Review - comparing genomes as texts:
In the last two posts in this series, we discussed what features we would expect to see in similar species if those species descended from a common ancestral population. Drawing again on our “copied book” analogy, we expect the following:
“Chapters” and “paragraphs” in the same order: closely related species should have large blocks of DNA sequence in the same order. These blocks may span entire chromosomes. Even if some rearrangements are present, the overall pattern should largely match between the two genomes.
“Sentences” and “words” that match each other: at the level of individual genes, we should see that they use the same (or nearly the same) DNA sequence, even when there is no biological necessity for them to do so.
“Typos” that may be shared between texts: if sequence changes (mutations) exist, we would expect them to be shared in some instances (if copied from a common ancestor) and unique in other cases (if they are new mutations that arose after two species separated).
In summary, the expectation is that genomes of species that share a common ancestral population will look like slightly modified copies of each other. As we saw previously, this expectation was easily met when comparing different fruit fly species. With this understanding in hand, we are now ready to explore the possibility that our own species arose through speciation events by making the same kinds of comparisons with other species.
Comparing primate genomes at the “chapter” level
The first line of evidence in favor of humans sharing ancestry with other forms of life is straightforward – there are other species that have a genome that is nearly identical to our own – the genomes found in great apes such as chimpanzees, gorillas and orangutans. Compared to our “book,” the “books” of these species match at the chapter and paragraph level – all three species have DNA sequences that have the same genes in the same basic order as we do. There are subtle differences, of course – blocks of sequence that have been rearranged through breakage and rejoining of chromosomes, as expected – but the overall pattern is clear. This large-scale match between our genome and the genomes of great apes has been known since the 1970s, when researchers began to compare the physical structure of ape and human chromosomes using light microscopes. For humans and chimpanzees, most chromosomes match precisely. In other words, the two genomes appear exactly as one would predict if in fact they are slightly modified copies of an ancestral genome. (For those interested in seeing the pattern for the entire human, chimpanzee, gorilla and orangutan genomes, you can refer to these figures (PDF) from a paper published in 1982.)
Despite the overwhelming identity between the structure of our genome and that of the great apes, the differences should be ones that can arise through known mechanisms if shared ancestry is the correct interpretation. For example, some human chromosomes have a region of their sequence that fails to line up with the corresponding chromosome in chimpanzees. When these chromosomes are stained using a dye that binds to DNA and are examined under a light microscope, the dye produces banding patterns that allows the chromosome sequences to be compared at the “chapter” level of organization:
Along their length, these two chromosomes match for the most part, but the region outlined in red does not. Closer inspection, however, reveals that even within this region, there is a match – but that the sequence is reversed between the two chromosomes. This pattern is one that is readily explained by what is known as a chromosome inversion event – a type of mutation where DNA breaks and rejoins at two places to “flip” a section of chromosome:
These types of mutations are fairly common, and have been observed many times in experimental organisms and humans (where an individual will have such a mutation on one of their chromosomes). As long as the breakpoints of the inversion do not destroy a needed gene or create some other problem, these sorts of mutations are relatively harmless to the individual that carries them. When comparing the human and chimpanzee genomes, there are several chromosomes that show evidence of inversions, and these contribute to the subtle differences between the two genomes.
The largest difference between humans and great apes at the chromosome level of organization is a match between one chromosome in the human genome (human chromosome 2) and two smaller chromosomes in great apes:
This difference is what gives humans a different number of chromosomes than chimpanzees – humans have 23 pairs of chromosomes (46 in total) while chimpanzees have 24 pairs (48 in total). This pattern immediately suggests one of two possibilities, if indeed humans and chimpanzees share a common ancestral population. The first option is that one chromosome broke apart into two chromosomes in one lineage but not the other. The second option is that two smaller chromosomes fused together to form one in one of the lineages. Recalling our “typo” analogy, we can represent these two options as unique events that alter an original “text.” In the first option, the original population has 46 chromosomes, and the lineage leading to chimpanzees has a chromosome splitting event.
The second option has the original population with 48 chromosomes, and a fusion event on the lineage leading to humans:
Both types of events are possible, so on the surface it is not possible to decide which is more likely. As we discussed previously when examining typos in copied books, the easiest way to determine what the original text was is to look at as many copies as possible. The other great apes (gorillas and orangutans) also have the two smaller chromosomes (total = 48), suggesting that this is the original structure that was present in the common ancestral population of humans and other great apes. To explain the pattern through chromosome splitting events, this rare event would have happened repeatedly in several lineages in exactly the same location:
Accordingly, the most parsimonious explanation is that human chromosome 2 resulted from a fusion event.
You might recall watching movies of cells dividing in high school biology class, complete with chromosomes being pulled around. Those chromosomes were being pulled apart towards the poles of the dividing cell using a special DNA sequence called a centromere. This sequence allows the cell’s machinery to grasp the chromosome and move it around. Every chromosome needs a centromere, or the cell won’t be able to pull it during cell division.
This observation makes a prediction: if indeed human chromosome 2 is the result of a fusion between two smaller chromosomes, it would have had two centromeres immediately after the fusion event. One of the centromeres would likely be rendered non-functional through mutation soon after, since two are redundant. Human chromosome 2 has only one active centromere, which lines up with the centromere of the smaller of the two chimpanzee chromosomes. When the genome project sequenced human chromosome 2, they found the mutated remains of a second centromere in precisely the spot one would predict it to be if in fact these chromosomes are modified copies of each other:
As an aside, we also now know that this fusion event predates the origin of our species, since the chromosome 2 fusion is present in the Denisovan hominids, a species more closely related to us than chimpanzees. This indicates that the fusion event is a “typo” shared between us and other closely related species. Recent work has also documented the events that shaped this region of our genome in exhaustive detail for those who desire more information.
Taken together, what we observe when comparing the overall structure of the human genome to other primates is that (a) our genomes do indeed have the features one would predict them to have if they are copies of a shared ancestral genome, and (b) the differences we do observe are easily accounted for by well-known mechanisms. These observations strongly support the hypothesis that our species arose through an evolutionary process.
In tomorrow’s post, we’ll delve past the “chapter” level of genome organization to see if the detailed sequence data of individual genes also supports this hypothesis.
Yunis, J.J. and O. Prakash. 1982. The origin of man: a chromosomal pictorial legacy. Science 215: 1525-1530.