Yeast with an over half synthetic genome is created in the lab

Researchers have combined over seven synthetic chromosomes that were made in the lab into a single yeast cell, resulting in a strain with more than 50% synthetic DNA that survives and replicates similarly to wild yeast strains. The team present the half-synthetic yeast November 8 in the journal Cell as part of a collection of papers across Cell, Molecular Cell,and Cell Genomics that showcase the Synthetic Yeast Genome Project (Sc2.0), a global consortium working to develop the first synthetic eukaryote genome from scratch. The team has now synthesized and debugged all sixteen yeast chromosomes.

"Our motivation is to understand the first principles of genome fundamentals by building synthetic genomes," says co-author and synthetic biologist Patrick Yizhi Cai of the University of Manchester, who is also senior author of two other papers in the collection. "The team has now re-written the operating system of the budding yeast, which opens up a new era of engineering biology -- moving from tinkering a handful of genes to de novo design and construction of entire genomes."

Though bacterial and viral genomes have been synthesized previously, this would be the first synthetic eukaryote genome, which introduces the complication of multiple chromosomes. The synthetic yeast is also a "designer" genome that differs substantially from the natural Saccharomyces cerevisiae (brewer's or baker's yeast) genome on which it is based.

"We decided that it was important to produce something that was very heavily modified from nature's design," says senior author and Sc2.0 leader Jef Boeke, a synthetic biologist at NYU Langone Health. "Our overarching aim was to build a yeast that can teach us new biology."

To this end, the researchers removed chunks of non-coding DNA and repetitive elements that could be considered "junk," added new snippets of DNA to help them more easily distinguish between synthesized and native genes, and introduced a built-in diversity generator called "SCRaMbLE" that shuffles the order of genes within and between chromosomes.

To increase genome stability, the team also removed many of the genes that encode transfer RNA (tRNA) and relocated them to an entirely new "neochromosome" consisting only of tRNA genes. "The tRNA neochromosome is the world's first completely de novo synthetic chromosome," says Cai. "Nothing like this exists in nature."

Since the yeast genome is organized into sixteen chromosomes, the researchers began by assembling each chromosome independently to create sixteen partially synthetic yeast strains that each contained 15 natural chromosomes and one synthetic chromosome. The next challenge was to begin combining these synthetic chromosomes into a single yeast cell.

To do this, Boeke's team started by using a method reminiscent of Mendel's peas: essentially, the researchers interbred different partially synthetic yeast strains and then searched amongst their progeny for individuals carrying both synthetic chromosomes. Though effective, this method is very slow, but the team gradually consolidated all previously synthesized chromosomes -- six full chromosomes and one chromosome arm -- into a single cell. The resulting yeast strain was more than 31% synthetic, had normal morphology, and showed only slight growth defects compared to wild-type yeast.

To more efficiently transfer specific chromosomes between yeast strains, the researchers developed a new method called chromosome substitution that is discussed in another paper in the new collection. As a proof of concept, they used chromosome substitution to transfer a newly synthesized chromosome (chromosome IV, the largest of all the synthetic chromosomes), resulting in a yeast cell with 7.5 synthetic chromosomes that is more than 50% synthetic.

When the synthetic chromosomes were consolidated into a single yeast strain, the team detected several genetic defects or "bugs" that were invisible in yeast strains that only carried one synthetic chromosome. "We knew in principle that this might happen -- that we might have a huge number of things that had tiny little effects and that, when you put them all together, it might result in death by a thousand cuts," says Boeke.

Some of these bugs were simply due to the additive impact of having many tiny defects within the genome, while others involved genetic interactions between genes on the different synthetic chromosomes. The researchers were able to map and fix several of these bugs and increase the synthetic yeast's fitness by using a method based on CRISPR/Cas9.

"We've now shown that we can consolidate essentially half of the genome with good fitness, which suggests that this is not going to be a big problem," says Boeke. "And from debugging, we learn new twists on the rules of life."

The next step will be to integrate the remaining synthetic chromosomes. "Now we're just this far from the finish line of having all 16 chromosomes in a single cell," says Boeke. "I like to call this the end of the beginning, not the beginning of the end, because that's when we're really going to be able to start shuffling that deck and producing yeast that can do things that we've never seen before."

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Researchers fully sequence the Y chromosome for the first time

What was once the final frontier of the human genome -- the Y chromosome -- has just been mapped out in its entirety.

Led by the National Human Genome Research Institute (NHGRI), a team of researchers at the National Institute of Standards and Technology (NIST) and many other organizations used advanced sequencing technologies to read out the full DNA sequence of the Y chromosome -- a region of the genome that typically drives male reproductive development. The results of a study published in Nature demonstrate that this advance improves DNA sequencing accuracy for the chromosome, which could help identify certain genetic disorders and potentially uncover the genetic roots of others.

DNA sequencing isn't as simple as reading genetic material from a genome's beginning to its end. DNA gets chopped up when it is extracted from cells, plus even the best sequencing equipment can only handle relatively small bits of DNA at a time. So, researchers and clinicians rely on special software to piece together fragments of sequenced code in the correct order like a puzzle.

A reference genome is a separate, already pieced-together genome that serves as a guide, similar to the pictures on the front of puzzle boxes. And because 99.9% of our species' genetic code is shared, any human genome would closely match a reference.

