You are on page 1of 37

DNA Mutation Rates



Sean D. Pitman M.D.

© August, 2005 (Updated)

Mitochondrial DNA Mutation Rates

Mitochondria are “organelles” within living cells that are responsible for making the

currency of energy called ATP (Adenosine Triphosphate), which all cells need to

function. Mitochondria carry their own separate DNA (mtDNA) that is independent of

the nuclear DNA of the same cell. Human mtDNA is composed of 37 genes totaling

about 16,000 base pairs. This mtDNA also mutates at a much faster rate than nuclear

DNA (nucDNA) does. Human mtDNA has been completely mapped and all the coding

regions are known (As well as the proteins or RNA for which they code). Some of the
mtDNA does not code for anything (thought to make these sections immune from

“natural selection pressure”), and are known as the "control regions". One particular

region appears to mutate faster than any other region (1.8 times faster), because the

variation among humans is greatest here.4 When the cell divides, each cell takes some

of the mitochondria with it. The mitochondria replicate themselves independently within

the cell. Beyond this, it has been generally assumed that mitochondria are always

passed on from the mother to the offspring without being involved with genetic shuffling

and recombining of mtDNA with the mtDNA of the father. Recently, however, this notion

has been challenged. As it turns out, many cases of paternally derived mtDNA have

been detected in modern families of humans as well as other species. Consider the

findings of an interesting study published by Schwartz and Vissing in the 2002 issue of

the New England Journal of Medicine:

"Mammalian mitochondrial DNA (mtDNA) is thought to be strictly maternally

inherited. Sperm mitochondria disappear in early embryogenesis by selective

destruction, inactivation, or simple dilution by the vast surplus of oocyte mitochondria. . .

The underlying mechanism responsible for the elimination of sperm mtDNA in normal

embryos is not well understood. We speculate that the process in some cases may be

defective, allowing sperm mitochondria to survive and giving those with a selective

advantage the possibility of prevailing in certain tissues. . . Very small amounts of

paternally inherited mtDNA have been detected by the polymerase chain reaction (PCR)

in mice after several generations of interspecific backcrosses. Studies of such hybrids

and of mouse oocytes microinjected with sperm support the hypothesis that sperm
mitochondria are targeted for destruction by nuclear-encoded proteins. We report the

case of a 28-year-old man with mitochondrial myopathy due to a novel 2-bp mtDNA

deletion in the ND2 gene (also known as MTND2), which encodes a subunit of the

enzyme complex I of the mitochondrial respiratory chain. We determined that the

mtDNA harboring the mutation was paternal in origin and accounted for 90 percent of

the patient's muscle mtDNA." 47

So, what does such a finding mean with regard to mtDNA mutation rates and

molecular clocks? Well, consider the following comments by Morris and Lightowlers

published in a 2000 edition of The Lancet:

Mitochondrial DNA (mtDNA) is generally assumed to be inherited exclusively from

the mother…. Several recent papers, however, have suggested that elements of mtDNA

may sometimes be inherited from the father. This hypothesis is based on evidence that

mtDNA may undergo recombination. If this does occur, maternal mtDNA in the egg must

cross over with homologous sequences in a different DNA molecule; paternal mtDNA

seems the most likely candidate…. If mtDNA can recombine, irrespective of the

mechanism, there are important implications for mtDNA evolution and for phylogenetic

studies that use mtDNA" 48

Before this evidence of paternal inheritance was discovered it was assumed that

mtDNA was strictly the result of maternal inheritance. Based on this assumption, it was

assumed that the mitochondrial offspring would get exact copies of the mitochondria
that the mother had except if there was a mutational error. This error rate in the non-

coding portion of mitochondrial DNA has long been thought to occur once every 300 to

600 generations, or every 6,000 to 12,000 years for humans.

The Berkeley biochemists who developed the theory, Allan Wilson, Rebecca Cann,

and Mark Stoneking, made several apparently reasonable assumptions. Since there

were no DNA changes due to genetic recombination events (ie: with paternal DNA - now

known to be a wrong assumption), they assumed that all changes in the mtDNA were

the result of mutations over time and that these mutations occurred at a constant rate.

On the basis of these assumptions, the researchers believed they had access to

something like a "molecular clock." Because mtDNA is thought to mutate faster than

nuclear DNA (nucDNA), it was thought that the faster mutation rate of mtDNA would

make for more accurate time keeping than nucDNA.

The original 1987 study involved mtDNA from 136 women from many parts of the

world having various racial backgrounds. The analysis seemed to support the idea of a

single ancestral mtDNA molecule from a woman living in sub-Saharan Africa about

200,000 years ago. Later, more detailed studies seemed to confirm this conclusion.

Unfortunately though, there was a undetected bias in the computer program as well as

with the researchers themselves. The researchers used a computer program designed

to reveal a "maximum parsimony" phylogeny or the family tree with the least number of

mutational changes. This was based on the assumption that evolution would have

taken the most direct and efficient path (which is not necessarily true, or even likely).

