Wednesday, June 15, 2011

I am a mutant and I am proud!

This post is about tracking the "origin" of human mutation and calculating it's rate!

In a scene in X-men 2,  a mother exclaim “this is all my fault” when discovering that her son is a mutant. The reply is “Actually , they discovered that it is the male that carries the mutant gene, so it is his fault”, refering to the father.

J.B.S. Haldane proposed in already in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane’s contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. We can explain it theoretically.

A woman’s eggs are created while she is a fetus inside her mothers womb. 50% of my blueprint originated from the time when my mum was “baking” inside her mother’s i.e. my grandmother’s womb. Once a girl reach puberty her eggs mature, but they were there all along. The meiosis took place when she was a feturs. Meiosis is the process that makes germ cells. It is a cell division that produces cells with half the gene content.
Men have meiosis all the time, they make new germ cells during their whole life cycle. Children that have elderly fathers have a higher risk to develop autism. The hypothesised cause has been the increased mutations found in sperms, as the cells producing them accumulate more and more mutations.
Men thus might be responsible for increasing the rate of mutations in humans. It is not  necessarliy bad. It increases the risk of some diseases yes. But it also increases the chance of survival. Genetic heterogenity is the basis for evolution. 
In this post I wrote about biological change constantly taking place in the body. Change is constant on every level in nature. That is why survival is partly dependent on plasticity and change. We are all mutants, although it is not expressing itself like in X-men.
Mitosis is the common cell division that produces two cells with the exact same gene content i.e. 46 chromosomes. But do the two cells have the EXACT same DNA? No.
Watson and Crick wrote, “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” The balance between correct and incorrect DNA synthesis is relevant to evolution of the species and to the health of the individual.

When a cell is going to divide it replicates it’s DNA i.e. it makes a copy. The protein that reads the mother strand and creates a daughter strand is called DNA polymerase. It is not 100% correct.  There are proofreading systems that correct errors/mutations (that might also be caused by ultraviolet light, chemicals, deamination of methylated cytosines etc.) but these are not 100% correct either. The system is slightly leaky. This is how mutations are caused.
(There are several ways that the genetic code can change, not just through the error of DNA polymerase.) It is the same process in mitosis as in meiosis.

Is it true that more mutations are inherited through the father?
Nature recently published the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. The work is extensive. And the paper reports;
“Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families”*
Thus the male germline contribution was responsible for the vast majority of mutations in one family as expected but not in the other. As always, science seems to need more data and larger cohorts. The study suggest considerable variation in mutation rates within and between families, which is really cool!

Why would we want to know more about mutational rates and how they are carried along the ancestral lines? One reason is that a more precise estimate of human mutational rates will help us understand evolution and help us understand how we could use DNA sequencing technology to increase knowledge in that field.

What is a mutation and what is genetic variation? I am myself a bit bewildered at this point, as scientists seem to use the word freely. Is mutation bad? Could be both. A buddist answer is that nothing is good or bad, it is what it is. The current environment decides what fits and does not fit.
One example is the cystic fibrosis gene. Cystic Fibrorsis (CF) a genetic disease that is too common in the European population for it to be there by chance. That means that at some point, to carry the gene gave a survival advantage. If you are homozygote (i.e. inherit the gene from both your mother and your father) you will die from bacterial infection as the lungs won’t be able to deal with the mucus production. It has been suggested that if you live in an environment where you are subjected to diseases that cause the body to secret fluid, people that were heterozygote for CF were better at keeping fluid in the body. They would have an advantage to survive in periods of dysentery.  

Another example showing that it is not necessary bad to have genetic variations/mutations is the famous 32 base deletion of CCR5. CCR5 is a chemokine receptor and it is one of the receptors that aids HIV uses to enter the cell. It confers resistance to HIV infection. This is common among people of nothern European descent at a higher degree than one would expect. The hypothesized explanation in this case is that people with the deletion had resistance to the bubonic plague (that took place in 1350 very approximately). This mutation is not present in Southern Africa and they never had the plague. Another theory suggests that the selective pressure was caused by smallpox.

So be a proud mutant, you might carry the survival of your offspring in those faulty genes!
And yes, I only wrote this post so that I could download images of Wolverine!


Galvani A, Slatkin M (2003). "Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele". Proc Natl Acad Sci USA 100 (25): 15276–9. doi:10.1073/pnas.2435085100. PMC 299980. PMID 14645720.

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