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1.  Strong Epistatic Selection on the RNA Secondary Structure of HIV 
PLoS Pathogens  2014;10(9):e1004363.
A key question in evolutionary genomics is how populations navigate the adaptive landscape in the presence of epistasis, or interactions among loci. This problem can be directly addressed by studying the evolution of RNA secondary structures, for which there is constraint to maintain pairing between Watson-Crick (WC) sites. Replacement of a nucleotide at one site of a WC pair reduces fitness by disrupting binding, which can be restored via a compensatory replacement at the interacting site. Here, I present the first genome-scale analysis of epistasis on the RNA secondary structure of human immunodeficiency virus type 1 (HIV-1). Comparison of polymorphism frequencies at ancestrally conserved sites reveals that selection against replacements is ∼2.7 times stronger at WC than at non-WC sites, such that nearly 50% of constraint can be attributed to epistasis. However, almost all epistatic constraint is due to selection against conversions of WC pairs to unpaired (UP) nucleotides, whereas conversions to GU wobbles are only slightly deleterious. This disparity is also evident in pairs with second-site compensatory replacements; conversions from UP nucleotides to WC pairs increase median fitness by ∼4.2%, whereas conversions from GU wobbles to WC pairs only increase median fitness by ∼0.3%. Moreover, second-site replacements that convert UP nucleotides to GU wobbles also increase median fitness by ∼4%, indicating that such replacements are nearly as compensatory as those that restore WC pairing. Thus, WC peaks of the HIV-1 epistatic adaptive landscape are connected by high GU ridges, enabling the viral population to rapidly explore distant peaks without traversing deep UP valleys.
Author Summary
Epistasis is an evolutionary process in which the effect of a nucleotide at one site in the genome is dependent on the presence or absence of particular nucleotides at other sites in the genome. One of the simplest types of epistasis occurs between Watson-Crick (WC) nucleotides in RNA secondary structures, which are under constraint to maintain base-pairing. In this study, I examine the effects of mutations at WC sites in the RNA secondary structure of HIV-1. I show that while epistasis plays a major role in the evolution of the HIV-1 secondary structure, different types of mutations have variable effects on fitness. Therefore, by favoring certain mutational trajectories, HIV-1 can evolve rapidly despite strong epistatic constraint on its RNA secondary structure.
PMCID: PMC4161434  PMID: 25210786
2.  Sex-Biased Transcriptome Evolution in Drosophila 
Genome Biology and Evolution  2012;4(11):1189-1200.
Sex-biased genes are thought to drive phenotypic differences between males and females. The recent availability of high-throughput gene expression data for many related species has led to a burst of investigations into the genomic and evolutionary properties of sex-biased genes. In Drosophila, a number of studies have found that X chromosomes are deficient in male-biased genes (demasculinized) and enriched for female-biased genes (feminized) and that male-biased genes evolve faster than female-biased genes. However, studies have yielded vastly different conclusions regarding the numbers of sex-biased genes and forces shaping their evolution. Here, we use RNA-seq data from multiple tissues of Drosophila melanogaster and D. pseudoobscura, a species with a recently evolved X chromosome, to explore the evolution of sex-biased genes in Drosophila. First, we compare several independent metrics for classifying sex-biased genes and find that the overlap of genes identified by different metrics is small, particularly for female-biased genes. Second, we investigate genome-wide expression patterns and uncover evidence of demasculinization and feminization of both ancestral and new X chromosomes, demonstrating that gene content on sex chromosomes evolves rapidly. Third, we examine the evolutionary rates of sex-biased genes and show that male-biased genes evolve much faster than female-biased genes, which evolve at similar rates to unbiased genes. Analysis of gene expression among tissues reveals that this trend may be partially due to pleiotropic effects of female-biased genes, which limits their evolutionary potential. Thus, our findings illustrate the importance of accurately identifying sex-biased genes and provide insight into their evolutionary dynamics in Drosophila.
PMCID: PMC3514954  PMID: 23097318
3.  Nested genes and increasing organizational complexity of metazoan genomes 
Trends in Genetics  2008;24(10):475-478.
The most common form of protein-coding gene overlap in eukaryotes is a simple nested structure, whereby one gene is embedded in an intron of another. Analysis of nested protein-coding genes in vertebrates, fruit flies and nematodes revealed substantially higher rates of evolutionary gains than losses. The accumulation of nested gene structures could not be attributed to any obvious functional relationships between the genes involved and represents an increase of the organizational complexity of animal genomes via a neutral process.
PMCID: PMC3380635  PMID: 18774620
4.  A Strong Deletion Bias in Nonallelic Gene Conversion 
PLoS Genetics  2012;8(2):e1002508.
Gene conversion is the unidirectional transfer of genetic information between orthologous (allelic) or paralogous (nonallelic) genomic segments. Though a number of studies have examined nucleotide replacements, little is known about length difference mutations produced by gene conversion. Here, we investigate insertions and deletions produced by nonallelic gene conversion in 338 Drosophila and 10,149 primate paralogs. Using a direct phylogenetic approach, we identify 179 insertions and 614 deletions in Drosophila paralogs, and 132 insertions and 455 deletions in primate paralogs. Thus, nonallelic gene conversion is strongly deletion-biased in both lineages, with almost 3.5 times as many conversion-induced deletions as insertions. In primates, the deletion bias is considerably stronger for long indels and, in both lineages, the per-site rate of gene conversion is orders of magnitudes higher than that of ordinary mutation. Due to this high rate, deletion-biased nonallelic gene conversion plays a key role in genome size evolution, leading to the cooperative shrinkage and eventual disappearance of selectively neutral paralogs.
Author Summary
Gene conversion is a process whereby a DNA sequence is copied from one segment of the genome (donor) to another (recipient), resulting in the replacement, insertion, or deletion of a DNA sequence in the recipient. This exchange is facilitated by the high sequence similarity of the two segments, which is due to their evolutionary relationship. Here, we study insertions and deletions produced by gene conversion between paralogs, segments related by DNA duplication events. By comparing paralog sequences in multiple species of fruit flies and primates, we find that deletions occur more than three times as frequently as insertions. We also discover that the rate of gene conversion between paralogs is quite high. The deletion bias and high rate of this process causes paralogs to shrink cooperatively and eventually be eliminated from the genome. Because of the abundance of paralogs in animal genomes, this phenomenon can lead to a significant reduction in genome size. Therefore, our finding enhances our understanding of the forces that lead to changes in genome size during evolution.
PMCID: PMC3280953  PMID: 22359514

Results 1-4 (4)