Selected heterozygosity at cis-regulatory sequences increases the expression homogeneity of a cell population in humans.
ABSTRACT: BACKGROUND:Examples of heterozygote advantage in humans are scarce and limited to protein-coding sequences. Here, we attempt a genome-wide functional inference of advantageous heterozygosity at cis-regulatory regions. RESULTS:The single-nucleotide polymorphisms bearing the signatures of balancing selection are enriched in active cis-regulatory regions of immune cells and epithelial cells, the latter of which provide barrier function and innate immunity. Examples associated with ancient trans-specific balancing selection are also discovered. Allelic imbalance in chromatin accessibility and divergence in transcription factor motif sequences indicate that these balanced polymorphisms cause distinct regulatory variation. However, a majority of these variants show no association with the expression level of the target gene. Instead, single-cell experimental data for gene expression and chromatin accessibility demonstrate that heterozygous sequences can lower cell-to-cell variability in proportion to selection strengths. This negative correlation is more pronounced for highly expressed genes and consistently observed when using different data and methods. Based on mathematical modeling, we hypothesize that extrinsic noise from fluctuations in transcription factor activity may be amplified in homozygotes, whereas it is buffered in heterozygotes. While high expression levels are coupled with intrinsic noise reduction, regulatory heterozygosity can contribute to the suppression of extrinsic noise. CONCLUSIONS:This mechanism may confer a selective advantage by increasing cell population homogeneity and thereby enhancing the collective action of the cells, especially of those involved in the defense systems in humans.
Project description:Known examples of ancient identical-by-descent genetic variants being shared between evolutionarily related species, known as trans-species polymorphisms (TSPs), result from counterbalancing selective forces acting on target genes to confer resistance against infectious agents. To date, putative TSPs between humans and other primate species have been identified for the highly polymorphic major histocompatibility complex (MHC), the histo-blood ABO group, two antiviral genes (ZC3HAV1 and TRIM5), an autoimmunity-related gene LAD1 and several non-coding genomic segments with a putative regulatory role. Although the number of well-characterized TSPs under long-term balancing selection is still very small, these examples are connected by a common thread, namely that they involve genes with key roles in the immune system and, in heterozygosity, appear to confer genetic resistance to pathogens. Here, we review known cases of shared polymorphism that appear to be under long-term balancing selection in humans and the great apes. Although the specific selective agent(s) responsible are still unknown, these TSPs may nevertheless be seen as constituting important adaptive events that have occurred during the evolution of the primate immune system.
Project description:Pathogen-mediated balancing selection is regarded as a key driver of host immunogenetic diversity. A hallmark for balancing selection in humans is the heterozygote advantage at genes of the human leukocyte antigen (HLA), resulting in improved HIV-1 control. However, the actual mechanism of the observed heterozygote advantage is still elusive. HLA heterozygotes may present a broader array of antigenic viral peptides to immune cells, possibly resulting in a more efficient cytotoxic T-cell response. Alternatively, heterozygosity may simply increase the chance to carry the most protective HLA alleles, as individual HLA alleles are known to differ substantially in their association with HIV-1 control. Here, we used data from 6,311 HIV-1-infected individuals to explore the relative contribution of quantitative and qualitative aspects of peptide presentation in HLA heterozygote advantage against HIV. Screening the entire HIV-1 proteome, we observed that heterozygous individuals exhibited a broader array of HIV-1 peptides presented by their HLA class I alleles. In addition, viral load was negatively correlated with the breadth of the HIV-1 peptide repertoire bound by an individual's HLA variants, particularly at HLA-B. This suggests that heterozygote advantage at HLA-B is at least in part mediated by quantitative peptide presentation. We also observed higher HIV-1 sequence diversity among HLA-B heterozygous individuals, suggesting stronger evolutionary pressure from HLA heterozygosity. However, HLA heterozygotes were also more likely to carry certain HLA alleles, including the highly protective HLA-B*57:01 variant, indicating that HLA heterozygote advantage ultimately results from a combination of quantitative and qualitative effects in antigen presentation.
