| James Noonan | at 11:00 |
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Affiliation: Yale University
Host: Ivan Ovcharenko
Genome regulation and the evolution of human development.
The evolution of biological differences that distinguish humans from
other species – such as increased brain size, bipedalism, and the
dexterity of the human hand – likely required genome sequence changes
that altered development. Although it has long been thought that gene
regulatory changes have been a major driver of human evolution, evidence
for human-specific developmental regulatory functions has remained
elusive. We are investigating this fundamental question from two
perspectives: through the identification of developmental regulatory
sequences with human-specific functions, and by comparative analysis of
gene expression of human, rhesus macaque and mouse at the earliest
embryonic stages when biological differences emerge. Using mouse
transgenic reporter assays, we have identified a set of developmental
enhancers that are highly conserved across non-human vertebrate species
but show extreme human-specific sequence divergence (HACNSs). These
elements are located near genes that encode developmental transcription
factors such as EN1, GLI2, and RUNX1T1 and act as enhancers in the
developing brain, limb, and other structures. As a paradigmatic case we
are focusing on the detailed functional characterization of the most
rapidly evolving enhancer, HACNS1, in vivo. HACNS1 is located downstream
of GBX2, an essential developmental transcription factor, and drives
human-specific gene expression in the developing mouse limb, most
notably in the mouse equivalent of the primordial thumb at embryonic day
13.5. To test the hypothesis that HACNS1 has influenced the evolution of
human-specific limb development by altering the expression of nearby
genes, we are characterizing transgenic mice that express a Gbx2 cDNA
under the control of the HACNS1 enhancer. We are combining these
cis-regulatory studies with global transcriptome sequencing of
developing cortex and limb in human, rhesus and mouse. We are using
laser capture microdissection to recover cortical stem cells and
cortical plate neurons and have obtained robust, biologically meaningful
transcriptome profiles from these samples using RNA-sequencing on the
Illumina Genome Analyzer. These studies provide the foundation for an
integrated understanding of how changes in developmental regulatory
programs contributed to human evolution.
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