Dataset Information

Evolutionary conservation and divergence of the human brain transcriptome.

ABSTRACT:

Background

Mouse models have allowed for the direct interrogation of genetic effects on molecular, physiological, and behavioral brain phenotypes. However, it is unknown to what extent neurological or psychiatric traits may be human- or primate-specific and therefore which components can be faithfully recapitulated in mouse models.

Results

We compare conservation of co-expression in 116 independent data sets derived from human, mouse, and non-human primate representing more than 15,000 total samples. We observe greater changes occurring on the human lineage than mouse, and substantial regional variation that highlights cerebral cortex as the most diverged region. Glia, notably microglia, astrocytes, and oligodendrocytes are the most divergent cell type, three times more on average than neurons. We show that cis-regulatory sequence divergence explains a significant fraction of co-expression divergence. Moreover, protein coding sequence constraint parallels co-expression conservation, such that genes with loss of function intolerance are enriched in neuronal, rather than glial modules. We identify dozens of human neuropsychiatric and neurodegenerative disease risk genes, such as COMT, PSEN-1, LRRK2, SHANK3, and SNCA, with highly divergent co-expression between mouse and human and show that 3D human brain organoids recapitulate in vivo co-expression modules representing several human cell types.

Conclusions

We identify robust co-expression modules reflecting whole-brain and regional patterns of gene expression. Compared with those that represent basic metabolic processes, cell-type-specific modules, most prominently glial modules, are the most divergent between species. These data and analyses serve as a foundational resource to guide human disease modeling and its interpretation.

SUBMITTER: Pembroke WG

PROVIDER: S-EPMC7844938 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Evolutionary conservation and divergence of the human brain transcriptome.

Pembroke William G WG Hartl Christopher L CL Geschwind Daniel H DH

Genome biology 20210129 1

<h4>Background</h4>Mouse models have allowed for the direct interrogation of genetic effects on molecular, physiological, and behavioral brain phenotypes. However, it is unknown to what extent neurological or psychiatric traits may be human- or primate-specific and therefore which components can be faithfully recapitulated in mouse models.<h4>Results</h4>We compare conservation of co-expression in 116 independent data sets derived from human, mouse, and non-human primate representing more than 1 ...[more]

PMID: 33514394

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Project description:UnlabelledBackgroundActivity of the Transforming growth factor-? (TGF?) pathway is essential to the establishment of body axes and tissue differentiation in bilaterians. Orthologs for core pathway members have been found in all metazoans, but uncertain homology of the body axes and tissues patterned by these signals raises questions about the activities of these molecules across the metazoan tree. We focus on the principal canonical transduction proteins (R-Smads) of the TGF? pathway, which instruct both axial patterning and tissue differentiation in the developing embryo. We compare the activity of R-Smads from a cnidarian (Nematostella vectensis), an arthropod (Drosophila melanogaster), and a vertebrate (Xenopus laevis) in Xenopus embryonic assays.ResultsOverexpressing NvSmad1/5 ventralized Xenopus embryos when expressed in dorsal blastomeres, similar to the effects of Xenopus Smad1. However, NvSmad1/5 was less potent than XSmad1 in its ability to activate downstream target genes in Xenopus animal cap assays. NvSmad2/3 strongly induced general mesendodermal marker genes, but weakly induced ones involved in specifying the Spemann organizer. NvSmad2/3 was unable to induce a secondary trunk axis in Xenopus embryos, whereas the orthologs from Xenopus (XSmad2 and XSmad3) and Drosophila (dSmad2) were capable of doing so. Replacement of the NvSmad2/3 MH2 domain with the Xenopus XSmad2 MH2 slightly increased its inductive capability, but did not confer an ability to generate a secondary body axis.ConclusionsVertebrate and cnidarian Smad1/5 have similar axial patterning and induction activities, although NvSmad1/5 is less efficient than the vertebrate gene. We conclude that the activities of Smad1/5 orthologs have been largely conserved across Metazoa. NvSmad2/3 efficiently activates general mesendoderm markers, but is unable to induce vertebrate organizer-specific genes or to produce a secondary body axis in Xenopus. Orthologs dSmad2 and XSmad3 generate a secondary body axis, but activate only low expression of organizer-specific genes that are strongly induced by XSmad2. We suggest that in the vertebrate lineage, Smad2 has evolved a specialized role in the induction of the embryonic organizer. Given the high level of sequence identity between Smad orthologs, this work underscores the functional importance of the emergence and fixation of a few divergent amino acids among orthologs during evolution.

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Dataset Information

Evolutionary conservation and divergence of the human brain transcriptome.

Background

Results

Conclusions

Publications

Evolutionary conservation and divergence of the human brain transcriptome.

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