Evolution in Health and Disease 2nd Edition Stephen C. Stearns

Evolution in Health and Disease 2nd Edition Stephen C. Stearns
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5. Evolution in Health
and Disease
Second Edition
EDITED BY
Stephen C. Stearns and Jacob C. Koella
1

6. 3
Great Clarendon Street, Oxford OX2 6DP
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This edition 2008
1st edition 1999
All rights reserved. No part of this publication may be reproduced,
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Oxford University Press, at the address above
You must not circulate this book in any other binding or cover
and you must impose the same condition on any acquirer
British Library Cataloguing in Publication Data
Data available
Library of Congress Cataloging in Publication Data
Evolution in health and disease / edited by Stephen C. Stearns and
Jacob C. Koella.—2nd ed.
p.; cm.
Includes bibliographical references and index.
ISBN 978–0–19–920745–9 (hardback: alk. paper)
ISBN 978–0–19–920746–6 (pbk.: alk. paper)
1. Medical genetics. 2. Human evolution. 3. Disease—Causes and theories
of causation. I. Stearns, S. C. (Stephen C.), 1946 II. Koella, Jacob C.
[DNLM: 1. Evolution, Molecular. 2. Disease. 3. Health. QU 475 E95 2008]
RB155.E96 2008
616’.042—dc22 2007033610
Typeset by Newgen Imaging Systems (P) Ltd., Chennai, India
Printed in Great Britain
on acid-free paper by
Antony Rowe, Chippenham, Wiltshire
ISBN 978–0–19–920745–9 (Hbk.) 978–0–19–920746–6 (Pbk.)
10 9 8 7 6 5 4 3 2 1

7. v
As in the first edition the book comes in five
parts:
Introduction1.
The history and variation of human genes2.
Natural selection and evolutionary conflicts3.
Pathogens: resistance, virulence, variation, and 4.
emergence
Non-infectious and degenerative disease, includ-5.
ing diseases associated with aging, cancer, nutri-
tion, lifestyle, and metabolism
The chapter ending each part was commissioned
as a survey of important issues not covered in
chapters that precede it. By using this technique
we hope to have achieved fairly complete coverage
of at least the most important issues.
Bringing evolutionary thought into medical
research and practice helps to explain how many
medical issues arose in the first place. It can also
help to save many lives and to reduce much suf-
fering. For those reasons we hope that the ideas
presented here find a broad and sympathetic audi-
ence open to fresh approaches that do not sacrifice
scientific rigor.
Stephen C. Stearns, New Haven, CT USA
Jacob C. Koella, Ascot, UK
May 2007
This book surveys the ways in which evolutionary
thought illuminates medical science. It is intended
for a broad audience that includes medical stu-
dents, graduate students in the biological sciences,
medical and biological educators, medical and
biological researchers, medical practitioners, and
the interested public. Readers with backgrounds
in biology or medicine should feel at home; those
without such backgrounds may at times feel chal-
lenged. We have asked the authors to reduce jargon
and introduce technical terms with clear defini-
tions; often we have succeeded, but not always.
Evolutionary thought illuminates medical
issues from a fresh angle; it does not replace other
approaches. It complements; it does not compete.
The content of this edition is almost entirely new.
Only in Chapters 1, 6, and 12 will you find pas-
sages that appeared in the first edition, and even
those three chapters are almost completely rewrit-
ten. The contributors are also mostly new. Only 11
of the 61 scientists who contributed to the first edi-
tion are represented here. Close to 60% of the cited
references were published after the first edition.
This does not, however, mean that the topics cov-
ered have changed radically. Many of the impor-
tant issues discussed in the first edition remain,
here viewed with fresh perspective.
Preface to the Second Edition

8. vii
List of Contributors xix
Part I Introduction 1
1 Introducing evolutionary thinking for medicine 3
Stephen C. Stearns, Randolph M. Nesse, and David Haig
Introduction 3
Mismatched to modernity 3
Adaptation takes time: lactose tolerance 3
Birth control and cancer risk 4
Early-life events with late-life consequences 4
Parasite load and autoimmune disease 4
Infection 5
Resistance 5
Virulence 5
Emerging diseases 5
Reproduction 5
Evolved confl icts between mother and offspring 5
Evolved confl icts between mother and father 6
Spontaneous abortions and complementary immune genes 6
Populations have histories 6
Evolutionary technologies 7
Phylogenetic reconstructions 7
Attenuated live vaccines 7
The nature of evolutionary explanations 7
Microevolution, macroevolution, and development 7
Mechanistic and evolutionary explanations 8
Natural selection 8
How selection works 8
Fitness is relative reproductive success 9
Natural selection has several components: individual, sexual, and kin selection 9
Traits do not evolve for the good of the species 10
Random events and neutral variation: how neutral evolution works 10
Trade-offs 11
Macroevolution 12
Relationships and fossils reveal history 12
Constraints: eyes and tubes 12
Contents

9. viii CONTENTS
Conclusion 13
Health, fi tness, and the pursuit of happiness 13
Human diversity 13
Implications for medical practice, research, and education 14
What doctors need to know about evolution and why 14
Part II The history and variation of human genes 17
2 Global spatial patterns of infectious diseases and human evolution 19
Jean-François Guégan, Franck Prugnolle, and Frédéric Thomas
Introduction 19
Geographical aspects of human diseases 19
Latitude and the species diversity of human pathogens 20
Longitude and the species diversity of human pathogens 21
Latitude and the nested pattern of human pathogens 21
Latitude and the geographical range of human pathogens 21
Geographical area and the species diversity of human pathogens 21
Historical patterns of the distribution of disease 22
Pathogen distribution and human genetic evolution 23
Pathogen distribution and human genetic evolution: the case of sickle cell disease 23
Variations in pathogen diversity and human genetic evolution: the HLA genes 25
Infectious diseases and human life-history traits 26
Human fertility and the species diversity of human pathogens 27
Human birthweight and the species diversity of human pathogens 27
Human behavior and culture, and the species diversity of human pathogens 27
Summary 28
Acknowledgments 29
3 Medically relevant variation in the human genome 31
Diddahally R. Govindaraju and Lynn B. Jorde
Introduction 31
Molecular markers 32
Microsatellites 32
Single nucleotide polymorphisms (SNPs) 34
Haplotypes 34
Determination of haplotypes 35
Linkage disequilibrium, recombination and haplotype blocks 35
Linkage disequilibrium 35
Recombination and recombination hotspots 36
The structured genome—haplotype blocks 37
TagSNPs 37
The HapMap project 37
Background 37
Findings 38
Structural variation 40
Inference of evolutionary processes 40
Natural selection 40

