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11.
Rajkumari Sanjukta Mohammad Samir Farooqi Naveen Sharma Anil Rai Dwijesh Chandra Mishra Dhananjaya P Singh 《Bioinformation》2012,8(22):1087-1095
Chromohalobacter salexigens, a Gammaproteobacterium belonging to the family Halomonadaceae, shows a broad salinity range for
growth. In order to reveal the factors influencing architecture of protein coding genes in C. salexigens, pattern of synonymous codon
usage bias has been investigated. Overall codon usage analysis of the microorganism revealed that C and G ending codons are
predominantly used in all the genes which are indicative of mutational bias. Multivariate statistical analysis showed that the genes
are separated along the first major explanatory axis according to their expression levels and their genomic GC content at the
synonymous third positions of the codons. Both NC plot and correspondence analysis on Relative Synonymous Codon Usage
(RSCU) indicates that the variation in codon usage among the genes may be due to mutational bias at the DNA level and natural
selection acting at the level of mRNA translation. Gene length and the hydrophobicity of the encoded protein also influence the
codon usage variation of genes to some extent. A comparison of the relative synonymous codon usage between 10% each of highly
and lowly expressed genes determines 23 optimal codons, which are statistically over represented in the former group of genes and
may provide useful information for salt-stressed gene prediction and gene-transformation. Furthermore, genes for regulatory
functions; mobile and extrachromosomal element functions; and cell envelope are observed to be highly expressed. The study
could provide insight into the gene expression response of halophilic bacteria and facilitate establishment of effective strategies to
develop salt-tolerant crops of agronomic value. 相似文献
12.
William T. Gibson Pavlos Pissios Daniel J. Trombly Jian'An Luan Julia Keogh Nicholas J. Wareham Eleftheria Maratos‐Flier Stephen O'Rahilly I. Sadaf Farooqi 《Obesity (Silver Spring, Md.)》2004,12(5):743-749
Melanin‐concentrating hormone (MCH), a neuropeptide highly expressed in the lateral hypothalamus, has an important role in the regulation of energy balance and body weight in rodents. We examined whether mutations in the two known MCH receptors might be associated with obesity‐related phenotypes in humans. Among 106 subjects with severe early onset obesity and a history of hyperphagia, we found two missense variants in MCHR1: Y181H and R248Q. Neither of these was found in 192 normal weight controls. R248Q cosegregated with obesity across two generations; family data were unavailable for Y181H. When expressed in HEK293 cells, R248Q showed no evidence of constitutive activation or ligand hypersensitivity for extracellular signal‐regulated kinase phosphorylation. In addition, R248Q showed no enhanced suppression of cAMP generation. Two common single‐nucleotide polymorphisms were found to be in linkage disequilibrium: g.‐114A>G and c.39C>T. No association between either of these single‐nucleotide polymorphisms and obesity‐related phenotypes was found among a population cohort of 541 whites. Only two rare noncoding variants were found in MCHR2. In conclusion, mutations in the MCH receptors are not commonly found in humans with severe early onset obesity. Clarification of the relationship of these variants to obesity must await study in other populations and/or in genetically modified mice. 相似文献
13.
Neha Agrawal Katherine Lawler Catherine M. Davidson Julia M. Keogh Robert Legg INTERVAL Inês Barroso I. Sadaf Farooqi Andrea H. Brand 《PLoS biology》2021,19(11)
The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.This study set out to identify novel gene variants that may contribute to human obesity, by combining human exosome sequencing analyses with systematic functional screening in Drosophila. This identifies a number of novel obesity-associated genes which control adiposity in flies, and uncovers a potential role for the Hippo signaling pathway in obesity.Obesity is a major risk factor for type 2 diabetes, cardiovascular disease, cancers, and, most recently, COVID-19 [1]. Despite the obvious environmental drivers to weight gain, multiple genetic studies have demonstrated that 40% to 70% of the variation in body weight is attributable to genetic variation [2]. The discovery of genes that contribute to the regulation of human body weight can provide insights into the mechanisms involved in energy homeostasis and identify potential targets for weight loss therapy. Moreover, drug targets supported by human genetic evidence are more likely to transit successfully through the drug discovery pipeline [3].A classical approach to the discovery of pathogenic variants is to investigate consanguineous populations with high degrees of parental relatedness (parents who are first or second cousins) where large portions of the genome are identical by descent as a result of family structure in preceding generations (long regions of homozygosity). Indeed, studies in consanguineous families led to the discovery of the first homozygous loss-of-function mutations in the genes encoding leptin (LEP; [4]) and