Insights into Human Brain Development and Evolution from Transcriptome Analyses

Speaker: Ying Zhu , Yale, School of Medicine, Sestan Lab, Neurobiology

Date: Wednesday, April 23, 2014

Time: 9:00 AM to 10:00 AM Note: all times are in the Eastern Time Zone

Public: Yes

Location: Kiva/Patil, 32G-449, 32 Vassar St, Gates Tower, 4th floor

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Host: Manolis Kellis, MIT

Contact: Manolis Kellis, 617-253-2419, manoli@mit.edu

Relevant URL: http://medicine.yale.edu/lab/sestan/Research/index.aspx

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Reminders to: seminars@csail.mit.edu, talks@broad.mit.edu

Reminder Subject: TALK: Insights into Human Brain Development and Evolution from Transcriptome Analyses

Insights into Human Brain Development and Evolution from Transcriptome Analyses
Ying Zhu
Yale, School of Medicine, Sestan Lab, Neurobiology

Despite decades of studies, the molecular basis of human-specific brain features remains unclear. For my thesis work, I participated in studies aimed at profiling transcriptome landscape of human brains across time span and compared human transcriptome with that of non-human primates -- chimpanzees and rhesus macaques, respectively.

In the first part of the study, we analyzed transcriptome data from 16 brain regions comprising the cerebellar cortex, mediodorsal nucleus of the thalamus, striatum, amygdala, hippocampus, and 11 areas of the cerebral neocortex (also known as isocortex). We identified approximately 86% of protein-coding genes to be expressed using stringent criteria, and over 90% of these were differentially regulated at the whole transcript or exon level across regions and/or time. The majority of these spatiotemporal differences occurred before birth, followed by an increase in the similarity among regional transcriptomes during postnatal lifespan. Genes were organized into functionally distinct co-expression networks, and sex differences were present in gene expression and exon usage. Moreover, we demonstrated that the trajectories of gene markers well represented the trajectories of biological processes.

In the second part of the study, we developed a computational framework that integrates previous approaches with multiple filters to improve the accuracy of inter-species transcriptome comparisons. The implementation of this approach in comparing RNA-seq data of human, chimpanzee, and rhesus macaque brain transcriptomes has reduced the false discovery of differentially expressed genes, while keeping the false negative rate low.

Finally, we applied our pipeline to analyze mRNA and small RNA-seq data from 16 brain regions of humans, chimpanzees and rhesus macaques. We found substantial species differences, including 19.2% of expressed mRNAs and 17.5% of expressed miRNAs displaying human-specific expression. mRNAs and miRNAs were also organized into conserved and species-specific co-expression modules. Analyses of regional patterns, revealed that the striatum, followed by the medio-dorsal nucleus of the thalamus and certain neocortical areas, had the highest number of human-specific changes. Genes encoding dopamine synthesis enzymes were up-regulated, while genes encoding dopamine receptors were down-regulated in the human striatum. Furthermore, the co-expression networks of glutamate and GABA receptor genes were more conserved across species than those of other neurotransmitter systems.

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Created by Manolis Kellis at Sunday, April 20, 2014 at 7:39 PM.