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

by Greg Gibson

  Arthur Knudson’s seminal paper developing the two-hit model for retinoblastoma was published in 1971 as Proceedings of the National Academy of Science (USA) 68: 820-823 “Mutation and cancer: statistical study of retinoblastoma.” He wrote a personal account of his life in science a couple of years ago: Knudson, A. G. (2005) Annual Review of Genomics and Human Genetics 6: 1-14 “A personal sixty-year tour of genetics and medicine.”

  Richard Dawkins’s second famous book about evolution is The Blind Watchmaker (Penguin, 1990, published in the United States by Norton).

  familial breast cancer

  The contributions of BRCA1 and BRCA2 were estimated by King, M. C., J. Marks, J. Mandell, and the New York Breast Cancer Study Group (2003) Science 302: 643-646 “Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2” and have been more recently reviewed by Fackenthal, J. D. and O. I. Olopade (2007) Nature Reviews Cancer 7: 937-948 “Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations.”

  A fact sheet about genetic testing for BRCA genes is provided by the National Cancer Institute at www.nci.nih.gov/cancertopics/factsheet/Risk/BRCA.

  The role of CHEK2 in hereditary breast cancer is discussed in Bogdanova, N., S. Feshchenko, C. Cybulski, and T. Dörk (2007) Journal of Clinical Oncology 25: 26e “CHEK2 mutation and hereditary breast cancer.” Also see Walsh, T. and M. C. King (2007) Cancer Cell 11: 103-105 “Ten genes for inherited breast cancer.”

  The distribution of BRCA1 mutations and high prevalence in Ashkenazi is reported in John, E. M., A. Miron, G. Gong, A. Phipps, A. Felberg, F. Li, D. West, and A. S. Whittemore (2007) Journal of the American Medical Association 298: 2869-2876 “Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups.”

  growth factors and the risk to populations

  There are hundreds of studies of association of one or several genes with aspects of breast cancer. The following take a more comprehensive genomewide look and are discussed in the text:

  A. Cox et al. (2007) Nature Genetics 39: 352-358 “A common coding variant in CASP8 is associated with breast cancer risk.”

  Pharoah, P. D., J. Tyrer, A. M. Dunning, D. F. Easton, B. A. Ponder, and the SEARCH Investigators (2007) PLoS Genetics 3: e42 “Association between common variation in 120 candidate genes and breast cancer risk.” See also Breast Cancer Association Consortium (2006) Journal of the National Cancer Institute 98: 1382-1396 “Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium.”

  D. F. Easton et al. (2007) Nature 447: 1087-1093 “Genome-wide association study identifies novel breast cancer susceptibility loci,” D. J. Hunter et al. (2007) Nature Genetics 39: 870-874 “A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer,” and S. N. Stacey et al. (2007) Nature Genetics 39: 865-869 “Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer.”

  pharmacogenetics and breast cancer

  You can download a copy of Senator Obama’s bill at www.personalizedmedicinecoalition.org/sciencepolicy/public-policy_senator.php.

  The use of TPMT genotyping to accompany drug administration is discussed in Maitland, M. L., K. Vasisht, and M. J. Ratain (2006) Trends in Pharmacological Science 27: 432-437 “TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy?”

  A very recent review of emerging cancer therapies is Doyle, D. M. and K. D. Miller (2008) Breast Cancer 15: 49-56 “Development of new targeted therapies for breast cancer.”

  For a brief history of tamoxifen, see http://en.wikipedia.org/wiki/Tamoxifen. New insight into the mechanism of tamoxifen resistance can be read about in Massarweh, S., C. Osborne, C. Creighton, L. Qin, A. Tsimelzon, S. Huang, H. Weiss, M. Rimawi, and R. Schiff (2008) Cancer Research 68: 826-833 “Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function.”

  Testing of Her2 status remains controversial but is recommended by Carlson, R. W. and the NCCN HER2 Testing in Breast Cancer Task Force (2006) Journal of the National Comprehensive Cancer Network 4 (Suppl 3): S1-22 “HER2 testing in breast cancer: NCCN Task Force report and recommendations.” Genentech’s drug, Herceptin (trastuzumab) is described at www.gene.com/gene/products/information/oncology/herceptin.

