Cracking the code of life: new AI model learns DNA's hidden language

DNA contains foundational information needed to sustain life. Understanding how this information is stored and organized has been one of the greatest scientific challenges of the last century. With GROVER, a new large language model trained on human DNA, researchers could now attempt to decode the complex information hidden in our genome. Developed by a team at the Biotechnology Center (BIOTEC) of Dresden University of Technology, GROVER treats human DNA as a text, learning its rules and context to draw functional information about the DNA sequences. This new tool, published in Nature Machine Intelligence, has the potential to transform genomics and accelerate personalized medicine.

Since the discovery of the double helix, scientists have sought to understand the information encoded in DNA. 70 years later, it is clear that the information hidden in the DNA is multilayered. Only 1-2 % of the genome consists of genes, the sequences that code for proteins.

"DNA has many functions beyond coding for proteins. Some sequences regulate genes, others serve structural purposes, most sequences serve multiple functions at once. Currently, we don't understand the meaning of most of the DNA. When it comes to understanding the non-coding regions of the DNA, it seems that we have only started to scratch the surface. This is where AI and large language models can help," says Dr. Anna Poetsch, research group leader at the BIOTEC.

DNA as a Language

Large language models, like GPT, have transformed our understanding of language. Trained exclusively on text, the large language models developed the ability to use the language in many contexts.

"DNA is the code of life. Why not treat it like a language?" says Dr. Poetsch. The Poetsch team trained a large language model on a reference human genome. The resulting tool named GROVER, or "Genome Rules Obtained via Extracted Representations," can be used to extract biological meaning from the DNA.

"GROVER learned the rules of DNA. In terms of language, we are talking about grammar, syntax, and semantics. For DNA this means learning the rules governing the sequences, the order of the nucleotides and sequences, and the meaning of the sequences. Like GPT models learning human languages, GROVER has basically learned how to 'speak' DNA," explains Dr. Melissa Sanabria, the researcher behind the project.

The team showed that GROVER can not only accurately predict the following DNA sequences but can also be used to extract contextual information that has biological meaning, e.g., identify gene promoters or protein binding sites on DNA. GROVER also learns processes that are generally considered to be "epigenetic," i.e., regulatory processes that happen on top of the DNA rather than being encoded.

"It is fascinating that by training GROVER with only the DNA sequence, without any annotations of functions, we are actually able to extract information on biological function. To us, it shows that the function, including some of the epigenetic information, is also encoded in the sequence," says Dr. Sanabria.

The DNA Dictionary

"DNA resembles language. It has four letters that build sequences and the sequences carry a meaning. However, unlike a language, DNA has no defined words," says Dr. Poetsch. DNA consists of four letters (A, T, G, and C) and genes, but there are no predefined sequences of different lengths that combine to build genes or other meaningful sequences.

To train GROVER, the team had to first create a DNA dictionary. They used a trick from compression algorithms. "This step is crucial and sets our DNA language model apart from the previous attempts," says Dr. Poetsch.

"We analyzed the whole genome and looked for combinations of letters that occur most often. We started with two letters and went over the DNA, again and again, to build it up to the most common multi-letter combinations. In this way, in about 600 cycles, we have fragmented the DNA into 'words' that let GROVER perform the best when it comes to predicting the next sequence," explains Dr. Sanabria.

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Evolution's recipe book: How 'copy paste' errors cooked up the animal kingdom

A series of whole genome and gene duplication events that go back hundreds of millions of years have laid the foundations for tissue-specific gene expression, according to a new study in the journal Nature Ecology and Evolution. The 'copy paste' errors allowed animals to keep one copy of their genome or genes for fundamental functions, while the second copy could be used as raw material for evolutionary innovation. Events like these, at varying degrees of scale, occurred constantly throughout the bilaterian evolutionary tree and enabled traits and behaviours as diverse as insect flight, octopus camouflage and human cognition.

700 million years ago, a remarkable creature emerged for the first time. Though it may not have been much to look at by today's standards, the animal had a front and a back, a top and a bottom. This was a groundbreaking adaptation at the time, and one which laid down the basic body plan which most complex animals, including humans, would eventually inherit.

The inconspicuous animal resided in the ancient seas of Earth, likely crawling along the seafloor. This was the last common ancestor of bilaterians, a vast supergroup of animals including vertebrates (fish, amphibians, reptiles, birds, and mammals), and invertebrates (insects, arthropods, molluscs, worms, echinoderms and many more).

To this day, more than 7,000 groups of genes can be traced back to the last common ancestor of bilaterians, according to a study of 20 different bilaterian species including humans, sharks, mayflies, centipedes and octopuses. The findings were made by researchers at the Centre for Genomic Regulation (CRG) in Barcelona and are published today in the journal Nature Ecology and Evolution.

Remarkably, the study found that around half of these ancestral genes have since been repurposed by animals for use in specific parts of the body, particularly in the brain and reproductive tissues. The findings are surprising because ancient, conserved genes usually have fundamental, important jobs that are needed in many parts of the body.

When the researchers took a closer look, they found a series of serendipitous 'copy paste' errors during bilaterian evolution were to blame. For example, there was a significant moment early in the history of vertebrates. A bunch of tissue-specific genes first appeared coinciding with two whole genome duplication events. Animals could keep one copy for fundamental functions, while the second copy could be used as raw material for evolutionary innovation. Events like these, at varying degrees of scale, occurred constantly throughout the bilaterian evolutionary tree.

"Our genes are like a vast library of recipes that can be cooked up differently to create or change tissues and organs. Imagine you end up with two copies of a recipe for paella by accident. You can keep and enjoy the original recipe while evolution tweaks the extra copy so that it makes risotto instead. Now imagine the entire recipe book is copied -- twice -- and the possibilities it opens for evolution. The legacy of these events, which took place hundreds of millions of years ago, lives on in most complex animals today," explains Federica Mantica, author of the paper and researcher at the Centre for Genomic Regulation (CRG) in Barcelona.

The authors of the study found many examples of new, tissue-specific functions made possible by the specialisation of these ancestral genes. For example, the TESMIN and tomb genes, which originated from the same ancestor, ended up independently playing a specialised role in the testis both in vertebrates and insects. Their importance is highlighted by the fact that problems with these genes can disrupt sperm production, affecting fertility in both mice and fruit flies.

The specialisation of ancestral genes also laid some foundations for the development of complex nervous systems. For example, in vertebrates, the researchers found genes critical for the formation of myelin sheaths around nerve cells, which are essential for fast nerve signal transmission. In humans they also identified FGF17, which is thought to play an important role in maintaining cognitive functions into old age.

In insects, specific genes became specialised in muscles and in the epidermis for cuticle formation, contributing to their ability to fly. In the skin of octopuses, other genes became specialised to perceive light stimulI, contributing to their ability to change colour, camouflage and communicate with other octopuses.

By studying the evolution of species at the tissue level, the study demonstrates that changes in the way genes are used in different parts of the body have played a big role in creating new and unique features in animals. In other words, when genes start acting in specific tissues, it can lead to the development of new physical traits or abilities, which ultimately contributes to animal evolution.

