Human Chromosome 2 – Evidence of Common Descent

chromosome

Since the mid-1800s, biologists have generally shared the belief that all living things descended from a single common ancestor. Based on fossil evidence and comparative anatomy, Charles Darwin proposed that humans and great apes, which including chimpanzees, gorillas, and orangutans, share a common ancestor that lived several million years ago. More recent research has propped up Darwin’s theory of common descent: genome analysis reveals the genetic difference between humans and chimps to be less than 2 percent. In other words, humans and chimps have DNA sequences that are greater than 98 percent similar.

After 1842, when Karl Wilhelm von Nägeli discovered structures in plant cells that came to be known as chromosomes, it was discovered that humans have 23 pairs of chromosomes.

In 1859, Charles Darwin published On the Origin of the Species which forever changed out view about how life is related to each other and the mechanism by which we gain biological diversity.

In 1869, Friedrich Miescher discovered DNA and in 1910, Russian biochemist Phoebus Levene (who became a naturalised American citizen after fleeing anti semiotic persecution) discovered the way RNA and DNA molecules are put together with nucleotide bases of adenine, thymine, (uracil for RNA), cytosine and guanine.

In 1953 English chemists Francis Crick and Rosalind Franklin, American chemist James Watson and New Zealander Maurice Wilkins discovered the double helix structure of DNA. Unfortunately, in 1962 Rosalind Franklin missed out on being one of the few women to win Nobel prizes and the Nobel Prize went to the three men. This was because she passed away and Nobel Prizes cannot be awarded posthumously.

 

© Quentin Blake 2009


While the emerging genetic similarity between human and ape strengthened Darwin’s theory, a significant, then-unexplained discrepancy remained. 

Humans have 23 pairs of chromosomes. However, all other members of Hominidae except humans have 24 pairs of chromosomes, including chimpanzees and bonobos, gorillas and orangutans. This is potentially a big problem for the theory of evolution. If chimpanzees and humans share a common ancestor, surely we must have the same number of chromosomes.

  
Throughout the years scientists have developed methods to look at chromosomes in ever more detail to try and find the reason behind this.

It wasn’t until 2003 when the Human Genome was finally sequenced and in 2005 when the Chimpanzee Genome Project was completed that scientists were able to solve this mystery.

PREDICTIONS – WHAT SHOULD WE FIND?

Before we reveal the discovery that led to discovering the reason for the discrepancy between human and other hominid  chromosome number, we need to look at some falsifiable scientific predictions.

Science works by making predictions based on the evidence that we have and then attempting to falsify those predictions by applying the scientific method.

Given that there are many independent lines of evidence that already support the conclusion that we share a common ancestor with other great apes, the differing number of chromosomes poses something of a conundrum: how is it that our species arrived at this specific chromosome number? To corroborate Darwin’s theory, scientists would need to find a valid explanation for why a chromosome pair is “missing” in humans that is present in apes. If we were to represent this “problem” on a phylogeny, or tree of relatedness, it would look something like this (not to scale):
  
  Image Credit: biologos.org 

Our closest living relatives, chimpanzees and bonobos, both have 48 chromosomes, as do all other great apes such as gorillas and orangutans. This pattern has one of two explanations, one of which is much more likely than the other. Either the common ancestor to these species had 48 chromosomes, and there was an event that reduced that number to 46 specifically on the lineage leading to humans (option A), or the common ancestor species had 46 chromosomes, and there were independent, repeated events that increased chromosome number in all other great ape species (option B). We can compare these options by placing the required event(s) on the phylogeny (again, not to scale):

  
 Image Credit: biologos.org 

It should be obvious that the option that requires the fewest events is the more likely one – in this case option A with an event that reduces chromosome number in the lineage leading to humans. The other option, that of repeated, independent events to increase chromosome number, remains a formal, but unlikely, possibility. Events that reduce chromosome number are not frequent occurrences, so Option A is more likely than Option B.

We can also find further support for Option A, because it predicts a specific type of event, namely one that reduces chromosome number. Since loss of a large amount of chromosomal material is almost always detrimental, we need an event that reduces chromosome number without losing information. One way for this to happen is for two chromosomes to fuse together and become one. Initially, this event would produce an individual with 47 chromosomes, where two different chromosomes get stuck together. Contrary to what is often assumed, this individual would be fertile and able to interbreed with the others in his or her population (who continue to have 48 chromosomes). In a small population, over time, two relatives who both have one copy of the fusion chromosome may mate and produce some progeny with two copies of the fused chromosome, or the first individuals with 46 chromosomes. Since either a 48-pair set or a 46-pair set is preferable for ease of cell division, this population will either eventually get rid of the fusion variant (the most likely outcome), or by chance will switch over completely to the “new” form, with everyone bearing 46 chromosome pairs. While not overly likely, this type of event is not especially rare in mammals, and we have observed this sort of thing happening within recorded human history in other species.

Some mammalian species even maintain distinct populations in the wild with differing chromosome numbers due to fusions, and these populations retain the ability to interbreed. (The ability of humans to interbreed with chimps is a very contentious issue for obvious ethical reasons, but it is likely to be impossible. Even more controversial is the ability to bring back clones of the Neanderthal DNA that we have found, Jurassic Park-style, and implant Neanderthal embryos in human surrogate mothers. I will discuss this ethical dilemma in a future blog post).

In conclusion, a fundamental part of the process by which science is done involves developing a testable prediction, also known as a hypothesis. Scientists have offered two possible explanations for the discrepancy: Either the common ancestor had 24 pairs, and humans carry a fused chromosome; or the ancestor had 23 pairs, and apes carry a split chromosome. If no evidence of either a fused or split chromosome could be found, the evidence for humans and the other great apes sharing a common ancestor would begin to show a slight crack. Scientists set to work analysing the human and chimpanzee genomes in order to either falsify or verify the hypothesis. Their focused research led them to find a mutation on one human chromosome that explained what had happened. In a moment,mwe’ll  look at how they identified this mutation.