10. CONTENTS ix
Genetic drift 41
Admixture 41
Causal SNPs and the magnitude of their effects 41
Summary 42
Acknowledgments 42
4 Health consequences of ecogenetic variation 43
Michael Bamshad and Arno G. Motulsky
Introduction 43
Genetic basis of variation in drug metabolism and response 44
Genetic basis of monogenic drug reactions 44
Genetic basis of complex pharmacogenetic traits 45
Genetic basis of chemosensory perception and food preferences 45
Bitter taste sensitivity 46
Sweet and umami taste sensitivity 47
Lactase persistence 48
The structure of human populations 49
Correspondence between race and population structure 49
Race as a proxy for genetic ancestry 50
Conclusions 50
Acknowledgments 50
5 Human genetic variation of medical signifi cance 51
Kenneth K. Kidd and Judith R. Kidd
Introduction 51
The pattern of human genetic variation 51
The amount and nature of human genetic variation 52
The human expansion out of Africa 52
The impact of genetic variants—or lack of it 53
The role of selection 55
The impact of population bottlenecks on genetic patterns 55
Disease can cause bottlenecks 56
Migration out of Africa 58
Complex disease and evolution 58
Genetic infl uences on alcoholism 59
Variation in ethanol metabolism and alcoholism 59
Variation in taste perception and alcohol dependence 61
Summary 62
Acknowledgments 62
Part III Natural selection and evolutionary confl icts 63
6 Intimate relations: Evolutionary confl icts of pregnancy and childhood 65
David Haig
Introduction 65
Parental justice 65

11. x CONTENTS
Internal confl icts 66
Credibility problems 67
Pregnancy termination 67
Menstruation 67
Selective abortion 68
Gestation length 69
Infanticide 70
Maternal circulation 71
Preeclampsia 72
Growth 73
Fat 73
Brains and bodies 74
Intergenerational confl icts 75
Summary 76
Acknowledgments 76
7 How hormones mediate trade-offs in human health and disease 77
Richard G. Bribiescas and Peter T. Ellison
Introduction: Hormones, life history, evolution, and health 77
Hormones and trade-offs 77
Hormones, population variation, and phenotypic plasticity 79
Hormones and trade-offs in males 80
Androgens and fetal development 80
Childhood quiescence 80
Adolescent development, morbidity, and mortality 81
What are the benefi ts of testosterone in adult males? 81
Testosterone and somatic investment 82
Testosterone and immune function 82
Fatherhood and paternal investment 84
The aging male 84
Hormones and female reproductive trade-offs 85
Constraints on female reproductive success 85
Birthweight and infant survival 86
Parturition 86
Lactation and birth spacing 87
The resumption of ovarian cycling 88
Waiting time to conception 88
The timing of conception and human reproductive seasonality 89
Age and female fecundity 90
Contemporary medical implications 91
Metabolic syndrome 91
Cancer 91
Hormonal supplementation 91
Hormonal caveats 92
Summary 92

12. CONTENTS xi
8 Functional signifi cance of MHC variation in mate choice, reproductive outcome,
and disease risk 95
Dagan A. Loisel, Susan C. Alberts, and Carole Ober
Introduction 95
Genes of the major histocompatibility complex 95
Form and function of MHC molecules 96
Evolution of MHC genes 96
Pathogen-mediated selection on MHC genes 97
Sexual selection on MHC genes 98
MHC-mediated mate choice in non-human vertebrates 99
Role of the MHC in human mate choice 100
Evolutionary implications of MHC-mediated mate choice 101
MHC-linked olfactory cues 102
Infl uence of MHC peptide-binding region on odor 102
MHC peptide ligands as olfactory cues 102
Detection of MHC-mediated odors 103
Peptide binding as an integrating principle in MHC evolution 103
MHC and reproductive outcome 103
MHC sharing and reproduction in outbred human populations 104
MHC sharing and reproductive outcome in an unselected population 104
MHC sharing, reproduction, and diversity 105
HLA-G in reproduction, immune regulation, and disease 105
HLA-G in reproductive, autoimmune, and infl ammatory pathologies 106
Evolution of HLA-G 106
The cost of protection: non-adaptive consequences of MHC diversity 106
Conclusions 107
Summary 108
Acknowledgments 108
9 Perspectives on human health and disease from evolutionary and behavioral ecology 109
Beverly I. Strassmann and Ruth Mace
Introduction 109
Phenotypic plasticity 109
Kin selection theory 112
Step-parents 113
Adoption 113
Life-history theory 114
Trade-offs 114
Offspring number versus quality 115
Parental effort versus longevity 115
Menopause and the post-reproductive life span 116
Parental investment theory 117
Infanticide 117
Sex ratios 117

13. xii CONTENTS
Sexual selection theory 118
Higher mortality of males than females 119
Sexual jealousy and genital cutting 120
Summary 120
Acknowledgments 121
Part IV Pathogens: resistance, virulence, variation, and emergence 123
10 The ecology and evolution of antibiotic-resistant bacteria 125
Carl T. Bergstrom and Michael Feldgarden
Introduction 125
History of clinical antibiotic resistance 126
Genetic mechanisms 127
Point mutations 127
Homologous recombination 128
Heterologous recombination 128
Natural ecology 129
Soil ecology 129
Agricultural use 129
Hospital transmission 130
Population genetics 131
Linked genes 131
Compensatory mutation 132
Applying evolution/approaches for the future 133
Predicting resistance evolution 133
Narrow spectrum antibiotics 133
Bacteriocins 133
Quorum sensing disruptors 134
Ecological modeling 135
Antibiotic cycling 135
Conclusions 136
Summary 137
Acknowledgments 137
11 Pathogen evolution in a vaccinated world 139
Andrew F. Read and Margaret J. Mackinnon
Introduction 139
Vaccines have consequences for pathogen evolution 139
Hepatitis B 139
Pertussis 141
Pneumococcal disease 141
Diphtheria 141
Malaria 141
Avian infl uenza 142
Marek’s disease 142
Infectious bursal disease (IBD) 142
Thus, vaccines are not evolution-proof 143