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Nerve cells not entirely 'young at heart'

Most human nerve cells last a lifetime without renewal. A trait echoed within the cells' components, some enduring as long as the organism itself. New research by Martin Hetzer, molecular biologist and president of the Institute of Science and Technology Austria (ISTA), and colleagues discovered RNA, a typical transient molecule, in the nerve cells of mice that remain stable for their entire lives. Published in Science, these findings contribute to unraveling the complexities of brain aging and associated diseases.

After two decades in the United States, Martin Hetzer returned home to Austria in 2023 to become the 2nd President of the Institute of Science and Technology Austria (ISTA). A year into his new role, the molecular biologist remains engaged in the realm of aging research.

Hetzer is fascinated by the biological puzzles surrounding the aging processes in organs like the brain, heart, and pancreas. Most cells comprising these organs are not renewed throughout a human's entire life span. Nerve cells (neurons) in the human brain, for instance, can be as old as the organism, even up to more than a century, and must function for a lifetime. This remarkable age of neurons might be a major risk factor for neurodegenerative disorders such as Alzheimer's disease. Crucial to comprehending these kinds of ailments is a deeper understanding of how nerve cells function over time and maintain control. This potentially opens doors to therapeutically counteract the aging processes of these specific cells.

The latest collaborative publication by Hetzer, Tomohisa Toda from the Friedrich-Alexander University Erlangen-Nürnberg (FAU), who is also associated with the Max Planck Center for Physics and Medicine, Erlangen, and colleagues, gives new insights into this underexplored field of intricate mechanisms. For the first time in mammals, the study shows that RNA -- an essential group of molecules important for various biological processes inside the cell -- can persist throughout life. The scientists identified specific RNAs with genome-protecting functions in the nuclei of nerve cells of mice that remain stable for two years, covering their entire lives. The findings, published in the journal Science, underpin the importance of long-lived key molecules for maintaining a cell's function.

Longevity of key molecules

The inside of cells is a very dynamic place. Some components are constantly renewed and updated; others stay the same their whole lives. It is like a city in which the old buildings blend in with the new ones. DNA found in the nucleus -- the city's heart -- for instance, is as old as the organism. "DNA in our nerve cells is identical to DNA within the developing nerve cells in our mother's womb," explains Hetzer.

Unlike stable DNA, which is constantly being repaired, RNA, especially messenger RNA (mRNA), which forms proteins upon DNA's information, is characterized by its transient nature. The cellular scope, however, extends beyond mRNA to a group of so-called non-coding RNAs. They do not turn into proteins; instead, they have specific duties to contribute to the overall organization and function of the cell. Intriguingly, their lifespan remained a mystery. Until now.

RNAs that last the whole life

Hetzer and Co. set out to decipher that secret. Therefore, RNAs were labeled, i.e. "marked," in the brains of newborn mice. "For this labeling, we used RNA analogs -- structurally similar molecules -- with little chemical hooks that click fluorescent molecules on the actual RNAs," explains Hetzer. This assured efficient tracking of the molecules and powerful microscopic snapshots at any given time point in the mice's lives.

"Surprisingly, our initial images revealed the presence of long-lived RNAs, in various cell types within the brain. We had to further dissect the data to identify the ones in the nerve cells," Hetzer explains. "Fruitful collaboration with Toda's lab enabled us to make sense of that chaos during brain mapping." Collaboratively, the researchers were able to focus solely on long-lived RNAs in neurons. They quantified the molecules' concentration throughout a mouse's life, examined their composition and analyzed their positions.

While humans have an average life expectancy of around 70 years, the typical lifespan of a mouse is 2.5 years. After one year, the concentration of long-lived RNAs was slightly reduced compared to newborns. However, even after two years, they remained detectable indicating a lifelong persistence of these molecules.

RNAs help protect the genome

Additionally, the scientists proved long-lived RNAs' prominent role in cellular longevity. They found out that long-lived RNAs in neurons consist of mRNAs and non-coding RNAs and accumulate near the heterochromatin -- the densely packed region of the genome, typically homing inactive genes. Next they further investigated the function of these long-lived RNAs.

In molecular biology, the most effective approach to achieve this is by reducing the molecule of interest and observing its subsequent effects. "As their name and our previous experiments suggest, these long-lived RNAs are extremely stable," says Hetzer. The scientists, therefore, employed an in vitro (outside a living organism) approach, using neuronal progenitor cells -- stem cells with the capacity to give rise to neural cells, including neurons. The model system allowed them to effectively intervene with these long-lived RNAs. A lower amount of long-lived RNAs caused problems in the heterochromatin architecture and stability of genetic material, eventually affecting the cells' viability. Thus, the important role of long-lived RNAs' in cellular longevity was clarified.

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'Genomic time machine' reveals secrets of our DNA

The human genome, an intricate tapestry of genetic information for life, has proven to be a treasure trove of strange features. Among them are segments of DNA that can "jump around" and move within the genome, known as "transposable elements" (TEs).

As they change their position within the genome, TEs can potentially cause mutations and alter the cell's genetic profile, but also are master orchestrators of our genome's organization and expression.

For example, TEs contribute to regulatory elements, transcription factor binding sites, and the creation of chimeric transcripts -- genetic sequences created when segments from two different genes or parts of the genome join together to form a new, hybrid RNA molecule.

Matching their functional importance, TEs have been recognized to account for half of the human DNA.

However, as they move and age, TEs pick up changes that mask their original form.

Over time, TEs "degenerate" and become less recognizable, making it difficult for scientists to identify and track them in our genetic blueprint.

In a new study, researchers in the group of Didier Trono at EPFL have found a way to improve the detection of TEs in the human genome by using reconstructed ancestral genomes from various species, which allowed them to identify previously undetectable degenerate TEs in the human genome.

The study is published in Cell Genomics.

The scientists used a database of reconstructed ancestral genomes from different kinds of species, like a genomic "time machine." By comparing the human genome with the reconstructed ancestral genomes, they could identify TEs in the latter that, over millions of years, have become degenerate (worn out) in humans.

This comparison allowed them to detect ("annotate") TEs that might have been missed in previous studies that used data only from the human genome.

Using this approach, the scientists uncovered a larger number of TEs than previously known, adding significantly to the share of our DNA that is contributed by TEs.

Furthermore, they could demonstrate that these newly unearthed TE sequences played all the same regulatory roles as their more recent, already identified relatives.

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Candida evolution disclosed: New insights into fungal infections

Global fungal infections, which affect one billion people and cause 1.5 million deaths each year, are on the rise due to the increasing number of medical treatments that heighten vulnerability. Patients undergoing chemotherapy or immunosuppressive treatments after organ transplant often present compromised immune systems. Given the emergence of resistant strains, the limited variety of current antifungal drugs as well as their cost and side effects, the treatment of these infections is challenging and brings about an urgent need for more effective treatments.

In this context, a team from the Institute for Research in Biomedicine (IRB Barcelona) and the Barcelona Supercomputing Center -- Centro Nacional de Supercomputación (BSC-CNS), led by the ICREA researcher Dr. Toni Gabaldón, has identified hundreds of genes subject to recent, clinically-relevant selection in six species of the fungal pathogen Candida.

"This work highlights how thesepathogens adapted to humans and antifungal drugs and provides valuable knowledge that could lead to better treatments for Candida infections," explains Dr. Gabaldón, head of the Comparative Genomics lab at IRB Barcelona and the BSC.

