Uncovering adaptive evolution in the human lineage

Background

The recent increase in human polymorphism data, together with the availability of genome sequences from several primate species, provides an unprecedented opportunity to investigate how natural selection has shaped human evolution.

Results

We compared human branch-specific substitutions with variation data in the current human population to measure the impact of adaptive evolution on human protein coding genes. The use of single nucleotide polymorphisms (SNPs) with high derived allele frequencies (DAFs) minimized the influence of segregating slightly deleterious mutations and improved the estimation of the number of adaptive sites. Using DAF ≥ 60% we showed that the proportion of adaptive substitutions is 0.2% in the complete gene set. However, the percentage rose to 40% when we focused on genes that are specifically accelerated in the human branch with respect to the chimpanzee branch, or on genes that show signatures of adaptive selection at the codon level by the maximum likelihood based branch-site test. In general, neural genes are enriched in positive selection signatures. Genes with multiple lines of evidence of positive selection include taxilin beta, which is involved in motor nerve regeneration and syntabulin, and is required for the formation of new presynaptic boutons.

Conclusions

We combined several methods to detect adaptive evolution in human coding sequences at a genome-wide level. The use of variation data, in addition to sequence divergence information, uncovered previously undetected positive selection signatures in neural genes.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-599) contains supplementary material, which is available to authorized users.     

Duplicated paralogous genes subject to positive selection in the genome of Trypanosoma brucei

Background

Whole genome studies have highlighted duplicated genes as important substrates for adaptive evolution. We have investigated adaptive evolution in this class of genes in the human parasite Trypanosoma brucei, as indicated by the ratio of non-synonymous (amino-acid changing) to synonymous (amino acid retaining) nucleotide substitution rates.

Methodology/Principal Findings

We have identified duplicated genes that are most rapidly evolving in this important human parasite. This is the first attempt to investigate adaptive evolution in this species at the codon level. We identify 109 genes within 23 clusters of paralogous gene expansions to be subject to positive selection.

Conclusions/Significance

Genes identified include surface antigens in both the mammalian and insect host life cycle stage suggesting that competitive interaction is not solely with the adaptive immune system of the mammalian host. Also surface transporters related to drug resistance and genes related to developmental progression are detected. We discuss how adaptive evolution of these genes may highlight lineage specific processes essential for parasite survival. We also discuss the implications of adaptive evolution of these targets for parasite biology and control.     

Comparing the retention mechanisms of tandem duplicates and retrogenes in human and mouse genomes

Background

Multiple models have been proposed to interpret the retention of duplicated genes. In this study, we attempted to compare whether the duplicates arising from tandem duplications and retropositions are retained by the same mechanisms in human and mouse genomes.

Results

Both sequence and expression similarity analyses revealed that tandem duplicates tend to be more conserved, whereas retrogenes tend to be more divergent. The duplicability of tandem duplicates is also higher than that of retrogenes. However, positive selection seems to play significant roles in the retention of both types of duplicates.

Conclusions

We propose that dosage effect is more prevalent in the retention of tandem duplicates, while ''escape from adaptive conflict'' (EAC) effect is more prevalent in the retention of retrogenes.     

Global copy number analyses by next generation sequencing provide insight into pig genome variation

Background

Copy number variations (CNVs) confer significant effects on genetic innovation and phenotypic variation. Previous CNV studies in swine seldom focused on in-depth characterization of global CNVs.

Results

Using whole-genome assembly comparison (WGAC) and whole-genome shotgun sequence detection (WSSD) approaches by next generation sequencing (NGS), we probed formation signatures of both segmental duplications (SDs) and individualized CNVs in an integrated fashion, building the finest resolution CNV and SD maps of pigs so far. We obtained copy number estimates of all protein-coding genes with copy number variation carried by individuals, and further confirmed two genes with high copy numbers in Meishan pigs through an enlarged population. We determined genome-wide CNV hotspots, which were significantly enriched in SD regions, suggesting evolution of CNV hotspots may be affected by ancestral SDs. Through systematically enrichment analyses based on simulations and bioinformatics analyses, we revealed CNV-related genes undergo a different selective constraint from those CNV-unrelated regions, and CNVs may be associated with or affect pig health and production performance under recent selection.

