Genetic risk factors for severe and fatigue dominant long COVID and commonalities with ME/CFS identified by combinatorial analysis.

BACKGROUND: Long COVID is a debilitating chronic condition that has affected over 100 million people globally. It is characterized by a diverse array of symptoms, including fatigue, cognitive dysfunction and respiratory problems. Studies have so far largely failed to identify genetic associations, the mechanisms behind the disease, or any common pathophysiology with other conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that present with similar symptoms. METHODS: We used a combinatorial analysis approach to identify combinations of genetic variants significantly associated with the development of long COVID and to examine the biological mechanisms underpinning its various symptoms. We compared two subpopulations of long COVID patients from Sano Genetics' Long COVID GOLD study cohort, focusing on patients with severe or fatigue dominant phenotypes. We evaluated the genetic signatures previously identified in an ME/CFS population against this long COVID population to understand similarities with other fatigue disorders that may be triggered by a prior viral infection. Finally, we also compared the output of this long COVID analysis against known genetic associations in other chronic diseases, including a range of metabolic and neurological disorders, to understand the overlap of pathophysiological mechanisms. RESULTS: Combinatorial analysis identified 73 genes that were highly associated with at least one of the long COVID populations included in this analysis. Of these, 9 genes have prior associations with acute COVID-19, and 14 were differentially expressed in a transcriptomic analysis of long COVID patients. A pathway enrichment analysis revealed that the biological pathways most significantly associated with the 73 long COVID genes were mainly aligned with neurological and cardiometabolic diseases. Expanded genotype analysis suggests that specific SNX9 genotypes are a significant contributor to the risk of or protection against severe long COVID infection, but that the gene-disease relationship is context dependent and mediated by interactions with KLF15 and RYR3. Comparison of the genes uniquely associated with the Severe and Fatigue Dominant long COVID patients revealed significant differences between the pathways enriched in each subgroup. The genes unique to Severe long COVID patients were associated with immune pathways such as myeloid differentiation and macrophage foam cells. Genes unique to the Fatigue Dominant subgroup were enriched in metabolic pathways such as MAPK/JNK signaling. We also identified overlap in the genes associated with Fatigue Dominant long COVID and ME/CFS, including several involved in circadian rhythm regulation and insulin regulation. Overall, 39 SNPs associated in this study with long COVID can be linked to 9 genes identified in a recent combinatorial analysis of ME/CFS patient from UK Biobank. Among the 73 genes associated with long COVID, 42 are potentially tractable for novel drug discovery approaches, with 13 of these already targeted by drugs in clinical development pipelines. From this analysis for example, we identified TLR4 antagonists as repurposing candidates with potential to protect against long term cognitive impairment pathology caused by SARS-CoV-2. We are currently evaluating the repurposing potential of these drug targets for use in treating long COVID and/or ME/CFS. CONCLUSION: This study demonstrates the power of combinatorial analytics for stratifying heterogeneous populations in complex diseases that do not have simple monogenic etiologies. These results build upon the genetic findings from combinatorial analyses of severe acute COVID-19 patients and an ME/CFS population and we expect that access to additional independent, larger patient datasets will further improve the disease insights and validate potential treatment options in long COVID.

Heterogeneous Histories of Recombination Suppression on Stickleback Sex Chromosomes.

How consistent are the evolutionary trajectories of sex chromosomes shortly after they form? Insights into the evolution of recombination, differentiation, and degeneration can be provided by comparing closely related species with homologous sex chromosomes. The sex chromosomes of the threespine stickleback (Gasterosteus aculeatus) and its sister species, the Japan Sea stickleback (G. nipponicus), have been well characterized. Little is known, however, about the sex chromosomes of their congener, the blackspotted stickleback (G. wheatlandi). We used pedigrees to obtain experimentally phased whole genome sequences from blackspotted stickleback X and Y chromosomes. Using multispecies gene trees and analysis of shared duplications, we demonstrate that Chromosome 19 is the ancestral sex chromosome and that its oldest stratum evolved in the common ancestor of the genus. After the blackspotted lineage diverged, its sex chromosomes experienced independent and more extensive recombination suppression, greater X-Y differentiation, and a much higher rate of Y degeneration than the other two species. These patterns may result from a smaller effective population size in the blackspotted stickleback. A recent fusion between the ancestral blackspotted stickleback Y chromosome and Chromosome 12, which produced a neo-X and neo-Y, may have been favored by the very small size of the recombining region on the ancestral sex chromosome. We identify six strata on the ancestral and neo-sex chromosomes where recombination between the X and Y ceased at different times. These results confirm that sex chromosomes can evolve large differences within and between species over short evolutionary timescales.

