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1.  Mycobacterium chelonae-abscessus Complex Associated with Sinopulmonary Disease, Northeastern USA 
Emerging Infectious Diseases  2011;17(9):1692-1700.
doi:10.3201/eid1709.101667
PMCID: PMC3322061  PMID: 21888796
bacteria; rapid-growing mycobacteria; multilocus sequencing; Mycobacterium chelonae-abscessus complex; Mycobacterium franklinii; sinopulmonary disease; tuberculosis and other mycobacteria; United States; CME; research; Suggested citation for this article: Simmon KE; Brown-Elliott BA; Ridge PG; Durtschi JD; Mann LB; Slechta ES; et al. Mycobacterium chelonae-abscessus complex associated with sinopulmonary disease; northeastern USA. Emerg Infect Dis [serial on the Internet]. 2011 Sep [date cited]. http://dx.doi.org/10.3201/eid1709.101667
2.  Genetics of Alzheimer's Disease 
BioMed Research International  2013;2013:254954.
Alzheimer's disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer's disease, early onset and the more common late onset. The genetics of early-onset Alzheimer's disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer's disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer's disease.
doi:10.1155/2013/254954
PMCID: PMC3741956  PMID: 23984328
3.  Genome-Wide Association Study of CSF Levels of 59 Alzheimer's Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation 
PLoS Genetics  2014;10(10):e1004758.
Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10−10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.
Author Summary
The use of quantitative endophenotypes from cerebrospinal fluid has led to the identification of several genetic variants that alter risk or rate of progression of Alzheimer's disease. Here we have analyzed the levels of 58 disease-related proteins in the cerebrospinal fluid for association with millions of variants across the human genome. We have identified significant, replicable associations with 5 analytes, Angiotensin-converting enzyme, Chemokine (C-C motif) ligand 2, Chemokine (C-C motif) ligand 4, Interleukin 6 receptor and Matrix metalloproteinase-3. Our results suggest that these variants play a regulatory role in the respective protein levels and are relevant to the inflammatory and amyloid processing pathways. Variants in associated with ACE and those associated with MMP3 levels also show association with risk for Alzheimer's disease in the expected directions. These associations are consistent in cerebrospinal fluid and plasma and in samples with only cognitively normal individuals suggesting that they are relevant in the regulation of these protein levels beyond the context of Alzheimer's disease.
doi:10.1371/journal.pgen.1004758
PMCID: PMC4207667  PMID: 25340798
4.  Cystic fibrosis testing in a referral laboratory: results and lessons from a six-year period 
Background
The recent introduction of high throughput sequencing technologies into clinical genetics has made it practical to simultaneously sequence many genes. In contrast, previous technologies limited sequencing based tests to only a handful of genes. While the ability to more accurately diagnose inherited diseases is a great benefit it introduces specific challenges. Interpretation of missense mutations continues to be challenging and the number of variants of uncertain significance continues to grow.
Results
We leveraged the data available at ARUP Laboratories, a major reference laboratory, for the CFTR gene to explore specific challenges related to variant interpretation, including a focus on understanding ethnic-specific variants and an evaluation of existing databases for clinical interpretation of variants. In this study we analyzed 555 patients representing eight different ethnic groups. We observed 184 different variants, most of which were ethnic group specific. Eighty-five percent of these variants were present in the Cystic Fibrosis Mutation Database, whereas the Human Mutation Database and dbSNP/1000 Genomes had far fewer of the observed variants. Finally, 21 of the variants were novel and we report these variants and their clinical classifications.
Conclusions
Based on our analyses of data from six years of CFTR testing at ARUP Laboratories a more comprehensive, clinical grade database is needed for the accurate interpretation of observed variants. Furthermore, there is a particular need for more and better information regarding variants from individuals of non-Caucasian ethnicity.
doi:10.1186/2043-9113-3-3
PMCID: PMC3563502  PMID: 23343000
Cystic fibrosis; CFTR; Novel variants; Next-generation sequencing; Interpretation of variants
5.  A direct comparison of next generation sequencing enrichment methods using an aortopathy gene panel- clinical diagnostics perspective 
BMC Medical Genomics  2012;5:50.
Background
Aortopathies are a group of disorders characterized by aneurysms, dilation, and tortuosity of the aorta. Because of the phenotypic overlap and genetic heterogeneity of diseases featuring aortopathy, molecular testing is often required for timely and correct diagnosis of affected individuals. In this setting next generation sequencing (NGS) offers several advantages over traditional molecular techniques.