Also, the computer program was biased by the order of data entry to favor the

information entered first. This problem was recognized when the computer gave
different results depending on the order that the data was entered. Now, after thousands

of computer runs with the data entered randomly, it appears that the "African origin" for

modern humans does not hold a statistical significance over other possibilities.26

The problems with these studies were so bad that Henry Gee, a member of the

editorial staff for the journal, Nature, harshly described the studies as "garbage." After

considering the number of sequences involved (136 mtDNA sequences), Gee

calculated that the total number of potentially correct parsimonious trees is somewhere

in excess of one billion.25 Geneticist Alan Templeton (Washington University) suggests

that low-level mixing among early human populations may have scrambled the DNA

sequences sufficiently so that the question of the origin of modern humans and a date

for "Eve" can never be settled by mtDNA.22 In a letter to Science, Mark Stoneking (one

of the original researchers) acknowledged that the theory of an "African Eve" has been


Another interesting aspect of the "molecular clock" theory is the way in which the

mutation rate itself was determined. Contrary to what many might think, the mutation

rate was not initially determined by any sort of direct analysis, but by supposed

phylogenic evolutionary relationships between humans and chimps. In other words, the

mutation rate was calculated based on the assumption that the theory in question was

already true. This is a rather circular assumption and as such all results that are based

on this assumption will be consistent with this assumption - like a self-fulfilling prophecy.

Since the rate was calculated based on previous assumptions of evolutionary time, then

the results will automatically "confirm" the previous assumptions. If one truly wishes

independent confirmation of a theory, then one cannot calibrate the confirmation test by
the theory, or any part of the theory, that is being tested. And yet, this is exactly what

was done by scientists such as Sarich, one of the pioneers of the molecular-clock idea.

Sarich began by calculating the mutation rates of various species "...whose divergence

could be reliably dated from fossils." He then applied that calibration to the chimpanzee-

human split, dating that split at from five to seven million years ago. Using Sarich's

mutation calibrations, Wilson and Cann applied them to their mtDNA studies, comparing

"...the ratio of mitochondrial DNA divergence among humans to that between humans

and chimpanzees."24 By this method, they calculated that the common ancestor of all

modern humans, the "African Eve", lived about 200,000 years ago.

Obviously then, these dates, calculated from the mtDNA analysis, must match the

presupposed evolutionary time scale since the calculation is based on this

presupposition. The circularity of this method is inconsistent with good scientific method

and is worthless as far as independent predictive value is concerned. The

"mitochondrial clock" theory was and is basically a theory within a theory in that it has

no independent predictive power outside of the theory of evolution. It is surprising then

that scientists did not catch this inherent flaw earlier. Interestingly enough though, this

flaw in reasoning was not detected for many years and perhaps would have remained

undetected for much longer if a more direct mutation-rate analysis had not been done.

Eventually, scientists, who study historical families and their genetic histories,

started questioning the mutation rates that were based on evolutionary phylogenetic

assumptions. These scientists were “stunned” to find that the mutation rate was in fact

much higher than previously thought. In fact it was about 20 times higher at around one

mutation every 25 to 40 generations (about 500 to 800 years for humans). It seems that
in this section of the control region, which has about 610 base pairs, humans typically

differ from one another by about 18 mutations. 3 By simple mathematics, it follows that

modern humans share a common ancestor some 300 generations back in time. If one

assumes a typical generation time of about 20 years, this places the date of the

common ancestor at around 6,000 years before present. But how could this be?!

Thomas Parsons seems just as mystified. Consider his following comments published

April of 1997, in the journal Nature Genetics:

"The rate and pattern of sequence substitutions in the mitochondrial

DNA (mtDNA) control region (CR) is of central importance to studies of

human evolution and to forensic identity testing. Here, we report a direct

measurement of the intergenerational substitution rate in the human CR.

We compared DNA sequences of two CR hypervariable segments from

close maternal relatives, from 134 independent mtDNA lineages spanning

327 generational events. Ten substitutions were observed, resulting in an

empirical rate of 1/33 generations, or 2.5/site/Myr. This is roughly twenty-

fold higher than estimates derived from phylogenetic analyses. This

disparity cannot be accounted for simply by substitutions at mutational hot

spots, suggesting additional factors that produce the discrepancy between

very near-term and long-term apparent rates of sequence divergence. The

data also indicate that extremely rapid segregation of CR sequence

variants between generations is common in humans, with a very small

mtDNA bottleneck. These results have implications for forensic

applications and studies of human evolution.

The observed substitution rate reported here is very high compared

to rates inferred from evolutionary studies. A wide range of CR substitution

rates have been derived from phylogenetic studies, spanning roughly

0.025-0.26/site/Myr, including confidence intervals. A study yielding one of

the faster estimates gave the substitution rate of the CR hypervariable

regions as 0.118 +- 0.031/site/Myr. Assuming a generation time of 20

years, this corresponds to ~1/600 generations and an age for the mtDNA

MRCA of 133,000 y.a. Thus, our observation of the substitution rate,

2.5/site/Myr, is roughly 20-fold higher than would be predicted from

phylogenetic analyses. Using our empirical rate to calibrate the mtDNA

molecular clock would result in an age of the mtDNA MRCA of only ~6,500

y.a., clearly incompatible with the known age of modern humans. Even

acknowledging that the MRCA of mtDNA may be younger than the MRCA

of modern humans, it remains implausible to explain the known

geographic distribution of mtDNA sequence variation by human migration

that occurred only in the last ~6,500 years." 27

The calculation is done in the following way: Let us consider two randomly chosen

human beings. Assuming all human beings initially have identical mitochondrial DNA,

after 33 generations, two such random human families will probably differ by two
mutations, since there will be two separate lines of inheritance and probably one

mutation along each line. After 66 generations, two randomly chosen humans will differ

by about four mutations. After 100 generations, they will differ by about six mutations.

