Genomics has come a long way since the central dogma (the notion that DNA is the master controller that calls all the shots) and junk DNA (the expectation that much of the genome is non-functional). If scientists ditch those old dogmas and approach the genome expecting to find reasons for things, they often do.
To-may-to or to-mah-to? The British write flavour; the Americans write flavor, but generally each understands the other without too much difficulty. Genomes, too, have alternate ways of spelling things: GGU and GGC in messenger RNA both spell glycine. No big deal, thought geneticists; these silent mutations cause no change in the resulting protein. At the University of Notre Dame, however, biochemists are finding that the differences in spelling are not just background noise; they alter the proteins folding. Is that good or bad?
Synonymous mutations were long considered to be genomic background noise, but we found they do indeed lead to altered protein folding, and in turn impair cell function, said Patricia Clark, the Rev. John Cardinal OHara professor of biochemistry at the University of Notre Dame, and lead author of the study. Our results show that synonymous variations in our DNA sequences which account for most of our genetic variation can have a significant impact on shaping the fitness level of cellular proteins.
Surely many of these mutations are harmful, as are random mutations in humans that cause genetic disease. But E. coli has been around for a long time. Wouldnt the species have gone extinct by now with the accumulation of defective spellings if they are always deleterious? Other work has suggested a secret code in synonymous variations that fine-tunes expression rates or regulates the supply of a given protein based on environmental conditions. The news release only mentions impairments caused by synonymous variations, but Notre Dame teams paper in PNAS suggests some possible advantages:
Synonymous codon substitutions alter the mRNA coding sequence but preserve the encoded amino acid sequence. For this reason, these substitutions were historically considered to be phenotypically silent and often disregarded in studies of human genetic variation. In recent years, however, it has become clear that synonymous substitutions can significantly alter protein function in vivo through a wide variety of mechanisms that can change protein level, translational accuracy, secretion efficiency, the final folded structure and posttranslational modifications. The full range of synonymous codon effects on protein production is, however, still emerging, and much remains to be learned regarding the precise mechanisms that regulate these effects. [Emphasis added.]
A design perspective would consider every possible function before rendering a judgment that all synonymous variations reduce fitness.
Keeping the genome accurate to a high degree preserves it from collapsing due to error catastrophe. At the time of cell division, proofreading enzymes (what a concept!) perform this vital function. Chelsea R. Bulock et al., writing in PNAS, have found one duplication enzyme that proofreads itself while proofreading its partner! DNA polymerase proofreads errors made by DNA polymerase , the paper is titled.
Pol and Pol are the two major replicative polymerases in eukaryotes, but their precise roles at the replication fork remain a subject of debate. A bulk of data supports a model where Pol and Pol synthesize leading and lagging DNA strands, respectively. However, this model has been difficult to reconcile with the fact that mutations in Pol have much stronger consequences for genome stability than equivalent mutations in Pol. We provide direct evidence for a long-entertained idea that Pol can proofread errors made by Pol in addition to its own errors, thus, making a more prominent contribution to mutation avoidance. This paper provides an essential advance in the understanding of the mechanism of eukaryotic DNA replication.
In other words, Pol is a proofreader of a proofreader. The paper says that Pol is a versatile extrinsic proofreading enzyme. One could think of it as a supervisor checking the work of a subordinate, or better yet, as an auditor or inspector able to fix errors before they cause harm to the product. Why would this be necessary during replication? The authors see a seniority system:
Thus, the high efficiency of Pol at correcting errors made by Pol may result from a combination of two factors: the high proclivity of Pol to yield to another polymerase and the greater flexibility and robustness of Pol when associating with new primer termini.
One proofreader is amazing to consider evolving by a Darwinian mechanism. A proofreader of a proofreader is astonishing. Consider, too, that this proofreading operation occurs in the dark by feel, automatically, without eyes to see.
Now that genetics is long past the heady days of finding that DNA forms a code that is translated, additional discoveries continue to show additional codes and factors that contribute to genomic function. One factor is the high-order structure of DNA. Researchers at South Koreas UNIST center have explored further into the formation of this structure, which involves chromatin wrapping around histone proteins so that long strands of DNA can fit within the compact space of the cell nucleus. As with everything else in genomics, the structure doesnt just happen. It requires a lot of help.
