Daily Archives: August 9, 2021

MIT researchers have devised a way to program memories into bacterial cells by rewriting their DNA more efficiently. Credit: MIT News, iStockphoto

Technique for editing bacterial genomes can record interactions between cells, may offer a way to edit genes in the human microbiome.

Biological engineers at MIT have devised a new way to efficiently edit bacterial genomes and program memories into bacterial cells by rewriting their DNA. Using this approach, various forms of spatial and temporal information can be permanently stored for generations and retrieved by sequencing the cells DNA.

The new DNA writing technique, which the researchers call HiSCRIBE, is much more efficient than previously developed systems for editing DNA in bacteria, which had a success rate of only about 1 in 10,000 cells per generation. In a new study, the researchers demonstrated that this approach could be used for storing memory of cellular interactions or spatial location.

This technique could also make it possible to selectively edit, activate, or silence genes in certain species of bacteria living in a natural community such as the human microbiome, the researchers say.

With this new DNA writing system, we can precisely and efficiently edit bacterial genomes without the need for any form of selection, within complex bacterial ecosystems, says Fahim Farzadfard, a former MIT postdoc and the lead author of the paper. This enables us to perform genome editing and DNA writing outside of laboratory settings, whether to engineer bacteria, optimize traits of interest in situ, or study evolutionary dynamics and interactions in the bacterial populations.

Timothy Lu, an MIT associate professor of electrical engineering and computer science and of biological engineering, is the senior author of the study, which was published on August 5, 2021, in Cell Systems. Nava Gharaei, a former graduate student at Harvard University, and Robert Citorik, a former MIT graduate student, are also authors of the study.

For several years, Lus lab has been working on ways to use DNA to store information such as memory of cellular events. In 2014, he and Farzadfard developed a way to employ bacteria as a genomic tape recorder, engineering E. coli to store long-term memories of events such as a chemical exposure.

To achieve that, the researchers engineered the cells to produce a reverse transcriptase enzyme called retron, which produces a single-stranded DNA (ssDNA) when expressed in the cells, and a recombinase enzyme, which can insert (write) a specific sequence of single-stranded DNA into a targeted site in the genome. This DNA is produced only when activated by the presence of a predetermined molecule or another type of input, such as light. After the DNA is produced, the recombinase inserts the DNA into a preprogrammed site, which can be anywhere in the genome.

That technique, which the researchers called SCRIBE, had a relatively low writing efficiency. In each generation, out of 10,000 E. coli cells, only one would acquire the new DNA that the researchers tried to incorporate into the cells. This is in part because the E. coli have cellular mechanisms that prevent single-stranded DNA from being accumulated and integrated into their genomes.

In the new study, the researchers tried to boost the efficiency of the process by eliminating some of E. colis defense mechanisms against single-stranded DNA. First, they disabled enzymes called exonucleases, which break down single-stranded DNA. They also knocked out genes involved in a system called mismatch repair, which normally prevents integration of single-stranded DNA into the genome.

With those modifications, the researchers were able to achieve near-universal incorporation of the genetic changes that they tried to introduce, creating an unparalleled and efficient way for editing bacterial genomes without the need for selection.

Because of that improvement, we were able to do some applications that we were not able to do with the previous generation of SCRIBE or with other DNA writing technologies, Farzadfard says.

In their 2014 study, the researchers showed that they could use SCRIBE to record the duration and intensity of exposure to a specific molecule. With their new HiSCRIBE system, they can trace those kinds of exposures as well as additional types of events, such as interactions between cells.

As one example, the researchers showed that they could track a process called bacterial conjugation, during which bacteria exchange pieces of DNA. By integrating a DNA barcode into each cells genome, which can then be exchanged with other cells, the researchers can determine which cells have interacted with each other by sequencing their DNA to see which barcodes they carry.

