Favourite part: the Onion test followed by a Simpsons reference (at 37:00). Can’t ask for more than that! (Incidentally, PZ gets the onion test right — it’s about onions vs. humans AND onions vs. other onions; see also Larry Moran’s summary).

1. New evolutionary research disproves living missing link theories

Evolution is not a steady march towards ever more sophisticated beings and therefore the search for the living “missing links” is pointless, according to findings published by a team of researchers led by Dr. Hervé Philippe of the Université de Montréal’s Department of Biochemistry.

And according to the most basic grasp of how evolution works.

2. Primates’ Unique Gene Regulation Mechanism: Little-Understood DNA Elements Serve Important Purpose

“Previously, no one knew what Alu elements and long noncoding RNAs did, whether they were junk or if they had any purpose. Now, we’ve shown that they actually have important roles in regulating protein production,” said Maquat, the J. Lowell Orbison Chair, professor of Biochemistry and Biophysics and director of the Center for RNA Biology at the University of Rochester Medical Center.

There’s been plenty of interest in possible roles for some Alu elements. There are more than 1,000,000 of them in the human genome. Seems like overkill, no?

One that I think is somewhat catchy and encompasses most of what we need it to, is “DN/A“. Now, “n/a” can stand for either “not available” or “not applicable”, and in this case it would be in reference to organism-level functions for the majority of DNA in the genome. In other words, it does not distinguish between sequences that have an unknown function, no gene-related function, or no function at all, which is what we want.

The only question is, how to pronounce it so that it is distinguished from DNA when spoken? Give us your suggestions in the comments.

If you have alternative suggestions, let us hear them too.

A transcript is available here in PDF. Note this statement in particular:

You mentioned earlier the possible significance of transposons. What part do you think they have played?

That is one of my many favourite topics. It is widely assumed – though not by everybody – that transposon-derived sequences are simply ‘selfish’ mobile genetic elements that have no function other than their own propagation. Books have been written about such things, and that is indeed one possibility. But the raw material for evolution is duplication and transposition, with the latter having the great advantage of being able to distribute functional cassettes. So it’s equally possible that a large fraction of the transposon-derived sequences that are in our genome are actually functional.

I have said it before, and I will say it again. The possibility that many transposable elements would be co-opted for organism-level functions has been around since the beginning of the “selfish DNA” idea. Moreover, the point of introducing the concept of selfish DNA in the first place was prompted by the standard assumption that just being present implied a function for all DNA.

“It would be surprising if the host genome did not occasionally find some use for particular selfish DNA sequences, especially if there were many different sequences widely distributed over the chromosomes. One obvious use … would be for control purposes at one level or another.” (Orgel and Crick 1980)

“In our recent experience most people will agree, after discussion, that ignorant DNA, parasitic DNA, symbiotic DNA (that is, parasitic DNA which has become useful to the organism) and ‘dead’ DNA of one sort or another are all likely to be present in the chromosomes of higher organisms. Where people differ is in their estimates of the relative amounts. We feel that this can only be decided by experiment.” (Orgel et al. 1980)

One can find examples like this all the way back to the earliest discussions of non-coding DNA. It simply is NOT TRUE that non-coding DNA was dismissed as functionless.

MYTH: JUNK DNA ISN’T JUNK AFTER ALL

Once the vast majority of our DNA was dismissed as junk, but now we know it is important – or so you might have read recently. In fact, it still appears likely that 85 to 95 per cent of our DNA is indeed useless. While many bits of DNA that do not code for proteins are turning out to have some function or other, this was predicted by some all along, and the overall proportion of our DNA with a proven function remains tiny.

It’s especially nice that they cited this blog!

Various visitors to this blog have brought up the hypothesis in one form or another, so even though little or no data is ever presented (and counter-examples are generally dismissed out of hand), I will once again treat the idea seriously.

Specifically, here is my overview of what proponents of the mutation protection hypothesis need to know and what they need to do if they want this to move out of the armchair and into the realm of science.

