Human evolutionary genetics

Human evolutionary genetics studies how one human genome differs from the other, the evolutionary past that gave rise to it, and its current effects. Differences between genomes have anthropological, medical and forensic applications. Genetic data can provide important insight into human evolution.

Origin of Apes
Humans are great apes and are one of the species in the family Hominidae along with only a few other species. The Hominidae include two distinct species of the genus Pan: Pan paniscus (bonobos) and Pan troglodytes (chimpanzees), two species of gorillas (Gorilla gorilla and Gorilla graueri), and two species of orangutans (Pongo pygmaeus and Pongo abelii).

Apes in turn belong to the Primates order (>375 species). Data from both mitochondrial and nuclear DNA indicates that primates belong to the group of Euarchontoglires, together with Rodentia, Lagomorpha, Dermoptera, and Scandentia. This is further supported by Alu-like SINEs which have been found only in members of the Euarchontoglires.

Sequence divergence between humans and apes
The complete mapping of the chimp genome in the summer of 2005 showed the genetic difference with humans to be 1.23% (ie 98.77% similarity). Nature (journal) of September published the seminal paper on this comparison studies by 67 prominent scientists. Almost half of that 1.23% change belongs to the human at 0.53%, whose genetic varience is slower than a chimp, and just over half to the chimp at 0.7%. If we also take into account that 'random genetic drift' takes up the bulk of the 0.54% difference, then that percentage difference where genes have a potential positive impact on human abilities, is between 0.01% and 0.02%. The bonobo is a sibling species of chimpanzee and is genetically about as different from humans as are chimps.

The sequence divergence has generally the following pattern: Human-Chimp < Human-Gorilla << Human-Orangutan, highlighting the close kinship between humans and the African apes. Alu elements diverge quickly due to their high frequency of CpG dinucleotides which mutate roughly 10 times more often than the average nucleotide in the genome. The mutation rate is higher in the male germ line, therefore the divergence in the Y chromosome - which is inherited solely from the father - is higher than in autosomes. The X chromosome is inherited twice as often through the female germ line as through the male germ line and therefore shows slightly lower sequence divergence. The sequence divergence of the Xq13.3 region is surprisingly low between humans and chimpanzees.

Mutations altering the amino acid sequence of proteins (Ka) are the least common. In fact ~29% of all orthologous proteins are identical between human and chimpanzee. The typical protein differs by only two amino acids.

The measures of sequence divergence shown in the table only take the substitutional differences, for example from an A (adenine) to a G (guanine), into account. DNA sequences may however also differ by insertions and deletions (indels) of bases. These are usually stripped from the alignments before the calculation of sequence divergence is performed. The overall sequence divergence between humans and chimpanzees for example is close to 5% if indels would be included.

Speciation of humans and the African apes
The separation of humans from their closest relatives, the African apes (chimpanzees and gorillas) has been studied for more than a century and the amount of scientific publications on that subject is huge. Four major questions have been addressed:
 * Which apes are our closest ancestors?
 * When did the separations occur?
 * What was the effective population size of the common ancestor before the split?
 * Are there traces of population structure (subpopulations) proceeding the speciation or partial admixture succeeding it?

General observations
As discussed before, different parts of the genome show different sequence divergence between different hominoids. It has also been shown that the sequence divergence between DNA from humans and chimpanzees varies greatly. For example the sequence divergence varies between 0% to 2.66% between non-coding, non-repetitive genomic regions of humans and chimpanzees. Additionally gene trees, generated by comparative analysis of DNA segments, do not always fit the species tree. Summing up:
 * The sequence divergence varies significantly between humans, chimpanzees and gorillas.
 * For most DNA sequences, humans and chimpanzees appear to be most closely related, but some point to a human-gorilla or chimpanzee-gorilla clade.

Divergence times
The divergence time of humans from apes is of great interest. One of the first molecular studies, published in 1967 measured immunological distances (IDs) between different primates. Basically the study measured the strength of immunological response that an antigen from one species (human albumin) induces in the immune system of another species (human, chimpanzee, gorilla and Old World monkeys). Closely related species should have similar antigens and therefore weaker immunological response to each other's antigens. The immunological response of a species to its own antigens (e.g. human to human) was set to be 1. The ID between humans and gorillas was determined to be 1.09, that between humans and chimpanzees was determined as 1.14. However the distance to six different Old World monkeys was on average 2.46 indicating that the African apes are far closer related to humans than to monkeys. The authors consider the divergence time between Old World monkeys and hominoids to be 30 MYA (Million Years Ago - based on fossil data) and the immunological distance was considered to grow at a constant rate. They concluded that divergence time of humans and the African apes to be roughly ~5 MYA. That was a surprising result. Most scientists at that time thought that humans and great apes diverged much earlier (>15 MYA). The gorilla was, in ID terms, closer to human than to chimpanzees, however the difference was so slight that the trichotomy could not be resolved with certainty. Later studies based on molecular genetics were able to solve the trichotomy: chimpanzees are closer related to humans than to gorillas. However, it is interesting to note, that the divergence times estimated later, using much more sophisticated methods in molecular genetics do not differ much from the very first estimate in 1967.

