Gene duplication events represent the possibility for major evolutionary innovation, and possibly hold the key to the evolution of complex molecular and phenotypic regimes. To this end, neofunctionalization, that is the processes whereby a newly duplicated gene gains a function not present in the progenitor gene, and its real-world representatives (ie newly paralogous genes) provide an interesting avenue for molecular and evolutionary study. De and Babu (2010) found that, in areas surrounding gene duplication events (and indels etc), sequence divergence is much higher than surrounding genomic divergence levels (likely due to the mechanics associated with DNA break, repair and template-dependent DNA synthesis), possibly fueling this exaptation of duplicated genes. Furthermore, due to the possibly relaxed selective pressures on duplicated genes, such genes might be better suited to explore sequence space through neutral or nearly-neutral mutations, providing an exploratory power not available to the initial (parent) gene, however it may also be argued that evolutionary interference or genetic "hitchhiking" (often associated with such gene duplications and diversifications) might confound evolutionary studies.
For these reasons, Hasselmann et al studied the duplication of a gene (complimentary sex determiner--csd) involved in the Hymenopteran sex-determination cascade (and the novel functions therein), in an effort to better understand the shifting of selective constraints and molecular mechanisms associated with such duplication and whether the parent gene's evolutionary patterns are affected by the presence of this ontologically similar paralog. csd is a particularly interesting candidate for evolutionary studies as it is (almost certainly) the product of the duplication of the sex-determining tra Hymenopteran ortholog (in dipterans and other insects) feminizer (fem), is held under a heterozygous advantage due to its specific ontology, and is relatively recently diverged from fem (between ~70-10mya).
The authors found a reduced n/s ratio in Apis lineages which experienced such gene duplication when contrasted to related non-Apis lineages which did not experience the duplication of fem. This might imply increased purifying selection associated with the gene duplication event at the fem locus. Alternatively, they speculate that this could be due to increased synonymous substitution rate in the lineage of Apis fem, possibly resulting from an increased mutation rate (associated with said duplication). In an effort to test these two hypotheses the authors applied a "relative rate test" to identify accelerations of synonymous substitution rates in the Apis tree branches as an indicator for increased mutation rates--which found no such increased mutation rates. The authors also found one protein-binding region of fem which exhibited a low dn/ds ratio between Apis and non-Apis and high dn/ds in non-Apis comparisons indicating lineage-specific evolutionary constraints.
Through this analysis the authors demonstrate that the origin of the fem paralog csd led to increased evolutionary constraints on the feminizer gene related to sex-determination in social Hymenopterans. They demonstrate a marked decrease in the dn/ds rates associated with Apis lineages when compared to non-Apis lineages--ie after vs before csd origin--indicating a functional interference in evolutionary rates associated with the origin of csd. They also conclude that these similar dn/ds values between Apis fem and csd are not the product of genetic linkage, but some other functional interference, possibly related to the balancing selection associated with complimentary sex determination (sex determination mechanism in Hymenoptera wherein homo or hemizygous individuals become one sex--male-- and heterozygous individuals become another--associated with haplodiploidy). Their results also support other authors An interesting, if not somewhat incomplete-feeling, study.
-Hasselmann,, Lechner, Schulte and Beye (2010). Origin of a function by tandem gene duplication limits the evolutionary capability of its sister copy. PNAS 107 (30): 13378-13383
-De and Babu (2010). A time-invariant principle of genome evolution. PNAS 107 (29): 13004-13010
Monday, November 22, 2010
Monday, November 15, 2010
pleiotropy and complexity
Pleiotropy, the condition when a single mutation in a gene affects multiple distinct phenotypic traits, has bold implications for the development and maintenance of complex organisms. It has been speculated to motivate a tendency towards cis-regulatory change-bias in morphological evolution (contrasted to actual protein sequence changes), because such regulatory changes exhibit less antagonistic pleiotropy. Furthermore, such antagonistic pleiotropy is speculated to lie behind the evolution of senescence (the theory posits that alleles beneficial to development and reproduction are deleterious after the reproductive age and cause senescence). Ultimately, pleiotropy heavily affects morphological evolution through the wide phenotypic effect many SNPs can have on an organism. Though many authors have asserted that pleiotropy charges organisms a "cost of complexity", Wang et al (2010) poses several reasons for why pleiotropy might not hinder the development of complex forms, and might actually drive it.
In an effort to explore pleiotropy across a broad phylogenetic scale, the authors compiled five (quite large) datasets in Saccharomyces cerevisiae (3), Caenorhabditis elegans (1), and Mus musculus (1). In all five datasets the authors observed that most genes affect only a small fraction of traits and only a minority of genes affect many traits--with the median degree of pleiotropy varying from 1-7 in the datasets. The authors predicted, from their data, that the median number of traits affected by a gene is no greater than a few percent of the total number of traits in an organism. Their observations, along with several others (referenced in the study), indicate a general patter of low pleiotropy in eukaryotes, which disagrees with the assumption of many models which evaluate the effects of such pleiotropy on complex organisms. Also, their datasets, once evaluated, indicate that gene networks are highly modular (i.e. gene-networks are mechanically insular and largely have much higher within-module effects than between-module effects), and that genes that are highly pleiotropic have high per-trait effects. These conclusions lead to a different conclusion regarding the 'cost of complexity' than previously indicated by other authors.
