Human Molecular Genetics and Genomics – Important Advances and Exciting Possibilities

The breathtaking advances in molecular genetics over the past 50 years and the transition to genomic medicine would have been difficult to imagine in the 1970s. The term genomics had not yet been coined, the tools and technologies underpinning modern biotechnology were still in their infancy, and even a few nucleotides could rarely undergo sequencing using the methods then available (creating a detailed map of our genetic code).

Advances That Could Not Have Been Predicted

The first steps in genomic medicine were paradigm-shifting DNA-related discoveries such as Boyer and Cohen's recombinant method, Sanger's DNA-sequencing work, and Mulli's polymerase chain reaction (PCR) technology. Even against this background, the concept of big science for an effort to sequence the human genome seemed radical.

In 1987, New York Times described the Human Genome Project, as the largest, most costly, and most provocative biomedical research project in history. However, between its launch in 1990 and its completion in 2003, genomic technology improved dramatically.

DNA sequencing throughput rose from 1000 base pairs per day to more than 1000 base pairs per second, opening the door to low-cost sequencing techniques that enabled genomic advances to be incorporated into routine medical care. Genomic research expanded across a broad spectrum: from seeking to understand the basis of the human genetic code, to explaining the ways this code differs between people, and then applying this information to interventions tailored to precisely target the underlying causes of disease.

DNA has a ladder-like, double-helical structure and consists of 4 types of nucleotides (adenine, thymine, cytosine, and guanine). In this form, DNA, our genetic code, can be thought of as a 4-letter language. DNA gives cells instructions about what to do. Human DNA consists of 3 billion nucleotide pairs, and approximately 2% of the DNA helix is responsible for producing proteins, the basic building blocks of cells; these meaningful sections of DNA are called genes. Our DNA contains approximately 20 thousand genes, and the combination of all genes is called the genome.

Genomic Advances Have Changed the Nature of Medicine

The development of genomic tools and datasets has changed the nature of medical discovery, allowing scientists to undertake comprehensive and powerful discovery efforts rather than being limited to testing hypotheses focused on candidate pathways. With the completion of the initial resource for sequencing the human genome, attention shifted from studying genes to discovering the functions of genes. Systematic genetic mapping in families and populations helped scientists pinpoint the exact location of genetic changes that cause human diseases. As a result of the Human Genome Project, medicine after 2000 was virtually rewritten.

The effects are profound. The discovery of more than 5000 genes responsible for rare Mendelian diseases (a type of inherited condition) facilitates genetic diagnosis for many patients, pregnancy-related counseling, new drug treatments, and, in some cases, gene therapies.

The discovery of more than 100,000 robust associations between genomic regions and common diseases revealed new biological mechanisms, such as the roles of microglia in Alzheimer's disease, autophagy in inflammatory bowel disease, and synaptic pruning in schizophrenia. It also enabled the development of polygenic risk scores to identify patients at high risk of cardiovascular disease, breast cancer, and other conditions, although further rigorous testing of such diseases, including assessment of clinical outcomes, is needed.

Cancer genome studies revealed hundreds of genes with somatic (noninherited) mutations that promote tumor initiation and growth, and this knowledge spurred the development of new drugs (in oncology, we call these smart drugs directed at genetic targets).

Genomic analyses (genetic tests) in cancer also help explain why some people respond to certain treatments or survive certain infections while others do not.

Highlights in Human Molecular Genetics and Genomics – A Brief History

Abbreviations: Cas9: CRISPR-associated protein 9 / CRISPR: Clustered regularly interspaced short palindromic repeats / İGP: Human Genome Project / NIH: United States National Institutes of Health

• 1973 – Herbert Boyer and Stanley Cohen developed recombinant DNA technology.
• 1977 – Walter Gilbert and Fredick Sanger discovered techniques for DNA sequencing.
• 1983 – Kary Mullis invented the polymerase chain reaction (PCR) application.
  The first disease-associated gene is molecularly mapped to a human chromosome by James Gusella and Nancy Wexler.
• 1986 – Leroy Hood invented an automated DNA sequencer.
• 1990 – The NIH and Department of Energy launch the Human Genome Project (İGP).
• 1994 – The İGP's goals for mapping human genetics were achieved. 
• 1995 – The İGP's goals for mapping human genetics were achieved.
• 1996 – The İGP begins testing strategies for large-scale sequencing of the human genome.
• 1997 – In what would become known as the "Bermuda Principles," İGP researchers endorsed the rapid, public release of genome sequence data without restrictions on use.
• 2001 – The İGP international consortium publishes the first draft of the human genome sequence; J. Craig Venter's group at the Celera Genomics Association publishes another version of the sequence.
• 2002 – The International HapMap Project is launched to collect data on human genetic variation that can be used to accelerate the identification of genes associated with common diseases.
• 2003 – The İGP is completed two years ahead of schedule, producing a reference sequence of the human genome.
• 2006 – The NIH launches The Cancer Genome Atlas (TCGA) to molecularly characterize more than 20,000 samples covering 33 cancer types.
• 2008 – The United States Genetic Information Nondiscrimination Act is enacted to protect against discriminatory use of genetic information in health insurance and employment.
• 2009 – In a clinical first, Wisconsin researchers sequence all the genes of a 5-year-old boy and use the data to pinpoint a new disease, leading to lifesaving treatment.
• 2012 – The Human Heredity and Health in Africa (H3Afrika) consortium holds its inaugural meeting in Addis Ababa, Ethiopia.
• Emanuella Charpentier and Jennifer Doudna show that CRISPR can edit DNA in vitro (earning them the 2020 Nobel Peace Prize in Chemistry); approximately 6 months later, Feng Zhang and George Church independently demonstrate CRISPR editing in mammalian cells.
• 2018 – TCGA publishes the Pan-Cancer Atlas, a collection of cross-cancer analyses based on the entire dataset.
  The NIH begins enrollment for the "All of Us" research program, a large-scale research resource of more than 1 million participants who will contribute genetic, health, and environmental data.
• 2020 – The first patient with sickle cell disease is treated using CRISPR – Cas9 through an ex vivo approach.