Conclusions

Our studies lay out one way for characterization of CNVs in the pig genome, provide insight into the pig genome variation and prompt CNV mechanisms studies when using pigs as biomedical models for human diseases.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-593) contains supplementary material, which is available to authorized users.     

A role for gene duplication and natural variation of gene expression in the evolution of metabolism

Background

Most eukaryotic genomes have undergone whole genome duplications during their evolutionary history. Recent studies have shown that the function of these duplicated genes can diverge from the ancestral gene via neo- or sub-functionalization within single genotypes. An additional possibility is that gene duplicates may also undergo partitioning of function among different genotypes of a species leading to genetic differentiation. Finally, the ability of gene duplicates to diverge may be limited by their biological function.

Methodology/Principal Findings

To test these hypotheses, I estimated the impact of gene duplication and metabolic function upon intraspecific gene expression variation of segmental and tandem duplicated genes within Arabidopsis thaliana. In all instances, the younger tandem duplicated genes showed higher intraspecific gene expression variation than the average Arabidopsis gene. Surprisingly, the older segmental duplicates also showed evidence of elevated intraspecific gene expression variation albeit typically lower than for the tandem duplicates. The specific biological function of the gene as defined by metabolic pathway also modulated the level of intraspecific gene expression variation. The major energy metabolism and biosynthetic pathways showed decreased variation, suggesting that they are constrained in their ability to accumulate gene expression variation. In contrast, a major herbivory defense pathway showed significantly elevated intraspecific variation suggesting that it may be under pressure to maintain and/or generate diversity in response to fluctuating insect herbivory pressures.

Conclusion

These data show that intraspecific variation in gene expression is facilitated by an interaction of gene duplication and biological activity. Further, this plays a role in controlling diversity of plant metabolism.     

Recent segmental and gene duplications in the mouse genome

Background

The high quality of the mouse genome draft sequence and its associated annotations are an invaluable biological resource. Identifying recent duplications in the mouse genome, especially in regions containing genes, may highlight important events in recent murine evolution. In addition, detecting recent sequence duplications can reveal potentially problematic regions of the genome assembly. We use BLAST-based computational heuristics to identify large (≥ 5 kb) and recent (≥ 90% sequence identity) segmental duplications in the mouse genome sequence. Here we present a database of recently duplicated regions of the mouse genome found in the mouse genome sequencing consortium (MGSC) February 2002 and February 2003 assemblies.

Results

We determined that 33.6 Mb of 2,695 Mb (1.2%) of sequence from the February 2003 mouse genome sequence assembly is involved in recent segmental duplications, which is less than that observed in the human genome (around 3.5-5%). From this dataset, 8.9 Mb (26%) of the duplication content consisted of 'unmapped' chromosome sequence. Moreover, we suspect that an additional 18.5 Mb of sequence is involved in duplication artifacts arising from sequence misassignment errors in this genome assembly. By searching for genes that are located within these regions, we identified 675 genes that mapped to duplicated regions of the mouse genome. Sixteen of these genes appear to have been duplicated independently in the human genome. From our dataset we further characterized a 42 kb recent segmental duplication of Mater, a maternal-effect gene essential for embryogenesis in mice.

Conclusion

Our results provide an initial analysis of the recently duplicated sequence and gene content of the mouse genome. Many of these duplicated loci, as well as regions identified to be involved in potential sequence misassignment errors, will require further mapping and sequencing to achieve accuracy. A Genome Browser database was set up to display the identified duplication content presented in this work. This data will also be relevant to the growing number of investigators who use the draft genome sequence for experimental design and analysis.

     

Asymmetric histone modifications between the original and derived loci of human segmental duplications

Background

Sequencing and annotation of several mammalian genomes have revealed that segmental duplications are a common architectural feature of primate genomes; in fact, about 5% of the human genome is composed of large blocks of interspersed segmental duplications. These segmental duplications have been implicated in genomic copy-number variation, gene novelty, and various genomic disorders. However, the molecular processes involved in the evolution and regulation of duplicated sequences remain largely unexplored.

