HGCA2.0: An RNA-Seq Based Webtool for Gene Coexpression Analysis in Homo sapiens.

Genes with similar expression patterns in a set of diverse samples may be considered coexpressed. Human Gene Coexpression Analysis 2.0 (HGCA2.0) is a webtool which studies the global coexpression landscape of human genes. The website is based on the hierarchical clustering of 55,431 Homo sapiens genes based on a large-scale coexpression analysis of 3500 GTEx bulk RNA-Seq samples of healthy individuals, which were selected as the best representative samples of each tissue type. HGCA2.0 presents subclades of coexpressed genes to a gene of interest, and performs various built-in gene term enrichment analyses on the coexpressed genes, including gene ontologies, biological pathways, protein families, and diseases, while also being unique in revealing enriched transcription factors driving coexpression. HGCA2.0 has been successful in identifying not only genes with ubiquitous expression patterns, but also tissue-specific genes. Benchmarking showed that HGCA2.0 belongs to the top performing coexpression webtools, as shown by STRING analysis. HGCA2.0 creates working hypotheses for the discovery of gene partners or common biological processes that can be experimentally validated. It offers a simple and intuitive website design and user interface, as well as an API endpoint.

The correlation of substitution effects across populations and generations in the presence of nonadditive functional gene action.

Allele substitution effects at quantitative trait loci (QTL) are part of the basis of quantitative genetics theory and applications such as association analysis and genomic prediction. In the presence of nonadditive functional gene action, substitution effects are not constant across populations. We develop an original approach to model the difference in substitution effects across populations as a first order Taylor series expansion from a "focal" population. This expansion involves the difference in allele frequencies and second-order statistical effects (additive by additive and dominance). The change in allele frequencies is a function of relationships (or genetic distances) across populations. As a result, it is possible to estimate the correlation of substitution effects across two populations using three elements: magnitudes of additive, dominance, and additive by additive variances; relationships (Nei's minimum distances or Fst indexes); and assumed heterozygosities. Similarly, the theory applies as well to distinct generations in a population, in which case the distance across generations is a function of increase of inbreeding. Simulation results confirmed our derivations. Slight biases were observed, depending on the nonadditive mechanism and the reference allele. Our derivations are useful to understand and forecast the possibility of prediction across populations and the similarity of GWAS effects.

ß-l; -lactamasas AmpC en bacilos gramnegativos de aislados clínicos en un centro hospitalario de tercer nivel en Colombia / AmpCß-l;-lactamases in Gram-negative bacilli from clinical isolates in a Colombian tertiary hospital

Introdución: Las ß-lactamasas AmpC son enzimas con capacidad hidrolítica, pueden ser de tipo constitutivo o inducible. No existe un método estandarizado para su determinación fenotípica por normas internacionales; la detección de estas mediante el uso de la biología molecular podría ser una alternativa útil para vigilancia y control de la diseminación de clones circulantes en el entorno hospitalario. Objetivo: Determinar el fenotipo de resistencia y genes expresados en la producción de ß-lactamasas AmpC en bacilos gramnegativos de aislados clínicos en un centro hospitalario. Métodos: Estudio observacional, descriptivo y de corte transversal. Se seleccionaron 78 cepas bacterianas como portadoras de ß- lactamasas AmpC. Se les realizó prueba de aproximación de disco; a las cepas con resultado positivo se seleccionaron para extracción de ADN y PCR multiplex para detección de 6 familias genes AmpC. Se determinó la frecuencia por tipo de muestra, servicio y comparación con el perfil de susceptibilidad. Resultados: De las cepas seleccionadas con fenotipo AmpC, el 57,6 por ciento (45/78) se consideró caso confirmado ß-lactamasas AmpC por su positividad para la prueba confirmatoria. La técnica molecular utilizada confirmó en el 40 por ciento (18/45) la presencia de genes AmpC. Se obtuvo con mayor frecuencia el gen MIR n= 9 (20 por ciento), seguido de DHA n= 7 (15 por ciento). Conclusiones: La detección oportuna de genes que codifican para ß-lactamasas AmpC permite establecer estrategias para evitar la circulación mediada por plásmidos en hospitales, así como utilizar mejores opciones terapéuticas que no induzcan a otros mecanismos de resistencia(AU)

