Recovery rate of deletions (red) and duplications (blue) from PennCNV using simulated intensity measurements as a function of CNV size.

<p>Recovery rate of deletions (red) and duplications (blue) from PennCNV using simulated intensity measurements as a function of CNV size.</p

Simulated statistical power to detect an association with a putative CNV as a function of false negative rate (ν_n).

<p>The CNV explains 1% of the phenotypic variation when present in 20% of the population. The CNV has a frequency of 1% (red), 5% (orange), 10% (green), or 20% (blue). False positive rate (ν_p) is zero.</p

Square root of the variance of Δ for the multiallelic CNV locus with and false negative (ν_n) and false positive error rates (ν_p).

<p>Square root of the variance of Δ for the multiallelic CNV locus with and false negative (ν_n) and false positive error rates (ν_p).</p

Square root of the variance of Δ for the deletion and duplication CNV loci with and false negative (ν_n) and false positive error rates (ν_p).

<p>Square root of the variance of Δ for the deletion and duplication CNV loci with and false negative (ν_n) and false positive error rates (ν_p).</p

ApoE genotypes by LRP-1 <i>I10701</i> genotype.

<p>ApoE genotypes by LRP-1 <i><u>I10701</u></i> genotype.</p

Parameter estimates from linear regression models looking at the effects of <i>LRP-1</i> I10701 SNP and <i>ApoE</i> isoforms on BMI in the GOLDN study population.

a<p><i>P</i>-values were derived from mixed linear models, specifying a Kenward Rogers correction on the estimator, with <i>LRP-1</i> I10701 SNP and <i>ApoE</i> genotype frequency, an interaction between ApoE and LRP-1 genotype frequency, age and age², sex, smoking, total alcohol and center of data collection as predictors, and BMI (logarithmically transformed) as the outcome.</p

N, mean age (standard deviation) and percentage of males and ApoE ε3 carriers, in the GOLDN study population by LRP-1 genotype group.

†<p>a = minor allele; A = major allele.</p>‡<p><i>P</i>-values were derived from tests of null hypothesis that no group is different, using a 1-way ANOVA for continuous traits or the χ² test for categorical variables.</p

POLG1 expression in primary breast tumors.

<p>Oncomine database analysis of POLG1 upregulation (A) and downregulation (B) in normal (N) versus tumor (T) human tissues. <b>A.</b> Increased POLG1 expression in salivary gland, myeloma, pancreas, kidney, skin, prostate and colorectal cancer. <b>B.</b> Decreased POLG1 expression in lung, head & neck, brain, bladder, cervix, leukemia and esophageal cancer. <b>C.</b> Oncomine database analysis of POLG1 expression in human breast cancer. POLG1 expression is significantly increased in both invasive and ductal breast carcinoma compared to normal breast tissues. <b>D.</b> Immunohistochemical (IHC) analysis of POLG1 expression in benign breast tissue, breast carcinoma and metastatic carcinomas in regional lymph nodes on tissue array containing 53 breast tissue cores with an anti-POLG1 antibody. <b>I & II.</b> Benign liver tissue incubated with (<b>II</b>) and without (<b>I</b>) POLG1 antibody serving as positive and negative control, respectively. <b>III & IV.</b> Representative non-neoplastic breast tissue from patients without and with breast carcinomas, respectively. <b>V & VI.</b> Representative low and high grade ductal carcinoma in situ (DCIS), respectively. Notice high expression of POLG1 in DCIS (arrow) compared to low level of expression in non-neoplastic ducts (arrow head). <b>VII & VIII.</b> Representative low and high grade invasive duct carcinoma (IDC) cases, respectively. <b>IX.</b> Representative invasive lobular carcinoma (ILC) case. <b>X.</b> Representative metastatic breast carcinoma in regional lymph node (LN met). Notice high expression of POLG1 in metastatic tumor (arrow) compared to low level of expression in lymhocytes (arrow head). POLG1 protein was visualized using DAB with hematoxylin counterstain. <b>E.</b> Graph representing the percentage of different immunohistochemistry score of immunoreactivity for POLG1 expression in benign breast tissue, DCIS, IDC, ILC, and LN met. IHC analysis was done on tissue array containing 53 breast tissue cores with anti-POLG1 antibody. Note high expression (score +++) of POLG1 protein in DCIS, IDC, ILC, and LN met compared to benign breast tissues. <b>F.</b> Representative gel pictures from RT PCR study of <i>POLG1</i> mRNA expression in a different set of control breast and breast tumor samples. Decreased expression of <i>POLG1</i> mRNA in two breast tumors and increased in other two breast tumors compared to normal breast tissues are represented here.</p

<i>POLG1</i> is frequently mutated in primary tumors.

<p><b>A.</b> Distribution of different types of variations such as mutations, deletions and amplifications in <i>POLG1</i> gene in different human cancers were analyzed using cBioPortal database and represented here as a bar graph. <b>B.</b> All the reported somatic mutations in human POLG1 in different human tumors were analyzed from Cosmic database as well as from published studies [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139846#pone.0139846.ref021" target="_blank">21</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139846#pone.0139846.ref022" target="_blank">22</a>] and a schematic showing location of these tumor somatic mutations in human POLG1 protein is presented here. <b>C.</b> Distribution pattern of different types of somatic mutations in POLG1 in human cancers was analyzed using Cosmic database and is presented here as a pie chart.</p

Functional analyses of <i>POLG1</i> variants and mutations.

<p><b>A.</b> Mitochondria-specific functionality of disease causing human POLG1 germline variants E1143G, T251I and P587L as well as double mutants (T251I/P587L) was analyzed using yeast petite formation assay. Individual expression as well as expression of double mutants in yeast increase petite mutants formation. <b>B.</b> Cellular ATP levels in POLG1 E1143G stable cells treated with 1000 ng/ml dox for 10 days. <b>C.</b> Glucose consumption in POLG E1143G stable cells treated with 1000 ng/ml dox for 10 days. <b>D & E.</b> Functionality of a site directed mutation (D1135A) in the conserved region of the polymerase domain of human POLG1 was analyzed. ATP levels (<b>D</b>) and glucose consumption (<b>E</b>) in POLG1 D1135A stable cells treated with 1000 ng/ml dox for 10 days. Bars represent the mean ± s.d. *<i>P</i> < 0.05; Student's t-test.</p