It's even harder to grasp the idea of a molecular clock even though it's been around for fifty years. It was back in the 1960s that scientists like Emanual Margoliash noted that the rate of substitution of amino acids in every lineage was remarkably similar [The Modern Molecular Clock]. We now know that this is because the alleles are fixed by random genetic drift and that the rate of fixation by drift depends only on the mutation rate. It looks like the mutation rate is relatively constant in all lineages (bacteria, protozoa, plants, animals, etc.). This isn't a big shock since the vast majority of mutations are due to errors in DNA replication and the fundamental biochemistry of DNA replication and repair are similar in all species.
Calibrating the molecular clock involves relating the rate of substitutions to the number of years that have passed since two lineages diverged. This is a lot more difficult than it seems because it requires fossils that lie close to the node and accurate dates. Dan Graur and Bill Martin have likened this to Reading the entrails of chickens. But you don't need to calibrate the molecular clock in order to show that it exists.
This brings me to a paper that's just been published in Nature. The authors sequenced a cartilaginous fish, the elephant shark (Callorhimchus milii). This is interesting because the cartilaginous fish (Chrondrichthyes) and the bony vertebrates (Osteichthyse) are thought to have diverged about 450 million years ago (Myr). This is the first complete genome of a cartilaginous fish.
The genome is only about 1/3 the size of the human genome and it has about 19.000 protein-coding genes and hundreds of other genes that specify various RNAs. The authors constructed phylogenetic trees using a set of 699 genes that had orthologues in 12 other chordates. They confirmed that the cartilaginous fish (sharks) diverged early from the bony vertebrates, as expected.
But the big news—see the cover of Nature—is that the genome of the elephant shark is the slowest evolving vertebrate genome. Here's how the authors describe their result ..
Previous studies based on a few mitochondrial and nuclear protein-coding genes indicated that the nucleotide substitution rate in elasmobranchs is an order of magnitude lower than that in mammals16, 17. Using the genome-wide set of 699 orthologues, we estimated the molecular evolutionary rate of C. milii and compared it with other gnathostomes, with sea lamprey as the outgroup. Callorhinchus milii protein-coding genes have evolved significantly slower than all other vertebrates examined (P < 0.01 for all comparisons; Supplementary Tables VI.1–VI.3), including the coelacanth, which has been considered to be the slowest evolving bony vertebrate.
The human/shark relative rate test is shown on the left. There were 15,046 amino acid changes in the lineage leading to modern humans and 14,154 along the branch leading to the elephant shark. Thus, the rate of evolution of sharks is only 94% of the rate for the human genes. The shark sequences showed the lowest number of substitutions in every single rate test. The lowest was 85% for coelacanth.
A neutral tree based on fourfold-degenerate sites indicated that the low evolutionary rate is a reflection of the neutral nucleotide mutation rate, and confirmed that the neutral evolutionary rate of C. milii is the lowest (Fig. 2a).The difference here is larger than that determined by the relative rate tests but it's still nowhere near the "order of magnitude" difference reported in previous publications.
It looks like there are about 10% fewer changes that have been fixed in the elephant shark genome compared to many other vertebrates. This doesn't seem like a big number to me since we're looking at stochastic changes over hundreds of millions of years. I prefer to see this glass as half full—there is an approximate molecular clock. I also remain a bit skeptical of the results since there are many potential sources of error.
But what if the data actually reflects a true slowing down of evolution in elephant sharks? What does this mean?
The whole-genome analysis of C. milii, a holocephalan cartilaginous fish, shows that the C. milii genome is evolving significantly slower than other vertebrates, including the coelacanth, which is considered a ‘living fossil’. Although several physiological and environmental factors have been proposed to explain the interspecific variation in molecular evolutionary rates, the factors contributing to the lower evolutionary rate of C. milii are not known.The simplest explanation is that the biochemical mutation rate in elephant sharks is lower than in other species. In other words, DNA replication is more accurate in sharks or repair is more efficient. While we can't rule this out, it doesn't seem very likely.
Perhaps the explanation is much more complicated. Michael Lynch has some good arguments for a correlation between genome size and overall per nucleotide mutation rate per generation. Species with larger genomes tend to have larger mutation rates (Lynch, 2007, 2010). Note that the elephant shark genome is only about 1 Gb whereas mammalian genomes are about 3 Gb in size.
Lynch, M. (2007) The origins of genome architecture. Sinauer Associates, Inc., Sunderland, Massachusetts, USA
Lynch, M. (2010) Evolution of the mutation rate. Trends in Genetics 26:345-352. [doi: 10.1016/j.tig.2010.05.003]
Venkatesh, B. et al. (2014) Elephant shark genome provides unique insights into gnathostome evolution. Nature 505:174–179. [doi: 10.1038/nature12826]