I. This is not a new idea.
If you have been following this blog, you will know that functions for non-coding DNA have been proposed regularly for decades. Not surprisingly, the notion that it protects genes from mutagens was one of them. This hypothesis dates back in a general form nearly 40 years to the paper in Nature by Yunis and Yasmineh (1971). As they wrote:

“Recent reports indicate that the DNA of constitutive heterochromatin is composed to a large extent of short repeated polynucleotide sequences, termed satellite DNA. This discovery has necessitated a critical review of current ideas concerning the origin and function of this portion of the genome of higher organisms (4-12). A careful appraisal of the information that has accumulated about heterochromatin since the time of Heitz [late 1920s, early 1930s] and on satellite DNA during the last decade suggests that these entities have vital structural functions: they maintain nuclear organization, protect vital regions of the genome, serve as an early pairing mechanism in meiosis, and aid in speciation.”

Yunis and Yasmineh (1971) focused primarily on structural roles for non-coding DNA, and I don’t think aiding in speciation can be considered a “function”, but they did also include the basic notion of genome defense.

True to the standard view of the 1970s (and, to a significant extent, of many authors today), they begin with an adaptationist assumption and build from there:

“With the assumption that a portion that comprises some 10 percent of the genomes in higher organisms cannot be without a raison d’etre, an extensive review led us to conclude that a certain amount of constitutive heterochromatin is essential in multicellular organisms at two levels of organization, chromosomal and nuclear. At the chromosomal level, constitutive heterochromatin is present around vital areas within the chromosomes. Around the centromeres, for example, heterochromatin is believed to confer protection and strength to the centromeric chromatin. Around secondary constrictions, heterochromatic blocks may ensure against evolutionary change of ribosomal cistrons by decreasing the frequency of crossing-over in these cistrons in meiosis and absorbing the effects of mutagenic agents. During meiosis heterochromatin may aid in the initial alignment of chromosomes prior to synapsis and may facilitate speciation by allowing chromosomal rearrangement and providing, through the species specificity of its DNA, barriers against cross-fertilization.”

A few years later — and three years after the rise of the term “junk DNA” (Ohno 1972; Comings 1972) — Hsu (1975) provided a much stronger argument for what he called the “bodyguard hypothesis”. To start, Hsu (1975) noted that many hypotheses had already been presented for the function of heterochromatin, of which he listed six. Importantly, he also noted the following, which seems to have been lost on most current authors:

“Some investigators consider the repeated DNA sequences as the equivalent of ‘appendices’ of gene evolution and therefore facetiously refer to them as ‘junk’. Actually few really think that ‘junk’ DNA is completely useless (cf. Ohno 1972; Comings 1972).”

Now, was Hsu saying that Ohno and Comings did or did not claim that junk DNA is completely useless? The “confer” is ambiguous (it can mean either “compare with” or “consult”), but Hsu was almost certainly aware that Comings was explicit in ascribing function to a large portion of junk DNA.

In any case, the “bodyguard hypothesis” was described as follows:

“The hypothesis proposed here is a simple-minded one: constitutive heterochromatin is used by the cell as a bodyguard to protect the vital euchromatin by forming a layer of dispensable shield on the outer surface of the nucleus. Mutagens, clastogens [inducing chromosome breakage] or even viruses attacking the nucleus must first make contact with the constitutive heterochromatin which absorbs the assault, thus sparing the euchromatic genes from damage, unless the detrimental agents are overpowering.”

Hsu did not apply this to all causes of mutation nor to all types of non-coding DNA — “Probably heterochromatin is ineffective in protecting euchromatic genes against penetrating ionizing radiations, but against chemicals (especially large molecules) and viruses, the layer of thick chromatin may be an excellent barrier” — but it has certainly been invoked more broadly by others since.

For example, the idea has been brought up with renewed vigour by some Russian geneticists (Patrushev 1997; Patrushev and Minkevitch 2006, 2007, 2008). In this case, the focus is on endogenous mutagens (i.e., free oxygen radicals generated through aerobic metabolism). They take this much farther than Hsu by applying it as a major explanation for genome size differences generally and by including transposable elements (which are much more abundant than satellite DNA). As they argued:

“Our data suggest the following molecular mechanism that controls the size of eukaryotic genome in phylogenesis. During the whole life, nuclear DNA of aerobic organisms is affected by a continuous flow of endogenous mutagens. Mutagens escaping the neutralizing effect of antimutagenesis system damage the nucleic bases of DNA, most of which are corrected by repair systems. This ensures a permissible genetically determined level of spontaneous mutagenesis. An increase in the intranuclear concentration of mutagens raises the mutation rate in genome-coding sequences,among which gene(s) of molecular sensor are present. Mutational alterations in the sensor mobilize retrotransposons, which results in a local growth in their copy number, enlargement of genome size, and a decrease inthe mutation in the corresponding coding sequences. As a result, the genome–endogenous mutagen system reaches a new steady-state level. A decrease in the intranuclear concentration of mutagens will be accompanied by a reduction of genome size as a result of spontaneous deletions in its now excessive (in view of accomplishing the protective functions) sequences.” (Patrushev and Minkevitch 2006)

