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Clinical Laboratories and Pathology Groups

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Clinical Laboratories and Pathology Groups

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Swedish Researchers Publish High-resolution Single-cell Transcriptomic Map of Human Tissues in Findings That May Advance Diagnostics and Medical Laboratory Testing

Teams from multiple Swedish organizations are investigating the relationship of protein-coding genes to antibodies

Scientists in Sweden are discovering new ways to map the expression of genes in cells, tissues, and organs within the human body thanks to advances in molecular profiling. Their study has successfully combined the analysis of single-cell transcriptomics with spatial antibody-based protein profiling to produce a high-resolution, single-cell mapping of human tissues.

The data links protein-coding genes to antibodies, which could help researchers develop clinical laboratory tests that use specific antibodies to identify and target infectious disease. Might this also lead to a new menu of serology tests that could be used by medical laboratories?

This research is another example of how various databases of genetic and proteomic information—different “omics”—are being combined to produce new understanding of human biology and physiology.

Scientists from the KTH Royal Institute of Technology in Stockholm, Uppsala University, Karolinska Institute, and the Karolinska University Hospital in Sweden, the Arctic University of Norway, and other institutions, used both RNA sequencing and antibody-based profiling to formulate a publicly-available map of 192 human cell types.

The researchers published their findings in the peer-reviewed journal Science Advances, titled, “A Single–Cell Type Transcriptomics Map of Human Tissues.” They wrote, “the marked improvements in massive parallel sequencing coupled with single-cell sample preparations and data deconvolution have allowed single-cell RNA sequencing (scRNA-Seq) to become a powerful approach to characterize the gene expression profile in single cells.”

In a Human Protein Atlas (HPA) project press release, Director of the HPA consortium and Professor of Microbiology at Royal Institute of Technology in Stockholm, Mathias Uhlén, PhD, said, “The [Science Advances] paper describes an important addition to the Human Protein Atlas (HPA) which has become one of the world’s most visited biological databases, harboring millions of web pages with information about all the human protein coding genes.”

Cecilia Lindskog, PhD

“We are excited that the new open-access Single Cell Type section constitutes a unique resource for studying the cell type specificity and exact spatial localization of all our proteins”, said Cecilia Lindskog, PhD (above), Head of the HPA Tissue Atlas and Associate Professor, Experimental Pathology, Uppsala University, in the Protein Atlas press release. Medical laboratories may soon have new serology tests to perform that were developed based on HPA data. (Photo copyright: Human Uterus Cell Atlas.)

Distinct Expression Clusters Consistent to Similar Cell Types

To perform their research, the scientists mapped the gene expression profile of all protein-coding genes across different cell types. Their analysis showed that there are distinct expression clusters which are consistent to cell types sharing similar functions within the same organs and between organs of the human body.

The scientists examined data from non-diseased human tissues and organs using three main criteria:

  • Publicly available raw data from human tissues containing good technical quality with at least 4,000 cells analyzed and at least 20 million read counts by the sequencing for each tissue.
  • High correlation between pseudo-bulk transcriptomics profile from the scRNA-Seq data and bulk RNA-Seq generated as part of the Human Protein Atlas (HPA).
  • High correlation between the cluster-specific expression and the expected expression pattern of an extensive selection of marker genes representing well-known tissue- and cell type-specific markers, including both markers from the original publications and additional markers used in pathology diagnostics.

According to the HPA press release, “across all analyzed cell types, almost 14,000 genes showed an elevated expression in particular cell types, out of which approximately 2,000 genes were found to be specific for only one of the cell types.”

The press release also states, “cell types in testis showed the highest numbers of cell type elevated genes, followed by ciliated cells. Interestingly, only 11% of the genes were detected in all analyzed cell types suggesting that the number of essential genes (‘house-keeping’) are surprisingly few.”