More than 2,000 genomes from 6 different species

The study delves into the evolutionary landscape of Candida pathogens by analysing approximately 2,000 genomes from clinical samples of six major Candida species.

These genomes are stored in public databases. The researchers compared these genomes to a reference, creating a comprehensive catalogue of genetic variants.

Building on previous work addressing drug-resistant strains, the researchers conducted a Genome-Wide Association Study (GWAS) to identify genetic variants linked to antifungal drug resistance in clinical isolates.

This approach provided insights into both known and novel mechanisms of resistance towards seven antifungal drugs in three Candida species.

"Additionally, a concerning finding has arisen from the study: the potential spread of resistance through mating between susceptible and resistant strains, contributing to the prevalence of drug-resistant Candida pathogens," explains Dr. Miquel Àngel Schikora-Tamarit, a postdoctoral researcher in the same lab and first author of the study.

In addition, by focusing on variants acquired recently among clinical strains, the researches detected shared and species-specific genetic signatures of recent selection that inform on which adaptations might be needed to thrive and spread in human-related environments.

Beyond the novel insights into the adaptation of Candida, the study provides a valuable resource, namely a comprehensive catalogue of variants, selection signatures, and drivers of drug resistance.

This knowledge not only contributes to our understanding of these infections but also lays the groundwork for future experiments and potential advancements in the development of more effective treatments for Candida infections.

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Evolution is not as random as previously thought

A groundbreaking study has found that evolution is not as unpredictable as previously thought, which could allow scientists to explore which genes could be useful to tackle real-world issues such as antibiotic resistance, disease and climate change.

The study, which is published in the Proceedings of the National Academy of Sciences (PNAS), challenges the long-standing belief about the unpredictability of evolution, and has found that the evolutionary trajectory of a genome may be influenced by its evolutionary history, rather than determined by numerous factors and historical accidents.

The study was led by Professor James McInerney and Dr. Alan Beavan from the School of Life Sciences at the University of Nottingham, and Dr. Maria Rosa Domingo-Sananes from Nottingham Trent University.

"The implications of this research are nothing short of revolutionary," said Professor McInerney, the lead author of the study.

"By demonstrating that evolution is not as random as we once thought, we've opened the door to an array of possibilities in synthetic biology, medicine, and environmental science."

The team carried out an analysis of the pangenome -- the complete set of genes within a given species, to answer a critical question of whether evolution is predictable or whether the evolutionary paths of genomes are dependent on their history and so not predictable today.

Using a machine learning approach known as Random Forest, along with a dataset of 2,500 complete genomes from a single bacterial species, the team carried out several hundred thousand hours of computer processing to address the question.

After feeding the data into their high-performance computer, the team first made "gene families" from each of the gene of each genome.

"In this way, we could compare like-with-like across the genomes," said Dr. Domingo-Sananes.

Once the families had been identified, the team analysed the pattern of how these families were present in some genomes and absent in others.

"We found that some gene families never turned up in a genome when a particular other gene family was already there, and on other occasions, some genes were very much dependent on a different gene family being present."

In effect, the researchers discovered an invisible ecosystem where genes can cooperate or can be in conflict with one another.

"These interactions between genes make aspects of evolution somewhat predictable and furthermore, we now have a tool that allows us to make those predictions," adds Dr. Domingo-Sananes.

Dr Beavan said: "From this work, we can begin to explore which genes "support" an antibiotic resistance gene, for example. Therefore, if we are trying to eliminate antibiotic resistance, we can target not just the focal gene, but we can also target its supporting genes.

"We can use this approach to synthesise new kinds of genetic constructs that could be used to develop new drugs or vaccines. Knowing what we now know has opened the door to a whole host of other discoveries."

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187 new genetic variants linked to prostate cancer found in largest, most diverse study of its kind

A globe-spanning scientific team has compiled the most comprehensive list of genetic variants associated with prostate cancer risk -- 451 in all -- through a whole-genome analysis that ranks as the largest and most diverse investigation into prostate cancer genetics yet. The research, led by the USC Center for Genetic Epidemiology, the Keck School of Medicine of USC and USC Norris Comprehensive Cancer Center, and in the United Kingdom by The Institute of Cancer Research, London, included major increases in representation among men from racial and ethnic groups that have often been left out of such research, revising what is known about genetic risk for the disease.

With these findings, the researchers improved a system they developed for measuring genetic risk so that it was more effective in predicting who would or wouldn't develop prostate cancer -- even distinguishing between the likelihood of aggressive and less-serious cases among men of African descent. The finding that higher risk scores based on the 451 variants correlated with more-aggressive disease in men of African ancestry is a meaningful step toward improving early detection and making better informed decisions about screening.

The study, published in Nature Genetics, builds on 2021 research documented in the same journal that found 269 genetic variants correlating with prostate cancer risk, based on a sample of nearly 235,000 men. The new results were derived from genomic information from close to 950,000 men.

"We're not going to learn everything there is to know about the genetics of prostate cancer by studying only white men," said co-senior author Christopher Haiman, ScD, holder of the AFLAC Chair in Cancer Research and professor of population and public health sciences at the Keck School of Medicine. "Larger and larger studies, engaging a broader spectrum of populations, are important if we're going to identify genetic markers of risk and develop risk prediction tools that are equally effective across populations."

A substantial revision of what's known about genetic risk for prostate cancer

The researchers compared genomic data from 156,319 prostate cancer patients with that of a control group totaling 788,443. From the previous study, there was an 87% increase in the number of prostate cancer cases included from men of African ancestry, 45% from Latino ethnicity, 43% from European ancestry and 26% from Asian ancestry.

Haiman and his colleagues found 187 new genetic variants associated with prostate cancer risk. They also found 150 genetic variants from earlier research that were replaced by variants in nearby spots on the DNA double helix that better correlated with prostate cancer risk through the lens of the larger, more diverse sample.

"It's an important refinement to find markers that are better at capturing risk across populations," said Haiman, who is also director of the USC Center for Genetic Epidemiology and co-leader of the Cancer Epidemiology Program at USC Norris cancer center. "The idea of precision medicine and global medicine for all rely on including and integrating information across populations, because the best marker determined in whites might not be the best marker overall."

Progress in assessing risk thanks to an international effort

In addition to fueling further research, the results have the potential to benefit human health by providing men with personalized risk information that they can use when having discussions with their doctors about screening and treatment. Ultimately the research could lay the ground work for genetic testing to identify those at greater risk for aggressive prostate cancer and enable early detection by screening them earlier and more often.

Because many prostate cancer cases diagnosed today might never reach the point where they are life-threatening -- leading to unnecessary treatment that can degrade quality of life -- differentiating between risk for aggressive disease is key. Up until now, the scientists' system for calculating risk scores has correlated with likelihood of developing prostate cancer, but lacked predictive value about how serious a given case may be.

"We'll continue to improve this risk score, and look for markers that help to distinguish aggressive from less aggressive disease," Haiman said. "Clinical trials will be required to evaluate the effectiveness of the risk score in helping doctors and patients make decisions about screening."

This research combined the data from virtually every study to date examining DNA for genetic variants associated with prostate cancer risk. The U.S. Veterans Health Administration's Million Veteran Program and Argonne National Laboratory proved to be essential partners [for including diverse populations in the study]. Bringing it all together required a team effort encompassing more than 300 researchers from well over 100 institutions, in 26 nations -- from Barbados to Bulgaria, Nigeria to the Netherlands and Japan to Ghana.

