With apologies to Numbers 24:5, “How goodly are thy tents, Oh Jacob” — a recent paper shows how shockingly error ridden our genomes actually are [ Science vol. 337 pp. 64 – 69 ’12 ]. The authors sequenced roughly three quarters of the genes coding for proteins in some 2,439 people — e.g. 15,585 protein coding genes. This left 98% of the genome untouched, primarily because we really don’t know what it does or how it does it, despite the fact that it controls, when, where and how much of each protein is made. So they basically looked at the bricks from which we are built (the proteins) and not the plans (the 98%).
The news is not very good. The subjects came from two groups: 1,351 Europeans and 1,088 Africans (the latter, because genetic diversity is far higher among Africans as that’s where humanity arose, and where mutations have had the longest time to accumulate).
The news is not very good. First, some background.
Recall that each nucleotide is one of four possibilities (A, T, G, C), and that each 3 nucleotides therefore has 4^3 = 64 possibilities. 61/64 combinations code for amino acids which, since we have only 20 gives a certain redundancy of the famed genetic code. The other 3 combinations code for no amino acid (usually) and tell the machinery making proteins to stop. Although crucial to our existence, these are called nonsense codons.
The genetic code is therefore 3fold degenerate (on average). However, some amino acids are coded for by just 1 combination of 3 nucleotides while others are coded by as many as 6. So some single nucleotide variants (SNVs) leave the amino acid coded for the same (these are the synonymous SNVs), while others change the amino acid (nonSynonymous SNVs), and possibly protein function.
Ask some one with sickle cell anemia how much trouble just one nonSynonymous SNV can cause — it’s only 1 amino acid out of 147. Even worse, ask someone with cystic fibrosis where just one of 1,480 amino acids is missing.
Here’s the bad news. In the population as a whole, they found 500,000 single nucleotide variants (SNVs). If you’re still not sure what is meant by this, the 5 articles in https://luysii.wordpress.com/category/molecular-biology-survival-guide/ should be all the background you need.
More than 400,000 of the variants were previously unknown. Also more than 400,000 of them were found either in Africans or Europeans but not both. If you divide 500,000 by 2,439 you get 205 variants per person. However, SNVs are far more common than that, and each individual contains an average of 14,000.
Well, how many of the 500,000 or so SNVs they found are nonSynonymous? One would think about 1/3 statistically. However, They found more than half 292,125/500,000 — nearly 60% — were nonSynonymous.
It gets worse: 6,165 of the nonSynonymous variants are nonSense codons. This means that the protein coded for by such a gene, terminates prematurely, meaning that it can terminate anywhere. On average one would expect that half of these nonsense codons result in a protein of less than half the normal length. This would very likely obliterate whatever function the protein had.
Obviously, they couldn’t test all 500,000 SNVs to see how they affected protein function (and we really only have a decent idea of what half our 20,000 or so proteins are doing). They had to guess. They came up with a figure of 2 – 4% of the 14,000 SNVs being functionally significant — That’s 280 – 560 significant mutations per individual.
Clearly, despite the horrible examples of cystic fibrosis and sickle cell anemia above, most of these can’t be doing very much, because these were normal people being studied.
There are all sorts of implications of this work. One is the subject of a future post — how hard this diversity makes drug discovery. Another reiterates the Tolstoy theme mentioned earlier about the genetic defects causing schizophrenia and autism — ““Happy families are all alike; every unhappy family is unhappy in its own way”. Thus beginneth Anna Karenina.
For details please see https://luysii.wordpress.com/2010/04/25/tolstoy-was-right-about-hereditary-diseases-imagine-that/ and https://luysii.wordpress.com/2010/07/29/tolstoy-rides-again-autism-spectrum-disorder/
A third is that this shows that the 1000 fold expansion of the human population has pretty much obviated much natural selection eliminating these variants. I’ll leave it to the geneticists to figure out what this means for the eventual survival of the species, as these mutants continue to accumulate.
The paper is fascinating, and sure to change our conception of what a ‘normal’ genome actually is. Nonetheless, all they did was follow Yogi Berra’s dictum — “You can observe a lot by watching.” It certainly wasn’t creative or ingenious in any sense. Sometimes grunt work like this wins the day. I’ll leave this to Ashutosh to write about its philosophical implications for research.
Chemiotics II 
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First the study on repeat polymorphisms, now this one on SNPs; we are getting an idea of the amount of genomic diversity in the human population.
But humans are said to be more similar to each other than most species’ populations, and this has implications for those of us doing bioinformatics against published reference genome sequences. The message being that without a good handle on actual genome sequence diversity within a population we are working with dodgy data.
[ Science vol. 276 pp. 35 – 36 ’95 ] Genetic sequences from two humans from diffferent continents are more similar than sequences from two lowland gorillas from the same forest in West Africa.
Of course this is from the dark ages of genome sequencing, even before the HGP. Is there any more recent evidence for this? Otherwise it’s a pretty thin reed. The short pagination means this is an abstract of something else.