Wayne State professor issues call to action for new approach to clinical cytogenetics, which play a 'vital role'

Clinical cytogenetics looks at the relationship of human disease and chromosomes, the long DNA molecules that contain an organism's genetic material. Historically, cytogenetics enabled the identification of the abnormal chromosomes responsible for Down syndrome and chronic myeloid leukemia, among other discoveries.

But as advances in DNA technology came into use, in particular sequencing technology, the field of medicine and genetics became more gene-centric. Molecular genetics came to replace cytogenetics, with an increased reliance on gene sequencing technologies.

Recently a group of researchers issued a "call to action" for medical scientists to "re-evaluate the importance of clinical cytogenetics," and its potential to contribute new discoveries for clinical diagnosis and treatment. In particular they emphasize the genome architecture theory, which focuses on the topology of genes on chromosomes and how these systems of genome topology are inherited as systems. 

In other words instead of single gene interactions, the genome architecture theory focuses on the overall geometric arrangement of chromosomes and its effect on human health.

The "call to action" appears in the journal Genes, Feb. 15. Senior author Henry H. Heng, is professor of molecular medicine and genetics and of pathology and the Karmanos Cancer Institute at Wayne State University in Detroit. (See interview below.)

Gene-centric vs genomic organization

The article reviews the history of cytogenetics and the technological innovations in the field, noting that new discoveries have appeared just as "some start to question the value of the field." 

The authors also point out that as gene research advances have produced "massive amounts of molecular data." They also have revealed the "key limitations of the gene-centric genetic theory." Specifically, they write, "the huge gap between genotypes and phenotypes cannot be bridged by the increased knowledge of the genes."

Instead, the researchers say, that gap "requires a search for different levels of genomic organization that are responsible for organizing genetic networks and managing highly heterogeneous information in the many codes found in the genome...." In other words, why continue with the same approach that has not produced the necessary results?

Genome architecture theory

The researchers propose a new theory for genome architecture that they think can advance the whole field, based on their work looking at how cancer evolves on the genome level generation by generation. 

With this framework, the authors explore many subfields that could benefit from using a new, higher-level genome research approach. They note that karyotypes play a key role in this. Karyotypes characterize the geometry of the chromosomes in an organism, for example, their size and number, which organize the order of genes on chromosomes in a species-specific manner.

Among the suggested areas of study is the dynamics of non-clonal chromosome aberrations, which are an "important evolutionary genomic feature" of disease evolution. 

Another area of study is mosaicism, which refers to different genetic lines resulting from a genetic mutation. This genomic heterogeneity can be an "active strategy" of an organism and not simply a mistake, they write.

The researchers also highlight individual genome instability as a factor in disease evolution as well as in aging. They suggest a cytogenetic monitoring system to "trace and predict the aging process and results of aging interventions." A similar approach will be useful in looking at the environmental impact on disease evolution, such as lifestyle conditions.

New methods needed

"Combinatorial platforms, including those that are yet to be developed, hold the key to the future of clinical cytogenetics," the authors state, and they outline some of the possibilities. These include encouraging the longitudinal profiling of karyotypes to cover different stages of the disease evolutionary process and corresponding treatment options, as well as establishing a database on non-clonal chromosome aberrations and diseases. This database should include baselines for different ethnic groups and be easy to access, they say.

In sum, the researchers state, "Our take-home message is that more effort should be applied to the new frontiers of cytogenetics and cytogenomics. With both novel theoretical and technological innovations, further discoveries and their clinical implication will soon follow. 

"We hope this brief review of both the challenges of current clinical cytogenetics and our personal experience/viewpoints will trigger more discussions in this field, which has huge potential to reshape genomic research and usage in the future," they add.

Interview with Dr. Henry H. Heng

Heng is professor of molecular medicine and genetics and pathology and the Karmanos Cancer Institute at Wayne State University in Detroit. His 2021 book, "Genome Chaos: Rethinking Genetics, Evolution, and Molecular Medicine," presents many of the ideas here in more detail.

Heng discussed the new proposal for clinical cytogenetics in an email correspondence with Current Science Daily.

You propose advancing the field of clinical cytogenetics to better understand human disease conditions and aging. How would you characterize cytogenetics for a non-specialist?

Cytogenetics is a subfield of genetics that focuses on the examination of chromosomes, including their structure, function, and abnormalities.

Cytogenetics plays a vital role in clinical genetics, prenatal testing, cancer research, and the diagnosis of genetic diseases, as chromosomal abnormalities are often associated with various disease conditions. For instance, an extra copy of chromosome 21 can result in Down syndrome, and specific chromosomal alterations can be utilized to classify different types of leukemia.

Commonly used methods in cytogenetics today include comparing the pattern of stained chromosomal bands between normal individuals and patients, studying copy number variations using array technologies, and utilizing molecular probes to confirm or reveal chromosomal abnormalities with high resolution.

Why do you think the importance of cytogenetics lapsed?

Before molecular biology became dominant in genetics, cytogenetics made significant contributions to genetic research. However, in the past 30 years or so, with the rise in popularity of the gene-centric perspective in biology and the significant reduction in DNA sequencing costs, there has been an unsupported prediction that clinical cytogenetics will soon be replaced by molecular biology techniques like DNA sequencing, leading to the end of clinical cytogenetics. 

