Sex Is Always Well Worth Its Two-Fold Cost

Title borrowed from Feigel et al. [1].

Sex is costly. In an asexual population, all individuals bear offsprings, resulting in a higher growth rate than in a sexual population (two-fold cost of sex). Finding a partner is risky, costly in terms of energy and resources, and it results in sexual selection which may not always favor survival. Finally, in sexual populations each individual passes only 50% of its genetic make-up to their offsprings and, furthermore, genetic recombination could break-up alleles that are in an epitastic relationship with one another (they are advantageous when together, but once separated they may incur into fitness loss).

However:

"The advantages of sexual reproduction stem from quite various roots. For instance, sex increases genetic variability by recombination of the parental chromosomes. It makes a population more resistant against many unpredictable threats, such as deleterious mutations, parasites, a fluctuating environment, or competing groups. It also optimizes the evolutionary search for the best gene combinations in a single individual (epistasis) [1]."

Let's try an understand this better. Different alleles in the genome are not always independent, as they may affect fitness in conjunction, a mechanism called epistasis. For example, two alleles may be beneficial together, but their benefit may be lost when separated by a recombination event. Or, it could be the other way around, that a mutation arises under certain constraints, and it's not until paired with a second mutation that it becomes beneficial. This is often observed in drug resistance, for example. A mutation that confers the organism (a virus, or a bacterium) drug resistance could potentially make it less fit (for example, if it makes the organism more "visible" to the immune system). In these cases, often one observes a new mutation arise in conjunction with the drug-resistant one, and the two together restore the organism's original fitness. These secondary mutations are called compensatory mutations because they compensate for the original loss of fitness.

Recombination of genomes can go either way: it can bring beneficial mutations together, or, it can break them apart. In a Nature Genetics review [2], the authors mention a study done on segmented viruses: in this case, "sex" is equivalent to two viruses co-infecting the same cell, as when this happens the enzyme that replicates the genes jumps back and forth between the two genomes and the resulting new genome is a reshuffle of the two parental ones. The advantage of using viruses to study the effect of sex is that you can compare the result of sexual reproduction versus asexual reproduction in the same population. In the case of the segmented virus study, it was observed that an adverse mutation was slower to get cleared in the sexual population than the asexual one.

The same review cites studies done on yeast that yielded mixed results: some showed that sex did increase the rate of adaptation of the population, and some showed the opposite. A paradox? Not quite, if you throw into the picture the size of the population.

"Two recent studies have also tested the effect of recombination on the rate of adaptation in evolving microbial populations. When populations of C. reinhardtii that initially lacked genetic variation were allowed to adapt to a novel growth medium in sexual and asexual populations of varying size, sex increased the rate of adaptation at all population sizes, but particularly in large populations [2]."

Another study done on sexual and asexual yeast strains, compared adaptation in two environments: the mouse brain, which represented a highly variable environment, and a test tube with minimal growth medium.

"When sex was induced, the sexual strain won the competition in the mouse brain but not in the test tube, despite the fact that it also showed general adaptation to this environment. These results indicate an advantage to sex during adaptation to variable or harsh environments [2]."

Despite all these studies, it is still unclear what drove the evolution of sex. Did sex prevail thanks to epistasis? Or was it just drift, the random accumulation of mutations due to pure chance? More recent studies have looked at a combination of mechanisms that may have been responsible for the rise in sexual populations. For example, other aspects to account for, besides epistasis and drift, are redundancy and genome complexity. As organisms have evolved, their genomes have increased in size and complexity. Redundancy allows for more than one gene or pathway to have same function, buffering the effect of deleterious mutations. It also maintains a reservoir of non-coding allele variants that are always available in the search for new evolutionary pathways. At the same time, sex and recombination together cause genomes to be more robust and overcome the short-term disadvantage in favor of long-term advantages like increased evolvability.

[1] Alexander Feigel,, Avraham Englander,, & Assaf Engel (2009). Sex Is Always Well Worth Its Two-Fold Cost PLoS ONE DOI: 10.1371/journal.pone.0006012

[2] J. Arjan G. M. de Visser & Santiago F. Elena (2007). The evolution of sex: empirical insights into the roles of epistasis and drift Nature Genetics Review DOI: 10.1038/nrg1985

Canalization and epigenetic landscapes: if horses and rhinoceroses share the same ancestor, why don't we have rhinohorses?

