A project on gene expression during primate development is urgently needed

Following the recent decision by the National Human Genome Research Institute (NHGRI) to assign'high priority' to sequencing the chimpanzee genome, it is appropriate to consider what is needed to understand the functional significance of the sequence differences that will be identified. One of the lessons learned from the Human Genome Project is that the sequence of a gene is only the first step toward understanding its spatial and temporal expression patterns, and the need for functional interpretation of human–chimpanzee genomic differences will be inescapable.Although there are considerable ethical and practical concerns, studying gene expression in chimpanzees is not completely impractical. Microarray analysis has already been done on cultured fibroblasts (J. Hacia, pers. commun.), and if stem cell lines can ever be established for chimps, many other cell types could become accessible to investigators. Biopsies are potentially available from several tissues when apes are anesthetized for routine veterinary care in zoos and animal colonies, and postmortem samples provide a full range of tissues. Enard et al. recently used such samples to examine gene expression in human and chimpanzee brains and livers with microarray analysis [1xIntra- and interspecific variation in primate gene expression patterns. Enard, W. et al. Science. 2002; 296: 340–343Crossref | PubMed | Scopus (564)See all References[1].However, many of the genomic sequence differences between humans and chimpanzees will not be susceptible to functional interpretation by studies on animals or cultured cells. The most obvious gap in our knowledge will be embryonic development. The first third of prenatal development is when the basic aspects of body form and all the major organs are established. The inescapable necessity of studying gene expression during human development to achieve the goals of the Human Genome Project was clearly presented by Strachan et al. [2xA new dimension for the human genome project: towards comprehensive expression maps. Strachan, T. et al. Nat. Genet. 1997; 16: 126–132Crossref | PubMed | Scopus (53)See all References[2]. Such information is a biomedical necessity, because so many genetic malfunctions affect prenatal development. It is equally necessary if we want to understand why humans are not apes.It is imperative that databases on gene expression during development be established concomitantly with genome sequencing projects. Such work is already being carried out by groups in the United Kingdom (Institute of Human Genetics, University of Newcastle, UK, and MRC Human Genetics Unit, Edinburgh, UK) for human (http://www.ncl.ac.uk/ihg/EADHB/mainpage.htm), in connection with the NIH-sponsored Human Brain Project (http://www.nimh.nih.gov/neuroinformatics/index.cfm). A similar study is underway for mouse (http://genex.hgu.mrc.ac.uk), as a collaboration between The Jackson Laboratory (Bar Harbor, ME, USA) and the Medical Research Council's Human Genetics Unit (Edinburgh, UK). Both groups are creating 3D anatomical reconstructions of many developmental stages, using the technique of optical projection tomography [3xOptical projection tomography as a tool for 3D microscopy and gene expression studies. Sharpe, J. et al. Science. 2002; 296: 541–545Crossref | PubMed | Scopus (687)See all References[3], and gene expression data will be mapped onto those 3D images as the information becomes available.The next step should be creation of a Primate Gene Expression During Development Project (PRIGEDD for short). Two types of study should be conducted: first, global analysis of gene expression at various embryonic stages and in various parts of the embryo using microarray analysis, and second, in situ analysis of specific gene expression in histological sections from various developmental stages. The first developmental gene expression analysis on a nonhuman primate should be on the rhesus macaque (Macaca mulatta), because it has been used in more physiological and behavioral studies than any other monkey (more than 22 500 references in Medline) and because it is readily available for research. Although NHGRI assigned sequencing of the rhesus genome only'moderate priority', this is a temporary problem, because progress of the Chimpanzee Genome Project will raise so many functional questions that the rhesus genome will have to be sequenced eventually.Is it feasible to consider obtaining developmental gene expression profiles on chimpanzees? Experimentation on chimpanzees is very expensive, and formidable ethical obstacles also exist. Although surgical termination of pregnancy to obtain first trimester embryos would not cause lasting physical harm to female chimps, the procedure would obviously not be in the apes' best interests, and animal rights activists would surely object strenuously. Whether our human need to understand our own evolution and our unique genetic functions will override chimpanzee rights is an issue that will be hotly debated for a long time.In any case, we can learn so much by comparing gene expression in rhesus monkey development with human and mouse development that the PRIGEDD project is easily justifiable on that basis alone. As the rhesus and human studies progress, some fundamentally important questions that cannot be answered without studying chimpanzee development are likely to arise. Those questions can be dealt with when that time comes.