This kind of mapping could help researchers study how bacteria communicate with each other within aggregates such as biofilms. If a similar approach could be deployed in mammalian cells, it could someday be used to map interactions between other types of cells such as neurons, Farzadfard says. Viruses that can cross neural synapses could be programmed to carry DNA barcodes that researchers could use to trace connections between neurons, offering a new way to help map the brains connectome.

We are using DNA as the mechanism to record spatial information about the interaction of bacterial cells, and maybe in the future, neurons that have been tagged, Farzadfard says.

The researchers also showed that they could use this technique to specifically edit the genome of one species of bacteria within a community of many species. In this case, they introduced the gene for an enzyme that breaks down galactose into E. coli cells growing in culture with several other species of bacteria.

This kind of species-selective editing could offer a novel way to make antibiotic-resistant bacteria more susceptible to existing drugs by silencing their resistance genes, the researchers say. However, such treatments would likely require several years more years of research to develop, they say.

The researchers also showed that they could use this technique to engineer a synthetic ecosystem made of bacteria and bacteriophages that can continuously rewrite certain segments of their genome and evolve autonomously with a rate higher than would be possible by natural evolution. In this case, they were able to optimize the cells ability to consume lactose consumption.

This approach could be used for evolutionary engineering of cellular traits, or in experimental evolution studies by allowing you to replay the tape of evolution over and over, Farzadfard says.

Reference: Efficient retroelement-mediated DNA writing in bacteria by Fahim Farzadfard, Nava Gharaei, Robert J. Citorik and Timothy K. Lu, 5 August 2021, Cell Systems.DOI: 10.1016/j.cels.2021.07.001

The research was funded by the National Institutes of Health, the Office of Naval Research, the National Science Foundation, the Defense Advanced Research Projects Agency, the MIT Center for Microbiome Informatics and Therapeutics, the NSF Expeditions in Computing Program Award, and the Schmidt Science Fellows Program.

Read more here:
MIT Researchers Devised a Way To Program Memories Into Bacterial Cells by Rewriting Their DNA - SciTechDaily

Apparently, it is so: Anatomically modern humans have been leaving Africa for almost a quarter million years, but they all went extinct until an exit around 50,000 to 60,000 years ago. A new study of genomes in the Middle East shores up this hypothesis, finding no trace of the early humans in any of the genomes tested.

One of the routes out of Africa for hominins going back 2 million years, and later, for humans too, was the Levant, Iraq and Arabia. Indeed, researchers have found evidence of human and hominin exits in various places, including Israel and Saudi Arabia: stuff like the odd bone or a batch of stone tools.

The prevailing belief is that the groups taking part in the earliest migrations went extinct (though not before encountering other hominins in Eurasia). Then about 50,000 to 60,000 years ago, anatomical humans left Africa and survived. They met and mixed with Neanderthals and heavens knows who else, and begat modern humanity.

This belief that the early exiters did not survive is now bolstered by an international team led by Mohamed Almarri of the Wellcome Genome Campus in Britain. In their study, published in Cell, they looked at the genomic history of the Middle East and concluded that present-day populations in Arabia, the Levant including Israel, and Iraq have no signals from those early modern humans.

We used a new whole genome sequencing technology to study human populations from the Levant [Lebanon, Syria, Jordan, Israel and the West Bank], Iraq and Arabia, and we reconstruct the population history of the region from over 125,000 years ago up to the last millennium, Almarri says. We show how changes in lifestyle and climate have affected the demography of human populations in the region.

How does one test latter-day DNA for signals older than 60,000 years? By the density of mutations, he explains: The more mutations there are, the older the segments will be.

Thats a generalization; some genetic sequences are more evolutionarily conserved than others. If you check the sequence for the protein ubiquitin, it will be the same from a human to a tree frog and obviously, for earlier humans. But if a given segment has a ton of mutations (that didnt kill the bearer), we may assume its old.

Also, obviously modern humans didnt descend from newly-created beings who sprang up some 60,000 years ago; we will have some very, very ancient DNA. But, Almarri explains, when a population expands, the migrants are a tiny percent of the original population. The same would have applied to the African exit.