Methods
The purpose of our study was to compare NGS enrichment methods for a clinical assay targeting the nine genes known to be associated with aortopathy. RainDance emulsion PCR and SureSelect RNA-bait hybridization capture enrichment methods were directly compared by enriching DNA from eight samples. Enriched samples were barcoded, pooled, and sequenced on the Illumina HiSeq2000 platform. Depth of coverage, consistency of coverage across samples, and the overlap of variants identified were assessed. This data was also compared to whole-exome sequencing data from ten individuals.
Results
Read depth was greater and less variable among samples that had been enriched using the RNA-bait hybridization capture enrichment method. In addition, samples enriched by hybridization capture had fewer exons with mean coverage less than 10, reducing the need for followup Sanger sequencing. Variants sets produced were 77% concordant, with both techniques yielding similar numbers of discordant variants.
Conclusions
When comparing the design flexibility, performance, and cost of the targeted enrichment methods to whole-exome sequencing, the RNA-bait hybridization capture enrichment gene panel offers the better solution for interrogating the aortopathy genes in a clinical laboratory setting.
doi:10.1186/1755-8794-5-50
PMCID: PMC3534588  PMID: 23148498
Aortopathy; Hybridization capture; Marfan syndrome; Next generation sequencing (NGS); Target enrichment; Emulsion PCR
6.  Rare coding variants in Phospholipase D3 (PLD3) confer risk for Alzheimer's disease 
Nature  2013;505(7484):550-554.
Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD)1,2. These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low frequency coding variants with large effects on LOAD risk, we performed whole exome-sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large case-control datasets. A rare variant in PLD3 (phospholipase-D family, member 3, rs145999145; V232M) segregated with disease status in two independent families and doubled risk for AD in seven independent case-control series (V232M meta-analysis; OR= 2.10, CI=1.47-2.99; p= 2.93×10-5, 11,354 cases and controls of European-descent). Gene-based burden analyses in 4,387 cases and controls of European-descent and 302 African American cases and controls, with complete sequence data for PLD3, indicate that several variants in this gene increase risk for AD in both populations (EA: OR= 2.75, CI=2.05-3.68; p=1.44×10-11, AA: OR= 5.48, CI=1.77-16.92; p=1.40×10-3). PLD3 is highly expressed in brain regions vulnerable to AD pathology, including hippocampus and cortex, and is expressed at lower levels in neurons from AD brains compared to control brains (p=8.10×10-10). Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular Aβ42 and Aβ40, while knock-down of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a two-fold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may be used to identify rare variants with large effects on risk for disease or other complex traits.
doi:10.1038/nature12825
PMCID: PMC4050701  PMID: 24336208
7.  Consensus: a framework for evaluation of uncertain gene variants in laboratory test reporting 
Genome Medicine  2012;4(5):48.
Accurate interpretation of gene testing is a key component in customizing patient therapy. Where confirming evidence for a gene variant is lacking, computational prediction may be employed. A standardized framework, however, does not yet exist for quantitative evaluation of disease association for uncertain or novel gene variants in an objective manner. Here, complementary predictors for missense gene variants were incorporated into a weighted Consensus framework that includes calculated reference intervals from known disease outcomes. Data visualization for clinical reporting is also discussed.
doi:10.1186/gm347
PMCID: PMC3506914  PMID: 22640420
8.  Variant Tool Chest: an improved tool to analyze and manipulate variant call format (VCF) files 
BMC Bioinformatics  2014;15(Suppl 7):S12.
Background
Since the advent of next-generation sequencing many previously untestable hypotheses have been realized. Next-generation sequencing has been used for a wide range of studies in diverse fields such as population and medical genetics, phylogenetics, microbiology, and others. However, this novel technology has created unanticipated challenges such as the large numbers of genetic variants. Each caucasian genome has more than four million single nucleotide variants, insertions and deletions, copy number variants, and structural variants. Several formats have been suggested for storing these variants; however, the variant call format (VCF) has become the community standard.
Results
We developed new software called the Variant Tool Chest (VTC) to provide much needed tools to work with VCF files. VTC provides a variety of tools for manipulating, comparing, and analyzing VCF files beyond the functionality of existing tools. In addition, VTC was written to be easily extended with new tools.
