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The number of researchers using multi-omics is growing. Though still expensive, every year it is cheaper to perform multi-omic studies, often exponentially so. In addition to its increasing accessibility, multi-omics reveals a view of systems biology to an unprecedented depth. Thus, multi-omics can be used to answer a broad range of biological questions in finer resolution than previous methods. We used six omic measurements—four nucleic acid (i.e., genomic, epigenomic, transcriptomics, and metagenomic) and two mass spectrometry (proteomics and metabolomics) based—to highlight an analysis workflow on this type of data, which is often vast. This workflow is not exhaustive of all the omic measurements or analysis methods, but it will provide an experienced or even a novice multi-omic researcher with the tools necessary to analyze their data. This review begins with analyzing a single ome and study design, and then synthesizes best practices in data integration techniques that include machine learning. Furthermore, we delineate methods to validate findings from multi-omic integration. Ultimately, multi-omic integration offers a window into the complexity of molecular interactions and a comprehensive view of systems biology.

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation. These involve processes such as cell proliferation, immune response, metabolic alterations (including amino acids and lipids), hormones and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin and other nonsteroidal anti-inflammatory drugs, a preventative treatment under investigation in persons with FAP. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in CRC formation and potential mechanisms of pharmaceutical prophylaxis. Snyder and colleagues present a comprehensive multiomic atlas of normal mucosal, benign polyps and dysplastic polyps from six persons with familial adenomatous polyposis, comprising transcriptomic, proteomic, metabolomic and lipidomic datasets.

With two genomes in the same organism, interspecific hybrids have unique opportunities and costs. In both plants and yeasts, wild, pathogenic, and domesticated hybrids may eliminate portions of one parental genome, a phenomenon known as loss of heterozygosity (LOH). Laboratory evolution of hybrid yeast recapitulates these results, with LOH occurring in just a few hundred generations of propagation. In this study, we systematically looked for alleles that are beneficial when lost in order to determine how prevalent this mode of adaptation may be, and to determine candidate loci that might underlie the benefits of larger-scale chromosome rearrangements. These aims were accomplished by mating Saccharomyces uvarum with the S. cerevisiae deletion collection to create hybrids, such that each nonessential S. cerevisiae allele is deleted. Competitive fitness assays of these pooled, barcoded, hemizygous strains, and accompanying controls, revealed a large number of loci for which LOH is beneficial. We found that the fitness effects of hemizygosity are dependent on the species context, the selective environment, and the species origin of the deleted allele. Further, we found that hybrids have a larger distribution of fitness consequences vs. matched S. cerevisiae hemizygous diploids. Our results suggest that LOH can be a successful strategy for adaptation of hybrids to new environments, and we identify candidate loci that drive the chromosomal rearrangements observed in evolution of yeast hybrids.

Interspecific hybrids play integral roles in society and are essential to industries worth hundreds of billions of dollars. They often have dominant genetic networks that allow them to be more fit than either parent, particularly in manmade settings. Hybrid Saccharomyces are amenable for scientific investigation because many hybrids are sterile, but Saccharomyces can grow indefinitely mitotically thereby bypassing this problem. Further, Saccharomyces cerevisiae is perhaps the best studied organism in the world, with countless tools to facilitate research. I sought to understand the genome-wide effects of single allele deletions on hybrids and determine their individual contributions to hybrid fitness. I mated the S. cerevisiae deletion collection, which contains a deletion strain for nearly every ORF, to WT S. uvarum, which is 20% diverged on the amino acid and nucleotide level. I also mated two S. cerevisiae collections with conditional knockouts of essential genes to WT S. uvarum. I then found the fitness of every deletion strain in three chemostat media, and the fitness of the essential genes knockouts on solid YPD. I found the hybrid deletion strains had more within condition and between condition variances than the purebreds, as well as large gene by genetic background effects. The essential genes had significantly less variance between conditions than the nonessential deletions, and significantly less gene by genetic background effects. To investigate the effects on fitness of each ortholog, I performed a reciprocal hemizygosity analysis showing that the effects of single allele deletions are dependent on the ortholog deleted. Together, our results show why hybrids are so abundant in manmade settings. They begin heterotic and they have new ways of exploring fitness landscape that have larger effects. To determine the molecular interactions between hybrid alleles, we developed a method, in conjunction with the Yates lab at Scripps, finding the preferences of particular orthologs in hybrid protein complexes, and showed that key amino acids can dramatically affect interspecific binding. Our findings show that hybrid proteins often have heterogeneous preferences for orthologs, which have been shown to confer heterosis. Lastly, I determined whether there are genes essential only to interspecific mating by mating the deletion collection to S. uvarum, and generating mating scores for every strain. Our findings did not identify any complete hybrid-specific mating incompatibilities, though there were significant incompatibilities suggesting it is possible to create a S. cerevisiae strain that does not mate with S. uvarum but that does mate with itself.

