Daily Archives: May 4, 2023

There are more than 6,000 mammalian species on Earth, each of them different. Over the past 100 million years, mammals have evolved to adapt to their surrounding environment, resulting in diverse features.However, certain parts of the genome have remained the same across species and over millions of years, a large international collaboration of 30 research teams has found. This suggests that these regions are important, and the researchers believe these could hold the key to understanding human disease better.

The findings were recently published in 11 papers in the journal Science. The collaboration, called Zoonomia Project, investigated the genomic basis of shared and specialised traits in mammals.

The reason why the authors compared 240 mammalian genomes is to observe which parts remained unchanged across species during the course of evolution. Since evolution is a natural phenomenon that helps species adapt over time in response to the changing environment, any part of the genome that remains unchanged must be important.

A genome is the complete set of genetic information in an organism, and provides all of the information the organism requires to function. It consists of two broad parts. One is the genes, which are responsible for manufacture of protein molecules by the organism.

The other part consists of regulatory elements. These regions do not code for proteins, but instruct other genes where, when and how many proteins they must produce.

The scientists hypothesised that mutations in these regions of the genome may give rise to new diseases, or may be responsible for some unique mammalian features.

One of the paper is about the sled dog Balto, who was partly descended from the Siberian Husky, and was one of the most famous dogs in the world.

In 1925, during an outbreak of diphtheria in Nome, Alaska, Balto helped deliver serum to children. The study examined Baltos genome and compared it with the genomes of other dogs of that time and the present. It found that sled dogs of that time (including Balto) were genetically healthier than modern dogs, while Balto had more genetic diversity than his contemporaries and also modern dogs.

ALSO READ | Elephant Habitats Across Asia Have Declined By More Than 64% Since 1700: Study

The scientists have found some genetic variants that may be responsible for rare and common human diseases, including cancer. They studied a disease called medulloblastoma. It is a type of brain cancer that originates in the cerebellum, and is the most common type of cancerous brain tumour in children.

In one of the papers, scientists studied patients with medulloblastoma and found mutations in regions of the human genome which are otherwise conserved across all mammalian species. According to the researchers, these mutations may be associated with the disease, or may slow down the treatment of the illness.

The fact that the regions are conserved across mammalian species, but show mutations in patients with medulloblastoma, supports the hypothesis that the reason these portions are conserved is because they are important.

Therefore, scientists may use this approach in future to identify genetic changes that could be responsible for diseases.

Other papers have described how some parts of the conserved genomic regions are associated with exceptional mammalian traits such as a superior sense of smell, the ability to hibernate in winters and an extraordinary brain size, among others.

According to one of the studies, mammals started changing and diverging about 65 million years ago. This was even before the Chicxulub impactor, the asteroid that killed dinosaurs, hit Earth.

Another study found a link between more than 10,000 genetic deletions in human genomes and the function of neurons.

One paper said that species that have had a small population size historically are at a higher risk of extinction in the present day.

See original here:
Genomes From 240 Mammalian Species Help Explain 100 Years Of Evolution And Human Disease - ABP Live

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 whats 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 nt from the word isnt 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.

These tools have the capability to allow us to start to identify the many small molecular building blocks that make us unique as a species, Reilly said.

James Xue of the Broad Institute is lead author of the study.

See the rest here:
'Deletions' from the human genome may be what made us human - Yale News

STAMFORD, Conn., May 04, 2023 (GLOBE NEWSWIRE) -- GeneDx (Nasdaq: WGS), a leader in delivering improved health outcomes through genomic and clinical insights, today announced the availability of its GenomeXpress and GenomeSeqDx whole genome sequencing tests with buccal swabs as an alternative sample collection option for biological parents or other immediate family members. Sequencing biological parent genomes alongside patient genomes known as trio analysis - aids in disease diagnosis and greatly increases diagnostic yield rates.

"We are continuously looking for ways to broaden adoption of genome sequencing and facilitate convenient access to families to aid in disease diagnosis, said Paul Kruszka, M.D., Chief Medical Officer at GeneDx. Research shows diagnostic rates are highest when we can include genomic data of biological parents to classify variants of unknown significance based on inheritance patterns. Adding buccal swab as an additional sample collection method for our GenomeSeqDx and GenomeXpress whole genome sequencing tests can make it easier for providers to collect parent samples for trio testing.