Last year, a team from the Telomere-to-Telomere (T2T) consortium, which is made up of experts from dozens of organizations such as NIST, generated the most complete reference genome at the time by using new sequencing technologies to crack previously indecipherable regions of the genome. But cells used in that work did not contain the most puzzling of all, the Y chromosome.

"Chromosomes all contain sections of very repetitive DNA, but well over half of the Y chromosome is like that," said study co-author Justin Zook, who leads NIST's Genome in a Bottle (GIAB) consortium. "If you use the puzzle analogy, a lot of the Y chromosome looks like the backgrounds often do, where all the pieces look really similar."

With this new endeavor, T2T was not starting at zero as the GIAB had already gotten the ball rolling.

The GIAB's mission is to produce test materials, or benchmarks, that can be used to evaluate sequencing technologies or methods. The materials themselves are highly accurate readouts of specific genes that can act as an answer key for checking the results of a particular sequencing method.

NIST has rigorously analyzed several individual human genomes to create their benchmarks. While GIAB has not yet produced a benchmark for the Y chromosome specifically, the consortium has studied one genome extensively, accumulating the largest collection of Y chromosome data prior to the new study.

That data served as a jumping-off point for the new study's authors, who focused their analysis on the best understood GIAB Y chromosome. They examined the sample with a combination of cutting-edge technologies -- namely high fidelity and nanopore sequencing -- that make the DNA fragment puzzle pieces larger and thus easier to assemble.

A machine-learning analysis tool and gamut of other advanced programs helped the team identify and assemble the pieces of the chromosome. More than 62 million letters of genetic code later, the authors had spelled out the GIAB Y chromosome front to back.

The researchers pitted their complete Y chromosome sequence, named T2T-Y, against the most widely used reference genome's Y chromosome parts, which are riddled with stretches of absent code. Using them both as guides for sequencing a diverse group of over 1,200 separate genomes, they found that T2T-Y drastically improved the outcomes.

T2T-Y, in combination with the group's previous reference genome, T2T-CHM13, represents the world's first complete genome for the half of the population with a Y chromosome.

The newest addition could be useful in identifying and diagnosing the few known conditions related to genes in the Y chromosome. But what's more is the new reference's potential to shed light on new genes and their function.

"There are certainly aspects of fertility and some genetic disorders that are connected to genes in the Y chromosome," Zook said. "But because it's been so hard to analyze up to this point, we may not even know yet just how important the Y chromosome is."

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How the motion of DNA controls gene activity

Performing cutting-edge science requires thinking outside the box and bringing together different scientific disciplines. Sometimes this even means being in the right place at the right time. For David Brückner, postdoctoral researcher and NOMIS fellow at ISTA, all the above-mentioned things came into effect as he attended an on-campus lecture by Professor Thomas Gregor from Princeton University. Inspired by the talk, Brückner reached out with an idea: to physically interpret the specific data sets Gregor presented. Now, the results of their collaboration are published in Science. They highlight the stochastic (random) motion of two specific gene elements on a chromosome, which have to come into contact for the gene to become active in 3D space.

How DNA fits into a cell nucleus

Living organisms like humans are built on genes that are stored in the DNA -- our molecular blueprint. DNA is a polymer, a huge molecule of smaller individual parts (monomers). It is located in every cell's nucleus. "Depending on the organism, the DNA polymer can be up to meters long, yet the size of the nucleus is on the order of microns," Brückner explains. To fit into the tiny nucleus, DNA gets compacted by being coiled as if on a spool and further compressed into the well-known shape of chromosomes, which we all encountered in a biology textbook.

"Despite being heavily condensed, chromosomes are not static; they are jiggling around all the time," the physicist continues. These dynamics are very important. Whenever a specific gene has to be activated, two regions on the polymer called "enhancer" and "promoter" need to come into close contact and bind to each other. Only when this happens, a cellular machinery reads off the gene's information and forms the RNA molecule, which eventually gives rise to proteins that are essential for all the processes a living organism requires.

Depending on the organism, the enhancer and promoter can be quite far from each other on the chromosome. "With previously used methods, you could get a static view of the distance between these elements, but not how the system evolves over time," Brückner explains. Intrigued by this missing information, the scientists set out to get a dynamic look at how these elements are organized and how they move in 3D space in real time.

Visualizing gene regions

To achieve this goal, the experimental scientists from Princeton established a method to track those two DNA elements over a certain time period in a fly embryo. Through genetic manipulation, the DNA elements were fluorescently labeled, with the enhancer region illuminating in green and the promoter in blue. Using live imaging (time-lapse microscopy of living cells) the scientists were able to visualize the fluorescent spots in fly embryos to see how they were moving around to find each other.

Once the two spots came into proximity, the gene was activated and an additional red light turned on as the RNA was also tagged with red fluorophores. Brückner excitedly adds, "We got a visual readout of when the enhancer and promoter got in contact. That gave us a lot of information about their trajectories."

DNA is densely packed and exhibits fast motion

The challenge then was how to analyze this huge data set of stochastic motion. His background in theoretical physics allowed Brückner to extract statistics to understand the typical behavior of the system. He applied two simplified, different physical models to cut through the data.

