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Entries in evolution (9)

Tuesday
Jun262012

If birds are baby dinosaurs and humans are baby apes...

A recent publication in Nature suggests that in many ways, birds are baby dinosaurs. The finding is less unusual than it might seem, afterall it is well established that humans have many traits of baby apes and dogs are in some ways baby wolves. The process is known as paedomorphosis or neoteny - the retention of juvenile traits in the adult form. This can take the form of enlarged eyes (birds), larger brains (humans) or retention of juvenile behaviour (dogs).

The reason why paedomorphosis works is that the basic body plan has much deeper evolutionary roots than the species-specific add-ons. Think of it this way, all mammals pretty much have the genetic program to make a nose, but only the elephant has evolved an additional genetic plan to turn that nose into a trunk. Deep in the genetic code of the elephant there is still the "standard nose" code (and indeed, the foetus has a relatively normal nose), it just has added lines of code that upgrade the standard nose into a trunk. This means that in theory, the elephant could evolve away from the trunk by just ditching the upgrade code, letting it default into the standard nose code. This is true for most of development - new code is never optimally created for the organ, rather it is always adding a bit of extra code to change the outcome. For a software engineer it would be the hight of laziness, creating bloated useless code, with every problem solved by kludge

Despite being inefficient and inelegant, the system of "generic code" plus "species specific" is very useful for evolution. This is because species evolve to be adapted to a specific environment. The flamingo beak is fantastic for a filter-feeder, but it has lost the generic functions that a sparrow could use its beak for.

Imagine an island with brine lakes that is populated only by flamingoes. If those brine lakes dried up, the flamingoes would go extinct. But what if new niches opened up? The ordinary "forward" process of evolving a generalist beak is quite slow, because you need to generate new code, but the "backwards" process of paedomorphosis could be quite fast, because it is just the process of deleting the species-specific code, defaulting back to the generic beak (as in anything else, destruction is faster and easier than generation). It is not difficult to imagine a relatively small set of genetic deletions that would mean the adult flamingo retained the juvenile generic beak, and then these "de-evolved" generalist birds could take advantage of the new habitat, and indeed start to evolve specific changes to specialise towards that new habitat.

As a general rule, following a large change in the environment, the generalised (juvenile) body plan is probably going to be more successful than the specialised (adult) body plan. Paedomorphosis in effect provides a default option to revert to in case of catastrophic change, allowing a species to shed its specialised features and start again. One possibility that interests me is that an open niche may drive paedomorphosis by selecting for rapid population growth. Consider the drying up of Africa that occured 5 million years ago. All of the apes that were specialised to live in rainforest would have seen dramatic contraction of their habitat, leaving just a few thousand gorillas left today. But the drying also created a new niche, the savanna, which could be exploited by any ape that was able to adapt. Paedomorphosis probably played a role in human evolution, by shedding the arboreal features required to swing in trees, allowing the pre-humans to venture onto the savana. Now consider the first pre-humans that were suitable for the savana - they has a continent to spread across, with the only limitation being the reproduction rate. We already know that a truly open niche creates an evolutionary pressure to fill it - such as the natural selection of cane toads in Australia with longer legs simply because they can move faster into virgin territory. What if this put selection on humans to reproduce at a younger age? Any variants that became fertile younger (and thus, while still carrying juvenile features) would outcompete the others, creating a population shift. In effect, there would be selection for paedomorphosis simply to increase the reproduction rate, with the retention of other juvenile traits (such as a larger brain) being a side-effect. 

If this model it correct, it would mean that open niches would drive paedomorphosis via two mechanisms - by selecting for the retention of juvenile traits to give a more generalist body plan, and by selecting for sexual maturity at a younger age to give more rapid reproduction. This dual selection force would drive much more rapid evolution, and may be responsible for some of the most remarkable evolutionary shifts, including the evolution of humans. 

Thursday
Sep292011

The Naked Baby hypothesis of human evolution

When thinking of the distinctiveness of Homo sapiens, the primary traits mentioned are our large brain, capacity for language and bipedal stance. Almost as unusual, however, is our lack of body hair (with notable exceptions). Two hypotheses have been put forward for this, but neither has ever really satisfied me, so I'll put forward a third.

 

The Savanna hypothesis is that hairlessness is an adaption to living on the African savanna. Under this model, humans evolved as high speed predators. One of the major limitations on running is in dissipating excess heat, indeed this is what stops most cheetah sprints. By losing hair and evolving sweat glands over the entire body, humans would have evolved to become better able to lose heat and therefore sustain high speeds over longer periods of time than other predators. There is a logical basis to this hypothesis, and it fits the location of human evolution, however there are also some relative weaknesses. Chiefly, why are human unique in losing their hair if hair is really such a limitation as a predator? The Big Cats are all sprint or ambush hunters, but wild dogs are marathon predators and they have a normal hair cover. And if this is such an advantage on the savanna, why haven't prey animals lost their hair? Like humans, horses sweat over their entire body and the presence of hair does not seem to inhibit their heat shedding.

 

The Aquatic Ape hypothesis is a novel alternative. This hypothesis postulates that humans evolved as a semi-aquatic ape, and have evolved numerous physiological adaptions to the water including voluntary breathe control and bipedalism. Almost all the examples of hairless mammals are aquatic (dolphins, seals, sealions, whales, manatees, hippos) or have semi-aquatic ancestors (elephants, rhinos), so hairlessness does not look as much an outlier as it does on the savanna. There are numerous other points in favour of this hypothesis, however the big disadvantage is that there is very little supporting evidence in the fossil record of any aquatic or semi-aquatic phase of human evolution. Hairlessness in aquatic mammals is also restricted to fully aquatic diving animals or extremely large semi-aquatic animals, with smaller semi-aquatic animals (such as otters) having a full coat of hair.

