Tuesday, July 16, 2013

How many mutations?

Co-posted at pandasthumb.org.

Tuuli Lappalainen tweeted a result presented by Daniel Wegmann:












A beach in Sri Lanka, by Denish C

Taipei Rapid Transit on New Year's Eve, by Changlc

School dedication ceremony, Pongwe, Tanzania, by Jesse Awalt

Urawa Reds vs Gamba Osaka in Tokyo, Japan, by Pocopen





C Harland said...

Nice quick calculation. Though I wonder what the impact of the non-random nature of spontaneous mutation is. Considering there are some sites/tri-nucleotides that have at least an order of magnitude greater mutation rate (CpG) than other tri-nucleotides. Be interesting to see a study big enough to give a per tri-nucleotide and possibly di-nucleotide mutation rate.

mathbionerd said...

Thanks. :)

There is definitely a lot of variation in rates and directionality of single nucleotide mutations, and I haven't even touched on microsatellites, indels or large structural variants!

I think these large studies are just around the corner.

Mark P said...

Cool idea! Two comments.

1. With regard to different rates at different sites, at the rate sequencing is accelerating it seems like the number of genomes fully sequenced to high accuracy should soon give us a pretty good order of magnitude estimate of that.

2. You end with the point: "*A mutation that results in death would not be tolerated, so we would not expect to observe mutations at a select set of very important sites.". This is accurate, but if our data from Drosophila extrapolates to mammals, the number of "haplolethal" mutations in the genome can be counted on one hand, assuming we're talking about single nucleotide changes. Things that are homozygous lethal will definitely be present in the population at lower frequencies due to selection, but, as the array of serious single gene traits illustrates, they clearly occur in the human genome, and if my memory of recent sequencing studies is right, we all carry about 100 hits that are essentially certain to largely or fully disrupt the function of the protein they affect.

Noah Dowell said...

Sorry, naive non-expert questions here:

A) Why does one say "there are about 172 mutations at each site... across the whole human population "?
In a case where maternal-site-1 = A and paternal-site-1 = A then there are "only" 3 substitution mutations: A to T, A to G, or A to C (x 2 for each chrom). And one would expect the observations of a T,G, or C at site 1 across the human population to add up to 172 events. But I must be missing something here?
B) When one says that "every non-lethal genome position is variable in the human population" I wonder about gametogenesis and how haploid gametes tolerate mutations. Has anyone tried to sequence single genomes from a population of sperm from a single male to see if the observed mutations in living humans represents the mutations in the haploid gamete? I guess the drosophila comment indicates most mutations are tolerated in haploids.

Thanks for the great blog.

mathbionerd said...

Hi Noah,

Thanks for commenting.

A) Yes, for any individual, at each diploid site, they can have at most two substitutions, one from the maternal side, and one from the paternal side. However, what I was trying to describe is that, if we consider a site, across all living humans, that site will have experience approximately 172 mutations (likely in 172 different individuals).

B) There has been some work looking at mutation accumulation in sperm, but there is still more to be done, especially in humans. I'm hoping to conduct some of this work!