14. CONTENTS xiii
Why has vaccination worked despite evolution? 143
Not all infectious diseases are alike 143
Is it too soon to be confi dent? 144
Pathogen adaptation in vaccinated populations 144
Epitope evolution 145
Virulence adaptation 145
Other possible vaccine-adapted phenotypes 147
The health consequences of vaccine-adapted pathogens 148
Predicting evolution 149
Watching evolution 150
Coda 151
Summary 152
Acknowledgments 152
12 The evolution and expression of virulence 153
Dieter Ebert and James J. Bull
Introduction 153
Outline of this chapter 154
Defi ning virulence 154
Artifi cial virulence evolution and live vaccines 155
The three phases of the evolution of infectious diseases 156
Phase 1: Accidental infections 156
Phase 2: Evolution of virulence soon after successful invasion 157
Phase 3: The evolution of optimal virulence 159
Mechanisms of virulence remain to be considered 162
Variation of hosts impacts the expression and evolution of virulence 163
Virulence has a direct benefi t for the parasite 163
Can we manage the evolution of virulence? 164
Summary 166
Acknowledgments 167
13 Evolutionary origins of diversity in human viruses 169
Paul M. Sharp, Elizabeth Bailes, and Louise V. Wain
Introduction 169
Origins of human viruses 169
Origins of diversity within human viruses 170
Herpesviruses 171
AIDS viruses 174
Infl uenza A viruses 177
Dengue viruses 180
Comparisons among viruses 181
Summary 183
14 The population structure of pathogenic bacteria 185
Daniel Dykhuizen and Awdhesh Kalia
Introduction 185

15. xiv CONTENTS
Population structure 185
Clonality versus panmixia 185
Population structure and disease type 186
Population structure and clonality 186
Population structure and genetic variation 186
Effective population size 187
Effective population size determined by infection dynamics 188
Helicobacter pylori 188
Geographic variation 188
Infection dynamics 188
Infection inoculum 189
Mutation rate 189
Recombination in H. pylori 190
Selective sweeps 190
Role of diversifying selection in maintaining nucleotide diversity 190
Expectation of high genetic variability in H. pylori 191
Streptococcus pyogenes 191
GAS epidemiology 192
Clonal expansion 192
Recombination 192
Why is there clonal expansion? 193
Interspecies horizontal gene transfer 193
Expectation of moderate genetic variability in GAS 195
Salmonella typhi 195
The last common ancestor of S. typhi 196
The origin of S. typhi 196
Carrier numbers determine N
e
196
Further considerations 196
Mutation 197
Inoculation size 197
Recombination 197
Selective sweeps 197
Diversifying selection 197
Species introgression and high diversity 197
Summary 198
Acknowledgments 198
15 Whole-genome analysis of pathogen evolution 199
Julian Parkhill
Introduction 199
Long-term evolution of pathogens 199
Horizontal exchange of genes 199
Mechanisms of gene exchange 200
Core and accessory genomes 201
Pathogenicity islands 202
Plasmids 202
Bacteriophage 203

16. CONTENTS xv
Homologous recombination 203
Short-term evolution of pathogens 204
Yersinia pestis 204
Bordetella pertussis 206
Stochastic variation/hypermutability 207
Phase variation 207
Simple sequence repeats 208
DNA inversion 209
Genomic discovery of phase variable genes 209
Identifi cation of rapid variation by genomic sampling 210
Campylobacter jejuni—simple sequence repeats 210
Bacteroides fragilis—DNA inversion 211
Phase-variable restriction modifi cation systems 212
Summary 213
Acknowledgments 213
16 Emergence of new infectious diseases 215
Mark Woolhouse and Rustom Antia
Introduction 215
Which diseases emerge? 217
Diversity of pathogens 217
Characteristics of emerging pathogens 218
Disease emergence as a biological process 220
The pathogen pyramid 220
Role of ecology 222
Role of evolution 222
Examples of emerging infectious diseases 224
HIV/AIDS 224
Infl uenza 224
SARS 225
Ebola 225
Monkeypox 225
Practical implications of disease emergence 226
Predicting pathogen emergence 226
Public health response 227
Summary 227
17 Evolution of parasites 229
Jacob C. Koella and Paul Turner
Virulence and transmission in public health and evolution 229
The evolution of virulence in control programs 229
General considerations 229
Vaccines 230
Drug treatment 230
The problem of virulence 231
The problem of the trade-off 232

17. xvi CONTENTS
Beyond the trade-off model 234
Coevolution 234
Emerging diseases 234
A molecular and an experimental approach to the evolution of parasites 235
Summary 236
Acknowledgments 237
Part V Noninfectious and degenerative disease 239
18 Evolutionary biology as a foundation for studying aging and aging-related disease 241
Martin Ackermann and Scott D. Pletcher
Introduction 241
Defi ning and measuring aging 242
The canonical evolutionary models of aging 242
Evolutionary genetics of aging 243
Predictions of the evolutionary models 244
Molecular mechanisms of aging 245
Dietary restriction 245
Conserved pathways that infl uence the rate of aging 246
Merging molecular mechanisms with evolutionary theory 248
Adaptive responses to environmental signals 248
Going beyond traditional evolutionary models of aging 249
New directions 250
Concluding remarks 251
Summary 252
Acknowledgments 252
19 Evolution, developmental plasticity, and metabolic disease 253
Christopher W. Kuzawa, Peter D. Gluckman, Mark A. Hanson, and Alan S. Beedle
Introduction: diseases of excess or defi ciency? 253
The developmental origins of health and disease (DOHaD) paradigm 254
Origin 254
Evidence from epidemiology 255
Experimental evidence 256
Epigenetic mechanisms 257
An integrated response to developmental cues 258
Reduced body size and lean mass 258
Muscle becomes insulin-resistant 258
Fat deposition is enhanced in highly labile visceral depots 259
Stress responses and reactivity are accentuated 259
A developmental and evolutionary synthesis 259
Anticipating the future from maternal cues: predictive developmental plasticity 260
Medical and public health implications 262
Policy implications 263
Summary 264
Acknowledgments 264

18. CONTENTS xvii
20 Lifestyle, diet, and disease: comparative perspectives on the determinants of
chronic health risks 265
William R. Leonard
Introduction 265
Evolutionary energetics 265
Infl uence of lifestyle change on daily energy expenditure 267
How changes in lifestyle infl uence energy intake and diet composition 269
Energy intake 269
Macronutrient composition 270
Health consequences of energy and nutritional imbalances 271
Obesity 271
Chronic metabolic disorders 274
Summary 275
Acknowledgments 276
21 Cancer: evolutionary origins of vulnerability 277
Mel Greaves
Introduction: a risky species? 277
Evolutionary basis of vulnerability to cancer 278
The proximate mechanisms 278
Some evolutionary ground rules 279
Lack of perfection in evolutionary engineering 279
Evolutionary adaptation has ‘no eyes to the future’ 282
Skin cancer 283
Breast and prostate cancer 283
Childhood leukemia 283
The inevitability of natural selection 284
The only evolutionary currency is reproductive success 285
Implications 286
Summary 287
Acknowledgments 287
22 Cancer as a microevolutionary process 289
Natalia L. Komarova and Dominik Wodarz
The concept of somatic evolution as a way of thinking about cancer 289
Cancer: a disease of the DNA 289
Cancer initiation and chromosomal instability 291
Multistage carcinogenesis of colon cancer 291
Genetic instability 291
Quantitative model of chromosome loss and genetic instability 292
Optimal (for cancer) rate of chromosome loss 293
What is the reason for CIN? 294
Chronic myeloid leukemia (CML) and resistance against small molecule inhibitors 295
Some facts about CML treatment 295
The computational strategy 296

