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Tuesday, September 01, 2009

Human Y Chromosome Mutation Rates

One thing men are really good at is making mistakes—just ask any woman. When it comes to mutations we are ten times better than women at ensuring the evolution of the species.

Knowing the actual rate of mutation in humans—or any other species—is important for many reasons. For one thing, it tells us about the maximum possible rate of evolution. For another, it gives us an important clue about the differences between beneficial, detrimental, and neutral alleles.

It's a lot more difficult to measure mutation rates than you might imagine. In theory, you could sequence the genomes of hundreds of parents and their offspring and identify mutations that must have occurred in the germ lines of the parents. In practice, this is far too expensive and time-consuming and, besides, it will miss any severely detrimental mutations.

But let's say you did the experiment in spite of the time and money. If the measured mutation rate turned out to be close to the calculated value, then you could assume that most of the mutations were neutral. A few might be beneficial.

Another possibility is to measure the number of differences between two individuals who are separated by a large number of generations. In this case you are measuring the combined effect of mutation and the fixation of alleles in a population. This is what we do whenever we compare gene sequences from different species.

ResearchBlogging.orgAlleles can be fixed by natural selection or by random genetic drift. If most are fixed by natural selection (adaptation) then you'll learn very little about the overall mutation rate aside from a minimum estimate. That's because you don't know the fitness of every allele and how fast it became fixed in the population and you don't know how many mutations were detrimental or neutral, and what happened to them.

Calculating the rate of evolution in terms of nucleotide substitutions seems to give a value so high that many of the mutations must be neutral ones.

Motoo Kimura (1968)

However, you have a fighting chance if most mutations give rise to neutral alleles. In that case, the overall rate of fixation by random genetic drift is the same as the mutation rate [see: Random Genetic Drift and Population Size]. The data suggest that this is the correct scenario. When we compare individual genes from different species, the observed differences are consistent with the expected result if most of the differences are due to the fixation of neutral alleles by random genetic drift.

For the comparison between humans and chimpanzees, the estimated rates are remarkably consistent. They range from about 2 × 10-8 to about 5 × 10-8 mutations per nucleotide (base pair) per generation (Nachman, 2004; Britten, 2002). This agrees with the known error rate of DNA replication, which is about 10-10 per nucleotide per replication. Since there are about 400 DNA replications between the male zygote and mature sperm, this translates to 4 × 10-8 mutations per nucleotide per generation [see, Mutation Rates].

This is where men come in. There are many fewer cell divisions in the female line—about 30—so the egg contributes fewer mutations than the sperm. In fact, for most purposes we can ignore women in these calculations. Men have another big advantage. They have a Y chromosomes that's passed down directly from father to son and it doesn't recombine with any female chromosomes.1 You don't need to worry about fixation.

If you sequence Y chromosomes from related men you can get a direct estimate of the mutation rate provided most of the alleles are neutral. It's best to choose men who are distantly related since there won't be many differences between closely related men. Two sons, for example, are likely to have identical Y chromosomes.

Xue et al. (2009) did the experiment [Human mutation rate revealed]. They sequenced the Y chromosomes of two men who were separated by 13 generations. After eliminating repetitive regions, the relevant region of comparison was 10.15 × 106 nucleotides (base pairs, 10.15 Mb). The men differ at four confirmed sites. This gives a mutation rate of 3.0 × 10-8 per generation or 0.75 × 10-10 per nucleotide per DNA replication.

The agreement is remarkable. What this means is that we have a good handle on the mutation rate in humans and we have growing evidence that most mutations are neutral (i.e. most of our genome is junk).

1. This isn't strictly correct but you can ignore the small regions where recombination is possible.

Britten, R.J. (2002) Divergence between samples of chimpanzee and human DNA sequences is 5%, counting indels. Proc. Nat. Acad. Sci. USA 99:13633-13635. [doi: 10.1073/pnas.172510699]

Nachman, M.W. (2004) Haldane and the first estimates of the human mutation rate. J Genet. 83:231-233. [PubMed]

Xue, Y., Wang, Q., Long, Q., Ng, B.L., Swerdlow, H., Burton, J., Skuce, C., Taylor, R., Abdellah, Z., Zhao, Y.; Asan, Macarthur, D.G., Quail, M.A., Carter, N.P., Yang, H., Tyler-Smith, C. (2009) Human Y Chromosome Base-Substitution Mutation Rate Measured by Direct Sequencing in a Deep-Rooting Pedigree. Curr Biol. Aug 26. [Epub ahead of print] [doi: 10.1016/j.cub.2009.07.032]

Xue, Y., Wang, Q., Long, Q., Ng, B., Swerdlow, H., Burton, J., Skuce, C., Taylor, R., Abdellah, Z., & Zhao, Y. (2009). Human Y Chromosome Base-Substitution Mutation Rate Measured by Direct Sequencing in a Deep-Rooting Pedigree Current Biology DOI: 10.1016/j.cub.2009.07.032


Bjørn Østman said...

most mutations are neutral (i.e. most of our genome is junk).

That most mutations are neutral does not mean that most of the genome is junk. Neutrality at functional sites increases robustness through canalization.

Rosie Redfield said...

For a different perspective on male mutation rates, I suggest this paper:

Male mutation rates and the cost of sex for females. Nature 369:145-147 (1994)

Georgi Marinov said...
This comment has been removed by the author.
Georgi Marinov said...