Introduction: AmpC ß--lactamases are enzymes with hydrolytic activity. They may be either constitutive or inducible. No standardized method is available for their phenotypical determination by international standards. Their detection by molecular biology could be a useful alternative for the surveillance and control of the spread of clones circulating in hospital environments. Objective: Determine the resistance phenotype and genes expressed in the production of AmpC ß-lactamases in Gram-negative bacilli from clinical isolates in a hospital. Methods: An observational descriptive cross-sectional study was conducted. A total 78 bacterial strains were selected as carriers of AmpC ß-lactamases. Disc approximation tests were performed. The strains testing positive were selected for DNA extraction and multiplex PCR for detection of six AmpC gene families. Determination was made of the frequency per sample type, service and comparison with the susceptibility profile. Results: Of the strains selected with AmpC phenotype, 57.6 percent (45/78) were considered to be AmpC β-lactamase confirmed cases, due to their positive confirmatory test. The molecular technique used confirmed the presence of AmpC genes in 40 percent (18/45) of the cases. The gene most commonly obtained was MIR n= 9 (20 percent), followed by DHA n= 7 (15 percent). Conclusions: Timely detection of genes encoding for AmpC ß-lactamases makes it possible to set up strategies to prevent plasmid-mediated circulation in hospitals, as well as apply better therapeutic options that do not induce other resistance mechanisms(AU)

Genome-wide CRISPR screen identifies protein pathways modulating tau protein levels in neurons.

Aggregates of hyperphosphorylated tau protein are a pathological hallmark of more than 20 distinct neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal dementia. While the exact mechanism of tau aggregation is unknown, the accumulation of aggregates correlates with disease progression. Here we report a genome-wide CRISPR screen to identify modulators of endogenous tau protein for the first time. Primary screens performed in SH-SY5Y cells, identified positive and negative regulators of tau protein levels. Hit validation of the top 43 candidate genes was performed using Ngn2-induced human cortical excitatory neurons. Using this approach, genes and pathways involved in modulation of endogenous tau levels were identified, including chromatin modifying enzymes, neddylation and ubiquitin pathway members, and components of the mTOR pathway. TSC1, a critical component of the mTOR pathway, was further validated in vivo, demonstrating the relevance of this screening strategy. These findings may have implications for treating neurodegenerative diseases in the future.

Comparative transcriptomic analysis for identification of candidate sex-related genes and pathways in Crimson seabream (Parargyrops edita).

Teleost fishes display the largest array of sex-determining systems among animals, resulting in various reproductive strategies. Research on sex-related genes in teleosts will broaden our understanding of the process, and provide important insight into the plasticity of the sex determination process in vertebrates in general. Crimson seabream (Parargyrops edita Tanaka, 1916) is one of the most valuable and abundant fish resources throughout Asia. However, little genomic information on P. edita is available. In the present study, the transcriptomes of male and female P. edita were sequenced with RNA-seq technology. A total of 388,683,472 reads were generated from the libraries. After filtering and assembling, a total of 79,775 non redundant unigenes were obtained with an N50 of 2,921 bp. The unigenes were annotated with multiple public databases, including NT (53,556, 67.13%), NR (54,092, 67.81%), Swiss-Prot (45,265, 56.74%), KOG (41,274, 51.74%), KEGG (46,302, 58.04%), and GO (11,056, 13.86%) databases. Comparison of the unigenes of different sexes of P. edita revealed that 11,676 unigenes (9,335 in females, 2,341 in males) were differentially expressed between males and females. Of these, 5,463 were specifically expressed in females, and 1,134 were specifically expressed in males. In addition, the expression levels of ten unigenes were confirmed to validate the transcriptomic data by qRT-PCR. Moreover, 34,473 simple sequence repeats (SSRs) were identified in SSR-containing sequences, and 50 loci were randomly selected for primer development. Of these, 36 loci were successfully amplified, and 19 loci were polymorphic. Finally, our comparative analysis identified many sex-related genes (zps, amh, gsdf, sox4, cyp19a, etc.) and pathways (MAPK signaling pathway, p53 signaling pathway, etc.) of P. edita. This informative transcriptomic analysis provides valuable data to increase genomic resources of P. edita. The results will be useful for clarifying the molecular mechanism of sex determination and for future functional analyses of sex-associated genes.

Lipocalin-type prostaglandin D synthase regulates light-induced phase advance of the central circadian rhythm in mice.