Buccal swab is a convenient, non-invasive method to collect DNA from cells found inside a persons cheek. In the case of trio testing, the diagnostic yield for positively identifying a disease-causing variant increases from 19% to 30%.1 In addition to its whole genome sequencing tests, GeneDx also makes buccal swab available as an alternative DNA collection method for its XomeDx and XomeDxXpress whole exome sequencing tests for patients and biological parent samples.

We continue to turn to GeneDx for whole genome sequencing testing to accurately identify pathogenic variants that explain our patients illnesses, said Tara Lynn Wenger, M.D., Ph.D., Associate Professor in the Department of Pediatrics at the University of Washington and Associate Medical Director for Inpatient Genetics Services at Seattle Childrens Hospital. Collecting DNA from biological parents or other relatives is not always so easy. Buccal swab DNA collection for parents will streamline the process and prevent delays in testing and enable us to do a more thorough whole genome analysis.

About GeneDx GenomeSeqDx and GenomeXpress Whole Genome Sequencing GenomeSeqDx and GenomeXpress clinical whole genome tests by GeneDx include evaluation and analysis of both the protein-coding and non-coding regions of the human nuclear genome, allowing for the broadest potential detection of characterized/pathogenic variants contributing to the molecular basis of a genetic disorder in an affected individual. Detecting and characterizing variants that may contribute to the molecular basis of a genetic disorder is most effective when at least one or both biological parents are included in the analysis. Several large, evidenced-based studies have demonstrated that genome sequencing identifies a causal variant in more than 40% of cases, with higher yields for cases that specifically include samples from family members for analysis.2,3,4

About GeneDxGeneDx (Nasdaq: WGS) delivers personalized and actionable health insights to inform diagnosis, direct treatment and improve drug discovery. The company is uniquely positioned to accelerate the use of genomic and large-scale clinical information to enable precision medicine as the standard of care. GeneDx is at the forefront of transforming healthcare through its industry-leading exome and genome testing and interpretation, fueled by one of the worlds largest, rare disease data sets. For more information, please visit http://www.genedx.com and connect with us on LinkedIn, Twitter, Facebook, and Instagram.

Investor ContactTricia TruehartInvestors@GeneDx.com

Media ContactMaurissa MessierPress@GeneDx.com

1 Data on file.2 Manickam K, McClain MR, Demmer LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021 Nov;23(11):2029-2037. doi: 10.1038/s41436-021-01242-6. Epub 2021 Jul 1.3 Sheidley BR, Malinowski J, Bergner AL, et al. Genetic testing for the epilepsies: A systematic review. Epilepsia. 2022 Feb;63(2):375-387. doi: 10.1111/epi.17141. Epub 2021 Dec 10.4 Dimmock D, Caylor S, Waldman B, et al. Project Baby Bear: Rapid precision care incorporating rWGS in 5 California childrens hospitals demonstrates improved clinical outcomes and reduced costs of care. Am J Hum Genet. 2021 Jul 1;108(7):1231-1238. doi:10.1016/j.ajhg.2021.05.008. Epub 2021 Jun 4.Yang et al. (2014) JAMA 312 (18):1870-9 (PMID: 25326635)

Follow this link:
GeneDx Adds Buccal Swab as Non-Invasive Whole Genome ... - GlobeNewswire

This article has been reviewed according to ScienceX's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

peer-reviewed publication

trusted source

proofread

by Bob Yirka , Medical Xpress

Proportion of the glioma exploratory cohort (green) or control cohort (blue) with variants in seven cancer genes and overall. P values were calculated with Fishers exact test and Bonferroni correction. Credit: Science Advances (2023). DOI: 10.1126/sciadv.ade2675

A team of gene therapists, oncologists, genetic sequencing experts and neurosurgeons affiliated with a host of institutions in the U.S. and one in Sweden has uncovered gene variants that appear to be responsible for passing on familial glioma from parent to offspring. In their study, reported in the journal Science Advances, the group sequenced the genomes of members of glioma-affected families.