 

So I would like to put forward a third hypothesis, the Naked Baby hypothesis. Rather than find an evolutionary explanation for why adult humans are hairless, I postulate that there was intense selection for hairless infants, and this trait has then been carried over to the adult human. What could have been the selective pressure for hairless infants? Well, human infants are born at a very immature state compared to most other mammals, with the first three months of birth often described as a fourth trimester. Most mammals are born with far more motor control, often being independently mobile within hours. Human infants, by contrast, are completely uncoordinated and incontinent, wallowing in its own filth (this hypothesis is dedicated to baby Hayden, who inspired it). A human baby with a thick coat of fur would certainly be disgusting beyond all imagination, putting it at risk of infection and enhanced predation. Once you accept a hairless infant, the hairless adult is evolutionarily plausible. Neoteny, the retention of infantile traits in adults, is a common feature of human evolution, in everything from jaw length and tooth number to limb proportions.

 

The Naked Baby hypothesis has quite a few parsimonious features:

1. It reduces the number of independent features of human evolution that need to be explained. Rather than hairlessness being an independent trait, it now becomes a byproduct of the premature birth due to enhanced brain size.

2. It explains the variation in adult human hairiness. If adult hairlessness was selected for, we would not expect to see such sexual dimorphism or such extreme variation even within a single sex. If, however, selection occurs at the infantile stage and the trait is being carried over in a neutral fashion to adults, variable penetrance would be expected. The large increase in hair at puberty and steady increase with advanced age also correlates with the loss of other infantile features (such as relative increases in jaw and nose length).

3. It removes human exclusivity. Hairless adult mammals are extremely rare, but hairless infant mammals are quite common among rodents. Like humans, rodent infants are born at an extremely premature state. The evolutionary reason is quite different - the large head size requires premature birth in humans, while the large litter size requires premature birth in rodents. However the conservation of hairlesses is, to me, quite striking. Could it be that infant rodents and humans are hairless for the same reason - to keep down attachment of their own filth? Of course in rodents, with a large surface area to volume ratio, there would be strong selection in adults to grow hair to retain heat, while for much larger humans the adult selection against hairlessness would be much weaker than the infantile selection for hairlessness.

 

Sunday
Jul032011

Facts and Myths about HIV & Circumcision

Fact: Circumcision protects against HIV infection

There are three tiers of evidence for the protective effect of circumcision against HIV infection. Firstly, there are the epidemiological observations, where rates of HIV in circumcised and uncircumcised populations are compared. Secondly, there are the case-control observations, where rates of HIV in circumcised and uncircumcised individuals are compared. And thirdly, there are the randomised clinical trials, where men are assigned to either circumcision or no circumcision and the effect of future HIV infection is compared. 

We can deal with these in turn. The first are the epidemiological surveys. There are multiple relevant studies, all with similar effects, but one of the best designed is the multicentre study set in four cities in different regions of Africa. These studies show a much lower rate of HIV infection in west and north Africa compared to east and south Africa. The infection prevalence closely mirrors the religious border, with lower rates in Muslim Africa and higher rates in Christian Africa. Despite the glee with which certain Muslim scholars touted this as a representation of increased sexual restraint among Muslims, the multicentre study showed very few differences in sexual activity (number of sex partners, prostitution levels, etc). This is not evidence for the role of circumcision in protection against HIV, but it is very strong evidence that something is different between these two communities and that it has a strong role in protection against HIV.

The epidemiological studies lead multiple groups of researchers to investigate the circumcision hypothesis using case-control experiments (comparing the infection rate in circumcised and uncircumcised men). With dozens of different studies, all of various quality, the best way to assess the results is from the systematic reviews that have been performed. General population studies. This systematic review in 2005 looked at all 36 studies into circumcision that had been performed to date. Among the 18 general population studies, seven studies showed a protective effect and two studies showed a harmful effect (right). The difficulty of general population studies is that the rate of HIV infection is low enough that it can be difficult to control for bias and to generate enough statistical power. High-risk studies, by contrast, tend to have higher HIV rates and to have less bias in risk factors, often leading to additional statistical power. Among the 18 high-risk group studies, 13 studies showed a protective effect and no studies showed a harmful effect (left). High-risk population studies Thus, over all, of the 36 studies, 20 showed a significant protective effect, 2 showed a significant detrimental effect, and 14 had insufficient power to draw a conclusion. For anyone who is used to looking at research on inbred mice or the like, this data looks very noisy, however with the immense variation of behaviour and exposure among the human population this type of noise is typical, and the noise in the results are comparable to that observed in condom use studies. One interesting observation is that the studies where circumcision status was actually assessed by the trial nurses showed a stronger (beneficial) effect than the studies where circumcision status was self-reported, other studies show that the error-rate in self-reporting circumcision can be as high as 10%. Overall, the average effect of these trials is a 60% protective effect on HIV infection, again comparable in scope to the average effect observed in condom use studies (~80%).

The key criticism of any case-control study is that there may be confounding effects. When these confounding effects are known (eg number of sexual partners) they can be controlled for, but when confounding effects are unknown they cannot be controlled for. It is therefore always theoretically possible that there is some unknown confounding effect that has a strong correlation with circumcision and is protective against HIV infection. The only way to control for this possibility is to have a randomised clinical trial, where HIV-negative men enroll and are then randomly assigned to either the control group or the circumcision group. In this ideal experiment any confounding factors will be randomised to the two different groups and the effect only of the treatment can be identified. This randomised clinical trial design is the exact experiment performed by three independent groups.  

The study by Auvert et al enrolled a total of 3,274 uncircumcised men in South Africa, tested for HIV and assigned half to be circumcised. The group then followed up both cohorts for HIV status, condom use, sexual activity and so forth, and found a 60% protective effect for HIV infection among the circumcised group. Condom use, sexual activity and the like were nearly identical among the two groups, normalisation for these factors resulted in a 61% protective effect. The study by Bailey et al enrolled uncircumcised 2784 men in Kenya, tested for HIV, assigned half to be circumcised and again followed up for HIV infection and behaviour change. Again, no changes in sexual behaviour were observed and the risk of HIV was reduced by 60%. Finally, the study by Gray et al, with a similar design in Uganda, enrolled 4996 uncircumcised men and found a net protective effect of 60%. All three trials were independently run along best practice guidelines with blinded tested, yet all three trials found the identical effect of 60% protection - which was also the average protective effect observed in the case-control studies. Together, with multiple independent lines of evidence pointing towards the same result, the effect can be considered conclusive, to the point that it is now considered unethical to conduct more clinical trials as it would mean withholding treatment to the control group - the same way that we cannot ethically conduct more clinical trials on proven vaccines.

