Tuesday, November 17, 2009

Genetic Load, Neutral Theory, and Junk DNA

The average human newborn has about 130 new mutations that were not found in either parent [Mutation Rates]. These mutations accumulate as a natural result of errors in DNA replication between the time that the zygote is first formed and the time that the sperm and egg cells are produced for the next generation.

A species cannot afford to accumulate deleterious mutations in the genomes of its individuals. Eventually the number of "bad" mutations will reach a level where most genes have multiple "bad" alleles and it becomes impossible to produce offspring.

This phenomenon is referred to as genetic load. It means that species can only survive if the genetic load is below some minimum value. A good rule of thumb is that there can't be more than 0.1 deleterious mutations per individual per generation but in actual populations this value can be a bit higher. [UPDATE: This should be one (1) deleterious mutation per generation.]

How do you reconcile this with the known mutation rate in humans? If there are, on average, 130 mutations per individual per generation, then hardly any of these can be deleterious if the species is to survive.

This is one of the arguments in favor of Neutral Theory. Most mutations are neither deleterious nor beneficial. They are simply neutral with respect to natural selection.

Let's think about a typical protein-encoding gene.1 The coding region is about 2,000 base pairs in length and consist of 666 codons. More than half these codons can be mutated to a new codon encoding a different amino acid without severe effects on the function of the protein.2 These are called amino acid substitutions. Of the "essential" codons, many can tolerate mutations that create synonymous codons. Putting these facts together suggests that only about 20% of mutations to protein encoding regions are detrimental. The rest are effectively neutral.

This partially explains why we can tolerate 130 mutations per individual per generation. If only 20% were detrimental then the genetic load is reduced to about 26 mutations per generation.

That's still unacceptably high. It leads to the idea that a large percentage of our genome must be unaffected by mutations. In other words, genes represent only a small percentage of our genome and mutations can freely accumulate in the rest without detrimental consequences.

In order to bring the genetic load down to acceptable levels, the number of genes has to be less than 40,000 according to the arguments made in the 1960s. We now know that we have only 20,000 genes. Most of them encode proteins and the coding regions of those genes make up about 40,000,000 bp or about 1.3% of our genome [Junk in Your Genome: Protein-Encoding Genes].

Recall that only 20% of mutations in coding regions are likely to be detrimental. That means that the effective target size for detrimental mutations is about 20% x 1.3% = 0.26% of our genome. Out of 130 mutations, only 0.3 per individual per generation will be detrimental.3

Since we are diploid organisms, the 130 mutations in the zygote are spread out over two copies of our genome but almost all of them will be in the chromosomes coming from the father. Every zygote inherits one complete set of chromosomes with hardly any mutations while the other set has less than one detrimental mutation.

Because a large percentage of gene mutations are neutral, and because most of our genome is junk, we can easily tolerate 130 mutations per individual per generation without going extinct.

Creationists will never understand this because: (a) they believe that modern evolutionary theory is all about "Darwinism" and Darwinian evolution doesn't recognize neutral mutations and random genetic drift, and (b) they can't admit to junk DNA because that's the opposite of what intelligent design would look like.

1. Similar arguments apply to genes that make functional RNAs and not proteins.

2. Over the course of several billion years of evolution it is unusual to see more than 30% sequence similarity between homologous genes. I realize that this is a somewhat circular argument but it's still a good one.

3. There are lots of other regions of the genome where mutations can be detrimental. I don't mean to imply that only protein encoding regions can be affected by mutations. Collectively, these other regions don't make up more than a few percent of our genome and they can tolerate many mutations [Genomes & Junk DNA]


  1. thanks. I found this very interesting. Why do the mutations almost always come from the chromosomes from the father? Did I read that right?

  2. Anon, there are a lot more rounds of replication in the male zygote (about 10-15x more IIRC).

  3. Kate asks,

    Why do the mutations almost always come from the chromosomes from the father?

    I explain this in Mutation Rates.

    Between zygote and egg there are about 30 cell divisions while between zygote and sperm there are about 400 cell divisions.

