Human evolutionary genetics

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 implications and applications. Genetic data can provide important insight into human evolution.

Origin of apes

Biologists classify humans, along with only a few other species, as great apes (species in the family Hominidae). The Hominidae include two distinct species of chimpanzee (the bonobo, "Pan paniscus", and the common chimpanzee, "Pan troglodytes"), two species of gorillas (the western gorilla, "Gorilla gorilla", and the eastern gorilla, "Gorilla graueri"), and two species of orangutans (the Bornean orangutan, "Pongo pygmaeus", and the Sumatran orangutan, "Pongo abelii").

Apes, in turn, belong to the primates order (>400 species). Data from both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) indicates that primates belong to the group of Euarchontoglires, together with Rodentia, Lagomorpha, Dermoptera, and Scandentia.cite journal | author = Murphy, W.J.; Eizirik, E.; O'Brien, S.J.; Madsen, O.; Scally, M.; Douady, C.J.; Teeling, E.; Ryder, O.A.; Stanhope, M.J.; de Jong, W.W. & Springer, M.S. | year = 2001 | title = Resolution of the early placental mammal radiation using Bayesian phylogenetics | journal = Science | volume = 294 | issue = 5550 | pages = 2348–2351 | doi = 10.1126/science.1067179 | pmid = 11743200] This is further supported by Alu-like short interspersed nuclear elements (SINEs) which have been found only in members of the Euarchontoglires.cite journal | author = Kriegs, J.O.; Churakov, G.; Kiefmann, M.; Jordan, U.; Brosius, J. & Schmitz, J. | year = 2006 | title = Retroposed elements as archives for the evolutionary history of placental mammals | journal = PLoS Biol | volume = 4 | issue = 4 | pages = e91 | doi = 10.1371/journal.pbio.0040091]

Sequence divergence between humans and apes

The draft sequence of the common chimpanzee genome published in the summer 2005 showed the regions that are similar enough to be aligned with one another account for 2400 million of the human genome’s 3164.7 million basescite journal | author = The Chimpanzee Sequencing and Analysis Consortium | year = 2005 | title = Initial sequence of the chimpanzee genome and comparison with the human genome | journal = Nature | volume = 437 | issue = 1 September 2005 | pages = 69-87 | doi = 10.1038/nature04072] – that is, 75.8% of the genome. This 75.8% of the human genome is 1.23% different from the chimpanzee genome in single nucleotide polymorphismscite journal | author = The Chimpanzee Sequencing and Analysis Consortium | year = 2005 | title = Initial sequence of the chimpanzee genome and comparison with the human genome | journal = Nature | volume = 437 | issue = 1 September 2005 | pages = 69-87 | doi = 10.1038/nature04072] (changes of single DNA “letters” in the genome). Another type of difference, called indels (insertions/deletions) account for another ~3 % difference between the alignable sequencescite journal | author = The Chimpanzee Sequencing and Analysis Consortium | year = 2005 | title = Initial sequence of the chimpanzee genome and comparison with the human genome | journal = Nature | volume = 437 | issue = 1 September 2005 | pages = 69-87 | doi = 10.1038/nature04072] . In addition, variation in copy number of large segments (> 20 kb) of similar DNA sequence provides a further 2.7% difference between the two species cite journal | author = Cheng, Z.; Ventura, M.; She, X.; Khaitovich, P.; Graves, T.; Osoegawa, K.; Church, D; Pieter DeJong, P.; Wilson, R. K.; Paabo, S.; Rocchi, M & Eichler, E. E. | year = 2005 | title = A genome-wide comparison of recent chimpanzee and human segmental duplications | journal = Nature | volume = 437 | issue = 1 September 2005 | pages = 88-93 | doi = 10.1038/nature04000] . Hence the total similarity of the genomes could be as low as about 70%.

The figures above do not take into account differences in the organization of the alignable sequences within the genomes of humans and chimps. Short stretches of alignable sequence may be in very different orders and locations within the two genomes. At present we cannot fully assess the difference in structure of the two genomes, because the human genome was used as a scaffold when the chimpanzee draft genome was assembled. When genomes are sequenced, relatively short sequences of DNA are produced, and these sequences have to be fitted together like a jigsaw puzzle. This requires us to have multiple overlapping reads accurately assemble the overall sequence. The human genome sequence is relatively accurate, with 8 to 9-fold coverage, but the chimpanzee draft genome only has 3.6-fold coverage.cite journal | author = The Chimpanzee Sequencing and Analysis Consortium | year = 2005 | title = Initial sequence of the chimpanzee genome and comparison with the human genome | journal = Nature | volume = 437 | issue = 1 September 2005 | pages = 69-87 | doi = 10.1038/nature04072] The human genome was sequenced using a hierarchical shotgun method which can deal with duplications and difficult-to-assemble sequences better than the whole genome shotgun method that was used for the chimpanzee draft genome. The human genome was used as a template for the assembly of the draft chimpanzee genome, on the assumption that the two genomes would be similar.