Omics-based Biomarkers for Accurate Diagnosis of Disease

The goal of this venture is to map all the human proteins in cells, tissues, and organs through various “omics” technologies. As Dark Daily wrote in “Spatial Transcriptomics Provide a New and Innovative Way to Analyze Tissue Biology, May Have Value in Surgical Pathology,” omics have the potential to deliver biomarkers which can be used for earlier and more accurate diagnoses of diseases and health conditions. Omics, such as genomics, epigenomics, proteomics, metabolomics, metagenomics, and transcriptomics, are taking greater roles in precision medicine diagnostics as well.

The Human Protein Atlas is the largest and most comprehensive database for spatial distribution of proteins in human tissues and cells. It provides a valuable tool for researchers who study and analyze protein localization and expression in human tissues and cells.

Ongoing improvements in gene sequencing technologies are making research of genes more accurate, faster, and more economical. Advances in gene sequencing also could help medical professionals discover more personalized care for patients leading to improved outcomes. A key goal of precision medicine.

One of the conclusions to be drawn from this work is that clinical laboratories and anatomic pathology groups will need to be able to handle immense amounts of data, while at the same time having the capabilities to analyze that data and identify useful patterns that can help diagnose patients earlier and more accurately.

It is another example of how and why those medical laboratories that succeed going forward will have robust laboratory information management systems (LIMS). Forward-looking lab leaders may want to make larger investments in their lab’s health information technology (HIT).

JP Schlingman

Related Information:

A Single Cell Type Map of Human Tissues

A Single-cell Type Transcriptomics Map of Human Tissues

The Human Protein Atlas Press Release – A Single Cell Type Map of Human Tissues

The Human Protein Atlas: A Spatial Map of the Human Proteome

Spatial Transcriptomics Provide a New and Innovative Way to Analyze Tissue Biology, May Have Value in Surgical Pathology

Discovery That Modern Humans Aren’t Especially Unique, Genetically Speaking, May Lead to Improved Precision Medicine Diagnostics and Therapeutics

Of interest to clinical pathologists is the finding that sequencing the genomes of Humans and Neanderthals revealed a link between severity of COVID-19 infections and Neanderthal DNA

Genetic scientists from the University of California Santa Cruz have learned that just 7%—or less—of our DNA is unique to the human species, with the remainder of our genomes coming from other archaic species, such as Neanderthal and Denisovan.

Why should this matter to pathologists and clinical laboratories? Because a broader knowledge of how DNA evolves may help researchers and healthcare providers better understand how a modern family’s DNA can change over generations. In turn, these insights may lead to precision medicine tools for personalized diagnosis and treatment.

The scientists published their study in Science Advances, a peer-reviewed journal of the American Association for the Advancement of Science (AAAS), titled, “An Ancestral Recombination Graph of Human, Neanderthal, and Denisovan Genomes.”

How Genetically Unique Are Humans?

“We find that a low fraction, 1.5 to 7%, of the human genome is uniquely human, with the remainder comprising lineages shared with archaic hominins from either ILS [incomplete lineage sorting] or [genetic] admixture,” wrote the paper’s authors.

To complete their study, the researchers used DNA extracted from fossils of Neanderthals and Denisovans, as well as genetic information from 279 people from various locations around the world.

One goal was to determine what part of a modern human’s genome is truly unique. Though only a small percentage of our entire genome, those portions are important.

“We can tell those regions of the genome are highly enriched for genes that have to do with neural development and brain function,” Richard Green, PhD, Associate Professor of Biomolecular Engineering at the University of California Santa Cruz and co-author of the paper, told the Associated Press (AP).

In addition to highlighting what makes modern humans unique as a species, the study also suggests, “That we’re actually a very young species. Not that long ago, we shared the planet with other human lineages,” said Joshua Akey, PhD, Professor of Ecology and Evolutionary Biology and the Lewis-Sigler Institute for Integrative Genomics at Princeton University. Akey co-authored the Science Advances research paper.

Human/Neanderthal Genetic Overlap

The genetic research being conducted at the University of California Santa Cruz is just the most recent in a flurry of studies over the past decade investigating the Neanderthal genome. Most of these studies point to the vast similarities between humans and Neanderthals, but also to how similar humans are to each other.

