It Takes a Genome: How a Clash Between Our Genes and Modern Life is Making Us Sick

by Greg Gibson

  Intriguingly, many are also linked to human diseases. Among those 25 growth genes that give or take a millimeter or two of height, are several also implicated in cancer and others that make a contribution to osteoporosis. When a scan was just completed for nicotine dependence, it found a gene that is also the major genetic risk factor for lung cancer. Partly because a brain that desires more cigarettes exposes it’s body to more carcinogens, but also, it seems, because the nicotine receptor it encodes is also active in the lungs. The journey from normality to disease susceptibility takes many twists and turns, but results such as these show just how intimate the link between human evolution and susceptibility to disease is.

  What is striking to me, though, is that there has been no eureka moment when as biologists we have been able to look at this extraordinary new data and realize “That’s it! That is the genetic switch for Homo sapienism. If that mutation over on chromosome 14 hadn’t occurred, we’d still all be back in Olduvai wondering whether we can make a better life for our families by swinging through trees or wandering the plains. Or without this other mutation, no one would be composing concertos or smashing baseballs out of Yankee Stadium.” No, just like every other species on the planet, we humans are a product of millions of little tinkerings. The secret to understanding our humanity is not so much in the individual genes as in the way those genes interact with one another as a genome.

  The Adolescent Genome Revisited

  As change is a hallmark of adolescence, so adolescence is a defining characteristic of the human genome. Change is ever present in the history of our species. We see it in the genetic upheavals that must have accompanied the origins of the genus a million years ago, and of the species 150,000 years ago. We also see it in the myriad ongoing genetic turnovers that have occurred as we have populated every nook and cranny of the planet. We see change in the environments and cultures that humans have occupied in their transitions from nomad to pastoralist to city-dweller, these too occurring over timescales that range from tens of thousands to just tens of years. And we see change in the distribution of disease prevalence, particularly with the rise of the complex diseases that will claim the great majority of our lives.

  This book has been an argument that these three modes of change are deeply connected. Specifically, the combination of genetic and environmental change has given rise to modern disease susceptibility. It is a more subtle formulation than the trite assessment that a gene makes you sick as a side effect of some benefit it also confers. To be sure, sometimes this is the case, but a more critical look tells us that just like a teenager, the genome is trying mightily to come to grips with its growing pains.

  At this point, I need to confess that this formulation, that “genetic + environmental change = increased disease susceptibility” falls well short of a syllogism. There is no logical reason why the right-hand side of the equation should follow from the left-hand side, and patently in many instances it does not. Genius exhibited by musicians and scientists, novelists and entrepreneurs is equally a product of the combination of the genetic evolution of the brain with centuries of cultural advance. The argument, then, is not so much that A + B = C, as that C is dependent on and explained by A and B. Without the twin sources of change, we should not expect to see so much human suffering at the whim of our genomes.

  The full argument is more sophisticated, but I have refrained from developing it but for occasional asides about canalization. In a nutshell, this is the notion that over millions of years, species evolve not just toward their genetic optima, but also to ensure that they are well buffered and robust, resistant to all kinds of perturbations. When change comes on a massive scale, it makes everything more variable than it would be under normal circumstances. And regarding health, that heightened variability is seen as susceptibility to each of the complex diseases for 10 or 20 percent of the population, instead of just a small minority.

  This reasoning is familiar enough to evolutionary biologists, but as yet holds little currency with biomedical geneticists—not for want of truth, but rather because clinicians are more concerned with the practical problem of finding the genes that contribute to disease. Only in the last couple of years have they been granted the tools with which to conduct their searches in a systematic manner. The first flushes of success have generated extraordinary excitement in the research community, but they come with a tinge of disappointment as well, because it is immediately apparent that simple answers will not be forthcoming.

  Each of the half dozen or so genes that we have discussed in each of the chapters of this book explain only a small percentage of the reason why some people get diabetes, depression, and so forth, while others do not. Over the next few years, hundreds of millions of dollars will be spent and hundreds of thousands of people will have their genomes scanned, as a result of which the number of genes implicated in each disease will likely rise to two dozen or more. Yet even then there is little reason to believe we will be a lot closer to explaining why specifically your relatives are more likely to suffer the same diseases as you.