After 300 generations, they will differ by about 18 mutations, which is about the

observed value.

These experiments are quite concerning to evolutionists who previously calculated

that the “mitochondrial eve” (who’s mitochondria is thought to be the ancestor

mitochondria to all living humans) lived about 100,000 to 200,000 years ago in Africa.1

The new calculations, based on the above experiments, would make her a relatively

young ~6,500 years old. Now, the previous notion that modern humans are up to

10,000 generations old has to be reevaluated or at least the mtDNA basis for that

assumption has to be reevaluated - and it has been.2

More recent direct mtDNA mutation rate studies also seem to confirm the earlier

findings by Parsons and others. In an 2001 article published in the American Journal of

Human Genetics, Evelyne Heyer et. al., presented their findings of the mtDNA mutation

rate in deep-rooted French-Canadian pedigrees.

Their findings "Confirm[ed] earlier findings of much greater mutation rates in

families than those based on phylogenetic comparisons. . . For the HVI sequences, we

obtained 220 generations or 6,600 years, and for the HVII sequences 275 generations

or 8,250 years. Although each of these values is associated with a large variance, they

both point to ~7,000-8,000 years and, therefore, to the early Neolithic as the time of

expansion [mostly northern European in origin] . . . Our overall CR mutation-rate

estimate of 11.6 per site per million generations . . . is higher, but not significantly

different, than the value of 6.3 reported in recent the recent pedigree study of

comparable size . . . In another study (Soodyall et al. 1997), no mutations were detected

in 108 transmissions. On the other hand, two substitutions were observed in 81

transmissions by Howell et al. (1996), and nine substitutions were observed in 327

transmissions by Parsons et al. (1997). Combining all these data (1,729 transmissions)

results in the mutation rate of 15.5 (Cl 10.3-22.1). Taking into account only those from

deep-rooting pedigrees (1,321 transmissions) (Soodyall et al. 1997; Sigurdardottir et al.

2000; the present study) leads to the value of 7.9. The latter, by avoiding experimental

problems with heteroplasmy, may provide a more realistic approximation of the overall
mutation rate."

Also, consider an even more recent paper published in a 2003 issue of the Annals

of Human Genetics by B. Bonne-Tamir et al. where the authors presented their results

of a their study of "Maternal and Paternal Lineages" from a small isolated Samaritan

community. In this paper they concluded:

"Compared with the results obtained by others on mtDNA mutation rates, our

upper limit estimate of the mutation rate of 1/61 mutations per generation is in close

agreement with those previously published." 45 [compared with the rate determined by

Parsons of 1/33 generations, a rate of 1/61 is no more than double]

One more interesting paper published in September 2000 in the Journal Scientist

by Denver et al. is also quite interesting. These scientists reported their work with the

mtDNA mutation rates of nematode worms and found that these worm's molecular

clocks actually run about "100 times faster than previously thought" [emphasis


"Extrapolating the results directly to humans is not possible, say the scientists. But

their results do support recent controversial studies suggesting that the human

molecular clock also runs 100 times faster than is usually thought. This may mean that

estimates of divergence between chimpanzees and humans, and the emergence of

modern man, happened much more recently than currently believed, says the team.

'Our work appears to support human analyses, which have suggested a very high rate,'

says Kelley Thomas of the University of Missouri. 'This work is relevant to humans,'

says Doug Turnbill of the institute for Human Genetics and Newcastle University, UK. 'If

the human mutation rate is faster than thought, it would have a lot of impact in looking

at human disease and forensics, as well as the evolutionary rate of humans.' . . .

Mutation rates of mtDNA in humans are usually estimated by comparing

sequences of DNA from people and other animals. 'This is kind of analysis that was

used to determine that the African origin of modern humans was about 200,000 years

ago,' says Thomas. 'The problem with this approach is that you are looking at both the

mutation rate and the effects of natural selection,' he says. The technique would also

miss multiple mutations in the same stretch of mtDNA, says Paul Sharp of the Institute

of Genetics at Nottingham University, UK.

More recent studies have looked at the mtDNA of people who are distantly related

but share a female ancestor. This approach has revealed higher mtDNA mutation

rates. But the results have not been accepted by many scientists [emphasis


Knowing the exact rate of mutation in humans is very important for forensic

science and studies of genetic disease, stresses Turnbill. Forensic identification often

rests on comparing samples of DNA with samples from suspected relatives. Faster

human molecular clocks could complicate established exact relationships, he says." 46