Several reoccurring criticisms come up for these three clinical trials. The most common objection is that all three trials were stopped early. This is true, however they were specifically stopped early by the ethical board review because the results were clear early on. It is now a built-in feature to clinicial trials that intermittent review will take place and the trials will be halted if adverse events surpass a particular level (so that excess participants are not exposed to the treatment) or if the protective effect surpasses a particular level (because it is considered unethical to withhold the treatment from the control group at this point). This is not a unique feature of the circumcision trials and is an agreed upon compromise between getting perfect scientific results and treating the participants of the trial in an ethical manner. The other main criticism that is raised is that the control group for circumcision is not like a traditional placebo - the trial doctors are blinded but the participants are not, and those assigned to the circumcision group may drop out at higher rates, creating a bias. While theoretically possible, each of the three studies investigated this possibility by looking at the drop-out rate. For example the Gray study found that out of 4996 enrollments, only 37 dropped out (24 in the circumcision group and 13 in the control group), not enough to create any substantial bias.

One further comment. The direct protective effect of circumcision is only known to protect men during vaginal intercourse. It is also likely to protect men during anal intercourse, but this has not been studied. It provides little to no direct protection to the woman, however mathematical modelling suggests that when the take-up of circumcision reaches 50% the "herd immunity" effect would reduce HIV infection among females and uncircumcised men by 25-30%. While not exactly a "silver bullet", this would make an impact to millions of people within southern Africa, where existing circumcision rates are low.

 

Myth: the foreskin must be functional or it would have been eliminated by evolution

This myth comes in two flavours. The first is that because it is present it must be functional, the second that if it actually was detrimental in HIV infection it would be selected against. As to the first, evolution does tend to result in the loss of anatomical features with no function, however there are strong exceptions for sexually dimorphic features. Thus a male nipple has no function, but there is strong sexual selection to keep the female nipple. In the absence of selection to create a suppressive pathway against nipple development in males, the useless male nipple is maintained. In all likelihood the foreskin is similar to the male nipple, as the male relic of the female labium. As to the second argument, it must be remembered that evolution is responsive, not predictive. Prior to the entry of widespread HIV infection there would have been no evolutionary pressure against the foreskin. If HIV had been a common infection for millions of years, the continued existence of a foreskin would indeed be a mystery, but this is not the case.

 

Myth: HIV protection is just a matter of cleanliness

A commonly stated myth about circumcision is that the HIV protection is simply due to the ease of keeping the circumcised penis clean and that good hygiene would replicate the effect. As a starting hypothesis, this is not an unreasonable model to test. A prediction of this model would be that circumcision would protect against a broad range of sexually transmitted infection (STIs), as the "cleanliness hypothesis" would not predict any special status for HIV protection. The ability of circumcision to protect against multiple STIs has been tested in epidemiological studies and randomised trials and so far no effect has been reliably measured for any STI other than HIV. It is possible that for some rare STIs in addition to HIV there may be protective effects and also possible that there is a weak effect against HSV, but to date the evidence against the "cleanliness hypothesis" is very strong - the protective effect of circumcision does not appear to be due to differential cleanliness and is almost certainly due to the unique biological properties of HIV outlined below.

 

Myth: there is no known biological mechanism to explain the protective effect of circumcision on HIV

The gold standard for incorporating a technique into evidence-based medicine is success in randomised clinical trials, as already proven for circumcision. However medical researchers prefer to understand the mechanism of protection for any intervention, as it allows optimisation or replacement with simpler strategies. It is sometimes claimed that there is no plausible mechanism by which circumcision protects against HIV, however a review of the literature demonstrates that the known biology of HIV suggests an optimal infection route via the foreskin. Unlike some sexually transmitted viruses, like HPV, that are able to directly infect through the skin, HIV is an exceptionally poor virus at crossing the epidermal barrier - purified HIV placed on the skin will remain safely external. Instead, HIV has to rely on two different mechanisms to breach the epidermal barrier - microabrasions and cellular trafficking.

Microabrasions are small tears in the skin barrier which expose the inner tissue and blood to the environment, allowing a direct passageway for HIV to enter. One common cause of microabrasions are sexually transmitted diseases, which often form small ulcers to allow increased shedding. These ulcers allow the reverse infection of HIV, which is why the transmission rate of HIV increases 100-fold with coinfection with other sexually transmitted infections (such as HSV-2). This accounts for the recent data suggesting that anti-HSV-2 treatment programs may reduce HIV spread. The skin of different organs is more or less prone to microabrasions. The mucosa of the anus is the thinnest, followed by the vagina, followed by the oral cavity, followed by the penis, which correlates with the increasing risk of HIV acquisition per sexual act (anal receptive > vaginal receptive > oral receptive > insertive).

 

The second mechanism is that of cellular traffic. HIV infects through the CD4 receptor, using the coreceptors CCR5 and CXCR4. The expression pattern of these receptors limits the infection of HIV to CD4 T cells, macrophages and dendritic cells. Typically, these cells are found in circulation (which is why intravenous injection of HIV in contaminated blood provides the highest efficiency infectious route), but activated CD4 T cells and naive dendritic cells also circulate into the tissue. In the skin, the top layer is a keratinised barrier with dead cells, with the living tissue deep below this layer. The mucosa is quite different - as a functional interface it requires living cells to directly border the environment. While most of these cells are epithelial in origin, and hence not infected by HIV, dendritic cells lie just below the surface. The reason for this is the role of dendritic cells in antigen sampling, ironically a defense mechanism against common mucosal pathogens. Critically, these dendritic cells do not only lie just below the surface, but the also push thin dendrites through the epithelial cell barrier so that they directly contact the surface (right). We even know exactly how the dendritic cells form these dendrites, as a key paper in Science demonstrated that dendritic cells that lack the chemokine receptor CX3CR1 still home to the epithelial cell surface, but they are unable to produce the dendrites that penetrate to the surface (left).