A concept that has always puzzled me is: how do new species arise? Of course, you're thinking, mutations accumulate, until you produce a brand new organism. But if that's the case, why don't we see human-monkey hybrids, or rhinohorses, or . . . you get the picture. What puzzles me is where do the intermediate steps between two closely related species go? There are so many mutations that make one species diverge from another, yet you don't see one organism for each new mutations that arises. You see the endpoints. What happens in the middle? At the DNA level you see all shades of gray, but at the species level all you see is black and white (horse or non-horse). Why aren't those mutations expressed in new organisms as things progress from rhinoceros to horses, for example?

I don't know if there's only one answer to this question, but what really helped me clarify the issue were the concepts of epigenetic landscape and canalization.

The expression "epigenetic landscape" was coined by British developmental biologist Conrad Hal Waddington (1905-1975). He compared gene regulation during development to marbles rolling downhill towards a wall. As cells differentiate, the different cell fates are represented by the lowest points in a landscape made of several pits, some lower than others. Waddington also coined the expression "canalization" to describe the ability of organisms to produce the same phenotype against genetic and environmental variations.

Let's understand this better. I often talk about mutations, genetic variation, and how mutations can cause diseases or increase the risk of disease. At the same time, there are mutations that have no effect whatsoever. The math geeks out there will appreciate this metaphor: genotypic variation is not in a 1-1 correspondence with phenotypic variation. In fact, there are phenotypic traits that do not change despite genetic and/or environmental changes.

"There seems to be a strong robustness of some phenotypes against genetic and non-genetic change or perturbation. More generally, the amount and quality of phenotypic variation can differ dramatically within and among populations. Some traits are highly invariant within species while simultaneously being highly variable among closely related species; other characters seem to be highly conserved among species or clades [1]."

On the one hand, canalization provides a buffer to phenotypes that are optimized in terms of fitness against genetic and environmental variation, making them more robust and stable. On the other hand, it allows for non-expressed genetic variation to accumulate: since it's not expressed, there's no selection, hence it persists in the population. So, even when a species "looks" homogeneous, it doesn't mean it's actually genetically homogeneous. There are underlying genetic differences that do not affect the phenotype. To me this represents a "hidden reservoir" of genetic variability. So long as the phenotype is fit, it is convenient to keep it that way. But once a selective sweep takes place, epigenetic changes take place and are likely to act differently on different genomes, thus providing a phenotypically homogeneous population with the potential for genetic change.

"The cryptic pool of genetic variation accumulated under canalization can be phenotypically expressed again if genetic or environmental change uncovers the silent genetic variation, thereby increasing phenotypic variation in the population. Decanalizing conditions can be due to environmental perturbations that change environment-dependent gene expression or allele substitutions that render canalizing mechanisms nonfunctional."

So, you see what's happening: when a certain phenotype is stable and fit, it doesn't mean it's not changing genetically. It is, but there's a buffering mechanism that prevents the genetic changes to be expressed. It's like a marble trying to get out of a pit: it rolls around the lowest point, and small perturbations will make it roll higher or lower along the walls of the pit. In order to make it out of the pit, it needs a big perturbation, one large enough to provide energy to make the jump. That's when the cryptic variation suddenly becomes expressed and forms a new species.

I'm sure biologists are raising their brows at me, as there are probably better and more technical ways to say this, but I wanted to express it in simple words.

Now to a more deeper look, for those of you who are interested in a bit more technicalities: what are the molecular mechanisms of canalization? In other words, what prevents genetic and environmental changes to affect the phenotype of an organisms?

"The proximate (molecular) mechanisms causing canalization, as well as the nature of the perturbations, can be manifold. For example, the canalizing mechanisms can potentially be located at any level of the biological hierarchy, from gene expression, RNA stability, protein structure and folding, intermediate metabolism and physiology to morphology, behavior, and life-history traits."

Furthermore, stability in one trait may depend on the variability of other traits, and the buffering may indeed involve complex epistatic pathways. In simpler words: a change in one locus may involve other genes whose expression needs to change in order to maintain the phenotype despite the change. This makes canalization particularly difficult to measure because not only it's not always obvious at what level the regulatory mechanisms are taking place, but also how many genes or loci it actually involves.

[1] Flatt T (2005). The evolutionary genetics of canalization. The Quarterly review of biology, 80 (3), 287-316 PMID: 16250465

 

Chaperon proteins do more than... chaperon

The full human genome was typed for the first time in 2003. Ever since, there has been a "hunt" for mutations and, more in general, associations between genotypes and phenotypes. As I have pointed out multiple times on this blog, things have turned out more complicated than originally anticipated: what happens between DNA and proteins (what we could consider the "end" product) is still very much a "black box" in which epigenetic changes and RNA editing can completely turn around the outcome. Furthermore, the interaction between genes and mutated loci can either increase or decrease the likelihood of certain phenotypes, given the genotype.

