human mutation rate

[ikke]

I came across this article claiming people have about 100 to 200 mutations per generation. To me this seems high. Even if only 5% of the genome is functional this means on average the genome breaks in 5-10 places
http://news.bbc.co.uk/2/hi/8227442.stm

[Numsgil]

Keep in mind how many embryos that are fertilized never result in a viable pregnancy.  Not just miscarriages, but "pregnancies" of only a week or less that we never really know about.  So there's a bit of a survivor's bias.

Maybe there's also some intelligent mutation-ing going on.  Maybe some parts of the genome are allowed to mutate more than other parts.

[ikke]

Keep in mind how many embryos that are fertilized never result in a viable pregnancy. Not just miscarriages, but "pregnancies" of only a week or less that we never really know about.  So there's a bit of a survivor's bias.

Sure, this begins with the sperm's rat race to fertilize. But estimates of spontaneous abortions are only (only is used in terms of the 5-10 mutations in functional code) in the 10-25% range. With half the women pregnant within 3-4 months these numbers don't seem to add up. I have to admit I haven't done any math and probabilities are hard to estimate beyond the simple draw

Maybe there's also some intelligent mutation-ing going on.  Maybe some parts of the genome are allowed to mutate more than other parts.

For me this means either the code is non functional and already discounted in the 95% mutations in junk or it is redundant, with other code partly or entirely absorbing loss of functionality

[Billy]

Perhaps most genes are repeated many times to maximize their effect. If one gene is ruined, there would probably be little impact because it would only mean a small amount less of whatever protein the gene is supposed to encode.

[ikke]

I just did the quick math: assuming 150 mutations per generation and 95% of DNA non functional the probability of not having a single mutation in functional DNA is 1-.95^150 (assuming random spread of mutations through the DNA. This is a one in 2200 chance.

Maybe there's also some intelligent mutation-ing going on.  Maybe some parts of the genome are allowed to mutate more than other parts.

I just realised I omitted DNA correction mechanisms. They may have enormous impact on the probability of mutations occurring in functional vs in non functional DNA. This would invalidate my random spread mutations assumption.

[shvarz]

A mutation in a functional part of the genome (which is certainly bigger than 5%) will not necessarily affect the functionality. Chances are very high that it will remain neutral or have a very small effect (positive or negative) on fitness.

[ikke]

A mutation in a functional part of the genome (which is certainly bigger than 5%)

If the definition of functional gene means functional for the phenotype, the 5 % is a low estimate. (A large part of DNA are selfish genes, genes with no benefit to the organism but the genes are good in inserting copies of themselves.) Higher estimates of % lead to higher numbers of broken genes.

Chances are very high that it will remain neutral or have a very small effect (positive or negative) on fitness.

Common assumption is that most mutations are detrimental.

[shvarz]

It's a wrong assumption. It appeared back when the only way to see a mutation was to observe its effect on fitness (which is usually negative). It's quite fair to say that most mutations are either neutral or effectively neutral (their effect is smaller than the reciprocal of the effective population size, see Kimura et al.).

The protein-coding part of the genome is only about 1-2%. The functional part of the genome is significantly larger (probably on the order of 20-30%) and will include a whole bunch of regulatory sequences and genome-maintenance sequences, but mutations there are much more likely to be neutral than in the protein-coding part of the genome. The functionality of most of those elements just doesn't depend upon the exact sequence.

[ikke]

Even at the 1% (protein) code and 100 mutations level the chances of  being hit by a mutation is 1-(1-0.01)^100=63%. For 2% and 200 the number is 98%. I still say that mutations cannot have an equal occurrence across the genome.

[shvarz]

Well, they don't. There are fairly well-known biases in mutation rates, for example CpG sites are hot-spots with mutations happening about 10 times more likely there as in other places, but that's a completely different questions.