Member (Idle past 3066 days)
Message 19 of 20 (349247)
09-15-2006 4:43 AM
Reply to: Message 18 by NosyNed
09-15-2006 4:23 AM
Direct estimate of human mutation rate from epidemiological data
EDIT: SORRY, I DIDN'T REALISE A LINK TO THE FIRST ARTICLE HERE HAD ALREADY BEEN POSTED. SOMEHOW I MISSED IT. APOLOGIES.
Here is an article containing direct empirical estimates of the human nuclear spontaneous mutation rate. The approach is to use data obtained from genetic screening of patients. These screens identify mutations from the wildtype allele which result in disease. From this nucleotide sequence data it is possible to estimate the rate at which various types of mutation occur spontaneously in human populations. The paper cited here used sequence data from 20 disease loci which have been widely sequenced across a large number of patients.
Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Kondrashov AS. Hum Mutat. 2003 Jan;21(1):12-27.
From the abstract:
I estimate per nucleotide rates of spontaneous mutations of different kinds in humans directly from the data on per locus mutation rates and on sequences of de novo nonsense nucleotide substitutions, deletions, insertions, and complex events at eight loci causing autosomal dominant diseases and 12 loci causing X-linked diseases. The results are in good agreement with indirect estimates, obtained by comparison of orthologous human and chimpanzee pseudogenes. The average direct estimate of the combined rate of all mutations is 1.8x10(-8) per nucleotide per generation, and the coefficient of variation of this rate across the 20 loci is 0.53. Single nucleotide substitutions are approximately 25 times more common than all other mutations, deletions are approximately three times more common than insertions, complex mutations are very rare, and CpG context increases substitution rates by an order of magnitude. There is only a moderate tendency for loci with high per locus mutation rates to also have higher per nucleotide substitution rates, and per nucleotide rates of deletions and insertions are statistically independent on the per locus mutation rate. Rates of different kinds of mutations are strongly correlated across loci. Mutational hot spots with per nucleotide rates above 5x10(-7) make only a minor contribution to human mutation. In the next decade, direct measurements will produce a rather precise, quantitative description of human spontaneous mutation at the DNA level.
I also found a second article using a similar approach:
Mutation rates in humans. II. Sporadic mutation-specific rates and rate of detrimental human mutations inferred from hemophilia B. Giannelli F, Anagnostopoulos T, Green PM. Am J Hum Genet. 1999 Dec;65(6):1580-7.
From the abstract:
|Giannelli et al writes:|
We estimated the rates per base per generation of specific types of mutations, using our direct estimate of the overall mutation rate for hemophilia B and information on the mutations present in the United Kingdom's population as well as those reported year by year in the hemophilia B world database. These rates are as follows: transitions at CpG sites 9.7x10-8, other transitions 7.3x10-9, transversions at CpG sites 5.4x10-9, other transversions 6.9x10-9, and small deletions/insertions causing frameshifts 3.2x10-10. By taking into account the ratio of male to female mutation rates, the above figures were converted into rates appropriate for autosomal DNA-namely, 1.3x10-7, 9.9x10-9, 7.3x10-9, 9.4x10-9, 6.5x10-10, where the latter is the rate for all small deletion/insertion events. Mutation rates were also independently estimated from the sequence divergence observed in randomly chosen sequences from the human and chimpanzee X and Y chromosomes. These estimates were highly compatible with those obtained from hemophilia B and showed higher mutation rates in the male, but they showed no evidence for a significant excess of transitions at CpG sites in the spectrum of Y-sequence divergence relative to that of X-chromosome divergence. Our data suggest an overall mutation rate of 2.14x10-8 per base per generation, or 128 mutations per human zygote. Since the effective target for hemophilia B mutations is only 1.05% of the factor IX gene, the rate of detrimental mutations, per human zygote, suggested by the hemophilia data is approximately 1.3.
I guess there are probably a few similar articles using this kind of dataset.
Edited by mick, : No reason given.
Edited by mick, : No reason given.
Edited by mick, : Combining several edits into a single post
Edited by mick, : stupidity
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Member (Idle past 2174 days)
From: Edinburgh, Scotland
Message 20 of 20 (522438)
09-03-2009 11:55 AM
Confirmation of previous estimates (also Thread Necromancy)
A paper is due to be published shortly in the journal Current Biology which compares the Y-chromosomes of two men from the same family but several generations apart (Xue et al., 2009).
They arrive at results showing similar levels of mutation to those discussed previously. They identify 4 new mutations to have arisen in vivo in the intervening 13 generations and from that derive a mutation rate of 3x10-8 mutations/nucleotide/generation. This gives roughly ~150 new single nucleotide mutations/ diploid genome/ generation, more than Kondrashov's estimate but within a very similar ball park.