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Clinical Laboratories and Pathology Groups

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Major Breakthrough in Human Genome Sequencing, as Full Y Chromosome Sequencing Completed after a More than 20 Year Journey

Clinical laboratories and pathology groups may soon have new assays for diagnosis, treatment identification, patient monitoring

It’s here at last! The human Y chromosome now has a full and complete sequence. This achievement by an international team of genetic researchers is expected to open the door to significant insights in how variants and mutations in the Y chromosome are involved in various diseases and health conditions. In turn, these insights could lead to new diagnostic assays for use by clinical laboratories and pathology groups.

After decades of attempts, genetic scientists led by the Telomere-to-Telomere Consortium—a team of researchers funded by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH)—have finally “generated the first truly complete sequence of a human Y chromosome,” which is “the final human chromosome to be fully sequenced,” of the 24 human chromosomes, SciTechDaily reported.

Pathologists and clinical laboratories involved in genetic research will understand the significance of this accomplishment. The full Y chromosome sequence “fills in gaps across more than 50% of the Y chromosome’s length, [and] uncovers important genomic features with implications for fertility, such as factors in sperm production,” SciTechDaily noted.

This breakthrough will make it possible for other research teams to gain further understanding of the functions of the Y chromosome and how specific gene variants and mutations contribute to specific health conditions and diseases. In turn, knowledge of those genetic sequences and mutations would give clinical laboratories the assays that help diagnosis, identify relevant therapies, and monitor a patient’s progress.

The researchers published their findings in the journal Nature titled, “The Complete Sequence of a Human Y Chromosome.”

“When you find variation that you haven’t seen before, the hope is always that those genomic variants will be important for understanding human health,” said Adam Phillippy, PhD, a senior investigator and head of the Genome Informatics Section at the National Human Genome Research Institute, in a press release. Clinical laboratories and anatomic pathology groups may soon have new assays based on the T2T study findings. (Photo copyright: National Human Genome Research Institute.)

Study Background and Recognition

Revolutionary thinking by the Telomere-to-Telomere (T2T) scientists led to the team’s breakthrough. The researchers “applied new DNA sequencing technologies and sequence assembly methods, as well as knowledge gained from generating the first gapless sequences for the other 23 human chromosomes,” SciTechDaily reported.

In 1977, the first complete genome of an organism was sequenced. Thus began the commencement of sequencing technology research. Twenty years ago the first human genome sequence was completed. The result was thanks to years of work through the preferred “chain termination” (aka, Sanger Sequencing) method developed by Fred Sanger and a $2.7 billion contribution from the Human Genome Project, according to a study published in the African Journal of Laboratory Medicine (AJLM).

By 2005, a new era in genomic sequencing emerged. Scientists now employed a technique called pyrosequencing and the change had great benefits. “Massively parallel or next-generation sequencing (NGS) technologies eliminated the need for multiple personnel working on a genome by automating DNA cleavage, amplification, and parallel short-read sequencing on a single instrument, thereby lowering costs and increasing throughput,” the AJLM paper noted.

The new technique brought great results. “Next-generation sequencing technologies have made sequencing much easier, faster and cheaper than Sanger sequencing,” the AJLM study authors noted.

The changes allowed more sequencing to be completed. Nevertheless, more than half of the Y chromosome sequence was still unknown until the new findings from the T2T study, SciTechDaily reported.

Why the TDT Breakthrough Is So Important

“The biggest surprise was how organized the repeats are,” said Adam Phillippy, PhD, a senior investigator and head of the NHGRI. “We didn’t know what exactly made up the missing sequence. It could have been very chaotic, but instead, nearly half of the chromosome is made of alternating blocks of two specific repeating sequences known as satellite DNA. It makes a beautiful, quilt-like pattern.”

Phillippy’s research was groundbreaking enough to earn him and his team finalist positions in the 2023 Science, Technology, and Environment segment of the Samuel J. Heyman Service to America Medals.

Much can be gained in knowing more about the Y chromosome. Along with the X chromosome, it is significant in sexual development. Additionally, current research is showing that genes on the Y chromosome are linked to the risk and severity of cancer.

Might What Comes Next Give Clinical Labs New Diagnostic Tools?

The variety of new regions of the Y chromosome that the T2T team discovered bring into focus several areas of new genetic research. For instance, the “azoospermia factor region, a stretch of DNA containing several genes known to be involved in sperm production” was uncovered, and “with the newly completed sequence, the researchers studied the structure of a set of inverted repeats or palindromes in the azoospermia factor region,” SciTechDaily reported.

“This structure is very important because occasionally these palindromes can create loops of DNA. Sometimes, these loops accidentally get cut off and create deletions in the genome,” said Arang Rhie, PhD, a staff scientist at NHGRI and first author of the Nature study.