With regards to circumcision, the key risk is the region of the inner foreskin, which has more in common with the mucosal surface of the vagina than with the keratinised surface of the rest of the penis. During an erection the inner foreskin of the uncircumcised penis is exposed (right), creating a region of relatively thin tissue that does not exist on the surface of an erect circumcised penis. This is the tissue that is thinner and populated by surface level dendritic cells, so it is also the tissue which is most prone to microabrasions and to cellular trafficking via infected dendritic cells. In the circumcised penis this tissue is absent, with the region covered in a thicker layer of non-mucosal skin. It is therefore likely that the biological mechanism of circumcision protection is simply the removal of this mucosal surface during intercourse.

 

Fact: Condoms are more protective than circumcision

The protective effect of circumcision on HIV is around a 60% lifetime protection. For single event condom use the protective factor is around 99% (with a 1.6% slippage factor), which results in an 80% protection rate. When condom usage is accompanied by sex ed classes on how to use a condom correctly the lifetime protection rate goes up to 95%. Clearly a correctly used condom is more protective than circumcision.

However, it is important to note that this does not mean that circumcision has no added value. In the randomised control trials men were still advised to wear condoms, but as you might expect 100% condom usage was not achieved (total condom usage was the same in both groups). The protective effect of circumcision in these trials is therefore an additive effect on top of typical condom usage. Public health is an experimental science and it needs to differentiate between the ideal effects of a treatment and the actual effects of implementation. For example, assuming that all sex was consensual (clearly not the case), voluntary abstinence would block the transmission of HIV. The ideal effect is therefore 100% protection. What happens when abstinence advice is rolled out as a campaign? Absolutely nothing. Circumcision may provide little additional protection when combined with ideal condom use, but in terms of public health what matters is that it provides substantial protection when combined with actual condom use.

 

Myth: Religious circumcision originated because of the health benefits

A number of religious supporters have lept upon the scientific evidence for the protective effects of HIV as support for ritual religious circumcision. They tout the proposition that the religious tradition of circumcision is validated by the scientific evidence, which therefore validates other aspects of their religion. This is by far an overly generous idea, for several important reasons:

1. While the western world tends to think of circumcision as the removal of the entire foreskin, anyone familiar with men would not be surprised to find out that religion has found many weird ways to manipulate the male penis. For example, there is the dorsal slit circumcision, where the foreskin is cut only along one side of the penis, leaving it flapping below. In some places it is then common to create a hole in the free foreskin and fold it back over the penis, sometimes called the "cowboy cut" as the result looks a little like a cowboy hat. While most of these traditional circumcisions have not been tested for protective effects, based on the biological mechanism of HIV protection, it is highly likely that only the full foreskin removal will result in substantial protection.

2. HIV only originated within the past 100 years, so any protective effect of circumcision would have been non-existent at the time these practices originated. As circumcision has little to no protective effect to other STIs, there is currently no scientific basis on which to claim the practice was beneficial at the time they originated.

3. Ritual circumcision in traditional contexts is highly dangerous. These surgical operations were carried out in non-sterile circumstances by untrained religious leaders. This stands in stark contrast to the modern non-surgical approach to circumcision, where typically a band is used to cut off blood circulation to the foreskin so that it falls off - in exactly the way the umbilical cord is removed, leaving behind the belly-button. While modern (secular) circumcision has extremely low rates of complication (on the order of 1.5% minor events such as swelling, 0% severe events), traditional/religious circumcision can have much higher rates of complication (with adverse event reports of over 10% reported, including severe events). The cost-benefit ratio of religious circumcision was therefore almost certainly a net negative, while the cost-benefit ratio of modern secular circumcision produces a net positive.

 

Myth: Circumcision reduces the pleasure of sex

This is a very common myth used in opposition of circumcision, often accompanied by an anecdote of some man they know who has a "botched" circumcision and now has pain during sex (anecdotes of uncircumcised men who have pain during sex are duly ignored). Fortunately, in science we can actually go beyond anecdotes and look at some hard data on sexual pleasure.

Who needs a peer-reviewed study when you have a placard and a website?Firstly, what are the effects of circumcision on subsequent adult sexual pleasure?

* when 1410 American 18-59 year old men were asked if they had "trouble achieving sexual gratification" in the past 12 months, around 45% of men reported sexual dysfunctional, with slightly higher rates in uncircumcised men. This small decrease in sexual dysfunctional in circumcised men remained significant even after controlling for variables such as race, age and sexual preference.

* the same study found that circumcised men had a more varied sexual practice, with more masturbation and oral sex, inconsistent with a hypothesis that sex is less enjoyable to circumcised men.

* Payne et al directly tested the sensitivity of circumcised and uncircumcised penises by measuring the response to touch on the ventral and dorsal surfaces. No difference was observed in sensitivity between the two groups.

* most studies are performed on men circumcised as infants, with relatively few men being circumcised as adults. The recent push for adult circumcision in Kenya has allowed a survey of men before and two years after adult circumcision (with a randomised control group). No increase was observed in sexual dysfunction and most men actually reported an increase in sexual pleasure (64% said their penis was "much more sensitive" and 55% said it was "much easier" to reach orgasm). A Ugandan study found that men circumcised as infants were more likely to have earlier and more promiscuous sex than uncircumcised men.

