Context-dependent effects of whole-genome duplication during mammary tumor recurrence

AbstractWhole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor types, suggesting a functional role for polyploidy in tumor progression. Experimental evidence suggests that polyploidy has both tumor-promoting and suppressing effects, but how polyploidy regulates tumor progression remains unclear. Using a genetically engineered mouse model of Her2-driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. While primary tumors in this model are invariably diploid, nearly 40% of recurrent tumors undergo WGD. WGD in recurrent tumors was associated with increased chromosomal instability, decreased proliferation and increased survival in stress conditions. The effects of WGD on tumor growth were dependent on tumor stage. Surprisingly, in recurrent tumor cells WGD slowed tumor formation, growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. These findings highlight the importance of identifying conditions that promote the growth of polyploid tumors, including the cooperating genetic mutations that allow cells to overcome the barriers to WGD tumor cell growth and proliferation.

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Context-dependent effects of whole-genome duplication during mammary tumor recurrence

10.1101/2021.05.03.442527 ◽

2021 ◽

Author(s):

Rachel Newcomb ◽

Emily Dean ◽

James V Alvarez

Keyword(s):

Tumor Growth ◽

Tumor Progression ◽

Whole Genome Duplication ◽

Genome Duplication ◽

Tumor Formation ◽

Genetically Engineered ◽

Whole Genome ◽

Primary Tumors ◽

Recurrent Tumors ◽

Genetically Engineered Mouse Model

Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor types, suggesting a functional role for polyploidy in tumor progression. Experimental evidence suggests that polyploidy has both tumor-promoting and suppressing effects, but how polyploidy regulates tumor progression remains unclear. Using a genetically engineered mouse model of Her2-driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. While primary tumors in this model are invariably diploid, nearly 40% of recurrent tumors undergo WGD. WGD in recurrent tumors was associated with increased chromosomal instability, decreased proliferation and increased survival in stress conditions. The effects of WGD on tumor growth were dependent on tumor stage. Surprisingly, in recurrent tumor cells WGD slowed tumor formation, growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. These findings highlight the importance of identifying conditions that promote the growth of polyploid tumors, including the cooperating genetic mutations that allow cells to overcome the barriers to WGD tumor cell growth and proliferation.

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Adaptation and Selection Shape Clonal Evolution During Residual Disease and Recurrence

10.1101/2020.04.22.055780 ◽

2020 ◽

Author(s):

Andrea Walens ◽

Jiaxing Lin ◽

Jeffrey S. Damrauer ◽

Ryan Lupo ◽

Rachel Newcomb ◽

...

Keyword(s):

De Novo ◽

Residual Disease ◽

Tumor Regression ◽

Clonal Evolution ◽

Genetic Alterations ◽

Genetically Engineered ◽

Primary Tumors ◽

Recurrent Tumors ◽

Genetically Engineered Mouse Model ◽

Clonal Composition

SummaryThe survival of residual tumor cells following therapy and their eventual recurrence constitutes one of the biggest obstacles to obtaining cures in breast cancer, but it remains unclear how the clonal composition of tumors changes during tumor relapse. We used cellular barcoding to directly monitor clonal dynamics during tumor recurrence in a genetically engineered mouse model. We found that the clonal diversity of tumors progressively decreased during tumor regression, residual disease, and recurrence. Only a fraction of subclones survived oncogene withdrawal and persisted in residual tumors. The minimal residual disease phase itself was accompanied by a continued attrition of clones, suggesting an ongoing process of selection during dormancy. The reactivation of dormant residual cells into recurrent tumors followed several distinct evolutionary routes. Approximately half of the recurrent tumors exhibited a striking clonal dominance in which one or two subclones comprised the vast majority of the tumor. The majority of these clonal recurrent tumors exhibited evidence of de novo acquisition of Met amplification, and were sensitive to small-molecule Met inhibitors. A second group of recurrent tumors exhibited marked polyclonality, with thousands of subclones and a clonal architecture very similar to primary tumors. These polyclonal recurrent tumors were not sensitive to Met inhibitors, but were instead dependent upon an autocrine IL-6 – Stat3 pathway. These results suggest that the survival and reactivation of dormant tumors can proceed via multiple independent routes, producing recurrent tumors with distinct clonal composition, genetic alterations, and drug sensitivities.

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Faculty Opinions recommendation of Reciprocal gene loss following experimental whole-genome duplication causes reproductive isolation in yeast.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.10069956.10824063 ◽

2011 ◽

Author(s):

Santiago F Elena ◽

Stéphanie Bedhomme

Keyword(s):

Reproductive Isolation ◽

Whole Genome Duplication ◽

Gene Loss ◽

Genome Duplication ◽

Whole Genome

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Phylogenetic Analysis of T-Box Genes Demonstrates the Importance of Amphioxus for Understanding Evolution of the Vertebrate Genome

Genetics ◽

10.1093/genetics/156.3.1249 ◽

2000 ◽

Vol 156 (3) ◽

pp. 1249-1257

Author(s):

Ilya Ruvinsky ◽

Lee M Silver ◽

Jeremy J Gibson-Brown

Keyword(s):

Phylogenetic Analysis ◽

Whole Genome Duplication ◽

Genome Duplication ◽

Gene Families ◽

Vertebrate Evolution ◽

Whole Genome ◽

Vertebrate Genome ◽

T Box ◽

Genetic Complexity ◽

History Of

Abstract The duplication of preexisting genes has played a major role in evolution. To understand the evolution of genetic complexity it is important to reconstruct the phylogenetic history of the genome. A widely held view suggests that the vertebrate genome evolved via two successive rounds of whole-genome duplication. To test this model we have isolated seven new T-box genes from the primitive chordate amphioxus. We find that each amphioxus gene generally corresponds to two or three vertebrate counterparts. A phylogenetic analysis of these genes supports the idea that a single whole-genome duplication took place early in vertebrate evolution, but cannot exclude the possibility that a second duplication later took place. The origin of additional paralogs evident in this and other gene families could be the result of subsequent, smaller-scale chromosomal duplications. Our findings highlight the importance of amphioxus as a key organism for understanding evolution of the vertebrate genome.

