I finished reading the chimpanzee genome paper last night, and it is not an easily digestible piece of work. It's fairly technical genetics, and it's actually a bit of a hodge-podge, as you might expect given the multitude of authors and the immensity of the project. In many places where the results were particularly interesting, the authors also got very cautious and tentative, and quite rightly so: this is just the first step in a very difficult research program, and there aren't any simple, clear answers to be expected…not yet, if ever.

I'm not even going to try to present a narrative summary of the work. The best I can do is dole out some little tidbits that I thought were interesting.

• The sequence as a whole was obtained from a single specimen of Pan troglodytes. However, they also analyzed sequences from four other West African and three Central African chimps.
• Humans and chimps are much more alike than different. 29% of our proteins are identical, and the average protein differs by only two amino acids. The genome wide nucleotide divergence rate is 1.23% (it's higher in the Y chromosome, which seems to be a special case—see John Hawks).
• While single nucleotides are different in 1.23% of the genome, 3% differs because of insertions and deletions; that is, largish chunks of DNA that are missing in one species relative to the other, or that have been added in one. The authors estimate that there have been about 5 million insertions and deletions in the combined chimp and human lineages in the last 5-7 million years since they diverged.
• Most of the differences are the result of the fixation of neutral or slightly deleterious alleles.
• One common question is which differences are important; which genetic changes are responsible for the obvious differences between chimps and humans? Of the 13,454 human-chimp gene orthologues they examined, they identified 585 that have a high level on non-synonymous sequence changes, and examined their function, where known. If you were hoping for an obvious 'big brain' or 'hairy-limb' gene, you will be disappointed. What they found were genes involved in:
  • immune responses, for instance against malaria and tuberculosis
  • reproduction, protamines and semenogelins
  • olfaction
  That's what's important, humbling as it may be.
• A search by functional category for relative acceleration in the rate of non-synonymous substitutions did find one interesting difference: humans have a greater than expected difference in genes involved in transcription factor activity. This includes some homeotic genes. This suggests that there may have been important changes in developmental regulatory genes in the human lineage, but because the absolute number of nucleotide changes is small, the authors suggest some caution about overinterpreting this at this point.
• 36 human genes are not present at all in the chimp, and and additional 17 are partially deleted. There are also genes present in chimps that are missing or damaged in humans, but deficiencies in the gene models for chimps makes them more difficult to quantify. One very interesting example is caspase-12, an important enzyme in apoptosis, which triggers cell death in response to problems in calcium levels. Humans have a damaged copy of the gene, while that of chimps and mice is intact. Loss of function in mice leads to a failure of amyloid-induced neuronal cell death; this may be a gene that contributes to Alzheimer's disease in humans.
• Another interesting analysis was to compare human alleles associated with disease to the chimp orthologues. As it turns out, some alleles we consider 'bad', or disease-related, are the wild-type forms. For example, a form of the gene called PPARG that has a proline at position 12 is associated with a greater risk of type 2 diabetes in humans, but is the most common allele in chimps. That suggests that the diabetes-resistant form of PPARG is the recent adaptation, and that we may be seeing the ongoing spread of this allele in our population.
• The authors identified evidence of selective sweeps in human history. Alleles that are selectively successful can rise rapidly in frequency in a population. Because recombination in any one region is relatively rare, when that allele becomes fixed, the other alleles that happen to be in the gene locations around it will also be fixed in the population. This process reduces diversity and also increases the frequency of a whole set of hitchhiking alleles in that same region. Comparison with the chimpanzee genome as a baseline allowed the authors to pick out 6 regions in the human genome that exhibit all the signs of having been subject to a selective sweep within the last quarter million years. One of these regions contains both the FOXP2 gene, involved in speech, and the CFTR gene which, when defective, is responsible for cystic fibrosis.

After all that abstract genetics, the paper ends on this note:

Our close biological relatedness to chimpanzees not only allows unique insights into human biology, it also creates ethical obligations. Although the genome sequence was acquired without harm to chimpanzees, the availability of the sequence may increase pressure to use chimpanzees in experimentation. We strongly oppose reducing the protection of chimpanzees and instead advocate the policy positions suggested by an accompanying paper. Furthermore, the existence of chimpanzees and other great apes in their native habitats is increasingly threatened by human civilization. More effective policies are urgently needed to protect them in the wild. We hope that elaborating how few differences separate our species will broaden recognition of our duty to these extraordinary primates that stand as our siblings in the family of life.

Several other articles in this issue emphasize the fragility of the existing great ape populations, and make recommendations for preserving them. It would be an ironic legacy to leave to posterity—that we were the generation that learned so much about the biology of our closest cousins, and we were the generation that killed them all.

The Chimpanzee Sequencing and Analysis Consortium (2005) Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437:69-87.