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Category: genetics – Page 451

Mitochondrial dysfunction is associated with many mitochondrial diseases, most of which are the result of dysfunctional mitochondrial oxidative phosphorylation (OXPHOS). Mitochondrial OXPHOS accounts for the generation of most of the cellular adenosine triphosphate (ATP) in a cell. The OXPHOS function largely depends on the coordinated expression of the proteins encoded by both nuclear and mitochondrial genomes. The human mitochondrial genome encodes for 13 polypeptides of the OXPHOS, and the nuclear genome encodes the remaining more than 85 polypeptides required for the assembly of OXPHOS system. Mitochondrial DNA (mtDNA) depletion impairs OXPHOS that leads to mtDNA depletion syndromes (MDSs)1, 2. The MDSs are a heterogeneous group of disorders, characterized by low mtDNA levels in specific tissues. In different target organs, mtDNA depletion leads to specific pathological changes. MDS results from the genetic defects in the nuclear-encoded genes that participate in mtDNA replication, and mitochondrial nucleotide metabolism and nucleotide salvage pathway1, 4,5,6,7,8,9,10. mtDNA depletion is also implicated in other human diseases such as mitochondrial diseases, cardiovascular11, 12, diabetes13,14,15, age-associated neurological disorders16,17,18, and cancer19,20,21,22,23,24,25.

A general decline in mitochondrial function has been extensively reported during aging26,27,28,29,30,31,32,33. Furthermore, mitochondrial dysfunction is known to be a driving force underlying age-related human diseases16,17,18, 34,35,36. A mouse that carries elevated mtDNA mutation is also shown to present signs of premature aging37, 38. In addition to mutations in mtDNA, studies also suggest a decrease in mtDNA content and mitochondrial number with age27, 29, 32, 33, 39. Notably, there is an age-related mtDNA depletion in a number of tissues40,41,42. mtDNA depletion is also frequently observed among women with premature ovarian aging43. Low mtDNA copy number is linked to frailty and, for a multiethnic population, is a predictor of all-cause mortality44. A recent study revealed that humans on an average lose about four copies of mtDNA every ten years. This study also identified an association of decrease in mtDNA copy number with age-related physiological parameters39.

To help define the role of mtDNA depletion in aging and various diseases, we created an inducible mouse expressing, in the polymerase domain of POLG1, a dominant-negative (DN) mutation that induces depletion of mtDNA in the whole animal. Interestingly, skin wrinkles and visual hair loss were among the earliest and most predominant phenotypic changes observed in these mice. In the present study, we demonstrate that mtDNA depletion-induced phenotypic changes can be reversed by restoration of mitochondrial function upon repletion of mtDNA.

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CRISPR has been heralded as one of the most important breakthroughs in modern science, but there could be a hidden and potentially dangerous side effect to the wonders of its genetic editing technology, a new study reveals.

A systematic investigation of CRISPR/Cas9 genome editing in mouse and human cells has discovered that the technique appears to frequently cause extensive mutations and genetic damage that the researchers say wouldn’t be detected by existing DNA tests.

“This is the first systematic assessment of unexpected events resulting from CRISPR/Cas9 editing in therapeutically relevant cells,” explains geneticist Allan Bradley from the Wellcome Sanger Institute in the UK.

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Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) and the FIRC Institute of Molecular Oncology (IFOM) in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification — by confining them to a defined geometric space for an extended period of time.

“Our breakthrough findings will usher in a new generation of stem cell technologies for tissue engineering and regenerative medicine that may overcome the negative effects of geonomic manipulation,” said Prof Shivashankar.

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Researchers isolated several mutations leading to melanoma and reproduced them in the lab using CRISPR.

Two papers authored by researchers at the University of California, San Francisco described the genetic changes that turn harmless moles into malignant melanomas and the experiment they devised to recreate the step-by-step evolution of normal skin cells into cancer cells [1], [2].

Summary ([1])

We elucidated genomic and transcriptomic changes that accompany the evolution of melanoma from pre-malignant lesions by sequencing DNA and RNA from primary melanomas and their adjacent precursors, as well as matched primary tumors and regional metastases. In total, we analyzed 230 histopathologically distinct areas of melanocytic neoplasia from 82 patients. Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas. UV radiation-induced point mutations steadily increased until melanoma invasion, at which point copy-number alterations also became prevalent.

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Derrick Broze, Guest Waking Times

New scientific research is causing scientists to rethink what they believe about the static nature of genes. What do these discoveries mean for a species increasingly facing environmental and political calamity?

Ongoing discoveries regarding how environmental factors can affect life on the genetic level are causing many scientists and researchers to rethink the notion that the genetic makeup of an individual is static and unchanging. Most recently, a team of researchers with Tufts University has found evidence which suggests stress or mistreatment during childhood can lead to genetic changes which are passed down to the victim’s children and grandchildren. Larry Feig and his team have shown that inducing stress on mice can lead to genetic changes which are imprinted on the sperm. This same effect has been found in male humans as well.

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Canadian researchers have discovered a new and direct molecular mechanism to stop cancer cells from proliferating. In the prestigious journal Nature Cell Biology, scientists from Université de Montréal show that a disruption of a fine balance in the composition of ribosomes (huge molecules that translate the genetic code into proteins) results in a shutdown of cancer cell proliferation, triggering a process called senescence.

“Ribosomes are complex machines composed of both RNAs and proteins that make all the proteins necessary for to grow,” said UdeM biochemistry professor Gerardo Ferbeyre, the study’s senior author. Cancer cells grow and proliferate relentlessly and thus require a massive amount of ribosomes, he explained. Growing cells must coordinate the production of both ribosomal RNAs and ribosomal proteins in order to assemble them together in strict proportion to each other.

“We were surprised, however, to find that if the production of ribosomal RNA– proportions are driven out of balance in a cancer cell, proliferation can be shut down by in a very simple and direct manner,” said Ferbeyre.

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