4 ms·

Genetics question: How many cells do you need in a population so that there is at least one variant at each position (ie a SNP)? This can be for any species or

by nonbel 10y ago

Genetics question: How many cells do you need in a population so that there is at least one variant at each position (ie a SNP)? This can be for any species or cell line for which the info is available.

toufka 10y ago
Humans have two copies of ~3 Billion base pairs. A reasonable error rate of DNA replication (not under stress) is about 1 write error in 1 billion reads. Many of those errors are actually immediately corrected by post-replication error correction mechanisms. Also, as cells divide, errors that happen early will be propagated more times than errors that happen late in development. Further, mutations are not uniformly distributed though the genome. A human has > 10^14 cells, so any given human might have a few thousand different variants among its cells. The error rates of human polymerase is way less than a bacterial polymerase. And a human genome is way larger than a bacterial (or viral) genome. Viruses actually have mechanisms to increase the error rate of DNA replication. For a human, you would need a LOT more than a single human to have a variant at each position. Something like HIV can actually have a small enough genome, a high enough error rate, and a large enough population in an infected patient, that it can realistically have a unique variant at each position in its genome within a single human host.
- nonbel 10y ago
  Thanks, I later found this paper that claims something different. Can you explain where this logic has gone wrong, they seem to start out with a similar error rate (~10^-9 per site per division): "For example, the intestinal epithelium contains approximately 10^6 independent stem cells, each of which generates transient daughter cells every week or two. Thus, the intestinal epithelium of a 60-y-old is expected to harbor >10^9 independent mutations. This implies that, not far beyond the age of 60 y, nearly every genomic site is likely to have acquired a mutation in at least one cell in this single organ." http://www.pnas.org/content/107/3/961.full http://www.pnas.org/content/107/3/961.full Edit: >"A reasonable error rate of DNA replication (not under stress) is about 1 write error in 1 billion reads" I think it is that you are using the 10^-9 value to be per genome while that reference uses it as per basepair
  - apathy 10y ago
    Write error == (fixed) base pair mutation. A classic example is a methylated cytosine spontaneously deaminating to yield thymine. Our DNA repair enzymes can't tell the difference (in terms of which is the "right" base) between the thymine and the guanine left behind, but since they don't match, one of them has got to go. Thus there is a 50-50 chance that the mutation will be fixed. That's the easiest example because it's not an "error" per se (rather a thermodynamics problem) but genuine proofreading errors also occur. The net rate is about one in a billion bases. These estimates ignore indels and SVs but empirical evidence suggests that the "everyone over 50 has a 50/50 chance of at least one adult stem cell harboring a mutation in at least one interesting gene". My personal favorite is http://www.nature.com/nature/journal/v518/n7540/abs/nature13968.html http://www.nature.com/nature/journal/v518/n7540/abs/nature13... but Druley's follow up was equally awesome: http://www.nature.com/articles/ncomms12484 http://www.nature.com/articles/ncomms12484 and the recent survey of adult stem cell mutations is nice: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature19768.html http://www.nature.com/nature/journal/vaop/ncurrent/full/natu... One take-away from all this is that, while 95% of a sensitively surveyed population of 50-60 year olds had at least one stem cell with at least one known preleukemic mutation, it is equally clear that most people aren't walking around with anything resembling an acute leukemia. The natural conclusion is that in individuals with a competent immune system and diverse enough pools of healthy stem cells, it's not that big of an issue. Only when bad luck and/or stresses to which the mutants are adapted (e.g. TP53 mutations in therapy-related leukemia) afflict people, or the natural diversity of their stem cell populations collapses (as with really old people and individuals whose immune system actively attacks their stem cells, as in severe aplastic anemia) do you see the sort of massive, life-endangering takeover that we recognize clinically as disease. Furthermore, nearly all of us are born with 5-10 predicted-to-be-lethal variants in our genomes. Clearly, we're also not dead, so our conception of "lethal" can't be quite right. There is an enormous amount of complexity in how real live multicellular organisms deal with variation and mutation, something we're really only just starting to grasp, and of course all of that then interacts with the person's environment to manifest (or not) their genetic tendencies. We build models of reality because the actual thing is too complicated to be tractable; it's important never to confuse the two :-)
amelius 10y ago
NCBI has dbSNP, a database of important SNPs, with statistics on the variation of alleles among different populations. See e.g. [1]. From there you could compute the answer to your question. [1] https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs6564851 https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs6564851

