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 Epidemiology 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.”

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 (2005) 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 Westerners 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

The first review of canine atopic dermatitis that I am aware of is by R. E. Halliwell (1971) The Veterinary Record 89:209-214 “Atopic disease in the dog,” as referenced in Hillier, A. and C. E. Griffin (2001) Veterinary Immunology and Immunopathology 81: 147-151 “The ACVD task force on canine atopic dermatitis (I): incidence and prevalence.”

For a brief description of the common asthma drugs, see www.healthcentral.com/asthma/find-drug.html.

A couple of recent reviews of the genetics and immunology behind asthma are Zhang, J., P. D. Pare, and A. J. Sandford (2007) Respiratory Research 9:4 “Recent advances in asthma genetics,” and Yamashita, M., A. Onodera, and T. Nakayama (2007) Critical Reviews in Immunology 27: 539-546 “Immune mechanisms of allergic airway disease: regulation by transcription factors.”

the hygiene hypothesis

David Strachan’s two papers on the hygiene hypothesis are D. P. Strachan (1989) British Medical Journal 299: 1259-1260 “Hay fever, hygiene, and household size,” and D.P. Strachan (2000) Thorax 55 (Suppl 1): S2-10 “Family size, infection and atopy: the first decade of the ‘hygiene hypothesis.’” One of several recent reviews is by E. von Mutius (2007) Immunobiology 212: 433-439 “Allergies, infections and the hygiene hypothesis—the epidemiological evidence.” Additionally, hundreds of papers examine specific environmental influences on asthma susceptibility.

A fascinating read about polio is David M. Oshinsky’s Polio: An American Story (Oxford University Press, 2006). For a history of the March of Dimes, try David W. Rose’s March of Dimes: Images of America (Arcadia Books, 2003).

asthma epidemiology

Prevalence by ethnicity and age in the United States in adults is around 11 percent for Caucasians and Africans, but less than 8 percent for Hispanics, and more than 20 percent in Puerto Rico. Full data for 2005 can be found at www.cdc.gov/asthma/nhis/05/table2-1.htm.

The association of ADAM33 with asthma was first described by P. van Eerdewegh et al. (2002) Nature 418: 426-430 “Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness.” The latest research on the mechanism by which it works is described in R. G. del Mastro et al. (2007) BMC Medical Genetics 8:46 “Mechanistic role of a disease-associated genetic variant within the ADAM33 asthma susceptibility gene.”

For a review of inflammation and neonatal lung development see Shi, W., S. Bellusci, and D. Warburton (2007) Chest 132: 651-656 “Lung development and adult lung diseases.”

The roles of T-cells in asthma are discussed in M. Larché (2007) Chest 132: 1007-1014 “Regulatory T cells in allergy and asthma,” and Umetsu, D. T. and R. H. DeKruyff (2006) Immunological Reviews 212: 238-255 “The regulation of allergy and asthma,” among many other places. An early review of the clinical applications of interleukin cytokines is P. J. Barnes (2001) European Respiratory Journal 34 (Suppl): 67-77 “Cytokine modulators as novel therapies for airway disease.” Genetic associations with asthma are updated in Zhang, J., P. D. Pare, and A. J. Sandford (2008) Respiratory Research 9:4 “Recent advances in asthma genetics.” The linkage with IRAK is described in L. Balaci et al. (2007) American Journal of Human Genetics 80: 1103-1114 “IRAK-M is involved in the pathogenesis of early-onset persistent asthma.”

An intriguing study of the maternal genotype contribution of HLA-G and the possible role of microRNAs is by Z. Tan et al. (2007) American Journal of Human Genetics 81: 829-834 “Allele-specific targeting of microRNAs to HLA-G and risk of asthma.” See also C. Ober (2005) Immunology and Allergy Clinics of North America 25: 669-679 “HLA-G: an asthma gene on chromosome 6p.”

