Independent amylase gene copy number bursts correlate with dietary preferences in mammals.
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ABSTRACT:
SUBMITTER: Pajic P
PROVIDER: S-EPMC6516957 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Starch consumption is a prominent characteristic of agricultural societies and hunter-gatherers in arid environments. In contrast, rainforest and circum-arctic hunter-gatherers and some pastoralists consume much less starch. This behavioral variation raises the possibility that different selective pressures have acted on amylase, the enzyme responsible for starch hydrolysis. We found that copy number of the salivary amylase gene (AMY1) is correlated positively with salivary amylase protein level and that individuals from populations with high-starch diets have, on average, more AMY1 copies than those with traditionally low-starch diets. Comparisons with other loci in a subset of these populations suggest that the extent of AMY1 copy number differentiation is highly unusual. This example of positive selection on a copy number-variable gene is, to our knowledge, one of the first discovered in the human genome. Higher AMY1 copy numbers and protein levels probably improve the digestion of starchy foods and may buffer against the fitness-reducing effects of intestinal disease.
| S-EPMC2377015 | biostudies-literature
Project description:Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10(-14)) and serum enzyme levels (P < 2.20 × 10(-16)), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = -0.15 (0.02) kg/m(2); P = 6.93 × 10(-10)) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10(-10)). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies.
| S-EPMC6485469 | biostudies-literature
Project description:Salivary amylase (AMY1) is the most abundant enzyme in human saliva, responsible for the hydrolysis of α-1,4 glycosidic linkages that aids in the digestion of starch. Recently studies have shown that the copy number of AMY1 is associated with obesity; however, the data varies with location. One-third of children are overweight/obese in Alabama. In this study, we aim to determine the relationship between the copy number of AMY1 gene and obesity measurements in children from Alabama. One hundred twenty-seven children aged between 6 to 10 years participated in this study. Anthropometric measurements were measured using WHO recommendations. Genomic DNA was extracted from saliva, and the copy number of the AMY1 gene was estimated by digital PCR. The association between AMY1 copy number and obesity measurements was analyzed by linear regression. The mean AMY1 copy number significantly decreased in overweight/obese (6.21 ± 1.48) compared to normal weight (7.97 ± 2.35) children. AMY1 copy number inversely associated with the obesity measurements. African Americans had a stronger association between low AMY1 copy number and obesity compared to white/European Americans. Our findings suggest that overweight/obese children have a low AMY1 copy number and the effect is more prominent in African Americans.
| S-EPMC6627241 | biostudies-literature
Project description:Prolonged human interactions and artificial selection have influenced the genotypic and phenotypic diversity among dog breeds. Because humans and dogs occupy diverse habitats, ecological contexts have likely contributed to breed-specific positive selection. Prior to the advent of modern dog-feeding practices, there was likely substantial variation in dietary landscapes among disparate dog breeds. As such, we investigated one type of genetic variant, copy number variation, in three metabolic genes: glucokinase regulatory protein (GCKR), phytanol-CoA 2-hydroxylase (PHYH), and pancreatic α-amylase 2B (AMY2B). These genes code for proteins that are responsible for metabolizing dietary products that originate from distinctly different food types: sugar, meat, and starch, respectively. After surveying copy number variation among dogs with diverse dietary histories, we found no correlation between diet and positive selection in either GCKR or PHYH. Although it has been previously demonstrated that dogs experienced a copy number increase in AMY2B relative to wolves during or after the dog domestication process, we demonstrate that positive selection continued to act on amylase copy number in dog breeds that consumed starch-rich diets in time periods after domestication. Furthermore, we found that introgression with wolves is not responsible for deterioration of positive selection on AMY2B among diverse dog breeds. Together, this supports the hypothesis that the amylase copy number expansion is found universally in dogs.
| S-EPMC4749313 | biostudies-literature
Project description:The digestion of dietary starch in humans is initiated by salivary ?-amylase, an endo-enzyme that hydrolyzes starch into maltose, maltotriose and larger oligosaccharides. Salivary amylase accounts for 40 to 50% of protein in human saliva and rapidly alters the physical properties of starch. Importantly, the quantity and enzymatic activity of salivary amylase show significant individual variation. However, linking variation in salivary amylase levels with the oral perception of starch has proven difficult. Furthermore, the relationship between copy number variations (CNVs) in the AMY1 gene, which influence salivary amylase levels, and starch viscosity perception has not been explored.Here we demonstrate that saliva containing high levels of amylase has sufficient activity to rapidly hydrolyze a viscous starch solution in vitro. Furthermore, we show with time-intensity ratings, which track the digestion of starch during oral manipulation, that individuals with high amylase levels report faster and more significant decreases in perceived starch viscosity than people with low salivary amylase levels. Finally, we demonstrate that AMY1 CNVs predict an individual's amount and activity of salivary amylase and thereby, ultimately determine their perceived rate of oral starch viscosity thinning.By linking genetic variation and its consequent salivary enzymatic differences to the perceptual sequellae of these variations, we show that AMY1 copy number relates to salivary amylase concentration and enzymatic activity level, which, in turn, account for individual variation in the oral perception of starch viscosity. The profound individual differences in salivary amylase levels and salivary activity may contribute significantly to individual differences in dietary starch intake and, consequently, to overall nutritional status.