Glioma is a form of cancerous brain tumor with a generally poor prognosis. Familial glioma is a subclass of glioma that persists along family lines, strongly suggesting a genetic component. In this new effort, the researchers set their sights on tracking down the specific genes responsible for passing on a propensity for developing glioma.

The researchers took tissue samples from 203 volunteers from 189 families with a history of glioma and performed whole-genome sequencing. They then repeated the whole exercise using tissue samples from another 122 people from 115 families. Once sequencing was completed, germline variants were compared with sequences done on more than 1,000 people who did not have a family history of glioma.

The researchers found 54 variants appearing in 28 genes that appeared to be overrepresented in families with a history of glioma. They found them in 50 of the families involved in the testing. More specifically, they found copy number changes in HERC2. They also found an overlap between genes they identified as possibly related to familial glioma and genes that have previously been associated with other kinds of cancer.

The data also showed variants they described as suspicious in some noncoding genes, which they suggest could play a role in mediating the activity of other genes. Such variants, they further note, appeared to coincide with heightened levels of transcription factor bind mutations upstream of some of the involved genes.

The researchers conclude by noting that theirs is the first study to link the HERC2 gene to predisposition to any type of cancer and the first to look at the role noncoding variants may play in glioma.

More information: Dong-Joo Choi et al, The genomic landscape of familial glioma, Science Advances (2023). DOI: 10.1126/sciadv.ade2675

Journal information: Science Advances

2023 Science X Network

See original here:
Whole-genome sequencing used to track down genes behind familial glioma - Medical Xpress

Tiny pores in the cell nucleus play an essential role for healthy aging by protecting and preserving the genetic material. A team in Germany from the Department of Theoretical Biophysics at the Max Planck Institute of Biophysics in Frankfurt am Main and the Synthetic Biophysics of Protein Disorder Group at Johannes Gutenberg University Mainz has literally filled a hole in the understanding of the structure and function of these nuclear pores. The scientists found out how intrinsically disordered proteins in the center of the pore can form a spaghetti-like mobile barrier that is permeable for important cellular factors but blocks viruses or other pathogens.

Human cells shield their genetic material inside the cell nucleus, protected by the nuclear membrane. As the control center of the cell, the nucleus must be able to exchange important messenger molecules, metabolites or proteins with the rest of the cell. About 2000 pores are therefore built into the nuclear membrane, each consisting of about 1000 proteins.

For decades, researchers have been fascinated by the three-dimensional structure and function of these nuclear pores, which act as guardians of the genome: substances that are required for controlling the cell are allowed to pass, while pathogens or other DNA-damaging substances are blocked from entry. The nuclear pores can therefore be thought of as molecular bouncers, each checking many thousands of visitors per second. Only those who have an entrance ticket are allowed to pass.

How do the nuclear pores manage this enormous task? About 300 proteins attached to the pore scaffold protrude deep into the central opening like tentacles. Until now, researchers did not know how these tentacles are arranged and how they repel intruders. This is because these proteins are intrinsically disordered and lack a defined three-dimensional structure. They are flexible and continuously moving -- like spaghetti in boiling water.

Combination of microscopy and computer simulations

As these intrinsically disordered proteins (IDPs) are constantly changing their structure, it is difficult for scientists to decipher their three-dimensional architecture and their function. Most experimental techniques that researchers use to image proteins only work with a defined 3D structure. So far, the central region of the nuclear pore has been represented as a hole because it was not possible to determine the organization of the IDPs in the opening.

The team led by Gerhard Hummer, Director at the Max Planck Institute of Biophysics, and Edward Lemke, Professor for Synthetic Biophysics at Johannes Gutenberg University Mainz, and Adjunct Director at the Institute of Molecular Biology Mainz has now used a novel combination of synthetic biology, multidimensional fluorescence microscopy and computer-based simulations to study nuclear pore IDPs in living cells.