And indeed, genomic studies of todays non-African populations show a genetic bottleneck around that time, Almarri says. Non-Africans all descend from exiters around 50,000 to 60,000 years ago and are much less genetically diverse than sub-Saharan Africans, who suffered no bottleneck.

The Neanderthals and the Levantines

Moving on, Levantines and Iraqis share the same Neanderthal signals as Eurasians, the team found. Arabians on the other hand have less Neanderthal DNA.

The reason apparently lies in origins. Levantines have more ancestry (than Arabians) from Europe and Anatolia. The Arabians have more ancestry (than Levantines) from Africans, who didnt mix with Neanderthals, and from Natufians, who were the prehistoric inhabitants of the Levant, including Israel.

The Natufians were prehistoric peoples living about 11,000 to 16,000 years ago in what is today Israel, Jordan and Lebanon. Its possible that they also reached Arabia, but their remains havent been found.

Also, present-day Africans are believed to have a contribution from Neanderthals after all, a very small one, conferred by early humans who trekked in reverse from Europe back to Africa after mixing with Neanderthals.

Anyway, the Arabians of today apparently didnt arise from early Levantine farmers but from Natufian hunter-gatherers who preceded these farmers and Africans, the study shows. Nor do the findings support the theory that Levantine farmers later replaced the indigenous Arabian population.

It bears stressing that human fossil remains are incredibly rare; from the deep prehistoric past Saudi Arabia has so far produced one finger bone from 85,000 years ago, but it has also produced tools that may have been special to humans (as opposed to other hominins) from 125,000 years ago. In Israel there are a lot more very ancient human remains, starting with the 200,000-year-old jawbone found in Misliya, and there are more when you get to the Natufian period but theyre still very rare.

Desertification and population collapse

Another difference the genomic analysis indicated relates to the Neolithic Revolution the invention of agriculture.

But here it bears stressing that the Middle East, Arabia and North Africa werent always baking-hot deserts. Sometimes, depending on planetary orbital cycles, they greened. Hippos and crocodiles cavorted in lakes and rivers, and hominins and later, modern humans could comfortably roam.

When the Neolithic Revolution the gradual transition from a life of hunting and gathering to agriculture and animal husbandry began over 10,000 years ago, Arabia and the Sahara were in such a lush period. The Arabian Desert as we know it today, the biggest sand desert in the world, didnt exist. It began to form sometime between 6,000 to 8,000 years ago. (That might help explain the paucity of prehistoric human remains.)

The Neolithic Revolution drove a massive population increase in the Levant and Iraq, but not in Arabia. The team even postulates that the small population groups of ancient Arabians may have perpetuated or descended from the local epipaleolithic hunting-gathering groups.

But as the Arabian Desert was forming, about 6,000 years ago its population imploded. The same would happen in the Levant about 4,200 years ago, commensurate with an intense aridification event.

We find that prehistorical aridification and desertification events have resulted in population crashes a few thousands of years ago, the team says a warning for today, with all due respect to desalination technology.

Say it in Semitic

Current-day peoples the team studied in the Levant, Arabia and Iraq turned out to form distinct core clusters: Populations from the Levant and Iraq (Lebanese, Syrians, Jordanians, Israeli Druze, and Iraqi Arabs) clustered together. The Iraqi Kurds clustered with central Iranians.

The Arabians (Emiratis, Saudis, Yemenis and Omanis) clustered with Bedouin who are from Israel, too. These samples were collected by the Human Genome Diversity Project and were sequenced by us, Almarri notes.

Fascinatingly, both the Iraqi Kurds and Iranians, who clustered together, speak Indo-Iranian languages Kurdish isnt Arabic or Semitic, its Indo-Iranian. All the other people sampled in the study speak Arabic, a Semitic language.

The clustering patterns we find reflect the historical ancestries present in modern-day populations. In the Levant [and Iraqi Arabs], all the populations we tested have higher Anatolian-like ancestry, which is much rarer in Arabia. Arabian populations in contrast have higher Natufian-like ancestry, Almarri says.