Ultimately, the authors find that three features of pleiotropy/eukaryotes that "substantially alleviate the cost of complexity in adaptive evolution". They conclude that 1) as addressed, the lower-than-previously-indicated level of pleiotropy in complex organisms means that mutations do not normally affect many traits simultaneously, 2) high modularity in gene networks (and gene network memberships) reduces the probability that a random mutation is deleterious ("because the mutation is likely to affect a set of related traits in the same direction rather than a set of unrelated traits in random directions"), and 3) the greater per-trait effect size for more pleiotropic mutations causes a greater probability of fixation and a larger amount of fitness gain when a beneficial mutation occurs in a more complex organism than in a less complex organism. These conclusions, drawn from five extensive datasets, seem to support the evolution of "moderately-complex" organisms and argue against the conclusions of previous authors which would suggest that pleiotropy stands against the observed biotic complexity in our world.
-Wang, Liao and Zhang (2010). Genomic patterns of pleiotropy and the evolution of complexity. PNAS. 107 (42): 18034-18039
-Williams GC (1957) Pleiotropy, natural selectioon, and the evolution of senescence. Evolution. 11: 398-411
In an effort to explore pleiotropy across a broad phylogenetic scale, the authors compiled five (quite large) datasets in Saccharomyces cerevisiae (3), Caenorhabditis elegans (1), and Mus musculus (1). In all five datasets the authors observed that most genes affect only a small fraction of traits and only a minority of genes affect many traits--with the median degree of pleiotropy varying from 1-7 in the datasets. The authors predicted, from their data, that the median number of traits affected by a gene is no greater than a few percent of the total number of traits in an organism. Their observations, along with several others (referenced in the study), indicate a general patter of low pleiotropy in eukaryotes, which disagrees with the assumption of many models which evaluate the effects of such pleiotropy on complex organisms. Also, their datasets, once evaluated, indicate that gene networks are highly modular (i.e. gene-networks are mechanically insular and largely have much higher within-module effects than between-module effects), and that genes that are highly pleiotropic have high per-trait effects. These conclusions lead to a different conclusion regarding the 'cost of complexity' than previously indicated by other authors.
Ultimately, the authors find that three features of pleiotropy/eukaryotes that "substantially alleviate the cost of complexity in adaptive evolution". They conclude that 1) as addressed, the lower-than-previously-indicated level of pleiotropy in complex organisms means that mutations do not normally affect many traits simultaneously, 2) high modularity in gene networks (and gene network memberships) reduces the probability that a random mutation is deleterious ("because the mutation is likely to affect a set of related traits in the same direction rather than a set of unrelated traits in random directions"), and 3) the greater per-trait effect size for more pleiotropic mutations causes a greater probability of fixation and a larger amount of fitness gain when a beneficial mutation occurs in a more complex organism than in a less complex organism. These conclusions, drawn from five extensive datasets, seem to support the evolution of "moderately-complex" organisms and argue against the conclusions of previous authors which would suggest that pleiotropy stands against the observed biotic complexity in our world.
-Wang, Liao and Zhang (2010). Genomic patterns of pleiotropy and the evolution of complexity. PNAS. 107 (42): 18034-18039
-Williams GC (1957) Pleiotropy, natural selectioon, and the evolution of senescence. Evolution. 11: 398-411
Tuesday, November 2, 2010
Neutralism and Selectionism
Ever since Kimura’s bold publication, which suggested that many of evolution’s innovations were more the product of neutral (or ‘nearly neutral’) mutations driven to fixation within a population through the action of genetic drift and its refinement, molecular and evolutionary biologists have had trouble agreeing upon whether natural selection or neutral drift-based evolution were the main motivators behind phenotypic evolution. Today, it would seem, we are hardly closer to closing the book on this debate than before.
As advanced methods for probing the molecular and genomic frameworks of phenotypic evolution are developed, findings seem to, at least on the surface, weaken the case for neutralism. For example, the McDonald-Kreitman tests provides evidence that between 30 and more than 90 percent off nucleotide changes in the Drosophila genus and in other organisms go to fixation because they are beneficial. Furthermore, recent genome-scale data seems to support selectionism (ie. the position that the majority of phenotypic evolution is driven by the fixation of beneficial alleles through the act of natural selection) when considering correlations between within-species allele polymorphisms and between species gene polymorphisms.
