Gene expression,chromosome heterogeneity and the fast-X effect in mammals

The higher rate of non-synonymous over synonymous substitutions (dN/dS) of the X chromosome compared with autosomes is often interpreted as a consequence of X hemizygosity. However, other factors, such as gene expression, are also known to vary between X and autosomes. Analysing 4800 orthologues in six mammals, we found that gene expression levels, associated with GC content, fully account for the variation in dN/dS between X and autosomes with no detectable effect of hemizygosity. We also report an extensive variance in dN/dS and gene expression between autosomes.     

Codon Bias and Noncoding GC Content Correlate Negatively with Recombination Rate on the Drosophila X Chromosome

The patterns and processes of molecular evolution may differ between the X chromosome and the autosomes in Drosophila melanogaster. This may in part be due to differences in the effective population size between the two chromosome sets and in part to the hemizygosity of the X chromosome in Drosophila males. These and other factors may lead to differences both in the gene complements of the X and the autosomes and in the properties of the genes residing on those chromosomes. Here we show that codon bias and recombination rate are correlated strongly and negatively on the X chromosome, and that this correlation cannot be explained by indirect relationships with other known determinants of codon bias. This is in dramatic contrast to the weak positive correlation found on the autosomes. We explored possible explanations for these patterns, which required a comprehensive analysis of the relationships among multiple genetic properties such as protein length and expression level. This analysis highlights conserved features of coding sequence evolution on the X and the autosomes and illuminates interesting differences between these two chromosome sets.[Reviewing editor: Dr. Richard Kliman]     

An Excess of Gene Expression Divergence on the X Chromosome in Drosophila Embryos: Implications for the Faster-X Hypothesis

The X chromosome is present as a single copy in the heterogametic sex, and this hemizygosity is expected to drive unusual patterns of evolution on the X relative to the autosomes. For example, the hemizgosity of the X may lead to a lower chromosomal effective population size compared to the autosomes, suggesting that the X might be more strongly affected by genetic drift. However, the X may also experience stronger positive selection than the autosomes, because recessive beneficial mutations will be more visible to selection on the X where they will spend less time being masked by the dominant, less beneficial allele—a proposal known as the faster-X hypothesis. Thus, empirical studies demonstrating increased genetic divergence on the X chromosome could be indicative of either adaptive or non-adaptive evolution. We measured gene expression in Drosophila species and in D. melanogaster inbred strains for both embryos and adults. In the embryos we found that expression divergence is on average more than 20% higher for genes on the X chromosome relative to the autosomes; but in contrast, in the inbred strains, gene expression variation is significantly lower on the X chromosome. Furthermore, expression divergence of genes on Muller''s D element is significantly greater along the branch leading to the obscura sub-group, in which this element segregates as a neo-X chromosome. In the adults, divergence is greatest on the X chromosome for males, but not for females, yet in both sexes inbred strains harbour the lowest level of gene expression variation on the X chromosome. We consider different explanations for our results and conclude that they are most consistent within the framework of the faster-X hypothesis.     

Gene content evolution on the X chromosome

Compared with autosomes, the X chromosome shows different patterns of evolution as a result of its hemizygosity in males. Additionally, inactivation of the X during spermatogenesis can make the X chromosome an unfavorable location for male-specific genes. These factors can help to explain why in many species gene content of the X chromosome differs from that of autosomes. Indeed, the X chromosome in mouse is enriched for male-specific genes while they are depleted on the X in Drosophila but show neither of these trends in mosquito. Here, we will discuss recent findings on the ancestral and neo-X chromosomes in Drosophila that support sexual antagonism as a force shaping gene content evolution of sex chromosomes and suggest that selection could be driving male-biased genes off the X.     

Increased differentiation and reduced gene flow in sex chromosomes relative to autosomes between lineages of the brown creeper Certhia americana

The properties of sex chromosomes, including patterns of inheritance, reduced levels of recombination, and hemizygosity in one of the sexes may result in the faster fixation of new mutations via drift and natural selection. Due to these patterns and processes, the two rules of speciation to describe the genetics of postzygotic isolation, Haldane's rule and the large‐X effect, both explicitly include quicker evolution on sex chromosomes relative to autosomes. Because sex‐linked mutations may be the first to become fixed in the speciation process, and appear to be due to stronger genetic drift (in birds), we may identify pronounced genetic differentiation in sex chromosomes in taxa experiencing recent speciation and diverging mainly via genetic drift. Here, we use nine sex‐linked and 21 autosomal genetic markers to investigate differential divergence and introgression between marker types in Certhia americana. We identified increased levels of genetic differentiation and reduced levels of gene flow on sex chromosomes relative to autosomes. This pattern is similar to those observed in other recently‐divergent avian species, providing another case study of the earlier role of sex chromosomes in divergence, relative to autosomes. Additionally, we identify three markers that may be under selection between Certhia americana lineages.     

