If you've ever wondered what really sets humankind apart from the other apes, we have part of an answer: it's our responses to disease and cancer, and our testes. I guess that's not too surprising, since death and reproduction are the two big things that matter heavily in evolution.

The answer comes from an exercise in comparative genomics. With all the data available from the human genome project and the ongoing chimpanzee genome project, we can start comparing DNA sequences. One parameter that can be assayed is the frequency of synonymous changes in the DNA: these are changes in the nucleotide sequence that produce synonyms in the triplet code, and therefore cause no changes at all in the protein sequence. These changes represent a kind of steady background noise, the rate of random, neutral changes in the genome. Non-synonymous changes, on the other hand, do change the amino acid sequence of the resulting protein, and are presumed to be more likely to have some kind of effect on the phenotype. The ratio of nonsynonymous to synonymous nucleotide changes within a gene, d_N/d_S, is a measure of the history of selection for change in that gene. High d_N/d_S values mean there has been selection pressure for novel forms, while low d_N/d_S values mean selection has been working to conserve the sequence.

So here's the analysis: go through the list of human genes, find each one's homolog in the chimpanzee, compute the d_N/d_S ratio, and rank them in order. What you end up with is a list, with the genes that have experienced the strongest selection for new properties between the two species at the top. Note that you can't tell which of the two species has changed the most from their common ancestor from this analysis (although comparison with an outgroup can help with that), so all we know is which genes have diverged the most. If we have naive expectations, you might expect that humans have undergone selection for genes for wisdom and meat-eating, while chimps have been selected for poop-flinging genes and banana-loving, and we might look for genes for all of those functions appearing near the top of the list.

The answer is nothing so simple or congruent with our stereotypes, of course. Here is the list of the The Top 50 Genes Showing Evidence for Positive Selection between Humans and Chimpanzees

There's a lot of "unknowns" and presumed functions in that list, which reflects the fact that we still have a long way to go in comprehending the functions of the genes in the genome. Many of them, though, we can guess from their sequence (genes that are imbedded in the membrane, for instance, have characteristic hydrophobic regions), from homology with genes of similar sequence, or from where the gene is expressed—genes that are only active in the liver are not likely to have functions in the brain. Most of these genes have functions that are very obscure and abstract, and there simply isn't a "wisdom" gene anywhere in the genome. For some of the genes, I've found entries in the Online Mendelian Inheritance in Man database, and if you're interested, you can dig a little deeper to figure out what they do, but otherwise, I'll give you the general breakdown.

The main gene categories that show positive selection between chimps and humans are:

Immunity and defense genes. Chimpanzees and humans have diffent histories of disease and epidemics that have shaped their genes. We fight off (or die of) urban epidemics like cholera and typhus, while chimps have struggled with their own pathogens.

Spermatogenesis and cell death genes. It may be curious that these are lumped together, but they are related. There is extensive apoptosis during sperm formation—we may make a lot of little wrigglers, but the number that don't make it out of the testicle is greater still. Mutations that help sperm escape the apoptotic culling are selectively favored, and many of the cell-death genes that are high on this list are associated with sperm cell death. In addition, changes in sperm proteins can confer advantages in sperm competition and sex conflict, and can be involved in selection for reproductive isolation.

Cancer-related genes. These are genes involved in cell-cycle control and apoptosis and tumor suppression, and some of these genes also show overlap with spermatogenesis genes. Their representation high on this list may be partly due to their involvement in sperm generation, but also with the fact that controlling tumors is an advantageous thing.

But wait! What about the brain? Shouldn't there have been selection for major differences in the brain? Sorry, no, that doesn't seem to be the case.

Genes with their maximal expression in the brain do not have an excess tendency toward positive selection. In fact, genes expressed in the brain seem to be among the most conserved genes with the least evidence for positive selection. MWUs [Mann-Whitney U test], comparing genes with their maximal expression in the brain (83 genes) to all other genes, show that these genes tend to have significantly higher p-values of the likelihood ratio test for positive selection (p = 0.035), indicating high levels of selective constraint. Genes that are expressed in the brain at a level of twice the expression level found in blood show an even stronger tendency toward avoidance of positive selection (p = 0.0002). Although studies of gene expression in the brain tissue are complicated by low-abundance transcripts and heterogeneous specialized brain regions, the overall evidence points toward a deficiency of positively, or fast evolving, genes among those expressed in the brain. The causes for the cognitive differences may instead be sought in adaptive changes in just a few genes, in changes in gene expression, or in changes in copy number and/or organization of genes relating to cognitive function.

Note that this doesn't mean there are no genetic changes in brain-related genes between humans and chimps, but that the differences may be in only a few genes that weren't picked up in this comparison, or that the differences may involve only subtle tweaks to patterns of gene expression.

Another possibility is that the changes are in developmental processes that are not exclusively affiliated with the formation of the nervous system. Genes that act early can have amplified effects late. One gene with such potential turned up in the assay, SCML1.

SCML1 has 16 substitutions (of which 15 are nonsynonymous) and zero polymorphisms. Such a pattern is consistent with repeated selective sweeps driving divergence between species, while eliminating variation within species. SCML1 is a repressor of expression of Hox genes and may play an important role in the control of embryonal development. This gene may be a prime candidate for explaining developmental differences between humans and chimpanzees.

SCML1 is a member of the Polycomb group of transcriptional repressors—it's a gene that fine-tunes the pattern of expression of Hox genes. Also amusingly, the name is short for "Sex Comb on Mid Leg". We have neither sex combs nor midlegs, but we've inherited this gene from our common ancestor with Drosophila.

In an odd coincidence, Carl Zimmer and I wrote about exactly the same article today, independently and without any communication between us. Now, unfortunately, you have the perfect opportunity to compare me with a professional writer.

Nielsen R, Bustamante C, Clark AG, Glanowski S, Sackton TB, Hubisz MJ, Fledel-Alon A, Tanenbaum DM, Civello D, White TJ, Sninsky JJ, Adams MD, Cargill M (2005) A Scan for Positively Selected Genes in the Genomes of Humans and Chimpanzees. PLoS Biol 3(6):170