Nevertheless, Andreas Wagner (2008) suggests that, instead of parsing evolutionary understanding into spectral poles (of likely the same underlying mechanism) of ‘selectionism’ vs ‘neutralism’ we should instead view them as complementary mechanics that operate at different strengths at different times. Selection acts to fix beneficial mutations throughout a population, often acting in large ‘selective sweeps’ that show punctuated periods of adaptation followed by periods of seemingly static existence. Wagner argues that during such periods of stasis (or even throughout the entire course of evolution), neutralism serves as a massively dynamic force in adaptation, allowing the exploration of so-called “neutral networks”, wherein all possible phenotypic/molecular possibilities are connected, and SNPs of near-neutrality represent explorations of such a network. This standing genetic variation within a population actually acts to “feel out” all the nearly-neutral phenotypic possibilities, sometimes acting to ‘discover’ adaptive innovations that, under a strictly selectionist regime, would be impossible.
Consider a molecular phenotype within a population. Within this functional molecule there are many possible mutations that would be neutral, or, at least, nearly neutral, in that they wouldn’t drastically alter the molecule’s function. Through neutral mechanisms (neutral SNPs that alter the underlying genetic code, or nearly neutral amino acid substitutions that do not noticeably alter the proteins function) large amounts of variation can be accrued over time within the population. As the molecule fills its neutral “coding space”, it is brought closer to possibly beneficial mutations than could have ever been possible by considering only beneficial mutations. Furthermore, neutrality’s power can be even more pronounced when one considers the often quixotic nature of selection in determining what is and is not a “fit” phenotype (or fit character). In some instances, mildly deleterious mutations might be allowed within a population due to the fact that the protein in question is not the primary predictor of fitness at that time (eg: being able to run from a lion is no longer the primary predictor of human fitness, and therefore less defining in terms of a given human's survivability). These mechanisms and others allow for evolutionary spurts, or punctuated innovation where a population undergoes molecular “exploration” at a specific loci (or many loci), followed by selective sweeps once a adaptive innovation is “discovered”.
Though pedestrian, this explanation is largely what lies at the root of Dr. Wagner’s contentions in support of a unified view of evolution. He argues that neutral and selective “regimes” dominate at different times, likely as the product of these different mechanisms, allowing for evolutionary innovation that would be otherwise impossible under strictly selectionist or strictly neutralist considerations.
-Fay, J.C. (2002) Testing the neutral theory of molecular evolution with genomic data from Drosophila DNA. Nature 415: 1024-1026
-Wagner (2008) Neutralism and selectionism: a network-based reconciliation. Nature Rev. Genetics 9: 965-974
Monday, November 1, 2010
CCD
Among beekeepers worldwide, Colony Collapse Disorder (CCD), a disorder in which European Honey Bee colonies suddenly experience a massive reduction in worker number, has become a prominent concern, afflicting up to 50% of colonies within certain regions, and posing a very real threat to the industry of apiculture. Though many possible causes of the disorder have been posed, ranging from the EM interference from cellular phones (in one questionable study) to pathogen-related stressors, no studies seem to agree, or even reach a reliable conclusion (with each other), on what seems to be causing this disorder.
Bromenshenk et al (2010) used mass spectrometry-based proteomics (MSP) to attempt to identify potential markers of CCD. "Mass spectrometry yielded unambiguous peptide fragment data that was processed by bioinformatics tools against the full library of peptide sequences based on both genomic and proteomic research." The authors contended that this method allowed for detection and classification of pathogens (fungi, bacteria, and viruses) or causative agents in "a single pass" which was "unrestricted by the need for amplification". Ultimately their analysis revealed the presence of two previously unreported RNA viruses, as well as a highly significant correlation between the presence of a (DNA) virus and Nosema ceranae in CCD afflicted colonies.
The most significant find of this study was the occurrence of the invertebrate iridescent DNA virus (IIV--IIV-6 to be more precise, however the authors go on to postulate that it might be a variant of this virus) in 100% of colonies that were collapsing or collapsed. Furthermore, there seemed to be a relationship between the level of infection/peptide presence and the effect on the colonies (with 75% of strong colonies being infected with the IIV-6 but at a much lower level). They also observed that a specific group of Nosema seemed to co-occur with IIV in failing colonies in a very significant way, and the pathogen levels increased (according to MSP) as the collapse progressed.
These data (along with another analysis in the paper not covered here) seem to indicate that CCD, a condition that has yet to be given a reliable causative agent till now, is caused by a co-occurrence of a DNA virus (IIV-6ish) and intracellular pathogen (Nosema). Though the authors results seem reliable, caution should be recommended given this condition's history of eliciting grandiose claims of significance.
-Bromenshenk et al. (2010) Iridovirus and Microsporidian linked to Honey Bee Colony Decline. PLoS One 5(10): e13181
doi:10.1371/journal.pone.0013181
Bromenshenk et al (2010) used mass spectrometry-based proteomics (MSP) to attempt to identify potential markers of CCD. "Mass spectrometry yielded unambiguous peptide fragment data that was processed by bioinformatics tools against the full library of peptide sequences based on both genomic and proteomic research." The authors contended that this method allowed for detection and classification of pathogens (fungi, bacteria, and viruses) or causative agents in "a single pass" which was "unrestricted by the need for amplification". Ultimately their analysis revealed the presence of two previously unreported RNA viruses, as well as a highly significant correlation between the presence of a (DNA) virus and Nosema ceranae in CCD afflicted colonies.