19. xviii CONTENTS
Emergence of resistant cells 296
Cancer turnover and the emergence of resistance 297
Combination therapy: strategies to prevent resistance 298
Conclusions 299
23 The evolutionary context of human aging and degenerative disease 301
Steven N. Austad and Caleb E. Finch
Introduction 301
Aging as a by-product of selection for reproductive performance 302
Genes and aging 304
Apolipoprotein E 305
Growth hormone/insulin/insulin-like growth factor 1 307
Summary 311
Acknowledgments 311
References 313
Index 365

20. xix
Martin Ackermann, ETH Zürich, Institute of
Integrative Biology, Universitätsstrasse 16,
ETH Zentrum, CHN J12.1, CH-8092 Zürich,
Switzerland.
[email protected]
Susan C. Alberts, Department of Biology, Duke
University, Box 90338, Durham, NC 27708 USA.
[email protected]
Rustom Antia, Emory University, Department
of Biology, 1510 Clifton Road, Atlanta,
GA 30322 USA.
[email protected]
Steven N. Austad, University of Texas Health
Science Center, STCBM Building, Room 3.100,
Department of Cellular & Structural Biology,
Barshop Center for Longevity and Aging
Studies, 15355 Lambda Drive, San Antonio,
TX 78245 USA.
[email protected]
Elizabeth Bailes, Institute of Genetics, University
of Nottingham, Queens Medical Centre,
Nottingham NG7 2UK, UK.
Michael Bamshad, Department of Pediatrics,
University of Washington School of Medicine
Box 356320, 1959 NE Pacifi c Street, HSB RR349,
Seattle, WA 98195 USA.
[email protected]
Alan S. Beedle, The Liggins Institute, The Faculty
of Medical and Health Sciences, The University
of Auckland, Private Bag 92019, Auckland,
New Zealand.
[email protected]
Carl T. Bergstrom, Department of Biology,
University of Washington, Box 351800, Seattle,
WA 98195–1800 USA.
[email protected]
Richard G. Bribiescas, Department of Anthropol-
ogy, Yale University, P.O. Box 208277,
New Haven, CT 06520–8277 USA.
[email protected]
James J. Bull, The University of Texas at Austin,
School of Biological Sciences, ESB 2, 1 University
Station, A6500, Austin, TX 78712 USA.
[email protected]
Daniel E. Dykhuizen, Department of Biology,
University of Louisville, Louisville,
KY 40292 USA.
[email protected]
Dieter Ebert, Zoology Institute, University of
Basel. Vesalgasse 1, CH-4051 Basel, Switzerland.
[email protected]
Peter T. Ellison, Department of Anthropol-
ogy, Peabody Museum, Harvard University,
Cambridge, MA 02138 USA.
[email protected]
Michael Feldgarden, Alliance for the Prudent Use
of Antibiotics, 75 Kneeland St., 2nd fl oor Boston,
MA 02111 USA.
[email protected]
Caleb E. Finch, Leonard Davis School of Geron-
tology, University of Southern California 1975
Zonal Avenue KAM-110, Los Angeles, California
90089–9023 USA.
cefi [email protected]
Peter D. Gluckman, The Liggins Institute,
The Faculty of Medical and Health Sciences,
The University of Auckland, Private Bag 92019,
Auckland, New Zealand.
[email protected]
Diddahally R. Govindaraju, Department of
Neurology, Boston University School of
Medicine, 715 Albany Street E-306,
Boston, MA 02118–2526, USA.
[email protected].
Mel Greaves, Section of Haemato-Onclogy,
Institute of Cancer Research, Sutton,
Contributors

21. xx CONTRIBUTORS
SM2 5NG UK.
[email protected]
Jean-Francois Guégan, Génétique & Evolution
des Maladies Infectieuses, UMR-2724
CNRS-IRD, Centre IRD de Montpellier, 911
avenue Agropolis, BP 64501, F-34394
Montpellier cedex 5 France.
[email protected]
David Haig, Department of Organismic and
Evolutionary Biology, Harvard University,
26 Oxford Street, Cambridge, MA 02138 USA.
[email protected]
Mark A. Hanson, Center for Developmental
Origins of Health and Disease, Institute of
Developmental Sciences, University of
Southampton, Mailpoint 887 Southampton
General Hospital, S016 6YD UK.
[email protected]
Lynn B. Jorde, Department of Human Genetics,
Eccles Institute of Human Genetics, University
of Utah, 15 North 2030 East, Room 2100, Salt
Lake City, UT 84112–5330 USA.
[email protected]
Awdhesh Kalia, Department of Biology, University
of Louisville, Louisville, KY 40292 USA.
[email protected]
Judith R. Kidd, Department of Genetics, Yale
University School of Medicine,
333 Cedar Street, P.O. Box 208005,
New Haven, CT 06520–8005 USA.
[email protected]
Kenneth K. Kidd, Department of Genetics,
Yale University School of Medicine, 333 Cedar
Street, P.O. Box 208005, New Haven,
CT 06520–8005 USA.
[email protected]
Jacob C. Koella, Department of Biological
Sciences, Imperial College London, Silwood
Park Campus, Ascot, Berkshire SL5 7PY UK.
[email protected]
Natalia L. Komarova, Department of
Mathematics, University of California-Irvine,
Irvine, CA 92697 USA.
[email protected]
Christopher W. Kuzawa, Department of Anthro-
pology, Northwestern University, 1810 Hinman
Avenue, Evanston, IL 60208 USA.
[email protected]
William R. Leonard, Department of Anthropology,
Northwestern University, 1810 Hinman Avenue,
Evanston, IL 60208 USA.
[email protected]
Dagan A. Loisel, Department of Biology, Duke
University, Box 90338, Durham, NC 27708 USA.
[email protected]
Ruth Mace, Department of Anthropology, Univer-
sity College London, London, WC1E 6BT UK.
[email protected]
Margaret J. Mackinnon, Department of Pathology,
Cambridge University, Tennis Court Road,
Cambridge CB2 1QP UK, and Wellcome Trust/
Kenya Medical Research Institute Collaborative
Programme, Kilifi , Kenya.
mmackinnon@kilifi .kemri-wellcome.org.
Arno G. Motulsky, University of Washington,
Departments of Medicine (Medical Genetics)
and Genome Sciences, Box 355065, 1705 NE
Pacifi c St , Seattle WA 98195–5065 USA.
[email protected]
Randolph M. Nesse, The University of Michigan,
426 Thompson St., Room 5261, Ann Arbor,
MI 48104 USA.
[email protected]
Carole Ober, Department of Human Genetics, 920
E. 58th St., CLSC 507, Chicago, IL 60637 USA.
[email protected]
Julian Parkhill, The Sanger Institute, Wellcome
Trust Genome Campus, Hinxton, Cambridge,
CB10 1SA UK.
[email protected]
Scott D. Pletcher, Huffi ngton Center on Aging and
Molecular and Human Genetics, Baylor College
of Medicine, One Baylor Plaza, N803, Houston
TX 77030 USA.
[email protected]
Franck Prugnolle, Génétique & Evolution des Mal-
adies Infectieuses, UMR-2724 CNRS-IRD, Centre
IRD de Montpellier, 911 avenue Agropolis,
BP 64501, F-34394 Montpellier cedex 5, France.
[email protected]
Andrew F. Read, Institutes of Evolution, Immunol-
ogy and Infection Research, School of Biological
Sciences, Ashworth Laboratories, The King’s
Buildings, University of Edinburgh, West Mains
Road, Edinburgh, EH9 3JT Scotland, UK.
[email protected]