Missing regions would challenge the production of sperm, impacting fertility, so being able to finally see a complete sequence will help research in this area.

Scientists are only just beginning to recognize the value of this breakthrough to future genetic research and development. As genetic sequencing costs continue to drop, the T2T research findings could mean new treatment options for pathologists and diagnostic assays for clinical laboratories are just around the corner.

—Kristin Althea O’Connor

Related Information:

Complete Human Y Chromosome Sequence Assembled for the First Time

The Complete Sequence of a Human Y Chromosome

Scientists Release the First Complete Sequence of a Human Y Chromosome

Will Long-Read Sequencing Technologies Replace Short-Read Sequencing Technologies in the Next 10 Years?

Researchers Assemble the First Complete Sequence of a Human Y Chromosome

Adam Phillippy Finalist in Samuel J. Heyman Service to America Medals for Science, Technology, and Environment

Genomic Scientists Are Working to Make Human Reference Genome More Inclusive by Expanding the Pangenome

Project aims to create a new pangenome for genetic testing that will ensure better clinical laboratory testing and healthcare outcomes

Recent advances in genetics are motivating some scientists to proclaim the need to update the existing “master human genome”—currently based on a single individual’s genetic sequence—to make it more inclusive. This international research effort will have implications for personalized clinical laboratory testing and precision medicine.

Genetic scientists at the Human Pangenome Reference Consortium (HPRC), a project funded by the National Human Genome Research Institute (NHGRI), are working “to sequence and assemble genomes from individuals from diverse populations in order to better represent [the] genomic landscape of diverse human populations,” according to the organization’s website.

The project plans to evaluate a wide variety of reference genomes and develop a more diverse human pangenome (a multi-genome reference sequence) that will contain a larger cross-section of the human population. The HPRC scientists will be looking at genomes from specific countries, including Denmark, Japan, South Korea, Sweden, and the United Arab Emirates, The Guardian reported.

The increased diversity of reference genetic data will enable genomic researchers to increase the accuracy of precision medicine diagnostics and clinical laboratory testing.

Pui-Yan Kwok, MD, PhD

“One person is not representative of the world,” Pui-Yan Kwok, MD, PhD (above), Henry Bachrach Distinguished Professor, Cardiovascular Research Institute at the University of California, San Francisco, told The Guardian. “As a result, most genome sequencing is fundamentally biased.” And that bias, the researchers claim, affects the accuracy of clinical laboratory treatments and diagnostics. (Photo copyright: UCSF.)

Reference Genome for Genetic Sequencing is Based on One Person

Launched in 1990, The Human Genome Project studied all DNA in a select set of organisms. The project completed its first sequence of the human genome in 2003, which became the reference genome for thousands of genomic discoveries since then.

But there’s a problem.

Although a revolutionary breakthrough in genetic sequencing, that reference genome came from just one person. This means a significant portion of the human population is not represented in genetic research, and that bias, according to some scientists, “limits the kind of genetic variation that can be detected, leaving some patients without diagnoses and potentially without proper treatment,” according to The Guardian.

“Getting the right medicine to the right patient at the right time is the tagline,” Neil Hanchard, MD, DPhil, physician scientist and senior investigator for precision health research at the NHGRI in Bethesda, Maryland, told The Guardian.

The HPRC’s goal is to help mitigate reference biases that could hamper disease diagnoses and ensure all populations receive the best treatments for illness. 

According to its website, the organization’s main purpose includes:

  • Gene sequencing from a diverse set of samples with the newest technologies.
  • Fostering an ecosystem of assembly and pangenome tools.
  • Creating and releasing high-quality assemblies and pangenomes.
  • Embedding a team of scholars to address ethical, legal, and social implications of their work.
  • Forming international partnerships for the research.

HPRC Scientists Find Never-Sequenced Genetic Variants in Africa

Standard gene sequencing works by dividing DNA into tiny portions known as short reads, then sequencing and organizing the reads into a genome using an existing reference as a guide. However, this process renders larger blocks of variants, called structural variants (SVs), more difficult to read or even remain undetected, which can translate to a sequence that does not completely represent personal variations.

In 2019, the HPRC team of scientists analyzed genetic samples from 154 people from various parts of the world and discovered SV content that was missing from their reference sequence. A further study of genetic samples from 338 individuals that examined only extra inserted DNA detected the presence of almost 130,000 new sequences.

More recently, the HPRC researchers sampled 426 individuals from 50 ethnolinguistic groups from Africa and discovered a few million new single nucleotide variants (SNVs). Most of these distinct SNVs derived from populations that had not been previously sampled.

“We haven’t even touched SVs,” Hanchard told The Guardian. “But our preliminary data suggests it’s going to be more of the same.”