The most significant find of this study was the occurrence of the invertebrate iridescent DNA virus (IIV--IIV-6 to be more precise, however the authors go on to postulate that it might be a variant of this virus) in 100% of colonies that were collapsing or collapsed. Furthermore, there seemed to be a relationship between the level of infection/peptide presence and the effect on the colonies (with 75% of strong colonies being infected with the IIV-6 but at a much lower level). They also observed that a specific group of Nosema seemed to co-occur with IIV in failing colonies in a very significant way, and the pathogen levels increased (according to MSP) as the collapse progressed.
These data (along with another analysis in the paper not covered here) seem to indicate that CCD, a condition that has yet to be given a reliable causative agent till now, is caused by a co-occurrence of a DNA virus (IIV-6ish) and intracellular pathogen (Nosema). Though the authors results seem reliable, caution should be recommended given this condition's history of eliciting grandiose claims of significance.
-Bromenshenk et al. (2010) Iridovirus and Microsporidian linked to Honey Bee Colony Decline. PLoS One 5(10): e13181
doi:10.1371/journal.pone.0013181
Friday, October 29, 2010
The human [cess]pool
Everybody wants life liberty and the pursuit of happiness. Everybody. Though most people will tell you this is a fantastic situation, leave it to me to tell you otherwise. This is a problem. No, not at first. At first it's good...almost euphorically good. But eventually, should this continue to be the status quo, this will become a problem (and, likely, already is). How, you ask, could such a wonderful system that feeds cripples and delinquents love and bunnies be anything but THE BEST SYSTEM IN THE WORLD? Well, for one, because it makes everyone praising the wonders of America sound like a bunch of raving lunatics who can't logically understand the nature of a country on a global scale, but that's nothing new to humanity. No, the real problem lies in the nature of our relaxed system and how it may affect our biological future.
As humans begin to fully understand the nature of what they are, several things are becoming clear. For one, nobody wants to admit what all fields of science (you know, that mumbo-jumbo that gave you TVs, computers, vaccinations, and almost everything else you cherish) are blatantly telling us. That humans are animals, derived from animals, and are where they are today (evolutionarily and biologically speaking) due to specific selective pressures applied to our ancestors. Pressures that equipped the standard human for specific tasks, imbued him with unprecedented information-sharing (and cooperative) capabilities, and endowed him with the tools to become the most successful replicating machine on a whole planet of successful replicating machines. Invariably, everything we learn from our history, biology, and surroundings (ie physical environment) screams that we are nothing more than extremely adept replicating machines who can trace our origins back to an event in earth's early history (assuming life started on Earth) where several molecular regimes began replicating themselves and haven't stopped since. Naturally, they accrued data as they went—both in the form of external inputs and internal inputs (life-on-life competition/interaction)—, evolved new methods of information-exchange, and redirected certain pressures to form different “units” under selection, but the basic principles are all the same, and the initial replication event was what set it all in motion. So, though amplified, glorified, and self-deified, humans are nothing more than replicating machines operating under various evolutionary pressures (molecular evolution, natural selection, ect), and all that they do and are is the product of said pressures, experienced throughout their evolutionary history.
All of that is old news. Any self-respecting biologist will pay lip-service to these concepts (though many only casually accept them), but only a few vehemently and fully believe and understand them. Under the above assumptions egalitarianism is far-from good. What egalitarianism does is pander to the individual, based upon each human's inherent aversion to subjugation—at least openly; many humans freely accept social subjugation—, desire for freedom from impending death, and other universal (or near-universal) needs. These needs, however, are simply biological imperatives fixed within our population through natural selection (see above), and, as any slightly logical person can see, rightfully so. The human aversion to subjugation is the product of the nature of the selfish psychology of a genetically-independent individual (contrast to the members of a eusocial network), the aversion towards death is an obvious product of how detrimental failing to have said aversion was to our less-than-fit ancestors (you know, the ones that didn't have that self-preservation instinct), and all of our other shared needs (the human need for love/companionship, the human need for religious belief, ect) hold a similar evolutionary origin—which I will not get into here; for more on these UTFSE. Ultimately, humans desire these things because having these desires was advantageous to our ancestors and, depending upon the prevalence of an ideal, provided varying levels of fitness to those with them (both, as a function of group and individual fitness). This leads us to the inherent problem within egalitarianism, its incompatibility with the nature of an organism/population of organisms.