Divergence times and ancestral effective population size


Current methods to determine divergence times use DNA sequence alignments and molecular clocks. Usually the molecular clock is calibrated assuming that the orangutan split from the African apes (including humans) 12-16 MYA. Some studies also include some old world monkeys and set the divergence time of them from hominoids to 25-30 MYA. Both calibration points are based on very little fossil data and have been criticized. If these dates are revised, the divergence times estimated from molecular data will change as well. However, the relative divergence times are unlikely to change. Even if we can't tell absolute divergence times exactly, we can be pretty sure that the divergence time between chimpanzees and humans is about sixfold shorter than between chimpanzees (or humans) and monkeys.

One study (Takahata et al, 1995) used 15 DNA sequence from different regions of the genome from human and chimpanzee and 7 DNA sequences from human, chimpanzee and gorilla. They determined that chimpanzees are more closely related to humans than gorillas. Using various statistical methods, they estimated the divergence time human-chimp to be 4.7 MYA and the divergence time between gorillas and humans (and chimps) to be 7.2 MYA. Additionally they estimated the effective population size of the common ancestor of humans and chimpanzees to be ~100,000. This was somewhat surprising since the present day effective population size of humans is estimate to be only ~10,000. If true that means that the human lineage would have experienced an immense decrease of its effective population size (and thus genetic diversity) in its evolution.



Another study (Chen & Li, 2001) sequenced 53 non-repetitive, intergenic DNA segments from a human, a chimpanzee, a gorilla, and orangutan. When the DNA sequences were concatenated to a single long sequence, the generated neighbor-joining tree supported the Homo-Pan clade with 100% bootstrap (that is that humans and chimpanzees are the closest related species of the four). When three species are fairly closely related to each other (like human, chimpanzee and gorilla), the trees obtained from DNA sequence data may not be congruent with the tree that represents the speciation (species tree). The shorter internodal time span (TIN) the more common are incongruent gene trees. The effective population size (Ne) of the internodal population determines how long genetic lineages are preserved in the population. A higher effective population size causes more incongruent gene trees. Therefore, if the internodal time span is known, the ancestral effective population size of the common ancestor of humans and chimpanzees can be calculated.

When each segment was analyzed individually, 31 supported the Homo-Pan clade, 10 supported the Homo-Gorilla clade, and 12 supported the Pan-Gorilla clade. Using the molecular clock the authors estimated that gorillas split up first 6.2-8.4 MYA and chimpanzees and humans split up 1.6-2.2 million years later (internodal time span) 4.6-6.2 MYA. The internodal time span is useful to estimate the ancestral effective population size of the common ancestor of humans and chimpanzees.

A parsimonious analysis revealed that 24 loci supported the Homo-Pan clade, 7 supported the Homo-Gorilla clade, 2 supported the Pan-Gorilla clade and 20 gave no resolution. Additionally they took 35 protein coding loci from databases. Of these 12 supported the Homo-Pan clade, 3 the Homo-Gorilla clade, 4 the Pan-Gorilla clade and 16 gave no resolution. Therefore only ~70% of the 52 loci that gave a resolution (33 intergenic, 19 protein coding) support the 'correct' species tree. From the fraction of loci which did not support the species tree and the internodal time span they estimated previously, the effective population of the common ancestor of humans and chimpanzees was estimated to be ~52 000 to 96 000. This value is not as high as that from the first study (Takahata), but still much higher than present day effective population size of humans.

A third study (Yang, 2002) used the same dataset that Chen and Li used but estimated the ancestral effective population of 'only' ~12,000 to 21,000, using a different statistical method.

Genetic differences between humans and great apes
The genomes of humans and chimpanzees differ by about 35 million single nucleotide substitutions. Additionally about 3% of the complete genomes differ by deletions, insertions and duplications.

Roughly one half of the changes occurred in the humans lineage. Only a very tiny fraction of those fixed differences gave rise to the different phenotypes of humans and chimpanzees and finding those is a great challenge. The vast majority of the differences is certainty neutral.

There are different ways though which molecular evolution may act. Usually protein evolution, gene loss, differential gene regulation and RNA evolution are thought to be involved. Probably all mechanisms have some share in the human evolution.

Gene loss
Many different mutations can inactivate a gene, but few will change its function in a specific way. Inactivation mutations will therefore be readily available for selection to act on. Gene loss could thus be a common mechanism of evolutionary adaptation (the "less-is-more" hypothesis).

80 genes that were specifically lost in the human lineage after separation from the last common ancestor with the chimpanzee. 36 of those were olfactory receptors. Genes involved in chemoreception and immune response are overrepresented.

Hair keratin gene KRTHAP1
A gene for type I hair keratin was lost in the human lineage. Keratins are a major component of hairs. Humans have still nine functional type I hair keratin genes but the loss of that particular gene might have had a dramatic effect. Interestingly, the gene loss apparently occurred in the recent human evolution (less than 240 000 years ago).

Myosin gene MYH16
Stedman et al. (2004) stated in an article in Nature, that The loss of the sarcomeric myosin gene MYH16 in the human lineage led to smaller masticatory muscles. They estimated that mutation that led to the inactivation (a two base pair deletion) occurred 2.4 MYA right before Homo ergaster/erectus showed up in Africa. This period that followed was marked by a strong increase in cranial capacity. The loss of that gene may have removed an evolutionary constrain on brain size in the genus Homo.

Another estimate for the loss of the MYH16 gene is 5.3 MYA, long before the Homo appeared.