  The first study using microarrays to perform gene expression profiling of blood cancers and suggesting that they may be predictive of long-term prognosis was A. A. Alizadeh et al. (2000) Nature 403: 503-511 “Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.” This approach was demonstrated for breast cancer by L.J. van ‘t Veer, et al. (2002) Nature 415: 530-536 “Gene expression profiling predicts clinical outcome of breast cancer.”

  Similar work has led to the development of a new test, Oncotype-DX, that is undergoing clinical evaluation. A report on this is L. A. Habel et al. (2006) Breast Cancer Research 8: R25 “A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients.” See the Web site at www.genomichealth.com/oncotype/default.aspx.

  why do genes give us cancer?

  Darwinian medicine arguments for cancer are advanced by Mel Greaves in (2006) Nature Reviews Cancer 7: 213-221 “Darwinian medicine: a case for cancer,” and (2002) Lancet Oncology 3: 244-250 “Cancer causation: the Darwinian downside of past success?” The same author has written a popular book on the topic, Cancer: The Evolutionary Legacy (Oxford University Press, 2001).

  Chapter 3

  jackie and ella

  A list of celebrity diabetics can be found on the Islets of Hope Web site at www.isletsofhope.com/family/famous_diabetics_1.html.

  For more information on the life of Jackie Robinson, see his official Web site at www.jackierobinson.com/ or visit his Foundation at www.jackierobinson.org.

  Ella Fitzgerald’s official Web site is www.ellafitzgerald.com/ where the quote attributable to Jimmy Rowles can be found. The link to her charitable foundation is www.ellafitzgeraldfoundation.org/.

  the pathology of diabetes

  Much basic information on the disease can be accessed through Wikipedia (http://en.wikipedia.org/wiki/Diabetes_mellitus), the World Health Organization (www.who.int/diabetes/en/), and the Centers for Disease Control (www.cdc.gov/diabetes/). The NIH’s National Institute of Diabetes and Digestive and Kidney Diseases also has an information clearinghouse at http://diabetes.niddk.nih.gov/.

  Statistics on incidence of diabetes can be found at www.cdc.gov/diabetes/statistics/incidence/.

  type 1 diabetes

  The genetics of diabetes is reviewed in Florez, J. C., J. Hirschhorn, and D. Altshuler (2003) Annual Review of Genomics and Human Genetics 4: 257-291 “The inherited basis of Diabetes mellitus: Implications for the genetic analysis of complex traits,” and of T1D specifically in Pociot, F. and M. F. McDermott (2002) Genes and Immunity 3: 235-249 “Genetics of type 1 diabetes mellitus,” as well as Kim, M. S. and C. Polychronakos (2005) Hormone Research 64: 180-188 “Immunogenetics of type 1 diabetes.” A large linkage scan is summarized by P. Concannon and the Type 1 Diabetes Genetics Consortium (2005) Diabetes 54: 2995-3001 “Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families.”

  Genomewide association studies for T1D are described by J. Todd et al. (2007) Nature Genetics 39: 857-864 “Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes,” and H. Hakonarson et al. (2007) Nature 448: 591-594 “A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.” The 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” also includes both T1D and T2D.

  For updates on the role of the HLA complex in promoting T1D and other autoimmune diseases, see Lie, B. A. and E. Thorsby (200
5) Current Opinion in Immunology 17: 526-531 “Several genes in the extended human MHC contribute to predisposition to autoimmune diseases,” and Larsen. C. E. and C. A. Alper (2004) Current Opinion in Immunology 16: 660-667 “The genetics of HLA-associated disease.”

  There is vast literature on the relationship between breast-feeding, baby formula, and both types of diabetes. Some of the studies in support of an association are an Australian study by H. Malcova et al. (2006) European Journal of Pediatrics 165: 114-119 “Absence of breast-feeding is associated with the risk of type 1 diabetes: a case-control study in a population with rapidly increasing incidence,” a Finnish one by S. M. Virtanen et al. (1992) Diabetic Medicine 9: 815-819 “Feeding in infancy and the risk of type 1 diabetes mellitus in Finnish children,” and an English one by P. A. McKinney et al. (1999) Diabetes Care 22: 928-932 “Perinatal and neonatal determinants of childhood type 1 diabetes. A case-control study in Yorkshire, U.K.” However, for a much more skeptical meta-analysis see Norris, J. M. and F. W. Scott (1996) Epidemiology 7: 87-92 “A meta-analysis of infant diet and insulin-dependent diabetes mellitus: do biases play a role?” For a comprehensive discussion of the mechanisms by which nutrition and genes may influence T1D, see Karges, W. J. P., J. Ilonen, B. H. Robinson, and H.M. Dosch (1995) Molecular Aspects of Medicine 16: 79-213 “Self and non-self antigen in diabetic autoimmunity: molecules and mechanisms.”