One was the Rouse model. It assumes that every monomer of the polymer is an elastic spring. It predicts a loose structure and fast diffusion -- a random movement, where occasionally the gene regions encounter each other. The other model is called the "fractal globule." It predicts a very compact structure and therefore slow diffusion. "Surprisingly, we found in the data that the system is described by a combination of these two models -- a highly dense structure you would expect based on the fractal globule model, and diffusion which is described by the statistics from the Rouse model," Brückner explains.

Due to the combination of dense packing and fast motion, the binding of these two gene regions depends much less on their distance along the chromosome than previously anticipated. "If such a system is in a fluid and dynamic state all the time, long-distance communication is much better than we might have thought," Brückner adds.

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How selfish genes succeed

New findings from the Stowers Institute for Medical Research uncover critical insights about how a dangerous selfish gene -- considered to be a parasitic portion of DNA -- functions and survives. Understanding this dynamic is a valuable resource for the broader community studying meiotic drive systems.

A new study, published in PLoS Genetics on Dec. 7, 2022, reveals how a selfish gene in yeast uses a poison-antidote strategy that enables its function and likely has facilitated its long-term evolutionary success. This strategy is an important addition for scientists studying similar systems including teams that are designing synthetic drive systems for pathogenic pest control. Collective and collaborative advancement on understanding drive may one day lead to the eradication of pest populations that harm crops or even humans in the case of vector borne diseases.

"It's quite dangerous for a genome to encode a protein that has the capacity to kill the organism," said Stowers Associate Investigator SaraH Zanders, Ph.D. "However, understanding the biology of these selfish elements could help us build synthetic drivers to modify natural populations."

Drivers are selfish genes that can spread in a population at higher rates than most other genes, without benefiting the organism. Previous research from the Zanders Lab revealed that a driver gene in yeast, wtf4, produces poison protein capable of destroying all offspring. However, for a given parent cell's chromosome pair, drive is achieved when wtf4 is found only on one chromosome. The effect is a simultaneous rescue of only those offspring that inherit the drive allele, by delivering a dose of a very similar protein that counteracts the poison, the antidote.

Building upon this work, the study, led by former Predoctoral Researcher Nicole Nuckolls, Ph.D., and current Predoctoral Researcher Ananya Nidamangala Srinivasa in the Zanders Lab, discovered that differences in the timing of generating poison and antidote proteins from wtf4 and their unique distribution patterns within developing spores are fundamental to the drive process.

The team has developed a model they are continuing to investigate for how the poison acts to kill the spore -- the equivalent of a human egg or sperm in yeast. Their results indicate that poison proteins cluster together, potentially disrupting proper folding of other proteins required for the cell to function. Because the wtf4 gene encodes both poison and antidote, the antidote is very similar in form and groups together with the poison. However, the antidote has an extra part that appears to isolate the poison-antidote clusters by bringing them to the cell's garbage can, the vacuole.

To understand how selfish genes function during reproduction, the researchers looked at the beginning of spore formation and found poison protein expressed within all developing spores and the sac surrounding them, while the antidote protein was only seen in low concentration throughout the sac. Later in development, the antidote was enriched inside of the spores that inherited wtf4 from the parent yeast cell.

The researchers found that spores that inherited the driver gene manufactured additional antidote protein inside the spore to neutralize the poison and ensure their survival.

The team also discovered that a particular molecular switch that controls many other genes involved in spore formation also controls the expression of poison, but not antidote, from the wtf4 gene. The switch is essential for yeast reproduction and is inextricably linked to wtf4, helping to explain why this selfish gene is so successful at evading any attempts by the host to disable the switch.

"One of the reasons we are thinking these things have stuck around for so long -- they've used this sneaky strategy of exploiting the same essential switch that turns on yeast reproduction," said Nidamangala Srinivasa.

"If we could manipulate these DNA parasites to be expressed in mosquitoes and drive their destruction, it may be a way to control pest species," said Nuckolls.

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Revealing the genome of the common ancestor of all mammals

An international team has reconstructed the genome organization of the earliest common ancestor of all mammals. The reconstructed ancestral genome could help in understanding the evolution of mammals and in conservation of modern animals. The earliest mammal ancestor likely looked like the fossil animal "Morganucodon" which lived about 200 million years ago. The work is published the scientific journal Proceedings of the National Academy of Sciences.

Every modern mammal, from a platypus to a blue whale, is descended from a common ancestor that lived about 180 million years ago. We don't know a great deal about this animal, but the organization of its genome has now been computationally reconstructed by an international team of scientists.

"Our results have important implications for understanding the evolution of mammals and for conservation efforts," says Harris Lewin, distinguished professor of evolution and ecology at the University of California, Davis, and senior author on the paper.

The scientists drew on high-quality genome sequences from 32 living species representing 23 of the 26 known orders of mammals. They included humans and chimps, wombats and rabbits, manatees, domestic cattle, rhinos, bats and pangolins. The analysis also included the chicken and Chinese alligator genomes as comparison groups. Some of these genomes are being produced as part of the Earth BioGenome Project and other large-scale biodiversity genome sequencing efforts. Lewin chairs the Working Group for the Earth BioGenome Project.