Apropos language, the team also suggests that a Bronze Age population in the Levant (meaning from about 5,000 years ago) plausibly was responsible for spreading Semitic languages to Arabia and East Africa.

A glass of milk and thou

Marc Haber of the University of Birmingham notes that the study detected positive selection for lactose digestion the ability to drink and eat dairy products without experiencing socially repulsive and painful consequences.

In the last 8,000 years this variant increased to a frequency of 50 percent in Arabians, coinciding with the transition from a hunter-gatherer to herder-gatherer lifestyle. This variant is much rarer in the Levant, and almost absent outside the region, Haber says.

For this study, researchers at the Wellcome Sanger Institute collected 137 samples from people in eight Middle Eastern populations for sequencing. The genomic data was then analyzed at Wellcome Sanger and the University of Birmingham to look for variations in the genomes that could help map out human evolution from 100,000 years ago to today, the researchers explain.

It bears adding that apparently the domestication of the sheep, goats and cows wasnt driven by a desire to exploit their milk but to eat the whole animal, instead of hunting for toothsome herbivores.

What have we learned? That we thrived after the advent of agriculture but were brought low by climate change. That we did not thrive in the Arabian Desert but did when it was wetter and greener. Did we do that?

We did not the greening and aridification of North Africa and Arabia were due to planetary cycles, not human impact. Today Arabia contains the largest sand desert in the world (though not the largest desert), but by the next time the cycle swings and the area should, theoretically, turn green again, it may not happen, and thats on us.

Read more:
Levantines and Arabians have different origins, Middle East genomic study finds - Haaretz

Genome editing, genome engineering or gene editing is a type of genetic engineering in which DNA is inserted, deleted, changed or replaced in the genome of a living organism. The genome editing market is expected to grow shortly because an important element driving the market is the increase in financial resources.

Governments in many regions are increasing funding and grants to support genome editing research. Because of the advantages of genome editing, various governments are promoting public and commercial research, as well as academic institutes, to increase research efforts in the field of genome editing and genetic engineering.

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Segment By Type

CRISPRTALENZFNAntisenseOther Technologies

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Cell Line EngineeringAnimal Genetic EngineeringPlant Genetic EngineeringOther Applications

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Genome Editing Market Research Report 2021 Elaborate Analysis With Growth Forecast To 2027 OriGene, Thermo Fisher Scientific, NEB, Integrated DNA...

Eur Urol Oncol. 2021 Aug 2:S2588-9311(21)00120-6. doi: 10.1016/j.euo.2021.07.001. Online ahead of print.

ABSTRACT

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrences and a risk of progression in stage and grade. Increased knowledge of underlying biological mechanisms is needed.

OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) associated with recurrence-free (RFS) and progression-free (PFS) survival in NMIBC.

DESIGN, SETTING, AND PARTICIPANTS: We analyzed outcome data from 3400 newly diagnosed NMIBC patients from the Netherlands, the UK, Canada, and Spain. We generated genome-wide germline SNP data using Illumina OmniExpress and Infinium Global Screening Array in combination with genotype imputation.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cohort-specific genome-wide association studies (GWASs) for RFS and PFS were performed using a Cox proportional hazard model. Results were combined in a fixed-effect inverse-variance weighted meta-analysis. Candidate genes for the identified SNP associations were prioritized using functional annotation, gene-based analysis, expression quantitative trait locus analysis, and transcription factor binding site databases. Tumor expression levels of prioritized genes were tested for association with RFS and PFS in an independent NMIBC cohort.