Regulation of histone proteins allows the DNA strands become more tightly or loosely coiled during the processes of DNA replication and gene expression. However, problems may arise when histones clump together or when DNA strands intertwine. Indeed, the misregulation of chromatin structures could result in aberrant gene expression and can ultimately lead to developmental disorders or cancers.
Histone chaperones are those proteins, responsible for adding and removing specific histones [found] at the wrong time and place during the DNA packaging process. Thus, they also play a key role in the assembly and disassembly of chromatin.
Cryo-EM imaging allowed the team to envision the molecular structure of some of these chaperone proteins. Their paper in Nature Communications begins, The fundamental unit of chromatin, the nucleosome, is an intricate structure that requires histone chaperones for assembly. Their cryo-EM images of one particular chaperone named Abo1 reveals a six-fold symmetry with precise locations for docking to histones, its hexameric ring thus creating a unique pocket where histones could bind with energy from ATP. Not only is Abo1 distinct as a histone chaperone, they write, but Abo1 is also unique compared to other canonical AAA+protein structures. Like Lego blocks, Abo1 features tight knob-and-hole packing of individual subunits plus linkers and other binding sites, such as for ATP. And unlike static blocks, these blocks undergo conformational changes as they work.
Such sophistication is far beyond the old picture of DNA as a master molecule directing all the work. It couldnt work without the help of many precision machines like this.
These stories are mere samples from a vast and growing literature indicating higher order in the genome than expected. Here are some more samples readers may wish to investigate:
Researchers at the University of Seville found additional factors involved in the repair of DNA strand breaks. These repairs are essential for the maintenance of genome integrity. The factors they discovered help maintain the right tension in cohesin molecules that hold the chromosomes together until the right time to separate. The news was relayed by EurekAlert!and published in Nature Communications.
Remember Paleys Watch? Researchers at the University of Basel discovered that Inner clockwork sets the time for cell division in bacteria. In PNAS and in Nature Communications, the Basel team elucidates the structure and function of a small signaling molecule that starts the clock, which then informs the cell about the right time to reproduce. They report in the news release:
A team at the Biozentrum of the University of Basel, led by Prof. Urs Jenal has now identified a central switch for reproduction in the model bacteriumCaulobacter crescentus: the signaling molecule c-di-GMP. In their current study,published in the journalNature Communications,they report that this molecule initiates a clock-like mechanism, which determines whether individual bacteria reproduce.
Proteins must fold properly to perform their functions. Small proteins usually fold successfully on their own, but large ones can fall into several misfolding traps that are equally likely as the canonical fold. It appears that the sequence of the sequence in a gene has something to do with this. Interestingly, many of these proteins sequences contain conserved rare codons that may slow down synthesis at this optimal window, explain Amir Bitran et al. in a January 21 paper in PNAS, discovering that Cotranslational folding (i.e., folding that begins as the polypeptide exits the ribosome) allows misfolding-prone proteins to circumvent deep kinetic traps.
Design advocates and evolutionists need to fathom what they are dealing with when discussing origins. Theres nothing like some low-level detail to put the challenge in perspective.
Image credit: Caulobacter crescentus, by University of Basel, Swiss Nanoscience Institute/Biozentrum, via EurekAlert!