The reconstruction shows that the mammal ancestor had 19 autosomal chromosomes, which control the inheritance of an organism's characteristics outside of those controlled by sex-linked chromosomes, (these are paired in most cells, making 38 in total) plus two sex chromosomes, said Joana Damas, first author on the study and a postdoctoral scientist at the UC Davis Genome Center. The team identified 1,215 blocks of genes that consistently occur on the same chromosome in the same order across all 32 genomes. These building blocks of all mammal genomes contain genes that are critical to developing a normal embryo.

Chromosomes stable over 300 million years

The scientists found nine whole chromosomes, or chromosome fragments in the mammal ancestor whose order of genes is the same in modern birds' chromosomes.

"This remarkable finding shows the evolutionary stability of the order and orientation of genes on chromosomes over an extended evolutionary timeframe of more than 320 million years," Lewin says. In contrast, regions between these conserved blocks contained more repetitive sequences and were more prone to breakages, rearrangements and sequence duplications, which are major drivers of genome evolution.

"Ancestral genome reconstructions are critical to interpreting where and why selective pressures vary across genomes. This study establishes a clear relationship between chromatin architecture, gene regulation and linkage conservation," says Professor William Murphy, Texas A&M University, who was not an author on the paper. "This provides the foundation for assessing the role of natural selection in chromosome evolution across the mammalian tree of life."

The scientists were able to follow the ancestral chromosomes forward in time from the common ancestor. They found that the rate of chromosome rearrangement differed between mammal lineages. For example, in the ruminant lineage (leading to modern cattle, sheep and deer) there was an acceleration in rearrangement 66 million years ago, when an asteroid impact killed off the dinosaurs and led to the rise of mammals.

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Plant breeding: Using 'invisible' chromosomes to pass on packages of positive traits

The ideal crop plant is tasty and high-yielding while also being resistant to diseases and pests. But if the relevant genes are far apart on a chromosome, some of these positive traits can be lost during breeding. To ensure that positive traits can be passed on together, researchers at Karlsruhe Institute of Technology (KIT) have used CRISPR/Cas molecular scissors to invert and thus genetically deactivate nine-tenths of a chromosome. The traits coded for on this part of the chromosome become "invisible" for genetic exchange and can thus be passed on unchanged. The researchers have reported on their findings in Nature Plants.

Targeted editing, insertion or suppression of genes in plants is possible with CRISPR/Cas molecular scissors. (CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats.) This method can be used to make plants more resistant to pests, diseases or environmental influences. "In recent years, we were able for the first time to use CRISPR/Cas not only to edit genes but also to change the structure of chromosomes," says Professor Holger Puchta, who for 30 years has been researching applications for gene scissors with his team at KIT's Botanical Institute. "Genes are linearly arranged along chromosomes. By changing their sequence, we were able to show how desired traits in plants can be separated from undesired ones."

Now the researchers have been able to prevent the genetic exchange that is normally part of the hereditary process but can break the links between traits. "We can shut down a chromosome almost completely, making it seem invisible, so that all traits on that chromosome can be passed on in a package," says Puchta. Until now, if a plant's traits were to be passed on together, the genes for those traits needed to be close to each other on the same chromosome. If such genes are spread farther apart on a chromosome, they are usually separated during inheritance, so a beneficial trait can be lost during the breeding process.

Learning from Nature: Chromosome Engineering Prevents Genetic Exchange

In their research, the scientists followed nature's example. "These reversals, or inversions -- a kind of genetic invisibility -- also occur frequently on a smaller scale in wild and cultivated plants. We've learned from nature and have applied and extended our knowledge about the natural process," says Puchta.

In collaboration with Professor Andreas Houben from the Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Puchta and his team inverted nine-tenths of a chromosome in the model organism Arabidopsis thaliana (thale cress). Only at the ends of the chromosome did the genes retain their original sequence. "With these fragments, the chromosome can be passed on to the next generation just like the other chromosomes and is not completely lost," says Puchta.

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Taking your time makes a difference

Neanderthals are the closest relatives to modern humans. Comparisons with them can therefore provide fascinating insights into what makes present-day humans unique, for example regarding the development of the brain. The neocortex, the largest part of the outer layer of the brain, is unique to mammals and crucial for many cognitive capacities. It expanded dramatically during human evolution in species ancestral to both Neanderthals and modern humans, resulting that both Neanderthals and modern humans having brains of similar sizes. However, almost nothing is known about how modern human and Neanderthal brains may have differed in terms of their development and function.

Researchers from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden and the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) in Leipzig have now discovered that neural stem cells -- the cells from which neurons in the developing neocortex derive -- spend more time preparing their chromosomes for division in modern humans than in Neanderthals. This results in fewer errors when chromosomes are distributed to the daughter cells in modern humans than in Neanderthals or chimpanzees, and could have consequences for how the brain develops and functions. This study shows cellular differences in the development of the brain between modern humans and Neanderthals.

After the ancestors of modern humans split from those of Neanderthals and Denisovans, their Asian relatives, about one hundred amino acids, the building blocks of proteins in cells and tissues, changed in modern humans and spread to almost all modern humans. The biological significance of these changes is largely unknown. However, six of those amino acid changes occurred in three proteins that play key roles in the distribution of chromosomes, the carriers of genetic information, to the two daughter cells during cell division.