The genomewide association study is M. F. Moffatt et al. (2007) Nature 448: 470-473 “Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.”

inflamed bowels and crohn’s disease

Genomewide association studies for Crohn’s disease have been published by M. Parkes et al. (2007) Nature Genetics 39: 830-832 “Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility,” J. D. Rioux et al. (2007) Nature Genetics 39: 596-604 “Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis,” J. V. Raelson et al. (2007) Proceedings of the National Academy of Science (USA) 104: 14747-14752 “Genome-wide association study for Crohn’s disease in the Quebec Founder Population identifies multiple validated disease loci,” J. Hampe et al. (2007) Nature Genetics 39: 207-211 “A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1,” and A. Franke et al. (2007) PLoS ONE 2: e691 “Systematic association mapping identifies NELL1 as a novel IBD disease gene.” For a review, see Xavier, R. J. and D. K. Podolsky (2007) Nature 448: 427-434 “Unraveling the pathogenesis of inflammatory bowel disease.”

The cold chain hypothesis was proposed by Hugot, J. P., C. Alberti, D. Berrebi, E. Bingen, and J. P. Cézard (2003) The Lancet 362: 2012-2015 “Crohn’s disease: the cold chain hypothesis.”

A meta-analysis of the protective effect of hookworm infection against asthma is Leonardi-Bee, J., D. Pritchard, and J. Britton (2006) American Journal of Respiratory and Critical Care Medicine 174: 514-523 “Asthma and current intestinal parasite infection: systematic review and meta-analysis.”

rheumatoid arthritis

A genomewide scan for rheumatoid arthritis is described by R. M. Plenge et al. (2007) New England Journal of Medicine 357: 1199-1209 “TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study.”

The role of the HLA in mediating arthritis via immunity to citrulline is reviewed in Klareskog, L., J. Rönnelid, K. Lundberg, L. Padyukov, and L. Alfredsson (2008) Annual Reviews of Immunology 26: 651-675 “Immunity to citrullinated proteins in Rheumatoid Arthritis.”

Nicotine’s connection to arthritis is reviewed in Harel-Meir, M., Y. Sherer, and Y. Shoenfeld (2007) Nature Clinical Practice. Rheumatology 3: 707-715 “Tobacco smoking and autoimmune rheumatic diseases.”

See Lie, B. A. and E. Thorsby (2005) Current Opinion in Immunology 17: 526-531 “Several genes in the extended human MHC contribute to predisposition to autoimmune diseases” for a brief discussion of the MHC in lupus. A more general review of autoimmunity is by A. M. Bowcock (2005) Annual Review of Genomics and Human Genetics 6: 93-122 “The genetics of psoriasis and autoimmunity.”

imbalance of the immune system

The impact of selection on the promoter of the IL4 gene is described by Rockman, M. V., M. W. Hahn, N. Soranzo, D. B. Goldstein, and G. A. Wray (2003) Current Biology 13: 2118-2123 “Positive selection on a human-specific transcription factor binding site regulating IL4 expression.”

Chapter 5

AIDS and the world

Global estimates of AIDS prevalence can be found online at the following informative site: www.avert.org/worldstats.htm or at www.aidsmap.com. The latest epidemiology of AIDS is presented by J. Cohen (2007) Science 318: 1360-1361 “New estimates scale back scope of HIV/AIDS epidemic.”

United States support policy and the ABCs of AIDS prevention are outlined by the USAID at www.usaid.gov/our_work/global_health/aids/News/abcfactsheet.html.

Al Gore’s The Assault on Reason was published by Penguin books in 2007.

The South African AIDS portal is www.doh.gov.za/aids/index.html.

Journalist Jonny Steinberg has just completed a book about the epidemic: Sizwe’s Test: A Young Man’s Journey through Africa’s AIDS Epidemic (Simon and Schuster, 2008).

For more on HAART, download the book at www.haart.com.

from HIV to AIDS

Severe Combined Immune Deficiency is a prime target for gene therapy in humans, as outlined for example in Cavazzana-Calvo, M., and A. Fischer (2007) Journal of Clinical Investigation 117: 1456-1465 “Gene therapy for severe combined immunodeficiency: are we there yet?”

AIDS-related cancer is reviewed in Arora, A., E. Chiao, and S. K. Tyring (2007) Cancer Treatment Research 133: 21-67 “AIDS malignancies.” For more on Gardasil and HPV, see www.gardasil.com/.