As we develop more and more epigenetic therapies (ie. therapies that leave the underlying genetics of those treated unchanged) for malady with our society, and apply them nearly-universally, we are relaxing the pressures that have been in place for all of life's history. As covered above, an organism is the product of physical pressures placed upon its species and population; and a population of organisms is constantly in genetic flux, as this is one of the mechanisms at the root of life's ability to churn out novelty. Mutations create variations on the organism's genetic code which are then acted upon by external pressures in the form of selective death. Some mutations have little effect (termed synonymous mutations) due to the fact that more than one DNA triplet can code for the same amino acid, while others alter the amino acid sequence of a protein (missense mutations). Some of these sequence-alterations have only minor effects on the protein product (termed quiet mutations) while others have detrimental effects (such as in sickle-cell anemia). There are far more variations on how a mutation can effect change in an organism and how transposable elements and other forms of molecular evolution can enact change, however this is not a dissertation on molecular evolution. Furthermore, traits (especially in more complex organisms) are usually the product of the interaction of many genes (polygenic) separated both spatially and temporally, and each represented by two copies (alleles) in an organism. Due to these factors many mutations only alter an organism's phenotype subtly and, should this alteration be beneficial, spread throughout the population quickly (thanks to sexual exchange, in many/most multi-cellular eukaryotes). All of these factors of life's biology lend to a species' ability to rapidly adapt to external pressures should the need and mechanisms arise, and, due to their often novelty-introducing nature, mutations are far from negative and far from uncommon—in fact, it is generally assumed that sex evolved largely to spread mutations about within a population. As such, a species is constantly being fixed in place by external and internal pressures, acting against one another in a delicate dance on the border between chaos and complexity/uniformity.
One of the seminal assumptions of evolution is that, within a population, more organisms will be produced than can possibly mate in the next generation--thereby creating the "excess" information from which to 'select'—if only as many organisms were produces as were needed mutations would run havoc throughout the population, or, more likely, the species would simply die out. In many human societies however, this is no longer the case (or has been heavily relaxed), as almost all humans reproduce that wish it (though, granted, some do not for various reasons). Hopefully, at this point, you can see where this is going. As human society continues to relax the external pressures acting on the human organism, the internal pressures covered above (mutation, molecular evolution, ect) are able to run (partially) rampant, sowing misinformation throughout our genetic code and gravely “expanding” the human form (“alteration” can only occur with culling). With the physical constraints placed on the individual all but absent (morbidly obese and hopelessly frail humans can still, and do still, have families), there is nothing holding the human form "in place"--physically and, in many cases, behaviorally. This problem cannot rectify itself as no human will optionally give up their reproductive rights simply to see a brighter future for the human race (that they, genetically speaking, will no longer be a part of). This, ladies and gentleman, is the probable fate of the American dream—human dream, to be more accurate. As freedom increases and everyone is entitled to reproduction and health-care support (which is ever-improving to meet the needs of an infinitely entitled population) the inevitable problem of mutation and expansion continue to be overlooked or ignored.
So, we see, life, liberty, and the pursuit of “happiness” doesn't necessarily have a happy ending (although, these predictions are, in no way, set in stone). The problem is that humans are still extremely reluctant to understand the picture painted so parsimoniously for us by biology, and as such, are nowhere near reaching a coherent understanding of their own bodies and species. This wouldn't be a problem if the USA wasn't a democracy, but, unfortunately, every moron out there gets a (admittedly partial) say in many matters. Instead of face the somewhat disillusioning music, they decide to ignore the discussion of evolution, the nature of an organism (as the product of selective pressures which define its genetic parameter-space), and how, without selective pressures, any population of organisms will (invariably) undergo extensive decay, due to the nature of information-sharing and novelty-induction (mutation, molecular evolutionary mechanisms, ect.) associated with sexual exchange and organisms in general. Naturally, there are still some constraints placed upon humans, but they are rare and often half-hearted (sexual assortment, other conditions we have yet to "excuse" through medical therapy). Much like how every use of an anti-biotic creates the potential for an evolutionary response in the target population of microbes, every epigenetic treatment for a pathology creates the potential for human genetic corruption—and though this “corruption” is already evident, should it continue it will have definite implications for fields such as health-care, where everyone is “equal” and entitled to service (a totally unsustainable situation). Add to this the fact that we are living in an almost certain statistical despotism (where what is popular is god, not what is right or logical), and what we find ourselves living in is not the American dream, but the American nightmare—BAZING!
A note should be made that, though this note has a very prophetic, doomsdayesque feel, genetic understanding and techniques are improving (within the scientific community), and it is probable that many of these problems could be alleviated in the future through genetic “therapies”. However we are far from feasible, economic solutions, and, while scientific progress is often impressively rapid, no easy solutions are around the corner; especially considering the state of current public understanding. There will likely not be any measurable issues within our lifetime, but rest assured that these issues are real and will not go away simply because we pour ignorance over them.
--In a recent "Inaugural Article" in PNAS this was addressed, as well as some of the novel features of human genetics/the human genome associated with somatic-cell mutation throughout the human's life--relatively unrelated to the subject of this "note", as it addresses within-generation human mortality. While admitting that this concept is not necessarily a new one, the author state that "the enormous change in the selective environment that human behavior has induced during approximately the past century. Innovations spawned by agriculture, architecture, industrialization, and most notably a sophisticated health care industry have led to a dramatic relaxation in selection against mildly deleterious mutations, and modern medical intervention is increasingly successful in ensuring a productive lifespan even in individuals carrying mutations with major morphological, metabolic, and behavioral defects."