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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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New secrets about cat evolution revealed

Researchers at the Texas A&M School of Veterinary Medicine & Biomedical Sciences (VMBS) and an interdisciplinary team of collaborators have uncovered new information about the history of cat evolution explaining how cats -- including well-known species like lions, tigers, and domestic cats -- evolved into different species and shedding light on how different genetic changes in cats relate to survival abilities like the ability to smell prey.

By comparing genomes of several cat species, the project, published today in Nature Genetics, has helped researchers understand why cat genomes tend to have fewer complex genetic variations (such as rearrangements of DNA segments) than other mammal groups, like primates. It also revealed new insights into which parts of cat DNA are most likely to evolve rapidly and how they play a role in species differentiation.

"Our goal was to better understand how cats evolved and the genetic basis of the trait differences between cat species," said Dr. Bill Murphy, a VMBS professor of veterinary integrative biosciences who specializes in cat evolution. "We wanted to take advantage of some new technologies that allow us to create more complete cat genomic maps.

"Our findings will open doors for people studying feline diseases, behavior, and conservation," he said. "They'll be working with a more complete understanding of the genetic differences that make each type of cat unique."

Variations On A Theme

Among the things the scientists were trying to better understand is why feline chromosomes -- cellular structures containing the genetic information for traits like fur color, size, and sensory abilities -- are more stable than in other mammal groups.

"We've known for a while now that cat chromosomes across species are very similar to each other," Murphy said. "For example, the chromosomes of lions and domestic cats hardly differ at all. There appear to be far fewer duplications, rearrangements, and other types of variation than what are commonly found in great apes."

In the primate order, this kind of genetic variation has led to the evolution of different species -- including humans and great apes.

"The great ape genomes tend to break and rearrange, and even human genomes have very unstable regions," Murphy said. "These variations may predispose certain individuals to have genetic conditions, like autism and other neurological disorders."

The key to this variation between cats and apes, as Murphy found out, appears to be the frequency of something called segmental duplications -- segments of DNA that are highly similar copies of other DNA segments found elsewhere in the genome.

"Primate genome researchers have been able to link these segmental duplications to chromosome rearrangements," he said. The more segmental duplications you have in your DNA, the more likely the chromosomes are to rearrange, etc.

"What we discovered by comparing a large number of cat species genomes is that cats have just a fraction of the segmental duplications found in other mammal groups -- primates actually have seven times more of these duplications than cats. That's a big difference, and now we believe we understand why cat genomes are more stable," he said.

A Needle In A (Double) Helix

While cats may not have as many large genetic rearrangements in their DNA, they still have plenty of differences. Through their research, Murphy and his colleagues now better understand which parts of cat DNA cause those variations, especially the variations that define speciation, or the differences between species.

"It turns out that there's a large region on the center of the X chromosome where most of the genetic rearrangements are happening," Murphy said. "In fact, there's one specific repetitive element within this region called DXZ4 that evidence tells us is largely responsible for the genetic isolation of at least two cat species, the domestic and jungle cat."

DXZ4 is what Murphy calls a satellite repeat -- it's not a typical gene that codes for a physical trait like fur color, but, rather, it aids in the three-dimensional structure of the X chromosome and likely played an important role in cat speciation.

"We still don't know the precise mechanism, but by comparing all these cat genomes, we can better measure the rate at which DXZ4 evolved in one species compared to all the others. What we learned is that DXZ4 is one of the most rapidly evolving parts of the cat genome; it's evolving faster than 99.5% of the rest of the genome," he explained.

"Because of the rate at which it mutates, we were able to demonstrate why DXZ4 is probably linked to speciation," Murphy said.

Sniffing Out Elusive Genes

Using new, highly detailed genome sequences, the team also uncovered clearer links between the number of olfactory genes, which govern scent detection in cats and variation in social behavior and how they relate to their surroundings.

"Since cats are predators who rely heavily on smell to detect their prey, their sense of smell is a pretty important part of who they are," he said. "Cats are a very diverse family, and we've always wanted to understand how genetic variation plays a role in different cat species' ability to smell in their different environments.

"Lions and tigers have a pretty big difference between certain odorant genes involved in detecting pheromones, which are chemicals that different animals release into the environment to communicate information about identity, territory, or danger," Murphy said.

"We think the large difference has to do with lions being very social animals living in family groups and tigers living a solitary lifestyle. Lions may have a reduced reliance on pheromones and other odorants because they're constantly around other lions, reflected in the fewer genes of this type in their genomes," he said.

Tigers, on the other hand, need to be able to smell prey across very large territories as well as find mates.

"Tigers, in general, have large olfactory and pheromone receptor repertoires," Murphy said. "We think this is directly tied to the size of their territories and the variety of environments in which they live."

Domestic cats, on the other hand, appear to have lost a wide range of olfactory genes.

"If they don't have to travel as far to find what they need because they're living with people, it makes sense that natural selection wouldn't preserve those genes," he said.

Murphy shared that his favorite example from the project is the odorant receptors from the fishing cat, an aquatically adapted wild cat species living in Southeast Asia.

"We were able to show that fishing cats have retained many genes for detecting waterborne odorants, which is a pretty rare trait in terrestrial vertebrates," he said. "All of the other cat species have lost these specific genes over time, but fishing cats still have them."

This new information about olfactory genes in cats was made possible through a new approach to genome sequencing called trio binning, which allows researchers to sequence the most difficult regions of a genome.

This new technology also makes separating maternal and paternal DNA much easier.

"With trio binning, you can now take DNA from an F1 hybrid -- an animal whose DNA is split 50-50 between parents of different species -- and cleanly separate the maternal and paternal DNA, giving you two complete sets of DNA, one for each parent species," Murphy said. "The process is much simpler, and the results are more complete."

Filling In The Blanks

One of the most important conclusions from the project is that cat species may be similar in many ways, but their differences matter.

"These differences are showing us how these animals are perfectly suited for their natural environments," Murphy said. "They're not interchangeable, and that's valuable information for conservationists and others working to preserve or restore species in their natural habitats.

"For example, you can't assume that tigers from Sumatra and Siberia are the same," he said. "Their environments are wildly different, and those tiger populations have likely developed specialized genetic adaptations to help them survive in these very different places."

It's also important for scientists to realize that the sections of genomes that are the most difficult to assemble may just be the key to understanding crucial bodily systems like immunity and reproduction.

"Olfactory genes aren't the only ones that have been challenging to sequence and study. Scientists have also struggled to sequence immune and reproductive genes, so previous studies are missing this kind of information. Imagine trying to study a genetic condition in cats, humans, or any species, for that matter, without having all the pieces; this is why assembling complete genomes matters," Murphy said.

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Study suggests that having common ancestors can jeopardize fertility for generations

When it comes to the architecture of the human genome, it's only a matter of time before harmful genes -- genes that could compromise future generations -- arise in a population. These mutations accumulate in the gene pool, primarily affected by a population's size and practices like marrying within a small community, according to researchers.

But much of the information about the effects of a population's mutation load is based on genetic theory, with limited direct evidence concerning the effects on evolutionary fitness, or fertility.