But as you point out, relying only on a gene-centric perspective presents a paradox.

Yes, interestingly, the Human Genome Project and numerous subsequent genome projects have paradoxically raised questions about the sole significance of individual genes in the majority of diseases. Unlike some infectious diseases, these common and complex diseases often involve a large number of contributing factors, both genomic and environmental. The promise that comprehending all genes would revolutionize medicine has proven far from reality. 

Based on this situation, we and others have begun to reconsider the informational foundation of genomics. This new synthesis reveals that chromosomes are not merely carriers of genes but also serve as key organizers of gene interactions, representing a novel system-level of information. 

Given that clinical cytogenetics primarily focuses on profiling this level, it should play a more significant role than individual gene profiles, particularly when studying diseases involving cellular evolution, such as cancer.

In fact cytogenetic data demonstrate much greater clinical prediction power than gene mutation profiles in cancer research. 

Clearly it is imperative to shift more attention toward karyotypic profiles instead of neglecting the essential field of cytogenetics. One of the goals of our manuscript is to advocate for cytogenetic research by introducing a novel genomic framework based on the genome or karyotype. 

You've proposed a genome architecture theory. What will this look like?

The theoretical basis of current gene-centric genetics is the gene theory, formed by Thomas Morgan in 1920s by integrating Mendel’s three laws of genetics with chromosome-mediated inheritance. According to gene theory, the gene serves as the fundamental unit of genetic information. 

After the completion of the Human Genome Project, it became evident that bridging the gaps between genotype and phenotype is much more challenging than expected, even with comprehensive gene sequencing and whole-genome scanning using large sample sizes. It is clear that gene function is context-dependent within the genomic framework, and it carries a high degree of uncertainty. 

To address this challenge and provide a genomic basis for genetic networks, the field requires a new framework of inheritance that extends beyond genes and encompasses epigenetics. Consequently, we propose the genome architecture theory, which is based on the collective information of genes organized within the karyotype, as a novel system-level genomic framework of inheritance. This theory presents a contrast to the gene-based gene theory. 

What are the basic differences between a gene-centric theory and the principles of the genome architecture theory?

Here are some of the major distinctions.

• Genes encode inheritance at the parts level, while the karyotype encodes inheritance at the system level. The specific arrangement of DNA fragments, including genes and other sequences, along and among chromosomes within a particular karyotype serves as a species-specific blueprint, defining the physical structure of genetic network interactions. 

• Cancer and organismal evolution follow a two-phased process, karyotype reorganization-mediated punctuated macroevolution and gene mutation-mediated stepwise and gradual micro-evolution. This significantly differs from current evolutionary theories that propose big changes result from the accumulation of small changes over time leading to speciation. 

• The whole genome, rather than individual genes, is the primary unit of heritable information responsible for macro-evolutionary processes. 

• Genome chaos, which refers to the massive and rapid reorganization of the genome during times of crisis, is an unrecognized evolutionary mechanism driving speciation and the formation of cancer, metastasis, and drug resistance. These are forms of macro-evolution followed by gene mutation-defined micro-evolution. 

• Information management, including creation, preservation, modification and usage, plays a crucial role. Contrary to the traditional belief in biology, sexual reproduction functions as a means of information preservation and is a key constraint for maintaining species. Genome chaos followed by sexual reproduction is an effective mechanism for creating new species and enabling new species to become the last species with a large population. 

• For cellular adaptation multiple genomic and non-genomic variations are required and generated. However, as a trade-off, these altered variations can contribute to disease formation. These seemingly stochastic variations can be used as biomarkers to monitor somatic evolution. 

You've summarized many of the main points of your article. Can you say more about the main research frontiers in cytogenetics that you see as opportunities?

Here are the main research frontiers:

• Validate and embrace the concept of karyotype coding, which serves as the foundation for understanding genetic networks. This is the theoretical aspect.

• Utilize the advantages of cytogenetics in monitoring both individual cell dynamics and population dynamics, incorporating a spatial perspective.

• Develop biomarkers based on cellular evolution and karyotype coding, with a specific focus on capturing karyotype heterogeneity and chromosome instability across the entire evolutionary process. 

• Monitor the two-phased cellular evolution for the purposes of diagnosis and treatment management, such as determining optimal dosage to prevent over-treatment in cancer cases. 

• Establish novel methodological platforms. These are outlined in detail in the article. 

Is there anything else to highlight?

Our cytogenetic and cytogenomic studies have led to the discovery of two-phased cancer evolution, stress-induced genome chaos and karyotype coding. 

Additionally, our further synthesis has reinterpreted the function of sexual reproduction. Rather than solely promoting genetic diversity at the gene level, sexual reproduction primarily serves to eliminate genome-level changes and maintain the identity of a given species. This is achieved through meiotic pairing, which checks the order of genes along chromosomes.

These findings have contributed to the development of new evolutionary mechanisms. These concepts have the potential to significantly reshape genomic and evolutionary frameworks and methodological platforms. Stay tuned for further advancements in this field!

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E. Heng et al. "Challenges and Opportunities for Clinical Cytogenetics in the 21st Century." Genes. Feb. 15, 2023.

DOI: https://doi.org/10.3390/genes14020493