the leptin receptor (LEPR; [5]) associated with severe obesity. However, at the time, the function of leptin and its receptor had already been established in ob/ob and db/db mice, respectively [6], so the pathogenicity of homozygous mutations that resulted in loss of function in cells was readily established.The situation is more complex when studying homozygous mutations in new candidate genes. Some of these genes may play a direct causal role in the development of obesity, others may increase susceptibility to obesity only in certain contexts, and some genes will play no role at all. Recent large-scale studies in healthy people in outbred populations have revealed that a significant proportion of rare homozygous variants that are predicted to cause a loss of function do not result in a clinically discernible phenotype [7,8]. As such, identifying the subset of genes that may be involved in the regulation of adiposity in large human genetic studies presents a major hurdle.For some diseases, functional screens in cultured cells permit rapid testing of candidate genes, as exemplified by studies of insulin secretion in islet cells for genes associated with type 2 diabetes [9]. However, obesity is a systems-level disorder that cannot be replicated in cells. As such, a functional screen in vivo is needed. Here, we use Drosophila to screen the functional consequences of knocking down expression of candidate human obesity genes and to explore the complex interactions between multiple organ systems that are regulated by environmental and genetic factors.Drosophila has been a useful tool in the functional characterisation of human disease-associated genes [10–12]. Many organ systems and metabolic enzymes are highly conserved in Drosophila, as are the major regulatory mechanisms involved in metabolic homeostasis [13,14]. As in humans, Drosophila accumulate lipids and become obese when raised on a high-fat or high-sugar diet, developing cardiomyopathy and diabetic phenotypes [15,16]. Furthermore, more than 60% of the genes identified in an unbiased genome-wide RNAi screen for increased fat levels in Drosophila have human orthologues [17]. Most studies in Drosophila have performed forward genetic screens resulting in obesity [18] before assessing whether misregulation of the corresponding mammalian orthologue affects adiposity [17]. Another report knocked down Drosophila orthologs of human genes near body mass index (BMI) loci from GWAS studies to identify genes regulating adiposity [19].Here, instead, we chose to take advantage of new data from a cohort of patients carrying rare genetic variants that might cause severe early-onset obesity. We set out to identify, in Drosophila, whether any of these genes are likely to be responsible for the obese phenotype. An additional advantage of working with Drosophila is the potential to identify interacting genes and signalling pathways. We proposed that it would then be possible to search for variants in human orthologues of these genes in larger cohorts of patients, to discover further as yet unidentified genes regulating human obesity.To increase our chances of finding pathogenic variants, we focused on rare homozygous variants identified in probands with severe obesity, many from consanguineous families. After knocking down expression of Drosophila orthologues of candidate human obesity genes, we discovered 4 genes that significantly increased triacylglyceride (TAG) levels. Importantly, none of these genes had been associated previously with human obesity, but the pathways in which they act are known and could be further analysed in Drosophila. Knockdown of further members of one of these signalling pathways, the Hippo pathway, also gave an obesity phenotype, highlighting the success of our approach. We then searched for variants in the novel obesity genes we identified in Drosophila, and their associated signalling pathways, in larger cohorts of unrelated obese people and healthy controls. This uncovered yet another gene, which, when knocked down in Drosophila, increased adiposity. We demonstrate that the cross-fertilisation of human and Drosophila genetics is a powerful system to provide novel insights into the genetic and cellular processes regulating adiposity and may ultimately contribute to strategies for the prevention and treatment of obesity. 相似文献
14.
Megan A. O'Neill I. Sadaf Farooqi Rachel Wevrick 《Obesity (Silver Spring, Md.)》2005,13(10):1841-1842
MAGEL2 is one of the five genes inactivated in Prader‐Willi Syndrome, a neurodevelopmental chromosome microdeletion disorder modified by genomic imprinting. By early childhood, individuals with Prader‐Willi Syndrome exhibit hypothalamic dysfunction, including hyperphagia, and become obese in the absence of behavioral intervention. Murine Magel2 is highly expressed in the hypothalamus during development. We screened the MAGEL2 open reading frame for mutations in genomic DNA samples from hyperphagic but non‐dysmorphic individuals with severe childhood‐onset obesity. Although no mutations likely to affect gene function were identified, we identified three variant alleles. We conclude that severe childhood‐onset obesity is not commonly caused by MAGEL2 mutations. 相似文献
15.
16.