We previously showed that mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) exhibit attenuated light-induced phase shift. To explore the underlying mechanisms, we performed gene expression analysis of laser capture microdissected suprachiasmatic nuclei (SCNs) and found that lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is involved in the impaired response to light stimulation in the late subjective night in PACAP-deficient mice. L-PGDS-deficient mice also showed impaired light-induced phase advance, but normal phase delay and nonvisual light responses. Then, we examined the receptors involved in the response and observed that mice deficient for type 2 PGD2 receptor DP2/CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) show impaired light-induced phase advance. Concordant results were observed using the selective DP2/CRTH2 antagonist CAY10471. These results indicate that L-PGDS is involved in a mechanism of light-induced phase advance via DP2/CRTH2 signaling.

Exploring the genetic basis of fatty liver development in geese.

Although geese possess an adaptive physiological capacity for lipid storage, few candidate genes contributing to this ability are characterised. By comparing the genomes of individuals with extremely high and low fatty liver weights (FLW), candidate genes were identified, including ARAP2, GABRE, and IL6. Single-nucleotide polymorphisms in or near these genes were significantly (p < 0.05) associated with carcass traits (FLW) and biochemical indexes (very-low-density lipoprotein and N-terminal procollagen III), suggesting contribution to trait variation. A common variant at the 5'-end of LCORL explained ~ 18% and ~ 26% of the phenotypic variance in body weight with/without overfeeding and had significant effects on FLW (p < 0.01). ZFF36L1, ARHGEF1 and IQCJ, involved in bile acid metabolism, blood pressure, and lipid concentration modulation, were also identified. The presence of highly divergent haplotypes within these genes suggested involvement in protection against negative effects from excessive lipids in the liver or circulatory system. Based on this and transcriptomic data, we concluded that geese hepatosteatosis results from severe imbalance between lipid accumulation and secretion, comparable to human non-alcohol fatty liver disease but involving other genes. Our results provided valuable insights into the genesis of geese fatty liver and detected potential target genes for treatment of lipid-related diseases.

Identification of key genes in calcific aortic valve disease by integrated bioinformatics analysis.

Calcific aortic valve disease (CAVD) is highly prevalent in our aging world and has no effective pharmaceutical treatment. Intense efforts have been made but the underlying molecular mechanisms of CAVD are still unclear.This study was designed to identify the critical genes and pathways in CAVD by bioinformatics analysis. Microarray datasets of GSE12644, GSE51472, and GSE83453 were obtained from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified and functional and pathway enrichment analysis was performed. Subsequently, the protein-protein interaction network (PPI) was constructed with Search Tool for the Retrieval of Interacting Genes and was visualized with Cytoscape to identify the most significant module. Hub genes were identified by Cytoscape plugin cytoHubba.A total of 179 DEGs, including 101 upregulated genes and 78 downregulated genes, were identified. The enriched functions and pathways of the DEGs include inflammatory and immune response, chemotaxis, extracellular matrix (ECM) organization, complement and coagulation cascades, ECM receptor interaction, and focal adhesion. The most significant module in the PPI network was analyzed and genes among it were mainly enriched in chemotaxis, locomotory behavior, immune response, chemokine signaling pathway, and extracellular space. In addition, DEGs, with degrees ≥ 10 and the top 10 highest Maximal Chique Centrality (MCC) score, were identified as hub genes. CCR1, MMP9, VCAM1, and ITGAX, which were of the highest degree or MCC score, were manually reviewed.The DEGs and hub genes identified in the present study help us understand the molecular mechanisms underlying the pathogenesis of CAVD and might serve as candidate therapeutic targets for CAVD.

Protein phosphatase 1 activity controls a balance between collective and single cell modes of migration.

Collective cell migration is central to many developmental and pathological processes. However, the mechanisms that keep cell collectives together and coordinate movement of multiple cells are poorly understood. Using the Drosophila border cell migration model, we find that Protein phosphatase 1 (Pp1) activity controls collective cell cohesion and migration. Inhibition of Pp1 causes border cells to round up, dissociate, and move as single cells with altered motility. We present evidence that Pp1 promotes proper levels of cadherin-catenin complex proteins at cell-cell junctions within the cluster to keep border cells together. Pp1 further restricts actomyosin contractility to the cluster periphery rather than at individual internal border cell contacts. We show that the myosin phosphatase Pp1 complex, which inhibits non-muscle myosin-II (Myo-II) activity, coordinates border cell shape and cluster cohesion. Given the high conservation of Pp1 complexes, this study identifies Pp1 as a major regulator of collective versus single cell migration.