Put more directly, and very much in line with Hsu’s depiction of a “bodyguard”,

“In such a situation, the noncoding DNA of eukaryotic genome behaves quite ‘altruistically’ by putting itself under injuries instead of coding DNA.” (Patrushev and Minkevitch 2008)

The model they propose is summarized in this figure from Patrushev and Minkevitch (2008):

From Patrushev and Minkevitch (2008). Click for larger image.

Hsu (1975) recognized the problem of speculating on functions for junk DNA without evidence or any clear means of empirical testing. Thus, he was careful to provide several specific predictions of his bodyguard hypothesis that are amenable to analysis:

1. “the mutation rate induced by chemical mutagens should be inversely correlated with the number of B chromosomes”.
2. heterochromatin should be “more concentrated at the periphery of the nucleus (and probably also at the nucleoli) than in the interior”.
3. “organisms with more constitutive heterochromatin [should be] more resistant to induced mutations, at least by chemical mutagens”.

Again, let’s take the idea seriously and ask how Hsu’s original predictions have fared over the past 35 years.


Prediction 1: B chromosomes vs. mutation rate
B chromosomes (also called supernumerary chromosomes) are something of an odd choice in this context, because they are not found in all species and they vary in size and number within and among species. By definition, they are not important for survival. They do appear to have effects on recombination (i.e., they increase its frequency), and this has in the past been suggested as a functional role. On the other hand, in high numbers they appear to have deleterious effects on the organisms carrying them. Indeed, B chromosomes were described very early on as parasitic elements (Östergren 1945; one of the first clear expositions of the “selfish DNA” idea), and this remains the most common interpretation (Camacho 2005).

I am not aware of many tests of the prediction that more B chromosomes will provide greater protection against mutations (iperhaps because I don’t follow the B chromosome literature very closely), and in any case the other deleterious impacts and obvious parasitic properties of B chromosomes challenge a primarily adaptive explanation for their presence. However, there are a few experiments that are relevant to this prediction. For example, here is the abstract from a recent study by Weber et al. (2007) on B chromosomes and mutations in maize:

Two hypotheses (the Bodyguard hypothesis and the ABCW hypothesis) have been proposed that predict that the amount and type of chromatin in the nucleus will affect induced mutation rates. The Bodyguard hypothesis proposes that a function of constitutive heterochromatin may be to protect euchromatin from chemical mutagens. The ABCW hypothesis, states that the mutation rate per locus from ionizing radiation is directly proportional to the haploid DNA content of a species. We altered the total amount of genomic DNA and also the amount of heterochromatin by adding supernumerary B chromosomes (which are largely composed of heterochromatin) to maize (Zea mays L.) cells. We compared induced mutation frequencies at the yellow-green2 (yg2) locus in near-isogenic plants that contained 0 (diploid) or 4 supernumerary B chromosomes (diploid + 4 Bs) to evaluate these hypotheses. We found that the chemical mutagen, EMS, caused significantly higher mutation frequencies in plants that contained 4 B chromosomes (and therefore additional constitutive heterochromatin) than in diploid controls. The Bodyguard hypothesis predicts precisely the opposite result. We also found that ionizing radiation caused significantly higher mutation frequencies in plants with 4 B chromosomes than in diploid control plants. This type of change is predicted by the ABCW hypothesis; however, the extent of the increase observed in this study is much higher than the ABCW hypothesis would predict. The higher mutation frequencies from EMS and radiation in plants that contained 4 B chromosomes was unanticipated, and is the first observation that cells may be more susceptible to mutagenesis when B chromosomes are present. We also compared spontaneous mutation frequencies at the waxy1 (wx1) locus in plants containing 0 or 4-5 B chromosomes, and found that the presence of B chromosomes had no detectable impact. However, the pollen abortion frequency was significantly increased by the presence of 5 B chromosomes.