Conclusions
Variant Tool Chest brings new and important functionality that complements and integrates well with existing software. VTC is available at https://github.com/mebbert/VariantToolChest
doi:10.1186/1471-2105-15-S7-S12
PMCID: PMC4110736  PMID: 25080132
9.  Population substructure in Cache County, Utah: the Cache County study 
BMC Bioinformatics  2014;15(Suppl 7):S8.
Background
Population stratification is a key concern for genetic association analyses. In addition, extreme homogeneity of ethnic origins of a population can make it difficult to interpret how genetic associations in that population may translate into other populations. Here we have evaluated the genetic substructure of samples from the Cache County study relative to the HapMap Reference populations and data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).
Results
Our findings show that the Cache County study is similar in ethnic diversity to the self-reported "Whites" in the ADNI sample and less homogenous than the HapMap CEU population.
Conclusions
We conclude that the Cache County study is genetically representative of the general European American population in the USA and is an appropriate population for conducting broadly applicable genetic studies.
doi:10.1186/1471-2105-15-S7-S8
PMCID: PMC4110730  PMID: 25078123
10.  Mitochondrial genomic variation associated with higher mitochondrial copy number: the Cache County Study on Memory Health and Aging 
BMC Bioinformatics  2014;15(Suppl 7):S6.
Background
The mitochondria are essential organelles and are the location of cellular respiration, which is responsible for the majority of ATP production. Each cell contains multiple mitochondria, and each mitochondrion contains multiple copies of its own circular genome. The ratio of mitochondrial genomes to nuclear genomes is referred to as mitochondrial copy number. Decreases in mitochondrial copy number are known to occur in many tissues as people age, and in certain diseases. The regulation of mitochondrial copy number by nuclear genes has been studied extensively. While mitochondrial variation has been associated with longevity and some of the diseases known to have reduced mitochondrial copy number, the role that the mitochondrial genome itself has in regulating mitochondrial copy number remains poorly understood.
Results
We analyzed the complete mitochondrial genomes from 1007 individuals randomly selected from the Cache County Study on Memory Health and Aging utilizing the inferred evolutionary history of the mitochondrial haplotypes present in our dataset to identify sequence variation and mitochondrial haplotypes associated with changes in mitochondrial copy number. Three variants belonging to mitochondrial haplogroups U5A1 and T2 were significantly associated with higher mitochondrial copy number in our dataset.
Conclusions
We identified three variants associated with higher mitochondrial copy number and suggest several hypotheses for how these variants influence mitochondrial copy number by interacting with known regulators of mitochondrial copy number. Our results are the first to report sequence variation in the mitochondrial genome that causes changes in mitochondrial copy number. The identification of these variants that increase mtDNA copy number has important implications in understanding the pathological processes that underlie these phenotypes.
doi:10.1186/1471-2105-15-S7-S6
PMCID: PMC4110732  PMID: 25077862
11.  Alzheimer’s Disease: Analyzing the Missing Heritability 
PLoS ONE  2013;8(11):e79771.
Alzheimer’s disease (AD) is a complex disorder influenced by environmental and genetic factors. Recent work has identified 11 AD markers in 10 loci. We used Genome-wide Complex Trait Analysis to analyze >2 million SNPs for 10,922 individuals from the Alzheimer’s Disease Genetics Consortium to assess the phenotypic variance explained first by known late-onset AD loci, and then by all SNPs in the Alzheimer’s Disease Genetics Consortium dataset. In all, 33% of total phenotypic variance is explained by all common SNPs. APOE alone explained 6% and other known markers 2%, meaning more than 25% of phenotypic variance remains unexplained by known markers, but is tagged by common SNPs included on genotyping arrays or imputed with HapMap genotypes. Novel AD markers that explain large amounts of phenotypic variance are likely to be rare and unidentifiable using genome-wide association studies. Based on our findings and the current direction of human genetics research, we suggest specific study designs for future studies to identify the remaining heritability of Alzheimer’s disease.
doi:10.1371/journal.pone.0079771
PMCID: PMC3820606  PMID: 24244562
12.  Strong Evidence for a Genetic Contribution to Late-Onset Alzheimer’s Disease Mortality: A Population-Based Study 
PLoS ONE  2013;8(10):e77087.
Background
Alzheimer’s disease (AD) is an international health concern that has a devastating effect on patients and families. While several genetic risk factors for AD have been identified much of the genetic variance in AD remains unexplained. There are limited published assessments of the familiality of Alzheimer’s disease. Here we present the largest genealogy-based analysis of AD to date.
