Maintenance of Complex Trait Variation: Classic Theory and Modern Data

Numerous studies have found evidence that GWAS loci experience negative selection, which increases in intensity with the effect size of identified variants. However, there is also accumulating evidence that this selection is not entirely mediated by the focal trait and contains a substantial pleiotropic component. Understanding how selective constraint shapes phenotypic variation requires advancing models capable of balancing these and other components of selection, as well as empirical analyses capable of inferring this balance and how it is generated by the underlying biology. We first review the classic theory connecting phenotypic selection to selection at individual loci as well as approaches and findings from recent analyses of negative selection in GWAS data. We then discuss geometric theories of pleiotropic selection with the potential to guide future modeling efforts. Recent findings revealing the nature of pleiotropic genetic variation provide clues to which genetic relationships are important and should be incorporated into analyses of selection, while findings that effect sizes vary between populations indicate that GWAS measurements could be misleading if effect sizes have also changed throughout human history.

Convergent evolution of polyploid genomes from across the eukaryotic tree of life

By modeling the homoeologous gene losses that occurred in fifty genomes deriving from ten distinct polyploidy events, we show that the evolutionary forces acting on polyploids are remarkably similar, regardless of whether they occur in flowering plants, ciliates, fishes or yeasts. The models suggest these events were nearly all allopolyploidies, with two distinct progenitors contributing to the modern species. We show that many of the events show a relative rate of duplicate gene loss prior to the first post-polyploidy speciation that is significantly higher than in later phases of their evolution. The relatively low selective constraint seen for the single-copy genes these losses produced lead us to suggest that most of the purely selectively neutral duplicate gene losses occur in the immediate post-polyploid period. We also find ongoing and extensive reciprocal gene losses (RGL; alternative losses of duplicated ancestral genes) between these genomes. With the exception of a handful of closely related taxa, all of these polyploid organisms are separated from each other by tens to thousands of reciprocal gene losses. As a result, it is very unlikely that viable diploid hybrid species could form between these taxa, since matings between such hybrids would tend to produce offspring lacking essential genes. It is therefore possible that the relatively high frequency of recurrent polyploidies in some lineages may be due to the ability of new polyploidies to bypass RGL barriers.

Fish and chips: the origin of human gene families is a predictor of the location of GWAS signals

GWAS have identified thousands of loci associated with human complex diseases and traits. How these loci are distributed through the genome has not been systematically evaluated. We hypothesised that the location of GWAS loci differ between ancestral linkage groups (ALGs) related to the paralogy and function of genes. We used data from the NHGRI-EBI GWAS catalog to determine whether the density of GWAS loci relative to HapMap variants in each ALG differed, and whether ALG’s were enriched for experimental factor ontological (EFO) terms assigned to the GWAS traits. In a gene-level analyses we explored the characteristics of genes linked to GWAS loci and those mapping to the ALG’s. We find that GWAS loci were enriched or deficient in 9 and 7 of the 17 ALG’s respectively, while there was no difference in the number of GWAS loci in regions of the human genome unassigned to an ALG. All but 2 ALG’s were significantly enriched or deficient for one or more EFO terms. Lastly, we find that genes assigned to an ALG are under higher levels of selective constraint, have longer coding sequences and higher median expression in the tissue of highest expression than genes not mapping to an ALG. On the other hand, genes associated with GWAS loci have longer genomic length and exhibit higher levels of selective constraint relative to non-GWAS genes.Collectively, this suggests that understanding the location and ancestral origins of GWAS signals may be informative for the development of tools for variant prioritization and interpretation.

Controlling for variable transposition rate with an age-adjusted site frequency spectrum

Recognition of the important role of transposable elements (TEs) in eukaryotic genomes quickly led to a burgeoning literature modeling and estimating the effects of selection on TEs. Much of the empirical work on selection has focused on analyzing the site frequency spectrum (SFS) of TEs. But TEs differ from standard evolutionary models in a number of ways that can impact the power and interpretation of the SFS. For example, rather than mutating under a clock-like model, transposition often occurs in bursts which can inflate particular frequency categories compared to expectations under a standard neutral model. If a TE burst has been recent, the excess of low frequency polymorphisms can mimic the effect of purifying selection. Here, we investigate how transposition bursts affect the frequency distribution of TEs and the correlation between age and allele frequency. Using information on the TE age distribution, we propose an age-adjusted site frequency spectrum to compare TEs and neutral polymorphisms to more effectively evaluate whether TEs are under selective constraints. We show that our approach can minimize instances of false inference of selective constraint, but also allows for a correct identification of even weak selection affecting TEs which experienced a transposition burst and is robust to at least simple demographic changes. The results presented here will help researchers working on TEs to more reliably identify the effects of selection on TEs without having to rely on the assumption of a constant transposition rate.

Site level factors that affect the rate of adaptive evolution in humans and chimpanzees; the effect of contracting population size.

It has previously been shown in other species that the rate of adaptive evolution is higher at sites that are more exposed in a protein structure and lower between amino acid pairs that are more dissimilar. We have investigated whether these patterns are found in the divergence between humans and chimpanzees using an extension of the MacDonald-Kreitman test. We confirm previous findings and find that the rate of adaptive evolution, relative to the rate of mutation, is higher for more exposed amino acids, lower for amino acid pairs that are more dissimilar in terms of their polarity, volume and lower for amino acid pairs that are subject to stronger purifying selection, as measured by the ratio of the numbers of non-synonymous to synonymous polymorphisms (pN/pS). However, the slope of this latter relationship is significantly shallower than in Drosophila species. We suggest that this is due to the population contraction that has occurred since humans and chimpanzees diverged. We demonstrate theoretically that population size reduction can generate an artefactual positive correlation between the rate of adaptive evolution and any factor that is correlated to the mean strength of selection acting against deleterious mutations, even if there has been no adaptive evolution (the converse is also expected). Our measure of selective constraint, pN/pS, is negatively correlated to the mean strength of selection, and hence we would expect the correlation between the rate of adaptive evolution to also be negatively correlated to pN/pS, if there is no adaptive evolution. The fact that our rate of adaptive evolution is positively correlated to pN/pS suggests that the correlation does genuinely exist, but that is has been attenuated by population size contraction.

