fem and csd. a drama of the paralogs.

    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

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

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

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