View original post here:
More Hints of Order in the Genome - Discovery Institute
- 1st draft of a human 'pangenome' published, adding millions of ... - May 17th, 2023
- A Brief Guide to Genomics - National Human Genome Research Institute - May 17th, 2023
- Human genetics - Immunogenetics | Britannica - April 23rd, 2023
- A Troublesome Inheritance - Wikipedia - April 23rd, 2023
- Human - Simple English Wikipedia, the free encyclopedia - January 29th, 2023
- Human Genetics and Genomics Training Program - Hopkins Medicine - January 4th, 2023
- Genetics vs. Genomics Fact Sheet - Genome.gov - December 18th, 2022
- Human Genetics and Molecular Biology, PhD - Johns Hopkins University - December 18th, 2022
- Race (human categorization) - Wikipedia - December 2nd, 2022
- Human Y-chromosome DNA haplogroup - Wikipedia - November 24th, 2022
- Abstracts | International Congress of Human Genetics 2023 - November 24th, 2022
- Human genetic variation - Wikipedia - November 6th, 2022
- Genetics | The Smithsonian Institution's Human Origins Program - October 29th, 2022
- Fluent BioSciences showcasing breakthrough solutions to enable unprecedented scale, cost-efficiency and access for single-cell RNA sequencing at the... - October 29th, 2022
- Researchers seek to unravel the mystery of susceptibility to drug addiction - Newswise - October 4th, 2022
- NIH initiative to systematically investigate and establish function of every human gene - National Institutes of Health (.gov) - October 4th, 2022
- ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma | Communications Biology - Nature.com - October 4th, 2022
- Does obesity have more to do with the brain than we initially thought? - Medical News Today - October 4th, 2022
- Who will get the call from Stockholm? It's time for STAT's 2022 Nobel Prize predictions - STAT - October 4th, 2022
- Solving medical mysteries: Physicians and researchers collaborate to study the most challenging cases - AAMC - October 4th, 2022
- Mystery gene matures the skeleton of the cell - EurekAlert - October 4th, 2022
- What Is The Most Important factor Driving The Global Human Genetics Market? - PharmiWeb.com - September 25th, 2022
- How Africa's genetic diversity can be harnessed to close the continent's 'drug and treatment gap' - Genetic Literacy Project - September 25th, 2022
- Ability to move to the pulse of music has genetic link - DTNEXT - September 25th, 2022
- Is the Spike Protein Changing Our Gene Expression? - The Epoch Times - September 25th, 2022
- How prehistoric DNA is helping to unlock the secrets of human evolution - EL PAS USA - September 25th, 2022
- Personalised medicine and the advantages of big data and AI-based diagnostics - Medical Device Network - September 25th, 2022
- Viewpoint: In the post Roe v Wade world, what changes should a biology textbook writer make to address the medical repercussions of Dobbs? - Genetic... - September 25th, 2022
- Bears' ability to regulate insulin narrowed down to eight proteins WSU Insider - WSU News - September 25th, 2022
- Sex, Selection and Biodiversity - Syracuse.edu - Syracuse University - September 25th, 2022
- Was the Russian Flu the first coronavirus pandemic? Find out at next Science Caf - University of Nebraska at Kearney - September 25th, 2022
- University of Chicago South Side Science Fest created to show off the fun, myriad pathways into field. - Chicago Tribune - September 25th, 2022
- The genetics of human personality - PubMed - August 14th, 2022
- Genetics - The Harvey Institute for Human Genetics - GBMC HealthCare in ... - August 14th, 2022
- Degrees of the Future 2022: Genetics - Gizmodo - August 14th, 2022
- U of U Health-Led Research Awarded $28 Million to Explore HIV's Inner Workings and Vulnerabilities - University of Utah Health Care - August 14th, 2022
- Revisiting Companies That Had Their IPO in 2018 - Investment U - August 14th, 2022
- Monkeypox Myth Busting: Here's What You Need to Know - The Mighty - August 14th, 2022
- Relay Therapeutics Reports Second Quarter 2022 Financial Results and Corporate Highlights - Yahoo Finance - August 5th, 2022
- Baylor receives NCI grant to study liver cancer risk and prevention - Baylor College of Medicine News - August 5th, 2022