O'Rahilly S Farooqi IS 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2006,361(1471):1095-1105
Considerable attention is currently being paid to the secular changes in food intake and physical activity that underlie the increase in the prevalence of obesity that is apparent in many societies. While this is laudable it would be unwise to view these environmental factors in isolation from the biological factors that normally control body weight and composition and the compelling evidence that inter-individual differences in susceptibility to obesity have strong genetic determinants. This is particularly important, as it is only in the past decade that we have begun to obtain substantive information regarding the molecular constituents of pathways controlling mammalian energy balance and therefore, for the first time, are in a position to achieve a better mechanistic understanding of this disease. Population-based association and linkage studies have highlighted a number of loci at which genetic variation is associated with obesity and related phenotypes and the identification and characterization of monogenic obesity syndromes has been particularly fruitful. While there is widespread acceptance that hereditary factors might predispose to human obesity, it is frequently assumed that such factors would influence metabolic rate or the selective partitioning of excess calories into fat. However, it is notable that, thus far, all monogenic defects causing human obesity actually disrupt hypothalamic pathways and have a profound effect on satiety and food intake. To conclude, the evidence we have to date suggests that the major impact of genes on human obesity is just as likely (or perhaps more likely) to directly impact on hunger, satiety and food intake rather than metabolic rate or nutrient partitioning. At the risk of oversimplification, it seems that from an aetiological/genetic standpoint, human obesity appears less a metabolic than a neuro-behavioural disease. 相似文献
17.
Hu B Gilkes DM Farooqi B Sebti SM Chen J 《The Journal of biological chemistry》2006,281(44):33030-33035
The p53 tumor suppressor plays a key role in maintaining genomic stability and protection against malignant transformation. MDM2 and MDMX are both p53-binding proteins that regulate p53 stability and activity. Recent development of the MDM2 inhibitor Nutlin 3 has greatly facilitated functional analysis of MDM2-p53 binding. We found that although MDMX is homologous to MDM2 and binds to the same region on p53 N terminus, Nutlin does not disrupt p53-MDMX interaction. The ability of Nutlin to activate p53 is compromised in tumor cells overexpressing MDMX. Combination of Nutlin with MDMX siRNA resulted in synergistic activation of p53 and growth arrest. These results suggest that MDMX is also a valid target for p53 activation in tumor cells. Development of novel compounds that are MDMX-specific or optimized for dual-inhibition of MDM2 and MDMX are necessary to achieve full activation of p53 in tumor cells. 相似文献
18.
Amit Kumar Singh Nikunj Sharma Humaira Farooqi Malik Zainul Abdin Shashi Kumar 《International journal of phytoremediation》2017,19(9):805-812
Municipal wastewater (WW), if not properly remediated, poses a threat to the environment and human health by carrying significant loads of nutrients and pathogens. These contaminants pollute rivers, lakes, and natural reservoirs where they cause eutrophication and pathogen-mediated diseases. However, the high nutrient content of WW makes it an ideal environment for remediation with microalgae that require high nutrient concentrations for growth and are not susceptible to toxins and pathogens. Given that an appropriate algal strain is used for remediation, the incurred biomass can be refined for the production of biofuel. Four microalgal species (Chlamydomonas reinhardtii, Chlorella sp., Parachlorella kessleri-I, and Nannochloropsis gaditana) were screened for efficient phycoremediation of municipal WW and potential use for biodiesel production. Among the four strains tested, P. kessleri-I showed the highest growth rate and biomass production in 100% WW. It efficiently removed all major nutrients with a removal rate of up to 98% for phosphate after 10 days of growth in 100% municipal WW collected from Delhi. The growth of P. kessleri-I in WW resulted in a 50% increase of biomass and a 115% increase of lipid yield in comparison to growth in control media. The Fatty acid methyl ester (FAME), and fuel properties of lipids isolated from cells grown in WW complied with international standards. The present study provides evidence that the green alga P. kessleri-I effectively remediates municipal WW and can be used to produce biodiesel. 相似文献
19.
Farooqi AA Bhatti S Nawaz A Khalid AM 《The International journal of biological markers》2011,26(2):75-81
The touchstone to evaluate accurately the aggressiveness and invasiveness of prostate cancer is something of a holy grail in the facet of urologic oncology. Gene expression and sequencing studies have improved our interpretations of the genetic determinants of the disease but are unsuccessful in the establishment of any unified classification to improve the molecular stratification. These questions addressing failure in rational drug design are difficult to answer in the multifaceted and heterogeneous pathogenesis of prostate cancer. In this review, we have developed a roadmap of the "recalcitrant prostate cancer proteome" to recognize the aspects of prostate cancer that may be helpful in effectively translating these findings to the clinic. 相似文献
20.