Project description:In vertebrate animals, genes of the major histocompatibility complex (MHC) determine the set of pathogens to which an individual's adaptive immune system can respond. MHC genes are extraordinarily polymorphic, often showing elevated nonsynonymous relative to synonymous sequence variation and sharing presumably ancient polymorphisms between lineages. These patterns likely reflect pathogen-mediated balancing selection, for example, rare-allele or heterozygote advantage. Such selection is often reinforced by disassortative mating at MHC. We characterized exon 2 of MHC class II, corresponding to the hypervariable peptide-binding region, in song sparrows (Melospiza melodia). We compared nonsynonymous to synonymous sequence variation in order to identify positively selected sites; assessed evidence for trans-species polymorphisms indicating ancient balancing selection; and compared MHC similarity of socially mated pairs to expectations under random mating. Six codons showed elevated ratios of nonsynonymous to synonymous variation, consistent with balancing selection, and we characterized several alleles similar to those occurring in at least four other avian families. Despite this evidence for historical balancing selection, mated pairs were significantly more similar at MHC than were randomly generated pairings. Nonrandom mating at MHC thus appears to partially counteract, not reinforce, pathogen-mediated balancing selection in this system. We suggest that in systems where individual fitness does not increase monotonically with MHC diversity, assortative mating may help to avoid excessive offspring heterozygosity that could otherwise arise from long-standing balancing selection.
Project description:BACKGROUND:Genetic diversity is known to confer survival advantage in many species across the tree of life. Here, we hypothesize that such pattern applies to humans as well and could be a result of higher fitness in individuals with higher genomic heterozygosity. RESULTS:We use healthy aging as a proxy for better health and fitness, and observe greater heterozygosity in healthy-aged individuals. Specifically, we find that only common genetic variants show significantly higher excess of heterozygosity in the healthy-aged cohort. Lack of difference in heterozygosity for low-frequency variants or disease-associated variants excludes the possibility of compensation for deleterious recessive alleles as a mechanism. In addition, coding SNPs with the highest excess of heterozygosity in the healthy-aged cohort are enriched in genes involved in extracellular matrix and glycoproteins, a group of genes known to be under long-term balancing selection. We also find that individual heterozygosity rate is a significant predictor of electronic health record (EHR)-based estimates of 10-year survival probability in men but not in women, accounting for several factors including age and ethnicity. CONCLUSIONS:Our results demonstrate that the genomic heterozygosity is associated with human healthspan, and that the relationship between higher heterozygosity and healthy aging could be explained by heterozygote advantage. Further characterization of this relationship will have important implications in aging-associated disease risk prediction.
Project description:Cells operate in noisy molecular environments via complex regulatory networks. It is possible to understand how molecular counts are related to noise in specific networks, but it is not generally clear how noise relates to network complexity, because different levels of complexity also imply different overall number of molecules. For a fixed function, does increased network complexity reduce noise, beyond the mere increase of overall molecular counts? If so, complexity could provide an advantage counteracting the costs involved in maintaining larger networks. For that purpose, we investigate how noise affects multistable systems, where a small amount of noise could lead to very different outcomes; thus we turn to biochemical switches. Our method for comparing networks of different structure and complexity is to place them in conditions where they produce exactly the same deterministic function. We are then in a good position to compare their noise characteristics relatively to their identical deterministic traces. We show that more complex networks are better at coping with both intrinsic and extrinsic noise. Intrinsic noise tends to decrease with complexity, and extrinsic noise tends to have less impact. Our findings suggest a new role for increased complexity in biological networks, at parity of function.
Project description:Biological cells operate in a noisy regime influenced by intrinsic, extrinsic and external noise, which leads to large differences of individual cell states. Stochastic effects must be taken into account to characterize biochemical kinetics accurately. Since the exact solution of the chemical master equation, which governs the underlying stochastic process, cannot be derived for most biochemical systems, approximate methods are used to obtain a solution.In this study, a method to efficiently simulate the various sources of noise simultaneously is proposed and benchmarked on several examples. The method relies on the combination of the sigma point approach to describe extrinsic and external variability and the ? -leaping algorithm to account for the stochasticity due to probabilistic reactions. The comparison of our method to extensive Monte Carlo calculations demonstrates an immense computational advantage while losing an acceptable amount of accuracy. Additionally, the application to parameter optimization problems in stochastic biochemical reaction networks is shown, which is rarely applied due to its huge computational burden. To give further insight, a MATLAB script is provided including the proposed method applied to a simple toy example of gene expression.MATLAB code is available at Bioinformatics firstname.lastname@example.org.Supplementary data are available at Bioinformatics online.