The effects of the modern human variants on brain development

To investigate the significance of these six changes for neocortex development, the scientists first introduced the modern human variants in mice. Mice are identical to Neanderthals at those six amino acid positions, so these changes made them a model for the developing modern human brain. Felipe Mora-Bermúdez, the lead author of the study, describes the discovery: "We found that three modern human amino acids in two of the proteins cause a longer metaphase, a phase where chromosomes are prepared for cell division, and this results in fewer errors when the chromosomes are distributed to the daughter cells of the neural stem cells, just like in modern humans." To check if the Neanderthal set of amino acids have the opposite effect, the researchers then introduced the ancestral amino acids in human brain organoids -- miniature organ-like structures that can be grown from human stem cells in cell culture dishes in the lab and that mimic aspects of early human brain development. "In this case, metaphase became shorter and we found more chromosome distribution errors." According to Mora-Bermúdez, this shows that those three modern human amino acid changes in the proteins known as KIF18a and KNL1 are responsible for the fewer chromosome distribution mistakes seen in modern humans as compared to Neanderthal models and chimpanzees. He adds that "having mistakes in the number of chromosomes is usually not a good idea for cells, as can be seen in disorders like trisomies and cancer."

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Loss of male sex chromosome leads to earlier death for men

The loss of the male sex chromosome as many men age causes the heart muscle to scar and can lead to deadly heart failure, new research from the University of Virginia School of Medicine shows. The finding may help explain why men die, on average, several years younger than women.

UVA researcher Kenneth Walsh, PhD, says the new discovery suggests that men who suffer Y chromosome loss -- estimated to include 40% of 70-year-olds -- may particularly benefit from an existing drug that targets dangerous tissue scarring. The drug, he suspects, may help counteract the harmful effects of the chromosome loss -- effects that may manifest not just in the heart but in other parts of the body as well.

On average, women live five years longer than men in the United States. The new finding, Walsh estimates, may explain nearly four of the five-year difference.

"Particularly past age 60, men die more rapidly than women. It's as if they biologically age more quickly," said Walsh, the director of UVA's Hematovascular Biology Center. "There are more than 160 million males in the United States alone. The years of life lost due to the survival disadvantage of maleness is staggering. This new research provides clues as to why men have shorter lifespans than women."

Chromosome Loss and Heart Health

While women have two X chromosomes, men have an X and a Y. But many men begin to lose their Y chromosome in a fraction of their cells as they age. This appears to be particularly true for smokers. The loss occurs predominantly in cells that undergo rapid turnover, such as blood cells. (Loss of the Y chromosome does not occur in male reproductive cells, so it is not inherited by the children of men who exhibit Y chromosome loss.) Scientists previously observed that men who suffer Y chromosome loss are more likely to die at a younger age and suffer age-associated maladies such as Alzheimer's disease. Walsh's new research, however, is believed to be the first hard evidence that the chromosome loss directly causes harmful effects on men's health.

Walsh, of UVA's Division of Cardiovascular Medicine and the Robert M. Berne Cardiovascular Research Center, and his team used cutting-edge CRISPR gene-editing technology to develop a special mouse model to better understand the effects of Y chromosome loss in the blood. They found that the loss accelerated age-related diseases, made the mice more prone to heart scarring and led to earlier death. This wasn't the result of just inflammation, the scientists determined. Instead, the mice suffered a complex series of responses in the immune system, leading to a process referred to as fibrosis throughout the body. This tug-of-war within the immune system, the researchers believe, may accelerate disease development.

The scientists also looked at the effects of Y chromosome loss in human men. They conducted three analyses of data compiled from the UK Biobank, a massive biomedical database, and found that Y chromosome loss was associated with cardiovascular disease and heart failure. As chromosome loss increased, the scientists found, so did the risk of death.

Potential Treatment

The findings suggest that targeting the effects of Y chromosome loss could help men live longer, healthier lives. Walsh notes that one potential treatment option might be a drug, pirfenidone, that has already been approved by the federal Food and Drug Administration for the treatment of idiopathic pulmonary fibrosis, a form of lung scarring. The drug is also being tested for the treatment of heart failure and chronic kidney disease, two conditions for which tissue scarring is a hallmark. Based on his research, Walsh believes that men with Y chromosome loss could respond particularly well to this drug, and other classes of antifibrotic drugs that are being developed, though more research will be needed to determine that.

At the moment, doctors have no easy way to determine which men suffer Y chromosome loss. Walsh's collaborator Lars A. Forsberg, of Uppsala University in Sweden, has developed an inexpensive polymerase chain reaction (PCR) test, like those used for COVID-19 testing, that can detect Y chromosome loss, but the test is largely confined to his and Walsh's labs. Walsh, however, can foresee that changing: "If interest in this continues and it's shown to have utility in terms of being prognostic for men's disease and can lead to personalized therapy, maybe this becomes a routine diagnostic test," he said.