Results

In this study, the profile of about 20 histone modifications within human segmental duplications was characterized using high-resolution, genome-wide data derived from a ChIP-Seq study. The analysis demonstrates that derivative loci of segmental duplications often differ significantly from the original with respect to many histone methylations. Further investigation showed that genes are present three times more frequently in the original than in the derivative, whereas pseudogenes exhibit the opposite trend. These asymmetries tend to increase with the age of segmental duplications. The uneven distribution of genes and pseudogenes does not, however, fully account for the asymmetry in the profile of histone modifications.

Conclusion

The first systematic analysis of histone modifications between segmental duplications demonstrates that two seemingly 'identical' genomic copies are distinct in their epigenomic properties. Results here suggest that local chromatin environments may be implicated in the discrimination of derived copies of segmental duplications from their originals, leading to a biased pseudogenization of the new duplicates. The data also indicate that further exploration of the interactions between histone modification and sequence degeneration is necessary in order to understand the divergence of duplicated sequences.     

The evolution of mitochondrial genomes in modern frogs (Neobatrachia): nonadaptive evolution of mitochondrial genome reorganization

Background

Although mitochondrial (mt) gene order is highly conserved among vertebrates, widespread gene rearrangements occur in anurans, especially in neobatrachians. Protein coding genes in the mitogenome experience adaptive or purifying selection, yet the role that selection plays on genomic reorganization remains unclear. We sequence the mitogenomes of three species of Glandirana and hot spots of gene rearrangements of 20 frog species to investigate the diversity of mitogenomic reorganization in the Neobatrachia. By combing these data with other mitogenomes in GenBank, we evaluate if selective pressures or functional constraints act on mitogenomic reorganization in the Neobatrachia. We also look for correlations between tRNA positions and codon usage.

Results

Gene organization in Glandirana was typical of neobatrachian mitogenomes except for the presence of pseudogene trnS (AGY). Surveyed ranids largely exhibited gene arrangements typical of neobatrachian mtDNA although some gene rearrangements occurred. The correlation between codon usage and tRNA positions in neobatrachians was weak, and did not increase after identifying recurrent rearrangements as revealed by basal neobatrachians. Codon usage and tRNA positions were not significantly correlated when considering tRNA gene duplications or losses. Change in number of tRNA gene copies, which was driven by genomic reorganization, did not influence codon usage bias. Nucleotide substitution rates and d_N/d_S ratios were higher in neobatrachian mitogenomes than in archaeobatrachians, but the rates of mitogenomic reorganization and mt nucleotide diversity were not significantly correlated.

Conclusions

No evidence suggests that adaptive selection drove the reorganization of neobatrachian mitogenomes. In contrast, protein-coding genes that function in metabolism showed evidence for purifying selection, and some functional constraints appear to act on the organization of rRNA and tRNA genes. As important nonadaptive forces, genetic drift and mutation pressure may drive the fixation and evolution of mitogenomic reorganizations.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-691) contains supplementary material, which is available to authorized users.     

Informatics enhanced SNP microarray analysis of 30 miscarriage samples compared to routine cytogenetics

Purpose

The metaphase karyotype is often used as a diagnostic tool in the setting of early miscarriage; however this technique has several limitations. We evaluate a new technique for karyotyping that uses single nucleotide polymorphism microarrays (SNP). This technique was compared in a blinded, prospective fashion, to the traditional metaphase karyotype.

Methods

Patients undergoing dilation and curettage for first trimester miscarriage between February and August 2010 were enrolled. Samples of chorionic villi were equally divided and sent for microarray testing in parallel with routine cytogenetic testing.

Results

Thirty samples were analyzed, with only four discordant results. Discordant results occurred when the entire genome was duplicated or when a balanced rearrangement was present. Cytogenetic karyotyping took an average of 29 days while microarray-based karytoyping took an average of 12 days.

Conclusions

Molecular karyotyping of POC after missed abortion using SNP microarray analysis allows for the ability to detect maternal cell contamination and provides rapid results with good concordance to standard cytogenetic analysis.     

Universal Global Imprints of Genome Growth and Evolution – Equivalent Length and Cumulative Mutation Density

Background

Segmental duplication is widely held to be an important mode of genome growth and evolution. Yet how this would affect the global structure of genomes has been little discussed.