Researchers Focused on Gene Expression

More recently, the focus of genetic research has moved beyond analyzing DNA variations (differences) to studying gene expression patterns in individual cells, a step driven by new methods for single-cell RNA sequencing and chromatin analysis. Tens of millions of cells have so far been characterized on the way toward a complete cell atlas of the human body. This effort is revealing hundreds of new cell types and characterizing the ways cell types differ between healthy people and people with various diseases.

With the cost of sequencing a complete genome falling from 3 billion dollars during the Human Genome Project to 600 dollars today, there are increasing efforts to create large-scale biobanks of whole-genome sequencing and phenotypic information from hundreds of thousands of people. Examples include the United Kingdom Biobank and the United States "All of Us" research program. The ultimate goal is for healthcare systems to combine medical records with genomic information.

• Related Topic: What Is Whole-Exome Sequencing and Genome Sequence Analysis?

We Still Have a Long Way to Go

Much work remains to understand human genetic differences and the genetic basis of diseases.

Despite the promise of insights into biological and health differences offered by studying people with diverse disease histories, both researchers and participants in genomic research are largely of European ancestry. This lack of diversity hinders our understanding of our own biology, worsens already unacceptable health disparities, and raises the question of whether polygenic risk scores, diagnoses, and drugs derived from genomic research will benefit all populations equally.

Studies of people with different family backgrounds have revealed the following:

• genomic variations in the risk of developing disease,
• drug responses, and
• the diagnostic accuracy of clinical approaches guided by genomic research show population-level differences.

Examples

The African-ancestry-specific APOL1 variant protects against African sleeping sickness but increases the risk of kidney failure: these variants account for approximately 70% of cases of nondiabetic kidney failure among people of African ancestry in the United States.

A risk haplotype for type 2 diabetes in SLC16A11, present in approximately half of Native Americans and rare in people of European or African ancestry, explains approximately 20% of the increased frequency of type 2 diabetes among Mexican Americans compared with European Americans.

Genomic research also shows that PCSK9 loss-of-function mutations are more common in people of African ancestry than in other populations; such mutations reduce cholesterol levels and the risk of heart disease.

Several initiatives designed to increase the involvement of researchers and study participants from previously underrepresented populations are underway. The Human Heredity and Health initiative in Africa, for example, developed a pan-African consortium of laboratories enabling more than 500 African scientists to access genomic technologies; more than 60,000 research participants were enrolled, and a bioinformatics network and three regional biorepositories were established.

The Goal: Gene-Editing Technologies

Genetic diseases can now be diagnosed much faster thanks to genomic sequencing technology. However, developing and validating treatments is more difficult. For some Mendelian disorders, molecularly targeted drugs have been developed using a detailed understanding of the pathology. The CFTR gene was discovered in 1989, and work based on that discovery means that safe and effective molecularly targeted drugs can, for example, be offered to 90% of people with cystic fibrosis. However, this approach can take decades and does not scale well to the thousands of genetic disorders whose precise molecular cause is not known.

A strategy enabling effective treatment that directly targets the gene could bring important advances. After years of ups and downs, some major successes of gene therapy are emerging, such as in spinal muscular atrophy and hemophilia. The pace of this research may increase substantially in the future; precisely targeted gene-editing technologies are now providing new paths to therapeutics.

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The 2020 Nobel Prize in Chemistry

Over the past 8 years and more, CRISPR – Cas9 (clustered regularly interspaced short palindromic repeats – CRISPR-associated protein 9) technologies have emerged as adaptable and accessible tools for studying and changing genomes. CRISPR – Cas9 can act at a specific site, triggering DNA repair by creating targeted DNA fragments to edit the genome. In next-generation formats, they can also control the transcriptional outputs of genes or change genome sequences using a nucleotide base-editing process that does not require repair of DNA fragments. As these technologies continue to mature, modifying cellular genomes effectively and accurately will become increasingly possible.

CRISPR technology, for both what it has delivered so far and its potential to change the future, was awarded the 2020 Nobel Prize in Chemistry.

Following closely behind engineered nucleases, CRISPR – Cas9 tools are accelerating the pace of genomic research by allowing highly efficient editing or knockout of nearly every gene in cells or model organisms. Multiple CRISPR – Cas9-based clinical trials are underway or expected to begin soon. Although Cas9-engineered cells have not yet demonstrated their effectiveness at scale, early trial results have shown that these cells are stable and do not cause immediate adverse reactions in humans. Long-term safety has not yet been established. Current applications focus largely on single-gene disorders so that gene editing can be performed ex vivo on appropriate cells, such as bone marrow hematopoietic stem cells in sickle cell disease. Discoveries are underway toward developing delivery systems that can target the gene-editing tool to the appropriate tissue in vivo.

Conclusion

Advances in genomic technology will continue to drive basic science forward in powerful ways, not all of which can be predicted. Although 10 years ago we could not even imagine immediate and free access to vast amounts of data on genomes, transcriptomes, and chromatin marks, this will be possible in the next 5-10 years—and increasingly these data will be available for individual cells. All biologists, geneticists, and bioinformaticians will need to be prepared for such datasets. Genomic data on this scale will provide opportunities for biological insight that require very complex computational analyses.