New research from University of California, Davis, provides rare direct evidence showing that increased homozygosity -- meaning two identical alleles in a genome -- leads to negative effects on fertility in a human population. The paper was published Oct. 17 in the Proceedings of the National Academy of Sciences journal.

"People have known since Darwin that if you take people who are first cousins and they have children together, the children are more likely to develop certain diseases or be less healthy," said Brenna Henn, an associate professor of anthropology in the College of Letters and Science at UC Davis.

The research assesses the consequences of homozygosity among Namibia's Himba community, an isolated, agro-pastoralist population in which marriage between people with the same ancestor occurs. The research was led by Natalie Swinford, who received her doctoral degree in 2022 in evolutionary anthropology and human population genetics, and Henn.

"They're what we call an 'endogamous population,' meaning people are meeting their partners just from within that Himba group," said Henn. "They also have a unique system of marriage and reproduction, where men and women can have multiple boyfriends or girlfriends during their marriage. That means there are a lot of half-siblings in the population. That's a unique feature and it means that we can leverage that social structure to look at different genetic effects."

Echoes in the genome

In the study, the team gathered genetic data from 681 individuals from the Himba population. Genetic analyses revealed that the Himba have genetic markers that show higher levels of inbreeding.

Known as runs of homozygosity, or ROH, these markers are multiple and particularly long in the genomes of the analyzed Himba, which indicates that their parents had a high likelihood of sharing an ancestor.

While the Himba population has historically exhibited a preference for consanguinity, Henn and Swinford were surprised to find that none of the individuals in their sample population had parents who were actually first cousins. The lengths of the ROH in the genomes indicated otherwise.

The researchers found that these genetic effects can pool and accumulate over time. So, bottleneck events, like a decrease in population that leads to inbreeding, can have genetic echoes that don't manifest until generations later. The researchers concluded that such events occurred within the past 12 to 18 generations of the Himba population.

"People may not be full first-cousins," Henn said. "But they may be half-cousins once removed and then their grandparents might have been half-cousins. Anytime something like that happens, it's going to contribute to there being identical DNA in the offspring."

A negative effect on fertility

The Himba are a pronatalist community, meaning they encourage their members to have many children. Typically, there are short intervals between births, roughly between one and three years, researchers said.

To gauge the effects of long ROH on fertility, the researchers measured the reproductive success of post-reproductive women in their sample population. The researchers defined reproductive success as the number of children who survived to at least 5.

The research team used statistical models to analyze the relationship between the amount of ROH in the genome and the number of children a woman had. They found that the greater the proportion of the genome that was in ROH, the more likely a woman was to have fewer children than a woman who had less ROH.

"This means that a woman who has parents who are more related is more likely to have fewer children throughout her lifetime than a woman who has parents who are less related," said Swinford.

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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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Bronze Age family systems deciphered: Mainz palaeogeneticists analyse a 3,800-year-old extended family

The diversity of family systems in prehistoric societies has always fascinated scientists. A groundbreaking study by Mainz anthropologists and an international team of archaeologists now provides new insights into the origins and genetic structure of prehistoric family communities.

Researchers Jens Blöcher and Joachim Burger from Johannes Gutenberg University Mainz (JGU) have analysed the genomes of skeletons from an extended family from a Bronze Age necropolis in the Russian steppe. The 3,800-year-old "Nepluyevsky" burial mound was excavated several years ago and is located on the geographical border between Europe and Asia. Using statistical genomics, the family and marriage relationships of this society have now been deciphered. The study was carried out in cooperation with archaeologists from Ekaterinburg and Frankfurt a. M. and was partly financially supported by the German Research Foundation (DFG) and the Russian Science Foundation (RSCF).

The kurgan (burial mound) investigated was the grave of six brothers, their wives, children and grandchildren. The presumably oldest brother had eight children with two wives, one of whom came from the Asian steppe regions in the east. The other brothers showed no signs of polygamy and probably lived monogamously with far fewer children.

Fascinating snapshot of a prehistoric family

"The burial site provides a fascinating snapshot of a prehistoric family," explains Jens Blöcher, lead author of the study. "It is remarkable that the first-born brother apparently had a higher status and thus greater chances of reproduction. The right of the male firstborn seems familiar to us, it is known from the Old Testament, for example, but also from the aristocracy in historical Europe."

The genomic data reveal even more. Most women buried in the kurgan were immigrants. The sisters of the buried brothers, in turn, found new homes elsewhere. Joachim Burger, senior author of the study, explains: "Female marriage mobility is a common pattern that makes sense from an economic and evolutionary perspective. While one sex stays local and ensures the continuity of the family line and property, the other marries in from the outside to prevent inbreeding."

The genomic diversity of the prehistoric women was higher than that of the men

Accordingly, the Mainz population geneticists found that the genomic diversity of the prehistoric women was higher than that of the men. The women who married into the family thus came from a larger area and were not related to each other. In their new homeland, they followed their husbands into the grave. From this the authors conclude that in Nepluyevsky there was both "patrilineality", i.e. the transmission of local traditions through the male line, and "patrilocality", i.e. the place of residence of a family is the place of residence of the men.

"Archaeology shows that 3,800 years ago, the population in the southern Trans-Ural knew cattle breeding and metalworking and subsisted mainly on dairy and meat products," comments Svetlana Sharapova, archaeologist from Ekaterinburg and head of the excavation, adding, "the state of health of the family buried here must have been very poor. The average life expectancy of the women was 28 years, that of the men 36 years."

In the last generation, the use of the kurgan suddenly stopped and almost only infants and small children were found. Sharapova adds, "it is possible that the inhabitants were decimated by disease or that the remaining population went elsewhere in search of a better life."

Multiple partners and many children for the putative firstborn son

"There is a global connection between different family systems and certain forms of life-style and economy," says Blöcher. "Nevertheless, human societies are characterised by a high degree of flexibility." He adds, "in Nepluyevsky, we find evidence of a pattern of inequality typical of pastoralists: multiple partners and many children for the putative firstborn son and no or monogamous relationships for most others."

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Iceman Ötzi: Dark skin, bald head, Anatolian ancestry

A research team has used advanced sequencing technology to analyze Ötzi's genome to obtain a more accurate picture of the Iceman's appearance and genetic origins.

Ötzi's genome was decoded for the first time more than ten years ago. This was also the first time the genome of a mummy had been sequenced. The results provided important insights into the genetic makeup of prehistoric Europeans. Advances in sequencing technology have now enabled a research team from the Max Planck Institute for Evolutionary Anthropology and Eurac Research to reconstruct Ötzi's genome more accurately. The results of this recent analysis refine the Iceman's genetic picture: compared to other contemporary Europeans, Ötzi's genome has an unusually high proportion of genes in common with those of early farmers from Anatolia. And, contrary to previous findings, at the time of his death, Ötzi had advanced hair loss and may have even been bald. Furthermore, his skin was darker than previously thought. Ötzi's genes also show a predisposition to diabetes and obesity.

The genetic makeup of most present-day Europeans has resulted mainly from the admixture of three ancestral groups: western hunter-gatherers gradually merged with early farmers who migrated from Anatolia about 8,000 years ago and who were later on joined by Steppe Herders from Eastern Europe, approximately 4,900 years ago.

