Forward-Looking Advances for Human Genetics and Genomics

Genomic sequencing, either exome or whole genome, for the rapid and accurate identification of the molecular cause of genetic disorders is now feasible, but it is not yet widely and routinely performed in most parts of the world. Not only has genomic diagnostics been shown to be effective in pinpointing the cause of genetic diseases, it also is cost effective for health care; it reduces the length of a patient’s diagnostic odyssey and the amount of unnecessary and inconclusive testing, leading to more targeted treatment and clinical management. While the cost of sequencing human genomes has decreased substantially in the last two decades, progress still needs to be made in improving the routine diagnosis of patients with suspected genetic disorders in low- and middle-income countries and other resource-limited settings. In the years to come, the field should aim to make genomic sequencing available, affordable, and accessible to patients with genetic diseases anywhere around the world. In some countries, like the United States and the United Kingdom, initiatives for newborn genomic sequencing screening to identify children at risk of developing genetic disorders before they present first symptoms are being explored and will likely be implemented in the years to come.

At this point, however, genomic sequencing is mostly being used in children with known genetic anomalies. Part of the hesitation about moving forward with widespread and newborn screening applications of whole-genome sequencing is that questions remain about how to use this information, how to interpret the results and conduct a risk assessment, and how to convey this information to patients and their families. There are also potential legal and ethical implications. These issues will have to be addressed before whole-genome sequencing will become standard in the clinic.

Sources: Whole Genome Sequencing > Fact Sheets > Yale Medicine ; Whole genome sequencing in the clinic: empowerment or too much information? – PMC (nih.gov)

Genomic sequencing and analyses are enabling the identification of highly penetrant disease-associated variation in individuals at risk of developing medically actionable, adult-onset conditions such as certain types of cancer or cardiovascular diseases. Sequencing, in combination with the exploration of polygenic scores and their clinical applications for risk assessment of more complex disorders, can enable the implementation of personalized precision medicine in the years to come. Researchers can now leverage a given person’s genomic information to develop a risk profile for the likelihood of developing a variety of common complex polygenic diseases. To be meaningful, however, this information should be interpreted in the context of the patient’s clinical and family history and the influence of environmental factors such as nutrition, exercise, exposures, and social determinants of health, a task that can be challenging to accomplish. Evaluating and addressing these challenges in the holistic interpretation of an individual’s genomic data can lead to the realization of precision medicine, improvements in population health, greater health equity, and reduced healthcare costs. [Sources: Has the Time Arrived to Incorporate Genetic Testing Into Health Care? (ajmc.com) ; Orchid Guides: What is the difference between monogenic and polygenic diseases? (orchidhealth.com) ] [Link to this ASHG article: Genetic Testing, Privacy, and Healthcare – ASHG ]

Although European populations represent only 16% of the world’s population, more than 90% of genomic sequencing has been performed in this group. The lack of diversity means that the full range of genetic variation is not being captured, limiting the benefits of genomics for underrepresented groups. This problem is also having a negative impact on health disparities, a longstanding issue. To increase diversity, several initiatives have been started, including the Human Heredity and Health in Africa Initiative and the All of Us Research Program in the United States. Additional efforts and initiatives should and will likely be directed to increasing representation and inclusion of underrepresented and genomically uncharacterized populations from around the world.

It is important, however, to do so in ways that are respectful of the communities and populations of interest, including indigenous and underserved groups, focusing on community engagement, benefit sharing, and equitable access to genomic information, benefiting the populations of origin, and genomic data protection and ownership.

Source: Gonzaga-Jauregui, Claudia. “The Human Genome.” In Brenner’s Encyclopedia of Genetics, 3rd Edition.

Link here: Importance of Diversity in Genetic Research – ASHG

With expertise in genomics knowledge increasing and sequencing costs decreasing, researchers are now starting to sequence specific populations and large biobanks. These efforts are expanding the amount of genomic information available to be used to further precision medicine initiatives in regional and national health care systems and for research purposes. Opportunities to create, sequence and leverage large population biobanks should be especially supported for genomically underrepresented populations, countries, and regions.

Source: Gonzaga-Jauregui, Claudia. “The Human Genome.” In Brenner’s Encyclopedia of Genetics, 3rd Edition.

Using human stem cells, researchers can now build organ-specific models, or organoids, that can test the efficacy of drugs under development. This is a major breakthrough because sometimes animals respond differently to drugs than humans, making comparisons difficult. Patient-derived tumor cells can also be used to create organoids to track individual responses to cancer treatments. Paired with tissue-derived organoids, which can show drug toxicities, it is becoming possible to create a picture of both response and safety of a new drug before it leaves the lab. The use of genomic editing approaches in preclinical experimental models can also help researchers investigate the potential for the application of these new technologies to correct genetic alterations before trying them in patients.

Sources: Normal and tumor-derived organoids as a drug screening platform for tumor-specific drug vulnerabilities – PMC (nih.gov) ; Frontiers | Human Organoids for Predictive Toxicology Research and Drug Development (frontiersin.org)

In the early days of genomic sequencing, the thought was that genetic disorders are mostly linked to DNA that codes for proteins, representing about 2% of the human genome. Great advancements have been made in understanding the role and function of the coding fraction of the human genome. Over the next several years, a more complete understanding of the 20,000 or so protein-coding genes in the human genome will be achieved, including their variation spectrum, their functions, and their roles in disease. Additionally, there is a growing realization of the important role that noncoding DNA plays in cell functioning through the regulation of gene expression. For example, some noncoding DNA helps determine when certain genes are turned on and off, which can be crucial to disease development. In the next few years, research will continue in this area to better understand the large noncoding fraction of the genome and its role in disease and to leverage this knowledge to influence gene expression and change disease outcomes.

Gonzaga-Jauregui, Claudia. “The Human Genome.” In Brenner’s Encyclopedia of Genetics, 3rd Edition.; What is noncoding DNA?: MedlinePlus Genetics

As precision medicine becomes more of a reality, it is clear that the general public needs to improve their knowledge and understanding of genetics and genomics and how they impact their lives and health. Some educational efforts are ongoing by ASHG and other organizations and universities, including ASHG’s public outreach initiatives and programs for K-12 students, along with a professional development program for teachers developed by the Jackson Laboratory called “Teaching the Genome Generation.” However, as genomics becomes more mainstream and becomes incorporated into everyday life, more such programs need to be developed and further efforts made to educate the next generations of genomic citizens, students and the general public at large.

Teaching the Genome Generation – Professional Development and Genetics Curriculum (jax.org)

Link here: American Society of Human Genetics: An Educator’s Resource on Discussing Cultural Awareness and Competency around Human Genetics (ashg.org)