Project description:It has been widely reported that the major histocompatibility complex (MHC) is under balancing selection due to its immune function across terrestrial and aquatic mammals. The comprehensive studies at MHC and other neutral loci could give us a synthetic evaluation about the major force determining genetic diversity of species. Previously, a low level of genetic diversity has been reported among the Indo-Pacific humpback dolphin (Sousa chinensis) in the Pearl River Estuary (PRE) using both mitochondrial marker and microsatellite loci. Here, the expression and sequence polymorphism of 2 MHC class II genes (DQB and DRB) in 32 S. chinensis from PRE collected between 2003 and 2011 were investigated. High ratios of non-synonymous to synonymous substitution rates, codon-based selection analysis, and trans-species polymorphism (TSP) support the hypothesis that balancing selection acted on S. chinensis MHC sequences. However, only 2 haplotypes were detected at either DQB or DRB loci. Moreover, the lack of deviation from the Hardy-Weinberg expectation at DRB locus combined with the relatively low heterozygosity at both DQB locus and microsatellite loci suggested that balancing selection might not be sufficient, which further suggested that genetic drift associated with historical bottlenecks was not mitigated by balancing selection in terms of the loss of MHC and neutral variation in S. chinensis. The combined results highlighted the importance of maintaining the genetic diversity of the endangered S. chinensis.
Project description:How common is balancing selection, and what fraction of phenotypic variance is attributable to balanced polymorphisms? Despite decades of research, answers to these questions remain elusive. Moreover, there is no clear theoretical prediction about the frequency with which balancing selection is expected to arise within a population. Here, we use an extension of Fisher's geometric model of adaptation to predict the probability of balancing selection in a population with separate sexes, wherein polymorphism is potentially maintained by two forms of balancing selection: (1) heterozygote advantage, where heterozygous individuals at a locus have higher fitness than homozygous individuals, and (2) sexually antagonistic selection (a.k.a. intralocus sexual conflict), where the fitness of each sex is maximized by different genotypes at a locus. We show that balancing selection is common under biologically plausible conditions and that sex differences in selection or sex-by-genotype effects of mutations can each increase opportunities for balancing selection. Although heterozygote advantage and sexual antagonism represent alternative mechanisms for maintaining polymorphism, they mutually exist along a balancing selection continuum that depends on population and sex-specific parameters of selection and mutation. Sexual antagonism is the dominant mode of balancing selection across most of this continuum.
Project description:Natural selection leaves imprints on DNA, offering the opportunity to identify functionally important regions of the genome. Identifying the genomic regions affected by natural selection within pathogens can aid in the pursuit of effective strategies to control diseases. In this study, we analyzed genome-wide patterns of selection acting on different classes of sequences in a worldwide sample of eight strains of the model plant-pathogenic fungus Colletotrichum graminicola. We found evidence of selective sweeps, balancing selection, and positive selection affecting both protein-coding and noncoding DNA of pathogenicity-related sequences. Genes encoding putative effector proteins and secondary metabolite biosynthetic enzymes show evidence of positive selection acting on the coding sequence, consistent with an Arms Race model of evolution. The 5' untranslated regions (UTRs) of genes coding for effector proteins and genes upregulated during infection show an excess of high-frequency polymorphisms likely the consequence of balancing selection and consistent with the Red Queen hypothesis of evolution acting on these putative regulatory sequences. Based on the findings of this work, we propose that even though adaptive substitutions on coding sequences are important for proteins that interact directly with the host, polymorphisms in the regulatory sequences may confer flexibility of gene expression in the virulence processes of this important plant pathogen.
Project description:The coding regions of many of the major histocompatibility complex (MHC) (human leukocyte antigen [HLA] in humans) molecules are believed to be subject to balancing selection. But it is less certain whether the regulatory regions of such coding sequences are also subject to the same type of selection. Here, we studied the polymorphism of the regulatory regions of the HLA-DPA1 and HLA-DPB1 genes among ethnic minorities in southwestern China. Phylogenetic analysis revealed two deep clades >10 million years old. There is almost complete linkage disequilibrium between the regulatory and coding regions of HLA-DPA1, which hints at coadaptive balancing selection on the entire region. Thus, the molecular mechanism of balancing selection in MHC may involve expression modulation in addition to coding-region polymorphisms. Although the frequency of clade II is >30% in some ethnic minorities, it decreases to <5% among southern Han Chinese and vanishes among Europeans. As suspected, some ancient balanced polymorphisms, lost in major populations, still exist in isolated ethnicities. These isolated populations may thus contribute disproportionately to the total diversity of modern humans.