"We used modern precision tools to mark several points of the spaghetti-like proteins with fluorescent dyes that we excite by light and visualize in the microscope," Lemke explains. "Based on the glow patterns and duration, we were able to deduce how the proteins must be arranged." Hummer adds, "We then used molecular dynamics simulations to calculate how the IDPs are spatially organized in the pore, how they interact with each other and how they move. For the first time, we could visualize the gate to the control center of human cells."

Dynamic protein network as transport barrier

The tentacles in the transport pore take on a completely different behavior compared to what we knew before, because they interact with each other and with the cargo. They move permanently like the aforementioned spaghetti in boiling water. So, in the center of the pore there is no hole, but a shield of wiggly, spaghetti-like molecules. Viruses or bacteria are too big to get through this sieve. However, other large cellular molecules needed in the nucleus can pass as they carry very specific signals. Such molecules have an entry ticket, whereas pathogens usually do not. "By disentangling the pore filling, we enter a new phase in nuclear transport research," adds Martin Beck, collaborator and colleague at the Max Planck Institute of Biophysics.

"Understanding how the pores transport or block cargo will help us identify errors. After all, some viruses manage to enter the cell nucleus despite the barrier," Hummer sums up. "With our combination of methods, we can now study IDPs in more detail to find why they are indispensable for certain cellular functions, despite being error-prone. In fact, IDPs are found in almost all species, although they carry the risk of forming aggregates during the aging process which can lead to neurodegenerative diseases such as Alzheimer's," Lemke says. By learning how IDPs function, researchers aim to develop new drugs or vaccines that prevent viral infections and help healthy aging.

Read the original post:
Wiggly proteins guard the genome: Dynamic network in the pores of ... - Science Daily

Alternative RNA splicing is an essential mechanism linking genetic variation to human diseases. While the signals from genome-wide association studies (GWAS) have been linked to expression quantitative trait loci (eQTL) in previous studies, further work is needed to better elucidate the relationship to other genetic regulatory mechanisms, such as splicing QTLs (sQTL). Here, we performed a genome-wide sQTL analysis to identify variants that might affect RNA splicing in 1,010 nonsmall cell lung cancer (NSCLC) samples from The Cancer Genome Atlas. The identified sQTLs were largely independent of eQTLs and were predominantly enriched in exonic regions, genetic regulatory elements, RNA-binding protein (RBP) binding sites, and known NSCLC risk loci. In addition, target genes affected by sQTLs (sGenes) were involved in multiple processes in cancer, including cell growth, apoptosis, metabolism, immune infiltration, and drug responses, and sGenes were frequently altered genetically in NSCLC. Systematic screening of sQTLs associated with NSCLC risk using GWAS data from 15,474 cases and 12,375 controls identified an sQTL variant rs156697-G allele that was significantly associated with an increased risk of NSCLC. The association between the rs156697-G variant and NSCLC risk was further validated in two additional large population cohorts. The risk variant promoted inclusion of GSTO2 alternative exon 5 and led to higher expression of the GSTO2 full-length isoform (GSTO2-V1) and lower expression of the truncated GSTO2 isoform (GSTO2-V2), which was induced by RBP quaking (QKI). Mechanistically, compared with GSTO2-V1, GSTO2-V2 inhibited NSCLC cells proliferation by increasing S-glutathionylation of AKT1 and thereby functionally blocking AKT1 phosphorylation and activation. Overall, this study provides a comprehensive view of splicing variants linked to NSCLC risk and provides a set of genetic targets with therapeutic potential.

Continue reading here:
Genome-Wide Splicing Quantitative Expression Locus Analysis ... - Cancer Discovery

PRESS RELEASE

Published May 4, 2023

The global Digital Genome Market was valued at USD 28.2 Billion in 2022 and it is anticipated to grow up to USD 64.6 Billion by 2032, at a CAGR of 8.6% during the forecast period.

Deep learning is a subset of machine learning in artificial intelligence (AI) that has networks capable of learning unsupervised from data that is unstructured or unlabeled. Also known as deep neural learning or deep neural networks (DNNs), deep learning models are neural networks (algorithms used to simulate the workings of the human brain in order to recognize patterns) that can learn and make predictions on their own by analyzing data, finding patterns, and making decisions.