22. CONTRIBUTORS xxi
Paul M. Sharp, Institute of Evolutionary
Biology, University of Edinburgh, Ashworth
Laboratories, Kings Buildings, Edinburgh,
EH9 3JT UK.
[email protected]
Stephen C. Stearns, Department of Ecology and
Evolutionary Biology, Yale University, Box
208106, New Haven, CT 06520–8106 USA.
[email protected]
Beverly I. Strassmann, Institute for Social
Research & Department of Anthropology,
101 West Hall, 1085 S. University Avenue,
Ann Arbor, MI 48109–1107 USA.
[email protected]
Frédéric Thomas, Génétique & Evolution
des Maladies Infectieuses, UMR-2724
CNRS-IRD, Centre IRD de Montpellier,
911 avenue Agropolis, BP 64501,
F-34394 Montpellier cedex 5, France.
[email protected]
Paul E. Turner, Department of Ecology and Evo-
lutionary Biology, Yale University, Box 208106,
New Haven, CT 06520–8106 USA.
[email protected]
Louise V. Wain, Institute of Genetics, University
of Nottingham, Queens Medical Centre,
Nottingham NG7 2UK, UK.
Dominik Wodarz, Department of Ecology and
Evolution, University of California-Irvine,
Irvine, CA 92697 USA.
[email protected]
Mark Woolhouse, Centre for Infectious Diseases.
University of Edinburgh, Ashworth Laborato-
ries, Kings Buildings, West Mains Rd,
Edinburgh EH9 3JT UK.
[email protected]

23. PART I
Introduction

24. 3
the origins of the current epidemics of obesity,
diabetes, and autoimmune diseases, and answer-
ing patients’ questions about aging. Evolution is
not an alternative to existing medical training and
research. It is a useful basic science that poses new
medical questions, contributing to research while
also improving practice.
We now present some significant evolutionary
insights into medical issues. The first is that our
evolved state is often mismatched to our modern
environment because that environment is chan-
ging more rapidly than we can adapt to it.
Mismatched to modernity
Adaptation takes time: lactose tolerance
That it takes time for a population to adapt to
envir onmental change is illustrated by the absorp-
tion of milk sugar, lactose, by adults (Simoons
1978; Durham 1991; Mace et al. 2003). Like other
mammals, human females provide their children
with the enzymes needed to digest lactose in their
milk. A minority of us now has the ability to digest
fresh milk into adulthood, including populations
in Europe, western India, and sub-Saharan Africa.
The ancestral human condition was the inability to
digest fresh milk after being weaned, and the new,
recently evolved condition is the ability to do that.
How long would it take that ability to evolve?
The ability to digest fresh milk after weaning
behaves as a single dominant autosomal gene,
and dominant genes increase in frequency under
selection more rapidly than do recessive genes.
Introduction
Should doctors and medical researchers think
about evolution? Does it bring useful insights?
Would doctors and researchers who learned a sub-
stantial amount about evolution be more effective
than a control group that learned only the usual
rudiments? Would providing such education
improve health enough to justify the cost?
Positive answers to these questions would have
profound implications for medical education,
research funding, and the future of human health.
To address them, we start with examples of sig-
nificant evolutionary insights into serious medical
issues. We then describe the principles of evolu-
tionary biology that produce these insights. We
conclude with a summary of what doctors should
know about evolution.
At the outset we acknowledge that much med-
ical practice proceeds just fine with little need for
a theoretical foundation. Medicine is a profession
that offers practical help. Surgeons need to know
how the organism is constructed, how it works,
and what procedures work best; knowledge about
how and why it evolved does not help in perform-
ing an operation. For internists, pediatricians, epi-
demiologists, and geneticists, evolution is more
often of practical concern. Evolutionary thinking
provides insight and saves lives when one is pre-
scribing antibiotics, managing virulent diseases,
administering vaccinations, advising couples who
have difficulty conceiving and carrying offspring
to term, treating the diabetes and high blood pres-
sure of pregnancy, treating cancer, understanding
CHAPTER 1
Introducing evolutionary thinking
for medicine
Stephen C. Stearns, Randolph M. Nesse, and David Haig