Obviously then, these rates, based on more direct observations, are nowhere near

those based on indirect evolutionary assumptions. This certainly does "complicate"

things just a bit now doesn't it? Isn't it strange though that many scientists are still loath

to accept these results? The bias in favor of both evolution as well as millions of years

for assumed divergence times between creatures like apes and humans is so strong

that changing the minds of those who hold such positions may be pretty much


There are many other potential problems for phylogenies that rely on mtDNA

sequence analysis and mutation rates. One problem is that mtDNA functions as a

single genetic locus, much like a single gene does in nucDNA. Studies that work off a

single genetic locus are more likely to be affected by random genetic changes than are

studies that include more than one locus (the more the better). Therefore, single locus

studies are less accurate in characterizing a population. Beyond this, the new evidence

for paternal mtDNA mixing is quite problematic.16

Also, as briefly discussed above, the use of control regions as a "molecular clock"

may not be as valid as was previously hoped. Some nucleotide regions mutate slowly,

while others can mutate relatively rapidly.17 These mutational "hotspots" can mutate

fairly rapidly even within a single lifetime and are intuitively rather common in the

aged.18 Of course such "somatic" mutations arise in mitochondria of various bodily

tissues and, unless they involve gametes, they are not passed on to the next

generation. However, they would still affect phylogenetic interpretations. Scientists

have tried to compensate for these problems, but the various methods have produced

divergent results.19 Also, as discussed above, direct comparisons of modern sequences

with historical sequences often yield very difference results from those estimated by

indirect methods that are based on present day sequence differences. For another

example from a different species, direct comparisons of modern penguins with

historically sequenced penguins have shown that their mtDNA mutation rates are 2 to 7

times faster than had previously been assumed through indirect methods.20 Certain of

these problems have in fact led some scientists to stop using control-region sequences

to reconstruct human phylogenies.21

Those scientist that continue to try and revise the molecular clock hypothesis have

tried to slow down the clock by showing that some mtDNA regions mutate much more

slowly than do other regions. The problem here is that such regions are obviously

affected by natural selection. In other words, they are not functionally neutral with

regard to selection pressures.

For example, real time experiments have shown that average mitochondrial

genome mutation rates are around 6 x 10-8 mut/site/mitochondrial generation - in line

with various estimates of average bacterial mutation rates (Compare with nDNA rate of

4.4 x 10-8 mut/site/human generation). With an average generation time of 45 days,

that's about 5 x 10-6 mut/site/year and 5 mut/site/myr.

This is about twice as high as Parsons' rate of 2.5/mut/site/myr and about 40 to 50

times higher than rates based on phylogenetic comparisons and evolutionary

assumptions. And, this is the average rate of the entire mitochondrial genome of

16,000pb. One might reasonably think that all aspects of the hypervariable regions

(HVI & HVII) would have a higher than average rate of mutation if truly neutral with

regard to functional selection pressures. Given this, those "slowly mutating sites" with

rates as slow as 0.065 mut/site/myr (Heyer et al, 2001) would seem to be maintained in

a biased way by natural selection.

Again, such non-neutral changes are not necessarily the reflection of elapsed time

since a common ancestor so much as they are the reflection of the different functional

needs of different creatures in various environments.

Nuclear DNA Mutation Rates

As with mitochondrial DNA mutation rates, the mutation rates of nuclear DNA have

often been calculated based on evolutionary scenarios rather than on direct methods.
By such methods, the average mutation rate for eukaryotes in general is estimated to

be about 2.2 x 10-9 mutations per base pair per year.29 With a 20 year average

generation time for humans, this works out to be around 4.4 x 10-8 mutations per base

pair per generation. Since most estimates of the size of the diploid human genome run

around 6.3 billion base pairs, this mutation rate would give the average child around 277

mutational differences from his or her parents. This sounds like quite a high number

and it is in fact on the high end of the spectrum when compared to studies looking more

specifically at human mutation rates verses eukaryotic mutation rates in general. A

particular study by Nachman and Crowell estimated the average mutation rate

specifically in humans by comparing control sequences in humans and chimpanzees.

Using these sequence comparisons, "The average mutation rate was estimated to be

~2.5 x 10-8 mutations per nucleotide site or 175 mutations per diploid genome per

generation" [Based on a higher diploid genome estimate of 7 billion base pairs]. 30

These estimates do actually seem reasonable since they seem to match the error

rates of DNA replication and repair that occur between the formation of a zygote in one

generation and the formation of a zygote in the next generation. In the illustration31

below, notice that from fertilization to the formation of a woman's first functional gamete,

it takes about 23 mitotic divisions. Men, on the other hand, contribute about twice as

many germ line mutations as women do.33 At least part of the reason is that their stem

cells keep dividing so that the older a man gets before having children more mitotic

divisions occur.
Now, consider that each diploid fertilized zygote contains around 6 billion base

pairs of DNA (~3 billion from each gamete/parent, using a conservative round

number).32 From cell division to cell division, the error rate for DNA polymerase

combined with other repair enzymes is about 1 mistake in 1 billion base pairs copied.42

At this rate, there are about 6 mistakes with each diploid cell replication event. With a

male/female average of 29 mitotic divisions before the production of the next

generation, this works out to be about 175 mutations per generation.

Of course, this is right in line with the mutation rates that are based on evolutionary

scenarios. However, some estimates place the overall mutation rate as low as 1

mistake in 10 billion base pairs copied.43 At this rate, one would expect around 0.6

mistakes with each replication event and only around 17 mutations per person per

generation. In any case, since the rate of 175 mutations per generation is more in line

with most of the current estimates for humans, this rate will be used as the basis for the

rest of this discussion.

Such a high mutation rate might be a more of a problem than it is for humans if it

were not for the fact that much of the human genome does not seem to code for

anything and can therefore sustain mutations without significant detrimental effects on

the overall function of the organism. The amount of this non-coding DNA has been

estimated by calculating the coding portion of DNA and subtracting this from the total

genomic real estate. It seems as though the average coding portion of a human gene is

around 1,350 base pairs in size. Of course, this gene would code for a protein
averaging 450 amino acids.38 Now, multiplying this number by the total number of

genes should give a reasonable estimate of the coding genetic real estate.

