**1. Introduction**

Microgravity in life sciences is an important field of study, not only because of our interest in exploring and living in space for extended periods, but also for the potential insights it gives on earthbound health problems. With genome-wide array technologies, the study of micro‐ gravity effects on living organisms can be examined in much greater detail at the cellular and molecular levels which is key to elucidating the molecular mechanisms of this environmental factor. Microgravity is a main environmental risk factor of spaceflight [1, 2] and the adverse effects of microgravity have much in common with earthbound health problems related to low physical activity or reduced mechanical loading. Bone loss and muscle atrophy as well as immune system dysfunction are some of the main consequences common to both extended spaceflight and physical inactivity such as that associated with premature aging and degen‐ erative disorders [3, 4]. Remarkable similarities have been noted between the clinical presen‐ tation of spinal cord injury and prolonged gravity unloading including atrophy in muscle and bone, cardiovascular disturbances, and alterations in renal, immune and sensory motor [5]. Microgravity research also holds promise in the area of tissue engineering. Microgravity simulation devices such as Rotating Wall Vessel (RWV) have been increasingly explored to generate 3-D organ mimics for liver and pancreatic islet transplantations [6-9]. Continued effort in microgravity research will deepen our understanding of space adaptation response and improve our ability to treat health-related problems, such as spinal cord injury, diabetes, osteoporosis, and premature aging. A better understanding of microgravity effects at the molecular level could help in the development of countermeasures that will protect astronauts from the deleterious effects of living in space as well as lead to the development of treatments for human diseases here on Earth.

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Cellular environmental changes such as sudden gravity change is likely to alter the funda‐ mental activities of genes and any change in the physiological function of a cell or an organism is most likely the result of changes in certain genes' expressions. Genes from many cell types have been shown to be sensitive to the microgravity environments (reviewed by Clement 2012). With the advent of high-throughput genomic technology such as microarrays, large scale genome-wide studies have been performed to assess the mRNA levels of cultured cells and organisms exposed to microgravity. This is an effective approach because the control of mRNA abundance of genes is effectively adapted by cells through controlling transcription (especially transcription initiation), nuclear pre-mRNA processing, mRNA transport, mRNA stability, etc. The cellular abundance of mRNAs is critical to gene function and protein production, which is intriguingly fine-tuned by non-coding regulatory RNAs such as miRNAs. Since the turn of the century, microarray studies have been increasingly used in space life sciences to assess the abundance of mRNAs in response to microgravity. The microgravity biotechnologies combined with microarray technology have been successfully used to study microgravity effect on gene expression on a wide variety of cell types. In a previous review, data was combined from all retrievable microarray-based microgravity research to identify the most frequently altered putative "major space genes" [10]. At that time we identified 26 microarray based microgravity studies in mammalian cells or tissue that had some form of published gene lists. In addition, we included the then available results (published gene lists) from four Xenopus studies. Candidate major space genes were defined as genes that appeared to have significantly altered expression levels in at least four studies. The resulting list of merely eight potential space genes were CD44, CTGF, CYR61, FN1, MT2, MT1, MARCKS, TUBA4A [4]

Since 2011, substantially more progress has been achieved in the literature because signifi‐ cantly more studies have been published with retrievable gene lists. The combination of a greater number of studies and a general increase in the availability of published gene lists, has enabled us to greatly expand our list of putative "major space genes" from the initial number of eight [4] to the present number of 129 at the same initial level of stringency, a gene's expression was found to be altered by microgravity in four or more studies. Thus, this paper is an extended review and meta-analysis of gene expression profiles to identify major space genes, with emphasis on findings on mammalian cells. To accomplish this, we first defined the method and scope of the current literature-based study to identify the putative major space genes from published data on microarray based microgravity studies in the literature. We proceeded to obtain our novel data at three different confidence levels for the putative major space genes. We further refined the criterion for putative major space genes to only include genes that were found to have altered expression patterns in five or more studies or model cell lines. This higher stringency of selection yielded a more focused group of 35 putative major space genes. Furthermore, we identified 13 genes as the most likely candidates for the major space genes because they have been reported most frequently (≥ 6 studies) as microgravity sensitive genes. We then proceeded to perform bioinformatics analysis at each of the three confidence levels of the putative major space genes. We will present and discuss the lists of candidate major space genes that are most frequently altered by microgravity environments. We also review and discuss recent advances in the area of microarray based microgravity research.