I saw the paper a few days ago and earlier today I was thinking exactly about these issues.

It has occurred many time to me that the whole "debate" about evolution is so tragically far removed from the actual science, that we often focus more on fighting with lunatics than on reflecting on the implications of the science.

Because I highly doubt there are any people in the creationism/ID crowd that actually understand how much worse than what they are fighting against the neutral theory of molecular evolution really is (from their persepctive), and on how solid ground (both theoretically and in terms of support by the data) it is.

Of course, this only shows how ignorant they are, but it also shifts the focus away from the more productive discussions we could be having.

Bryan said...

The "Human Mutation Rate Revealed" like does not seem to be working.

The Other Jim said...

Should be

Their is some odd
text string in the middle of the link address that is disabling the link.

Anonymous said...

To add to what Bjørn said, the mutations might also appear neutral because they make a functional difference but it is too small to observe easily or to cause a significant selection pressure.

Suppose a human baby is born able to synthesise vitamin C. How would we know? Well, in theory it might go for a long time without eating any citrus fruits, and it wouldn't develop scurvy. OK, and how likely is that? Well, not likely. And would anyone report it? Probably not, they'd chalk it up to good luck.

So is that just "junk" ?

Bjørn Østman said...

So is that just "junk" ?

Obviously not.

More generally one could say that two alleles that code for different trait values may very well happen to result in equal fitness. Brown eyes vs. blue eyes in populations where there are plenty of both, for example.

Dave Carlson said...

Now somebody please correct me if I'm wrong, but doesn't the fact that there is redundancy in the third position of many codons mean that even functional dna sites (ie. those that are expressed and result in protein formation) can experience neutral mutations?

Anonymous said...

To Dave, yes... but this assumes there is no extreme codon bias in the organism in question. Strong codon bias may have an effect on translation of these "redundant" codons. Probably not an issue for mammalian Y chromosomes.

Anonymous said...

The meme, that most of our genome is junk, should have died in the 1970s. It appears that the human ability, to recirculate bad copies of an opinion, is quite resilient. Alternative splicing discoveries continue to leave the classic gene expression model behind. Go in peace and marginalize my introns no more.

Georgi Marinov said...

Then what are all those broken transposons doing in your genome?

BTW, not only is the claim that there is no junk DNA in human genome bogus, but a number of features of the human and other eukaryotic genomes are only explainable in the light of understanding the quantitative balance between selection and mutational processes (and how the latter can end up dominating the process under certain conditions which happen to be met in most eukaryotes).

Alternative splicing is a particularly bad example to use because while there might be advantage of having alternative isoforms of genes, this:

A) does not explain how introns arose initially
B) does not explain why we have so many of them compared to the number of functional alternative splicing events
C) does not explain why introns are so long in humans and so short in other species
D) does not explain why there are no introns in prokaryotes
E) does not explain a number of other peculiar features of the system in mammals and other eukaryotes

All of the above are only explainable by the neutral theory of molecular evolution

Alejandro Montenegro-Montero said...
This comment has been removed by the author.
Alejandro Montenegro-Montero said...

Hi Larry,

Very provocative post.
I selected it as one of my MolBio picks of the week at ResearchBlogging in my blog.
You can check my picks here:


John Ryskamp said...

I think you should find out more about Kimura as a constructivist mathematician. The question of the moment is:

where is the constructivist intervention in Kimura's argument?

As you will see from the paper below, historians are now approaching this question with respect to Darwin.

They will certainly start approaching it with regard to Kimura.

You definitely owe it to yourself to read A. Garciadiego, BERTRAND RUSSELL AND THE ORIGINS OF THE SET-THEORETIC 'PARADOXES.'

Kimura's mathematical orientation--indeed his whole rhetorical orientation--comes from Malecot, who got his approach from Borel.

Borel, along with Russell and Poincare, was one of the now-discredited purveyors of the "paradoxes" and they renewed the constructivist insistence that argumentation avoid "paradox" by containing an arbitrary insertion in the logic.

Hence the quesion posed about Kimura.

You are very, very out of touch with what is going on in theoretical biology. Hurry up and put yourself in touch with it.

Ryskamp, John Henry,Paradox, Natural Mathematics, Relativity and Twentieth-Century Ideas(June 17, 2008). Available at SSRN:

Larry Moran said...

John Ryskamp says,

You are very, very out of touch with what is going on in theoretical biology. Hurry up and put yourself in touch with it.

Who are you referring to? Your comment doesn't make any sense.

athel said...

Larry Moran said...
"John Ryskamp says,

" 'You are very, very out of touch with what is going on in theoretical biology. Hurry up and put yourself in touch with it.'

Who are you referring to? Your comment doesn't make any sense."

The things John Ryskamp says tend not to make very much sense, and he has an obsession with Motoo Kimura. It is quite revealing to read his "review" of Kimura's classic book at Amazon.

John Ryskamp said...


Unfortunately, the confused ideas and faulty understanding of Borel and a huge and pernicious influence on Malecot, and through him, on Kimura.

You don't understand Kimura as a constructivist--in fact, you don't know anything about his mathematical orientation, do you?

Just try to identify where Kimura makes his constructivist intervention in his argument.

Your own presumptuous constructivism is on the way out.