The Human Genome Project 10 Years Out: Reviewing the Past, Present, and Future of Genomic Medicine

Shelley D. Smith, PhD


January 04, 2011

The 60th Annual Meeting of the American Society of Human Genetics held in Washington, DC, was the largest meeting of this Society ever held.

The meeting was flanked by the Distinguished Speakers' Symposium highlighting scientific progress since the completion of the Human Genome Project[1] and a Special Symposium on the future of the National Institutes of Health (NIH).[2] In between, the 7200 registrants attended more than 400 platform presentations and viewed more than 2700 posters, many of which focused on research advances in the inheritance of complex disorders. This review will summarize key points from the bookend symposia and focus on a few key presentations that might help clinicians appreciate how genetic research affects our understanding -- and ultimately our management -- of disease.

The Human Genome Project: Where Are We Now?

As part of a Distinguished Speakers' Symposium, Eric Lander,[1] President of the Broad Institute at the Massachusetts Institute of Technology and Harvard University, reviewed some of the advances made in the 10 years since the announcement of the completion of the human genome sequence.

Although there has been some public perception that expected gains in diagnosis and treatment haven't been realized, Dr. Lander outlined the tremendous gains that have been made and illustrated how they are leading to a more comprehensive knowledge of gene function and regulation.

Sequencing of the human genome has led to major advances in the identification of genes contributing to Mendelian and non-Mendelian disorders. In 1990, only 70 genes causing dominant or recessive disorders had been cloned; by 2000, this increased to 1300, and currently more than 2900 genes have been identified.

The increase has been even more striking for non-Mendelian traits, which include most common disorders. In 2000, only about 25 genes contributing to common disorders were known, including the contribution of APOE4 to Alzheimer disease. Since then, genome-wide association studies have identified more than 1100 disease-associated genes, including those influencing diabetes, age-related macular degeneration, inflammatory bowel disease, and heart disease. Cancer genetics has made similar strides, starting from 12 genes in 1990 known to influence the development or progression of cancer, 80 in 2000, and now at least 240. Although individual genes identified for common disorders might have only a small effect on the variance of the disorder (implying that the individual genes do not have much clinical meaning), Dr. Lander emphasized that the "missing heritability" is probably in the greater effects produced by the interactions of genes (termed epistasis) than from each gene acting alone. Moreover, the identification of individual genes and pathways is critical to understanding the biology of a disorder, which is much more important clinically than is accounting for the total variance.

Biological Pathways and Epistasis

These 2 themes of the clinical value of understanding biological pathways and epistasis were carried through in many of the individual sessions. For example, Jo Knight[3] of King's College in London, presenting on behalf of the Genetic Analysis of Psoriasis Consortium, noted the discovery of several new genes contributing to psoriasis, and the kind of gene-gene interaction that Dr. Lander predicted. Together, the genes helped define the genetic pathways behind the functions of the skin in pathogen detection, inflammation, and antigen processing, as well as their role in the pathogenesis of psoriasis.

The themes of biological pathways and gene-gene interaction were addressed again in later sessions: Lars Alfredsson[4] of the Karolinska Institute demonstrated gene-gene and gene-environment (ie, smoking) interactions for both rheumatoid arthritis and multiple sclerosis, and Braxton Mitchell[5] of the University of Maryland demonstrated an interaction between the gene ANRIL, smoking, and stroke. Of note, ANRIL produces a noncoding RNA; the functions of such genes were themselves the subject of other sessions describing the role of noncoding RNAs in gene regulation.[6]

The challenge of testing all possible single nucleotide polymorphism (SNP) interactions on a genome-wide scale was highlighted by Marylyn Ritchie[7] of Vanderbilt University: Just testing 3 SNPs at a time from a 500,000-SNP array -- small by today's standards -- results in 2 x 1016 tests, which strains most computational systems: Analysis of 5 SNPs at a time, given 1 second of computing time per test, would take more than 8 x 1018 years! A practical solution is to test candidate genes for epistatic effects, but the selection of candidates depends on some knowledge of the underlying biology of the disorder, which too often is still unknown.

New Technologies and Gene Identification

"Next-generation" massively parallel sequencing has made sequencing of a full genome much cheaper and faster than it was in the days when the human genome was being sequenced, but the cost is still out of the range of most research and clinical studies. Some have suggested extracting the "exome," or protein-coding regions, and sequencing only this much smaller amount of DNA. Alternatively, linkage or SNP association studies of a disorder can identify genomic regions that are likely to contain important genes -- and sequencing just these regions is probably more affordable.

These new technologies have enabled researchers to identify a wide range of genes for complex disorders that help to shed light on the pathogenesis of disease. Examples include the identification of 3 genes that influence stuttering, all of which are in lysosomal pathways and thus may be amenable to therapy[8]; identification of mutations in the gene coding for the connective protein fibrillin 1 in thoracic aortic aneurysms and dissection, independent of its causation of Marfan syndrome[9]; identification of a dinucleotide repeat in the promoter of the gene DYPSL2 that confers risk for schizophrenia through its effects on axon growth[10]; and mutations of the X-linked gene PTCHD1 in families with autism or intellectual disability that is in the Hedgehog pathway of developmental signaling genes.[11]

Type 2 diabetes, otherwise known as "the geneticists' nightmare," has had at least 42 risk loci identified through genome-wide association studies, and, as Michael Boehnke[12] of the University of Michigan noted on behalf of his colleagues, these studies have contributed to the knowledge of the biology of this disorder by demonstrating that most of the genes are involved in pancreatic B-cell dysfunction rather than insulin function.