They then go on to state that "the fundamental requirement for the maintenance of a species’ genetic integrity and long-term viability is that the loss of mean fitness by the recurrent input of deleterious mutations each generation must be balanced by the removal of such mutations by natural selection. If the effectiveness of the latter is eliminated, normal viability and fertility can be maintained to a certain extent by modifying the environment to ameliorate the immediate effects of mutations, but this is ultimately an unsustainable situation, as buffering the effects of degenerative mutations would require a matching cumulative level of investment in pharmaceuticals, behavioral therapies, and other forms of medical intervention. Given the relatively high human mutation rate and the fact that a relaxation of natural selection typically leads to 0.1% to 1.5% decline in fitness per generation in other animal species with lower mutation rates (51), this type of scenario has now gained a level of quantitative credence that was absent when Muller (49) first raised the issue." And finally, "although there is considerable uncertainty in the preceding numbers, it is difficult to escape the conclusion that the per-generation reduction in fitness due to recurrent mutation is at least 1% in humans and quite possibly as high as 5%"--note that these estimates do not account for the probable increase in mutagen-intake associated with modern human industrial society (processed foods, ect). The irony in all of this is the fact that the future of human genetic "purity" lies within the genomes of those in the least industrialized societies, where selection is still far less relaxed.
-Lynch (2010), Rate, molecular spectrum, and consequences of human mutation. PNAS 107(3): 961-968
As humans begin to fully understand the nature of what they are, several things are becoming clear. For one, nobody wants to admit what all fields of science (you know, that mumbo-jumbo that gave you TVs, computers, vaccinations, and almost everything else you cherish) are blatantly telling us. That humans are animals, derived from animals, and are where they are today (evolutionarily and biologically speaking) due to specific selective pressures applied to our ancestors. Pressures that equipped the standard human for specific tasks, imbued him with unprecedented information-sharing (and cooperative) capabilities, and endowed him with the tools to become the most successful replicating machine on a whole planet of successful replicating machines. Invariably, everything we learn from our history, biology, and surroundings (ie physical environment) screams that we are nothing more than extremely adept replicating machines who can trace our origins back to an event in earth's early history (assuming life started on Earth) where several molecular regimes began replicating themselves and haven't stopped since. Naturally, they accrued data as they went—both in the form of external inputs and internal inputs (life-on-life competition/interaction)—, evolved new methods of information-exchange, and redirected certain pressures to form different “units” under selection, but the basic principles are all the same, and the initial replication event was what set it all in motion. So, though amplified, glorified, and self-deified, humans are nothing more than replicating machines operating under various evolutionary pressures (molecular evolution, natural selection, ect), and all that they do and are is the product of said pressures, experienced throughout their evolutionary history.
All of that is old news. Any self-respecting biologist will pay lip-service to these concepts (though many only casually accept them), but only a few vehemently and fully believe and understand them. Under the above assumptions egalitarianism is far-from good. What egalitarianism does is pander to the individual, based upon each human's inherent aversion to subjugation—at least openly; many humans freely accept social subjugation—, desire for freedom from impending death, and other universal (or near-universal) needs. These needs, however, are simply biological imperatives fixed within our population through natural selection (see above), and, as any slightly logical person can see, rightfully so. The human aversion to subjugation is the product of the nature of the selfish psychology of a genetically-independent individual (contrast to the members of a eusocial network), the aversion towards death is an obvious product of how detrimental failing to have said aversion was to our less-than-fit ancestors (you know, the ones that didn't have that self-preservation instinct), and all of our other shared needs (the human need for love/companionship, the human need for religious belief, ect) hold a similar evolutionary origin—which I will not get into here; for more on these UTFSE. Ultimately, humans desire these things because having these desires was advantageous to our ancestors and, depending upon the prevalence of an ideal, provided varying levels of fitness to those with them (both, as a function of group and individual fitness). This leads us to the inherent problem within egalitarianism, its incompatibility with the nature of an organism/population of organisms.
