Abstract
Changes in developmental regulatory programs drive both disease and phenotypic differences among species. Linking human-specific traits to alterations in development is challenging, because we have lacked the tools to assay and manipulate regulatory networks in human and primate embryonic cells. This field was transformed by the sequencing of hundreds of genomes--human and non-human--that can be compared to discover the regulatory machinery of genes involved in human development. This approach has identified thousands of human-specific genome alterations in developmental genes and their regulatory regions. With recent advances in stem cell techniques, genome engineering, and genomics, we can now test these sequences for effects on developmental gene regulation and downstream phenotypes in human cells and tissues.
Highlights
Humans differ from chimpanzees, our closest living relatives, and other mammals in a variety of traits, including disease susceptibilities
The fossil record shows that some human traits, such as the pelvic morphology associated with upright walking (Harcourt-Smith et al, 2004), evolved around the time of divergence from our common ancestor with chimpanzees about six million years ago
Single nucleotide substitutions The human and chimpanzee genomes differ by >30 million single nucleotide substitutions (1.2% of the human genome), and slightly less than half of these occurred on the human lineage, mostly in non-coding DNA (The Chimpanzee Sequencing and Analysis Consortium, 2005)
Summary
Humans differ from chimpanzees, our closest living relatives, and other mammals in a variety of traits, including disease susceptibilities. Fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) arrays identified >60 human-specific segmental duplications (Goidts et al, 2006; Jauch et al, 1992; Wilson et al, 2006) and 152 genes displaying copy number variation (Armengol et al, 2010; Fortna et al, 2004) Many of these structural variants have altered gene expression or downstream phenotypes in humans. Indels Human-specific duplications and deletions of DNA shorter than one kilobase are numerous and comprise ∼3.5% of the human genome, most of which is non-coding (Britten, 2002; The Chimpanzee Sequencing and Analysis Consortium, 2005; Varki and Altheide, 2005) They contribute more base pairs to human-chimp differences than do individual DNA substitutions (see below), albeit fewer than larger chromosomal alterations. Evolutionary advantages of having more AMY1 copies is not clear, but may be related to accessing novel high-energy food sources (e.g. tubers)
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