Accelerated evolution of sex chromosomes in aphids, an x0 system

Sex chromosomes play a role in many important biological processes, including sex determination, genomic conflicts, imprinting, and speciation. In particular, they exhibit several unusual properties such as inheritance pattern, hemizygosity, and reduced recombination, which influence their response to evolutionary factors (e.g., drift, selection, and demography). Here, we examine the evolutionary forces driving X chromosome evolution in aphids, an XO system where females are homozygous (XX) and males are hemizygous (X0) at sex chromosomes. We show by simulations that the unusual mode of transmission of the X chromosome in aphids, coupled with cyclical parthenogenesis, results in similar effective population sizes and predicted levels of genetic diversity for X chromosomes and autosomes under neutral evolution. These results contrast with expectations from standard XX/XY or XX/X0 systems (where the effective population size of the X is three-fourths that of autosomes) and have deep consequences for aphid X chromosome evolution. We then localized 52 microsatellite markers on the X and 351 on autosomes. We genotyped 167 individuals with 356 of these loci and found similar levels of allelic richness on the X and on the autosomes, as predicted by our simulations. In contrast, we detected higher dN and dN/dS ratio for X-linked genes compared with autosomal genes, a pattern compatible with either positive or relaxed selection. Given that both types of chromosomes have similar effective population sizes and that the single copy of the X chromosome of male aphids exposes its recessive genes to selection, some degree of positive selection seems to best explain the higher rates of evolution of X-linked genes. Overall, this study highlights the particular relevance of aphids to study the evolutionary factors driving sex chromosomes and genome evolution.     

THE EFFECTS OF SELECTION AND GENETIC DRIFT ON THE GENOMIC DISTRIBUTION OF SEXUALLY ANTAGONISTIC ALLELES

Sexual antagonism (SA) occurs when an allele that is beneficial to one sex, is detrimental to the other. This conflict can result in balancing, directional, or disruptive selection acting on SA alleles. A body of theory predicts the conditions under which sexually antagonistic mutants will invade and be maintained in stable polymorphism under balancing selection. There remains, however, considerable debate over the distribution of SA genetic variation across autosomes and sex chromosomes, with contradictory evidence coming from data and theory. In this article, we investigate how the interplay between selection and genetic drift will affect the genomic distribution of sexually antagonistic alleles. The effective population sizes can differ between the autosomes and the sex chromosomes due to a number of ecological factors and, consequently, the distribution of SA genetic variation in genomes. In general, we predict the interplay of SA selection and genetic drift should lead to the accumulation of SA alleles on the X in male heterogametic (XY) species and, on the autosomes in female heterogametic (ZW) species, especially when sexual competition is strong among males.     

Genome partitioning of genetic variation for height from 11,214 sibling pairs

Height has been used for more than a century as a model by which to understand quantitative genetic variation in humans. We report that the entire genome appears to contribute to its additive genetic variance. We used genotypes and phenotypes of 11,214 sibling pairs from three countries to partition additive genetic variance across the genome. Using genome scans to estimate the proportion of the genomes of each chromosome from siblings that were identical by descent, we estimated the heritability of height contributed by each of the 22 autosomes and the X chromosome. We show that additive genetic variance is spread across multiple chromosomes and that at least six chromosomes (i.e., 3, 4, 8, 15, 17, and 18) are responsible for the observed variation. Indeed, the data are not inconsistent with a uniform spread of trait loci throughout the genome. Our estimate of the variance explained by a chromosome is correlated with the number of times suggestive or significant linkage with height has been reported for that chromosome. Variance due to dominance was not significant but was difficult to assess because of the high sampling correlation between additive and dominance components. Results were consistent with the absence of any large between-chromosome epistatic effects. Notwithstanding the proposed architecture of complex traits that involves widespread gene-gene and gene-environment interactions, our results suggest that variation in height in humans can be explained by many loci distributed over all autosomes, with an additive mode of gene action.     