Overcoming constraints on the detection of recessive selection in human genes from population frequency data

The identification of genes that evolve under recessive natural selection is a longstanding goal of population genetics research with important applications to disease gene discovery. We found that commonly used methods to evaluate selective constraint at the gene level are highly sensitive to genes under heterozygous selection but ubiquitously fail to detect recessively evolving genes. Additionally, more sophisticated likelihood-based methods designed to detect recessivity similarly lack power for a human gene of realistic length from current population sample sizes. However, extensive simulations suggested that recessive genes may be detectable in aggregate. Here, we offer a method informed by population genetics simulations designed to detect recessive purifying selection in gene sets. Applying this to empirical gene sets produced significant enrichments for strong recessive selection in genes previously inferred to be under recessive selection in a consanguineous cohort and in genes involved in autosomal recessive monogenic disorders.

Understanding Oral Diseases: Exploring Opportunities from Filipino Oral Microbiome Research

The human mouth houses the second most diverse microbial community in the body, with almost 700 species of bacteria colonizing the hard surfaces of teeth and the soft tissues of the oral mucosa. To compete in the relatively exposed oral cavity, resident microbes must avoid being replaced by newcomers. This selective constraint, coupled with pressure on the host to cultivate a beneficial microbiome, has rendered a commensal oral microbiota that displays colonization resistance, protecting the human host from invasive species, including pathogens. Current control of dental plaque-related diseases is non-specific and is centered on the removal of plaque by mechanical means. Several new methods based on the modulation of the microbiome that aim at maintaining and re-establishing a healthy oral ecosystem have been developed and has greatly expanded our knowledge of the composition and function of the oral microbiome in health and disease. Promoting a balanced microbiome is therefore important to effectively maintain or restore oral health. This review provides an updated body of knowledge on oral microbiome in health and disease and discusses the implications for modern-day oral healthcare. Filipino Oral Microbiome Research to develop a policy framework for microbiome-based management of dental diseases and opportunities will be discussed.

The Evolutionary Rate Variation Among Genes of MVA and MEP Pathways in Plant Terpenoid Biosynthesis

Background: Terpenoids are one of the most important compounds in plants, play an significant biological defense and developmental roles in numerous plant species, and widely used for industrial chemicals. Many previous studies have completed the identification of terpenoid biosynthetic pathway and related genes. However, few studies have focused on the molecular evolution analysis of terpenoid pathway genes in plants. In this study, we researched the evolutionary rate variation pattern of 16 terpenoid pathway genes in 12 species with a broad taxonomic span. Results: We retrieved 14 genes in MVA and MEP pathways and 2 extra genes from 12 species, respectively. The evolutionary parameters dN values and dN/ dS ratios are varied significantly among genes, and the dN/ dS ratios of most genes are varied substantially among lineages. The MVA and MEP pathways genes have different evolutionary rate variation pattern, although no significant difference in dN/ dS ratios between two pathways genes. For MVA pathway, the downstream genes exhibits the greater dN/ dS ratio than upstream genes. For MEP pathway, the three midstream genes evolves more rapidly than other genes, and most of MEP pathway genes were detected the signature of positive selection under random sites models. Moreover, the dN/ dS ratios of MVA and MEP pathways genes are negatively correlated with pathway position and PPI, and coding sequence length, respectively. Conclusions: Taken together, the results indicated that the evolutionary rate variation of MVA pathway genes is mainly attributed to differential selective constraint rather than the positive selection. However, the differential selective constraint relaxation and positive selection collectively shaped the evolutionary rate heterogeneity of MEP pathway genes.

Comparative Gene Expression Analysis Reveals Mechanism of Pinus contorta Response to the Fungal Pathogen Dothistroma septosporum

Many conifers have distributions that span wide ranges in both biotic and abiotic conditions, but the basis of response to biotic stress has received much less attention than response to abiotic stress. In this study, we investigated the gene expression response of lodgepole pine (Pinus contorta) to attack by the fungal pathogen Dothistroma septosporum, which causes Dothistroma needle blight (DNB), a disease that has caused severe climate-related outbreaks in northwestern British Columbia. We inoculated tolerant and susceptible pines with two D. septosporum isolates and analyzed the differentially expressed genes, differential exon usage, and co-expressed gene modules using RNA-seq data. We found a rapid and strong transcriptomic response in tolerant lodgepole pine samples inoculated with one D. septosporum isolate, and a late and weak response in susceptible samples inoculated with another isolate. We mapped 43 of the DEG- or gene-module-identified genes to the reference plant-pathogen interaction pathway deposited in KEGG database. These genes are present in PAMP-triggered and effector-triggered immunity pathways. Genes comprising pathways and gene modules had signatures of strong selective constraint, while the highly expressed genes in tolerant samples appear to have been favored by selection to counterattack the pathogen. We identified candidate resistance genes that may respond to D. septosporum effectors. Taken together, our results show that gene expression response to D. septosporum infection in lodgepole pine varies both among tree genotypes and pathogen strains, and involves both known candidate genes and a number of genes with previously unknown functions.