Unique transcriptional signatures of sleep loss across independently evolved cavefish populations.

Animals respond to sleep loss with compensatory rebound sleep, and this is thought to be critical for the maintenance of physiological homeostasis. Sleep duration varies dramatically across animal species, but it is not known whether evolutionary differences in sleep duration are associated with differences in sleep homeostasis. The Mexican cavefish, Astyanax mexicanus, has emerged as a powerful model for studying the evolution of sleep. While eyed surface populations of A. mexicanus sleep approximately 8 hr each day, multiple blind cavefish populations have converged on sleep patterns that total as little as 2 hr each day, providing the opportunity to examine whether the evolution of sleep loss is accompanied by changes in sleep homeostasis. Here, we examine the behavioral and molecular response to sleep deprivation across four independent populations of A. mexicanus. Our behavioral analysis indicates that surface fish and all three cavefish populations display robust recovery sleep during the day following nighttime sleep deprivation, suggesting sleep homeostasis remains intact in cavefish. We profiled transcriptome-wide changes associated with sleep deprivation in surface fish and cavefish. While the total number of differentially expressed genes was not greater for the surface population, the surface population exhibited the highest number of uniquely differentially expressed genes than any other population. Strikingly, a majority of the differentially expressed genes are unique to individual cave populations, suggesting unique expression responses are exhibited across independently evolved cavefish populations. Together, these findings suggest sleep homeostasis is intact in cavefish despite a dramatic reduction in overall sleep duration.

Rapid sex-specific adaptation to high temperature in Drosophila.

The pervasive occurrence of sexual dimorphism demonstrates different adaptive strategies of males and females. While different reproductive strategies of the two sexes are well-characterized, very little is known about differential functional requirements of males and females in their natural habitats. Here, we study the impact environmental change on the selection response in both sexes. Exposing replicated Drosophila populations to a novel temperature regime, we demonstrate sex-specific changes in gene expression, metabolic and behavioral phenotypes in less than 100 generations. This indicates not only different functional requirements of both sexes in the new environment but also rapid sex-specific adaptation. Supported by computer simulations we propose that altered sex-biased gene regulation from standing genetic variation, rather than new mutations, is the driver of rapid sex-specific adaptation. Our discovery of environmentally driven divergent functional requirements of males and females has important implications-possibly even for gender aware medical treatments.

Male and female animals of the same species sometimes differ in appearance and sexual behavior, a phenomenon known as sexual dimorphism. Both sexes share most of the same genes, but differences can emerge because of the way these are read by cells to create proteins ­ a process called gene expression. For instance, certain genes can be more expressed in males than in females, and vice-versa. Most studies into the emergence of sexual dimorphism have taken place in stable environments with few changes in climate or other factors. Therefore, the potential impact of environmental changes on sexual dimorphism has been largely overlooked. Here, Hsu et al. used genetic and computational approaches to investigate whether male and female fruit flies adapt differently to a new, hotter environment over several generations. The experiment showed that, after only 100 generations, the way that 60% of all genes were expressed evolved in a different direction in the two sexes. This led to differences in how the males and females made and broke down fat molecules, and in how their neurons operated. These expression changes also translated in differences for high-level biological processes. For instance, animals in the new settings ended up behaving differently, with the males at the end of the experiment spending more time chasing females than the ancestral flies. These findings demonstrate that male and female fruit flies adapt many biological processes (including metabolism and behaviors) differently to cope with changes in their environment, and that many different genes support these sex-specific adaptations. Ultimately, the work by Hsu et al. may inform medical strategies that take into account interactions between the patient's sex and their environment.

Integrated analysis of H2A.Z isoforms function reveals a complex interplay in gene regulation.

