Identification of large-scale human-specific copy number differences by inter-species array comparative genomic hybridization

Abstract

Copy number differences (CNDs), and the concomitant differences in gene number, have contributed significantly to the genomic divergence between humans and other primates. To assess its relative importance, the genomes of human, common chimpanzee, bonobo, gorilla, orangutan and macaque were compared by comparative genomic hybridization using a high-resolution human BAC array (aCGH). In an attempt to avoid potential interference from frequent intra-species polymorphism, pooled DNA samples were used from each species. A total of 322 sites of large-scale inter-species CND were identified. Most CNDs were lineage-specific but frequencies differed considerably between the lineages; the highest CND frequency among hominoids was observed in gorilla. The conserved nature of the orangutan genome has already been noted by karyotypic studies and our findings suggest that this degree of conservation may extend to the sub-microscopic level. Of the 322 CND sites identified, 14 human lineage-specific gains were observed. Most of these human-specific copy number gains span regions previously identified as segmental duplications (SDs) and our study demonstrates that SDs are major sites of CND between the genomes of humans and other primates. Four of the human-specific CNDs detected by aCGH map close to the breakpoints of human-specific karyotypic changes [e.g., the human-specific inversion of chromosome 1 and the polymorphic inversion inv(2)(p11.2q13)], suggesting that human-specific duplications may have predisposed to chromosomal rearrangement. The association of human-specific copy number gains with chromosomal breakpoints emphasizes their potential importance in mediating karyotypic evolution as well as in promoting human genomic diversity.

Copy number variation: New insights in genome diversity

“…Gene duplication is known to be an important long-term evolutionary force, and as suggested for different strains of mice, some lineage-specific copy number differences may contribute to the phenotypic differences among taxa, including those that distinguish humans from chimpanzees and bonobos (Pan paniscus) (Ohno 1970;Samonte and Eichler 2002;Locke et al 2003;Shaw and Lupski 2004;Feuk et al 2005;Newman et al 2005;Goidts et al 2006;Wilson et al 2006). Two studies have presented data suggesting that the fixation rate of unique duplications and genecontaining duplications on the human lineage was elevated relative to that of the chimpanzee (Fortna et al 2004;Cheng et al 2005).…”

Copy number variation and evolution in humans and chimpanzees

“…In contrast to singlenucleotide polymorphism data, for which population genetic tools were traditionally developed and matured in model organism studies (especially Drosophila), CNV research has thus far focused predominantly on humans. Moreover, we have yet to examine fully patterns of within-species CNVs and betweenspecies copy number differences (CNDs) (e.g., Locke et al 2003;Fortna et al 2004;Demuth et al 2006;Goidts et al 2006;Wilson et al 2006;Dumas et al 2007) together under an evolutionary framework.…”

Gene copy number variation spanning 60 million years of human and primate evolution

“…More recently it has been used to look at normal variations both within (Iafrate et al 2004;Sebat et al 2004) and between species (Fortna et al 2004;Goidts et al 2006;Wilson et al 2006) and has become one of the most widely used strategies for genome-wide studies of copy number variation. We previously reported the first genome-wide (and gene-based) cross-species aCGH study of human and great ape lineages, using full-insert cDNA arrays to detect lineage-specific (LS) gene copy number variations (Fortna et al 2004).…”