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Researchers Propose Integrated Genomic View of Human Disease

By Andrea Anderson

NEW YORK (GenomeWeb News) – In the latest issue of Cell, four Texas-based genomics researchers presented a model for thinking about the interconnected genetic and genomic patterns contributing to human traits and diseases.

The purpose of the perspectives paper was to "put forward a unified genomic model of human disease," co-author Eric Boerwinkle, a researcher affiliated with the University of Texas Health Science Center at Houston's Human Genetics Center and Baylor College of Medicine Human Genome Sequencing Center, told GenomeWeb Daily News.

Rather than thinking of human diseases in terms of the type and/or frequency of genetic variations contributing to them, he explained, the model attempts to bring together information on all manner of genetic variation in the genome — from chromosomal rearrangements and copy number variations down to individual nucleotide changes.

The picture of human disease architecture that the team presents encompasses a spectrum of mutation types found at varying frequencies in the population, including variants that turn up in many members of a given population, rare variations found at a lower frequency, and private mutations detected in just one individual or in closely related family members.

"The debate [over the importance of rare or common variants] may not be helping us," Boerwinkle noted, "because the genetic architecture of human disease can be attributed to both of these things — rare and common — and also sequence variants and copy number variants or structural variants."

"[T]he most important thing is not to focus disproportionately on specific variants," the researchers wrote, "but rather to integrate across all classes or risk-associated variants. In some individuals, risk may be caused by an unusual combination of common variants, whereas in others it will be due to a smaller number of large effect rare variants."

Nevertheless, the extent to which private or rare genetic variation are turning up in large-scale genome sequencing studies, personal genome analyses, and targeted gene sequencing work hints that these mutations have a previously unappreciated influence over traits and diseases, they argued.

The authors reasoned that there is a good deal of medically actionable information that can be gleaned from genetic and genomic studies of these recent mutations in the genome that are shared between family members. And, they say, this "clan genomics" model could help in interpreting personal genome and disease data.

Recent mutations found within a "clan" or extended pedigree appear to have a large impact on human disease, Boerwinkle said. These may not necessarily be limited to mutations occurring between parents and their children, he explained, but include the accumulation of mutations that occur over several generations.

"We're proposing that we better understand the role of clan genomics and we leverage that to promote a better gene discovery," he said. "We haven't fully leveraged the power in extended pedigrees and clan genomics."

Another goal of the paper, Boerwinkle noted, was to encourage a move away from a preoccupation with accounting for all of the heritability for a given disease. "In order to better understand biology and improve human health we don't need to account for all of the heritability," he said. "I think we need to move our focus back towards good basic biology, building off of gene discovery, and also translating gene discovery, both rare and common variation, to better diagnose and treat disease."

The researchers also emphasized the importance of considering the influence that rare and common variants can have on one another, noting that "each personal genome has a collection or 'ecology' of deleterious and protective variations, which in combination (not necessarily in sum) dictate the health of the individual."

Finally, using examples from numerous disease studies, the authors argued that common diseases involving many genes and Mendelian diseases associated with high penetrance, rare genetic variants are not necessarily separate entities, since they sometimes involve different types of alterations to the same genes or pathways.

"When we looked at the GWAS hits, many times those same genes had rare variants with very large effects contributing to the Mendelian diseases," Boerwinkle said. "And the converse is also true. Common variations in the so-called Mendelian disease genes are also contributing to more common chronic disease in the population."