X-linked Variation Research Articles

Competition shapes the landscape of X-chromosome-linked genetic diversity

X chromosome inactivation (XCI) generates clonal heterogeneity within XX individuals. Combined with sequence variation between human X chromosomes, XCI gives rise to intra-individual clonal diversity, whereby two sets of clones express mutually exclusive sequence variants present on one or the other X chromosome. Here we ask whether such clones merely co-exist or potentially interact with each other to modulate the contribution of X-linked diversity to organismal development. Focusing on X-linked coding variation in the human STAG2 gene, we show that Stag2variant clones contribute to most tissues at the expected frequencies but fail to form lymphocytes in Stag2WTStag2variant mouse models. Unexpectedly, the absence of Stag2variant clones from the lymphoid compartment is due not solely to cell-intrinsic defects but requires continuous competition by Stag2WT clones. These findings show that interactions between epigenetically diverse clones can operate in an XX individual to shape the contribution of X-linked genetic diversity in a cell-type-specific manner.

Abstract 10884: X-Linked Genetic Associations in Sporadic Thoracic Aortic Aneurysm and Dissection

Introduction: The male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) and the high prevalence of TAD in Turner syndrome patients suggest the contribution of X chromosome genes to TAD. However, such role has not been explored. Methods: We investigated whether X-linked variation, both common (Minor Allele Frequency (MAF) ≥0.01) and rare (MAF <0.01), was associated with sporadic TAD in three datasets of European descent (dataset-1: 753 cases, 2247 controls; dataset-2: 253 cases, 282 controls; dataset-3: 364 cases, 874 controls). All cases were obtained from McGovern School of Medicine and Baylor College of Medicine; however, controls were obtained from the Atherosclerosis Risk in Communities study (dataset-1), the University of Washington Center for Mendelian Genomics (dataset-2), and the National Institute of Neurological Disorders and Stroke Repository (dataset-3). We applied a sex-stratified logistic regression model, followed by a meta-analysis of sex specific odds ratios for common variants, and an optimized sequence kernel association test model for rare variants. For top (P≤1x10 -3 ) common X-linked variants from the three datasets, we performed tissue enrichment analysis using a hypergeometric test. Results: The majority of cases (75%) were males. In dataset-2, common variant, rs55936630, in IGSF1 (P meta-analysis: 2.43x10 -7 ), reached X chromosome-wide significance. An additional 125 variants were suggestive of an association (P meta-analysis ≤1x10 -3 ) in at least one of the three datasets. Tissue enrichment identified a set of 12 X-linked genes that was significantly enriched in blood vessels (P: 3x10 -2 ). RTL9 (P: 5.15x10 -5 ; dataset-1) reached X chromosome-wide significance in rare variants analyses. Conclusions: This is the most comprehensive X-chromosome association analysis of TAD to date. Although most of our common variants did not reach X chromosome-wide significance, collectively testing these variants in tissue enrichment analysis identified a set of 12 X-linked genes that was significantly enriched in blood vessels. Among these 12 X-linked genes were C1GALT1C1 and DMD which were previously associated with vasculitis and arterial stiffness, respectively, both of which are risk factors for TAD.

Downregulation, Blood Type, Paternal Lineage, and Genetic Variants in Ovarian Cancer: A Call for Tumor Suppressor Genes Effectiveness

This article calls for a deeper look at the role of downregulation, blood type, paternal lineage, and genetic variants in ovarian cancer. While considering the importance of oncogenes, associated tumors, expression, or overexpression, signal transducers, and downregulation, it suggests that a viable platform for tumor suppressor genes effectiveness is needed for early detection. The role of DNA methylation to gene silencing, proteins, RNA alteration in the development of metastatic tissues in late stage of ovarian cancer, which require further elucidation and research, continue to suggest that methylation, and tumor suppressor genes from BRCA1 and BRCA2 mutations are exceptionally critical, and warrant further monitoring of genetic predispositions. The role of controlled induction of ARHI associated with the X chromosome, or loss of ARHI expression and faulty breast genes is another quest for added oncological inquiries. Additionally, arguments relating to ABO blood group and its association to epithelial ovarian cancer, throughout the literature postulate that ABO genes on chromosomes 9q34 are of high consideration. Reviewing blood type correlation with ovarian cancer, through a paternal lineage connection suggesting strong inheritance patterns in first degree relatives, suggests there is an X-linked variation, and X-chromosome variation in the process. A better understanding of cancer screening by means of genetic testing, as an early detection tool, and downregulation are worthy research lenses in the fight of ovarian cancer.

Autosomal and X-Linked Additive Genetic Variation for Lifespan and Aging: Comparisons Within and Between the Sexes in Drosophila melanogaster.