Prediction 2: Arrangement of chromatin
The idea that chromatin is arranged non-randomly in the nucleus is at least 100 years old. Theodor Boveri described chromatin “territories” in 1909, for example. According to Hsu’s hypothesis, heterochromatin should be localized on the outer region of the nucleus as a shield for the sensitive euchromatin in the interior. Again, I do not follow the literature on nuclear structure carefully, but there are some papers that deal with this issue of which I am aware. For example, Tanabe et al. (2002) concluded the following in their study of chromatin arrangement and mutational patterns:

“Evidence for evolutionary conservation argues for a still unknown functional significance of distinct radial higher-order chromatin arrangements. In 1975, T.C. Hsu proposed the ‘bodyguard’ hypothesis for a possible function of constitutive heterochromatin. He argued that constitutive heterochromatin localized in the nuclear periphery might protect the centrally localized euchromatin against mutagens, clastogens, and viruses. However, evidence for the existence of a protection shield has not been provided so far. The fact that later replicating, gene-poor chromatin is incorporated in the constitutive, gene free heterochromatin to form a chromatin shield in the nuclear periphery cannot be easily integrated into this hypothesis. While G-dark band chromatin contains tissue-specific genes, these genes are certainly not of minor importance as compared with the housekeeping genes that are localized in G-light band chromatin in the interior nuclear compartment. The finding in the human fibroblast nuclei that—in contrast to lymphocyte nuclei—both HSA18 and 19 territories are apparently in contact with the nuclear envelope and thus similarly exposed to mutagens, which will enter the nucleus, presents another difficulty. Why should gene dense HSA19 be better protected in lymphocyte nuclei than in fibroblast nuclei? Furthermore, in the light of the bodyguard hypothesis, we would expect to observe DNA damage preferentially in the peripheral chromatin shield. However, several reports indicate a non-random distribution of double strand breaks, as well as endonuclease- or radiation-induced chromosome aberration sites were preferentially observed in the gene-dense G-light bands.”

Again, there may be data out there that support the mutation protection idea, but so far it is not looking good for the hypothesis.


Prediction 3: Non-coding DNA content vs. mutation rate
It is an interesting bit of historical trivia that some early work on genome size diversity was funded by the US Atomic Energy Commission, much as the human genome sequencing initiative was supported by the Department of Energy. In the 1960s and 1970s, there was interest in patterns of sensitivity to radiation and their potential relation to genomic properties including genome size. In general, these studies reported a positive correlation between mutagenic sensitivity to radiation and DNA content (Sparrow and Evans 1961; Sparrow and Miksche 1961; Sparrow et al. 1965, 1968; Baetcke et al. 1967; Abrahamson et al. 1973; Wolff and Abrahamson 1974; Athanasiou and Heddle 1975; Heddle and Athanasiou 1975; Trujillo and Dugan 1975). That is to say, more DNA means more, not less, sensitivity to radiation-induced mutations on a per-locus basis.

From Abrahamson et al. (1973). Click for larger image

From Trujillo and Dugan (1975). Click for larger image.

From Heddle and Athanasiou (1975). Click for larger image.

From Heddle and Athanasiou (1975). Click for larger image.

III. Previous observations need to be explained.
One of the reasons that the mutation protection hypothesis does not have widespread acceptance is that there seem to be too many well-known phenomena that do not jive well with it. Consider the following patterns:

1. Species exposed to intense UV (e.g., on land or in freshwater in the Arctic, pelagic plankton, etc.) do not appear to have large genomes. On the other hand, some very large genomes are found in deep-sea invertebrates.
2. Among vertebrates, species with high metabolic rates, and presumably more free oxygen radicals, have smaller genomes than species with lower metabolic rates.
3. There can be substantial differences in genome size among similar organisms, for example as in onion and its relatives or among salamanders.
4. Despite claims to the contrary based on small and questionable analyses, there are no clear relationships between genome size and lifespan.
5. Transposable elements, which are the primary contributor to genome size, can cause a range of mutations through insertion into genes or by causing large deletions by illegitimate recombination, the latter of which is especially likely with the long terminal repeat (LTR) elements that are common in plants.
6. DNA content obviously can be amplified in somatic cells by endoreduplication, but this tends to be in cells involved in ion exchange, protein production, etc., and not ones exposed most to mutagens (such as the skin exposed to UV).