A strong statement of how we know HIV causes AIDS is O’Brien, S. J. and J. J. Goedert (1996) Current Opinion in Immunology 8: 613-618 “HIV causes AIDS: Koch’s postulates fulfilled.” This is in response to the contrary opinion expressed by P. H. Duesberg (1988) Science 241: 514-517 “HIV is not the cause of AIDS” and elsewhere. Koch’s postulates were initially published in German in 1891, but appear in T. M. Rivers (1937) Journal of Bacteriology 33: 1-12 “Viruses and Koch’s postulates.”

why HIV is so nasty

Drugs that inhibit the co-receptors that HIV uses to get into T-cells are reviewed in Biswas, P., G. Tambussi, and A. Lazzarin (2007) Expert Opinion in Pharmacotherapy 8: 923-933 “Access denied? The status of co-receptor inhibition to counter HIV entry,” while the co-receptors themselves are described in Arenzana-Seisdedos, F. and M. Parmentier (2006) Seminars in Immunology 18: 387-403 “Genetics of resistance to HIV infection: Role of co-receptors and co-receptor ligands.”

The evolution of resistance by HIV to even triple cocktails of drugs is described in N. Lohse et al. (2007) Antiviral Therapy 12: 909-917 “Genotypic drug resistance and long-term mortality in patients with triple-class antiretroviral drug failure.”

Various AIDS medications are described at www.aidsmeds.com/list.shtml.

how to resist a virus with your genes

The ability of HIV to evolve resistance by switching from one co-receptor to another is established in Moncunill, G., M. Armand-Ugón, E. Pauls, B. Clotet, and J. A. Esté (2008) AIDS 22: 23-31 “HIV-1 escape to CCR5 coreceptor antagonism through selection of CXCR4-using variants in vitro.”

The case for selection acting on CCR5 is challenged by P. C. Sabeti et al. (2005) PLoS Biology 3: e378. “The case for selection at CCR5-Delta32.” For a discussion of selection and inclusive fitness, see P. Schliekelman (2007) Evolution 61: 1277-1288 “Kin selection and evolution of infectious disease resistance.”

For more on Maraviroc, search for it at http://hivinsite.ucsf.edu.

The whole genome scan that turned up the associations between MHC and HIV traits is described in J. Fellay et al. (2007) Science 317: 944-947 “A whole-genome association study of major determinants for host control of HIV-1.”

HIV imbalance

The feline and simian immunodeficiency viruses are discussed in S. VandeWoude and C. Apetrei (2006) Clinical Microbiology Reviews 19: 728-762 “Going wild: lessons from naturally occurring T-lymphotropic lentiviruses.”

The argument that HIV was released as a result of the fight against polio was made in a book by Edward Hooper, The River: A Journey Back to the Source of HIV and AIDS (Penguin, 1999). The theory was refuted using evolutionary approaches by M. Worobey et al. (2004) Nature 428: 820 “Origin of AIDS: contaminated polio vaccine theory refuted.”

The latest data on the origin of the two viral types can be found in B. F. Keele et al. (2006) Science 313: 523-526 “Chimpanzee reservoirs of pandemic and nonpandemic HIV-1,” and Van Heuverswyn, F. and M. Peeters (2007) Current Infectious Disease Reports 9: 338-346 “The origins of HIV and implications for the global epidemic.”

Chapter 6

creative depression

A useful Web site for sufferers of affective disorders is www.pendulum.org.

Many sites list celebrities who have suffered, including www.geocities.com/coverbridge2k/artsci/famous_people_depression.html.

Much of the information on Winston Churchill, Harrison Ford, and others was gleaned from Wikipedia and linked sites.

The National Institute of Mental Health site is www.nimh.nih.gov/health/publications/depression/complete-publication.shtml, and the WHO’s is www.who.int/mental_health/management/depression/definition/en.

an epidemic of mood swings

For a brief discussion of whether depression is epidemic, see D. Summerfield (2006) Journal of the Royal Society of Medicine 99: 161-162 “Depression: epidemic or pseudo-epidemic?”

Andrew Solomon’s book is The Noonday Demon: An Atlas of Depression (Scribner, 2001).

bipolar and monopolar disorders

Wikipedia is as good a place as any to get some quick background: see http://en.wikipedia.org/wiki/Clinical_depression and http://en.wikipedia.org/wiki/Bipolar_disorder.

Major and bipolar depressive disorders are reviewed in Belmaker, R. H. and G. Agam (2008) New England Journal of Medicine 358: 55-68 “Major depressive disorder,” and Miklowitz, D. J. and S. L. Johnson (2006) Annual Review of Clinical Psychology 2: 199-235 “The psychopathology and treatment of bipolar disorder,” respectively.