Gut microbial communities can respond to antibiotic perturbations by rapidly altering their taxonomic and functional composition. However, little is known about the strain-level processes that drive this collective response. Here we characterize the gut microbiome of a single individual at high temporal and genetic resolution through a period of health, disease, antibiotic treatment, and recovery. We used deep, linked-read metagenomic sequencing to track the longitudinal trajectories of thousands of single nucleotide variants within 36 species, which allowed us to contrast these genetic dynamics with the ecological fluctuations at the species level. We found that antibiotics can drive rapid shifts in the genetic composition of individual species, often involving incomplete genome-wide sweeps of pre-existing variants. These genetic changes were frequently observed in species without obvious changes in species abundance, emphasizing the importance of monitoring diversity below the species level. We also found that many sweeping variants quickly reverted to their baseline levels once antibiotic treatment had concluded, demonstrating that the ecological resilience of the microbiota can sometimes extend all the way down to the genetic level. Our results provide new insights into the population genetic forces that shape individual microbiomes on therapeutically relevant timescales, with potential implications for personalized health and disease. Competing Interest Statement The authors have declared no competing interest. Footnotes * New analysis on absolute microbial densities; new methods section added in main text.

Cancer is generally thought to be caused by expansion of a single mutant cell . However, analyses of early colorectal cancer lesions suggest that tumors may instead originate from multiple, genetically distinct cell populations . Detecting polyclonal tumor initiation is challenging in patients, as it requires profiling early-stage lesions before clonal sweeps obscure diversity. To investigate this, we analyzed normal colorectal mucosa, benign and dysplastic premalignant polyps, and malignant adenocarcinomas (123 samples) from six individuals with familial adenomatous polyposis (FAP). Individuals with FAP have a germline heterozygous mutation, predisposing them to colorectal cancer and numerous premalignant polyps by early adulthood . Whole-genome and/or whole-exome sequencing revealed that many premalignant polyps-40% with benign histology and 28% with dysplasia-were composed of multiple genetic lineages that diverged early, consistent with polyclonal origins. This conclusion was reinforced by whole-genome sequencing of single crypts from multiple polyps in additional patients which showed limited sharing of mutations among crypts within the same lesion. In some cases, multiple distinct mutations co-existed in different lineages of a single polyp, consistent with polyclonality. These findings reshape our understanding of early neoplastic events, demonstrating that tumor initiation can arise from the convergence of diverse mutant clones. They also suggest that cell-intrinsic growth advantages alone may not fully explain tumor initiation, highlighting the importance of microenvironmental and tissue-level factors in early cancer evolution.

The short-chain fatty acids (SCFA) propionate and butyrate have beneficial health effects, are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. In order to better understand the function of these modifications we used ChIP-seq to map the genome-wide location of four short-chain acyl histone marks H3K18pr, H3K18bu, H4K12pr and H4K12bu in treated and untreated colorectal cancer (CRC) and normal cells, as well as in mouse intestines . We correlate these marks with open chromatin regions along with gene expression to access the function of the target regions. Our data demonstrate that propionate and butyrate bind and act as promoters of genes involved in growth, differentiation as well as ion transport. We propose a mechanism involving direct modification of specific genomic regions, by SCFA resulting in increased chromatin accessibility, and in case of butyrate, opposing effects on the proliferation of normal versus CRC cells.

Depression is a leading cause of disability worldwide yet its underlying factors, particularly microbial associations, are poorly understood. We examined the longitudinal interplay between the microbiome and immune system in the context of depression during an immersive psychosocial intervention. 142 multi-omics samples were collected from 52 well-characterized participants before, during, and three months after a nine-day inquiry-based stress reduction program. We found that depression was associated with both an increased presence of putatively pathogenic bacteria and reduced microbial beta-diversity. Following the intervention, we observed reductions in neuroinflammatory cytokines and improvements in several mental health indicators. Interestingly, participants with a -dominant microbiome showed milder symptoms when depressed, along with a more resilient microbiome and more favorable inflammatory cytokine profile, including reduced levels of CXCL-1. Our findings reveal a protective link between the Prevotella-dominant microbiome and depression, associated with a less inflammatory environment and moderated symptoms. These insights, coupled with observed improvements in neuroinflammatory markers and mental health from the intervention, highlight potential avenues for microbiome-targeted therapies in depression management.

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Exercises that move your body rather than the weight (such as the push-up) have been shown to fire more muscle fibres than exercises that move the weight rather than your body (such as the bench press). This means that the push-up has the potential to activate a lot of muscle fibres. Next, we know that exercising in an unstable environment also increases muscle fibre activation. This is because your body compensates for the instability by firing more muscle fibres in order to stabilize the resistance. Anyone who's run barefoot on sand knows the tremendous work your calves get from it. The same concept is put to work in the following exercises. The exercise: Keeping your upper body in a straight line with your legs, bend the elbows so that your body lowers until it's one to two inches from touching the floor. Hold this position for one to two seconds, and then bring the body up to starting position. You will find that the ball will shift around as you are doing the exercise and you'll be forced to move your body around to keep your legs on top of it. The ball will roll slightly forward with you as you drop down to the bottom of the push-up position and roll slightly back as you push yourself up. Repeat 10 to 12 reps or as many as you can complete.