  For those who might be hoping for some sort of test to be taken at birth that will tell a person just which of the common diseases to look out for, don’t hold your breath. For the foreseeable future, you’re probably going to be just as well off making common-sense inferences from the health of your brothers, sisters, parents, and Great-Aunt Bessies. Ultimately, knowing the genes should help the drug companies develop more effective therapies, and the nutritionists and lifestyle counselors to promote better ways of living. Whether their recommendations will be personalized based on knowledge of your genome is still debatable.

  The genetics will tell us, though, why our genes make us sick. Why hundreds of places in the genome influence every disease, and how the environment works with them. Genetics will tell us that some genetic variants are there because they used to be beneficial at an earlier stage of human evolution, but now are bad for us. It will tell us that some have a yin and yang good and bad side to them in today’s world. More often it will be apparent that variants are there because they are an unavoidable part of the way life is, their effects suppressed as much as possible, but never perfectly so. And in some cases we will see that risky alleles carried over from earlier times have not yet been replaced by better ones that truly protect our health.

  If we come back in a few million years, perhaps we will find that our adolescent genome has evolved to a more mature equilibrium that offers greater protection from disease. In the meantime we must make do with a system that gives way more than it takes. It is after all also responsible for the extravagant and bountiful diversity of the human condition.

  Notes

  Chapter 1

  genetic imperfection

  It should not be necessary for readers new to genetics to have an understanding of how genes work, but a good place to start would be Larry Gonick and Mark Wheelis’s The Cartoon Guide to Genetics (Harper Collins, 1991).

  unselfish genes

  An interesting online discussion of “gay genes” and how they have been portrayed in mainstream media can be found at www.leaderu.com/jhs/satinover.html.

  Of all the excellent books written by Harvard geneticist Richard Lewontin on population genetics, I recommend Human Diversity (Scientific American Library, 1991—a general discussion of human variation) and It Ain’t Necessarily So (Granta Books, 2001—a critique of the Human Genome Project).

  The title of this section is a play on Richard Dawkins’s popular book The Selfish Gene (Oxford University Press, 1978), which paints a very deterministic picture of genes and evolution.

  how genes work and why they come in different flavors

  For a technical description of staufen’s role in memory, see the article by Dubnau, J., A. S. Chiang, L. Grady, J. Barditch, S. Gossweiler, J. McNeil, P. Smith, F. Buldoc, R. Scott, U. Certa, C. Broger, and T. Tully (2003) Current Biology 13: 286-296 “The staufen/pumilio pathway is involved in Drosophila long-term memory,” and
the earlier review by Roegiers, F. and Y-N. Jan (2000) Trends in Cell Biology 10: 220-224 “Staufen: a common component of mRNA transport in oocytes and neurons?”

  Most papers on mutation-selection-drift balance are highly mathematical and technical, so not for the faint-of-heart. An oft-cited one is Barton, N. H. and M. Turelli (1989) Annual Review of Genetics 23: 337-370 “Evolutionary quantitative genetics: how little do we know?” while a more recent contribution is by Zhang, X. S., J. Wang, and W. G. Hill (2002) Genetics 161: 419-433 “Pleiotropic model of maintenance of quantitative genetic variation at mutation-selection balance.”

  There is vast literature on evolutionary psychology and evolutionary medicine, championed by Randolph Nesse in a popular book, Why We Get Sick: The New Science of Darwinian Medicine (Knopf, 1994), as well as in the scientific literature: Nesse, R. M., S. C. Stearns, and G. S. Omenn (2006) Science 311: 1071 “Medicine needs evolution.” In this book, I espouse quite a different view of the role of genetic evolution in disease.

  three reasons why genes might make us sick

  Genetic modifiers of cystic fibrosis are discussed in Knowles, M. R. (2006) Current Opinion in Pulmonary Medicine 12: 416-421 “Gene modifiers of lung disease,” while variation in the CFTR gene is described in Rowntree, R. K. and A. Harris (2003) Annals of Human Genetics 67: 471-485 “The phenotypic consequences of CFTR mutations.”