To Remain Ahead Of Your Competitors, Request for A Sample https://www.globalinsightservices.com/request-sample/GIS10511

Market Trends and Drivers

Surge in adoption of precision medicine will remain a key growth driver

The demand for digital genome is rapidly gaining popularity owing to continuous reduction in the cost and time required. The sequencing is widely used in the field of oncology, reproductive health and genetics. As a result, firms such as Illumina, Thermo Fisher and Qiagen are developing new innovative technologies in the field of genomics. Digital genomics market will further grow as rising application of sequencing in diagnosis of genetic disorders such as Duchenne Muscular Dystrophy, Fragile X syndrome and FAM Hypercholesterolemia etc. Advent of new technology coupled with rising demand of precision medicines will escalate market over forecast period. The major factors limiting the growth of digital genome market is lack of awareness regarding the digital genome, security & privacy of patient data, and incorrect results. In addition, lack of trained staff for digital genome in various developing economies will further impede the industry growth.

Get A Customized Scope to Match, Your Need Ask an Expert https://www.globalinsightservices.com/request-customization/GIS10511

Global Digital Genome Market Segmentation

By Product

By Application

By End-user

Major Players in the Global Digital Genome Market

The key players in the Digital Genome Market Agilent Technologies, Inc., Becton Dickinson, Pacific Biosciences, Perkin Elmer, Sigma Aldrich and Thermo Fisher, among others.

New Report Published by Global Insight Services:https://www.globalinsightservices.com/reports/hydrogen-projects-database/

About Global Insight Services:

Global Insight Services (GIS) is a leading multi-industry market research firm headquartered in Delaware, US. We are committed to providing our clients with highest quality data, analysis, and tools to meet all their market research needs. With GIS, you can be assured of the quality of the deliverables, robust & transparent research methodology, and superior service.

Contact Us:

Global Insight Services LLC16192, Coastal Highway, Lewes DE 19958E-mail:[emailprotected]Phone: +1-833-761-1700Website:https://www.globalinsightservices.com/

See more here:
Digital Genome Market is expand at a CAGR of 8.6% to reach USD ... - Digital Journal

The goal of the program is not only to make base editing accessible to high school students, but also to encourage critical thinking and reflect on base editing in social and cultural contexts. Komors team asked students to think about the difference between a disease and a trait and to consider the implications of germline genome editing, in which edits are inherited by all future descendants of the edited individual, regardless of whether those descendants consent to the procedure.

The ethical discussion is what hits a home run with the students, said Vasquez. Theyll be responsible for future gene-editing policies. Its interesting to see them thinking about the ethical side of science.

Weve had some really good discussions about what is a disease and what is a trait, stated Evanoff. If we have the ability to make genetic-disease corrections, who will be able to afford those treatments? Where does the equitability lie in this technology? We don't have the answers to that. I say to students, That's going to be your job to figure out!

This research was supported by the National Science Foundation (MCB-2048207), the National Institute of General Medical Sciences (T32 GM007240-41), the National Institute of Health (T32 GM112584), the Howard Hughes Medical Institute (GT13672 and the Gilliam Fellowship Program) and the National Academies of Sciences, Engineering, and Medicine Ford Foundation Predoctoral Fellowship Program.

Read more here:
High School Students Learn the Basics of Base Editing to Cure GFP ... - University of California San Diego

Genome-wide association studies (GWAS) play a crucial role in medical research. By examining millions of genetic variants across the entire genome in large populations, these studies can identify genetic variations that contribute to a particular disease or trait. GWAS have already led to breakthroughs in disease prevention, personalised medicine and drug development.

However, Dr Denis Bauer, who leads the Transformational Bioinformatics Group at the Commonwealth Scientific and Industrial Research Organisation (CSIRO), notes that traditional GWAS evaluate disease association for each genomic location individually, which can be limiting for complex diseases.

These diseases, such as dementia, represent the largest burden on the healthcare system and involve genes that interact with each other to create disease risk, she explains.