If an individual “is from a population quite different from the person from which the genome referenced is derived, there will be more misalignment when their short reads are mapped to the reference,” Pui-Yan Kwok, MD, PhD, Henry Bachrach Distinguished Professor, Cardiovascular Research Institute at the University of California, San Francisco, told The Guardian

“We may miss risk variants in those regions not represented in the reference,” he added.

HPRC Receives Clearance from NHGRI to Continue Research

Hanchard recognizes the benefits of regional references in genomic sequencing and is optimistic about the future of genomics and the ability to sequence more diverse populations.

“I would love to get to a point where everyone feels represented and that this is for them, as much as it is for any particular group,” he told The Guardian. “We are from one humanity, that’s the important part.”

On February 13, the HPRC received concept clearance for renewal of the program from the NHGRI, which plans to commit up to $10 million in total costs per year for the program over the next five years.

Genetic sequencing continues to emerge as a vital tool in the diagnoses and treatment of diseases. Ensuring that as many diverse populations as possible are included in genomic research is an important element for precision medicine and optimal healthcare.

Clinical laboratory managers and pathologists will want to stay updated on these developments, because much of this new knowledge about the pangenome will need to be incorporated when interpreting genetic sequences and developing diagnoses in support of personalized medicine.   

JP Schlingman

Related Information:

The Human Genome Needs Updating. But How Do We Make It Fair?

The Human Pangenome Project: A Global Resource to Map Genomic Diversity

Human Genome Project Fact Sheet

National Advisory Council for Human Genome Research (NACHGR)

Two New York City Hospitals Join New Genetic Study to Perform Whole Genome Sequencing on 100,000 Newborn Babies to Search for 250 Rare Diseases

Global Consortium of Scientists Develop New Whole Genome Sequencing Method That Brings Costs Down to $10 per Genome

More Countries Are Now Capable of Genome Sequencing and Contributing to Global COVID-19 GISAID Database than Ever Before

GISAID hosts a vast, open database of genomic sequences of SARS-CoV-2 coronavirus samples, and medical laboratory scientists in countries across the globe are contributing

Clinical laboratories around the world have been contributing to the global scientific community’s database of knowledge about SARS-CoV-2, the coronavirus that caused the COVID-19 pandemic, and its variants, through an ingenious and crucial network known as GISAID. This cooperative sharing of the coronavirus’ genetic data (now four million genomic sequences strong) has greatly contributed to understanding the spread of infections and progress obtained in developing effective treatments and vaccines.

Headquartered in Munich, Germany, GISAID, which stands for Global Initiative on Sharing Avian Influenza Data, was created in 2008 during the Avian Influenza (Bird Flu) pandemic. The GISAID initiative promotes “the rapid sharing of data from all influenza viruses and the coronavirus causing COVID-19. This includes genetic sequence and related clinical and epidemiological data associated with human viruses, and geographical as well as species-specific data associated with avian and other animal viruses, to help researchers understand how viruses evolve and spread during epidemics and pandemics,” according to the GISAID website.

Clinical pathologists are likely familiar with GISAID. The initiative has become an indispensable tool for researchers battling SARS-CoV-2. GISAID allows scientists and organizations worldwide to upload genetic sequences of COVID-19 samples. Those sequences can then be used in research for treatments, vaccines, and to track emerging variants. The information is invaluable, freely available, and represents the collaborative efforts of scientists around the world in the fight against COVID-19 and other infectious diseases.

An article published in The World, titled, “From Congo to Chile, Small Labs Are Playing a Growing Role in Global Understanding of COVID,” noted that more than four million genomic sequences have been submitted as of October 15, 2021. The more countries around the world that submit sequences to GISAID, the more understanding scientists have of how the virus is mutating. And, as the cost of performing genomic sequencing declines, the number of countries submitting genomes of SARS-CoV-2 to GISAID is rising.

How GISAID Ensures Contributors Receive Credit for Their Work

One of the reasons that GISAID has been so successful in gathering data is that it requires anyone who uses data downloaded from the massive database to give credit to the person or organization who uploaded it. In other words, if a scientist in the United Kingdom (UK) does breakthrough research using genomes that were originally uploaded to GISAID by a scientist in the Congo, the UK scientist must credit the work of the scientist from the Congo.

Other genomic databases do not have this requirement and genetic researchers are often hesitant to share information due to fear their work will be co-opted by others. According to The World, scientists in lower income countries are particularly vulnerable to having their work appropriated.

Even worse is having one’s work appropriated, used to create a product, and then not being given access to that product.

Christian Happi, PhD

“Unfortunately, we’ve seen also the situation whereby people have leveraged that data and created the solution and refused to share the solution with those that shared the data,” virologist Christian Happi, PhD (above), who directs the African Center of Excellence for Genomics of Infectious Diseases (ACEGID) at Redeemer’s University in Nigeria, told The World. “And that is definitely going to roll back this whole open data sharing and access principle.” Happi is also a Visiting Scientist in the Department of Immunology and Infectious Diseases at Harvard’s T.H. Chan School of Public Health. (Photo copyright: Pius Utomi Ekpei/AFP/News 24.)