  For an early review of Dystrophin see Worton, R. G. and M. W. Thompson (1988) Annual Review of Genetics 22: 601-629 “Genetics of Duchenne muscular dystrophy.”

  Spinocerebellar ataxias and triplet expansion diseases are described in a provocatively titled article by Petronis, A. and J. L. Kennedy (1995) American Journal of Psychiatry 152: 164-172 “Unstable genes—unstable mind?”

  The difficulties involved in dissecting the genetics of schizophrenia are clearly laid out in Sanders, A. R. et al. (2008) American Journal of Psychiatry 165: 497-506 “No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: Implications for psychiatric genetics.”

  A standard textbook of quantitative genetics that includes the theory behind threshold liability is Michael Lynch and Bruce Walsh’s Genetics and Analysis of Quantitative Traits (Sinaeur, 1998).

  For a technical review of canalization see Gibson, G. and G. Wagner (2000) Bioessays 22: 372-380 “Canalization in evolutionary genetics: a stabilizing theory?” The original observation in mice was described by Dunn, R. B. and A. S. Fraser (1958) Nature 181: 1018-1019 “Selection for an invariant character—‘vibrissae number’—in the house mouse,” and the idea was first popularized by C. H. Waddington in The Strategy of the Genes (McMillan, 1957).

  One of the best descriptions of modern human evolution is by Luigi Luca and Francesco Cavalli-Sforza, The Great Human Diasporas: The History of Diversity and Evolution (Addison Wesley, 1996).

  the human genome project

  Amazon.com lists nearly 7,000 entries under the heading of “human genome project.” Two good starting points are Daniel Kevles and Leroy Hood’s The Code of Codes: Scientific and Social Issues in the Human Genome Project (Harvard University Press, 1993) and Michael Palladino’s Understanding the Human Genome Project, 2nd edition (Benjamin Cummings, 2005). Another very readable and interesting summary of the project is Matt Ridley’s Genome: An Autobiography of the Species in 23 Chapters (Harper Perennial, 2000).

  The two papers describing the draft sequence of the human genome were published simultaneously in February 2001. J. C. Venter et al. (2001) Science 291: 1304-1351 “The sequence of the human genome,” and E. S. Lander et al. (2001) Nature 413: 860-921 “Initial sequencing and analysis of the human genome.” Both journals provide public Web sites for perusal of the papers and commentaries.

  Scientists use three major Web sites to access all the genome project data: the USNIH site at www.ncbi.nlm.nih.gov, the European molecular biology organization site at www.ensembl.org, and the University of California at Santa Cruz browser at http://genome.ucsc.edu.

  The SNP at position 102,221,163 on chromosome 11, also known as rs3025058, is actually in front of a gene called MMP3 and is known to promote heart disease. See Beyzade, S., S. Zhang, Y-k. Wong, I. Day, P. Eriksson, and S. Ye (2003) Journal of the American College of Cardiology 41: 2130-2137 “Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of mycocardial infarction,” and Rockman, M. V., M. Hahn, N. Soranzo, D. Loisel, D. B. Goldstein, and G. A. Wray (2004) Current Biology 14: 1531-1539 “Positive selection on MMP3 regulation has shaped heart disease risk.”

  genomewide association

  The study of human genetic variation using the GWA approach garnered Science journal’s “Breakthrough of the Year” accolade for 2007. While dozens of papers were published, the one that marked a turning point was: Wellcome Trust Case Control Consortium (2007) Nature 447: 661-678 “Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.”

  Chapter 2

  cancer of the breast

  Wikipedia is a useful source of information on all of the diseases discussed in the next several chapters. Lists of celebrity survivors and patients can be found in many places on the Internet, such as http://en.wikipedia.org/wiki/List_of_notable_breast_cancer_patients_according_to_survival_status. The full breast cancer site is at http://en.wikipedia.org/wiki/Breast_cancer.

  In addition to her Uplift: Secrets from the Sisterhood of Breast Cancer Survivors (Simon and Schuster, 2003), Barbara Delinsky has a Web site for survivors at www.barbaradelinsky.com/delinsky-uplift.htm.