Theory makes several predictions concerning differences in genetic variation between the X chromosome and the autosomes due to male X hemizygosity. The X chromosome should: (i) typically show relatively less standing genetic variation than the autosomes, (ii) exhibit more variation in males compared to females because of dosage compensation, and (iii) potentially be enriched with sex-specific genetic variation. Here, we address each of these predictions for lifespan and aging in Drosophila melanogaster. To achieve unbiased estimates of X and autosomal additive genetic variance, we use 80 chromosome substitution lines; 40 for the X chromosome and 40 combining the two major autosomes, which we assay for sex-specific and cross-sex genetic (co)variation. We find significant X and autosomal additive genetic variance for both traits in both sexes (with reservation for X-linked variation of aging in females), but no conclusive evidence for depletion of X-linked variation (measured through females). Males display more X-linked variation for lifespan than females, but it is unclear if this is due to dosage compensation since also autosomal variation is larger in males. Finally, our results suggest that the X chromosome is enriched for sex-specific genetic variation in lifespan but results were less conclusive for aging overall. Collectively, these results suggest that the X chromosome has reduced capacity to respond to sexually concordant selection on lifespan from standing genetic variation, while its ability to respond to sexually antagonistic selection may be augmented.

Looking for signatures of sex-specific demography and local adaptation on the X chromosome

A genome-wide study of X chromosome genetic diversity in human populations shows the impact of social organization and local adaptation.

X-Linked Variation in Immune Response in Drosophila melanogaster

This study quantifies the effects of naturally occurring X-linked variation on immune response in Drosophila melanogaster to assess associations between immunity genotypes and innate immune response. We constructed a set of 168 X-chromosomal extraction lines, incorporating X chromosomes from a natural population into co-isogenic autosomal backgrounds, and genotyped the lines at 88 SNPs in 20 X-linked immune genes. We find that genetic variation in many of the genes is associated with immune response phenotypes, including bacterial load and immune gene expression. Many of the associations act in a sex-specific or sexually antagonistic manner, supporting the theory that with the selective pressures facing genes on the X chromosome, sexually antagonistic variation may be more easily maintained.

The Impact of Founder Events on Chromosomal Variability in Multiply Mating Species

In species with heterogametic males, the relative levels of X chromosome versus autosome diversity hold key information about the evolutionary forces at work in a population. It has been shown that population size changes alter the ratio of X linked to autosomal (X/A) variation, with population size reductions and recent bottlenecks leading to decreased X/A diversity ratios. Here we use theory and simulation to investigate a separate demographic effect-that of founder events involving multiply mated females-and find that it leads to much stronger reductions in X/A diversity ratios than are produced by simple population size changes. Investigating the potential of this process to account for sharply reduced X-linked diversity in European Drosophila melanogaster, we find that this model yields predictions that are compatible with the empirical data.

Distinctly Different Sex Ratios in African and European Populations ofDrosophila melanogasterInferred From Chromosomewide Single Nucleotide Polymorphism Data

It has been hypothesized that the ratio of X-linked to autosomal sequence diversity is influenced by unequal sex ratios in Drosophila melanogaster populations. We conducted a genome scan of single nucleotide polymorphism (SNP) of 378 autosomal loci in a derived European population and of a subset of 53 loci in an ancestral African population. On the basis of these data and our already available X-linked data, we used a coalescent-based maximum-likelihood method to estimate sex ratios and demographic histories simultaneously for both populations. We confirm our previous findings that the African population experienced a population size expansion while the European population suffered a population size bottleneck. Our analysis also indicates that the female population size in Africa is larger than or equal to the male population size. In contrast, the European population shows a huge excess of males. This unequal sex ratio and the bottleneck alone, however, cannot account for the overly strong decrease of X-linked diversity in the European population (compared to the reduction on the autosome). The patterns of the frequency spectrum and the levels of linkage disequilibrium observed in Europe suggest that, in addition, positive selection must have acted in the derived population.

POPULATION SIZE CHANGES RESHAPE GENOMIC PATTERNS OF DIVERSITY

Elucidating the forces responsible for genomic variation is critical for understanding evolution. Under standard conditions, X-linked diversity is expected to be three-quarters the level of autosomal diversity. Empirical data often deviate from this prediction, but the reasons for these departures are unclear. We demonstrate that population size changes can greatly alter relative levels of X-linked and autosomal variation: population size reductions lead to particularly low X-linked diversity, whereas growth elevates X-linked relative to autosomal diversity. Genetic variation from a diverse array of taxa supports an important role for this effect in accounting for population differences in the ratio of X-linked to autosomal diversity. Consideration of this effect may improve the inference of population history and other evolutionary processes.