The genetic component of depression is established by McGuffin, P., F. Rijsdijk, M. Andrew, P. Sham, R. Katz, and A. Cardno (2003) Archives of General Psychiatry 60: 497-502 “The heritability of bipolar affective disorder and the genetic relationship to unipolar disorder.”

A. Halfin (2007) American Journal of Managed Care 13: (4 Suppl) S92-S97 “Depression: the benefits of early and appropriate treatment” covers the medical and financial costs of failure to treat depression when it first appears.

the pharmacology of despair

The role of serotonin in depression is reviewed in Ressler, K. J. and C. B. Nemeroff (2000) Depression and Anxiety 12 (Suppl 1): 2-19 “Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders.” That of cortisol can be found in Thomson, F. and M. Craighead (2007) Neurochemical Research 33: 691-707) “Innovative Approaches for the Treatment of Depression: Targeting the HPA Axis.”

Antidepressants are considered in J. J. Mann (2005) New England Journal of Medicine 353: 1819-1834 “The medical management of depression,” and H. J. Gijsman (2004) American Journal of Psychiatry 161: 1537-1547 “Antidepressants for bipolar depression: a systematic review of randomized, controlled trials.”

misbehaving serotonin

The two studies describing interactions between genes and culture are Caspi, A. et al. (2002) Science 297: 851-854 “Role of genotype in the cycle of violence in maltreated children,” and Caspi, A. et al. (2003) Science 301: 386-389 “Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene.”

For more on genes and suicide, see Bondy, B., A. Buettner, and P. Zill (2006) Molecular Psychiatry 11: 336-351 “Genetics of suicide.”

The hypothesis that depression may be due to serotonin resistance is articulated by Smolin, B., E. Klein, Y. Levy, and D. Ben-Shachar (2007) International Journal of Neuropsychopharmacology 10: 839-850 “Major depression as a disorder of serotonin resistance: inference from diabetes mellitus type II.”

faint genetic signals

The genetics of depression is reviewed by D. F. Levinson (2006) Biological Psychiatry 60: 84-92 “The genetics of depression: a review,” and of bipolar disorder by T. Kato (2007) Psychiatry and Clinical Neurosciences 61: 3-19 “Molecular genetics of bipolar disorder and depression.”

A linkage scan for bipolar disorder is described in M. B. McQueen et al. (2005) American Journal of Human Genetics 77: 582-595 “Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q.” BD is one of the diseases that failed to show any associations in 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.”

The connection to variation in the serotonin transporter gene is reviewed in Uher, R. and P. McGuffin (2007) Molecular Psychiatry 13: 131-146 “The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis,” and in H. A. Mansour et al. (2005) Annals of Medicine 37: 590-602 “Serotonin gene polymorphisms and bipolar I disorder: focus on the serotonin transporter.”

schizophrenic spectrum and other mental disturbances

Iceland’s deCODE Genetics was reported by Michael Specter in The New Yorker (January 18, 1999, 40-51) “Decoding Iceland: the next big medical breakthroughs may result from one scientist’s battle to map the Viking gene pool.”

One of the deCODE studies of schizophrenia is Stefansson, H., V. Steinthorsdottir, T. E. Thorgeirsson, J. Gulcher, and K. Stefansson (2004) Annals of Medicine 36: 62-71 “Neuregulin 1 and schizophrenia.” The same group, and another consortium, discuss the contribution of CNV to schizophrenia in two papers in Nature released online on July 30, 2008, by H. Stefansson et al., “Large recurrent microdeletions associated with schizophrenia,” and by The International Schizophrenia Consortium, “Rare chromosomal deletions and duplications increase risk of schizophrenia.”

Cannon, T. D. and M. C. Keller (2006) Annual Review of Clinical Psychology 2: 267-290 “Endophenotypes in the genetic analyses of mental disorders” describes how it may be more fruitful to study attributes related to schizophrenia than the disease itself.