The initial analysis of the Iceman's genome revealed genetic traces of these Steppe Herders. However, the refined new results no longer support this finding. The reason for the inaccuracy: the original sample had been contaminated with modern DNA. Since that first study, not only have sequencing technologies advanced enormously, but many more genomes of other prehistoric Europeans have been fully decoded, often from skeletal finds. This has made it possible to compare Ötzi's genetic code with his contemporaries. The result: among the hundreds of early European people who lived at the same time as Ötzi and whose genomes are now available, Ötzi's genome has more ancestry in common with early Anatolian farmers than any of his European counterparts.

Ötzi's ancestry and appearance

The research team concludes that the Iceman came from a relatively isolated population that had very little contact with other European groups. "We were very surprised to find no traces of Eastern European Steppe Herders in the most recent analysis of the Iceman genome; the proportion of hunter-gatherer genes in Ötzi's genome is also very low. Genetically, his ancestors seem to have arrived directly from Anatolia without mixing with hunter gatherer groups," explains Johannes Krause, head of the Department of Archaeogenetics at the Max Planck Institute for Evolutionary Anthropology in Leipzig, and co-author of the study.

The study also yielded new results about Ötzi's appearance. His skin type, already determined in the first genome analysis to be Mediterranean-European, was even darker than previously thought. "It's the darkest skin tone that has been recorded in contemporary European individuals," explains anthropologist Albert Zink, study co-author and head of the Eurac Research Institute for Mummy Studies in Bolzano: "It was previously thought that the mummy's skin had darkened during its preservation in the ice, but presumably what we see now is actually largely Ötzi's original skin color. Knowing this, of course, is also important for the proper conservation of the mummy."

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Genome analysis of 46,000-year-old roundworm from Siberian permafrost reveals novel species

Some organisms, such as tardigrades, rotifers, and nematodes, can survive harsh conditions by entering a dormant state known as "cryptobiosis." In 2018, researchers from the Institute of Physicochemical and Biological Problems in Soil Science RAS in Russia found two roundworms (nematode) species in the Siberian Permafrost. Radiocarbon dating indicated that the nematode individuals have remained in cryptobiosis since the late Pleistocene, about 46,000 years ago. Researchers from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, the Center for Systems Biology Dresden (CSBD), and the Institute of Zoology at the University of Cologne, all located in Germany, used genome sequencing, assembly, and phylogenetic analysis and found that the permafrost nematode belongs to a previously undescribed species, Panagrolaimus kolymaensis. They showed that the biochemical mechanisms employed by Panagrolaimus kolymaensis to survive desiccation and freezing under laboratory conditions are similar to those of a life-cycle stage in the important biological model Caenorhabditis elegans.

When Anastasia Shatilovich at the Institute of Physicochemical and Biological Problems in Soil Science RAS in Russia revived two frozen individual nematodes from a fossilized burrow in silt deposits in the Siberian permafrost, she and her colleagues were beyond excited. After thawing the worms in the lab, a radiocarbon analysis of plant material from the burrow revealed that these frozen deposits, 40 meters below the surface, had not thawed since the late Pleistocene, between 45,839 and 47,769 years ago. At the same time, the research group of Teymuras Kurzchalia at the MPI-CBG (Teymuras Kurzchalia is now retired) was already addressing the question of how larval stages of the nematode Caenorhabditis elegans survive extreme conditions. When the team heard about the permafrost nematodes, they immediately reached out for a collaboration with Anastasia Shatilovich.

Vamshidhar Gade, a doctoral student at that time in the research group of Teymuras Kurzchalia, started to work with the permafrost nematodes. "What molecular and metabolic pathways these cryptobiotic organisms use and how long they would be able to suspend life are not fully understood," he says. Vamshidhar is now working at the ETH in Zurich, Switzerland.

The researchers in Dresden conducted a high-quality genome assembly of one of the permafrost nematodes in collaboration with Eugene Myers, Director Emeritus and research group leader at the MPI-CBG, the DRESDEN-concept Genome Center, and the research group of Michael Hiller, research group leader at that time at the MPI-CBG and now Professor of Comparative Genomics at the LOEWE-TBG and the Senckenberg Society for Nature Research. Despite having DNA barcoding sequences and microscopic pictures, it was difficult to determine whether the permafrost worm was a new species or not. Philipp Schiffer, research group leader at the Institute of Zoology, co-lead of the incipient Biodiversity Genomics Center Cologne (BioC2) at the University of Cologne, and expert in biodiversity genomics research, joined forces with the Dresden researchers to determine the species and analyze its genome with his team. Using phylogenomic analysis, he and his team were able to define the roundworm as a novel species, and the team decided to call it "Panagrolaimus kolymaensis." In recognition of the Kolyma River region from which it originated, the nematode was given the Latin name Kolymaensis.

By comparing the genome of Panagrolaimus kolymaensis with that of the model nematode Caenorhabditis elegans, the researchers in Cologne identified genes that both species have in common and that are involved in cryptobiosis. To their surprise, most of the genes necessary for entering cryptobiosis in Caenorhabditis elegans so-called Dauer larvae were also present in Panagrolaimus kolymaensis. The research team next evaluated Panagrolaimus kolymaensis's ability to survive and discovered that mild dehydration exposure before freezing helped the worms prepare for cryptobiosis and increased survival at -80 degrees Celsius. At a biochemical level, both species produced a sugar called trehalose when mildly dehydrated in the lab, possibly enabling them to endure freezing and intense dehydration. Caenorhabditis elegans larvae also benefited from this treatment, surviving for 480 days at -80 degrees Celsius without suffering any declines in viability or reproduction following thawing.

According to Vamshidhar Gade and Temo Kurzhchalia, "Our experimental findings also show that Caenorhabditis elegans can remain viable for longer periods in a suspended state than previously documented. Overall, our research demonstrates that nematodes have developed mechanisms that allow them to preserve life for geological time periods."

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Artificial cells demonstrate that 'life finds a way'

"Listen, if there's one thing the history of evolution has taught us is that life will not be contained. Life breaks free. It expands to new territories, and it crashes through barriers painfully, maybe even dangerously, but . . . life finds a way," said Ian Malcolm, Jeff Goldblum's character in Jurassic Park, the 1993 science fiction film about a park with living dinosaurs.

You won't find any Velociraptors lurking around evolutionary biologist Jay T. Lennon's lab; however, Lennon, a professor in the College of Arts and Sciences Department of Biology at Indiana University Bloomington, and his colleagues have found that life does indeed find a way. Lennon's research team has been studying a synthetically constructed minimal cell that has been stripped of all but its essential genes. The team found that the streamlined cell can evolve just as fast as a normal cell -- demonstrating the capacity for organisms to adapt, even with an unnatural genome that would seemingly provide little flexibility.

"It appears there's something about life that's really robust," says Lennon. "We can simplify it down to just the bare essentials, but that doesn't stop evolution from going to work."

For their study, Lennon's team used the synthetic organism, Mycoplasma mycoides JCVI-syn3B -- a minimized version of the bacterium M. mycoides commonly found in the guts of goats and similar animals. Over millennia, the parasitic bacterium has naturally lost many of its genes as it evolved to depend on its host for nutrition. Researchers at the J. Craig Venter Institute in California took this one step further. In 2016, they eliminated 45 percent of the 901 genes from the natural M. mycoides genome -- reducing it to the smallest set of genes required for autonomous cellular life. At 493 genes, the minimal genome of M. mycoides JCVI-syn3B is the smallest of any known free-living organism. In comparison, many animal and plant genomes contain more than 20,000 genes.