- Whole Exome Sequencing Market reach a valuation of US$ 4,256.30 Mn, at a CAGR of 19.24% in the Forecast 2030 - BioSpace - August 5th, 2022
- Mendels Genetic Revolution and the Legacy of Scientific Racism - NewsClick - August 5th, 2022
- AMGEN TO ACQUIRE CHEMOCENTRYX FOR $4 BILLION IN CASH - BioSpace - August 5th, 2022
- Cotton Buds Market Value Is Estimated to Reach USD 747.16 BN By 2028, With 3.2% CAGR Credence Research - Digital Journal - August 5th, 2022
- Verve Therapeutics Shares Up 84%; ARKG Offers Exposure - ETFdb.com - July 27th, 2022
- Double up on the guac? Those avocados are good for your heart health - American Heart Association - July 27th, 2022
- Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome | European Journal of Human Genetics - Nature.com - July 27th, 2022
- Scientists Unravel the Mystery of Junk Genes That Are Key to Brain Development - SciTechDaily - July 27th, 2022
- COVID-19 Can Make the Brain Age by 2 Decades; Here's 1 Way to Reverse Aging - The Epoch Times - July 27th, 2022
- Mice Model Market Forecast to 2028 - COVID-19 Impact and Global Analysis By Type, Service, Technology, Indication, End User, Application, and Mode -... - July 27th, 2022
- Master's Degree in Human Genetics | Human Genetics | Michigan Medicine ... - July 11th, 2022
- Here's how the $100 Human Genome will Change Medicine - BioSpace - July 11th, 2022
- Genomic medicine: the role of the nursing workforce - Nursing Times - July 11th, 2022
- AbbVie Half Breaks Up with Alector on Alzheimer's - BioSpace - July 11th, 2022
- The human identification market size is projected to reach - GlobeNewswire - July 11th, 2022
- Global wheat production can be doubled to feed millions and save land, say scientists - Sky News - July 11th, 2022
- Huntsville native among TIMEs 100 most influential people - WHNT News 19 - July 3rd, 2022
- New hope for IVF patients as global study published in Human Reproduction shows AI can effectively assess genetic integrity of embryos - Yahoo Finance - July 3rd, 2022
- A Week At The Most Secretive Conference On Aging - Forbes - July 3rd, 2022
- Human genetics shape the gut microbiome - PMC - June 13th, 2022
- expert reaction to a conference abstract on retinal screening predicting risk of myocardial infarction - Science Media Centre - June 13th, 2022
- New Comprehensive Map Ties Every Human Gene to Its Function - SciTechDaily - June 13th, 2022
- Buffalo shooters manifesto quoted a university researcher. Thats raising questions about racism in academia - Yahoo News - June 13th, 2022
- Thalidomide could be used as a therapeutic for AVMs - Cosmos - June 13th, 2022
- How Electric Fish Were Able to Evolve Electric Organs - UT News - University of Texas - June 4th, 2022
- Survival of the Best: The Past, Present and Future of Plants - CSRwire.com - June 4th, 2022
- AMGEN ANNOUNCES WEBCAST OF 2022 JEFFERIES HEALTHCARE CONFERENCE | News | wfmz.com - 69News WFMZ-TV - June 4th, 2022
- Experts Discover New Disease Caused by Faulty Genes Affecting the Kidney and Liver: Newcastle University Study - Nature World News - June 4th, 2022
- At-Home Colorectal Cancer Testing and Follow-Up Vary by Ethnicity - Medscape - June 4th, 2022
- Who is your real parent? Our Father on Netflix depicts the dark side of 'secret serial sperm donation'. My birth has a similar origin but with a more... - June 4th, 2022
- Autism and the complete human genome: Q&A with Evan Eichler | Spectrum - Spectrum - May 15th, 2022
- Increased Mutations in Children Can Be Traced Back to Mistakes in Father's Sperm - Neuroscience News - May 15th, 2022
- Not All Is Rosy For The Pink Pigeon - Eurasia Review - May 15th, 2022
- Why haven't we cloned a human yet? - Livescience.com - May 15th, 2022
- Study probes the relationship between genetics, proteins, and disease risk - The Hub at Johns Hopkins - May 15th, 2022
- Singular Genomics Announces Formation of Scientific Advisory Board - BioSpace - May 15th, 2022
- COVID Resistance Might Be Tied To Genetics: Experts - Medical Daily - May 15th, 2022
- Letter: Why no to Roe and abortion - INFORUM - May 15th, 2022
- Gut Microbiome Composition Predictive of Patient Response to Statins - Business Wire - May 15th, 2022
- Finding A Place In Science - Texas A&M Today - Texas A&M University Today - May 15th, 2022