by nonbel 10y ago

toufka 10y ago

Humans have two copies of ~3 Billion base pairs. A reasonable error rate of DNA replication (not under stress) is about 1 write error in 1 billion reads. Many of those errors are actually immediately corrected by post-replication error correction mechanisms. Also, as cells divide, errors that happen early will be propagated more times than errors that happen late in development. Further, mutations are not uniformly distributed though the genome. A human has > 10^14 cells, so any given human might have a few thousand different variants among its cells. The error rates of human polymerase is way less than a bacterial polymerase. And a human genome is way larger than a bacterial (or viral) genome. Viruses actually have mechanisms to increase the error rate of DNA replication. For a human, you would need a LOT more than a single human to have a variant at each position. Something like HIV can actually have a small enough genome, a high enough error rate, and a large enough population in an infected patient, that it can realistically have a unique variant at each position in its genome within a single human host.

nonbel 10y ago
Thanks, I later found this paper that claims something different. Can you explain where this logic has gone wrong, they seem to start out with a similar error rate (~10^-9 per site per division): "For example, the intestinal epithelium contains approximately 10^6 independent stem cells, each of which generates transient daughter cells every week or two. Thus, the intestinal epithelium of a 60-y-old is expected to harbor >10^9 independent mutations. This implies that, not far beyond the age of 60 y, nearly every genomic site is likely to have acquired a mutation in at least one cell in this single organ." http://www.pnas.org/content/107/3/961.full http://www.pnas.org/content/107/3/961.full Edit: >"A reasonable error rate of DNA replication (not under stress) is about 1 write error in 1 billion reads" I think it is that you are using the 10^-9 value to be per genome while that reference uses it as per basepair
- apathy 10y ago
  Write error == (fixed) base pair mutation. A classic example is a methylated cytosine spontaneously deaminating to yield thymine. Our DNA repair enzymes can't tell the difference (in terms of which is the "right" base) between the thymine and the guanine left behind, but since they don't match, one of them has got to go. Thus there is a 50-50 chance that the mutation will be fixed. That's the easiest example because it's not an "error" per se (rather a thermodynamics problem) but genuine proofreading errors also occur. The net rate is about one in a billion bases. These estimates ignore indels and SVs but empirical evidence suggests that the "everyone over 50 has a 50/50 chance of at least one adult stem cell harboring a mutation in at least one interesting gene". My personal favorite is http://www.nature.com/nature/journal/v518/n7540/abs/nature13968.html http://www.nature.com/nature/journal/v518/n7540/abs/nature13... but Druley's follow up was equally awesome: http://www.nature.com/articles/ncomms12484 http://www.nature.com/articles/ncomms12484 and the recent survey of adult stem cell mutations is nice: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature19768.html http://www.nature.com/nature/journal/vaop/ncurrent/full/natu... One take-away from all this is that, while 95% of a sensitively surveyed population of 50-60 year olds had at least one stem cell with at least one known preleukemic mutation, it is equally clear that most people aren't walking around with anything resembling an acute leukemia. The natural conclusion is that in individuals with a competent immune system and diverse enough pools of healthy stem cells, it's not that big of an issue. Only when bad luck and/or stresses to which the mutants are adapted (e.g. TP53 mutations in therapy-related leukemia) afflict people, or the natural diversity of their stem cell populations collapses (as with really old people and individuals whose immune system actively attacks their stem cells, as in severe aplastic anemia) do you see the sort of massive, life-endangering takeover that we recognize clinically as disease. Furthermore, nearly all of us are born with 5-10 predicted-to-be-lethal variants in our genomes. Clearly, we're also not dead, so our conception of "lethal" can't be quite right. There is an enormous amount of complexity in how real live multicellular organisms deal with variation and mutation, something we're really only just starting to grasp, and of course all of that then interacts with the person's environment to manifest (or not) their genetic tendencies. We build models of reality because the actual thing is too complicated to be tractable; it's important never to confuse the two :-)

amelius 10y ago

NCBI has dbSNP, a database of important SNPs, with statistics on the variation of alleles among different populations. See e.g. [1]. From there you could compute the answer to your question. [1] https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs6564851 https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs6564851