Almost half of that 1.23% SNP change belongs to the human at 0.53%, whose genetic variance is lower 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 SNPs have a potential positive impact on human abilities, is between 0.01% and 0.02%. The bonobo is a sibling species of common chimpanzee and is genetically about as different from humans as are common 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.cite journal | author = Kaessmann, H.; Heissig, F.; von Haeseler, A. & Pääbo, S. | year = 1999 | title = DNA sequence variation in a non-coding region of low recombination on the human X chromosome | journal = Nat Genet | volume = 22 | issue = 1 | pages = 78–81 | doi = 10.1038/8785]

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.cite journal | author = Chimpanzee Sequencing & Analysis Consortium | year = 2005 | title = Initial sequence of the chimpanzee genome and comparison with the human genome | journal = Nature | volume = 437 | issue = 7055 | pages = 69–87 | doi = 10.1038/nature04072]

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. Five 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) preceding the speciation or partial admixture succeeding it?
*What were the specific events (including fusion of chromosomes 2a and 2b) prior to and subsequent to the separation?

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.cite journal | author = Sarich, V.M. & Wilson, A.C. | year = 1967 | title = Immunological time scale for hominid evolution | journal = Science | volume = 158 | issue = 805 | pages = 1200–1203 | doi = 10.1126/science.158.3805.1200 | pmid = 4964406] 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 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.cite journal | author = Yoder, A.D. & Yang, Z. | year = 2000 | title = Estimation of primate speciation dates using local molecular clocks | journal = Mol Biol Evol | volume = 17 | issue = 7 | pages = 1081–1090 | url = | pmid = 10889221] 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.cite journal | author = Takahata, N.; Satta, Y. & Klein, J. | year = 1995 | title = Divergence time and population size in the lineage leading to modern humans | journal = Theor Popul Biol | volume = 48 | issue = 2 | pages = 198–221 | doi = 10.1006/tpbi.1995.1026] 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. (see Toba catastrophe theory)

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.cite journal | author = Yang, Z. | year = 2002 | title = Likelihood and Bayes estimation of ancestral population sizes in hominoids using data from multiple loci | journal = Genetics | volume = 162 | issue = 4 | pages = 1811–1823 | url = | pmid = 12524351 | format = abstract page]

Genetic differences between humans and other great apes

The alignable sequences within 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).cite journal | author = Olson, M.V. | year = 1999 | title = When less is more: gene loss as an engine of evolutionary change | journal = Am J Hum Genet | volume = 64 | issue = 1 | pages = 18–23 | url = | doi = 10.1086/302219 | pmid = 9915938]

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.cite journal | author = Wang, X.; Grus, W.E. & Zhang, J. | year = 2006 | title = Gene losses during human origins | journal = PLoS Biol | volume = 4 | issue = 3 | pages = e52 | doi = 10.1371/journal.pbio.0040052]

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 (human body hair thinning). Interestingly, the gene loss apparently occurred in the recent human evolution (less than 240 000 years ago).cite journal | author = Winter, H.; Langbein, L.; Krawczak, M.; Cooper, D.N.; Suarez, L.F.J.; Rogers, M.A.; Praetzel, S.; Heidt, P.J. & Schweizer, J. | year = 2001 | title = Human type I hair keratin pseudogene phihHaA has functional orthologs in the chimpanzee and gorilla: evidence for recent inactivation of the human gene after the Pan-Homo divergence | journal = Hum Genet | volume = 108 | issue = 1 | pages = 37–42 | doi = 10.1007/s004390000439]

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 constraint on brain size in the genus "Homo".cite journal | author = Stedman, H.H.; Kozyak, B.W.; Nelson, A.; Thesier, D.M.; Su, L.T.; Low, D.W.; Bridges, C.R.; Shrager, J.B.; Purvis, N.M. & Mitchell, M.A. | year = 2004 | title = Myosin gene mutation correlates with anatomical changes in the human lineage | journal = Nature | volume = 428 | issue = 6981 | pages = 415–418 | doi = 10.1038/nature02358]

Another estimate for the loss of the MYH16 gene is 5.3 MYA, long before the "Homo" appeared.cite journal | author = Perry, G.H.; Verrelli, B.C. & Stone, A.C. | year = 2005 | title = Comparative analyses reveal a complex history of molecular evolution for human MYH16 | journal = Mol Biol Evol | volume = 22 | issue = 3 | pages = 379–382 | doi = 10.1093/molbev/msi004 | pmid = 15470226]

ee also

* ""
* Chromosome 2 (human)
* Chimpanzee genome project
*Genetic history of Europe
*Genetic history of South Asia


External links

* [ Human Ancestors May Have Interbred With Chimpanzees]

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