  The Insulin gene VNTR polymorphism, as well as PTPN22 and CTLA4, are discussed in Anjos, S. and C. Polychronakos (2004) Molecular Genetics and Metabolism 81: 187-195 “Mechanisms of genetic susceptibility to type I diabetes: beyond HLA,” and Jahromi, M. M. and G. S. Eisenbarth (2006) Annals of the New York Academy of Science 1079: 289-299 “Genetic determinants of type 1 diabetes across populations.”

  SUMO4 is reviewed in Wang, C. Y. and J. X. She (2008) Diabetes/metabolism Research and Reviews 24: 93-102 “SUMO4 and its role in type 1 diabetes pathogenesis.”

  an epidemic genetic disease

  Michael Pollan’s excellent book is The Omnivore’s Dilemma: A Natural History of Four Meals (Penguin, 2007).

  The politics of corn subsidies has just become yet more interesting with the growth of interest in bioethanol. See these recent articles in the Washington Post and New York Times: www.washingtonpost.com/wpdyn/content/article/2007/09/27/AR2007092702054_pf.html and www.nytimes.com/2005/11/09/business/09harvest.html.

  genetics of obesity

  For a review of leptin in humans, see E. Jéquier (2002) Annals of the New York Academy of Science 967: 379-388 “Leptin signaling, adiposity, and energy balance.” More gut hormones are reviewed in Murphy, K. G. and S. R. Bloom (2006) Nature 444: 854-859 “Gut hormones and the regulation of energy homeostasis.”

  A guide to weight loss drugs that have been approved for use in the United States can be found at www.healthnetwork.com.au/weight-loss/drugs.asp. This is one area where there is an enormous amount of disinformation on the Web, but sites such as WebMD may help: www.webmd.com/diet/guide/weight-loss-prescription-weight-loss-medicine.

  The various hormonal mechanisms of appetite regulation are described by E. T. Rolls (2007) Obesity Reviews 8 (Suppl. 1): 67-72 “Understanding the mechanisms of food intake and obesity.” For a broader view of the reasons for the onset of T2, see Kahn, S. E., R. L. Hull and K. M. Utzschneider (2006) Nature 444: 840-846 “Mechanisms linking obesity to insulin resistance and type 2 diabetes.”

  The Obesity Gene Map database of all genes implicated in the condition is available online at http://obesitygene.pbrc.edu/ and in print through T. Rankinen et al. (2006) Obesity 14: 529-644 “The human obesity gene map: the 2005 update.”

  The association of FTO with obesity was first reported by L. J. Scott et al. (2007) Science 316: 1341-1345 “A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants,” C. Dina et al. (2007) Nature Genetics 39: 724-726 “Variation in FTO contributes to childhood obesity and severe adult obesity,” and A. Scuteri et al. (2007) PLoS Genetics 3: e115 “Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits.” The first insights into the molecular function of the gene were reported in: T. Gerken et al. (2007) Science 318: 1469-1472 “The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.”

  The INSIG2 association was first reported by A. Herbert et al. (2006) Science 312: 279-283 “A common genetic variant is associated with adult and childhood obesity.” More data can be found in H. N. Lyon et al. (2007) PLoS Genetics 3: e61 “The association of a SNP upstream of INSIG2 with Body Mass Index is reproduced in several but not all cohorts.” A critical review of ENPP1 that references several studies is H. N. Lyon et al. (2006) Diabetes 55: 3180-3184 “Common variants in the ENPP1 gene are not reproducibly associated with diabetes or obesity.” Melanocortin receptors are reviewed by R. D. Cone (2006) Endocrine Reviews 27: 736-749. Studies on the physiological functions of the melanocortin system and the association with obesity can be found in I. M. Heid et al. (2005) Journal of Medical Genetics 42: 21-26 “Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys.”