  The National Cancer Institute’s Web site provides updated statistics on the incidence of breast cancer and information about treatment and prognosis at www.nci.nih.gov/cancertopics/types/breast.

  broken genes, broken lives

  Some recent studies of the influences of socioeconomic status and race on cancer incidence include Chu, K. C., B. A. Miller, and S. A. Springfield (2007) Journal of the National Medical Association 99: 1092-1104 “Measures of racial/ethnic health disparities in cancer mortality rates and the influence of socioeconomic status,” Albano, J. D., E. Ward, A. Jemal, R. Anderson, V. Cokkinides, T. Murray, J. Henley, J. Liff, and M. J. Thun (2007) Journal of the National Cancer Institute 99: 1384-1394 “Cancer mortality in the United States by education level and race,” and Baquet, C. R. and P. Commiskey (2000) Cancer 88 (Suppl.): 1256-1264 “Socioeconomic factors and breast carcinoma in multicultural women.”

  epidemiology and relative risk

  For more on Janet Lane Claypon see an article by medical historian Warren Winkelstein (2004) American Journal of Epidemiology 160: 97-101 “Vignettes of the history of epidemiology: Three firsts by Janet Elizabeth Lane-Claypon” as well as the Wikipedia site at http://en.wikipedia.org/wiki/Janet_Lane-Claypon.

  A comprehensive review of global trends in breast cancer rates can be found in Althuis, M. D., J. Dozier, W. Anderson, S. Devesa, and L.A. Brinton (2005) International Journal of Epidemiology 34: 405-412 “Global trends in breast cancer incidence and mortality 1973-1997.” The Center for Disease Control provides a free online file containing cancer statistics for the United States at http://apps.nccd.cdc.gov/uscs (it is over 8Mb). A site that conveniently allows you to visualize customizable color maps of incidence is at www3.cancer.gov/atlasplus/index.html.

  The role of estrogen in breast cancer is reviewed in Clemons, M. and P. Goss (2004) New England Journal of Medicine 344: 276-285 “Estrogen and the risk of breast cancer.” Many studies have examined the effect of hormone replacement therapy, including one of more than a million women, and a lively discussion of the issues can be found in The Lancet (2003) volume 362, issue 9392. Reproductive factors are discussed in N. Andrieu et al. (1998) British Journal of Cancer 77: 1525-1536 “The effects of interaction between familial and reproductive factors on breast cancer risk: a combined analysis of seven case-control studies,” and in Becher, H., S. Schmidt, and J. Chang-Claude (2003) International Journal of Epide
miology 32: 38-48 “Reproductive factors and familial predisposition for breast cancer by age 50 years. A case-control-family study for assessing main effects and possible gene-environment interaction.”

  brakes, accelerators, and mechanics

  An excellent introduction to cancer biology for the general public is Robert A. Weinberg’s One Renegade Cell (Basic Books, 1999).

  There are thousands of reviews of the three different classes of cancer-related genes. Here are some classics from the Annual Reviews series: Levine, A. J. (1993) Annual Review of Biochemistry 62: 623-651 “The tumor suppressor genes,” Riley, D. J., E. Lee, and W. H. Lee (1994) Annual Review of Cell Biology 10: 1-29 “The Retinoblastoma protein: more than a tumor suppressor,” Knudson, A. G. (2000) Annual Review of Genetics 34: 1-19 “Chasing the cancer demon,” Bishop, J. M. (1983) Annual Review of Biochemistry 52: 301-354 “Cellular oncogenes and retroviruses,” Varmus, H. E. (1984) Annual Review of Genetics 18: 553-612 “The molecular genetics of cellular oncogenes,” and McKinnon, P. J. and K. W. Caldecott (2007) Annual Review of Genomics and Human Genetics 8: 37-55 “DNA strand break repair and genetic disease.” The genetics of colon cancer is reviewed in de la Chapelle, A. (2004) Nature Reviews Cancer 4: 769-780 “Genetic predisposition to colorectal cancer.”