Not all studies find such strong results as the Kenyan survey, which suggests a strong increase in sexual pleasure. Indeed, the three randomised clinical trials for HIV protection found no change in sexual behaviour. Thus the conservative reading of these studies would be that there is no decrease in sexual pleasure among circumcised men, whether circumcised as infants or adults. The only plausible exception may be within the group of men who have religious-traditional (non-modern) circumcision, where relatively little study has been performed.

 

Myth: Circumcision is the male equivalent of female genital mutilation

Female genital mutilation is the practice of scraping away part or all of the external genitalia of a woman, typically the removal of the clitoris and labium. While it is euphemistically called "female circumcision" it has almost nothing in common with male circumcision. Sexual dysfunctional, while not ubiquitous, is increased in women who have been genitally mutilated, and sexual pleasure is generally decreased. Multiple health risks are associated with the practice, especially increased risk of complication and even death during childbirth. Female genital mutilation is not protective against HIV, and may even increase the risk of HIV infection, either during the mutilation procedure itself or due to additional tissue damage during sexual intercourse. Male circumcision should never be compared to female genital mutilation, a procedure that is more akin to penectomy.

 

Do parents have a right to circumcise an infant, or should they wait until he can make his own decision in adulthood?

The Declaration of the Rights of the Child upholds the right of children to have autonomy as individuals. This does not, however, preclude parents making decisions in the interest of the child, as a child cannot be considered to be truly autonomous. There are multiple examples that are widely accepted for parents making decisions for a child - such as in the area of education. The best comparison to infant circumcision is that of vaccination: both confer protection to infectious disease, both are irreversible and both result in a small chance of minor side-effects (such as swelling for a few hours to days). While this provides a basis for parental right to circumcision, it does not provide an unrestricted mandate - the least damaging form of intervention must be used (ie, non-surgical sterile circumcision over religious circumcision) and the benefits need to be placed in context to alternative (eg, if a vaccine for HIV is successfully generated the rationale for circumcision will be lost, just as the eradication of smallpox eliminates the rationale for the smallpox vaccine - a procedure with more complications than infant circumcision).

Another version of this objection, with somewhat more validity, is that since HIV is generally a sexually transmitted disease the protective effects do not kick in until the child reaches adulthood and has sex, at which time he can decide for himself. Well... perhaps, although it would be naive to assume that all men wait until they are 18 to have sex. Even if you were to wait until the age of 16, the surgical advice for adult circumcision is to have no sexual intercourse or masturbation for at least two weeks following the procedure. That may be quite a hard sell to a 16 year old boy, while being entirely irrelevant to an infant. Again, the best comparison is to vaccination. We have available an outstanding vaccine against human papilloma virus (HPV), which provides substantial (but not 100%) protection against cervical cancer in women who catch HPV. As HPV is a sexually transmitted disease you could advocate that this procedure should also be delayed until the age of 18, but with such mild side-effects as tenderness for a couple of days why not vaccinate all children as young as possible? Several Christian groups object to the HPV vaccine of girls on the basis that it will create "moral hazard" and promote promiscuous sex, but there is no actual evidence to suggest that girls are refraining from sex due to a fear of cervical cancer, and no evidence to suggest that the vaccine changes the rate of sexual activity.

Thursday
May052011

Humans are maladapted to believe in religion

Every now and again you will see someone tout some piece of evidence or another to suggest that humans are evolved to be prone to believe in religion (eg, that many different societies have developed religion - of course, many different societies have also developed atheism). The argument will then follow that if humans are evolved to believe in religion, then religion must be beneficial (and then the leap of faith - that if religion is beneficial, then God exists).

Unfortunately for the proponents of this hypothesis, there is no evidence that humans are actually prone to believe in religion. There is, however, a large amount of evidence to suggest that humans are prone to mimic rituals which they are taught, even after it becomes obvious that the ritual is useless. This video illustrates one example of this trait:

Since humans are evolved to copy ritual and to hold to tradition, it is probably safe to assume that at some point in our recent evolutionary history this was an advantage (and may be so today). Humans have a wider range of habitats and diets than any other animal, if a child sees that cassava is always beaten and soaked before eating it would be good for them to mindlessly mimic that tradition. Other traditions that the child may mimic may be detrimental, but not as much as the cyanide that would be eaten in raw cassava, so on the whole the net effect of mimicry was positive.

What does this mean for religion? Well, it means that the instinct to carry on tradition is not an evolved trait unique to religion, it is a general evolved trait in humans. Within this general evolved trait the specific example of mimicked rituals being religious in nature is simply a maladaptation, the minor detrimental cost we pay for the major benefit of surviving a complex diet.

Saturday
Jan162010

Sex determination

If yeast sex is simple, how complicated is sex in multicellular organisms? Actually, the act of sexual reproduction in plants and animals (including humans) is essentially identical to that of yeast, fungi, plants and animals, including humans. Multicellular organisms have two different copies of the genome in every cell. Like yeast, to undergo sex we need meiosis to occur. Specialised sexual cells duplicate the two genomes, cut and paste them into four unique genomes, and then divide into four daughter cells. These cells are either large cells containing a single genome and lots of energy (the female egg) or small cells containing nothing more than just a single genome (the male sperm). When they combine the new cell has two genomes, one from the female parent and one from the male parent. Importantly, just like yeast, the offspring that results has a unique genetic composition. The two genomes that the offspring possesses are each novel, created by the combination of the two unique genomes in each parent.

While sex for multicellular organisms is identical to yeast at the cellular level, at the sex determination level things get very complicated. There are many different ways for determining whether an individual is male or female. As a measure of the broad diversity of ways in which species have solved the sex determination problem we can look at a few different examples: clownfish, crocodiles, humans, whiptail lizards and komodo dragons. And this is not including some of the really complicated systems that exist, such as in earthworms, bees and platypi.