Statistical models struggle to evaluate the joint contribution of variants across the genome. So other common approaches compromise by investigating interactions between locations that have already shown association with the disease. Unfortunately, this approach runs the risk of not including the real drivers of disease that may have no effect individually but jointly contribute to disease development.

This limitation in traditional GWAS is one of the main reasons CSIRO created VariantSpark. The scalable machine learning framework, which recently became available on Microsofts Azure Marketplace. VariantSpark enables researchers to quickly and accurately analyse high-dimensional genomic data data sets with a large number of variables to find novel disease genes or predictive biomarkers.

In complex diseases, we are hunting very subtle signals, which means we need very large data sets to make robust statements, says Dr Bauer. VariantSpark can scale to mega-biobanks with millions of samples and is 90 per cent faster than traditional compute frameworks.

This puts researchers on the right track for finding evidence of epistasis, the non-additive gene-gene interactions that are postulated to drive complex diseases. It also boosts their ability to find predictive biomarkers that allow disease to be diagnosed early to potentially stop or delay progression.

Another reason CSIRO created VariantSpark was to help its research collaborators analyse their increasingly large and complex genomic data sets.

We were involved in analysing a cohort of several thousand individuals, and all the other tools failed on the size. So we either needed to compromise by analysing only a subset of the data, or innovate, says Dr Bauer.

We wanted to make VariantSpark publicly available because if we have problems processing large volumes of data or deeply interrogating complex cohorts, a lot of other researchers probably have that problem too.

While VariantSpark can scale to handle large and complex data sets, Dr Bauer notes that the solution also caters to researchers with smaller volumes of data.

View original post here:
Genomic researchers gain access to CSIRO's AI-powered data ... - Microsoft

Machine-learning-based prediction of splicing in extinct hominin species highlights the effect of natural selection on splice-altering variants and reveals phenotypic differences with modern humans.

The sequencing of the genomes of archaic hominins has fostered a renewed interest in the identity of our extinct relatives and their legacy in the genome of modern humans. However, characterization of the phenotypes of archaic hominins is limited by the scarcity of remains and the rapid degradation of soft tissues after death. Various attempts have been made to infer archaic phenotypes on the basis of their DNA methylation patterns1 or through the study of the regulatory alleles that they share with modern humans2. Yet, the extensive purge of archaic DNA from the genome of modern humans3 and the possibility of regulatory divergence between archaic and modern humans4 limit the effectiveness of these approaches. Writing in Nature Ecology & Evolution, Brand et al.5 implemented a solution to this issue by focusing on alternative splicing, which informs us on the phenotypes of archaic hominins and reveals how splice-altering variants (SAVs) that modern humans inherited from their archaic relatives helped them to adapt to their environment, but also contributed to disease (Fig. 1).

a, Brand et al. infer genetic differences between modern humans and four lineages of archaic hominin. b, They evaluate the effect on splicing of thousands of archaic alleles and show an increased deleteriousness of SAVs that are specific to one or more archaic lineages relative to those that are shared with modern humans. c,d, They further overlap these SAVs with disease genes to reveal specific traits of archaic humans (c) and explore the effect of introgressed SAVs on human phenotypes and adaptation to environmental pressures (d). Created with BioRender.com.

Alternative splicing the process by which exons of a gene are joined in different combinations to form alternative mRNA molecules is a major contributor to the heritability of complex traits, on a par with variants that affect gene expression levels6. Because molecular mechanisms that underlie alternative splicing are deeply conserved across eukaryotes7, Brand et al. reasoned that the same rules should govern alternative splicing in modern humans and archaic hominins. They used a deep-learning algorithm known as SpliceAI8 to predict allele-specific effects on splicing at more than 1.5 million loci that differ between modern humans and four archaic hominins (three Neanderthals and one Denisovan). The authors identified thousands of SAVs present in archaic hominins, of which 37% are specific to these hominins (referred to as archaic-specific SAVs). The remainder included both ancient alleles that predate the split between modern humans and their archaic relatives and have survived in modern humans to this day (59%) (referred to as ancient SAVs), as well as alleles of archaic origin that were introgressed into modern humans through admixture (4%) (referred to as introgressed SAVs).