As we develop more and more epigenetic therapies (ie. therapies that leave the underlying genetics of those treated unchanged) for malady with our society, and apply them nearly-universally, we are relaxing the pressures that have been in place for all of life's history. As covered above, an organism is the product of physical pressures placed upon its species and population; and a population of organisms is constantly in genetic flux, as this is one of the mechanisms at the root of life's ability to churn out novelty. Mutations create variations on the organism's genetic code which are then acted upon by external pressures in the form of selective death. Some mutations have little effect (termed synonymous mutations) due to the fact that more than one DNA triplet can code for the same amino acid, while others alter the amino acid sequence of a protein (missense mutations). Some of these sequence-alterations have only minor effects on the protein product (termed quiet mutations) while others have detrimental effects (such as in sickle-cell anemia). There are far more variations on how a mutation can effect change in an organism and how transposable elements and other forms of molecular evolution can enact change, however this is not a dissertation on molecular evolution. Furthermore, traits (especially in more complex organisms) are usually the product of the interaction of many genes (polygenic) separated both spatially and temporally, and each represented by two copies (alleles) in an organism. Due to these factors many mutations only alter an organism's phenotype subtly and, should this alteration be beneficial, spread throughout the population quickly (thanks to sexual exchange, in many/most multi-cellular eukaryotes). All of these factors of life's biology lend to a species' ability to rapidly adapt to external pressures should the need and mechanisms arise, and, due to their often novelty-introducing nature, mutations are far from negative and far from uncommon—in fact, it is generally assumed that sex evolved largely to spread mutations about within a population. As such, a species is constantly being fixed in place by external and internal pressures, acting against one another in a delicate dance on the border between chaos and complexity/uniformity.
One of the seminal assumptions of evolution is that, within a population, more organisms will be produced than can possibly mate in the next generation--thereby creating the "excess" information from which to 'select'—if only as many organisms were produces as were needed mutations would run havoc throughout the population, or, more likely, the species would simply die out. In many human societies however, this is no longer the case (or has been heavily relaxed), as almost all humans reproduce that wish it (though, granted, some do not for various reasons). Hopefully, at this point, you can see where this is going. As human society continues to relax the external pressures acting on the human organism, the internal pressures covered above (mutation, molecular evolution, ect) are able to run (partially) rampant, sowing misinformation throughout our genetic code and gravely “expanding” the human form (“alteration” can only occur with culling). With the physical constraints placed on the individual all but absent (morbidly obese and hopelessly frail humans can still, and do still, have families), there is nothing holding the human form "in place"--physically and, in many cases, behaviorally. This problem cannot rectify itself as no human will optionally give up their reproductive rights simply to see a brighter future for the human race (that they, genetically speaking, will no longer be a part of). This, ladies and gentleman, is the probable fate of the American dream—human dream, to be more accurate. As freedom increases and everyone is entitled to reproduction and health-care support (which is ever-improving to meet the needs of an infinitely entitled population) the inevitable problem of mutation and expansion continue to be overlooked or ignored.
So, we see, life, liberty, and the pursuit of “happiness” doesn't necessarily have a happy ending (although, these predictions are, in no way, set in stone). The problem is that humans are still extremely reluctant to understand the picture painted so parsimoniously for us by biology, and as such, are nowhere near reaching a coherent understanding of their own bodies and species. This wouldn't be a problem if the USA wasn't a democracy, but, unfortunately, every moron out there gets a (admittedly partial) say in many matters. Instead of face the somewhat disillusioning music, they decide to ignore the discussion of evolution, the nature of an organism (as the product of selective pressures which define its genetic parameter-space), and how, without selective pressures, any population of organisms will (invariably) undergo extensive decay, due to the nature of information-sharing and novelty-induction (mutation, molecular evolutionary mechanisms, ect.) associated with sexual exchange and organisms in general. Naturally, there are still some constraints placed upon humans, but they are rare and often half-hearted (sexual assortment, other conditions we have yet to "excuse" through medical therapy). Much like how every use of an anti-biotic creates the potential for an evolutionary response in the target population of microbes, every epigenetic treatment for a pathology creates the potential for human genetic corruption—and though this “corruption” is already evident, should it continue it will have definite implications for fields such as health-care, where everyone is “equal” and entitled to service (a totally unsustainable situation). Add to this the fact that we are living in an almost certain statistical despotism (where what is popular is god, not what is right or logical), and what we find ourselves living in is not the American dream, but the American nightmare—BAZING!
A note should be made that, though this note has a very prophetic, doomsdayesque feel, genetic understanding and techniques are improving (within the scientific community), and it is probable that many of these problems could be alleviated in the future through genetic “therapies”. However we are far from feasible, economic solutions, and, while scientific progress is often impressively rapid, no easy solutions are around the corner; especially considering the state of current public understanding. There will likely not be any measurable issues within our lifetime, but rest assured that these issues are real and will not go away simply because we pour ignorance over them.
--In a recent "Inaugural Article" in PNAS this was addressed, as well as some of the novel features of human genetics/the human genome associated with somatic-cell mutation throughout the human's life--relatively unrelated to the subject of this "note", as it addresses within-generation human mortality. While admitting that this concept is not necessarily a new one, the author state that "the enormous change in the selective environment that human behavior has induced during approximately the past century. Innovations spawned by agriculture, architecture, industrialization, and most notably a sophisticated health care industry have led to a dramatic relaxation in selection against mildly deleterious mutations, and modern medical intervention is increasingly successful in ensuring a productive lifespan even in individuals carrying mutations with major morphological, metabolic, and behavioral defects."