RESULTS AND LIMITATIONS: This meta-analysis revealed a genome-wide significant locus for RFS on chromosome 14 (lead SNP rs12885353, hazard ratio [HR] C vs T allele 1.55, 95% confidence interval [CI] 1.33-1.82, p = 4.0 10-8), containing genes G2E3 and SCFD1. Higher expression of SCFD1 was associated with increased RFS (HR 0.70, 95% CI 0.59-0.84, pFDR = 0.003). Twelve other loci were suggestively associated with RFS (p < 10-5), pointing toward 18 additional candidate genes. For PFS, ten loci showed suggestive evidence of association, indicating 36 candidate genes. Expression levels of ten of these genes were statistically significantly associated with PFS, of which four (IFT140, UBE2I, FAHD1, and NME3) showed directional consistency with our meta-analysis results and published literature.

CONCLUSIONS: In this first prognostic GWAS in NMIBC, we identified several novel candidate loci and five genes that showed convincing associations with recurrence or progression.

PATIENT SUMMARY: In this study, we searched for inherited DNA changes that affect the outcome of non-muscle-invasive bladder cancer (NMIBC). We identified several genes that are associated with disease recurrence and progression. The roles and mechanisms of these genes in NMIBC prognosis should be investigated in future studies.

PMID:34353775 | DOI:10.1016/j.euo.2021.07.001

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Genome-wide Meta-analysis Identifies Novel Genes Associated with Recurrence and Progression in Non-muscle-invasive Bladder Cancer - DocWire News

Nestled in the middle of the Himalayas is the Tibetan plateaua large, flat, largely grassy expanse with an average elevation of over 4,500 meters. At such heights, the air is thin, and because of the surrounding mountains, the region receives little rain. Its a cold, harsh environmentone that many animals simply arent cut out for.

Homo sapiensmanaged to settle in this unforgiving landscape around 30,000 to 40,000 years ago, and around 10,000 years ago, they brought their dogs. While that might suggest our species is especially rugged or adaptable, we now know that neither the people nor their pets toughed it out aloneboth cribbed DNA notes from other species in order to adapt. Either before, during, or shortly after their migration to the plateau, H. sapiensgot friendly with Denisovans, while their domesticated dogs interbred with Tibetan wolves. And from those hybridizations, both picked up adaptive variants of the EPAS1 gene, which encode version of the protein that help their bodies, and especially their blood, cope with lower levels of oxygen. You have the exact same [phenomenon] between dogs and wolves as you have between humans and Denisovans, explains Rasmus Nielsen, a geneticist with the University of California, Berkeley. Its so cool.

But it turns out that, for the canines, thats not the whole story. Nielsen and his colleagues discovered that before wolves passed EPAS1 along to dogs, the wild canids obtained the helpful EPAS1variant by breeding with another canine speciesone that, to this day, remains unknown.

Researchers refer to these extinct species, whose genes linger in the genomes of living animals, as ghost lineages, and we now know theyre everywhere in the tree of lifethey simply remained obscured until recently, when advances in sequencing technology and genomic analyses began to reveal them.

The more genomes that have been sequenced from the more different lineages and species and places in the world, the more we see that when things interact with each other in space and can interbreed, they do.

Beth Shapiro, University of California, Santa Cruz

For example, while scientists have known for more than a decade that modern humans carry sequences from ancient hybridizations with Neanderthals and Denisovans, more recent analyses suggest there are other ancestors haunting our genomes. Discovering when and where species of humans interbred with and interacted with each other will tell the hidden stories of our past and help us understand why H. sapiens is the only hominin species left alive today. And were just one caseThere are instances where these kinds of events are even more profound, even more dramatic, in other species, says Sriram Sankararaman, a computational biologist at the University of California, Los Angeles, who has studied ancient hybridizations in humans.

The more genomes that are sequenced, the more researchers are finding that these ancient genetic whispers have many secrets to tell about all kinds of animals.

Wolves are not alone, of course, in their penchant for mating with more distant kin. Thanks to similar genetic echoes of hybridization, scientists know brown bears cozied up to cave bears before the latter went extinct (and they continue to romp with polar bears), elephant species interbred frequently back in the time of mammoths, and cats apparently fornicate with other felines at almost any opportunity. The more genomes that have been sequenced from the more different lineages and species and places in the world, the more we see that when things interact with each other in space and can interbreed, they do, says Beth Shapiro, an evolutionary biologist at the University of California, Santa Cruz, who worked with Nielsen on the Tibetan dogs paper.