Clownfish and crocodiles

Clownfish and crocodiles both have non-genetic sex-determination systems. Males and females have the same genetic make-up and every genome has potential to encode either a male or female individual. The physical manifestations of sex occur due to environmental influences on which set of genetic controls to activate. In clownfish the important environmental influence is the social interaction of other clownfish. All clownfish start out as males. When the sole female in the group dies, the largest male undergoes a rapid sex change and becomes a female. Interestingly, this sex change is reversible – a female moved into a new group where she is no longer the largest will revert back to a male. This plasticity ensures that there is always a breeding female in every group, and that the female comes from the most successful individual in the group.

Like clownfish, crocodiles have no genetic difference between males and females. Unlike clownfish, however, there is no sex plasticity. A male hatches as a male and stays a male for life, a female hatches as a female and stays a female for life. The important environmental influence in this case is the temperature of the egg. If the temperature of the egg is between 31.7°C and 34.5°C the embryo is set as a male, if the temperature of the egg is outside this range the embryo is set as a female. There are several important restraints that this sex determination system has had on crocodile evolution. Firstly, the crocodilian mother has become very active in nest maintenance, as a temperate far from the threshold will result in hatchlings of a single sex. Secondly, this sex determination system has forced crocodiles to maintain a link to land. Other aquatic species, such as dolphins and sea snakes, have been able to become entirely aquatic by giving live birth in the water. These species all have genetic sex determination systems (below). By contrast, crocodiles and turtles need to return to land to lay eggs because a temperature-dependent sex determination system is incompatible with live birth – internal body temperatures are too stable to give the diversity in temperatures required.

Humans and whiptail lizards

Humans and whiptail lizards both use the XX/XY sex determination system. In this system, sex is determined by the combination of sex chromosomes inherited from the parents. XX results in females and XY results in males. As females can only pass on an X chromosome while males can pass on either an X (50% chance) or Y (50% chance) chromosome, this system results in roughly equal numbers of females and males being born. It is very important to note that differences between the sexes are largely not due to genetic differences. Both males and females have the X chromosome, and while females have two copies one of these copies is “inactivated”, making them equivalent to males. The only substantial genetic difference between males and females is the presence of the Y chromosome in males. This Y chromosome is tiny (only 2% of the human genome) and is mostly made of up junk. The only essential gene on the Y chromosome is the SRY gene.

All human embryos, whether XX or XY, spend the first six weeks as females. At this point embryos with the XY genome express the SRY gene in the genital tissue, starting the development of testes. The testes then express testosterone and the embryo detects this testosterone production through the androgen receptor. The effect of this production is a complete remodelling of the genitalia from female into male between 7 and 12 weeks gestation. Many different genes are used to initiate the “male” program instead of the “female” program, but only the SRY gene is on the Y chromosome. In other words, females have all the genes required to develop the physical attributes of a male, and males have all the genes required to develop the physical attributes of a female, and only a single gene decides which program is used. When thinking about physical differences between males and females it is not helpful to think about genetic variation, such as exists between different populations of humans. Instead the best comparison is to think about your heart and your liver. Both cells have the same genome, the same genetic code, but the two cells have initiated different programs from the same code so that the cells can perform different functions.

Most whiptail lizards use the same XX/XY system as humans, with XX lizards being female and XY lizards being male. However 15 species of whiptail lizards have reverted to an asexual system of reproduction. These species consist only of XX females. The females still undergo sexual meiosis to create an egg with a single X chromosome, however in the absence of sperm these eggs spontaneously duplicate their genome to become XX females, in a sexual system called parthenogenesis. It is unclear as to why these whiptail lizards have evolved to abandon the advantages to sexual reproduction, however a clue may be the environment they live in – the dry deserts of North America. It is likely that with the low population densities of lizards living in a desert finding a mate becomes very difficult. By breeding through parthenogenesis females can still reproduce even if they fail to find another lizard, and furthermore every individual offspring is capable of bearing young, allowing more efficient use of resources during dry times, and faster population growth during wet ones.

Komodo dragons

The ZW/ZZ sex determination system used by Komodo dragons is essentially the opposite of the XX/XY system. Here, ZW results in a female while ZZ results in a male. As with the Y chromosome, the W chromosome is a minor chromosome with few functions beyond sex determination. When breeding, a female Komodo dragon can pass on either a Z or W chromosome while a male Komodo dragon can only pass on a Z chromosome. This results in 50%:50% females to males. Interestingly, the Komodo dragon has also developed parthenogenesis, like the whiptail lizard. A female Komodo dragon kept alone will have spontaneous genome duplication of an egg. The outcome, however, is the opposite of that occurring in the whiptail lizard. The whiptail lizard female, using the XY sex determination system, can only pass on an X chromosome, so duplication results in an XX female. The female Komodo dragon, however, uses the ZW sex determination system, so the egg could either have a Z chromosome and duplication to be a ZZ male, or it could have a W chromosome and duplication to become an unviable WW embryo. In practise, therefore, this means that female Komodo dragons that revert to parthenogenesis will always generate ZZ males. This means that a lone female washed up on a new island will generate male offspring by parthenogenesis, allowing later sexual reproduction. What is the advantage of this system of parthenogenesis? There are two likely possibilities. The first is that it avoids the spiral into an inbred population that occurs in whiptail lizards, with only a single necessary parthenogenic generation interrupting sexual reproduction. This may be a more appropriate adaption to the “rich uninhabited island” scenario, with the XX parthenogenic strategy more suitable for the “low population desert” context. Alternatively, and equally plausible, the ZW parthogenesis strategy is less efficient than XX parthenogenesis in both contexts (or vice versa). Since evolution always works from the current genetic situation in incremental steps, non-ideal compromises are common.

Tuesday
Jan122010

The role of sex in evolution

Sex is a powerful force for evolution. On the face of it, sex seems like an absurdly complicated way to reproduce. Prokaryotic organisms, bacteria and archea, have a much faster a simpler system, where the cell simply duplicates its DNA and splits in half into two identical daughter cells. The entire process, called mitosis, only takes 20 minutes. This means that under ideal circumstances a single bacterium can divide to produce 8 offspring in the first hour. In the second hour that single precursor cell could form 64 offspring, after 6 hours a single cell could form over 200,000 daughter cells. This asexual reproduction is so efficient that it only operates at capacity for very short durations, as exponential growth of a single cell could use up the resources of an entire planet within days. Typically a bacterium ticks over slowly by scavenging what resources are available, only to explode into exponential asexual growth when new resources become available and a race to exploit them occurs.