  4. "Darwinian evolution doesn't recognize neutral mutations and random genetic drift"

    Sure? Let's read Darwin:

    "I am inclined to suspect that we see, at least in some [cases], variations which are of no service to the species, and which consequently have not been seized on and rendered definite by natural selection.… Variations neither useful nor injurious would not be affected by natural selection, and would be left either a fluctuating element, as perhaps we see in certain polymorphic species, or would ultimately become fixed.… We may easily err in attributing importance to characters, and in believing that they have been developed through natural selection;… many structures are now of no direct use to their possessors, and may never have been of any use to their progenitors.… [On the other hand,] we are much too ignorant in regard to the whole economy of any organic being to say what slight modifications would be of importance or not."

    It's a well known quotation from The Origin. Perhaps Darwin was not being "darwinian" all the time, or maybe he was not writing about "darwinian" evolution but about the evolution of someone else ;o)

  5. About the finding that only 20% of point mutations in genes are non-neutral: how was this determined? By looking at the effects of individual substitutions in isolation?

    Given the existence of highly conserved gene regions, it seems a bit odd if 80% of nucleotides in a gene are free to mutate randomly. I'm guessing there must be lots of epistasis (in which case you oversimplified a bit when you went from 120 to 26).

  6. LM said: "This is one of the arguments in favor of Neutral Theory. Most mutations are neither deleterious nor beneficial. They are simply neutral with respect to natural selection."

    As we are talking here about mutation, and not fixation, this alone does not support neutral theory. Neither neutral theory nor selection theory differ substantially with respect to the distribution of selection coefficients entering a population through mutation. Perhaps neutralists are more likely to downplay the possiblity of beneficial mutations. Selectionists have always maintained that many new mutations may be neutral, they have simply argued that such mutations are unimportant at the population genetics level.

    So, the differences lie in the population level processes that determine the fate of mutations. Neutral theory predicts that the mutations that fix are primarily neutral and fixed by drift, selection theory predicts a primary role for positive natural selection.

  7. Alexander,

    About 2% of the genome codes for proteins and ncRNAs with some function, and roughly another 2-3% contains DNA coding elements. This 5% of the genome is conserved - so by chance alone 95% of all mutations will land in "junk" DNA. That cuts the level of non-junk DNA mutation by a factor of 20 fold.

  8. Sorry, I meant to write DNA elements, such as promoters, enhancers and other regulators of chromosomal structure.

  9. I understand that, but Larry was talking about protein-coding regions.

  10. So instead of 'junk', maybe we should call it 'padding', or 'protective'.

    Chicken or egg? Do we have a high genetic load because we have a largely neutral genome or do we have a largely neutral genome because we have a high genetic load?

    If 80% of the human genome can be successfully deleted (as Dawkins claims) does the human mutation rate somehow go down? Wouldn't this lead to unacceptable numbers of deleterious mutations?

    Data point: The enslaved genome of a rhizarian alga, the chlorarachniophyte Bigelowiella natans nucleomorph, has only 331 genes and is the world's smallest eukaryote nucleous. 3 chromosomes. It is still 27% 'junk' DNA, mostly in telemere and subtelemere regions. Doesn't have centromeres, which is interesting. The genes still have original introns although they are 9-21 bp. The exons remain even where the transcription promoters are on adjacent genes. Also, it has a pseudogene! Five copies of one gene.

    Complete nucleotide sequence of the
    chlorarachniophyte nucleomorph: Nature’s smallest nucleus

    PR Gilson et al, PNAS 2006

  11. Alas, within-organism selection acting on germ-line cells will concentrate those 130 mutations in non-coding regions. If a mutation will kill or sterilize an adult, there's at least a fair chance that it will kill or sterilize the cells ancestral to gametes. 399 generations of spermatocytes in each male results in a significant opportunity for selection to act in this way. This blunts the strength of the argument for most of the genome being junk from genetic load.

    1. You are referring to dominant lethal mutations that affect developing sperm cells. Let's assume, as you do, that such mutations are a significant proportion of mutations in functional DNA. The genetic load argument stills applies. It says that if all of the genome were functional, such mutations would lead rapidly to extinction because there's bound to be one or two every generation.

      Is that your point?

    2. No, it isn't. Mutations strike stochastically. There won't be 'one or two' lethal mutations every spermatocyte generation. Some spermatocytes will have 4 lethal mutations and some will have 0 lethal mutations. The ones with 0 lethal mutations are the ones that go on to form the next generation of spermatocytes. Mutations in junk regions will not be similarly selected against - so more of those 130 mutations will be in the junk region than chance would suggest.