AN IMPERFECT COPYING MECHANISM & TELOMERES

Before the Big Reveal, in order to fully understand the solution to the mystery, we need to explain something important about both the structure of DNA and the mechanism for copying it. I will try and explain it in the most comprehensible way possible.

http://www.youtube.com/watch?v=Hi4J15hBO6Y#t=07m32s

If you look at the above video from 7 minutes 32 seconds, you will observe the replication of DNA. A molecule known as helicase unwinds and splits the double helix of DNA, the two strands of DNA which are wound together. Another molecule known as DNA polymerase then builds up the two strands of the DNA to make a (usually) exact copy of the original DNA. This process is an elegant one, that natural selection has honed and perfected over millions of years, but it has a major flaw.

The phases through which chromosomes replicate, divide, shuffle, and recombine are imperfect, as DNA is subject to random mutations and an imperfect copying mechanism.

Because we have linear chromosomes, DNA replication is unable to reach the very end of the chromosomes. This is very similar to how a cleaner who starts at the door might mop the entire floor, mopping himself into a corner being  unable to mop the area where he is standing, or to how a painter might paint herself into a corner, and be unable to paint the area where she is standing.

  

The helicase and DNA polymerase copy the DNA faithfully until they reach the end of the chromosome. The DNA polymerase molecule is not able to copy the section directly under itself that it has grabbed onto, therefore lets go, leaving a short section on DNA u copied.

This means that the ‘daughter’ DNA strand is ever so slightly shorter than the ‘parent’ strand, and that each time a cell divides, the DNA gets slightly shorter and shorter, losing information.

In order to solve this problem, DNA has developed stretches of ‘nonsense’ DNA at the ends of the chromosomes which repeat the same sequence of nucleotide letters “TTAGGG” many thousands of times at each end of the chromosome meaning that the only information that is lost in the imperfect copying mechanism is non-coding “nonsense”. 

  

These telomeres, these stretches of DNA with repeating sequences of nonsensical information, allow the chromosomes and hence the cell, to divide many many times without losing important coding information. Telomeres are in many ways, very much like ‘shoelace aglets‘, the plastic ends which prevent the ends of shoelaces from falling apart. When the shoelace aglets wear out and fall off, the laces unravel and fray. Similarly, when the telomeres shorten, the chromosome becomes unstable and ceases to be able to copy itself faithfully.

image

Like shoelace aglets, telomeres cannot be infinitely long, so a result, cells can only divide a certain number of times before DNA loss prevents further faithful division. (This is known as the Hayflick limit). Incidentally, this is one of the reasons why we age and our cells finally die. If telomeres were infinite, we could hypothetically live forever and never die.

image

Scientists have been experimenting with extending telomeres, but unfortunately, when telomeres are too long, it results in cancerous cells which divide uncontrollably. It seems the ideal telomere length is a result of a trade off between immortality and cancer.

This article published in Nature magazine explains why we grow old and die:

  

CHROMOSOME 2 & INTERNAL TELOMERES PREDICTION 

In order for us to know whether option A or option B were correct, we needed to know about the detailed sequence of the DNA of both humans and at least one other hominid. In 2005, when both the human and chimpanzee genomes were in front of us, we were finally able to solve the mystery. 

In 2005, a peer-reviewed scientific journal published results of the tests. It turns out that chromosome 2, which is unique to the human lineage of evolution, emerged as a result of the head-to-head fusion of two ancestral chromosomes that remain separate in other primates. 

Chromosome 2 is the second largest human chromosome, spanning more than 243 million base pairs and representing almost 8% of the total DNA in cells. The fact that we have 23 chromosomes makes us something of an oddity among living great apes, all the rest of whom have 24 pairs of chromosomes (for a total of 48).

Three genetic indicators provide strong, if not conclusive, evidence of fusion.

  1. First, the banding (or dye pattern) of the single human chromosome 2 closely matches that of two separate chromosomes found in apes (chimp chromosome 2 and an extra chromosome that does not match any other human chromosome). 
  2. Second, a chromosome normally has one centromere, or central point at which a chromosome’s two identical strands are joined. Yet remnants of a second, presumably inactive centromere can be found on human chromosome 2.
  3. And third, whereas a normal chromosome has readily identifiable, repeating DNA sequences (of TTAGGG) called telomeres at both ends, human chromosome 2 also has telomere sequences not only at both ends but also in the middle. 

  
 How do we know that there is a fused telomere in the middle human of chromosome 2?

  

From this image above of several sequences of human DNA, you can see that the telomere at the end of the chromosome has the sequence TTAGGG repeated many times, and although the repeated sequences are not uniform in the fused telomere sequence (because of other point mutations which have taken place since the fusion event), nevertheless, right in the middle of the chromosome, you can clearly see TTAGGG repeated (imperfectly) many times followed closely by a repetition of the opposite sequence CCCTAA.

We can therefore see the exact point where the two chromosomes fused. Mystery solved! 

According to researcher J. W. IJdo, 

“We conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomere-telomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2.”

 

  

The most salient structural difference between human and chimpanzee chromosomes is that human chromosome 2 reveals itself through genetic analysis to have been derived from two smaller chromosomes in our common ancestor, which are also found in all of the other Great Apes, chimpanzees, bonobos, gorillas and orangutans.

Human chromosome 2 therefore presents very strong evidence in favour of the common descent of humans and other apes in the form of definitive evidence of an end-to-end fusion of two ancestral chromosomes.

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