Take molecular chaperones, for example. These are proteins that assist the folding and unfolding of other macromolecules. They are typically involved in protein folding, but they also assist the assembly of nucleosomes from folded histones and DNA in the nucleus (see this earlier post on chromatin) and thus, by changing the topology of the nucleus, they play an important role in regulating gene expression.

A study published in the last issue of Science [1] looks at the role of chaperon proteins in compensating for deleterious mutations in Caenorhabditis elegans. Casanueva et al. found that worms with higher expression of protective chaperon genes were more resistant to deleterious mutations: worms with a potentially deadly mutation received a mild heat stress when still larvae. The heat stress promoted the expression of protective chaperon genes, and in some of the worms this prevented the deleterious misfolding of proteins, resulting in a 35% increase in chance of survival.

"We subjected animals to a transient heat shock as larvae to induce a stress response, allowed them to develop to adults, and examined the proportion of individuals affected by late-acting mutations. When a mutation was chaperone-dependent, a mild environmental challenge stimulated a reduction in penetrance."

Paradoxically, they also found that individuals with higher chaperon expression reproduced less. Why, if the higher expression seems advantageous and protective? Casanueva et al. hypothesize that the net effect is to maintain a heterogeneous population in levels of expression, and this is more advantageous to the survival of the population than homogeneous levels of gene expression. In other words, what is advantageous to the individual is not necessarily advantageous to the species.

From the paper abstract:

"The induced mutation buffering varies across isogenic individuals because of interindividual differences in stress signaling. This variation has important consequences in wild-type animals, producing some individuals with higher stress resistance but lower reproductive fitness and other individuals with lower stress resistance and higher reproductive fitness. This may be beneficial in an unpredictable environment, acting as a “bet-hedging” strategy to diversify risk. These results illustrate how transient environmental stimuli can induce protection against mutations, how environmental responses can underlie variable mutation buffering, and how a fitness trade-off may make variation in stress signaling advantageous."

Of course, it's not clear how this could apply to humans. However, it does prompt caution when treating a person's full genome as a key to disease risks. We are still far from unraveling the complete interactions between genome, epigenome, and proteome, and, as I've often said before, Mother Nature has made us far more complex than any of our models can predict.

[1] Casanueva, M., Burga, A., & Lehner, B. (2011). Fitness Trade-Offs and Environmentally Induced Mutation Buffering in Isogenic C. elegans Science, 335 (6064), 82-85 DOI: 10.1126/science.1213491

Photo: it's not what it looks like! This is eggs, water and vegetable oil all mixed in a blue bowl to make brownies. Seriously. You just set the bowl under a lamp and suddenly it behaves like a mirror. Eventually the mix turned into brownies, but not before my daughter and I had a little fun shooting pictures.

Genetic epistasis

A while ago, in a post titled the Missing Heritability, I discussed the fact that some risk alleles (gene copies that have been found to increase the risk for a certain disease) may turn out to be counter-effected by other genes and thus explain why some people with these alleles never develop the particular disease. At the time I did a quick search on PubMed but couldn't come up with anything in the literature. Well, I was missing the keyword: epistasis. The word comes from the Greek "epi", which means "upon," and "stasis," which means to stop (I see my mom gloating out there in the audience!): compositional epistasis is the mechanism by which the effect of one allele is modified, and in some cases even blocked, by other gene alleles. This of course is hard to detect, but intuition tells us that it is a rather diffuse phenomenon. Genes are far from being "push-buttons," rather, they work in concert, initiating complex pathways, and therefore more often than not, a single gene is unlikely to give us a complete picture.

Back to my quest. I searched "genetic epistasis" on PubMed and this time I found a lot of interesting stuff. As a disclaimer I should say that for some of these studies there are contrasting outcomes in the literature (some results weren't reproduced in different populations). Nonetheless, I think that we are just starting to scrape the tip of the iceberg: gene-to-gene interaction are complex and poorly understood, but they certainly hold the key to the mysterious ways in which our genome works. Despite the skepticism expressed by some in the field, I do believe that single-gene studies are limited and should eventually give way to whole-genome studies.