Finally, further illustrating the advances in gene identification made possible by these new technologies, Mark Hannibal and colleagues of the University of Washington in Seattle used exome sequencing to discover the MLL2 gene that underlies most cases of Kabuki syndrome. MLL2 is a histone methyltransferase and is therefore involved in the epigenetic regulation of other genes. This finding confirms the autosomal dominant nature of the syndrome and provides a means of molecular diagnosis. Further studies will define the genes that are regulated by MLL2 and that cause the craniofacial features and developmental delays associated with Kabuki syndrome.

Epigenetic Regulation

The role of epigenetic regulation in clinical disorders, an emerging area of intense interest, was highlighted in several other sessions. Epigenetic regulation refers to regulatory processes that are not mediated by DNA codes but that are carried out through mechanisms such as methylation of DNA or histone modification, which presumably affect the access of transcription mechanisms to coding DNA.

In a session highlighting the effects of epigenetic mechanisms on such disorders as schizophrenia, bipolar illness, and addiction, Ezra Susser[13] of Columbia University described his research on the long-term effects of prenatal famine on the later development of schizophrenia, as documented by follow-up studies of the 1945 "Hunger Winter" in The Netherlands during World War II and the1959-1961 famine in the Anhui and Guangxi provinces of China. Preliminary data indicate an association of schizophrenia in exposed individuals with decreased methylation of an insulin growth factor gene (IGF2); presumably, this altered methylation was affected by the effects of the famine in utero, and was maintained into adulthood. Additional work to detect other epigenetic changes is in progress. However, the methylation changes were seen in peripheral blood cells, which may not necessarily reflect the regulatory patterns in tissues in the brain.

Mouse models of human disease can circumvent this problem, as demonstrated by a study of the addiction process by Eric Nestler[14] of the Mount Sinai School of Medicine in New York. Using mice addicted to cocaine, the researchers focused on the deltaFosB gene, which affects histone methylation and acetylation in the nucleus accumbens, and found that exposure to cocaine caused increased expression of a particular isoform of the gene. This was associated with an overall decrease in gene repression, an increase in the number of dendritic synapses, and an increase in addictive behaviors. Some of the epigenetic changes persisted even after withdrawal from cocaine. Determination of the genes that are regulated by these histone changes may provide targets for therapy.

Expanding Research Avenues and Technologie

The translation of basic science knowledge into clinical science and therapeutic strategies was a major focus of the closing talk by Francis Collins,[15] Director of the NIH.

Dr. Collins described the new initiatives being taken by the NIH to facilitate movement through the drug development pipeline: from gene discovery as a target for therapeutic intervention, through the testing and optimization of small molecule compounds that might serve as drugs against these targets, and finally the very risky and expensive venture of clinical testing.

Four NIH Molecular Library Centers are available for high-throughput testing of 350,000 potentially therapeutic compounds, and the NIH Therapeutics for Rare and Neglected Diseases (TRND) program facilitates further testing. This program can support collaborations between researchers outside of the NIH and the NIH laboratories to move through the pipeline to the point where external funding sources are willing to take the risks for further development.

There are currently 5 projects supported by TRND: 1 on hookworm and 4 for genetic disorders, namely Neimann-Pick type C, hereditary inclusion body myopathy, chronic lymphocytic leukemia, and sickle cell anemia.

Clinical testing of therapies can be coordinated through institutions with NIH-supported Clinical Translational Service Awards and drug development can be further enhanced by the Cures Accelerated Network, authorized by the new Healthcare Affordability Act, which would provide new and flexible mechanisms to fund this research.

An important part of the development of new therapeutics is comparative effectiveness research, also supported by the new healthcare legislation. Treatment comparisons can be facilitated by the NIH, and Dr. Collins envisioned the combination of efficacy testing with personalized medicine, in which genomic information could be used to determine the best therapies for individuals with different genotypes.

Dr. Collins also noted some challenges for biomedical research in the future, including the relatively flat federal funding for research, the increase in direct-to-consumer genetic testing and its lack of regulation, and the uncertain legal status of stem cell research and patents on human genomic DNA sequences.

The NIH has been particularly active in addressing the challenges raised by the latter 2 issues. The challenge of poorly regulated direct-to-consumer testing is being addressed through a proposed voluntary registry of laboratories and companies providing molecular diagnostic testing, although Dr. Collins recognized that this proposal has been somewhat contentious, and the American Society of Human Genetics has formally questioned its need given the currently available and curated GeneTests Website. On the gene patenting front, the NIH participated in an amicus brief in the currently pending appeal of the ruling that found that DNA sequences should not be patentable. The brief made the distinction between human-engineered DNA sequences, which should be patentable, and genomic DNA sequences, which should be considered a product of nature and thus not subject to patents. It is hoped that this change will facilitate research into different means of molecular diagnosis and treatment.

Finally, Dr. Collins turned to the allegations cited by Dr. Lander in his opening talk[1] that claimed there has been a lack of progress in human genetics in the 10 years after completion of the Human Genome Project.

Dr. Collins also refuted those claims, saying that after reading one such article making this claim, he had immediately come up with 29 recent advancements that affected peoples' lives.

Advances produced by the Human Genome Project have been most visible to biomedical researchers, however, and he urged researchers and clinicians to make themselves available to media representatives to be sure that accurate information is available. At the same time, he cautioned us to not let our enthusiasm lead us to overpromise or oversell the consequences of our own research because failure to deliver on those promises can lead to cynicism toward research progress later.

Although it is important to convey our passion for our science, he concluded, this must be balanced by the recognition that the process of going from an insight to a clinically relevant treatment is very difficult. "It is a long and expensive and failure-prone road, but it is the best hope we have, and I don't think we should be shy to describe how this affects our hopes for the future, for all those people who need that hope, because right now they don't have what they need."


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