cis-regulatory changes, but might be driven by human-specific changes in expression of trans-acting regulators. We show that developmental profiles of miRNAs, as well as their target genes, show the fastest rates of human-specific evolutionary change, and using a combination of computational and experimental methods, we identify miR-92a, miR-454, and miR-320b as possible regulators of human-specific neural development. Our results suggest that different mechanisms underlie adaptive and neutral transcriptome divergence, and that changes in the expression of a few key regulators may have been a major driving force behind rapid evolution of the human brain.

Suggestions

Molecular footprint of Medawar's mutation accumulation process in mammalian aging
Turan, Zeliha Gozde; Parvizi, Poorya; Donertas, Handan Melike; Tung, Jenny; Khaitovich, Philipp; Somel, Mehmet (2019-08-01)
Medawar's mutation accumulation hypothesis explains aging by the declining force of natural selection with age: Slightly deleterious germline mutations expressed in old age can drift to fixation and thereby lead to aging-related phenotypes. Although widely cited, empirical evidence for this hypothesis has remained limited. Here, we test one of its predictions that genes relatively highly expressed in old adults should be under weaker purifying selection than genes relatively highly expressed in young adults...
Gene expression reversal toward pre-adult levels in the aging human brain and age-related loss of cellular identity
Donertas, Handan Melike; İzgi, Hamit; Kamacioglu, Altug; He, Zhisong; Khaitovich, Philipp; Somel, Mehmet (2017-07-19)
It was previously reported that mRNA expression levels in the prefrontal cortex at old age start to resemble pre-adult levels. Such expression reversals could imply loss of cellular identity in the aging brain, and provide a link between aging-related molecular changes and functional decline. Here we analyzed 19 brain transcriptome age-series datasets, comprising 17 diverse brain regions, to investigate the ubiquity and functional properties of expression reversal in the human brain. Across all 19 datasets,...
MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain
Somel, Mehmet; Fu, Ning; Yan, Zheng; Hu, Hai Yang; Xu, Ying; Yuan, Yuan; Ning, Zhibin; Hu, Yuhui; Menzel, Corinna; Hu, Hao; Lachmann, Michael; Zeng, Rong; Chen, Wei; Khaitovich, Philipp (2010-09-01)
Changes in gene expression levels determine differentiation of tissues involved in development and are associated with functional decline in aging. Although development is tightly regulated, the transition between development and aging, as well as regulation of post-developmental changes, are not well understood. Here, we measured messenger RNA (mRNA), microRNA (miRNA), and protein expression in the prefrontal cortex of humans and rhesus macaques over the species' life spans. We find that few gene expressio...
Metabolic changes in schizophrenia and human brain evolution
Khaitovich, Philipp; Lockstone, Helen E.; Wayland, Matthew T.; Tsang, Tsz M.; Jayatilaka, Samantha D.; Guo, Arfu J.; Zhou, Jie; Somel, Mehmet; Harris, Laura W.; Holmes, Elaine; Paeaebo, Svante; Bahn, Sabine (2008-01-01)
Background: Despite decades of research, the molecular changes responsible for the evolution of human cognitive abilities remain unknown. Comparative evolutionary studies provide detailed information about DNA sequence and mRNA expression differences between humans and other primates but, in the absence of other information, it has proved very difficult to identify molecular pathways relevant to human cognition.
A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice
Enard, Wolfgang; et. al. (2009-05-29)
It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal...
Citation Formats
M. Somel et al., “MicroRNA-Driven Developmental Remodeling in the Brain Distinguishes Humans from Other Primates,” PLOS BIOLOGY, pp. 0–0, 2011, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/38592.