Genetica 118: 193–208, 2003. © 2003 Kluwer Academic Publishers. Printed in the Netherlands. 193 Birth of ‘human-specific’ genes during primate evolution Jean-Louis Nahon Institut de Pharmacologie Mol´ eculaire et Cellulaire, CNRS UMR 6097, 660 route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France (Phone: +33-4-93-95-77-54; Fax: +33-4-93-95-77-08; E-mail: nahonjl@ipmc.cnrs.fr) Key words: anthropoids, molecular evolution, primates, retroposition, segmental duplications Abstract Humans and other Anthropoids share very similar chromosome structure and genomic sequence as seen in the 98.5% homology at the DNA level between us and Great Apes. However, anatomical and behavioral traits distinguish Homo sapiens from his closest relatives. I review here several recent studies that address the issue by using different approaches: large-scale sequence comparison (first release) between human and chimpanzee, characterization of recent segmental duplications in the human genome and analysis of exemplary gene families. As a major breakthrough in the field, the heretical concept of ‘human-specific’ genes has recently received some supporting data. In addition, specific chromosomal regions have been mapped that display all the features of ‘gene nurseries’ and could have played a major role in gene innovation and speciation during primate evolution. A model is proposed that integrates all known molecular mechanisms that can create new genes in the human lineage. Introduction What makes us different at the genetic level from other primates and particularly from our closest relatives, the Great Apes? This central question in biology, with major consequences on our social life, ethical and philosophical perception of ourselves, has obsessed for decades and yet attracts many geneticists and evo- lutionary biologists. Genetic differences may lie at dif- ferent levels including gross alterations in cytogenetic architecture, local chromosomal rearrangements, gene family duplication, single gene modifications (creation or loss) and differences in gene transcription and al- ternative splicing of mRNA (reviewed by Gagneux & Varki, 2001). Using the R-banding technique in the 1970s, a very close organization of chromosome ban- ding with an identical euchromatin was revealed in the karyotypes of human and other primates (reviewed by Dutrillaux, 1979). Later, chromosome painting results not only confirmed the high degree of conservation of chromosomal synteny but also identified translocation and fission events that were genomic landmarks for the origin of Anthropoids (Müller et al., 2000; reviewed by Hacia, 2001). The widespread use of cloning and molecular biology techniques in the early 1980s gave a direct access to genomic sequences and allowed us to trace the evolutionary history in primates of single genes, or gene families such as the β-globin gene cluster (reviewed by Goodman, 1999). Fi- nally the completion of numerous whole-genome- sequencing projects culminated in February 2001 with the publication by public and private laboratories of a working draft sequence of the human genome (IHGSC, 2001; Venter et al., 2001). This paved the road for a Primate Genome Project (or Human Ge- nome Evolution Project) which was initially called for by McConkey and Goodman (1997) and is now underway with the recent release of the first gener- ation human–chimpanzee comparative genome map (Fujiyama et al., 2002). DNA sequence comparison at many different loci among human and African Great Apes revealed a strong similarity, close to 98.5% sequence identities (Fujiyama et al., 2002; reviewed in Hacia, 2001). Even higher percentage of amino acid sequence iden- tities was estimated in coding regions (99%). This led to the proposal that few novel genes are associ- ated with the ‘human-specific’ traits such as biped- ism and higher cognitive functions (Gibbons, 1998) and that marked differences should be found in the