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Most cancers carry a substantial deleterious load due to Hill-Robertson interference

Introduction Cancer genomes exhibit surprisingly weak signatures of negative selection[1][1],[2][2]. This may be because tumors evolve either under very weak selective pressures (‘weak selection') or under conditions that prevent the elimination of …

Mapping the in vivo fitness landscape of lung adenocarcinoma tumor suppression in mice

The functional impact of most genomic alterations found in cancer, alone or in combination, remains largely unknown. Here we integrate tumor barcoding, CRISPR/Cas9-mediated genome editing and ultra-deep barcode sequencing to interrogate pairwise …

Multiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity

Large-scale genomic analyses of human cancers have cataloged somatic point mutations thought to initiate tumor development and sustain cancer growth. However, determining the functional significance of specific alterations remains a major bottleneck …

The Damaging Effect of Passenger Mutations on Cancer Progression.

Genomic instability and high mutation rates cause cancer to acquire numerous mutations and chromosomal alterations during its somatic evolution; most are termed passengers because they do not confer cancer phenotypes. Evolutionary simulations and …

A quantitative and multiplexed approach to uncover the fitness landscape of tumor suppression in vivo

A modified ziggurat algorithm for generating exponentially and normally distributed pseudorandom numbers

The ziggurat algorithm is a very fast rejection sampling method for generating pseudorandom numbers (PRNs) from statistical distributions. In the algorithm, rectangular sampling domains are layered on top of each other (resembling a ziggurat) to …

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. …

Oncogene-triggered suppression of DNA repair leads to DNA instability in cancer.

DNA instability is an important contributor to cancer development. Previously, defects in the chromosome segregation and excessive DNA double strand breaks due to the replication or oxidative stresses were implicated in DNA instability in cancer. …

Impact of deleterious passenger mutations on cancer progression

Cancer progression is driven by the accumulation of a small number of genetic alterations. However, these few driver alterations reside in a cancer genome alongside tens of thousands of additional mutations termed passengers. Passengers are widely …