| S-EPMC2954178 | biostudies-literature
Project description:BackgroundSalivary amylase, encoded by the AMY1 gene, initiate the digestion of starch. Whether starch intake or AMY1 copy number is related to disease risk is currently rather unknown. The aim was to investigate the association between starch intake and AMY1 copy number and risk of cardiovascular disease (CVD) and mortality and whether there is an interaction. In addition, we aim to identify CVD-related plasma proteins associated with starch intake and AMY1 copy number.MethodsThis prospective cohort study used data from 21,268 participants from the Malmö Diet and Cancer Study. Dietary data were collected through a modified diet history method and incident CVD and mortality were ascertained through registers. AMY1 gene copy number was determined by droplet digital polymerase chain reaction, a risk score of 10 genetic variants in AMY1 was measured, and a total of 88 selected CVD-related proteins were measured. Cox proportional hazards regression was used to analyze the associations of starch intake and AMY1 copy number with disease risk. Linear regression was used to identify plasma proteins associated with starch intake and AMY1 copy number.ResultsOver a median of 23 years' follow-up, 4443 individuals developed CVD event and 8125 died. After adjusting for potential confounders, a U-shape association between starch intake and risk of CVD (P-nonlinearity = 0.001) and all-cause mortality (P-nonlinearity = 0.03) was observed. No significant association was found between AMY1 copy number and risk of CVD and mortality, and there were no interactions between starch intake and AMY1 copy number (P interaction > 0.23). Among the 88 plasma proteins, adrenomedullin, interleukin-1 receptor antagonist protein, fatty acid-binding protein, leptin, and C-C motif chemokine 20 were associated with starch intake after adjusting for multiple testing.ConclusionsIn this large prospective study among Swedish adults, a U-shaped association between starch intake and risk of CVD and all-cause mortality was found. Several plasma proteins were identified which might provide information on potential pathways for such association. AMY1 copy number was not associated with CVD risk or any of the plasma proteins, and there was no interaction between starch intake and AMY1 copy number on disease risk.
| S-EPMC9872432 | biostudies-literature
Project description:Studies assessing the impact of amylase genes copy number (CN) on adiposity report conflicting findings in different global populations, likely reflecting the impact of ancestral and ethnic-specific environment and lifestyle on selection at the amylase loci. Here, we leverage population size and detailed adiposity measures from a large population biobank to resolve confounding effects and determine the relationship between salivary (AMY1) and pancreatic (AMY2A) amylase genes CN and adiposity in 2935 Qatari individuals who underwent whole-genome sequencing (WGS) as part of the Qatar Genome Programme. We observe a negative association between AMY1 CNs and trunk fat percentage in the Qatari population (P = 7.50 × 10-3) and show that Qataris of Arab descent have significantly lower CN at AMY1 (P = 1.32 × 10-10) as well as less favorable adiposity and metabolic profiles (P < 1.34 × 10-8) than Qataris with Persian ancestry. Indeed, lower AMY1 CN was associated with increased total and trunk fat percentages in Arabs (P < 4.60 × 10-3) but not in Persians. Notably, overweight and obese Persians reported a significant trend towards dietary restraint following weight gain compared to Arabs (P = 4.29 × 10-5), with AMY1 CN showing negative association with dietary self-restraint (P = 3.22 × 10-3). This study reports an association between amylase gene CN and adiposity traits in a large Middle Eastern population. Importantly, we leverage rich biobank data to demonstrate that the strength of this association varies with ethnicity, and may be influenced by population-specific behaviors that also contribute to adiposity traits.
| S-EPMC7873199 | biostudies-literature
Project description:UnlabelledThe CRISPR/Cas9 system enables genome editing and somatic cell genetic screens in mammalian cells. We performed genome-scale loss-of-function screens in 33 cancer cell lines to identify genes essential for proliferation/survival and found a strong correlation between increased gene copy number and decreased cell viability after genome editing. Within regions of copy-number gain, CRISPR/Cas9 targeting of both expressed and unexpressed genes, as well as intergenic loci, led to significantly decreased cell proliferation through induction of a G2 cell-cycle arrest. By examining single-guide RNAs that map to multiple genomic sites, we found that this cell response to CRISPR/Cas9 editing correlated strongly with the number of target loci. These observations indicate that genome targeting by CRISPR/Cas9 elicits a gene-independent antiproliferative cell response. This effect has important practical implications for the interpretation of CRISPR/Cas9 screening data and confounds the use of this technology for the identification of essential genes in amplified regions.SignificanceWe found that the number of CRISPR/Cas9-induced DNA breaks dictates a gene-independent antiproliferative response in cells. These observations have practical implications for using CRISPR/Cas9 to interrogate cancer gene function and illustrate that cancer cells are highly sensitive to site-specific DNA damage, which may provide a path to novel therapeutic strategies. Cancer Discov; 6(8); 914-29. ©2016 AACR.See related commentary by Sheel and Xue, p. 824See related article by Munoz et al., p. 900This article is highlighted in the In This Issue feature, p. 803.