The H2A.Z histone variant plays major roles in the control of gene expression. In human, H2A.Z is encoded by two genes expressing two isoforms, H2A.Z.1 and H2A.Z.2 differing by three amino acids. Here, we undertook an integrated analysis of their functions in gene expression using endogenously-tagged proteins. RNA-Seq analysis in untransformed cells showed that they can regulate both distinct and overlapping sets of genes positively or negatively in a context-dependent manner. Furthermore, they have similar or antagonistic function depending on genes. H2A.Z.1 and H2A.Z.2 can replace each other at Transcription Start Sites, providing a molecular explanation for this interplay. Mass spectrometry analysis showed that H2A.Z.1 and H2A.Z.2 have specific interactors, which can mediate their functional antagonism. Our data indicate that the balance between H2A.Z.1 and H2A.Z.2 at promoters is critically important to regulate specific gene expression, providing an additional layer of complexity to the control of gene expression by histone variants.

A new biological definition of life.

Here we have proposed a new biological definition of life based on the function and reproduction of existing genes and creation of new ones, which is applicable to both unicellular and multicellular organisms. First, we coined a new term "genetic information metabolism" comprising functioning, reproduction, and creation of genes and their distribution among living and non-living carriers of genetic information. Encompassing this concept, life is defined as organized matter that provides genetic information metabolism. Additionally, we have articulated the general biological function of life as Tetz biological law: "General biological function of life is to provide genetic information metabolism" and formulated novel definition of life: "Life is an organized matter that provides genetic information metabolism". New definition of life and Tetz biological law allow to distinguish in a new way living and non-living objects on Earth and other planets based on providing genetic information metabolism.

The role of the estrogen receptor-α gene, Esr1, in maternal-like behavior in juvenile female and male rats.

The estrogen receptor-alpha (ER-α) is an important ligand activated transcription factor that works to control gene transcription in many species. Previous studies have shown estrogen to be an important hormone in the regulation of maternal behavior. Like adult female rats, both male and female juvenile rats exhibit increased level of maternal-like behavior when exposed to pups. The aim of this study was to determine whether ER-α is critical for the expression of maternal-like behavior in juvenile male and female rats. ER-α knock-out and wildtype (WT) juvenile male and female rats were generated and tested for maternal behaviors. Latencies to display maternal-like behaviors that included retrieval, grouping and crouching responses, revealed no genotype differences between KO and WT subjects. Male juvenile rats exhibited slightly shorter latencies than WT juvenile female rats indicating a sex difference in the latency to display these responses. Additionally, ER-α KO females exhibited a delay in onset of vaginal opening compared to WT females, indicating a role for ER-α in sexual maturation. The behavioral findings indicate that ER-α is not obligatory for the expression of full maternal-like behavior in male and female juvenile rats. Understanding this neurobiological system will help to elucidate the developmental involvement of the endocrine and brain networks in the regulation of maternal behaviors in mammals.

NMFGO: Gene Function Prediction via Nonnegative Matrix Factorization with Gene Ontology.

Gene Ontology (GO) is a controlled vocabulary of terms that describe molecule function, biological roles, and cellular locations of gene products (i.e., proteins and RNAs), it hierarchically organizes more than 43,000 GO terms via the direct acyclic graph. A gene is generally annotated with several of these GO terms. Therefore, accurately predicting the association between genes and massive terms is a difficult challenge. To combat with this challenge, we propose an matrix factorization based approach called NMFGO. NMFGO stores the available GO annotations of genes in a gene-term association matrix and adopts an ontological structure based taxonomic similarity measure to capture the GO hierarchy. Next, it factorizes the association matrix into two low-rank matrices via nonnegative matrix factorization regularized with the GO hierarchy. After that, it employs a semantic similarity based k nearest neighbor classifier in the low-rank matrices approximated subspace to predict gene functions. Empirical study on three model species (S. cerevisiae, H. sapiens, and A. thaliana) shows that NMFGO is robust to the input parameters and achieves significantly better prediction performance than GIC, TO, dRW- kNN, and NtN, which were re-implemented based on the instructions of the original papers. The supplementary file and demo codes of NMFGO are available at http://mlda.swu.edu.cn/codes.php?name=NMFGO.

Bioinformatic analysis of the molecular mechanism underlying bronchial pulmonary dysplasia using a text mining approach.