Unexpected high genetic diversity in small populations suggests maintenance by associative overdominance

The effective population size (N_e) is a central factor in determining maintenance of genetic variation. The neutral theory predicts that loss of variation depends on N_e, with less genetic drift in larger populations. We monitored genetic drift in 42 Drosophila melanogaster populations of different adult census population sizes (10, 50 or 500) using pooled RAD sequencing. In small populations, variation was lost at a substantially lower rate than expected. This observation was consistent across two ecological relevant thermal regimes, one stable and one with a stressful increase in temperature across generations. Estimated ratios between N_e and adult census size were consistently higher in small than in larger populations. The finding provides evidence for a slower than expected loss of genetic diversity and consequently a higher than expected long‐term evolutionary potential in small fragmented populations. More genetic diversity was retained in areas of low recombination, suggesting that associative overdominance, driven by disfavoured homozygosity of recessive deleterious alleles, is responsible for the maintenance of genetic diversity in smaller populations. Consistent with this hypothesis, the X‐chromosome, which is largely free of recessive deleterious alleles due to hemizygosity in males, fits neutral expectations even in small populations. Our experiments provide experimental answers to a range of unexpected patterns in natural populations, ranging from variable diversity on X‐chromosomes and autosomes to surprisingly high levels of nucleotide diversity in small populations.     

POSITIVE SELECTION DRIVES FASTER‐Z EVOLUTION IN SILKMOTHS

Genes linked to X or Z chromosomes, which are hemizygous in the heterogametic sex, are predicted to evolve at different rates than those on autosomes. This “faster‐X effect” can arise either as a consequence of hemizygosity, which leads to more efficient selection for recessive beneficial mutations in the heterogametic sex, or as a consequence of reduced effective population size of the hemizygous chromosome, which leads to increased fixation of weakly deleterious mutations due to genetic drift. Empirical results to date suggest that, while the overall pattern across taxa is complicated, systems with male heterogamy show a faster‐X effect attributable to more efficient selection, whereas the faster‐Z effect in female‐heterogametic taxa is attributable to increased drift. To test the generality of the faster‐Z pattern seen in birds and snakes, we sequenced the genome of the lepidopteran silkmoth Bombyx huttoni. We show that silkmoths experience faster‐Z evolution, but unlike in birds and snakes, the faster‐Z effect appears to be attributable to more efficient positive selection. These results suggest that female heterogamy alone is unlikely to explain the reduced efficacy of selection on vertebrate Z chromosomes. It is likely that many factors, including differences in overall effective population size, influence Z chromosome evolution.     

Evolution on the X chromosome: unusual patterns and processes

Although the X chromosome is usually similar to the autosomes in size and cytogenetic appearance, theoretical models predict that its hemizygosity in males may cause unusual patterns of evolution. The sequencing of several genomes has indeed revealed differences between the X chromosome and the autosomes in the rates of gene divergence, patterns of gene expression and rates of gene movement between chromosomes. A better understanding of these patterns should provide valuable information on the evolution of genes located on the X chromosome. It could also suggest solutions to more general problems in molecular evolution, such as detecting selection and estimating mutational effects on fitness.     

The distribution of transposable elements within and between chromosomes in a population of Drosophila melanogaster. II. Inferences on the nature of selection against elements.

Data were collected on the distribution of nine families of transposable elements among a sample of autosomes isolated from a natural population of Drosophila melanogaster, by means of in situ hybridization of biotinylated probes to polytene chromosomes. There is no general tendency for elements to accumulate at the tips of chromosomes. Elements tend to be present in excess of random expectation in the euchromatin proximal to the centromeres of the major autosomes, and on chromosome four. There is considerable heterogeneity between different families in the extent of this excess. The overall abundance of element families is inversely related to the extent to which they accumulate proximally. The level of proximal accumulation for the major autosomes is similar to that on the fourth chromosome, but less than that for the X chromosome. There is an overall deficiency of elements in the mid-section of the X compared with the mid-sections of the major autosomes, with considerable heterogeneity between families. The magnitude of this deficiency is positively related to the extent to which elements accumulate proximally. No such deficiency is seen if the proximal regions of the X and autosomes are compared. There is a small and non-significant excess of elements in third chromosomes carrying inversions. There is some between-year heterogeneity in element abundance. The implications of these findings are discussed, and it is concluded that they generally support the hypothesis that transposable element abundance is regulated primarily by the deleterious fitness consequences of meiotic ectopic exchange between elements. If this is the case, such exchange must be very infrequent in the proximal euchromatin, and the elements detected in population surveys of this kind must be inserted into sites where they have negligible mutational effects on fitness.     