For an update on mental retardation see Debacker, K. and R. F. Kooy (2007) Human Molecular Genetics 2007 16 (Spec 2): R150-R158 “Fragile sites and human disease.” An intriguing link between common deletions and autism was reported by J. Sebat et al. (2007) Science 316: 445-449 “Strong association of de novo copy number mutations with autism.”

the genetic tightrope of the mind

The books referenced in this section are Tom Wolfe’s I am Charlotte Simmons: A Novel (Farrar, Straus and Giroux, 2004) and Martha Stout’s The Paranoia Switch: How Terror Rewires Our Brains and Reshapes Our Behavior—and How We Can Reclaim Our Courage (Farrar, Straus and Giroux, 2007).

a kindling theory for the modern world

The kindling theory is evaluated in Kendler, K. S., L. M. Thornton, and C. O. Gardner (2000) American Journal of Psychiatry 157: 1243-1251 “Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the ‘kindling’ hypothesis.” It traces back to Emil Kraepelin: Manic-Depressive Insanity and Paranoia (Foundations of Modern Psychiatry) available in English from Thoemmes Continuum (2002), and was articulated by Segal, Z. V., J. M. Williams, J. D. Teasdale, and M. Gemar (1996) Psychological Medicine 26: 371-380 “A cognitive science perspective on kindling and episode sensitization in recurrent affective disorder.”

For an account of flies on cocaine, see Andretic, R., S. Chaney, and J. Hirsh (1999) Science 285: 1066-1068 “Requirement of circadian genes for cocaine sensitization in Drosophila.” Kindling in epilepsy and bipolar disorder is discussed in Bertram, E. (2007) Epilepsia 48 (Suppl 2): 65-74 “The relevance of kindling for human epilepsy,” and in Amann, B. and H. Grunze (2005) Epilepsia 46 (Suppl 4): 26-30 “Neurochemical underpinnings in bipolar disorder and epilepsy.”

For overviews of the addiction, see Carlton K. Erickson The Science of Addiction: From Neurobiology to Treatment (W.W. Norton, 2007), or the companion book to an HBO television series on the topic, John Hoffman and Susan Froemke’s Addiction, Why Can’t They Just Stop? New Knowledge, New Treatments, New Hope.

Chapter 7

slow walk to dementia

For a satirical view opinion about Ronald Reagan and Alzheimer’s, see www.theonion.com/content/node/27646. An actual Congressional effort to aid research in the name of the former President is an Act introduced in 2004: http://olpa.od.nih.gov/legislation/108/pendinglegislation/reagonalzheimer.asp.

An analysis of healthcare costs is by Alemayehu, B. and K. E. Warner (2004) Health Services Research 39: 627-642 “The lifetime distribution of healthcare costs.”

Elan’s AN1792 vaccine is described in Schenk, D. B., P. Seubert, M. Grundman, and R. Black (2005) Neurodegenerative Disease 2: 255-260 “A beta immunotherapy: Lessons learned for potential treatment of Alzheimer’s disease.”

alzheimer’s on the march

See Goedert, M. and B. Ghetti (2007) Brain Pathology 17: 57-62 “Alois Alzheimer: his life and times” for more about the man who first described AD.

Global population statistics and age pyramids for every country can be downloaded at www.census.gov/ipc/www/idb/.

An opinion piece on the epidemiology of AD is C. Brayne (2007) Nature Reviews 8: 233-239 “The elephant in the room—healthy brains in later life, epidemiology and public health.”

tangles and plaques

For recent discussions of the roles of Aβ and Tao in AD see Cappai, R. and K. J. Barnham (2008) Neurochemical Research 33: 526-532 “Delineating the mechanism of Alzheimer’s disease Aβ peptide neurotoxicity,” and Ballatore, C., V. M. Lee, and J. Q. Trojanowski (2007) Nature Reviews 8: 663-672 “Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders.”

The correct identification of Alzheimer’s patients before death is important for the development of new drugs in clinical trials; new methods are described in Cummings, J. L., R. Doody, C. Clark (2007) Neurology 69: 1622-1634 “Disease-modifying therapies for Alzheimer disease: challenges to early intervention.” Efforts to track the course of dementia are described in R. Lambon et al. (2003) Brain 126: 2350-2362 “Homogeneity and heterogeneity in mild cognitive impairment and Alzheimer’s disease: a cross-sectional and longitudinal study of 55 cases.”

early onset FAD

The diversity of Presenilin mutations is reviewed in M. Menéndez (2004) Journal of Alzheimer’s Disease 6: 475-482 “Pathological and clinical heterogeneity of presenilin 1 gene mutations.” The spectrum of APP mutations is described in A. Kowalska (2003) Folia Neuropathology 41: 35-40 “Amyloid precursor protein gene mutations responsible for early-onset autosomal dominant Alzheimer’s disease.” An old review of the genetics of FAD is P. H. St. George-Hyslop (2000) Biological Psychiatry 47: 183-199 “Molecular genetics of Alzheimer’s disease.”