"The DNA of all our cells inevitably accumulate mutations as we age. This includes the loss of the entire Y chromosome within a subset of cells within men. Understanding that the body is a mosaic of acquired mutations provides clues about age-related diseases and the aging process itself," said Walsh, a member of UVA's Department of Biochemistry and Molecular Genetics. "Studies that examine Y chromosome loss and other acquired mutations have great promise for the development of personalized medicines that are tailored to these specific mutations."

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Researchers generate the first complete, gapless sequence of a human genome

Scientists have published the first complete, gapless sequence of a human genome, two decades after the Human Genome Project produced the first draft human genome sequence. According to researchers, having a complete, gap-free sequence of the roughly 3 billion bases (or "letters") in our DNA is critical for understanding the full spectrum of human genomic variation and for understanding the genetic contributions to certain diseases. The work was done by the Telomere to Telomere (T2T) consortium, which included leadership from researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health; University of California, Santa Cruz; and University of Washington, Seattle. NHGRI was the primary funder of the study.

Analyses of the complete genome sequence will significantly add to our knowledge of chromosomes, including more accurate maps for five chromosome arms, which opens new lines of research. This helps answer basic biology questions about how chromosomes properly segregate and divide. The T2T consortium used the now-complete genome sequence as a reference to discover more than 2 million additional variants in the human genome. These studies provide more accurate information about the genomic variants within 622 medically relevant genes.

"Generating a truly complete human genome sequence represents an incredible scientific achievement, providing the first comprehensive view of our DNA blueprint," said Eric Green, M.D., Ph.D., director of NHGRI. "This foundational information will strengthen the many ongoing efforts to understand all the functional nuances of the human genome, which in turn will empower genetic studies of human disease."

The now-complete human genome sequence will be particularly valuable for studies that aim to establish comprehensive views of human genomic variation, or how people's DNA differs. Such insights are vital for understanding the genetic contributions to certain diseases and for using genome sequence as a routine part of clinical care in the future. Many research groups have already started using a pre-release version of the complete human genome sequence for their research.

The full sequencing builds upon the work of the Human Genome Project, which mapped about 92% of the genome, and research undertaken since then. Thousands of researchers have developed better laboratory tools, computational methods and strategic approaches to decipher the complex sequence. Six papers encompassing the completed sequence appear in Science, along with companion papers in several other journals.

That last 8% includes numerous genes and repetitive DNA and is comparable in size to an entire chromosome. Researchers generated the complete genome sequence using a special cell line that has two identical copies of each chromosome, unlike most human cells, which carry two slightly different copies. The researchers noted that most of the newly added DNA sequences were near the repetitive telomeres (long, trailing ends of each chromosome) and centromeres (dense middle sections of each chromosome).

"Ever since we had the first draft human genome sequence, determining the exact sequence of complex genomic regions has been challenging," said Evan Eichler, Ph.D., researcher at the University of Washington School of Medicine and T2T consortium co-chair. "I am thrilled that we got the job done. The complete blueprint is going to revolutionize the way we think about human genomic variation, disease and evolution."

The cost of sequencing a human genome using "short-read" technologies, which provide several hundred bases of DNA sequence at a time, is only a few hundred dollars, having fallen significantly since the end of the Human Genome Project. However, using these short-read methods alone still leaves some gaps in assembled genome sequences. The massive drop in DNA sequencing costs comes hand-in-hand with increased investments in new DNA sequencing technologies to generate longer DNA sequence reads without compromising the accuracy.

Over the past decade, two new DNA sequencing technologies emerged that produced much longer sequence reads. The Oxford Nanopore DNA sequencing method can read up to 1 million DNA letters in a single read with modest accuracy, while the PacBio HiFi DNA sequencing method can read about 20,000 letters with nearly perfect accuracy. Researchers in the T2T consortium used both DNA sequencing methods to generate the complete human genome sequence.

"Using long-read methods, we have made breakthroughs in our understanding of the most difficult, repeat-rich parts of the human genome," says Karen Miga, Ph.D., a co-chair of the T2T consortium whose research group at the University of California, Santa Cruz is funded by NHGRI. "This complete human genome sequence has already provided new insight into genome biology, and I look forward to the next decade of discoveries about these newly revealed regions."

According to consortium co-chair Adam Phillippy, Ph.D., whose research group at NHGRI led the finishing effort, sequencing a person's entire genome should get less expensive and more straightforward in the coming years.

"In the future, when someone has their genome sequenced, we will be able to identify all of the variants in their DNA and use that information to better guide their healthcare," Phillippy said. "Truly finishing the human genome sequence was like putting on a new pair of glasses. Now that we can clearly see everything, we are one step closer to understanding what it all means."

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Male Y chromosome facilitates the evolution of sex differences in body size

Females and males differ in many ways and yet they share the same genome. The only exception is the male Y chromosome. Using beetles as a study system, new research from Uppsala University, now published in Nature Ecology & Evolution, shows that despite of the Y chromosome containing very few genes, it can dramatically change male body size and thus facilitate the evolution of sex differences.

Females and males typically differ in many ways in their morphology, physiology and behaviour. How such sex differences, known as sexual dimorphism, evolve is a puzzle because females and males share the same set of genes and an evolutionary change in one sex should cause a correlated change even in the other sex, thereby preventing sex differences from evolving. The new study shows that even small amounts of genetic differences between the sexes can facilitate the evolution of sexual dimorphism such that it can evolve in just a few generations.