25. 4 INTRODUCTION
the right level of estrogen for maintaining bone
strength and avoiding osteoporosis while avoid-
ing the risks of cancer. The first step, however, is
to recognize that there is nothing biologically nor-
mal about the regular monthly period. Too many
menses are harmful because they increase cancer
risk, but merely suppressing them without appro-
priate adjustments in hormone exposure to protect
against osteoporosis might not, on average, help.
Early-life events with late-life consequences
Low-birthweight infants are at higher risk of
becoming obese and developing diabetes, high
blood pressure, and atherosclerosis later in life.
Early nutritional stress is a signal whose evolved
response sets the individual on a special devel-
opmental course with a physiology effective for
conserving energy but ill-prepared for abundant
food (Barker et al . 2002). Obesity rates have risen
threefold or more since 1980 in many countries,
both industrialized and developing, with the rate
of increase often faster in developing countries.
While agencies like the WHO ascribe the world-
wide obesity epidemic solely to increased food con-
sumption and decreased physical activity (http://
www.who.int/dietphysicalactivity/publications/
facts/obesity), the mismatch between early- and
late-life nutritional status also contributes, render-
ing those born in poverty and growing into plenty
especially vulnerable.
Parasite load and autoimmune disease
In the environment in which we evolved, we were
frequently exposed to severe, persistent infections;
most people carried parasitic worms most of the
time. Worms, which inhabit their hosts for many
years, evolved to down-regulate host immune
responses to enhance their survival and persist-
ence in the host. In so doing they reduced our sus-
ceptibility to autoimmune diseases by reducing the
overall production of antibodies, a small percentage
of which leak through our surveillance systems to
react with self. Our environment is now so antisep-
tic that few have worms and few adults die from
infection, but many have autoimmune diseases
that are becoming much more common now that
Individuals without lactase who drink milk suffer
from flatulence, intestinal cramps, diarrhea, nau-
sea, and vomiting. A mutation for lactose tolerance
had an advantage for herding peoples who could
use milk from their animals. Selection for lactase
activity could have been particularly strong dur-
ing serious famines. If the ability to absorb lactose
conferred a selective advantage of 5%, how long
would it take to increase from a frequency 1% to
a frequency of 90%? The answer is about 325 gen-
erations or roughly 8000 years (Crow and Kimura
1970). If adults have drunk milk for only 8000 years,
then it must have conferred substantial bene fits
for selection to increase it so quickly to its current
high frequency in northern Europe. Even for a gene
under strong selection—and a 5% advantage is
strong selection—time is a constraint. The lactose
example suggests that it is quite plausible that we
are mismatched to modernity.
Birth control and cancer risk
Women in cultures without contraception and
with normal birth intervals of two and a half years
because of breastfeeding have about 100 menses per
lifetime; in postindustrial cultures women have up
to 400 cycles per lifetime (Strassmann 1997). Women
who are nearly perennially cycling experience
increased cell divisions, which put them at risk for
breast cancer (Strassmann 1999). In the 1990s, breast
cancer rates, for example, were 20–30 per 100,000
for females of all ages in Columbia, Costa Rica, and
Ecuador, and 100–150 per 100,000 for females of all
ages in the USA and Western Europe (International
Agency for Research on Cancer, http://www.-dep.
iarc.fr)—just about five times higher. Women who
experience first birth at a young age and who spend
most of their reproductive years pregnant or in lac-
tational amenorrhea (a time when the ovaries shut
down during breastfeeding) have demonstrably
lower breast cancer rates. Although we do not rec-
ommend a return to this reproductive pattern, it
is clear that Western women are experiencing too
much endogenous hormone exposure and that
this exposure comes from women’s own ovaries
rather than from external environmental sources.
Contraceptives need not induce a monthly period.
Hopefully a solution can be found that gives women

26. INTRODUCING EVOLUTIONARY THINKING FOR MEDICINE 5
by natural selection. It increases when infection
spreads easily—by mosquitoes, fleas, lice, hands, or
needles—and when pathogens compete with other
pathogen strains within a host. Peaceful coexistence
with the host occurs only when it benefits both par-
ties. If the illness or death of the host increases the
chances that the pathogen will be transmitted, the
pathogen will evolve greater virulence. Genes that
influence virulence do not need to arise by mutation;
the viruses that integrate into bacterial genomes
transmit them among bacteria. They include the
toxin genes of cholera, botulinum, diphtheria, and
scarlet fever (Waldor 1998). Plasmids, small circular
genomes that inhabit bacterial cytoplasm and can
induce their hosts to conjugate (have bacterial sex),
also transmit virulence genes among bacteria. Thus
much of the information that a bacterium needs to
become more virulent evolved long ago, now exists
in pre-packaged modules, and is mobile.
Emerging diseases
New diseases that emerge from other species can
persist and spread in humans only if they evolve
changes that allow them to enter, survive, repro-
duce in, and be transmitted from the new host.
Without these evolutionary steps, SARS and avian
flu would not be threats: to evaluate such threats,
we need to understand their evolution. For some
diseases, including AIDS, introduction into human
hosts, by whatever route, starts the process mov-
ing. The implications for organ transplantation
from other species are obvious and serious.
Reproduction
Evolved conflicts between mother and
offspring
The mother is equally interested in the success of
each of her offspring, for she shares exactly half her
genes with each of them. The fetus, however, has
evolutionary interests that differ from its mother’s
with respect to its siblings, because it ‘shares’ all
of its genes with itself but only some of its genes
with its siblings. Thus there is a conflict between
the genes in the mother and the genes in the fetus
over how much the mother invests in the fetus
children rarely have parasites. Some doctors are
successfully treating autoimmune disease by inject-
ing preparations of the coats of parasitic worms,
activating an inhibitory arm of the immune system
suppressed in modern populations (Michaeli et al.
1972). Gabonese schoolchildren with schistosomia-
sis have fewer allergic reactions to dust mites, and
Ethiopian, Brazilian, Venezuelan, and Gambian
adults have less asthma when infected with nema-
todes (Wilson and Maizels 2004). This idea helps
to explain the current epidemics of asthma, type
I diabetes, and even leukemia (Greaves 2000;
Wilson and Maizels 2004). It may take hundreds
of generations for evolution to bring the screening
mechanisms of our immune systems, located in the
thymus and bone marrow, into equilibrium with
the cleanliness of modern environments.
Infection
Resistance
Most doctors and many patients recognize anti-
biotic resistance as an example of rapid evolution.
When it evolves at all, antibiotic resistance evolves
much faster than we can evolve defenses. Much
work remains to understand why some bacteria
remain susceptible, such as streptococcus to peni-
cillin, while others escape a new antibiotic in just
a few years. Part of the answer is that bacteria and
viruses do not always have to wait for mutations;
many receive resistance genes from other patho-
gens (Lederberg 1998). Another part of the answer
is that most antibiotics, created by selection during
millions of years of competition between bacteria,
are weapons against which some bacteria have
already evolved effective responses (D’Costa et al.
2006). The same principles that govern the evolu-
tion of antibiotic resistance apply also to cancer
chemotherapy, where resistant cell lines displace
others. Triple chemotherapy for cancer is effective
for the same reasons that triple antibiotic therapy
is now routine for tuberculosis.
Virulence
Virulence—the ability of a pathogen to cause mor-
bidity and mortality—is also shaped dynamically