That is why GISAID’s policy of giving credit is so important, as molecular biologist Francine Ntoumi, PhD, told The World. “This means that we are going to participate in the game. We are able to say what is circulating. You are no more an observer and I think it makes a difference.” Ntoumi is Founder and Executive Director of the Congolese Foundation for Medical Research (CFMR) in the Republic of Congo, a lecturer in Immunology at Marien Ngouabi University, and Associate Professor and Head of a Research Group at the Institute of Tropical Medicine at the University of Tübingen, Germany.

The guarantee that credit will be given softens some of those fears and explains why the GISAID database is so vast, and increasingly contains sequences from scientists in Africa, South American, and other places where genomic sequencing was not widespread prior to the pandemic. Information from all over the world is crucial for scientists monitoring the mutations of the SARS-CoV-2 coronavirus.

Criticisms of GISAID

The fact that more countries are contributing to the GISAID database is certainly a positive, but the non-profit is not without its critics. There have been complaints about the lack of transparency, and some researchers claim to have had their access denied to the data without any explanation.

An article published in Science reported that “Scientists live in fear of losing access to the GISAID database.”

One scientist who requested anonymity told Science, “I am so tired of being scared all the time, of being terrified that if I take a step wrong, I will lose access to the data that I base my research on. [GISAID] has that sword hanging over any scientist that works on SARS-CoV-2.”

In response to these criticisms, GISAID said in a statement, “Any individual who registers with GISAID and agrees to the GISAID terms of use will be granted access credentials. … On rare occasions, GISAID has found it necessary to temporarily suspend access credentials to protect the GISAID sharing mechanism,” The World reported.

The strict sharing rules may be necessary to encourage researchers in lower income countries to contribute their genomic data on SARS-CoV-2. Charles Rotimi, PhD, a geneticist at the National Human Genome Research Institute (NHGRI), told Science, “To make scientists, especially from developing countries, more comfortable—making sure that they are recognized in the work that they are doing—sometimes you have to create an extra layer [of protection].”

GISAID has certainly accomplished much in its assembling four million SARS-CoV-2 genetic sequences. The initiative’s efforts have contributed to a substantial increase in the number of countries around the world that now have gene sequencing capabilities.

This is another illustration for clinical laboratory managers and pathologists of how continual technology advances in gene sequencing equipment and data analysis software make it significantly cheaper, faster, and more accurate to do genetic sequencing. This was not true, just a few years ago.

—Dava Stewart

Related Information:

From Congo to Chile, Small Labs Are Playing a Growing Role in Global Understanding of COVID

Africa CDC Ramps Up Training on SARS-CoV-2 Genomics and Bioinformatics

The Cost of Sequencing a Human Genome

Critics Decry Access, Transparency Issues with Key Trove of Coronavirus Sequences

Get the Poop on Organisms Living in Your Gut With a New Consumer Laboratory Test Offered by American Gut and uBiome

American Gut is using test results to create a microbiome database for use by researchers to better understand how microbes impact human health

Have you ever wondered what lurks in the dark corridors of your bowels? Now you can find out. Two entrepreneurial organizations—one a not-for-profit and the other a new clinical lab company—are charting new medical laboratory territory with the offer of an inexpensive poop test that reveals the type of microbes residing in your gut.

Where to Get Your Gut Microbes Analyzed

The not-for-profit organization American Gut, or British Gut in the United Kingdom (UK), which launched as crowd-funding projects on FundRazr, involve a private research project called the Human Food Project (HFP), which was initiated to compare the microbiomes of populations around the world. The Human Food Project is seeking a better understanding of modern disease by studying the coevolution of humans and their microbes.

People who pay American Gut’s $99 test fee (£75 for the UK project) receive a test kit to collect a stool sample to mail back for DNA sequencing. The test results will be provided to participants, but also benefit microbiome research. (more…)

New Insights into Genetic Mechanisms Common to Humans and Simpler Species May Form the Basis for New Diagnostic Tests Performed by Clinical Pathology Laboratories

Scientists participating in the modENCORE study have the goal of understanding the causes of hereditary genetic diseases in humans

New discoveries about the interaction of genes and transcription factors in creating different types of RNA will be of interest to pathologists and clinical chemists performing genetic tests and molecular diagnostic assays in their medical laboratories.

The goal of this research is to better understand hereditary genetic disease in humans. The new knowledge is based on studies of the common fruit fly, or Drosophila melanogaster (D. Melanogaster), and to a lesser extent a tiny worm Caenorhabditis elegans (C. elegans). Both have been used as research models to study the human condition.

Research Could Give Pathologists New Diagnostic Tools (more…)