Methods/Principal Findings

Here, we show that equivalent length, or , a quantity determined by the variance of fluctuating part of the distribution of the -mer frequencies in a genome, characterizes the latter''s global structure. We computed the s of 865 complete chromosomes and found that they have nearly universal but (-dependent) values. The differences among the of a chromosome and those of its coding and non-coding parts were found to be slight.

Conclusions

We verified that these non-trivial results are natural consequences of a genome growth model characterized by random segmental duplication and random point mutation, but not of any model whose dominant growth mechanism is not segmental duplication. Our study also indicates that genomes have a nearly universal cumulative “point” mutation density of about 0.73 mutations per site that is compatible with the relatively low mutation rates of (15)10/site/Mya previously determined by sequence comparison for the human and E. coli genomes.     

Molecular Evolution of the Primate Antiviral Restriction Factor Tetherin

Background

Tetherin is a recently identified antiviral restriction factor that restricts HIV-1 particle release in the absence of the HIV-1 viral protein U (Vpu). It is reminiscent of APOBEC3G and TRIM5a that also antagonize HIV. APOBEC3G and TRIM5a have been demonstrated to evolve under pervasive positive selection throughout primate evolution, supporting the red-queen hypothesis. Therefore, one naturally presumes that Tetherin also evolves under pervasive positive selection throughout primate evolution and supports the red-queen hypothesis. Here, we performed a detailed evolutionary analysis to address this presumption.

Methodology/Principal Findings

Results of non-synonymous and synonymous substitution rates reveal that Tetherin as a whole experiences neutral evolution rather than pervasive positive selection throughout primate evolution, as well as in non-primate mammal evolution. Sliding-window analyses show that the regions of the primate Tetherin that interact with viral proteins are under positive selection or relaxed purifying selection. In particular, the sites identified under positive selection generally focus on these regions, indicating that the main selective pressure acting on the primate Tetherin comes from virus infection. The branch-site model detected positive selection acting on the ancestral branch of the New World Monkey lineage, suggesting an episodic adaptive evolution. The positive selection was also found in duplicated Tetherins in ruminants. Moreover, there is no bias in the alterations of amino acids in the evolution of the primate Tetherin, implying that the primate Tetherin may retain broad spectrum of antiviral activity by maintaining structure stability.

Conclusions/Significance

These results conclude that the molecular evolution of Tetherin may be attributed to the host–virus arms race, supporting the Red Queen hypothesis, and Tetherin may be in an intermediate stage in transition from neutral to pervasive adaptive evolution.     

Recent Adaptive Events in Human Brain Revealed by Meta-Analysis of Positively Selected Genes

Background and Objectives

Analysis of positively-selected genes can help us understand how human evolved, especially the evolution of highly developed cognitive functions. However, previous works have reached conflicting conclusions regarding whether human neuronal genes are over-represented among genes under positive selection.

Methods and Results

We divided positively-selected genes into four groups according to the identification approaches, compiling a comprehensive list from 27 previous studies. We showed that genes that are highly expressed in the central nervous system are enriched in recent positive selection events in human history identified by intra-species genomic scan, especially in brain regions related to cognitive functions. This pattern holds when different datasets, parameters and analysis pipelines were used. Functional category enrichment analysis supported these findings, showing that synapse-related functions are enriched in genes under recent positive selection. In contrast, immune-related functions, for instance, are enriched in genes under ancient positive selection revealed by inter-species coding region comparison. We further demonstrated that most of these patterns still hold even after controlling for genomic characteristics that might bias genome-wide identification of positively-selected genes including gene length, gene density, GC composition, and intensity of negative selection.

Conclusion

Our rigorous analysis resolved previous conflicting conclusions and revealed recent adaptation of human brain functions.     

A computational study of elongation factor G (EFG) duplicated genes: diverged nature underlying the innovation on the same structural template

Background

Elongation factor G (EFG) is a core translational protein that catalyzes the elongation and recycling phases of translation. A more complex picture of EFG''s evolution and function than previously accepted is emerging from analyzes of heterogeneous EFG family members. Whereas the gene duplication is postulated to be a prominent factor creating functional novelty, the striking divergence between EFG paralogs can be interpreted in terms of innovation in gene function.