27. 6 INTRODUCTION
infection as infants. Remarkably, the female repro-
ductive tract can identify and discard such fetuses
at a very early stage (Ober 1992) when they have
not yet cost the mother much time or energy, free-
ing her to try again, perhaps with a different mate.
Repeated spontaneous abortions are both emotion-
ally and evolutionarily costly, and avoiding them
would be advantageous. Intriguingly, humans tend
to choose mates whose MHC alleles differ from
their own (Wedekind et al. 1995; Ober et al. 1997),
using mechanisms not yet fully understood.
The existence of this process suggests two things
about the ancestral environment in which it was
selected. We then lived in small, inbred groups
where the probability of encountering a mate with
the same MHC alleles was significant. And infec-
tious disease then accounted for a significant por-
tion of infant and child mortality, as it still does in
much of the world.
Populations have histories
Human populations have diverged genetically
since we emerged from Africa about 100,000 years
ago, and nearly every human individual has a
unique genome and has had a unique develop-
mental history of environmental interactions. As
we colonized the planet, each branch of our family
tree encountered different pathogens and differ-
ent diets, and those pathogens and diets left their
traces on our innate abilities to resist disease and
metabolize drugs. As a result genetic diseases vary
among populations of different geographical ori-
gin and ethnicity.
Doctors practicing in South Africa, in Quebec,
or on Pitcairn Island need to be aware of the high
incidences of certain genetic diseases frequent in
those populations but not in others because each
of them was founded by a small group of people
in which those genetic defects just happened to be
relatively frequent.
Not all genetic diseases found at unusually
high frequency in specific ethnic groups are the
result of such founder events. Some confer disease
resistance when present as heterozygotes, such as
sickle-cell anemia and glucose-5-phosphate dehy-
drogenase (G6PD) deficiency, which confer resist-
ance to malaria. In other cases such connections are
suspected but not yet well established: Tay-Sachs
(Trivers 1974; Burt and Trivers 2006), and the fetus
is equipped with placental morphology and endo-
crine function to manipulate the physiological state
of the mother to its benefit. By-products of this evo-
lutionary conflict include increased maternal blood
pressure (pre-eclampsia) and diabetes (Haig 1993).
Evolved conflicts between mother and father
The paths to reproductive success of fathers and
mothers differ fundamentally. The reproductive
success of a mother depends on the number of
children she bears in her lifetime. The reproductive
success of a father depends on the number of times
he mates successfully per lifetime. Starkly put, he
can father a child on this female, then go off and
father another on a different female, leaving her
to raise his child. This asymmetry in reproductive
opportunities is ancient, predating the origin of
humans by hundreds of millions of years, and we
may have inherited its consequences from ancestor
species. Because of this asymmetry, genes from the
father have been selected to manipulate the mother
to provide more nutrition to the current fetus than
she has been selected to give, while genes from
the mother counter this manipulation to reserve
resources for her survival and her future offspring,
which she may have by other males (Haig 1992).
Such manipulations are possible because of a pro-
cess called germ-line imprinting that inactivates
some genes during early fetal development when
they come through the father, and other genes
when they come through the mother.
Genetic imprinting may also explain the genetic
component of several serious diseases, includ-
ing autism and schizophrenia. It is also a major
impedi ment to cloning.
Spontaneous abortions and complementary
immune genes
Early spontaneous abortions are especially common
in women whose fetuses are immunologically defi-
cient because their parents share the same versions
of one or more major histocompatibility complex
(MHC) genes. The immune systems of such fetuses
cannot produce the recombinant antibody diver-
sity needed to counter rapidly evolving pathogens
and if carried to term would be poor at resisting

28. INTRODUCING EVOLUTIONARY THINKING FOR MEDICINE 7
on tissues from other species. As they evolve to
specialize genetically on the new host, they lose
most of their virulence in humans. Every time this
procedure succeeds—as it has for the oral polio
and typhoid vaccines—it demonstrates the evolu-
tionary principle that a jack of all trades is a master
of none.
We now discuss the other basic evolutionary prin-
ciples that inform the examples presented above.
The nature of evolutionary explanations
Microevolution, macroevolution, and
development
To understand the current state of any population,
we must consider the interactions of both micro-
and macroevolutionary processes. Microevolution
refers to changes in traits and gene frequencies
resulting from selection and drift in each gener-
ation; its causes operate at the level of populations.
Macroevolution refers to the broad patterns and
deep time perceived in comparisons among spe-
cies and with fossil evidence; it is revealed in com-
parisons at the level of the phylogenetic lineage,
at and above the species level. Micro- and macro-
evolution explain why populations and species are
the way they are, but they do not explain individ-
uals. Understanding individuals requires adding
consideration of development. In the process of
development, genes and environments interact to
produce the organism at all stages of its life cycle.
Microevolution has shaped developmental reac-
tions to the environment across the entire trajec-
tory from conception to death. Those reactions also
carry the macroevolutionary traces of phylogenetic
history.
Thus, every trait in every organism arises from
two interactions. One is between relatively rapid
microevolutionary changes and relatively slow
macroevolutionary trends and constraints in the
population and lineage. The other is between genes
and environments during the development of each
individual. As a consequence:
Every evolutionary change in traits involves •
changes in genes that influence development—for
all traits develop.
All traits arise from interactions between genes •
and environment; it is an elementary mistake to say
disease, carried by up to 11% of Ashkenazi Jews, is
thought to confer resistance to tuberculosis; cystic
fibrosis is thought to confer resistance to cholera;
phenylketonuria to fungal toxins implicated in
spontaneous abortions.
Genetic susceptibility to risk factors associated
with circulatory disease also varies geograph-
ically. For example, people whose ethnic origin is
closer to the equator are at higher risk of suffering
from high blood pressure (Young et al. 2005), and
susceptibility to smoking, cholesterol, and obes-
ity is influenced by interactions among at least
five genes each of which exists in several variants.
Certain combinations of these variants are associ-
ated with much greater susceptibility; others with
much less. This is crucial practical information for
cardiac prevention.
Evolutionary technologies
Evolutionary biology has also produced technolo-
gies with medical applications. Two are particularly
important: the new methods of inferring relation-
ships and history using phylogenetic reconstruc-
tion, and the production of live attenuated vaccines
through serial transfer.
Phylogenetic reconstructions
The phylogenetic methods developed to recon-
struct relationships among species, and thus the
history of life, have been used on RNA sequences
recovered from HIV infections: they identified the
Florida dentist who infected his patients (Crandall
1995) and the sailor who introduced AIDS to
Sweden, and they also showed that routine dental
care does not transmit HIV (Jaffe et al. 1994).
The same methods reveal that smallpox exists
in three major lineages, one from West Africa, one
from South America, and one from Asia. If small-
pox is ever used as a biological weapon, knowing
the strain will be crucial to developing the correct
vaccine.
Attenuated live vaccines
Serial transfer is used to produce attenuated live
vaccines, which are evolved by passing human
pathogens through several generations of culture