  type 2 diabetes

  TCF7L2 turned up in several genomewide scans: V. Steinsthorsdottir et al. (2007) Nature Genetics 39: 770-775 “A variant in CDKAL1 influences insulin response and risk of type 2 diabetes,” L. J. Scott et al. (2007) Science 316: 1341-1345 “A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants,” J. T. Salonen et al. (2007) American Journal of Human Genetics 81: 338-345 “Type 2 diabetes whole-genome association study in four populations: the DiaGen consortium.” It has been further studied in dozens of places around the world, while A. Helgason et al. (2007) Nature Genetics 39: 218-225 “Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution” describe the recent history of the gene.

  The initial paper introducing the thrifty genes hypothesis was J. V. Neel (1962) American Journal of Human Genetics 14: 353-362 “Diabetes mellitus: a ‘thrifty’ genotype rendered detrimental by ‘progress’?” One of the strongest critiques of it is J. R. Speakman (2006) Diabetes and Vascular Disease Research 3: 7-11 “Thrifty genes for obesity and the metabolic syndrome—time to call off the search?” Jared Diamond discusses the notion in Nature 423: 599-602 “The double puzzle of diabetes.” His two books mentioned in the text are Guns, Germs, and Steel: The Fates of Human Societies (Norton, 1997) and Collapse: How Societies Choose to Fail or Succeed (Viking, 2005).

  Recent work on the evolution of lactose tolerance is described in S. A. Tishkoff et al. (2006) Nature Genetics 39: 31-40 “Convergent adaptation of human lactase persistence in Africa and Europe.” See also my commentary: Gibson, G. (2007) Current Biology 17: R295-R296 “Human evolution: thrifty genes and the dairy queen.”

  A strong argument that much of the susceptibility to human disease can be attributed to ancient alleles shared with other primates can be found in Di Rienzo, A. and R. R. Hudson (2005) Trends in Genetics 21: 596-601 “An evolutionary framework for common diseases: the ancestral-susceptibility model.”

  disequilibrium and metabolic syndrome

  Another recent book also introduces the idea that disequilibrium is responsible for diabetes: Peter Gluckman and Mark Hanson’s Mismatch: Why Our World No Longer Fits Our Bodies (Oxford University Press, 2006). It enhances the thrifty phenotype hypothesis first introduced by Hales, C. N. and D. J. Barker (2001) British Medical Bulletin 60: 5-20 “The thrifty phenotype hypothesis,” a notion that is gaining more traction as it becomes apparent that maternal health during pregnancy impacts T2D susceptibility. A more current update including the concept of epigenetic reprogramming can be found in de Moura, E. G. and M. C. Passos (2005) Bioscience Reports 25: 251-269 “Neonatal programming of body weight regulation and energetic metabolism.”

  Metabolic syndrome is a somewhat controversial concept, but it is estimated that well more than a third of all West
erners suffer from the joint predisposition to diabetes and coronary heart disease due to metabolic problems. See J. B. Meigs (2002) American Journal of Managed Care 8(Suppl): S283-S292 “Epidemiology of the metabolic syndrome, 2002,” and Batsis, J. A., R. E. Nieto-Martinez, and F. Lopez-Jimenez (2007) Clinical Pharmacology and Therapeutics 82: 509-524 “Metabolic syndrome: from global epidemiology to individualized medicine.” The connection with obesity is explored in Després, J.-P. and I. Lemieux (2006) Nature 444: 881-887 “Abdominal obesity and metabolic syndrome.”

  Chapter 4

  athletic asthmatics

  For information about asthma education, see www.asthmaactionamerica.com/. The Asthma All-Stars and other famous people with asthma are introduced at www.healthsmart.org/ibreathe/2_0_asthma/2_2_6_famous_people.htm.

  Jackie Joyner-Kersey has a Foundation at http://jackiejoyner-kerseefoundation.org; Jerome Bettis’s “The Bus Stops Here” Foundation is at www.thebus36.com/foundation/foundation.htm.

  The CDC’s statistics on asthma can be found at www.cdc.gov/asthma/ while the World Health Organization site is www.who.int/topics/asthma/en/.

  inflammation and respiration