Genetic risk factors for ME/CFS identified using combinatorial analysis.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease that lacks known pathogenesis, distinctive diagnostic criteria, and effective treatment options. Understanding the genetic (and other) risk factors associated with the disease would begin to help to alleviate some of these issues for patients. METHODS: We applied both GWAS and the PrecisionLife combinatorial analytics platform to analyze ME/CFS cohorts from UK Biobank, including the Pain Questionnaire cohort, in a case-control design with 1000 cycles of fully random permutation. Results from this study were supported by a series of replication and cohort comparison experiments, including use of disjoint Verbal Interview CFS, post-viral fatigue syndrome and fibromyalgia cohorts also derived from UK Biobank, and compared results for overlap and reproducibility. RESULTS: Combinatorial analysis revealed 199 SNPs mapping to 14 genes that were significantly associated with 91% of the cases in the ME/CFS population. These SNPs were found to stratify by shared cases into 15 clusters (communities) made up of 84 high-order combinations of between 3 and 5 SNPs. p-values for these communities range from 2.3 × 10-10 to 1.6 × 10-72. Many of the genes identified are linked to the key cellular mechanisms hypothesized to underpin ME/CFS, including vulnerabilities to stress and/or infection, mitochondrial dysfunction, sleep disturbance and autoimmune development. We identified 3 of the critical SNPs replicated in the post-viral fatigue syndrome cohort and 2 SNPs replicated in the fibromyalgia cohort. We also noted similarities with genes associated with multiple sclerosis and long COVID, which share some symptoms and potentially a viral infection trigger with ME/CFS. CONCLUSIONS: This study provides the first detailed genetic insights into the pathophysiological mechanisms underpinning ME/CFS and offers new approaches for better diagnosis and treatment of patients.

Sex Differences in the Recombination Landscape.

Sex differences in overall recombination rates are well known, but little theoretical or empirical attention has been given to how and why sexes differ in their recombination landscapes: the patterns of recombination along chromosomes. In the first scientific review of this phenomenon, we find that recombination is biased toward telomeres in males and more uniformly distributed in females in most vertebrates and many other eukaryotes. Notable exceptions to this pattern exist, however. Fine-scale recombination patterns also frequently differ between males and females. The molecular mechanisms responsible for sex differences remain unclear, but chromatin landscapes play a role. Why these sex differences evolve also is unclear. Hypotheses suggest that they may result from sexually antagonistic selection acting on coding genes and their regulatory elements, meiotic drive in females, selection during the haploid phase of the life cycle, selection against aneuploidy, or mechanistic constraints. No single hypothesis, however, can adequately explain the evolution of sex differences in all cases. Sex-specific recombination landscapes have important consequences for population differentiation and sex chromosome evolution.

Searching for signatures of sexually antagonistic selection on stickleback sex chromosomes.

Intralocus sexually antagonistic selection occurs when an allele is beneficial to one sex but detrimental to the other. This form of selection is thought to be key to the evolution of sex chromosomes but is hard to detect. Here we perform an analysis of phased young sex chromosomes to look for signals of sexually antagonistic selection in the Japan Sea stickleback (Gasterosteus nipponicus). Phasing allows us to date the suppression of recombination on the sex chromosome and provides unprecedented resolution to identify sexually antagonistic selection in the recombining region of the chromosome. We identify four windows with elevated divergence between the X and Y in the recombining region, all in or very near genes associated with phenotypes potentially under sexually antagonistic selection in humans. We are unable, however, to rule out the alternative hypothesis that the peaks of divergence result from demographic effects. Thus, although sexually antagonistic selection is a key hypothesis for the formation of supergenes on sex chromosomes, it remains challenging to detect. This article is part of the theme issue 'Genomic architecture of supergenes: causes and evolutionary consequences'.