However, there is some argument as to the total number of genes in the human

genome. For many years it was thought that humans had between 70,000 to 140,000

genes. However, scientists working on the human genome project made a surprising

discovery. When they finished the project in February of 2001, they estimated that the

actual gene count was somewhere between 30,000 to 40,000 genes.39 But a year later,

in February of 2002, at the annual meeting of the American Association for the

Advancement of Science (publisher of Science), one of the presenters, Victor

Velculescu, suggested that the real number of genes in the human genome may

actually be closer to 70,000 genes after all. He and his colleagues, at Johns Hopkins

University in Baltimore, Maryland, have gone back to the lab to look for genes that the

computer programs may have missed. Their technique, called serial analysis of gene

expression (SAGE), works by tracking RNA molecules back to their DNA sources. After

isolating RNA from various human tissues, the researchers copy it into DNA, from which

they cut out a kind of genetic bar code of 10 to 20 base pairs. Velculescu proposes that

the vast majority of these tags are unique to a single gene. If so, the tags can then be

compared to the human genome to find out if they match up with genes discovered by

the computer algorithms. Velculescu stated that only about half of the tags he used

match the genes identified earlier in the genome project. Therefore, he suggests that

the human inventory of genes had been underestimated by about half.

The reason for the disparity may be that the standard computer programs were

largely developed for the genomes of simple (prokaryotic) organisms, not for the more
complex sequences found in the genomes of humans and other eukaryotes. "We're still

not very good at predicting genes in eukaryotes," said Claire Fraser of The Institute for

Genomic Research in Rockville, Maryland. “It is entirely possible that there could be

more than 32,000 genes, and SAGE is an important approach to finding them… You

absolutely have to go back into the lab and get away from the computer terminal." 40

So, it seems as though there is still some question as to exactly how many genes

the human genome contains. But, for the sake of argument, lets go with a lower

estimate of ~40,000 genes. With each gene averaging 1,350 base pairs in size, only

around 108 million base pairs out of 6 billion base pairs (diploid) would code for

anything. This is only around 1.8% of the total genome. Much of the rest of the human

genome (At least 50%) is composed of a large amount of “repetitive DNA” that is made

up of similar sequences occurring over and over.33,38 At least some of the other 48% of

the genome is thought to provide structural integrity as well as regulating the production

of the coding sequences of DNA as far as when, where, and how much protein to

make. However, exactly how much of the non-protein-coding genome is functional is

not clearly understood. In any case, for the purposes of this discussion a rough figure

of 2% will be used as the amount of functional DNA in the human genome.

Since mutations are the only possible source of novel genomic function in the

evolution of living things, we should consider a few facts about these mutations.

Mutations are thought to be purely random events causes by errors of replication and

maintenance over time. They occur anywhere in the entire genome in a fairly random

fashion with each generation. Given this information, lets consider how these mutations

would build up and what effect, if any, they would have on a human lineage.
Newer research suggests a detrimental mutation rate (Ud) of 1 to 3 per person per

generation with at least some scientists (Nachmann and Crowell, 2000) favoring at least

3 or more.30 Since detrimental mutations outnumber beneficial mutations by at least

1,000 to 1, it seems like the build up of detrimental mutations in a population might lead

toward extinction. 34,36

Nachmann and Crowell detail the perplexing situation at hand in the following

conclusion from their fairly recent paper on human mutation rates:

The high deleterious mutation rate in humans presents

a paradox. If mutations interact multiplicatively, the genetic

load associated with such a high U [detrimental mutation

rate] would be intolerable in species with a low rate of

reproduction [like humans and apes etc.] . . .

The reduction in fitness (i.e., the genetic load) due to

deleterious mutations with multiplicative effects is given by 1

- e -U (Kimura and Moruyama 1966). For U = 3, the average

fitness is reduced to 0.05, or put differently, each female

would need to produce 40 offspring for 2 to survive and

maintain the population at constant size. This assumes that

all mortality is due to selection and so the actual number of

offspring required to maintain a constant population size is

probably higher.
The problem can be mitigated somewhat by soft

selection or by selection early in development (e.g., in

utero). However, many mutations are unconditionally

deleterious and it is improbable that the reproductive

potential on average for human females can approach 40

zygotes. This problem can be overcome if most deleterious

mutations exhibit synergistic epistasis; this is, if each

additional mutation leads to a larger decrease in relative

fitness. In the extreme, this gives rise to truncation selection

in which all individuals carrying more than a threshold

number of mutations are eliminated from the population.

While extreme truncation selection seems unrealistic [the

death of all those with a detrimental mutational balance], the

results presented here indicate that some form of positive

epistasis among deleterious mutations is likely.30

Nachmann and Crowell find the situation a very puzzling one. How does one get

rid of all the bad mutations faster than they are produced? Does their hypothesis of

“positive epistasis” adequately explain how detrimental mutations can be cleared faster

than they are added to a population? If the functional effects of mutations were

increased in a multiplicative instead of additive fashion, would fewer individuals die than

before? As noted above, even if every detrimental mutation caused the death of its
owner, the reproductive burden of the survivors would not diminish, but would remain

the same.