Conclusions
Overall, the mutation protection idea has intuitive appeal, which is why it was proposed so early and why it continues to pop up as an apparently independent invention among interested non-experts. As I said, I am happy to consider it as a legitimate hypothesis — but only if it moves well beyond the usual pattern in which it is proposed as though it were new, accepted without supporting evidence, and defended through dismissal of obvious counter-evidence. The null hypothesis, that much of the non-coding DNA in eukaryotic genomes does not have an organismal function, also has to be acknowledged as at least equally plausible in light of our understanding of genome biology.

References

Abrahamson, S., M.A. Bender, A.D. Conger, and S. Wolff (1973). Uniformity of radiation-induced mutation rates among different species. Nature 245: 460-462.

Athanasiou, K. and J.A. Heddle (1975). EMS induced mutation rates and their relation to genome size. Canadian Journal of Genetics and Cytology 17: 455.

Baetcke, K.P., A.H. Sparrow, C.H. Nauman, and S.S. Schwemmer (1967). The relationship of DNA content to nuclear and chromosome volumes and to radiosensitivity (LD50). Proceedings of the National Academy of Sciences of the USA 58: 533-540.

Camacho, J.P.M. (2005). B chromosomes. In: The Evolution of the Genome, ed. T.R. Gregory. Elsevier, San Diego, pp.223-286.

Comings, D. E. (1972). “The structure and function of chromatin.” Advances in Human Genetics 3: 237-431.

Heddle, J.A. and K. Athanasiou (1975). Mutation rate, genome size and their relation to the rec concept. Nature 258: 359-361.

Hsu, T.S. (1975). A possible function of constitutive heterochromatin: the bodyguard hypothesis. Genetics 79 (Suppl. 2): 137-150

Ohno, S. (1972). So much “junk” DNA in our genome. Evolution of Genetic Systems. H. H. Smith. New York, Gordon and Breach: 366-370.

Östergren, G. (1945). “Parasitic nature of extra fragment chromosomes.” Botaniska Notiser 2: 157-163.

Patrushev, L.I. (1997). Altruistic DNA: About protective functions of the abundant DNA in the eukaryotic genome and its role in stabilizing genetic information. Biochemistry and Molecular Biology International 41: 851-860

Patrushev, L.I. and I.G. Minkevich (2006). Eukaryotic non-coding DNA sequences provide genes with an additional protection against chemical mutagens. Russian Journal of Bioorganic Chemistry 32: 408-413

Patrushev, L.I. and I.G. Minkevich (2007).Genomic non-coding sequences and the size of eukaryotic cell nucleus as important factors of gene protection from chemical mutagens. Russian Journal of Bioorganic Chemistry 33: 474-477

Patrushev, L.I. and I.G. Minkevich (2008). The problem of eukaryotic genome size. Biochemistry 73: 1519-1552.

Sparrow, A.H. and H.J. Evans (1961). Nuclear factors affecting radiosensitivity. I. The influence of nuclear size and structure, chromosome complement, and DNA content. Brookhaven Symposia in Biology 14: 76-100.

Sparrow, A.H. and J.P. Miksche (1961). Correlation of nuclear volume and DNA content with higher plant tolerance to chronic radiation. Science 134: 282-283.

Tanabe, H., F.A. Habermann, I. Solovei, M. Cremer, and T. Cremer (2002). Non-random radial arrangements of interphase chromosome territories: evolutionary considerations and functional implications. Mutation Research 504: 37-45.

Sparrow, A.H., K.P. Baetcke, D.L. Shaver, and V. Pond (1968). The relationship of mutation rate per Roentgen to DNA content per chromosome and to interphase chromosome volume. Genetics 59: 65-78.

Trujillo, R. and V.L. Dugan 1975. Radiosensitivity and radiation-induced mutability: an empirical relationship. Rad. and Environm. Biophys. 12: 253-256.

Vinogradov, A.E. (1998). Buffering: a possible passive-homeostasis role for redundant DNA. Journal of Theoretical Biology 193: 197-199.

Weber, D.F., M.J. Plewa, and R. Feazel (2007). Effect of B chromosomes on induced and spontaneous mutation frequencies in maize. Maydica 52: 109-115.

Wolff, S., S. Abrahamson, M.A. Bender, and A.D. Conger (1974). The uniformity of normalized radiation-induced mutation rates among different species. Genetics 78: 133-134.

Yunis, J.J. and W.G. Yasmineh (1971). Heterochromatin, satellite DNA, and cell function. Science 174: 1200-1209.