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Comparative Mapping Between Coho Salmon (Oncorhynchus kisutch) and Three Other Salmonids Suggests a Role for Chromosomal Rearrangements in the Retention of Duplicated Regions Following a Whole Genome Duplication Event

G3 Genes|Genome|Genetics ◽

10.1534/g3.114.012294 ◽

2014 ◽

Vol 4 (9) ◽

pp. 1717-1730 ◽

Cited By ~ 37

Author(s):

M. Kodama ◽

M. S. O. Brieuc ◽

R. H. Devlin ◽

J. J. Hard ◽

K. A. Naish

Keyword(s):

Comparative Mapping ◽

Whole Genome Duplication ◽

Genome Duplication ◽

Coho Salmon ◽

Chromosomal Rearrangements ◽

Oncorhynchus Kisutch ◽

Duplication Event ◽

Whole Genome ◽

Genome Duplication Event ◽

Whole Genome Duplication Event

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Comparative regulomics supports pervasive selection on gene dosage following whole genome duplication

Genome Biology ◽

10.1186/s13059-021-02323-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Gareth B. Gillard ◽

Lars Grønvold ◽

Line L. Røsæg ◽

Matilde Mengkrog Holen ◽

Øystein Monsen ◽

...

Keyword(s):

Genome Evolution ◽

Whole Genome Duplication ◽

Genome Stability ◽

Genome Duplication ◽

Gene Dosage ◽

Whole Genome ◽

Specific Expression ◽

Tissue Specific ◽

Genome Doubling ◽

Expression Evolution

Abstract Background Whole genome duplication (WGD) events have played a major role in eukaryotic genome evolution, but the consequence of these extreme events in adaptive genome evolution is still not well understood. To address this knowledge gap, we used a comparative phylogenetic model and transcriptomic data from seven species to infer selection on gene expression in duplicated genes (ohnologs) following the salmonid WGD 80–100 million years ago. Results We find rare cases of tissue-specific expression evolution but pervasive expression evolution affecting many tissues, reflecting strong selection on maintenance of genome stability following genome doubling. Ohnolog expression levels have evolved mostly asymmetrically, by diverting one ohnolog copy down a path towards lower expression and possible pseudogenization. Loss of expression in one ohnolog is significantly associated with transposable element insertions in promoters and likely driven by selection on gene dosage including selection on stoichiometric balance. We also find symmetric expression shifts, and these are associated with genes under strong evolutionary constraints such as ribosome subunit genes. This possibly reflects selection operating to achieve a gene dose reduction while avoiding accumulation of “toxic mutations”. Mechanistically, ohnolog regulatory divergence is dictated by the number of bound transcription factors in promoters, with transposable elements being one likely source of novel binding sites driving tissue-specific gains in expression. Conclusions Our results imply pervasive adaptive expression evolution following WGD to overcome the immediate challenges posed by genome doubling and to exploit the long-term genetic opportunities for novel phenotype evolution.

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Chromosome-level genome assembly of Ophiorrhiza pumila reveals the evolution of camptothecin biosynthesis

Nature Communications ◽

10.1038/s41467-020-20508-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Amit Rai ◽

Hideki Hirakawa ◽

Ryo Nakabayashi ◽

Shinji Kikuchi ◽

Koki Hayashi ◽

...

Keyword(s):

Genome Assembly ◽

Whole Genome Duplication ◽

Experimental Validation ◽

Genome Duplication ◽

Indole Alkaloids ◽

Whole Genome ◽

Comparative Genome Analysis ◽

Plant Genomes ◽

Genome Triplication ◽

Chromosome Level

AbstractPlant genomes remain highly fragmented and are often characterized by hundreds to thousands of assembly gaps. Here, we report chromosome-level reference and phased genome assembly of Ophiorrhiza pumila, a camptothecin-producing medicinal plant, through an ordered multi-scaffolding and experimental validation approach. With 21 assembly gaps and a contig N50 of 18.49 Mb, Ophiorrhiza genome is one of the most complete plant genomes assembled to date. We also report 273 nitrogen-containing metabolites, including diverse monoterpene indole alkaloids (MIAs). A comparative genomics approach identifies strictosidine biogenesis as the origin of MIA evolution. The emergence of strictosidine biosynthesis-catalyzing enzymes precede downstream enzymes’ evolution post γ whole-genome triplication, which occurred approximately 110 Mya in O. pumila, and before the whole-genome duplication in Camptotheca acuminata identified here. Combining comparative genome analysis, multi-omics analysis, and metabolic gene-cluster analysis, we propose a working model for MIA evolution, and a pangenome for MIA biosynthesis, which will help in establishing a sustainable supply of camptothecin.

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