Varki et al. (2008) on Human Uniqueness in Nature Reviews Genetics

From the paper:

Remarkable similarities of known human and chimpanzee protein sequences initially led to the suggestion that significant differences might be primarily in gene and protein expression, rather than protein structure6. Further analysis of alignable non-coding sequences affirmed this ~1% difference. However, the subsequent identification of non-alignable sequences that were due to small- and large-scale segmental deletions and duplications21–23 showed that the overall difference between the two genomes is actually ~4%.

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Why are coding-sequence changes in brain genes under a larger degree of purifying selection than in other tissues? The reason for this is not immediately clear as a wide range of brain function supports life to reproductive age in humans.

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But this notion, which is based on single nucleotide changes in protein-coding sequence, has to be reconciled with the CNV data, because CNVs in humans seem to be enriched among genes involved in neurodevelopmental processes.

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However, connecting such genes involved in disorders of human cognition to the specific phenotypes undergoing selection poses significant challenges. A salient example involves two genes, abnormal spindle homologue microcephaly associated (ASPM) and microcephalin (MCPH1), the adaptive evolution of these genes in humans was claimed to be related to normal variation in brain size, on the basis of the fact that Mendelian mutations in each results in microcephaly in humans152,153. However, not all investigators have found evidence for the adaptive evolution of ASPM or MCPH1 (ref. 154). Also, neither gene is likely to contribute significantly
to normal variation in human brain size155. This case illustrates the challenges of interpreting genetic data in the face of complex phenotypes, especially those that are poorly understood.

Nature Reviews Genetics doi:10.1038/nrg2428

Human uniqueness: genome interactions with environment, behaviour and culture

Ajit Varki et al.

Abstract

What makes us human? Specialists in each discipline respond through the lens of their own expertise. In fact, 'anthropogeny' (explaining the origin of humans) requires a transdisciplinary approach that eschews such barriers. Here we take a genomic and genetic perspective towards molecular variation, explore systems analysis of gene expression and discuss an organ-systems approach. Rejecting any 'genes versus environment' dichotomy, we then consider genome interactions with environment, behaviour and culture, finally speculating that aspects of human uniqueness arose because of a primate evolutionary trend towards increasing and irreversible dependence on learned behaviours and culture — perhaps relaxing allowable thresholds for large-scale genomic diversity.

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