[1] Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depressionEpistasis of BDNF and SLC6A4 in depression.

SERT is a protein whose function is to terminate and recycle the neurotransmitter serotonin. Historically, serotonin has been associated to happiness and well-being, which explains why SERT is the target of numerous drugs addressing psychiatric disorders. SLC6A4, the gene encoding SERT, has been extensively studied and one polymorphism in particular, 5-HTTLPR (which is not a SNP, a single-base mutation, rather some individuals present a long allele with a 44 base-pair insertion, compared to the short allele) has been associated to the efficacy of some antidepressants and also to other psychiatric disorders. On the other hand, the brain-derived neurotrophic factor (BDNF) protein is involved in the growth, proliferation, and differentiation of certain neurons. The gene encoding BDNF has been associated to bipolar disorder and improved general cognitive ability. Two genes, two (apparently) distinct pathways and signaling systems. Using anatomical neuroimaging techniques in a sample of healthy subjects (n=111), Pezawas et al. showed

"that the BDNF MET allele, which is predicted to have reduced responsivity to 5-HT signaling, protects against 5-HTTLPR S allele-induced effects on a brain circuitry encompassing the amygdala and the subgenual portion of the anterior cingulate (rAC). Our analyses revealed no effect of the 5-HTTLPR S allele on rAC volume in the presence of BDNF MET alleles, whereas a significant volume reduction (P<0.001) was seen on BDNF VAL/VAL background. [...] These data provide in vivo evidence of biologic epistasis between SLC6A4 and BDNF in the human brain by identifying a neural mechanism linking serotonergic and neurotrophic signaling on the neural systems level, and have implications for personalized treatment planning in depression."

[2] Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction.

Tsai et al. [2] recruited 1254 patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) and individually matched them with controls based on corresponding risk factors for coronary artery disease. The researchers genotyped several polymorphisms: one in the angiotensin-converting enzyme gene, six in the angiotensinogen gene, and one in the angiotensin II type I receptor gene. In single-locus analyses, no locus was associated with coronary artery disease or acute myocardial infarction. However:

"Significant three-locus (G-217A, M235T and I/D) gene-gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P=0.017) and many even higher order gene-gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT1R genes). Our study is the first to demonstrate epistatic, high-order, gene-gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches."

I've added below a few more references on epistasis for those interested in researching the topic further.

Photo: Walt Disney Concert Hall, Los Angeles, CA. Shutter speed 1/15, focal length 24mm, F-stop 22, ISO speed 100.

[1] Pezawas, L., Meyer-Lindenberg, A., Goldman, A., Verchinski, B., Chen, G., Kolachana, B., Egan, M., Mattay, V., Hariri, A., & Weinberger, D. (2008). Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression Molecular Psychiatry, 13 (7), 709-716 DOI: 10.1038/mp.2008.32

[2] Tsai CT, Hwang JJ, Ritchie MD, Moore JH, Chiang FT, Lai LP, Hsu KL, Tseng CD, Lin JL, & Tseng YZ (2007). Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction. Atherosclerosis, 195 (1), 172-80 PMID: 17118372

[3] Wiltshire S, Bell JT, Groves CJ, Dina C, Hattersley AT, Frayling TM, Walker M, Hitman GA, Vaxillaire M, Farrall M, Froguel P, & McCarthy MI (2006). Epistasis between type 2 diabetes susceptibility Loci on chromosomes 1q21-25 and 10q23-26 in northern Europeans. Annals of human genetics, 70 (Pt 6), 726-37 PMID: 17044847

[4] Abou Jamra R, Fuerst R, Kaneva R, Orozco Diaz G, Rivas F, Mayoral F, Gay E, Sans S, Gonzalez MJ, Gil S, Cabaleiro F, Del Rio F, Perez F, Haro J, Auburger G, Milanova V, Kostov C, Chorbov V, Stoyanova V, Nikolova-Hill A, Onchev G, Kremensky I, Jablensky A, Schulze TG, Propping P, Rietschel M, Nothen MM, Cichon S, Wienker TF, & Schumacher J (2007). The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder: strong evidence of epistatic effects between loci on chromosomes 2q and 6q. American journal of human genetics, 81 (5), 974-86 PMID: 17924339

[5] Coutinho AM, Sousa I, Martins M, Correia C, Morgadinho T, Bento C, Marques C, Ataíde A, Miguel TS, Moore JH, Oliveira G, & Vicente AM (2007). Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels. Human genetics, 121 (2), 243-56 PMID: 17203304