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Migration-selection balance at multiple Loci and selection on dominance and recombination.

ABSTRACT: A steady influx of a single deleterious multilocus genotype will impose genetic load on the resident population and leave multiple descendants carrying various numbers of the foreign alleles. Provided that the foreign types are rare at equilibrium, and all immigrant genes are eventually eliminated by selection, the population structure can be inferred explicitly from the branching process taking place within a single immigrant lineage. Unless the migration and recombination rates were high, this novel method gives a close approximation to the simulation with all possible multilocus genotypes considered. Once the load and the foreign genotypes frequencies are known, it becomes possible to estimate selection acting on the invading modifiers of (i) dominance and (ii) recombination rate on the foreign gene block. We found that the modifiers of the (i) type are able to invade faster than the type (ii) modifier, however, this result only applies in the strong selection/low migration/low recombination scenario. Varying the number of genes in the immigrant genotype can have a non-monotonic effect on the migration load and the modifier's invasion rate: although blocks carrying more genes can give rise to longer lineages, they also experience stronger selection pressure. The heaviest load is therefore imposed by the genotypes carrying moderate numbers of genes.

SUBMITTER: Yanchukov A

PROVIDER: S-EPMC3925130 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Migration-selection balance at multiple Loci and selection on dominance and recombination.

Yanchukov Alexey A Proulx Stephen R SR

PloS one 20140214 2

A steady influx of a single deleterious multilocus genotype will impose genetic load on the resident population and leave multiple descendants carrying various numbers of the foreign alleles. Provided that the foreign types are rare at equilibrium, and all immigrant genes are eventually eliminated by selection, the population structure can be inferred explicitly from the branching process taking place within a single immigrant lineage. Unless the migration and recombination rates were high, this ...[more]

PMID: 24551127

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Project description:Vascular abnormalities contribute to many diseases such as cancer and diabetic retinopathy. In angiogenesis new blood vessels, headed by a migrating tip cell, sprout from pre-existing vessels in response to signals, e.g., vascular endothelial growth factor (VEGF). Tip cells meet and fuse (anastomosis) to form blood-flow supporting loops. Tip cell selection is achieved by Dll4-Notch mediated lateral inhibition resulting, under normal conditions, in an interleaved arrangement of tip and non-migrating stalk cells. Previously, we showed that the increased VEGF levels found in many diseases can cause the delayed negative feedback of lateral inhibition to produce abnormal oscillations of tip/stalk cell fates. Here we describe the development and implementation of a novel physics-based hierarchical agent model, tightly coupled to in vivo data, to explore the system dynamics as perpetual lateral inhibition combines with tip cell migration and fusion. We explore the tipping point between normal and abnormal sprouting as VEGF increases. A novel filopodia-adhesion driven migration mechanism is presented and validated against in vivo data. Due to the unique feature of ongoing lateral inhibition, 'stabilised' tip/stalk cell patterns show sensitivity to the formation of new cell-cell junctions during fusion: we predict cell fates can reverse. The fusing tip cells become inhibited and neighbouring stalk cells flip fate, recursively providing new tip cells. Junction size emerges as a key factor in establishing a stable tip/stalk pattern. Cell-cell junctions elongate as tip cells migrate, which is shown to provide positive feedback to lateral inhibition, causing it to be more susceptible to pathological oscillations. Importantly, down-regulation of the migratory pathway alone is shown to be sufficient to rescue the sprouting system from oscillation and restore stability. Thus we suggest the use of migration inhibitors as therapeutic agents for vascular normalisation in cancer.

Dataset Information

Migration-selection balance at multiple Loci and selection on dominance and recombination.

Publications

Migration-selection balance at multiple Loci and selection on dominance and recombination.

Similar Datasets

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