Compare this to the elaborate, time-consuming and often bizarre process of eukaryotic sex, which multicellular organisms from plants to fungi to animals use to reproduce. Sex (and the accompanying mate selection) is one of the most difficult and dangerous parts of an individual’s life, and even passionate advocates of the activity find it difficult to explain. Yet through an evolutionary lens, sex provides very concrete advantages. The best illustration of the advantages of sex come from yeast mating, as these simple organisms are capable of both asexual and sexual reproduction.

Simple sex

Yeast can be thought of as being halfway between simple bacteria and complex multicellular organisms like humans. In terms of lifestyle and behaviour, yeast operate like bacteria – single celled organisms capable of an independent existence through the use of resources in their direct environment. Inside the cell, however, yeast are clearly eukaryotic organisms, with the same basic machinery for cell division, metabolism and survival as plants and animals. It is therefore convenient to think of yeast as essentially human-like cells, trapped in an early bacterial-like lifestyle. This is an oversimplification of course: bacteria, yeast and humans are all highly evolved organisms and none have remained static in evolutionary time, but it is a useful oversimplification.

So how do yeast reproduce? Asexually, like the bacteria they share a lifestyle with? Or sexually, like the multicellular organisms they are genetically closest to? The answer is both. When yeast are in a rich nutrient environment they reproduce asexually like bacteria. A single cell undergoes mitosis, duplicating its DNA and then splitting into two daughter cells, each identical to the parental cell. This gives the yeast all the advantages of bacterial reproduction – very simple rapid reproduction to win the race for abundant resources. The parental cell was successful in the environment, so the identical daughter cells should be equally successful and proliferate likewise.

However as noted above, exponential growth can never continue unabated, sooner rather than later resources become limiting or some other factor stresses the survival of the yeast. At this point yeast have a trick available that bacteria do not – sex. Instead of undergoing dormancy, the yeast mate.

In the best understood system, that of Saccharomyces cerevisiae, there are two sexes of yeast, a and a, controlled by a single gene. Mating is very simple, the a cells release a chemical called ‘a factor’ and produce a receptor that causes them to migrate towards the chemical ‘a factor’. By contrast, the a cells release a chemical called ‘a factor’ and produce a receptor that causes them to migrate towards the chemical ‘a factor’. The two yeast cells, one a and one a, attract each other and fuse into a single cell. This cell now has two different copies of the yeast genome, one from each parent.

The a-a fused yeast cell can now undergo a complicated cellular division process called meiosis. Unlike mitosis, where the cell duplicates its genome and divides in two, meiosis involves duplicating the genome and dividing in four. This is possible because the a-a fused yeast cell has two copies of the genome to start with, so duplication gives four copies, one for each of the four daughter cells that result.

The important difference between mitosis and meiosis is the splicing of two different genomes to form unique combinations. Mitosis just duplicates the existing genome. Meiosis starts with two different genomes, and during the duplication processes these genomes are jumbled up together, creating new combinations of old characteristics. This means that all four daughter cells at the end are unique and different from the original parental cells.

The advantage conferred by sex is very straight forward – the parental cells were not dealing well with the environment they were in, since yeast mating occurs only under stress. Therefore why reproduce more cells that cannot cope with the environment? Instead the yeast takes a life-or-death gamble that a combination of genetic information from another cell will produce offspring better able to deal with the environment. In a simple scenario there would be two yeast strains, one able to deal with acidity and one able to digest complex carbohydrates. A change in environment to a high acidity environment where the only resources available are complex carbohydrates will stress both parental strains. However, by sex there is a chance that one of the daughter cells will inherit the acid resistance of one parent and the ability to digest complex carbohydrates from the other parent. Other daughter cells will not be so lucky and will die, but that one daughter cell with the chance combination of two necessary characteristics will be able to divide asexually and rapidly reap the rewards of a new resource.

In one final complication, yeast can change sex. A single gene makes yeast either a or a, so after mating and meiosis the four daughter cells include two a cells and two a cells. If a single a cell is successful in the new environment, asexual reproduction creates exact copies, so all progeny will be a cells. This would create an obvious problem if a new environmental stress requires another round of mating, so yeast carry spare “silent” copies of a and a genes and use these backup copies to flip from one sex to another, to make sure a population is always a mixture of a and a yeast.

Sunday
Dec062009

The inefficient consequences of evolution

Vertebrates are unique in developing an immune system capable of anticipating pathogens that are yet to evolve. Birds and mammals have taken this "adaptive" immune system to the pinnacle, with T cells and B cells using a randomised form of genomic engineering. The advantage of a system based on randomised generation is striking - by making every T cell and B cell unique it becomes exceptionally difficult for pathogens to "out-evolve" their hosts. Regardless of how a pathogen will change, pre-existing T cells and B cells will be capable of recognising the new modified pathogen. The importance of the adaptive immune system to humans is evident in the fatal consequences of its absence, such as patients with end-stage AIDS or primary immunodeficiencies caused by genetic mutations. These benefits greatly outweigh the cost of the adaptive immune system in resources used and the threat of autoimmune disease.

But does the adaptive immune system make vertebrates more healthy? There is no obvious evidence that it does. In a key essay on the topic, Hedrick argues that vertebrates do not appear to have a lower pathogen-induced mortality rate than invertebrates. Instead, he argues that the development of the adaptive immune system provided only a short-term benefit, with pathogens rapidly being specialised to vertebrate hosts. The result is an immunological arms race, with each side incrementally ratcheting up the armaments. Vertebrates are essentially impervious to non-specialised pathogens unless rendered immunodeficient, but the additional mortality from specialised pathogens is probably equivalent to the invertebrate state.