Bronchopulmonary dysplasia (BPD) is a common disease of premature infants with very low birth weight. The mechanism is inconclusive. The aim of this study is to systematically explore BPD-related genes and characterize their functions.Natural language processing analysis was used to identify BPD-related genes. Gene data were extracted from PubMed database. Gene ontology, pathway, and network analysis were carried out, and the result was integrated with corresponding database.In this study, 216 genes were identified as BPD-related genes with P < .05, and 30 pathways were identified as significant. A network of BPD-related genes was also constructed with 17 hub genes identified. In particular, phosphatidyl inositol-3-enzyme-serine/threonine kinase signaling pathway involved the largest number of genes. Insulin was found to be a promising candidate gene related with BPD, suggesting that it may serve as an effective therapeutic target.Our data may help to better understand the molecular mechanisms underlying BPD. However, the mechanisms of BPD are elusive, and further studies are needed.

Gene co-expression network analysis reveals key potential gene modules in utero-vaginal junction associated with duration of fertility trait of breeder hens.

The number of days (DN) when hens lay fertile eggs as well as the number of fertile eggs (FN) were produced after a single artificial insemination (AI), including the two duration of fertility (DF) traits. Indeed, they are the key production performance that associates with the production cost of hatching egg when its determination the interval between successive artificial inseminations. However, the relevant genes response for regulating the DF has not been uncovered yet. Therefore, we performed a weighted gene co-expression network analysis (WGCNA) to investigate the insight into co-expression gene modules on DF process in hens. The total mRNA was extracted from the utero-vaginal junction (UVJ, with the sperm storage function in hen's oviduct which is the biological basis for DF) of 20 hens with several levels of DF traits, and performed transcriptome sequences of mRNA. As a result, three co-expression gene modules were identified to be highly correlated with DF traits. Moreover, the expression changes of top 5 hub genes in each module with DF traits were further confirmed in other 20 hens by RT-PCR. These findings highlighted the co-expression modules and their affiliated genes as playing important roles in the regulation of DF traits.

New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders.

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

Lipid metabolism participates in human membranous nephropathy identified by whole-genome gene expression profiling.

A genomics approach is an effective way to understand the possible mechanisms underlying the onset and progression of disease. However, very limited results have been published regarding whole-genome expression analysis of human idiopathic membranous nephropathy (iMN) using renal tissue. In the present study, gene expression profiling using renal cortex tissue from iMN patients and healthy controls was conducted; differentially expressed genes (DEGs) were filtered out, and 167 up- and 291 down-regulated genes were identified as overlapping DEGs (ODEGs). Moreover, enrichment analysis and protein-protein network construction were performed, revealing enrichment of genes mainly in cholesterol metabolism and arachidonic acid metabolism, among others, with 38 hub genes obtained. Furthermore, we found several associations between circulating lipid concentrations and hub gene signal intensities in the renal cortex. Our findings indicate that lipid metabolism, including cholesterol metabolism and arachidonic acid metabolism, may participate in iMN pathogenesis through key genes, including apolipoprotein A1 (APOA1), apolipoprotein B (APOB), apolipoprotein C3 (APOC3), cholesteryl ester transfer protein (CETP), and phospholipase A2 group XIIB (PLA2G12B).

Genes that make you fat, but keep you healthy.

Obesity prevalence continues to rise worldwide, posing a substantial burden on people's health. However, up to 45% of obese individuals do not suffer from cardiometabolic complications, also called the metabolically healthy obese (MHO). Concurrently, up to 30% of normal-weight individuals demonstrate cardiometabolic risk factors that are generally observed in obese individuals, the metabolically obese normal weight (MONW). Besides lifestyle, environmental factors and demographic factors, innate biological mechanisms are known to contribute to the aetiology of the MHO and MONW phenotypes, as well. Experimental studies in animal models have shown that adipose tissue expandability, fat distribution, adipogenesis, adipose tissue vascularization, inflammation and fibrosis, and mitochondrial function are the main mechanisms that uncouple adiposity from its cardiometabolic comorbidities. We reviewed current genetic association studies to expand insights into the biology of MHO/MONW phenotypes. At least four genetic loci were identified through genome-wide association studies for body fat percentage (BF%) of which the BF%-increasing allele was associated with a protective effect on glycemic and lipid outcomes. For some, this association was mediated through favourable effects on body fat distribution. Other studies that characterized the genetic susceptibility of insulin resistance found that a higher susceptibility was associated with lower overall adiposity due to less fat accumulation at hips and legs, suggesting that an impaired capacity to store fat subcutaneously or a preferential storage in the intra-abdominal cavity may be metabolically harmful. Clearly, more work remains to be done in this field, first through gene discovery and subsequently through functional follow-up of identified genes.