In principle, the simplest organism would have no functional redundancies and possess only the minimum number of genes essential for life. Any mutation in such an organism could lethally disrupt one or more cellular functions, placing constraints on evolution. Organisms with streamlined genomes have fewer targets upon which positive selection can act, thus limiting opportunities for adaptation.

Although M. mycoides JCVI-syn3B could grow and divide in laboratory conditions, Lennon and colleagues wanted to know how a minimal cell would respond to the forces of evolution over time, particularly given the limited raw materials upon which natural selection could operate as well as the uncharacterized input of new mutations.

"Every single gene in its genome is essential," says Lennon in reference to M. mycoides JCVI-syn3B. "One could hypothesize that there is no wiggle room for mutations, which could constrain its potential to evolve."

The researchers established that M. mycoides JCVI-syn3B, in fact, has an exceptionally high mutation rate. They then grew it in the lab where it was allowed to evolve freely for 300 days, equivalent to 2000 bacterial generations or about 40,000 years of human evolution.

The next step was to set up experiments to determine how the minimal cells that had evolved for 300 days performed in comparison to the original, non-minimal M. mycoides as well as to a strain of minimal cells that hadn't evolved for 300 days. In the comparison tests, the researchers put equal amounts of the strains being assessed together in a test tube. The strain better suited to its environment became the more common strain.

They found that the non-minimal version of the bacterium easily outcompeted the unevolved minimal version. The minimal bacterium that had evolved for 300 days, however, did much better, effectively recovering all of the fitness that it had lost due to genome streamlining. The researchers identified the genes that changed the most during evolution. Some of these genes were involved in constructing the surface of the cell, while the functions of several others remain unknown.

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New method traces ancestry of hybrid plants and animals

If you've ever kept a garden, you're probably familiar with hybrids, from disease-resistant tomatoes to Stargazer lilies.

Hybrids -- common in agriculture as well as in nature -- have chromosomes from two or more parent species. In some cases, including strawberries, goldfish and several other species, these disparate parental chromosomes become doubled, a condition known as allopolyploidy.

In "Transposon signatures of allopolyploid subgenome evolution," a recent article published in the journal Nature Communications, Binghamton University Assistant Professor of Biological Sciences Adam Session and Daniel S. Rokhsar, a professor of genetics, evolution and development at the University of California, Berkeley, outline a way to trace these genomes back to the polypoid hybrid's parent species.

Unlike previous methods, which use comparison with related non-hybrid species to decipher polypoid ancestry, the authors' method allows them to discover distinct ancestries by looking at genomic patterns in the hybrid itself.

"Each ancestral genome carries a unique set of repetitive elements," Session explained. "So if we find sets of chromosomes in a polypoid that carry different repetitive elements, that proves hybrid ancestry and allows us to figure out which chromosomes were inherited together coming from the various progenitor species."

In the article, they apply the method to some well-studied cases of polyploid hybrids, such as tobacco, cotton and cyprinid fish, such as goldish and carp. They also use it to tease out the disputed ancestries of other hybrids, including false flax and strawberries.

"In many cases, the ancestors of living polyploids are not known. Using our method, we can figure out the ancestral origin of different chromosomes just by studying the polyploid genome itself, and divide the chromosomes into sets, or 'sub-genomes,' derived from its various ancestors," he said. "In addition to identifying the subgenomes, we can also tell you the order in which they were put together."

Polyploidization -- the duplication of genomes in a hybrid that stabilizes its ancestry -- is much more common in plants than animals, since plants can better tolerate multiple copies of their genomes, Session explained. The process of polyploidization is more involved with animal species, although it does happen in some fish and amphibians. In the case of goldfish, the authors prove for the first time that they share the same duplicated gene sequences as common carp, and thus a common hybrid ancestor.

Polyploidy is unknown in mammals, although hybridization is still possible. Take mules, for instance, which are a hybrid between horses and donkeys: Male mules are effectively sterile, although female mules can mate with either parent species. But without genomic duplication, the distinctive hybrid type cannot be stably propagated.

A tetraploid such as cotton has four copies of each chromosome, two from each of two ancestors, while hexaploids -- such as false flax -- have six chromosomes derived from three parent species. With eight copies of each chromosome, an octoploid such as strawberry ultimately has four ancestral species.

Polyploids have complex biology that is still being deciphered, and figuring out the sub-genome structure of their genomes is a step forward. Over millions of years, the genes contributed by each of the parental species evolve in their new polyploid context. Some redundant genes are lost or inactivated; others can develop new functions or novel interactions with their counterparts in the other sub-genomes. The new work argues that the order in which parental species are added to the emerging polyploid mix in a higher polyploid like strawberry can have profound impact on how these evolutionary processes occur. Sorting out the impact of these duplicated on the evolving polyploid is an ongoing challenge, the authors said.

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Lingering effects of Neanderthal DNA found in modern humans

Recent scientific discoveries have shown that Neanderthal genes comprise some 1 to 4% of the genome of present-day humans whose ancestors migrated out of Africa, but the question remained open on how much those genes are still actively influencing human traits -- until now.

A multi-institution research team including Cornell University has developed a new suite of computational genetic tools to address the genetic effects of interbreeding between humans of non-African ancestry and Neanderthals that took place some 50,000 years ago. (The study applies only to descendants of those who migrated from Africa before Neanderthals died out, and in particular, those of European ancestry.)

In a study published in eLife, the researchers reported that some Neanderthal genes are responsible for certain traits in modern humans, including several with a significant influence on the immune system. Overall, however, the study shows that modern human genes are winning out over successive generations.

"Interestingly, we found that several of the identified genes involved in modern human immune, metabolic and developmental systems might have influenced human evolution after the ancestors' migration out of Africa," said study co-lead author April (Xinzhu) Wei, an assistant professor of computational biology in the College of Arts and Sciences. "We have made our custom software available for free download and use by anyone interested in further research."

Using a vast dataset from the UK Biobank consisting of genetic and trait information of nearly 300,000 Brits of non-African ancestry, the researchers analyzed more than 235,000 genetic variants likely to have originated from Neanderthals. They found that 4,303 of those differences in DNA are playing a substantial role in modern humans and influencing 47 distinct genetic traits, such as how fast someone can burn calories or a person's natural immune resistance to certain diseases.

Unlike previous studies that could not fully exclude genes from modern human variants, the new study leveraged more precise statistical methods to focus on the variants attributable to Neanderthal genes.

While the study used a dataset of almost exclusively white individuals living in the United Kingdom, the new computational methods developed by the team could offer a path forward in gleaning evolutionary insights from other large databases to delve deeper into archaic humans' genetic influences on modern humans.

"For scientists studying human evolution interested in understanding how interbreeding with archaic humans tens of thousands of years ago still shapes the biology of many present-day humans, this study can fill in some of those blanks," said senior investigator Sriram Sankararaman, an associate professor at the University of California, Los Angeles. "More broadly, our findings can also provide new insights for evolutionary biologists looking at how the echoes of these types of events may have both beneficial and detrimental consequences."