This still-controversial hypothesis high-lights an important aspect of evolution by natural selection. It has highly inefficient consequences. Natural selection takes place at the level of the individual and evolution takes place at the level of the species. Most importantly, natural selection only occurs in the present. An individual who has an advantage for even a single generation will be over-represented in the next generation. A species that has an advantage for a single generation will be able to exploit more resources for reproduction. The long-term consequences - that each species will waste more resources in an ever more expensive battle - is irrelevant.

The evolutionary arms-race between host and pathogen is one incredibly important example. A more illustrative example of the patent futility of this arms-race comes from Sir David Attenborough, one of the leading science communicators of all time. In Life in the Undergrowth, he films two species of harvest ants living in the desert. Each population needs to collect seeds to survive, however the number of seeds produced in the desert is so low that there is fierce inter-species competition. One species of ant is diurnal, the other nocturnal, and each is capable of collecting the entire daily seed dispersal. In order to survive, every second night the nocturnal ants spend an evening carrying rocks to cover the entry hole of the diurnal ants. The diurnal ants can't collect seeds the next day as they need to spend a day clearing the rocks from the entrance. This gives the nocturnal ants a night to harvest the uncollected seeds. The following day the diurnal ants are able to collect every seed and that night the nocturnal ants spend carrying rocks. Two species end up literally carrying rocks backwards and forwards every second day.

The elegance of evolution is the beauty of such specialised behaviour, but the consequences are gross inefficiency in resource use. If each species simply spent alternative cycles conserving resources both species could survive with a higher population density than currently exists. But neither species can be the first to stop the wasteful use of resources, as that would give a fatal advantage to the other, and so they are trapped together in a cycle of carrying stones. The battles of night ants vs day ants and of hosts vs pathogens illustrate the bizarre, elaborate and ofttimes perverse consequences of evolution by natural selection

Monday
Sep212009

The evolution of sex chromosomes

An interesting study in this week's edition of Nature by Organ and colleagues looks at the evolution of sex chromosomes. While humans use the XY system for determining sex (XX for females, XY for males), this is by no means the only system for determining sex. Most reptiles, for example, determine sex by the temperature at which the young develops. For example crocodiles develop as males if the eggs are between 31.7°C and 34.5°C, and females if the eggs are above or below this temperature.

A chromosome-based method for determining sex has arisen not just once, but several times. Mammals use the XY system, but birds use the ZW system (where ZZ is male and ZW is female). These systems create problems, such as the dosage compensation question (how to stop excess / insufficient production of genes on the X or Z chromosomes in the gender with two copies / one copy), however they have a major advantage. This advantage is most evident in mammals - mammals are endothermic, meaning that we keep a constant body temperature. We also bear live young. Obviously, this combination of characteristics would be fatal to a species with temperature-dependent sex determination - all offspring would be of one sex.

In this paper the Pagel laboratory has used an evolutionary analysis to consider the relationship between bearing live offspring and having a chromosome-dependent sex determination system. There are multiple examples of animals with chromosome-dependent sex systems that lay eggs (all birds) and even examples of animals with temperature-dependent sex systems that bear live offspring (some lizards). However in one group of animals the relationship was very strong - amniotes that have fully returned to the sea (sea snakes, sirenians and cetaceans) are all live-bearing and have chromosome-dependent sex systems. An evolutionary analysis predicts that other extinct lineages of sea reptiles, mosasaurs, sauropterygians and ichthyosaurs, also developed chromosome-dependent sex systems before evolving life birth and spreading out over the ocean.

Like mammals with endothermic body temperatures, the constant temperatures of the ocean would have spelt doom to any species that evolved life oceanic birth before evolving a chromosome-based sex system. This is probably the reason why otherwise entirely aquatic species that use temperature-based sex determination systems (such as crocodiles and sea turtles) remain bound to laboriously climb out of the water to lay their eggs.

Tuesday
Sep152009

Recreating the thymus

I am writing today from the European Congress for Immunology in Berlin. A talk by Thomas Boehm was the highlight of the first day for me.

The Boehm laboratory has been looking at the genetic evolution of thymus development. The thymus is the nursery for T cells, the coordinator of the adaptive immune response. The Boehm laboratory analysed the genetic phylogeny of sample species spanning the 500 million years of thymus evolution and found several key genes that have been conserved through this process. The master coordinator of thymus development, Foxn1, had already been known, but how this master coordinator worked was a mystery, so the Boehm laboratory used the evolutionary analysis to try to recapitulate thymic development in zebrafish and mice.

In zebrafish, Weyn and colleages were able to use live imaging to analyse the genes that the thymus needs to express in order to recruit progenitor cells. This was done by using genetic expression of coloured dyes, making the primordial thymus glow red and the progenitor cells glow green. They found that just two conserved genes, Ccl25a and Cxcl12a, were synergistically acting to draw in all the precursor cells.

In mice, Bajoghli and colleages tried to use the knowledge gleaned from evolutionary analysis to completely bypass Foxn1. The rationale is that if we know exactly what Foxn1 does to drive thymic development then we should be able to recapitulate thymic development in the absence of Foxn1 by simply expressing the downstream genes. So the Boehm team took the four key genes that were conserved over 500 million years of thymic development, Ccl25, Cxcl12, KitL and Dll4, and expressed them in isolation or in combination in thymic cells that were genetically deficient in Foxn1. Normally, these deficient thymic cells cannot attract T cell precursors. However, Bajoghli and colleages found that just as in zebrafish, two genes in mice were able to essentially restore the capacity to recruit precursors, Ccl25 and Cxcl12. A third gene, KitL, allowed these cells to proliferate and increase in number. What these three genes could not do, however, was turn the precursors into T cells. That job required the fourth gene, Dll4, which had no role in recruitment or proliferation but which was essential for the differentiation of recruited precursors into T cells. Through evolutionary genetics the gene network of an entire organ is being unravelled.

Some of this research is current unpublished, other aspects just came out in the journal Cell.