Now, scientists are realizing those matings arent just fruitful in the sense that they produce surviving offspring. I think theres a growing sense that this could be a way for a population or a species to quickly adapt as it moves into new environments, says Sankararaman. In fact, this kind of adaptation via hybridization, or whats often referred to as adaptive introgression, seems to happen all the time.

The idea that hybridization plays a significant role in evolution is old hat to botanists, but fairly new for zoologistsfrom within the last five years, says Nielsen. The prevailing view, thanks to influential 20th century biologists such as Ernst Mayr, had been that the comingling of distant relatives was rare and of little importance, especially in mammals.

One of the earliest pieces of evidence for adaptive introgression in mammals came from a 2015 study on domesticated pigs (Sus scrofa domesticus) where a ghost Sus lineage was uncovered. Researchers in China were looking for genomic signatures of adaptation to northern latitudes (and, therefore, genes that may confer cold tolerance) in 11 domesticated breeds when they spotted something strange: A 14-megabase region of the X chromosome that not only differed between northern and southern breeds, it appeared that the northern version emerged some 3.5 million years before the entire Sus scrofaspecies split from from other wild pigs.

A 2015 study in Nature Genetics found that pig breeds from northern China, such as the Meishan pig above, possess DNA from an unknown, extinct Susspecies.

When the team created an evolutionary tree for that chunk of the genome, which included their domesticated pig breeds as well as Chinese and European wild boars (S. scrofa) and four other pigs (genus Sus), they found that the southern breeds clustered with the other Sus species, as one might expect, but the northern breeds formed their own distinctive group with European wild boarsa pattern which suggested they both received the 14-Mb chunk from an unknown and likely extinct pig species. Two years later, the same research group found another genethis time, one that may have been involved in domesticationthat also appears to have entered the domestic pig genome through hybridization with another, as-yet-unidentified Sus species.

Whether people intentionally bred their pigs with other swine species or just happened to select for genes from a natural hybridization event is unknown. Either way, these findings are far from the only documented examples of adaptive introgression. In addition to the EPAS1 examples in humans and dogs, genetic research has confirmed that western European house mice (Mus musculus domesticus) obtained a gene conferring resistance to the rodenticide warfarin from the Algerian mouse (Mus spretus) and gulf killifish (Fundulus grandis) can tolerate heavily polluted waters thanks to genes garnered from Atlantic killifish (F. heteroclitus). These and numerous other instances of adaptive introgression from recent years have bolstered the idea that hybridization is a key mechanism for evolution. Its a new way of thinking about evolution, that really species . . . [are] not isolatedtheyre connected to other species, says Nielsen, and when the environment changes, they can pick up DNA to adapt to new environmental conditions.

If thats broadly true, then looking for ghost sequences could be a way to find useful genes, argue Yunnan Universitys Yan Li and the Kunming Institute of Zoologys Dong-Dong Wu in a July Journal of Genetics and Genomicsreview paper. [T]he search for a genetic legacy of unknown species, particularly adaptive introgressed variants, in the genomes of extant livestock and crops will provide new sources of genetic variation for breeding and therefore help solve a pressing issue for humans, they write.

Nielsen agrees with that premise. Those genes that have been jumping from one species to another species and so on, theyre probably the important genes for that environment, he says, and could be used to grant species desirable traits. Humans have long been trying to capture such traits through hybridization. Some 10,000 years ago, people bred Chinese pigs with European ones, passing along key fertility and immunity traits to the latter. Similarly, research has revealed that domesticated cattle in China were bred with yak and banteng, a species of cattle endemic to Southeast Asia, to help them survive high altitudes and tropical environments, respectively.

