Genetic Variation in Parthenogenetic Collembolans Is Associated with Differences in Fitness and Cadmium-Induced Transcriptome Responses

Ecotoxicological tests may be biased by the use of laboratory strains that usually contain very limited genetic diversity. It is therefore essential to study how genetic variation influences stress tolerance relevant for toxicity outcomes. To that end we studied sensitivity to cadmium in two distinct genotypes of the parthogenetic soil ecotoxicological model organism <i>Folsomia candida</i>. Clonal lines of both genotypes (TO1 and TO2) showed divergent fitness responses to cadmium exposure; TO2 reproduction was 20% less affected by cadmium. Statistical analyses revealed significant differences between the cadmium-affected transcriptomes: i) the number of genes affected by cadmium in TO2 was only minor (∼22%) compared to TO1; ii) 97 genes showed a genotype × cadmium interaction and their response to cadmium showed globally larger fold changes in TO1 when compared to TO2; iii) the interaction genes showed a concerted manner of expression in TO1, while a less coordinated pattern was observed in TO2. We conclude that (1) there is genetic variation in parthenogenetic populations of <i>F. candida</i>, and (2) this variation affects life-history and molecular end points relative to cadmium toxicity. This sheds new light on the sources of biological variability in test results, even when the test organisms are thought to be genetically homogeneous because of their parthenogenetic reproduction

Genetic Variation in Parthenogenetic Collembolans Is Associated with Differences in Fitness and Cadmium-Induced Transcriptome Responses

Ecotoxicological tests may be biased by the use of laboratory strains that usually contain very limited genetic diversity. It is therefore essential to study how genetic variation influences stress tolerance relevant for toxicity outcomes. To that end we studied sensitivity to cadmium in two distinct genotypes of the parthogenetic soil ecotoxicological model organism <i>Folsomia candida</i>. Clonal lines of both genotypes (TO1 and TO2) showed divergent fitness responses to cadmium exposure; TO2 reproduction was 20% less affected by cadmium. Statistical analyses revealed significant differences between the cadmium-affected transcriptomes: i) the number of genes affected by cadmium in TO2 was only minor (∼22%) compared to TO1; ii) 97 genes showed a genotype × cadmium interaction and their response to cadmium showed globally larger fold changes in TO1 when compared to TO2; iii) the interaction genes showed a concerted manner of expression in TO1, while a less coordinated pattern was observed in TO2. We conclude that (1) there is genetic variation in parthenogenetic populations of <i>F. candida</i>, and (2) this variation affects life-history and molecular end points relative to cadmium toxicity. This sheds new light on the sources of biological variability in test results, even when the test organisms are thought to be genetically homogeneous because of their parthenogenetic reproduction

Excluded newly identified driver genes.

<p>Excluded newly identified driver genes.</p

Genes in focal losses with underexpression (FC<0.75, A) and in focal gains with overexpression (FC>1.5, B) in more than 35% of osteosarcomas.

<p>Green: expression fold change (FC) <0.75 of the gene in the tumor relative to osteoblasts (underexpression). Red: expression fold change (FC) >1.50 of the gene in the tumor relative to osteoblasts (overexpression). For each gene, the number (n) and fraction (%) of osteosarcomas with the indicated fold change (FC) are given.</p

Genome-wide frequency plot of all copy number aberrations (top) and of focal copy number aberrations (bottom) in 26 osteosarcoma samples.

<p>Frequencies of gains (in red) and losses (in blue) are indicated. Vertical bars in B represent detected focal copy number aberrations (<3 Mb).</p

High frequency regions (HFRs) of focal aberrations and gene(s) within or overlapping these HFRs.

1<p>HFR: common region of focal aberration (gain or loss);</p>2<p>Focal: number of samples with focal aberration;</p>3<p>Total: total number of samples containing the HFR of the focal aberration. Genes in bold have been reported in the Cancer Gene Census list.</p><p>High frequency regions (HFRs) of focal aberrations and gene(s) within or overlapping these HFRs.</p

Representative examples of focal copy number aberrations.

<p>Log2ratio for each SNP is plotted against its genomic location. Gray lines indicate segment values as derived using circular binary segmentation (CBS). A, Focal deletion encompassing<i>PAPSS2</i>, <i>AFDC1</i>, and <i>PTEN</i> on chromosome 10; B, Focal deletion restricted to <i>NBEA</i> on chromosome 13; C, Focal gain including <i>POU5F1P1</i>, <i>MYC</i>, and <i>TMEM75</i> on chromosome 8.</p

Validation of identified candidate tumor suppressor genes and oncogenes in an independent dataset.

<p>Frequency of involvement (percentage underexpression of a candidate tumorsuppressor gene and percentage overexpression of a candidate oncogene) in the original and validation set</p><p>Known tumor suppressor genes (<i>DOCK5</i>, <i>PTEN</i>) and oncogene (<i>MYC</i>) between brackets</p>1<p>No information. Applied probe does not recognize <i>ODZ3</i> in 4q35.1</p>2<p>No information. Applied probe recognizes not only <i>PTEN</i> on 10q23.31, but also the expressed pseudogene (<i>PTENP1</i>) in 9p13.3.</p><p>Validation of identified candidate tumor suppressor genes and oncogenes in an independent dataset.</p

Clinicopathological characteristics of patients and tumors.

<p>Clinicopathological characteristics of patients and tumors.</p

Lack of Genomic Heterogeneity at High-Resolution aCGH between Primary Breast Cancers and Their Paired Lymph Node Metastases

<div><p>Lymph-node metastasis (LNM) predict high recurrence rates in breast cancer patients. Systemic treatment aims to eliminate (micro)metastatic cells. However decisions regarding systemic treatment depend largely on clinical and molecular characteristics of primary tumours. It remains, however, unclear to what extent metastases resemble the cognate primary breast tumours, especially on a genomic level, and as such will be eradicated by the systemic therapy chosen. In this study we used high-resolution aCGH to investigate DNA copy number differences between primary breast cancers and their paired LNMs. To date, no recurrent LNM-specific genomic aberrations have been identified using array comparative genomic hybridization (aCGH) analysis. In our study we employ a high-resolution platform and we stratify on different breast cancer subtypes, both aspects that might have underpowered previously performed studies.To test the possibility that genomic instability in triple-negative breast cancers (TNBCs) might cause increased random and potentially also recurrent copy number aberrations (CNAs) in their LNMs, we studied 10 primary TNBC–LNM pairs and 10 ER-positive (ER+) pairs and verified our findings adding additionally 5 TNBC-LNM and 22 ER+-LNM pairs. We found that all LNMs clustered nearest to their matched tumour except for two cases, of which one was due to the presence of two distinct histological components in one tumour. We found no significantly altered CNAs between tumour and their LNMs in the entire group or in the subgroups. Within the TNBC subgroup, no absolute increase in CNAs was found in the LNMs compared to their primary tumours, suggesting that increased genomic instability does not lead to more CNAs in LNMs. Our findings suggest a high clonal relationship between primary breast tumours and its LNMs, at least prior to treatment, and support the use of primary tumour characteristics to guide adjuvant systemic chemotherapy in breast cancer patients.</p></div