For the latest on AD and Down syndrome, see Visootsak, J. and S. Sherman (2007) Current Psychiatry Reports 9: 135-140 “Neuropsychiatric and behavioral aspects of trisomy 21.”

late onset LOAD

The original report of an association between ApoE and AD was W. J. Strittmatter et al. (1993) Proceedings of the National Academy of Science USA 90: 1977-1981 “Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.” Singh, P. P., M. Singh, and S. S. Mastana (2006) Annals of Human Biology 33: 279-308 “APOE distribution in world populations with new data from India and the UK” describe how LOAD genetic susceptibility due to ApoE is distributed around the globe.

The disconcordance between African and African American rates of AD is reported in Hendrie, H. C., J. Murrell, S. Gao, F. W. Unverzagt, A. Ogunniyi, and K. S. Hall (2006) Alzheimer Disease and Associated Disorders 20(Suppl 2): S42-S46 “International studies in dementia with particular emphasis on populations of African origin.”

A genomewide association study for LOAD has just been published: H. Li et al. (2008) Archives of Neurology 65: 45-53 “Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease.” It has not yet led to any more really convincing leads.

just growing old

A list of animal life spans is at www.wonderquest.com/LifeSpan-MaxMin.htm.

A review of aging in model organisms is A. Antebi (2007) PLoS Genetics 3: e129 “Genetics of aging in Caenorhabditis elegans.” The role of FOXO in mediating stress is reviewed in van der Horst, A. and B. M. Burgering (2007) Nature Reviews Molecular Cell Biology 8: 440-450 “Stressing the role of FoxO proteins in lifespan and disease.”

A good online introduction to evolutionary theories of aging is by L. A. Gavrilov and N. S. Gavrilova (2002) The Scientific World Journal 2: 339-356 “Evolutionary theories of aging and longevity,” also at http://longevity-science.org/Evolution.htm.

The mutation accumulation theory is generally attributed to Nobel Laureate Peter Medawar, who introduced it in An Unsolved Problem of Biology (H. K. Lewis, London, 1952). The antagonistic pleiotropy theory was formalized by Williams, G. C. (1957) Evolution 11: 398-411 “Pleiotropy, natural selection and the evolution of senescence.”

http://en.wikipedia.org/wiki/Life_expectancy is an interesting site, though it is not clear where all the data and estimates come from.

Chapter 8

height and weight

The first phase genome scan for height was published by M. Weedon et al. (2007) Nature Genetics 39: 1245-1250 “A common variant of HMGA2 is associated with adult and childhood height in the general population.” A follow-up has been submitted, while a second group presented S. Sanna et al. (2008) Nature Genetics 40: 198-203 “Common variants in the GDF5-UQCC region are associated with variation in human height.”

Canine size is described in N. B. Sutter et al. (2007) Science 316: 112-115 “A single IGF1 allele is a major determinant of small size in dogs.” Spady, T. C. and E. A. Ostrander (2008) American Journal of Human Genetics 82: 10-18 “Canine behavioral genetics: pointing out the phenotypes and herding up the genes” review the genetics of dog behavior.

Several references to FTO and obesity were given in the notes to Chapter 3, “Not so Thrifty Diabetes Genes.” but interestingly, one that just came out suggests a difference in Chinese populations: H. Li et al. (2008) Diabetes 57: 264-268 “Variants in the fat mass- and obesity-associated (FTO) gene are not associated with obesity in a Chinese Han population.”

pigmentation

For a thoughtful essay on human pigmentation, see E. J. Parra (2007) American Journal of Physical Anthropology 45 (Suppl): 85-105 “Human pigmentation variation: evolution, genetic basis, and implications for public health.” Selection on pigmentation genes is described in Lao, O., J. de Gruijter, K. van Duijn, A. Navarro, and M. Kayser (2007) Annals of Human Genetics 71(Pt 3): 354-369 “Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms.” See also a meeting review of the American Association of Physical Anthroplogists by Ann Gibbons (2007) Science 316: 364 “European skin turned pale only recently, gene suggests” Science 316: 364.