Modern genetic science enables a more surgical approach: using gene editing to insert specific genes or variants into animals genomes, rather than producing hybrid offspring with a mishmash of genes from different species and using selective breeding to fine-tune the traits of future generations. This type of gene editing is already being done with plants and is being explored in livestock, so in the future, ghost DNA could be targeted to confer desired traits to the plants and animals we cultivate.

Not all of these spectral sequences are adaptive. Still, even genomic ghosts that have persisted through chance could prove invaluable to researchers, as they may reveal novel insights about evolution and the ecology of bygone ecosystems.

Studies on ancient introgression in felines have noted that interspecies dalliances have a marked impact on our ability to accurately reconstruct evolutionary relationships, so theyre important for evolutionary biologists to consider when reconstructing the tree of life. These sequences arent mere noise, thoughon the contrary, analyzing them is like another way of looking into the fossil record, says Shapiro, but rather than having fossils that are actual bones, we have tiny little snippets of the genomes of these extinct species that tell us that they existed.

Take those pigs, for example. The identified ancient genes suggest that the origin story of domesticated pigs is more complex than previously thought and point to gaps in our knowledge of the ecosystems where domestication occurred. After all, the genomic findings imply that there are two species of pigs weve never sequenced that were common enough in the past to leave a genetic footprint on our swine.

The investigation of genomic ghosts for ecological and evolutionary purposes is still in its infancy, as cutting-edge statistical methods for detecting ancient introgression have only recently been developed. Plus, these methods have mostly been designed to delve deeper into the hybridizations that occurred in hominins, says Martin Kuhlwilm, an evolutionary biologist at the University of Vienna. Because of that, they may not work as well in other species.

For instance, many of these methods require full genomes from the ancient relatives in questionsomething we have for Neanderthals and Denisovans, but which are rare for other extinct animals. Still, the field of ancient DNA is exploding, so its not hard to imagine a future where scientists can employ tools developed for human ancestry studies on any animal species, yielding information that could help explain why they, and not their ghost kin, are the ones still around today.

Analytical tools arent the only challenge to this kind of work. For some species, especially endangered ones, simply obtaining specimens can be onerous or expensive. And when the science doesnt directly teach us more about human health, Kuhlwilm says, its difficult to convince someone to pay for all of that.

Kuhlwilm maintains that such research is worth the investment, because beyond being cool, the data they provide is invaluable and often impossible to obtain through other methods. His work on chimpanzees and bonobos (Pan troglodytesand P. paniscus), our closest living relatives, is a perfect example. These animals are similar in many ways, but they differ markedly in behaviorwith bonobos often noted for being less aggressive and more sexual than chimpsand have subtler variations in their physiology and ecology. Many researchers are interested in understanding the origin of these differencesunfortunately, the fossil record for great apes is particularly spotty, so there is little to draw on when seeking answers about their evolutionary history.

Bonobos received DNA from a now-extinct ape approximately 500,000 years ago.

So Kuhlwilm and his colleagues looked to the apes genomes for clues instead. Introgression analyses run on 69 chimpanzee and bonobo genomes revealed that the two species had hybridized in the past, but even more surprisingly, 0.94.2 percent of the bonobo genome was made up of DNA from an otherwise unknown ape. These segments contained genes related to immunity, physiology, and behavior, all of which suggests some of the notable differences between bonobos and chimpanzees may stem in part from the formers hybridization with another species.

So far, we dont know much about this ghost ape that likely shaped bonobos into the gentler of our great ape cousins. The researchers were able to reconstruct an estimated 4.8 percent of its genome from their samples, but widespread sequencing of bonobos could reveal much more, allowing researchers to dig into questions about the apes physiologyanswers that could provide novel insights.

Indeed, Sankararaman notes that with enough data, ghost sequences could bring the past to life in an unprecedented way. We might be able to use [reconstructed archaic] genomes to say something about the phenotypes of these extinct populations, he says. From such reconstructions, researchers could garner even more information about extinct animals biology and ecology, as some things are just easier to glean from a visual.