For example, lets say that all those with at least three detrimental mutations die

before reproducing. The population average would soon hover just above 3 deleterious

mutation rates. Over 95% of each subsequent generation would have 3 or more

deleterious mutations as compared with the original "neutral" population. The death

rate would increase dramatically. In order to keep up, the reproductive rates of those

surviving individuals would have to increase in proportion to the increased death rate.

The same thing would eventually happen if the death line were drawn at 100, 500,

1000, 10000 or more deleterious mutations. The only difference would be the length of

time it would take a given population to build up a lethal number of deleterious

mutations in its gene pool beginning at a relatively "neutral" starting point. The

population might survive fairly well for many generations without having to resort to

huge increases in the reproduction rate. However, without getting rid of the

accumulating deleterious mutations, the population would eventually find itself

experiencing an exponential rise in its death rate as its average population crossed the

line of lethal mutations.

Since the theory of positive epistasis does not seem to help the situation much,

some other process must be found to explain how to preferentially get rid of detrimental

mutations from a population. Consider an excerpt from a fairly recent Scientific

American article entitled, "Mutations Galore":

According to standard population genetics theory, the

figure of three harmful mutations per person per generation

implies that three people would have to die prematurely in

each generation (or fail to reproduce) for each person who

reproduced in order to eliminate the now absent deleterious

mutations [75% death rate]. Humans do not reproduce fast

enough to support such a huge death toll. As James F. Crow

of the University of Wisconsin asked rhetorically, in a

commentary in ‘Nature’ on Eyre-Walker and Keightley's

analysis: “Why aren't we extinct?”

Crow's answer is that sex, which shuffles genes

around, allows detrimental mutations to be eliminated in

bunches. The new findings thus support the idea that sex

evolved because individuals who (thanks to sex) inherited

several bad mutations rid the gene pool of all of them at

once, by failing to survive or reproduce.

Yet natural selection has weakened in human

populations with the advent of modern medicine, Crow

notes. So he theorizes that harmful mutations may now be

starting to accumulate at an even higher rate, with possibly

worrisome consequences for health. Keightley is skeptical:

he thinks that many mildly deleterious mutations have

already become widespread in human populations through

random events in evolution and that various adaptations,

notably intelligence, have more than compensated. “I doubt

that we'll have to pay a penalty as Crow seems to think,” he

remarks. “We've managed perfectly well up until now." 37

Well, the answer might be found in a combination of processes where both sexual

replication and natural selection play a role to keep a slowly reproducing population

from going extinct. For example consider the following chart showing how deleterious

mutations build up in a population that reproduces via asexual means: 49

Notice how the most fit "Progenitor Class" (P) loss numbers in each generation

while the numbers of those that have greater numbers of deleterious mutations build up

more and more. In this article Rice notes that in asexual populations the only way to

really overcome this buildup of detrimental mutations is to increase the reproductive rate

substantially. But, what about beneficial mutations? Rice comments, "Rare reverse and

compensatory mutations can move deleterious mutations, via genetic hitchhiking,

against the flow of genetic polarization. But this is a minor influence, analogous to water

turbulence that occasionally transports a pebble a short distance upstream." 49 So, how

do sexually reproducing populations overcome this problem?

When it comes to sexually reproducing populations, the ability for genetic

recombination during the formation of gametes makes it possible to concentrate both

good and bad mutations. For example, lets say we have two individuals, each with 2

detrimental mutations. Given sexual recombination between these two individuals, there

is a decent chance that some of their offspring (1 chance in 32) will not have any

inherited detrimental mutations. But what happens when the rate of additional

detrimental mutations is quite high - higher than 3?

To look into this just a bit more, consider another example of a steady state

population of 5,000 individuals each starting out with 7 detrimental mutations and an

average detrimental mutation rate of 3 per individual per generation. Given a

reproductive rate of 4 offspring per each one of the 2,500 couples (10,000 offspring), in

one generation, how many offspring will have the same or fewer detrimental mutations

than the parent generation?

Inherited After Ud = 3
7 901
6 631
5 378
4 189
3 76
2 23
1 5
0 0.45
< or = 7 2202

This Poisson approximation shows that out of 10,000 offspring, only 2,202 of them

would have the same or less than the original number of detrimental mutations of the

parent population. This leaves 7,798 with more detrimental mutations than the parent

population.51 Of course, in order to maintain a steady state population of 5,000, natural

selection must cull out 5,000 of these 10,000 offspring before they are able to

reproduce. Given a preference, those with more detrimental mutations will be less fit by

a certain degree and will be removed from the population before those that are more fit

(less detrimental mutations). Given strong selection pressure, the second generation

might be made up of ~2,200 more fit individuals and only ~2,800 less fit individuals with

the overall average showing a decline as compared with the original parent generation.

If selection pressure is strong, so that the majority of those with more than 7 detrimental

mutations are removed from the population, the next generation will only have about

1,100 mating couples as compared to 2,500 in the original generation. With a

reproductive rate of 4 per couple, only 4,400 offspring will be produced as compared to

10,000 originally. In order to keep up with this loss, the reproductive rate must be

increased or the population will head toward extinction. In fact, given a detrimental

mutation rate of Ud = 3 in a sexually reproducing population, the average number of

offspring needed to keep up would be around 20 per breeding couple (2eUd/2). While

this is about half that required for an asexual population (2eUd), it is still quite


In this light, consider that more recent estimates suggest that the deleterious

mutation rate is even higher. "extrapolations from studies of humans and Drosophila

(Mukai, 1979; Kondroshov, 1988; Crow, 1993) suggest that Ud > 5 is feasible." 49

However, the number of required offspring needed to compensate for such a high

detrimental mutation rate would soar to 148 per female per generation! The various

forms of positive epistasis (see illustration by Rice below) 49 do not solve this problem.
Also, what about the Y-chromosome in males? The Y-chromosome does not

undergo significant sexual recombination. Are the males of slowly reproducing species,

like humans, therefore headed for extinction at an even faster rate than females?