"Our experiments show that the autosomes as well as both sex chromosomes, the X and Y, can harbor genetic variation important for sexual dimorphism, but the Y chromosome alone can alter the sex difference in size by as much as 30 percent. This is remarkable because in these beetles the Y chromosome contains just a handful of genes and represents a very small fraction of the genome, just like in humans. Many have thought that the Y only affects the most important reproductive processes in males, namely sperm production. Our findings suggest that the Y chromosome may have a broader role than previously appreciated," says Philipp Kaufmann, a PhD student at the Uppsala University's Department of Ecology and Genetics and the first author of the study.

The evolution of sexual dimorphism is however not only dependent on where in the genome genetic variation resides, but also on how natural and sexual selection can act on it. With the help of lab evolution, the research team showed that sexual size dimorphism could evolve when selecting on male size, but that when selection acted only on females, the shared part of the genome caused a correlated evolutionary response in males preventing dimorphism from evolving.

"The most drastic change in sexual dimorphism, an increase by 50 percent in only ten generations, occurred when we applied selection sexually antagonistically -- favoring the opposite body size in the two sexes. This shows that under right kind of selection sex differences can clearly evolve rapidly, perhaps more easily than was previously thought," says Elina Immonen, Assistant Professor at the Department of Ecology and Genetics, Uppsala University, and the principle investigator of the study.

"Combining information of what kind of genetic variation is available to selection with different forms of selection is a powerful way to test the determinants of evolution of sex differences. By isolating the effect of Y chromosome variation from the rest of the genome, we could directly demonstrate how large the effect of the Y chromosome is, something we didn't expect to see when we started the work and this has helped understand how sexual dimorphism has evolved in this species. Future work will tell us more regarding how the Y chromosome can have such a large effect on males and how general its role is in the evolution of sex differences across taxa," Immonen concludes.

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Mass of human chromosomes measured

Mass of human chromosomes have been measured for the first time.

The mass of human chromosomes, which contain the instructions for life in nearly every cell of our bodies, has been measured with X-rays for the first time in a new study led by UCL researchers.

For the study, published in Chromosome Research, researchers used a powerful X-ray beam at the UK's national synchrotron facility, Diamond Light Source, to determine the number of electrons in a spread of 46 chromosomes which they used to calculate mass.

They found that the chromosomes were about 20 times heavier than the DNA they contained -- a much larger mass than previously expected, suggesting there might be missing components yet to be discovered.

As well as DNA, chromosomes consist of proteins that serve a variety of functions, from reading the DNA to regulating processes of cell division to tightly packaging two-metre strands of DNA into our cells.

Senior author Professor Ian Robinson (London Centre for Nanotechnology at UCL) said: "Chromosomes have been investigated by scientists for 130 years but there are still parts of these complex structures that are poorly understood.

"The mass of DNA we know from the Human Genome Project, but this is the first time we have been able to precisely measure the masses of chromosomes that include this DNA.

"Our measurement suggests the 46 chromosomes in each of our cells weigh 242 picograms (trillionths of a gram). This is heavier than we would expect, and, if replicated, points to unexplained excess mass in chromosomes."

In the study, researchers used a method called X-ray ptychography, which involves stitching together the diffraction patterns that occur as the X-ray beam passes through the chromosomes, to create a highly sensitive 3D reconstruction. The fine resolution was possible as the beam deployed at Diamond Light Source was billions of times brighter than the Sun (ie, there was a very large number of photons passing through at a given time).

The chromosomes were imaged in metaphase, just before they were about to divide into two daughter cells. This is when packaging proteins wind up the DNA into very compact, precise structures.

Archana Bhartiya, a PhD student at the London Centre for Nanotechnology at UCL and lead author of the paper, said: "A better understanding of chromosomes may have important implications for human health.

"A vast amount of study of chromosomes is undertaken in medical labs to diagnose cancer from patient samples. Any improvements in our abilities to image chromosomes would therefore be highly valuable."

Each human cell, at metaphase, normally contains 23 pairs of chromosomes, or 46 in total. Within these are four copies of 3.5 billion base pairs of DNA.

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Genetics of the tree of life

 The African baobab tree (Adansonia digitata) is called the tree of life. Baobab trees can live for more than a thousand years and provide food, livestock fodder, medicinal compounds, and raw materials. Baobab trees are incredibly significant. However, there are growing conservation concerns and until now, a lack of genetic information.

The African baobab tree has 168 chromosomes -- critical knowledge for further genetic studies, conservation, and improvement for agricultural purposes. The findings were published in the journal Scientific Reports. Previous studies estimated that the tree has between 96 and 166 chromosomes.

"We were able to unequivocally count the chromosomes," says Nurul Faridi, a USDA Forest Service research geneticist who co-led the study with Hamidou Sakhanokho, a USDA Agricultural Research Service research geneticist.

The researchers used fluorescent probes to see the genetic components of individual chromosomes within the cells -- which glow like jewels.

The analysis also revealed that the tree has a massive nucleolus organizer region (NOR). Relative to the main chromosome body, this region appears larger than that of any other plant species. During certain stages of the cell cycle, nucleoli form at the NORs. The nucleoli are essential for ribosome assembly and protein synthesis in eukaryotes and are an important feature that differentiates eukaryotes from prokaryotes.