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Genomes of 233 primate species sequenced

Researchers from 24 countries have analyzed the genomes of 809 individuals from 233 primate species, generating the most complete catalog of genomic information about our closest relatives to date. The project, which consists of a series of studies in which researchers from the German Primate Center -- Leibniz Institute for Primate Research (DPZ) were also involved, provides new insights into the evolution of primates, including humans, and their diversity. In baboons, for example, hybridization and gene flow between different species occurred in the past and is still ongoing in several regions of their range. This makes baboons a good model for the evolution of early human lineages within and outside Africa. In addition, using a specially designed AI algorithm, the genomic data enable new insights into the genetic causes of human diseases (Science, Special Issue).

Primates show great genetic diversity that varies between species and geographic regions. "Studying this diversity is crucial also for understanding human evolution, the causes of human diseases, and for preserving our closest relatives," says Christian Roos, a scientist in the Primate Genetics Laboratory at the German Primate Center and one of the authors. Led by researchers from Universitat Pompeu Fabra, Spain, Baylor College of Medicine, USA, and Illumina Inc, USA, the genomes of 809 individuals from 233 primate species have been sequenced. This covers nearly half of the extant primate species and increases the number of available primate genomes fourfold.

New insights into primate evolution and the uniqueness of humans

The comparative analyses provide fundamental information on the genetic diversity and evolutionary history of primates and important insights into what distinguishes humans from other primates. The genomic data have halved the number of genomic variants thought to occur exclusively in humans. "This makes it easier to look for mutations that we do not share with other primates and that could therefore be the basis for the traits that make us human," says Dietmar Zinner, a scientist in the Cognitive Ethology Laboratory at the German Primate Center and also one of the authors. One of the studies looks more closely at baboon evolution and finds that there have been several, previously unknown episodes of hybridization and gene flow between baboon species. "We found that baboons from western Tanzania are the first nonhuman primates to have received input from three genetic lineages," said Liye Zhang, a doctoral student at the German Primate Center and one of the lead authors of the baboon study. "These results suggest that the genetic structure of the baboon population and its history of genetic exchange between species is more complex than previously thought and show that baboons make a good model for similar processes in the evolution of early human lineages in and outside Africa," says Dietmar Zinner.

Species conservation with the help of genome data

High genetic diversity enables species to better adapt to changing environmental conditions and pathogens. Especially in small populations, there is a risk of inbreeding and thus a reduction in genetic diversity. Already, 63 percent of all primate species are threatened with extinction, and the analysis of genetic diversity provides information which species most urgently need to be protected, at least from a genetic point of view. "We found particularly low genetic diversity in the golden snub-nosed monkey of China and the aye-aye in Madagascar," says Christian Roos.

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Information 'deleted' from the human genome may be what made us human

What the human genome is lacking compared with the genomes of other primates might have been as crucial to the development of humankind as what has been added during our evolutionary history, according to a new study led by researchers at Yale and the Broad Institute of MIT and Harvard.

The new findings, published April 28 in the journal Science, fill an important gap in what is known about historical changes to the human genome. While a revolution in the capacity to collect data from genomes of different species has allowed scientists to identify additions that are specific to the human genome -- such as a gene that was critical for humans to develop the ability to speak -- less attention has been paid to what's missing in the human genome.

For the new study researchers used an even deeper genomic dive into primate DNA to show that the loss of about 10,000 bits of genetic information -- most as small as a few base pairs of DNA -- over the course of our evolutionary history differentiate humans from chimpanzees, our closest primate relative. Some of those "deleted" pieces of genetic information are closely related to genes involved in neuronal and cognitive functions, including one associated with the formation of cells in the developing brain.

These 10,000 missing pieces of DNA -- which are present in the genomes of other mammals -- are common to all humans, the Yale team found.

The fact that these genetic deletions became conserved in all humans, the authors say, attests to their evolutionary importance, suggesting that they conferred some biological advantage.

"Often we think new biological functions must require new pieces of DNA, but this work shows us that deleting genetic code can result in profound consequences for traits make us unique as a species," said Steven Reilly, an assistant professor of genetics at Yale School of Medicine and senior author of the paper.

The paper was one of several published in Science from the Zoonomia Project, an international research collaboration that is cataloging the diversity in mammalian genomes by comparing DNA sequences from 240 species of mammals that exist today.

In their study, the Yale team found that some genetic sequences found in the genomes of most other mammal species, from mice to whales, vanished in humans. But rather than disrupt human biology, they say, some of these deletions created new genetic encodings that eliminated elements that would normally turn genes off.

The deletion of this genetic information, Reilly said, had an effect that was the equivalent of removing three characters -- "n't" -- from the word "isn't" to create a new word, "is."

"[Such deletions] can tweak the meaning of the instructions of how to make a human slightly, helping explain our bigger brains and complex cognition," he said.

The researchers used a technology called Massively Parallel Reporter Assays (MPRA), which can simultaneously screen and measure the function of thousands of genetic changes among species.

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Male yellow crazy ants are real-life chimeras

The yellow crazy ant, or Anoplolepis gracilipes, has the infamous distinction of being among the worst invasive species in the world. However, this is not the reason for which this particular ant is studied by a team of international researchers. What interests them is how the insects reproduce, because males of this ant have long perplexed scientists. "The results of previous genetic analyses of the yellow crazy ant have shown that the males of this species have two copies of each chromosome. This was highly unexpected, as males usually develop from unfertilized eggs in ants, bees, and wasps -- and thus should only have one maternal copy of each chromosome," explained Dr. Hugo Darras, Assistant Professor at Johannes Gutenberg University Mainz (JGU) and lead author of the corresponding article recently published in Science. "With this in view, we decided to investigate this puzzling phenomenon with subsequent experiments."

Two genomes in different cell clusters

The results were quite extraordinary. It had been assumed to date that the males of the yellow crazy ant carried the same two sets of chromosomes in all cells of their body. However, the team was able to demonstrate that this premise was anything but correct. "We discovered that the male ants have maternal and paternal genomes in different cells of their body and are thus chimeras. To put it another way, all males have two genomes, but each cell of their bodies contains only one or the other of the two genomes," summarized Darras. Normally, in a multicellular life form -- be this a human, a dog, or a bat -- all cells contain identical genetic material.

The research team concludes that male yellow crazy ants are chimeras: they develop from fertilized eggs in which the two parental gametes do not actually fuse. Instead, the maternal and paternal nuclei divide separately within the same egg, meaning that the resultant adult males have both parental DNA sequences but in different body cells. When the gametes do fuse, either a queen or a worker develops from the egg, depending on the genetic information carried by the sperm. It is yet unknown what mechanisms determine whether fusion of the parental gametes takes place or not.

Chimerism and the yellow crazy ant: A mode of reproduction previously unknown to science

Chimeras are individuals whose cells contain different genetic materials. They naturally occur in certain species, such as corals and angler fish, in which separate individuals can merge to become one. Chimerism can also be found in humans and other placenta mammals. During gestation, mother and fetus can exchange a small number of cells so the offspring usually has a few cells that contain the same genetic material as the mother. Such small-scale exchanges also occur between twins in the womb. "In contrast to these known cases, chimerism in the yellow crazy ant does not result from the fusion of two separate individuals or an exchange of cells between them. Instead, this process has its origin within a single fertilized egg. This is unique," concluded Darras. Hence, the development of the male yellow crazy ant appears to contravene one of the fundamental laws of biological inheritance in which all cells of an individual should contain the same genome.

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