"The absence of recombination with a homologous partner means that it [The Y-

chromosome] can never be ‘repaired’ by recombination. This has led to suggestions that

the Y is destined for extinction – it will eventually dwindle to nothing. According to this
model, its role in sex determination will eventually be taken on by genes elsewhere in
the genome."

The author of the above quoted article goes onto point out that several species,

like the Armenian mole vole, are able to reproduce without the Y chromosome. While

this might explain where humans are headed, it doesn't seem quite clear as to just how

the Y-chromosome could have evolved over millions of years of time given its relative

inability to combat high detrimental mutation rates.

1. Gibbons, A. Calibrating the Mitochondrial Clock, Science 279, Volume

279, Number 5347 Issue of 2 Jan 1998, pp. 28 – 29
2. Collins, F., M. Guyer, and A. Chakravarti, Variations on a Theme: Human
DNA Sequence Variation, Science 278:1580-1581, 28 November 1997,
page 1581.
3. Genetics vol. 15, April 1997, pp. 363-367.
4. S. Horai, K. Hayasaka, R. Kondo, K. Tsugane, and N. Takahata, Recent
African origin of modern humans revealed by complete sequences of
hominoid mitochondrial DNAs, Proc. Natl. Acad. Sci. USA 1995 Jan
5. Dorit, R.L., Akashi, H. and Gilbert, W. 1995. Absence of polymorphism at
the ZFY locus on the human Y chromosome, Science 268 (26 May
6. L. Simon Whitfield, John E. Sulston, and Peter N. Goodfellow, Sequence
Variation of the Human Y Chromosome, Nature 378 (1995), pp. 379-380.
7. V. Morell. The Origin of Dogs: Running With the Wolves, Science 1997
June 13; 276 (5319):1647 (in Research News).
8. C. Vila, P. Savolainen, J. E. Maldonado, I. R. Amorim, J. E. Rice, R. L.
Honeycutt, K. A. Crandall, J. Lundeberg, and R. K. Wayne, Multiple and
Ancient Origins of the Domestic Dog, Science, June 13, 1997, vol. 276,
no. 5319, pp. 1687-1689 (in Reports).
9. Multiple independent transpositions of mitochondrial DNA control region
sequences to the nucleus, PNAS 1996 93: pp. 15239-15243.
10. J. Klicka and R. M. Zink. The Importance of Recent Ice Ages in
Speciation: A Failed Paradigm, Science 1997 September 12; 277 (5332):
p. 1666 (in Reports).
11. Spetner, Not by Chance, Judaica Press, Brooklyn, New York, 1997, page
12. Moreel, V., Bacteria Diversify Through Warfare, Science, Volume 278,
October 24, 1997, page 575.
13. Kondrashev, A.S., 1988, Deleterious mutations and the origin of sexual
reproduction, Nature vol. 336 Dec. 1 pp. 435-440.
14. Ninth International Conference on Microbial Genomes, October 28th-
November 1st, 2001. Gatlinburg, TN ( )
16. Williams, Sloan R., Napoleon A. Chagnon, and Richard S. Spielman
(2002) "Nuclear and mitochondrial genetic variation in the Yanomamö: A
test case for ancient DNA studies of prehistoric populations." American
Journal of Physical Anthropology 117: 246-259.
17. Stoneking, Mark (2000) "Hypervariable sites in the mtDNA control region
are mutational hotspots." American Journal of Human Genetics 67: 1029-
18. Nekhaeva, E., N.D. Bodyak, Y. Kraytsberg, S.B. McGrath, N.J. Van
Orsouw, A. Pluzhnikov, J.Y. Wei, J. Vijg, and K. Khrapko (2002) "Clonally
expanded mtDNA point mutations are abundant in individual cells of
human tissues." Proceedings of the National Academy of Sciences 99:
19. Heyer, Evelyne, Ewa Zietkiewicz, Andrzej Rochowski, Vania Yotova, Jack
Puymirat, and Damian Labuda (2001) "Phylogenetic and familial estimates
of mitochondrial substitution rates: Study of control region mutations in
deep-rooting pedigrees." American Journal of Human Genetics 69: 1113-
20. Lambert, D.M., P.A. Ritchie, C.D. Millar, B. Holland, A.J. Drummond, and
C. Baroni (2002) "Rates of evolution in ancient DNA from Adélie
penguins." Science 295: 2270-2273.
21. Ingman, Max, Henrik Kaessmann, Svante Pääbo, and Ulf Gyllensten
(2000), Mitochondrial genome variation and the origin of modern humans,
Nature 408: 708-713.
22. Barinaga, Marcia , African Eve' Backers Beat a Retreat, Science, 255 (7
February 1992): 687.
23. Hedges, S. Blair , Sudhir Kumar, Koichiro Tamura, and Mark Stoneking,
Human Origins and Analysis of Mitochondrial DNA Sequences, Science,
255 (7 February 1992): 737-739.
24. Wilson, Allan C., Cann, Rebecca L., The Recent African Genesis of
Humans, Scientific American, April 1992.
25. Gee, Henry, Statistical Cloud over African Eden, Nature, 355 (13 February
1992): 583.
26. Lubenow, Marvin, The Apple Computer Bites the African Eve, Impact No.
229, Institute for Creation Research, July 1992
( )
27. Parsons, Thomas J. A high observed substitution rate in the human
mitochondrial DNA control region, Nature Genetics vol. 15, April 1997, pp.
28. Coghlan, Andy, Proceedings of the National Academy of Sciences (DOI:
29. Sudhir Kumar, Sankar Subramanian, Mutation Rates in Mammalian
Genomes, PNAS, January 22, 2002, Vol. 99, No. 2, p. 803-808. ( )
30. Nuchman, Michael W., Crowell, Susan L., Estimate of the Mutation Rate
per Nucleotide in Humans, Genetics, September 2000, 156: 297-304 ( )
35. Ben Shouse, American Association for the Advancement of Science
Annual Meeting, Human Gene Count on the Rise, Science Feb 22 2002:
1457. ( )
37. Beardsley, Tim , Mutations Galore, Scientific American, Apr99, Vol. 280
Issue 4, p32, 2p
39. Lemonick, M. Gene Mapper, Time, Vol. 156, No. 26, pp110, 2001.
40. Shouse, Ben. American Association for the Advancement of Science
Annual Meeting: Human Gene Count on the Rise, Science, 22 Feb. 2002:
1457. (
44. Evelyn Heyer, Ewa Zietkiewicz, Andrezej Rochowski, Vania Yotova, Jack
Puymirat, and Damian Labuda, Phylogenetic and Familial Estimates of
Mitochondrial Substitution Rates: Study of Control Region Mutations in
Deep-Rooting Pedigrees. Am. J. Hum. Genet., 69:1113-1126. 2001 (
122.text.html )
45. B. Bonné-Tamir, M. Korostishevsky, A. J. Redd, Y. Pel-Or, M. E. Kaplan
and M. F. Hammer, Maternal and Paternal Lineages of the Samaritan
Isolate: Mutation Rates and Time to Most Recent Common Male Ancestor,
Annals of Human Genetics, Volume 67 Issue 2 Page 153 - March 2003 (
1809.2003.00024.x/full/ )
46. Denver DR, Morris K, Lynch M, Vassilieva LL, Thomas WK. High direct
estimate of the mutation rate in the mitochondrial genome of
Caenorhabditis elegans. Science. 2000 Sep 29;289(5488):2342-4. ( )
Also reported by: Emma Young, Running Slow, New Scientist, September
28, 2000. ( )
47. Schwartz, Marianne and John Vissing (2002), “Paternal Inheritance of
Mitochondrial DNA,” New England Journal of Medicine, 347:576-580,
August 22. ( http://0- )
48. Morris, Andrew A. M., and Robert N. Lightowlers (2000), “Can Paternal
mtDNA be Inherited?,” The Lancet, 355:1290-1291, April 15. ( Full Text )
49. William R. Rice, Requisite mutational load, pathway epistasis, and
deterministic mutation accumulation in sexual versus asexual populations,
Genetica 102/103: 71–81, 1998. 71 (Full Text)
50. IJ, Sex and Death, The Human Genome - In The Genome, September,
2003 (Full Text)
51. Poisson Distribution Calculator (Link)
52. Binomial Calculator (Link)