"These genetic findings are foundational and will make genetic conservation of the African baobab tree more efficient and effective," says Dana Nelson, a coauthor and project leader of the Southern Research Station's genetic unit. "This research is also a precursor for tree breeding programs seeking to improve baobab for silvicultural applications."

From Science Daily

Virgin birth has scientists buzzing

In a study published today in Current Biology, researchers from University of Sydney have identified the single gene that determines how Cape honey bees reproduce without ever having sex. One gene, GB45239 on chromosome 11, is responsible for virgin births.

"It is extremely exciting," said Professor Benjamin Oldroyd in the School of Life and Environmental Sciences. "Scientists have been looking for this gene for the last 30 years. Now that we know it's on chromosome 11, we have solved a mystery."

Behavioural geneticist Professor Oldroyd said: "Sex is a weird way to reproduce and yet it is the most common form of reproduction for animals and plants on the planet. It's a major biological mystery why there is so much sex going on and it doesn't make evolutionary sense. Asexuality is a much more efficient way to reproduce, and every now and then we see a species revert to it."

In the Cape honey bee, found in South Africa, the gene has allowed worker bees to lay eggs that only produce females instead of the normal males that other honey bees do. "Males are mostly useless," Professor Oldroyd said. "But Cape workers can become genetically reincarnated as a female queen and that prospect changes everything."

But it also causes problems. "Instead of being a cooperative society, Cape honey bee colonies are riven with conflict because any worker can be genetically reincarnated as the next queen. When a colony loses its queen the workers fight and compete to be the mother of the next queen," Professor Oldroyd said.

The ability to produce daughters asexually, known as "thelytokous parthenogenesis," is restricted to a single subspecies inhabiting the Cape region of South Africa, the Cape honey bee or Apis mellifera capensis.

Several other traits distinguish the Cape honey bee from other honey bee subspecies. In particular, the ovaries of worker bees are larger and more readily activated and they are able to produce queen pheromones, allowing them to assert reproductive dominance in a colony.

These traits also lead to a propensity for social parasitism, a behaviour where Cape bee workers invade foreign colonies, reproduce and persuade the host colony workers to feed their larvae. Every year in South Africa, 10,000 colonies of commercial beehives die because of the social parasite behaviour in Cape honey bees.

"This is a bee we must keep out of Australia," Professor Oldroyd said.

The existence of Cape bees with these characters has been known for over a hundred years, but it is only recently, using modern genomic tools, that we have been able to understand the actual gene that gives rise to virgin birth.

"Further study of Cape bees could give us insight into two major evolutionary transitions: the origin of sex and the origin of animal societies," Professor Oldroyd said.

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New technique delivers complete DNA sequences of chromosomes inherited from mother and father

An international team of scientists led by the University of Adelaide's Davies Research Centre has shown that it is possible to disentangle the DNA sequences of the chromosomes inherited from the mother and the father, to create true diploid genomes from a single individual.

In a report published in Nature Communications, and funded by the Davies Research Centre over the past 15 years, the researchers have shown that genomes of two important modern-day cattle breeds, Angus (Bos taurus taurus) and Brahman (Bos taurus indicus), can be completely decoded from a single hybrid individual carrying the genetics of both breeds, using an innovative genome assembly strategy.

Although demonstrated in cattle, the approach is applicable to other species including humans.

Dr Lloyd Low, from the University of Adelaide's School of Animal and Veterinary Science, says the technique, called trio binning, gives the true genome sequence of each chromosome in an individual.

Obtaining a full genome from an organism that inherits half the chromosomes from the mother and the other half from the father is difficult due to the high similarity between the parental chromosomes.

"Back in 2018 we were able to demonstrate that with this method it was possible to identify large sections of the DNA from the parents. Now in 2020 we have used the same concept to create the sequence of full chromosomes," Lloyd said.

Professor John Williams added: "Disentangling maternal and paternal genomes is very difficult, but we have now been able to do this and create the best genome assemblies available for any livestock, and arguably any species."

"These high quality genome sequences will make it easier to more accurately study the genetics of cattle to improve production and welfare traits."

Brahman and Angus cattle subspecies were domesticated separately thousands of years ago and have been subjected to very different selection pressures since then; pest and humid environments in the case of the Brahman cattle and beef production in Angus cattle. These different characteristics and histories are reflected in their genomes, which makes them ideal test subjects.

Indian breeds such as Brahman cattle are better able to regulate body temperature and are routinely crossed with European breeds such as Angus to produce cattle that are better adapted to tropical climates.

Considering the large differences in production and adaptation traits between taurine and indicine cattle, comparing the genomes helps us understand how the animals adapt to their environment, which is of substantial scientific and economic interest.

Professor Stefan Hiendleder said high-quality genomes of both cattle subspecies were needed to decipher the differences between taurine and indicine cattle.

"This technology will ultimately lead to breeding cattle which are more productive in harsh environments and also better suited from an animal welfare perspective," he said.

"Comparison between the Brahman and Angus revealed an indicus-specific extra copy of fatty acid enzyme which may be important for the regulation of the metabolism related to heat tolerance."

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