Methods
We assessed the familiality of AD in The Utah Population Database (UPDB), a population-based resource linking electronic health data repositories for the state with the computerized genealogy of the Utah settlers and their descendants. We searched UPDB for significant familial clustering of AD to evaluate the genetic contribution to disease. We compared the Genealogical Index of Familiality (GIF) between AD individuals and randomly selected controls and estimated the Relative Risk (RR) for a range of family relationships. Finally, we identified pedigrees with a significant excess of AD deaths.
Results
The GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected. This excess of relatedness was observed for both close and distant relationships. RRs for death from AD among relatives of individuals dying from AD were significantly increased for both close and more distant relatives. Multiple pedigrees had a significant excess of AD deaths.
Conclusions
These data strongly support a genetic contribution to the observed clustering of individuals dying from AD. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases) and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified.
doi:10.1371/journal.pone.0077087
PMCID: PMC3792903  PMID: 24116205
13.  Mitochondrial Haplotypes Associated with Biomarkers for Alzheimer’s Disease 
PLoS ONE  2013;8(9):e74158.
Various studies have suggested that the mitochondrial genome plays a role in late-onset Alzheimer’s disease, although results are mixed. We used an endophenotype-based approach to further characterize mitochondrial genetic variation and its relationship to risk markers for Alzheimer’s disease. We analyzed longitudinal data from non-demented, mild cognitive impairment, and late-onset Alzheimer’s disease participants in the Alzheimer’s Disease Neuroimaging Initiative with genetic, brain imaging, and behavioral data. We assessed the relationship of structural MRI and cognitive biomarkers with mitochondrial genome variation using TreeScanning, a haplotype-based approach that concentrates statistical power by analyzing evolutionarily meaningful groups (or clades) of haplotypes together for association with a phenotype. Four clades were associated with three different endophenotypes: whole brain volume, percent change in temporal pole thickness, and left hippocampal atrophy over two years. This is the first study of its kind to identify mitochondrial variation associated with brain imaging endophenotypes of Alzheimer’s disease. Our results provide additional evidence that the mitochondrial genome plays a role in risk for Alzheimer’s disease.
doi:10.1371/journal.pone.0074158
PMCID: PMC3770576  PMID: 24040196
14.  Mitochondrial Genomic Analysis of Late Onset Alzheimer’s Disease Reveals Protective Haplogroups H6A1A/H6A1B: The Cache County Study on Memory in Aging 
PLoS ONE  2012;7(9):e45134.
Background
Alzheimer’s disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain.
Methodology/Principal Findings
We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p = 0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status.
Conclusions/Significance
Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary.
doi:10.1371/journal.pone.0045134
PMCID: PMC3444479  PMID: 23028804
15.  Association and Expression analyses with SNPs in TOMM40 in Alzheimer’s Disease 
Archives of neurology  2011;68(8):1013-1019.
Objectives
Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer’s disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all of the association signal is derived from APOE or if there is an independent signal from a nearby gene. In this study we attempted to replicate a recently reported association of APOE 3-TOMM40 haplotypes with risk and age at onset.
Design
We used standard techniques to genotype several polymorphisms in the APOE-TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data and in brain tissue.
Results
We failed to replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk for LOAD among APOE 33 homozygotes but in the opposite direction to the previously reported association (the very-long allele was underrepresented in cases compared to controls in our study (allele frequency: 0.41 vs. 0.48 respectively; p=0.004)). We found no association between rs10524523 and CSF tau or Aβ42 levels or TOMM40 or APOE gene expression.
Conclusions
Although we were not able to replicate the earlier association between the APOE 3-TOMM40 haplotypes and age at onset, we did observe that the polyT polymorphism is associated with risk for LOAD among APOE 33 homozygotes in a large case-control series, but in the opposite direction to the previous report. Additional studies in very large samples will be needed to confirm this association.
doi:10.1001/archneurol.2011.155
PMCID: PMC3204798  PMID: 21825236
16.  Composition and Evolution of the Vertebrate and Mammalian Selenoproteomes 
PLoS ONE  2012;7(3):e33066.
Background
Selenium is an essential trace element in mammals due to its presence in proteins in the form of selenocysteine (Sec). Human genome codes for 25 Sec-containing protein genes, and mouse and rat genomes for 24.