. Home Page . Truth, the Scientific

Method, and Evolution

. Methinks it is Like a Weasel . The Cat and the Hat -

The Evolution of Code

. Maquiziliducks - The Language of Evolution . Defining Evolution

. The God of the Gaps . Rube Goldberg

. Evolving the Irreducible . Gregor Mendel

. Natural Selection . Computer Evolution

. The Chicken or the Egg . Antibiotic


. The Immune System . Pseudogenes

. Genetic Phylogeny . Fossils and DNA

. DNA Mutation Rates . Donkeys, Horses,

Mules and Evolution

. The Fossil Record . The Geologic


. Early Man . The Human Eye

. Carbon 14 and Tree Ring Dating . Radiometric Dating

. Amino Acid Racemization Dating . The Steppingstone

. Quotes from Scientists . Ancient Ice

. Meaningful Information . The Flagellum

. Harlen Bretz

Search this site or the web powered by FreeFind

Site search Web search

Since June 1, 2002


Stacking the Deck

God of the Gaps

The Density of Beneficial Functions

All Functions are Irreducibly Complex

Ladder of Complexity

Chaos and Complexity

Confusing Chaos with Complexity

Evolving Bacteria

Irreducible Complexity

Scientific Theory of Intelligent Design

A Circle Within a Circle

Crop Circles

Mindless vs. Mindful

Single Protein Functions

BCR/ABL Chimeric Protein

Function Flexibility

The Limits of Functional Flexibility

Functions based on Deregulation

Neandertal DNA

Human/Chimp phylogenies


The Geologic Column

Fish Fossils

Matters of Faith

Evidence of Things Unseen

The Two Impossible Options

Links to Design, Creation, and Evolution Websites

Since June 1, 2002