Such inferences are still a long way off. Connecting mutations to anatomy or behaviors is an incredibly hard problem, he notes, and even in humans, our ability to go from genome to a phenotype or trait is pretty limited. Still, such work would be really exciting, he says.

Unfortunately, research into the ghosts in animal genomes is racing against the clock, says Kuhlwilm, because it relies on sequencing many genomes from extant species. I think the main obstacle right now is the speed at which these species disappear. Finding enough genomes from wild individuals and getting them sequenced is becoming a challenge . . . and that is very sad.

All people alive today carry ghost sequences from other human species. According to a Science Advances paper published July 16 that Shapiro coauthored, about half of the human genome can contain sequences from introgression events, during which DNA flowed in by mating with Neanderthals, Denisovans, and potentially other as yet uncharacterized hominin specieseven though each individuals proportion of DNA from other species is only about 2 to 4 percent.

Shapiro and her colleagues largely focused their study on the parts of the genome without these introgressions. Their reasoning, says Shapiro, is that those segments make us, well, human. Its probably in there, in that little, tiny portion of the genome where nobody has any archaic DNA . . . where we really need to look hard for those genes that make us unique, she says.

Shapiro explains that even if you sequenced the genome of every person on the planet today and pieced together all the ancient bits of DNA that exist within them, you wouldnt be able construct a complete Neanderthal or Denisovan genome. Parts of their genomes simply dont exist in modern humans.

Its probable that some, if not most, of these missing pieces dropped out of the genomes of modern humans by chance, but Shapiro says that for others, you just couldnt have the Neanderthal or Denisovan version and still be a human, so those segments of archaic DNA were eliminated from modern humans through negative selection.

Ed Green, a biomolecular engineer at University of California, Santa Cruz, Shapiro, and their graduate student at the time, Nathan Schaefer (now a postdoc at University of California, San Francisco), went in search of those incompatible regions.

First, they developed a method for detecting archaic introgression that they called SARGE because its based on whats known as an ancestral recombination graph (ARG). Essentially, Green says, it creates an evolutionary tree for every locus, which gives it the power needed to separate archaic introgression from genes shared with other species because of ancestry, as well as the ability to detect what Green and his colleagues refer to as archaic deserts that genetically separate us from our kin.

Using SARGE, the team examined 279 modern human genomes from the Simons Genome Diversity Project, which sampled from populations all over the world, as well as two Neanderthal genomes and one Denisovan genome. The analysis suggested at least one major wave of breeding between Neanderthals and modern humans and several smaller mixing events with Denisovans. The algorithm also detected other archaic genesgenetic variation retained from the common ancestors that gave rise to us and our closest kin (what geneticists refer to as incomplete lineage sorting). A mere 7 percent of our genomes lacked any trace of archaic DNA.

Within these archaic deserts, the team zeroed in on regions that also had high-frequency mutations totally unique to modern humans, reasoning that these changes occurred after Homo sapiens split from our kin and then spread through much of the human population. Theyre where any H. sapiens-specific novelty lies, says Green.

The team estimates that such human-specific regions make up roughly 1.5 percent of our genomes. Per base, these regions have more genes, coding regions of genes, and regulatory element binding sites than other parts of the genomeanother clue that theyre especially important to us. In addition, that 1.5 percent turned out to be highly enriched in genes that have to do with nervous system function, says Green.

Other groups have reached similar conclusions, especially with regard to the uniqueness of human nervous system genes, notes University of Vienna evolutionary biologist Martin Kuhlwilm, who did not participate in the study, but the new work provides higher resolution than past studies. Thats the most valuable contribution of their new method, he says, adding that with their methods, they can basically go down to a handful of genes, which can be the target of further studies to uncover the functional consequences of human-specific variants.

He adds that he hopes to see this kind of detailed work occur in nonhuman animals, especially primates. For instance, analyzing what the human-specific parts of the genome look like in chimpanzees could reveal whether those regions are broadly species-defining, or if theyre only special in us. Such analyses could further refine what makes us really human, he says.

The rest is here:
The Extinct Species Within - The Scientist