It is clear that the field of life science is undergoing a major shift in the way research is conducted and curricula are designed at various universities. There is an increasing focus on OMICs (Genomics, Transcriptomics, Proteomics, and Metabolomics) for data gathering. As a result, obtaining high-quality data is no longer a hurdle in understanding human biology. However, this shift has also brought about a new challenge to our previous understanding of basic biology, particularly in the context of molecular signaling that determines interaction and communication among cells, influenced by factors such as nutrition, genetics, and the environment.
One aspect that got me seriously thinking is the finding that I published in the year 2020 in Scientific Reports after analyzing the entire human variome. An analysis of the protein sequence of cell surface proteins has shown that almost every amino acid is subjected to polymorphic genetic variations, regardless of whether the genetic variation is a simple one-nucleotide change that does not alter the length of the protein or a deleterious frameshift or delins, which often truncate the proteins. This was the state before the release of gnomAD and UK Biobank genetic data (see Figure 1).
Figure 1. Scatter plots depicting dbSNP data mapped to the domains of membrane proteins. Scatter plots for genetic mutations mapped to the coding regions of human membrane proteins. The chromosome position loci is plotted on the abscissa and normalized domain lengths along the ordinate axes. For each domains namely Signal, Extracellular, Transmembrane and Cytoplasm separate scatter plots are depicted. Each dots represents a genetic variant recorded in vcf files with colour coding namely, frameshift mutations (red), and missense mutations (blue) and stop created mutations (green). Genotyping datasets
analyzed here were obtained from dbSNP.
Since then, I have been proactively looking at the genetic makeup of diverse human individuals using Harvard Personal Genome Project data and patient germline sequencing data from routine genetic diagnostic tests. As we sequence more individuals' genomes, we indeed discover an increasing number of genetic variants that have not been previously identified. To put it simply, every time we sequence a human individual, we detect new genetic variants that have never been described before. This means we can safely conclude that almost every amino acid position in a protein sequence is susceptible to polymorphic genetic variations. This expansion of genetic variation poses a challenge to our current understanding of biology in several ways.
Uncharted Territory: With every new genome sequenced, we encounter previously unseen genetic variants. These novel variations challenge our existing knowledge and databases. Clinical geneticists must grapple with the task of annotating and understanding these uncharted regions. And in many cases, previous knowledge does not help in automating the curation process, demanding investigations powered by experimental hypotheses and biological validation in appropriate systems.
Functional Significance: Not all genetic variants are equal. Some may be benign, while others could have functional consequences. Identifying which variants impact gene function, protein structure, or regulatory elements is one of the biggest hurdles in the progress of human genetics and applied genomics. Functional annotation tools and predictive algorithms play a crucial role in this endeavor, but they are not necessarily helpful in many cases. This is because we have only scratched the surface of how molecular signaling works in the context of nutrition, genetics, and environment. Additionally, biology seems to be full of exceptions when it comes to human biology, suggesting many unknowns at the basic levels of our understanding. This renders most predictive computational tools ineffective, and I doubt even an AI-powered tool can help clarify human biology at the molecular level without appropriate training datasets in this regard.
Clinical Interpretation: In clinical genomics, the challenge lies in distinguishing pathogenic variants (associated with diseases) from benign ones. As the pool of variants expands, clinicians must navigate an ever-growing catalog to provide accurate diagnoses and personalized treatment recommendations. Variants that were initially classified as pathogenic based on existing knowledge may turn out to be benign in certain individuals. Similarly, variants considered benign may have pathogenic effects in specific genetic backgrounds or environmental contexts. This highlights the complexity of genotype-phenotype relationships that are unique to certain individuals and the need for comprehensive functional studies to accurately assess variant pathogenicity.
Population Diversity: Genetic variation is influenced by ancestry, geography, and historical migrations. The increasing diversity of sequenced genomes highlights the need for representative reference panels. A broader range of populations ensures better accuracy in variant interpretation. In this regard, work from the All of Us Research Program and the Human Pangenome Reference Consortium is expected to fill a major gap. This is important when curating genetic variants whose pathogenicity may be ethnicity-dependent. An idea that has not yet caught the major attention in the community of geneticists and clinical geneticists in their everyday clinical practice.
Rare Diseases and Precision Medicine: Rare diseases often result from rare variants. As we uncover more of these, precision medicine gains traction. Tailoring treatments based on an individual’s genetic makeup becomes feasible but requires robust databases and functional insights. As of now, most N-of-1 clinical trials are making progress but again lack proper context as the field of individualized signaling biology is not yet established. How rare disease-associated rare genetic variants function in the backdrop of an individual's unique genetic makeup, nutrition, and environment is a hard question to answer as it would require dedicated collaboration from various experts from diverse fields of clinical and basic science research.
Ethical and Privacy Concerns: Given that an individual's genetic makeup is unique to that individual, it raises well-recognized privacy concerns. No research ever makes or made sense that ignored ethical aspects. As genomic data accumulates, safeguarding privacy becomes paramount. Balancing data sharing for research with protecting individual identities is an ongoing challenge.
Paradigm Shift Needed: Our understanding of basic biology often relies on the assumption that proteins must have specific features to function properly. Genetic variants that alter these features, such as truncations or changes in crucial amino acid residues, can potentially compromise protein function. However, the functional consequences of many such genetic variants within the context of an individual patient's unique biology are still not fully understood, especially for variants that are rare or novel. Currently, we study them assuming that a large majority of polymorphic genetic variants are harmless and that the biology of every patient is identical, as generally applied to the entire human species. There are various challenges emerging due to this school of thought. For instance, the observation on the pathogenicity of cancer-predisposing genetic variants. Why a pathogenic genetic variant functions as benign in some individuals while some benign variants appear to be pathogenic from the perspective of disease association remains quite puzzling. The increasing diversity of genetic variation underscores the importance of personalized biology approaches. Different individuals may respond differently to the same treatment or exhibit varying disease susceptibilities based on their unique genetic makeup, thus creating a biology unique to each individual. Understanding the functional implications of genetic variants in the context of individual genomes is crucial for optimizing personalized healthcare strategies.
Overall, the ongoing expansion of genetic variation challenges our current biological paradigms and emphasizes the need for continued research to elucidate the functional significance of genetic variants in health and disease. The Human Genetic Variant Characterization Challenge represents a significant shift in the field of human genetics. While the initial focus was on discovering genetic variations, the current challenge lies in thoroughly characterising the associations between genetic variants and phenotypes. In recent times, researchers have directed their efforts toward understanding the causal mechanisms through which genetic variations impact human biology. This pursuit has gained momentum due to significant progress in detecting genetic variants that are rare and specific to individual humans. In essence, this challenge involves moving beyond mere identification of genetic variants to unravelling their functional roles and impact on human health.
In summary, the ever-expanding genetic variation enriches our understanding of biology but also demands innovative approaches to annotation, interpretation, and ethical handling of genomic data.
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