Anna Goldfield, PhD

“Humans have more than three billion letter pairs of DNA in their genome: It turns out less than 2% of that spells out around 20,000 specific genes, or sets of instructions that code for the proteins that make our tissues,” wrote  zooarcheologist Anna Goldfield, PhD (above), Adjunct Instructor Cosumnes River College in Sacramento, Calif., and at the University of California, Davis, in Sapiens. “All humans share the same basic set of genes (we all have a gene for earwax consistency, for example), but there are subtle variations in the DNA spelling of those genes from individual to individual that result in slightly different proteins (sticky earwax versus dry earwax) … Overall, any given human being is about 99.9% similar, genetically, to any other human being,” she added. It is those variations that could lead to precision medicine treatments, personalized drug therapies, and clinical laboratory tests that inform physicians about relevant genetic variations. (Photo copyright: Boston University.)

Practically Everyone Has Neanderthal DNA

Understanding that humans and Neanderthals are 93-98.5% similar genetically may—or may not—come as a surprise. In delving into those similarities and differences researchers are making interesting and potentially important discoveries.

For example, researchers have studied a gene that occurs in both modern humans and Neanderthal fossils that has to do with how the body responds to carcinogenic hydrocarbons, such as smoke from burning wood. Neanderthals were far more sensitive to the carcinogens, but also had more genetic variants, such as single-nucleotide polymorphisms, that could neutralize their effects.

Most modern humans carry some Neanderthal DNA. For some time, scientists thought that Africans likely did not carry Neanderthal DNA, since ancient people tended to migrate out of Africa and met Neanderthals in Europe. More recent research, however, shows that migration patterns were more complex than previously thought, and that the ancient people migrated back to Africa bringing Neanderthal DNA with them.

“Our results show this history was much more interesting and there were many waves of dispersal out of Africa, some of which led to admixture between modern humans and Neanderthals that we see in the genomes of all living individuals today,” Akey told CNN.

Neanderthal DNA and COVID-19

Researchers have found that having Neanderthal DNA may affect the health of modern people who carry it. Perception of pain, immune system function, and even hair color and sleeping patterns have been associated with having Neanderthal DNA.

Scientists have even found a potential link between severe COVID-19 infection and Neanderthal DNA, CNN reported.

In “The Major Genetic Risk Factor for Severe COVID-19 Is Inherited from Neanderthals,” published in the journal Nature, scientists with the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and the Okinawa Institute of Science and Technology Graduate University in Onna-son, Japan, wrote, “Here, we show that the risk is conferred by a genomic segment … that is inherited from Neanderthals and is carried by about 50% of people in South Asia and about 16% of people in Europe today.”

The researchers added, “It turns out that this gene variant was inherited by modern humans from the Neanderthals when they interbred some 60,000 years ago. Today, the people who inherited this gene variant are three times more likely to need artificial ventilation if they are infected by the novel coronavirus SARS-CoV-2.”

Of course, these links and associations are preliminary science. John Capra, PhD, Research Associate Professor of Biological Sciences and Associate Professor of Biomedical Informatics at the University of California, San Francisco says, “We can’t blame Neanderthals for COVID. That’s a damaging response, and that’s why I want to emphasize so much [that] the social and environmental factors are the real things that people should be worrying about,” he told CNN.

“That said,” he continued, “as a geneticist, I think it is important to know the evolutionary history of the genetic variants we find that do have effects on traits. The effects of Neanderthal DNA traits are detectable, but they’re modest.”

Nevertheless, genetic scientists agree that understanding the genetic roots of disorders could lead to breakthroughs that result in new types of clinical laboratory tests designed to guide precision medicine treatments.

—Dava Stewart

Related Information

An Ancestral Recombination Graph of Human, Neanderthal, and Denisovan Genomes

Just 7% of Our DNA Is Unique to Modern Humans, Study Shows

Mapping Human and Neanderthal Genomes

All Modern Humans Have Neanderthal DNA, New Research Finds

Neanderthal Genes May Be to Blame in Some Severe Coronavirus Cases

How Neanderthal DNA Affects Human Health—Including the Risk of Getting COVID-19

The Major Genetic Risk Factor for Severe COVID-19 Is Inherited from Neanderthals

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