Methodology/Principal Findings
We characterized the selenoproteomes of 44 sequenced vertebrates by applying gene prediction and phylogenetic reconstruction methods, supplemented with the analyses of gene structures, alternative splicing isoforms, untranslated regions, SECIS elements, and pseudogenes. In total, we detected 45 selenoprotein subfamilies. 28 of them were found in mammals, and 41 in bony fishes. We define the ancestral vertebrate (28 proteins) and mammalian (25 proteins) selenoproteomes, and describe how they evolved along lineages through gene duplication (20 events), gene loss (10 events) and replacement of Sec with cysteine (12 events). We show that an intronless selenophosphate synthetase 2 gene evolved in early mammals and replaced functionally the original multiexon gene in placental mammals, whereas both genes remain in marsupials. Mammalian thioredoxin reductase 1 and thioredoxin-glutathione reductase evolved from an ancestral glutaredoxin-domain containing enzyme, still present in fish. Selenoprotein V and GPx6 evolved specifically in placental mammals from duplications of SelW and GPx3, respectively, and GPx6 lost Sec several times independently. Bony fishes were characterized by duplications of several selenoprotein families (GPx1, GPx3, GPx4, Dio3, MsrB1, SelJ, SelO, SelT, SelU1, and SelW2). Finally, we report identification of new isoforms for several selenoproteins and describe unusually conserved selenoprotein pseudogenes.
Conclusions/Significance
This analysis represents the first comprehensive survey of the vertebrate and mammal selenoproteomes, and depicts their evolution along lineages. It also provides a wealth of information on these selenoproteins and their forms.
doi:10.1371/journal.pone.0033066
PMCID: PMC3316567  PMID: 22479358
17.  Predicting Phenotypic Severity of Uncertain Gene Variants in the RET Proto-Oncogene 
PLoS ONE  2011;6(3):e18380.
Although reported gene variants in the RET oncogene have been directly associated with multiple endocrine neoplasia type 2 and hereditary medullary thyroid carcinoma, other mutations are classified as variants of uncertain significance (VUS) until the associated clinical phenotype is made clear. Currently, some 46 non-synonymous VUS entries exist in curated archives. In the absence of a gold standard method for predicting phenotype outcomes, this follow up study applies feature selected amino acid physical and chemical properties feeding a Bayes classifier to predict disease association of uncertain gene variants into categories of benign and pathogenic. Algorithm performance and VUS predictions were compared to established phylogenetic based mutation prediction algorithms. Curated outcomes and unpublished RET gene variants with known disease association were used to benchmark predictor performance. Reliable classification of RET uncertain gene variants will augment current clinical information of RET mutations and assist in improving prediction algorithms as knowledge increases.
doi:10.1371/journal.pone.0018380
PMCID: PMC3068179  PMID: 21479187
18.  Comparative Genomic Analyses of Copper Transporters and Cuproproteomes Reveal Evolutionary Dynamics of Copper Utilization and Its Link to Oxygen 
PLoS ONE  2008;3(1):e1378.
Copper is an essential trace element in many organisms and is utilized in all domains of life. It is often used as a cofactor of redox proteins, but is also a toxic metal ion. Intracellular copper must be carefully handled to prevent the formation of reactive oxygen species which pose a threat to DNA, lipids, and proteins. In this work, we examined patterns of copper utilization in prokaryotes by analyzing the occurrence of copper transporters and copper-containing proteins. Many organisms, including those that lack copper-dependent proteins, had copper exporters, likely to protect against copper ions that inadvertently enter the cell. We found that copper use is widespread among prokaryotes, but also identified several phyla that lack cuproproteins. This is in contrast to the use of other trace elements, such as selenium, which shows more scattered and reduced usage, yet larger selenoproteomes. Copper transporters had different patterns of occurrence than cuproproteins, suggesting that the pathways of copper utilization and copper detoxification are independent of each other. We present evidence that organisms living in oxygen-rich environments utilize copper, whereas the majority of anaerobic organisms do not. In addition, among copper users, cuproproteomes of aerobic organisms were larger than those of anaerobic organisms. Prokaryotic cuproproteomes were small and dominated by a single protein, cytochrome c oxidase. The data are consistent with the idea that proteins evolved to utilize copper following the oxygenation of the Earth.
doi:10.1371/journal.pone.0001378
PMCID: PMC2147054  PMID: 18167539

Results 1-18 (18)