So what did Gregor Mendel leave us?
Many people forget that Mendel’s "laws of inheritance" predate – by approximately 80 years – the concept of DNA as the basis of genes. And so when I ask this opening question, I sometimes feel like Jay Leno on late-night television, as I tend to get answers that are all over the place, even from sophisticated audiences.
My answer is that he left us the notion that traits (including human diseases) can travel through generations as discrete, inheritable phenomena, and that this travel can fall into recognizable patterns.
Thanks to Mendel’s work, we can interview a patient in our adult genetics clinic tomorrow, generate a pedigree, track a disease through multiple generations in a family, interpret the pedigree as autosomal dominant (or recessive, or x-linked), and then – if we are correct in our interpretation – we can be confident that a single mutated gene is at work in the patient’s family. We do not need to know the name of the gene, and in fact often we do not know the name of the gene.
One estimate is that more than 5,000 distinct, monogenic diseases have been clinically described; however, the gene is known in only about 2,500 diseases to date. In 2007, Jacques S. Beckmann, Ph.D., of the University of Lausanne (Switzerland), and Dr. Stylianos E. Antonarakis of the University of Geneva lamented a decline in the number of new, single-gene diseases (that is, mendelian diseases) that were being described in the literature, compared with the growing number of research reports on the genetic basis of common, complex, and multigenic diseases.
However in 2009, the value of a new tool for linking mendelian diseases to their genes was demonstrated (Nature 2009;461:272-6). This tool is called WES (whole exome sequencing), and the motivation to apply it in this "genomic era" is fairly straightforward. While WGS (whole genome sequencing) gives information on 3 billion letters of DNA sequence and is cost prohibitive and slow, WES gives information on a mere 30 million (1%) letters of DNA sequence and is cheaper and faster, and for the time being is just as likely to yield an answer in a search to link genes and diseases.
Although WES isn’t perfect for finding new disease-gene associations – it identifies new mendelian disease genes in approximately 60% of cases (Eur. J. Hum. Genet. 2012 Jan. 18 [doi:10.1038/ejhg.2011.258]) – it is powerful, and it is currently sparking a bit of a mendelian comeback. When one considers the painstaking work of teams of researchers for over a decade to link the CFTR gene to cystic fibrosis in 1989, it is absolutely remarkable that now, with WES, it is possible to find the gene-disease association in a couple of months, with one or two affected individuals, a few thousand dollars, and some powerful interpretive software programs.
So why should the practicing clinician care about WES and mendelian disease? Because the aggregate burden of mendelian diseases on humans is significant, the role of mendelian diseases in medical progress is unmistakable, and many "common diseases" that you treat have important single-gene forms that you have likely seen in practice.
Recall that the road to the use of statins in many ways started with familial hypercholesterolemia, an autosomal dominant disease. Note that renal failure in African Americans can now frequently be linked to autosomal recessive inheritance of common APOL1 mutations. And check out a paper in the New England Journal of Medicine, which just last month described autosomal dominant mutations in a gene called TTN as a significant cause of "idiopathic" dilated cardiomyopathy (N. Engl. J. Med. 2012;366:619-28).
This July will be Gregor Mendel’s 190th birthday, and although you may not be planning a celebration, you may want to sit back for a minute and recognize the continued power of those long-ago observations about peas that form the basis of the laws of inheritance. Our tools for exploration will change, but those observations will continue to influence the course of modern medicine for the foreseeable future.
Dr. Murray is the clinical chief of genetics at Brigham and Women’s Hospital and an instructor at Harvard Medical School, both in Boston.