Evolution of the canonical sex chromosomes of the guppy and its relatives.

The sex chromosomes of the guppy, Poecilia reticulata, and its close relatives are of particular interest: they are much younger than the highly degenerate sex chromosomes of model systems such as humans and Drosophila melanogaster, and they carry many of the genes responsible for the males' dramatic coloration. Over the last decade, several studies have analyzed these sex chromosomes using a variety of approaches including sequencing genomes and transcriptomes, cytology, and linkage mapping. Conflicting conclusions have emerged, in particular concerning the history of the sex chromosomes and the evolution of suppressed recombination between the X and Y. Here, we address these controversies by reviewing the evidence and reanalyzing data. We find no evidence of a nonrecombining sex-determining region or evolutionary strata in P. reticulata. Furthermore, we find that the data most strongly support the hypothesis that the sex-determining regions of 2 close relatives of the guppy, Poecilia wingei and Micropoecilia picta, evolved independently after their lineages diverged. We identify possible causes of conflicting results in previous studies and suggest best practices going forward.

Sex Differences in Recombination in Sticklebacks.

Recombination often differs markedly between males and females. Here we present the first analysis of sex-specific recombination in Gasterosteus sticklebacks. Using whole-genome sequencing of 15 crosses between G. aculeatus and G. nipponicus, we localized 698 crossovers with a median resolution of 2.3 kb. We also used a bioinformatic approach to infer historical sex-averaged recombination patterns for both species. Recombination is greater in females than males on all chromosomes, and overall map length is 1.64 times longer in females. The locations of crossovers differ strikingly between sexes. Crossovers cluster toward chromosome ends in males, but are distributed more evenly across chromosomes in females. Suppression of recombination near the centromeres in males causes crossovers to cluster at the ends of long arms in acrocentric chromosomes, and greatly reduces crossing over on short arms. The effect of centromeres on recombination is much weaker in females. Genomic differentiation between G. aculeatus and G. nipponicus is strongly correlated with recombination rate, and patterns of differentiation along chromosomes are strongly influenced by male-specific telomere and centromere effects. We found no evidence for fine-scale correlations between recombination and local gene content in either sex. We discuss hypotheses for the origin of sexual dimorphism in recombination and its consequences for sexually antagonistic selection and sex chromosome evolution.

Hybridization following recent secondary contact results in asymmetric genotypic and phenotypic introgression between island species of Myzomela honeyeaters.

Hybridization and introgression can have important evolutionary consequences for speciation, especially during early stages of secondary contact when reproductive barriers may be weak. Few studies, however, have quantified dynamics of hybridization and introgression in systems in which recent natural dispersal across a geographic barrier resulted in secondary contact. We investigated patterns of hybridization and introgression between two Myzomela honeyeaters (M. tristrami and M. cardinalis) that recently achieved secondary contact on Makira in the Solomon Islands. Hybridization in this system was hypothesized to be a byproduct of conspecific mate scarcity during early stages of colonization. Our research, however, provides evidence of ongoing hybridization more than a century after secondary contact. Mitochondrial sequencing revealed strongly asymmetric reproductive isolation that is most likely driven by postzygotic incompatibilities rather than prezygotic behavioral barriers. Nuclear introgression was observed from the native species (M. tristrami) to the colonizing species (M. cardinalis). Nuclear introgression in the reverse direction is almost exclusively limited to birds that are phenotypically M. tristrami but possess M. cardinalis mitochondrial haplotypes, consistent with introgression of plumage-related alleles into the genomic background of M. cardinalis. These results provide unique insight into the dynamics and consequences of hybridization and introgression during early stages of secondary contact.