Reduced X-Linked Diversity in Derived Populations of House Mice

Contrasting patterns of X-linked vs. autosomal diversity may be indicative of the mode of selection operating in natural populations. A number of observations have shown reduced X-linked (or Z-linked) diversity relative to autosomal diversity in various organisms, suggesting a large impact of genetic hitchhiking. However, the relative contribution of other forces such as population bottlenecks, variation in reproductive success of the two sexes, and differential introgression remains unclear. Here, we survey 13 loci, 6 X-linked and 7 autosomal, in natural populations of the house mouse (Mus musculus) subspecies complex. We studied seven populations of three different subspecies, the eastern house mouse M. musculus castaneus, the central house mouse M. m. musculus, and the western house mouse M. m. domesticus, including putatively ancestral and derived populations for each. All populations display lower diversity on the X chromosomes relative to autosomes, and this effect is most pronounced in derived populations. To assess the role of demography, we fit the demographic parameters that gave the highest likelihood of the data using coalescent simulations. We find that the reduction in X-linked diversity is too large to be explained by a simple demographic model in at least two of four derived populations. These observations are also not likely to be explained by differences in reproductive success between males and females. They are consistent with a greater impact of positive selection on the X chromosome, and this is supported by the observation of an elevated K(A) and elevated K(A)/K(S) ratios on the rodent X chromosome. A second contribution may be that the X chromosome less readily introgresses across subspecies boundaries.

A Pseudohitchhiking Model of X vs. Autosomal Diversity

We study levels of X-linked vs. autosomal diversity using a model developed to analyze the hitchhiking effect. Repeated bouts of hitchhiking are thought to lower X-linked diversity for two reasons: first, because sojourn times of beneficial mutations are shorter on the X, and second, because adaptive substitutions may be more frequent on the X. We investigate whether each of these effects does, in fact, cause reduced X-linked diversity under hitchhiking. We study the strength of the hitchhiking effect on the X vs. autosomes when there is no recombination and under two different recombination schemes. When recombination occurs in both sexes, X-linked vs. autosomal diversity is reduced by hitchhiking under a broad range of conditions, but when there is no recombination in males, as in Drosophila, the required conditions are considerably more restrictive.

Microsatellite variation among divergent populations of stalk-eyed flies, genus Cyrtodiopsis

Microsatellite primers are often developed in one species and used to assess neutral variability in related species. Such analyses may be confounded by ascertainment bias (i.e. a decline in amplification success and allelic variability with increasing genetic distance from the source of the microsatellites). In addition, other factors, such as the size of the microsatellite, whether it consists of perfect or interrupted tandem repeats, and whether it is autosomal or X-linked, can affect variation. To test the relative importance of these factors on microsatellite variation, we examine patterns of amplification and allelic diversity in 52 microsatellite loci amplified from five individuals in each of six populations of Cyrtodiopsis stalk-eyed flies that range from 2.2 % to 11.2% mitochondrial DNA sequence divergence from the population used for microsatellite development. We find that amplification success and most measures of allelic diversity declined with genetic distance from the source population, in some cases an order of magnitude faster than in birds or mammals. The median and range of the repeat array length did not decline with genetic distance. In addition, for loci on the X chromosome, we find evidence of lower observed heterozygosity compared with loci on autosomes. The differences in variability between X-linked and autosomal loci are not adequately explained by differences in effective population sizes of the chromosomes. We suggest, instead, that periodic selection events associated with X-chromosome meiotic drive, which is present in many of these populations, reduces X-linked variation.

X-linked gene expression in the Virginia opossum: differences between the paternally derived Gpd and Pgk-A loci.

Expression of X-linked glucose-6-phosphate dehydrogenase (G6PD) and phosphoglycerate kinase-A (PGK-A) in the Virginia opossum (Didelphis virginiana) was studied electrophoretically in animals from natural populations and those produced through controlled laboratory crosses. Blood from most of the wild animals exhibited a common single-banded phenotype for both enzymes. Rare variant animals, regardless of sex, exhibited single-banded phenotypes different in mobility from the common mobility class of the respective enzyme. The laboratory crosses confirmed the allelic basis for the common and rare phenotypes. Transmission of PGK-A phenotypes followed the pattern of determinate (nonrandom) inactivation of the paternally derived Pgk-A allele, and transmission of G6PD also was consistent with this pattern. A survey of tissue-specific expression of G6PD phenotypes of heterozygous females revealed, in almost all tissues, three-banded patterns skewed in favor of the allele that was expressed in blood cells. Three-banded patterns were never observed in males or in putatively homozygous females. These patterns suggest simultaneous, but unequal, expression of the maternally and paternally derived Gpd alleles within individual cells (i.e., partial paternal allele expression). The absence of such partial expression was noted in a parallel survey of females heterozygous at the Pgk-A locus. Thus, it appears that Gpd and Pgk-A are X-linked in D. virginiana and subject to preferential paternal allele inactivation, but that dosage compensation may not be complete for all paternally derived X-linked genes. The data establish the similarity between the American and Australian marsupial patterns of X-linked gene regulation and, thus, support the hypothesis that this form of dosage compensation was present in the early marsupial lineage that gave rise to these modern marsupial divisions. In addition, the data provide the first documentation of the differential expression of two X-linked genes in a single marsupial species. Because of its combination of X-linked variation, high fecundity, and short generation time, D. virginiana is a unique model for pursuing questions about marsupial gene regulation that have been difficult to approach through studies of Australian species.