Cis-acting transmission of genomic instability

Genomic instability is a highly pleiotropic phenotype, which may reflect a variety of underlying mechanisms. Destabilization has been shown in some cases to involve mutational alteration or inactivation of trans-acting cellular factors, for example, p53 or mismatch repair functions. However, aspects of instability are not well explained by mutational inactivation of trans-acting factors, and other epigenetic and cis-acting mechanisms have recently been proposed. The trans and cis models result in divergent predictions for the distribution of instability-associated genetic alterations within the genome, and for the inheritance of genomic instability among sibling sub-clones of unstable parents. These predictions have been tested in this study primarily by tracking the karyotypic distribution of chromosomal rearrangements in clones and sub-clones exhibiting radiation-induced genomic instability; inheritance of mutator phenotypes was also analyzed. The results indicate that genomic instability is unevenly transmitted to sibling sub-clones, that chromosomal rearrangements within unstable clones are non-randomly distributed throughout the karyotype, and that the majority of chromosomal rearrangements associated with instability affect trisomic chromosomal segments. Observations of instability in trisomic regions suggests that in addition to promoting further alterations in chromosomal number, aneuploidy can affect the recovery of structural rearrangements. In summary, these findings cannot be fully explained by invoking a homogeneously distributed factor acting in trans, but do provide support for previous suggestions that genomic instability may in part be driven by a cis-acting mechanism.     

EFFECTIVE POPULATION SIZE AND THE FASTER‐X EFFECT: EMPIRICAL RESULTS AND THEIR INTERPRETATION

The X or Z chromosome has several characteristics that distinguish it from the autosomes, namely hemizygosity in the heterogametic sex, and a potentially different effective population size, both of which may influence the rate and nature of evolution. In particular, there may be an accelerated rate of adaptive change for X‐linked compared to autosomal coding sequences, often referred to as the Faster‐X effect. Empirical studies have indicated that the strength of Faster‐X evolution varies among different species, and theoretical treatments have shown that demography and mating system can substantially affect the degree of Faster‐X evolution. Here we integrate genomic data on Faster‐X evolution from a variety of animals with the demographic factors, mating system, and sex chromosome regulatory characteristics that may influence it. Our results suggest that differences in effective population size and mechanisms of dosage compensation may influence the perceived extent of Faster‐X evolution, and help to explain several clade‐specific patterns that we observe.     

mRNA stability: in trans-it.

The regulation of mRNA stability is an important step in the control of gene expression. Characterization of the mechanisms involved in the turnover of individual mRNAs has identified a requirement for specific cis-acting sequences and trans-acting factors, as well as an involvement of the translation apparatus. In the past year, significant progress has been made in the identification of trans-acting factors by both biochemical and genetic approaches. This review summarizes that progress and promotes the notion that the ribosome itself should also be considered as a trans-acting component of the mRNA decay machinery.     

How replicable are mRNA expression QTL?

Applying quantitative trait analysis methods to genome-wide microarray-derived mRNA expression phenotypes in segregating populations is a valuable tool in the attempt to link high-level traits to their molecular causes. The massive multiple-testing issues involved in analyzing these data make the correct level of confidence to place in mRNA abundance quantitative trait loci (QTL) a difficult problem. We use a unique resource to directly test mRNA abundance QTL replicability in mice: paired recombinant inbred (RI) and F₂ data sets derived from C57BL/6J (B6) and DBA/2J (D2) inbred strains and phenotyped using the same Affymetrix arrays. We have one forebrain and one striatum data set pair. We describe QTL replication at varying stringencies in these data. For instance, 78% of mRNA expression QTL (eQTL) with genome-wide adjusted p ≤ 0.0001 in RI data replicate at a genome-wide adjusted p < 0.05 or better. Replicated QTL are disproportionately putatively cis-acting, and approximately 75% have higher apparent expression levels associated with B6 genotypes, which may be partly due to probe set generation using B6 sequence. Finally, we note that while trans-acting QTL do not replicate well between data sets in general, at least one cluster of trans-acting QTL on distal Chr 1 is notably preserved between data sets.     

Sex-biased evolutionary forces shape genomic patterns of human diversity

Comparisons of levels of variability on the autosomes and X chromosome can be used to test hypotheses about factors influencing patterns of genomic variation. While a tremendous amount of nucleotide sequence data from across the genome is now available for multiple human populations, there has been no systematic effort to examine relative levels of neutral polymorphism on the X chromosome versus autosomes. We analyzed ~210 kb of DNA sequencing data representing 40 independent noncoding regions on the autosomes and X chromosome from each of 90 humans from six geographically diverse populations. We correct for differences in mutation rates between males and females by considering the ratio of within-human diversity to human-orangutan divergence. We find that relative levels of genetic variation are higher than expected on the X chromosome in all six human populations. We test a number of alternative hypotheses to explain the excess polymorphism on the X chromosome, including models of background selection, changes in population size, and sex-specific migration in a structured population. While each of these processes may have a small effect on the relative ratio of X-linked to autosomal diversity, our results point to a systematic difference between the sexes in the variance in reproductive success; namely, the widespread effects of polygyny in human populations. We conclude that factors leading to a lower male versus female effective population size must be considered as important demographic variables in efforts to construct models of human demographic history and for understanding the forces shaping patterns of human genomic variability.