Understanding redundancy and resilience

Hunter, Philip

doi:10.15252/embr.202254742

Cited by 3 publications

(3 citation statements)

References 17 publications

(15 reference statements)

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“…The functional loss of one gene can be compensated for through functional redundancy ( Chen et al, 2013 ). Genes that contain high numbers of PTVs in general population cohorts and thus are less likely to cause adverse phenotypes were found to belong to larger gene families than genes that contain known pathogenic PTVs ( Ng et al, 2008 ), suggesting functional redundancy as a mechanism affecting penetrance ( Hunter, 2022 ). Further research is needed to find robust evidence of this mechanism in humans.…”

Section: Global Modifiersmentioning

confidence: 99%

Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts

Kingdom

Wright

2022

Front. Genet.

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The same genetic variant found in different individuals can cause a range of diverse phenotypes, from no discernible clinical phenotype to severe disease, even among related individuals. Such variants can be said to display incomplete penetrance, a binary phenomenon where the genotype either causes the expected clinical phenotype or it does not, or they can be said to display variable expressivity, in which the same genotype can cause a wide range of clinical symptoms across a spectrum. Both incomplete penetrance and variable expressivity are thought to be caused by a range of factors, including common variants, variants in regulatory regions, epigenetics, environmental factors, and lifestyle. Many thousands of genetic variants have been identified as the cause of monogenic disorders, mostly determined through small clinical studies, and thus, the penetrance and expressivity of these variants may be overestimated when compared to their effect on the general population. With the wealth of population cohort data currently available, the penetrance and expressivity of such genetic variants can be investigated across a much wider contingent, potentially helping to reclassify variants that were previously thought to be completely penetrant. Research into the penetrance and expressivity of such genetic variants is important for clinical classification, both for determining causative mechanisms of disease in the affected population and for providing accurate risk information through genetic counseling. A genotype-based definition of the causes of rare diseases incorporating information from population cohorts and clinical studies is critical for our understanding of incomplete penetrance and variable expressivity. This review examines our current knowledge of the penetrance and expressivity of genetic variants in rare disease and across populations, as well as looking into the potential causes of the variation seen, including genetic modifiers, mosaicism, and polygenic factors, among others. We also considered the challenges that come with investigating penetrance and expressivity.

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Section: Global Modifiersmentioning

confidence: 99%

Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts

Kingdom

Wright

2022

Front. Genet.

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“…increased resilience and survival of cells in dynamic environments [8][9][10] . Elucidation of this cellular capacity will translate to design criteria in support of tissue engineering and regenerative medicine endeavors, e.g., enabling proactive steering of targeted of stem cell differentiation and creation of tissue templates emulating specific, targeted developmental stages 4 .…”

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confidence: 99%

“…c The mechanome map of the cells' actual stress-strain data upon introduction of mechanical and biochemical cues and the corresponding fates. Cells experience intrinsic mechanical cues during development such as volume-changing (dilatational) stress (red plane, x axis) (i.e., hydrostatic compression and tension [log 10 Pa]) and shape-changing shear stress (blue plane, y axis) (shear stress magnitudes [dyn/cm 2 or 0.1 Pa], that dictate their lineage commitment over time (z axis) (adapted with permission from ref. 82 , ref.…”

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confidence: 99%

Biomechanical, biophysical and biochemical modulators of cytoskeletal remodelling and emergent stem cell lineage commitment

Putra

Kilian

Tate³

2023

Commun Biol

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Across complex, multi-time and -length scale biological systems, redundancy confers robustness and resilience, enabling adaptation and increasing survival under dynamic environmental conditions; this review addresses ubiquitous effects of cytoskeletal remodelling, triggered by biomechanical, biophysical and biochemical cues, on stem cell mechanoadaptation and emergent lineage commitment. The cytoskeleton provides an adaptive structural scaffold to the cell, regulating the emergence of stem cell structure-function relationships during tissue neogenesis, both in prenatal development as well as postnatal healing. Identification and mapping of the mechanical cues conducive to cytoskeletal remodelling and cell adaptation may help to establish environmental contexts that can be used prospectively as translational design specifications to target tissue neogenesis for regenerative medicine. In this review, we summarize findings on cytoskeletal remodelling in the context of tissue neogenesis during early development and postnatal healing, and its relevance in guiding lineage commitment for targeted tissue regeneration. We highlight how cytoskeleton-targeting chemical agents modulate stem cell differentiation and govern responses to mechanical cues in stem cells’ emerging form and function. We further review methods for spatiotemporal visualization and measurement of cytoskeletal remodelling, as well as its effects on the mechanical properties of cells, as a function of adaptation. Research in these areas may facilitate translation of stem cells’ own healing potential and improve the design of materials, therapies, and devices for regenerative medicine.

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