“Junk DNA myth”, interpretation #1: There is no “junk DNA”, where “junk DNA” is defined as non-functional DNA.  That is, there is no non-functional DNA.  I do not think this is a myth — lots of non-coding DNA is probably non-functional.  However, lots isn’t.  It’s not either-or.

“Junk DNA myth”, interpretation #2: That non-coding DNA was “long dismissed as useless junk but now we’re finding functions”.  This is a myth.  There was no such period of dismissal.  Even if there was, it could only have been between about 1985 and 1995, which is less time than the period since this claim started being made.  I have tried to show this by referring directly to the primary literature of the 1970s, 1980s, and 1990s.

So, to clarify, I do not particularly like the term “junk DNA” because a) it has changed since its original meaning, and b) it clearly is too loaded to be used effectively in objective discourse.  I do think there is a large amount of DNA in most animal genomes that does not have any function at the organism level, but I also think some of it has been co-opted for very important roles. The originators of the “selfish DNA” idea thought so too:

“It would be surprising if the host genome did not occasionally find some use for particular selfish DNA sequences, especially if there were many different sequences widely distributed over the chromosomes. One obvious use … would be for control purposes at one level or another.”
- Orgel and Crick 1980

How much is functional?  I don’t know, but I can say that since there very beginning — in the first detailed discussion of “junk DNA” ever published — the proposed figure was higher than the current data suggest:

These considerations suggest that up to 20% of the genome is actively used and the remaining 80+% is junk. But being junk doesn’t mean it is entirely useless. Common sense suggests that anything that is completely useless would be discarded. There are several possible functions for junk DNA.
- Comings (1972)

I don’t know how to state it any more clearly than this.

Reduced genome works fine with 2000 chunks missing

To put a figure on how much of our DNA is non-essential, Vrijenhoek and his colleagues screened the genomes of 600 healthy students, searching for chunks of DNA at least 10,000 base pairs in length that were missing in some individuals. Across all the genomes, about 2000 such chunks were missing – amounting to about 0.12 per cent of the total genome.

Some people will over-interpret this as strong evidence for a majority of “junk DNA”. Comprising only 0.12% of the genome, it isn’t. However, as these are natural deletions >10kb, it gets around the objections to the deletion studies (i.e., that the conditions in the lab weren’t the same as the challenges faced in the wild). Then again, it may be that you can have one or two deletions and be ok because there is some redundancy, but if you were missing all of these bits you’d be in trouble. Others will dismiss it as an artifact or somehow not really testing the claim (read: dogmatic assumption) that all DNA is functional, but what else is new.

(Oh, and it gets bonus points for using one of my figures!)

Distributions of selectively constrained sites and deleterious mutation rates in the hominid and murid genomes.
Eory L, Halligan DL, Keightley PD

Protein-coding sequences make up only about 1% of the mammalian genome. Much of the remaining 99% has been long assumed to be junk DNA, with little or no functional significance. Here we show that in hominids, a group with historically low effective population sizes, all classes of non-coding DNA evolve more slowly than ancestral transposable elements, and so appear to be subject to significant evolutionary constraints. Under the nearly neutral theory, we expected to see lower levels of selective constraints on most sequence types in hominids than murids, a group that is thought to have a higher effective population size. We found that this is the case for many sequence types examined, the most extreme example being 5′ UTRs, for which constraint in hominids is only about one-third that of murids. Surprisingly, however, we observed higher constraints for some sequence types in hominids, notably four-fold sites, where constraint is more than twice as high as in murids. This implies that more than about one-fifth of mutations at four-fold sites are effectively selected against in hominids. The higher constraint at four-fold sites in hominids suggests a more complex protein-coding gene structure than murids, and indicates that methods for detecting selection on protein coding sequences (e.g., using the d(N) /d(S) ratio), with four-fold sites as a neutral standard, may lead to biased estimates, particularly in hominids. Our constraint estimates imply that 5.4% of nucleotide sites in the human genome are subject to effective negative selection, and that there are three times as many constrained sites within non-coding sequences as within protein-coding sequences. Including coding and non-coding sites, we estimate that the genomic deleterious mutation rate U = 4.2. The mutational load predicted under a multiplicative model is therefore about 99% in hominids.

Update: See BIOpinionated for a silly critique and Sandwalk for a fine reply.