The genomewide association for eye and hair color is P. Sulem et al. (2007) Nature Genetics 39: 1443-1452 “Genetic determinants of hair, eye and skin pigmentation in Europeans.” One for skin color in Asians is R. P. Stokowski et al. (2007) American Journal of Human Genetics 81: 1119-1132 “A genomewide association study of skin pigmentation in a South Asian population.”

How a gene identified in fish was shown to impact human skin color is described in Lamason, R.L. et al. (2005) Science 310: 1782-1786 “SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans.” The reference to Neanderthal skin color is C. Lalueza-Fox et al. (2007) Science 318: 1453-1455 “A melanocortin 1 receptor allele suggests varying pigmentation among Neanderthals.”

Consumers are warned about the relationship between sunlight, vitamin D, and osteoporosis at www.osteoporosis.org.au/files/internal/CalciumVitD_consumer.pdf.

the God gene

The Web sites for personal genomics are https://www.23andme.com, www.decodeme.com, and www.personalgenomes.org.

J. Craig Venter’s book is A Life Decoded: My Genome: My Life (Viking Adult, 2007).

The paper describing his own genome sequence is S. Levy et al. (2007) PLoS Biology 5: e254 “The diploid genome sequence of an individual human.”

James Watson’s sequencing project can be accessed at www.454.com/watson/. For the New York Times viewpoint, see www.nytimes.com/2007/05/31/science/31cndgene.html

Dean Hamer’s two books are The God Gene: How Faith Is Hardwired into Our Genes (Anchor, 2005) and The Science of Desire: The Gay Gene and the Biology of Behavior (Touchstone, 1995).

The heritability of spirituality measure is explored in Kirk, K. M., L. J. Eaves, and N. G. Martin (1999) Twin Research 2: 81-87 “Self-transcendence as a measure of spirituality in a sample of older Australian twins.” To my knowledge, the association with VMAT2 has never been published in a peer-reviewed journal. Hamer’s group reports their latest on the genetics of sexual orientation in B. S. Mustanski et al. (2005) Human Genetics 116: 272-278 “A genomewide scan of male sexual orientation.”

a few words about IQ

The paper that showed selection on Microcephalin is P. D. Evans et al. (2005) Science 309: 1717-1720 “Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans,” while the linkage to IQ is refuted by N. Bekel-Bobrov et al. (2007) Human Molecular Genetics 16: 600-608 “The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence.”

A controversial book that touches on genetics, race, and IQ is Herrnstein, R. J. and C. Murray The Bell Curve: Intelligence and Class Structure in American Life (Free Press, 1994). For a series of articles on this matter, see American Psychologist Volume 60, Issue 1 (Jan 2005), or for an example of a blog, see http://shrinkwrapped.blogs.com/blog/2007/11/iq-genetics-and.html.

The link between breast-feeding, FAS2, and IQ is reported in A. Caspi et al. (2007) Proceedings of the National Academy of Science USA 104: 18860-18865 “Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism.”

on being human

Several studies detect selection on parts of the human genome, as reviewed in Nielsen, R., I. Hellmann, M. Hubisz, C. Bustamante, and A. G. Clark (2007) Nature Reviews Genetics 8: 857-868 “Recent and ongoing selection in the human genome” and Sabetti, P. C. et al. (2006) Science 312: 1614-1620 “Positive natural selection in the human lineage.” See also Clark, A. G. et al. (2003) Science 302: 1960-1963 “Inferring nonneutral evolution from human-chimp-mouse orthologous gene trios,” C. D. Bustamante et al. Nature 437: 1153-1157 “Natural selection on protein coding genes in the human genome,” and Haygood, R., O. Fedrigo, B. Hanson, K. Yokoyama, and G. A. Wray (2007) Nature Genetics 39:1140-1144 “Promoter regions of many neural- and nutrition-related genes have experienced positive selection during human evolution.”

The first of several studies of gene expression in human and chimpanzee brains was W. Enard et al. (2002) Science 296: 340-343 “Intra- and interspecific variation in primate gene expression patterns.” These are reviewed in Khaitovich, P., W. Enard, M. Lachmann, and S. Pääbo (2006) Nature Reviews Genetics 7: 693-702 “Evolution of primate gene expression.”

the adolescent genome revisited

A scientific synopsis of the argument in this book is in press: Gibson, G. (February 2009) Nature Reviews Genetics “Decanalization and the Origin of Complex Disease.”