Methodology/Principal Findings

We present a computational study of the EFG protein family to cover the role of gene duplication in the evolution of protein function. Using phylogenetic methods, genome context conservation and insertion/deletion (indel) analysis we demonstrate that the EFG gene copies form four subfamilies: EFG I, spdEFG1, spdEFG2, and EFG II. These ancient gene families differ by their indispensability, degree of divergence and number of indels. We show the distribution of EFG subfamilies and describe evidences for lateral gene transfer and recent duplications. Extended studies of the EFG II subfamily concern its diverged nature. Remarkably, EFG II appears to be a widely distributed and a much-diversified subfamily whose subdivisions correlate with phylum or class borders. The EFG II subfamily specific characteristics are low conservation of the GTPase domain, domains II and III; absence of the trGTPase specific G2 consensus motif “RGITI”; and twelve conserved positions common to the whole subfamily. The EFG II specific functional changes could be related to changes in the properties of nucleotide binding and hydrolysis and strengthened ionic interactions between EFG II and the ribosome, particularly between parts of the decoding site and loop I of domain IV.

Conclusions/Significance

Our work, for the first time, comprehensively identifies and describes EFG subfamilies and improves our understanding of the function and evolution of EFG duplicated genes.     

Interlocus gene conversion explains at least 2.7?% of single nucleotide variants in human segmental duplications

Background

Interlocus gene conversion (IGC) is a recombination-based mechanism that results in the unidirectional transfer of short stretches of sequence between paralogous loci. Although IGC is a well-established mechanism of human disease, the extent to which this mutagenic process has shaped overall patterns of segregating variation in multi-copy regions of the human genome remains unknown. One expected manifestation of IGC in population genomic data is the presence of one-to-one paralogous SNPs that segregate identical alleles.

Results

Here, I use SNP genotype calls from the low-coverage phase 3 release of the 1000 Genomes Project to identify 15,790 parallel, shared SNPs in duplicated regions of the human genome. My approach for identifying these sites accounts for the potential redundancy of short read mapping in multi-copy genomic regions, thereby effectively eliminating false positive SNP calls arising from paralogous sequence variation. I demonstrate that independent mutation events to identical nucleotides at paralogous sites are not a significant source of shared polymorphisms in the human genome, consistent with the interpretation that these sites are the outcome of historical IGC events. These putative signals of IGC are enriched in genomic contexts previously associated with non-allelic homologous recombination, including clear signals in gene families that form tandem intra-chromosomal clusters.

Conclusions

Taken together, my analyses implicate IGC, not point mutation, as the mechanism generating at least 2.7 % of single nucleotide variants in duplicated regions of the human genome.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1681-3) contains supplementary material, which is available to authorized users.     

Genome-wide and molecular evolution analysis of the subtilase gene family in Vitis vinifera

Background

Vitis vinifera (grape) is one of the most economically significant fruit crops in the world. The availability of the recently released grape genome sequence offers an opportunity to identify and analyze some important gene families in this species. Subtilases are a group of subtilisin-like serine proteases that are involved in many biological processes in plants. However, no comprehensive study incorporating phylogeny, chromosomal location and gene duplication, gene organization, functional divergence, selective pressure and expression profiling has been reported so far for the grape.

Results

In the present study, a comprehensive analysis of the subtilase gene family in V. vinifera was performed. Eighty subtilase genes were identified. Phylogenetic analyses indicated that these subtilase genes comprised eight groups. The gene organization is considerably conserved among the groups. Distribution of the subtilase genes is non-random across the chromosomes. A high proportion of these genes are preferentially clustered, indicating that tandem duplications may have contributed significantly to the expansion of the subtilase gene family. Analyses of divergence and adaptive evolution show that while purifying selection may have been the main force driving the evolution of grape subtilases, some of the critical sites responsible for the divergence may have been under positive selection. Further analyses of real-time PCR data suggested that many subtilase genes might be important in the stress response and functional development of plants.

Conclusions

Tandem duplications as well as purifying and positive selections have contributed to the functional divergence of subtilase genes in V. vinifera. The data may contribute to a better understanding of the grape subtilase gene family.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-1116) contains supplementary material, which is available to authorized users.