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Abstract
Development progresses through a sequence of cellular identities which are determined by the activities of networks of transcription factor genes. Alterations in cis-regulatory elements of these genes play a major role in evolutionary change, but little is known about the mechanisms responsible for maintaining conserved patterns of gene expression. We have studied the evolution of cis-regulatory mechanisms controlling the SCL gene, which encodes a key transcriptional regulator of blood, vasculature, and brain development and exhibits conserved function and pattern of expression throughout vertebrate evolution. SCL cis-regulatory elements are conserved between frog and chicken but accrued alterations at an accelerated rate between 310 and 200 million years ago, with subsequent fixation of a new cis-regulatory pattern at the beginning of the mammalian radiation. As a consequence, orthologous elements shared by mammals and lower vertebrates exhibit functional differences and binding site turnover between widely separated cis-regulatory modules. However, the net effect of these alterations is constancy of overall regulatory inputs and of expression pattern. Our data demonstrate remarkable cis-regulatory remodelling across the SCL locus and indicate that stable patterns of expression can mask extensive regulatory change. These insights illuminate our understanding of vertebrate evolution.
We thank Michelle Hammett, Jacinta Carter, and Sandie Piltz for generating transgenic mice, Amy Chaney and Rebecca Kelley for sectioning embryos, and Pat Simpson and James C. Smith for constructive comments on the manuscript. We are also indebted to Jane Rogers, Darren Grafham, and the entire sequencing teams 40 and 47 at the Wellcome Trust Sanger Institute, Chris Drake for the chicken anti-SCL antibody, and Atsushi Miyawaki for the Venus/pSC2 construct.
Work in our laboratories is supported by the Wellcome Trust, the Leukemia Research Fund, the Medical Research Council, and the Leukemia and Lymphoma Society of America.