They then go on to state that "the fundamental requirement for the maintenance of a species’ genetic integrity and long-term viability is that the loss of mean fitness by the recurrent input of deleterious mutations each generation must be balanced by the removal of such mutations by natural selection. If the effectiveness of the latter is eliminated, normal viability and fertility can be maintained to a certain extent by modifying the environment to ameliorate the immediate effects of mutations, but this is ultimately an unsustainable situation, as buffering the effects of degenerative mutations would require a matching cumulative level of investment in pharmaceuticals, behavioral therapies, and other forms of medical intervention. Given the relatively high human mutation rate and the fact that a relaxation of natural selection typically leads to 0.1% to 1.5% decline in fitness per generation in other animal species with lower mutation rates (51), this type of scenario has now gained a level of quantitative credence that was absent when Muller (49) first raised the issue." And finally, "although there is considerable uncertainty in the preceding numbers, it is difficult to escape the conclusion that the per-generation reduction in fitness due to recurrent mutation is at least 1% in humans and quite possibly as high as 5%"--note that these estimates do not account for the probable increase in mutagen-intake associated with modern human industrial society (processed foods, ect). The irony in all of this is the fact that the future of human genetic "purity" lies within the genomes of those in the least industrialized societies, where selection is still far less relaxed.
-Lynch (2010), Rate, molecular spectrum, and consequences of human mutation. PNAS 107(3): 961-968
intersection of ribozyme folds and support for neutrality
Though recently many authors have argued that molecular neutralism (ie. the position that the vast majority of changes at the molecular level occur due to genetic drift of selectively neutral mutations) is 'on the rocks', this study provides resounding evidence for the continued support for the viewpoint (or, at least, a balanced viewpoint such as the one addressed by Wagner (2008)).
The authors examine two ribozymes (ribonucleic 'enzymes') with grossly differing sequence (<25% identity--the human hepatitis delta virus self-cleavage ribozyme and a class III self-ligating ribozyme) and folding, and, through a 'mutational walk', succeed in transforming them into one another.
Furthermore, they show that through most of the 'walk' the enzymatic activity of the mutated molecules do not change dramatically. This supports the contention that neutral mutations that have little effect on the molecular function of proteins can accumulate during 'neutral' evolutionary activity (through synonymous or nearly neutral alterations in nucleotide sequence, or, in the case of proteins, functional substitutions), allowing single polymorphisms to have drastic effects on structure and function when paired with said neutral alterations.
Finally, the authors further create 'prototype' molecules of each 'fold'-type that share nearly 100% sequence identity (the shift in folding occurs through the changing of 2 nucleotides), demonstrating that, even with highly similar (near-identical) sequence identity, highly different functions can manifest. Taken, together these results demonstrate how specific molecules (namely, robust proteins or ribozymes) can undergo a large number of neutral changes while retaining largely stable functionality. It is only when these nearly-neutral changes are paired with a single (or few) highly structurally significant changes that large evolutionary/functional changes can occur. This may explain how many multi-step evolutionary changes come about despite several neutral (or even mildly deleterious) intermediate states that would not be intuitively fixed through selection alone.
-Schultes E and Bartel D (2000) One Sequence, Two Ribozymes: Implications for the Emergence of New Ribozyme Folds . Science 289: 448-452.
-Wagner (2008) Neutralism and selectionism: a network-based reconciliation. Nature Reviews: Genetics 9:965-974
The authors examine two ribozymes (ribonucleic 'enzymes') with grossly differing sequence (<25% identity--the human hepatitis delta virus self-cleavage ribozyme and a class III self-ligating ribozyme) and folding, and, through a 'mutational walk', succeed in transforming them into one another.
Furthermore, they show that through most of the 'walk' the enzymatic activity of the mutated molecules do not change dramatically. This supports the contention that neutral mutations that have little effect on the molecular function of proteins can accumulate during 'neutral' evolutionary activity (through synonymous or nearly neutral alterations in nucleotide sequence, or, in the case of proteins, functional substitutions), allowing single polymorphisms to have drastic effects on structure and function when paired with said neutral alterations.
Finally, the authors further create 'prototype' molecules of each 'fold'-type that share nearly 100% sequence identity (the shift in folding occurs through the changing of 2 nucleotides), demonstrating that, even with highly similar (near-identical) sequence identity, highly different functions can manifest. Taken, together these results demonstrate how specific molecules (namely, robust proteins or ribozymes) can undergo a large number of neutral changes while retaining largely stable functionality. It is only when these nearly-neutral changes are paired with a single (or few) highly structurally significant changes that large evolutionary/functional changes can occur. This may explain how many multi-step evolutionary changes come about despite several neutral (or even mildly deleterious) intermediate states that would not be intuitively fixed through selection alone.
-Schultes E and Bartel D (2000) One Sequence, Two Ribozymes: Implications for the Emergence of New Ribozyme Folds . Science 289: 448-452.
-Wagner (2008) Neutralism and selectionism: a network-based reconciliation. Nature Reviews: Genetics 9:965-974
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