| S-EPMC4972686 | biostudies-literature
Project description:The human salivary amylase genes display extensive copy number variation (CNV), and recent work has implicated this variation in adaptation to starch-rich diets, and in association with body mass index. In this work, we use paralogue ratio tests, microsatellite analysis, read depth and fibre-FISH to demonstrate that human amylase CNV is not a smooth continuum, but is instead partitioned into distinct haplotype classes. There is a fundamental structural distinction between haplotypes containing odd or even numbers of AMY1 gene units, in turn coupled to CNV in pancreatic amylase genes AMY2A and AMY2B. Most haplotypes have one copy each of AMY2A and AMY2B and contain an odd number of copies of AMY1; consequently, most individuals have an even total number of AMY1. In contrast, haplotypes carrying an even number of AMY1 genes have rearrangements leading to CNVs of AMY2A/AMY2B. Read-depth and experimental data show that different populations harbour different proportions of these basic haplotype classes. In Europeans, the copy numbers of AMY1 and AMY2A are correlated, so that phenotypic associations caused by variation in pancreatic amylase copy number could be detected indirectly as weak association with AMY1 copy number. We show that the quantitative polymerase chain reaction (qPCR) assay previously applied to the high-throughput measurement of AMY1 copy number is less accurate than the measures we use and that qPCR data in other studies have been further compromised by systematic miscalibration. Our results uncover new patterns in human amylase variation and imply a potential role for AMY2 CNV in functional associations.
| S-EPMC4498156 | biostudies-literature
Project description:Carbapenemase production is one of the leading mechanisms of carbapenem resistance in Gram-negative bacteria. An increase in carbapenemase gene (blaCarb) copies is an important mechanism of carbapenem resistance. No currently available bioinformatics tools allow for reliable detection and reporting of carbapenemase gene copy numbers. Here, we describe the carbapenemase-encoding gene copy number estimator (CCNE), a ready-to-use bioinformatics tool that was developed to estimate blaCarb copy numbers from whole-genome sequencing data. Its performance on Klebsiella pneumoniae carbapenemase gene (blaKPC) copy number estimation was evaluated by simulation and quantitative PCR (qPCR), and the results were compared with available algorithms. CCNE has two components, CCNE-acc and CCNE-fast. CCNE-acc detects blaCarb copy number in a comprehensive and high-accuracy way, while CCNE-fast rapidly screens blaCarb copy numbers. CCNE-acc achieved the best accuracy (100%) and the lowest root mean squared error (RMSE; 0.07) in simulated noise data sets, compared to the assembly-based method (23.4% accuracy, 1.697 RMSE) and the OrthologsBased method (78.9% accuracy, 0.395 RMSE). In the qPCR validation, a high consistency was observed between the blaKPC copy number determined by qPCR and that determined with CCNE. Reverse transcription-qPCR transcriptional analysis of 40 isolates showed that blaKPC expression was positively correlated with the blaKPC copy numbers detected by CCNE (P < 0.001). An association study of 357 KPC-producing K. pneumoniae isolates and their antimicrobial susceptibility identified a significant association between the estimated blaKPC copy number and MICs of imipenem (P < 0.001) and ceftazidime-avibactam (P < 0.001). Overall, CCNE is a useful genomic tool for the analysis of antimicrobial resistance genes copy number; it is available at https://github.com/biojiang/ccne. IMPORTANCE Globally disseminated carbapenem-resistant Enterobacterales is an urgent threat to public health. The most common carbapenem resistance mechanism is the production of carbapenemases. Carbapenemase-producing isolates often exhibit a wide range of carbapenem MICs. Higher carbapenem MICs have been associated with treatment failure. The increase of carbapenemase gene (blaCarb) copy numbers contributes to increased carbapenem MICs. However, blaCarb gene copy number detection is not routinely conducted during a genomic analysis, in part due to the lack of optimal bioinformatics tools. In this study, we describe a ready-to-use tool we developed and designated the carbapenemase-encoding gene copy number estimator (CCNE) that can be used to estimate the blaCarb copy number directly from whole-genome sequencing data, and we extended the data to support the analysis of all known blaCarb genes and some other antimicrobial resistance genes. Furthermore, CCNE can be used to interrogate the correlations between genotypes and susceptibility phenotypes and to improve our understanding of antimicrobial resistance mechanisms.
| S-EPMC9431437 | biostudies-literature