The authors showed that archaic alleles that are specific to a single lineage (for example, specific to the Neanderthals from Vindija Cave) are enriched for SAVs compared to archaic alleles that are shared across multiple lineages of archaic hominin. This result, which they attribute to the purging of SAVs that appeared early in archaic hominin evolution, is consistent with SAVs being more frequently found within Neanderthal lineages. Indeed, Neanderthals had a smaller effective population size relative to Denisovans and natural selection was thus less efficient at purging deleterious alleles from their genomes. Brand et al. further showed that archaic-specific SAVs are more likely than ancient SAVs to alter conserved sites and disrupt protein function. Finally, the authors analysed the phenotypic effect of the genetic burden carried by our late archaic relatives, by intersecting archaic-specific SAVs with known disease genes (identified by genome-wide association studies or associated with rare Mendelian disorders). In doing so, they pinpointed the specific phenotypes that are associated with SAV-containing genes in each archaic lineage, such as fragile skin in Neanderthals or muscular abnormalities in Denisovans.

Next, Brand et al. focused on SAVs that were introgressed in modern humans. The authors found that introgressed SAVs are enriched near genes that are expressed in a tissue-specific manner and show that the vast majority of SAVs observed in humans today are older than the split between Denisovans and Neanderthals. These results suggest that natural selection purged more-recent SAVs from human genomes shortly after their introgression, leaving only SAVs with more-localized effects on gene expression. Yet, the authors further showed that introgressed SAVs are enriched near susceptibility genes for several phenotypes, including hay fever and allergies, Helicobacter pylori serological status or systemic sclerosis, which suggests that SAVs inherited from archaic hominins still contribute to disease today.

Finally, the authors explored how SAVs that modern humans inherited from their archaic relatives helped them to adapt to their environment. In addition to previously described SAVs associated with COVID-19 susceptibility at the OAS1 locus and rhinitis at the TLR1 locus, the authors report SAVs at the EPAS1 locus, where an Denisovan-introgressed haplotype has contributed to the adaptation of Tibetan peoples to high altitudes9. The reported SAV leads to nonsense-mediated decay of EPAS1 and correlates with lower haemoglobin levels in Tibetan individuals10, consistent with the positive effect of EPAS1 on altitude-induced erythropoiesis11. At the ERAP2 locus, the authors identify three introgressed SAVs of potential evolutionary importance. First, they identify an ancient SAV evolving under balancing selection that is associated with stimulation-induced splicing of ERAP212 and increased survival during the Black Death13. In addition, they report two Neanderthal-specific SAVs of unknown functional relevance, one of which is predicted to induce nonsense-mediated decay of ERAP2. Together, these results highlight how SAVs inherited from archaic hominins have contributed to human adaptation.

The work presented by Brand et al. shows us how the prediction of molecular phenotypes from DNA sequence8 can teach us about extinct species and their effect on the evolutionary history of their living relatives. Yet, it also has some limitations. First, it relies heavily on the accuracy of the underlying predictions. Its conclusions could thus suffer from the poor performance of current prediction methods when applied to deep intronic variants and distal enhancers. Second, Brand et al. only consider variants with a widespread effect on splicing. Yet, context-specific splicing has been shown to have an essential role in the development of the brain and testis14 and may have had a role in the purging of archaic variants observed in these tissues4. Although the general splicing machinery is extremely conserved, such dynamic and tissue-specific splicing may be much more variable across species, which may complicate the portability of predictions across hominins. More-accurate models powered by massively parallel splicing assays15 and the mapping of splice quantitative trait loci6 are needed to embrace the complexity of such context-specific splicing. Finally, structural variants (for example, insertions and/or deletions) and variants located on sex chromosomes have so far been left aside, despite their relevance for human phenotypes and hybrid infertility. Future efforts must assess the role of these variants in the purge of archaic alleles from modern human genomes.

The work of Brand et al. is a powerful proof of concept that lays the foundations for future studies that aim to resurrect the alternative splicing landscape of extinct species.

More:
Archaic hominin traits through the splicing lens - Nature.com