29. 8 INTRODUCTION
disease. Ancient neuroendocrine mechan isms
mediate the allocations among these essential
functions as well as the transition from the juve-
nile to the adult state. Those mechanisms have
been shaped by selection to adjust allocations to
the current situation. Not all such adjustments
need be adaptive. For example, one seems to switch
the neuroendocrine system to a premature state
when nutrition is scant, a finding that helps us
understand anorexia nervosa. And while seeking
calories and storing them as fat was once useful in
most environments, today it shortens lives (Neel
et al. 1998).
Thus, an evolved system of proximate mechan-
isms interacts with environments to shape pheno-
types and behavior. Individuals whose proximate
mechanisms improve reproductive success pass on
more of their genes to future generations. Others
are selected against.
Natural selection
How selection works
Selection operates to change a trait whenever three
conditions are satisfied. When a trait varies among
individuals, that variation affects how many suc-
cessful offspring an individual has, and the genes
that vary among individuals influence at least some
of the variation in the trait, the reproduction of the
successful individuals then changes the frequency
of the genes and traits in the next generation. As
this process continues over generations, the inher-
itance of the changes accumulates and can be
measured in changes in the genetic composition of
the population. The evidence for natural selection
is overwhelming.
Selection is not a theory. It is a principle that must
hold when certain conditions are present: variation
in traits, variation in reproductive success, correl-
ation of trait variation with reproductive success,
and inheritance of trait variation. If objects in any
population vary in ways that influence which ones
persist, then the population will change over time.
It has to. Consider the water glasses in an inexpen-
sive furnished apartment that has been repeatedly
rented. They can be explained by selection. Some
collection of glasses came into the apartment. The
that a trait is ‘environmental’ or ‘genetic,’ the prod-
uct of ‘nature’ or ‘nurture,’ for all traits are products
of both. However, it is perfectly sensible to estimate
what proportion of variation in a given population is
attributable to genetic differences, to environmental
differences, and to their interactions.
An organism’s traits form a mosaic: some ancient, •
some new, some static, others rapidly evolving.
Doctors do not treat genes; they treat traits influ-
enced by genes expressed in whole organisms, such
as infection, inflammation, blood pressure and
chemistry, and anxiety. To do this well for many, if
not all traits, they need to understand genetic evo-
lution, trait evolution, and development.
Mechanistic and evolutionary explanations
Most medical research has been limited to ques-
tions about the mechanisms of the body. The evolu-
tionary perspective asks questions about why those
mechanisms are the way they are. The distinction
between ‘proximate’ or mechanistic and ‘ultimate’
or evolutionary explanations was emphasized by
Tinbergen (1963) and Mayr (2004) but remains
unfamiliar in the medical sciences. Both types of
explanations are necessary, neither substitutes for
the other, and they inform each other.
In humans, the presence of some mechanisms
and not others is the result of our ancestry and
relationships. Like all other vertebrates, humans
counter infection with an adaptive immune sys-
tem and have an inside-out eye whose vessels and
nerves run between the light and the receptors.
Like all mammals, humans have internal fertiliza-
tion, pregnancy, and lactation, and females store
fat before and during pregnancy. Like all primates,
humans provide extended offspring care. Like
all hominids we have late maturation, a long life,
and a relatively low reproductive rate. Among
hominids we stand out for our relatively short
interbirth intervals and a significant period of
post-reproductive survival in females.
Like birds and mammals, but unlike fish and
trees, humans have determinate growth: we stop
growing at maturation. After maturation, energy is
devoted to reproductive competition and caring for
offspring as well as storing calories and resisting

30. INTRODUCING EVOLUTIONARY THINKING FOR MEDICINE 9
individual over its lifetime. This is the most gen-
eral component of reproductive success, individual
fitness: a shorthand way of referring to long-term
reproductive success.
In sexually reproducing organisms, reproductive
success depends substantially on mating success.
This component of natural selection is called sexual
selection. Sexual selection shapes traits that improve
mating success even if they decrease individual
health or survival. For example, the male peacock’s
tail improves his reproductive success by making
him attractive to females but reduces his chances
for survival by making it harder for him to fly.
Human males have shorter lives than females; at
sexual maturity in most modern cultures, mortal-
ity rates for men are three times higher than those
for women (Kruger and Nesse 2004). Sexual selec-
tion can involve the two sexes in a complex inter-
action with fascinating properties. Females choose
mates for a variety of reasons, and their preferences
shape male behavior and morphology. The process
stops when the costs and benefits of mating success
balance. At that point, survival has often been com-
promised by investment in reproduction.
Organisms living with relatives experience a
third kind of selection. At one level, what matters
to evolution is only the relative number of copies
of genes that exist in the population in the next
generation. Whether those genes are contributed
directly, by an individual, or indirectly, by its rela-
tives, is of no consequence. The closer the relation-
ship, the more genes are shared. An individual can
increase the frequency of its genes if it acts in ways
that increase the reproductive success of its kin
whenever the benefits to the kin’s reproductive suc-
cess, weighted by its degree of relationship, exceed
the costs to the individual’s reproductive success
(Hamilton 1964). This process, called kin selection,
has helped us understand the evolution of appar-
ently self-sacrificial, cooperative, altruistic, and
nepotistic behavior. It also explains why organisms
are more likely to help close relatives than distant
ones; full sibs, and parents and offspring, share
half their genes, but first cousins share only one-
eighth. The empirical success of kin selection has
convinced evolutionary biologists that their focus
on genes is correct (Williams 1966; Dawkins 1976;
Dawkins 1982; Williams 1992).
fragile ones broke. The attractive ones left when
renters departed. The nonfunctional ones with
odd shapes were thrown out. What is left is what
you find—a collection of sturdy, ugly, functional
glasses. Selection can equally well account for why
your coin jar is now mostly full of pennies, why the
vegetables at the grocery store on a Sunday evening
are mostly damaged, and why some television
shows persist and spawn imitators, while others
are long gone. Natural selection is just the special
kind of selection that occurs when the objects are
individuals in a population whose variations are
caused partly by genes and whose contributions to
future generations are influenced by how many of
their offspring survive to reproduce in turn.
Fitness is relative reproductive success
The basic insight of population genetics is simple
and powerful—the evolutionary process can be
reduced to the analysis of the factors that increase
or decrease the number of copies of a gene in a
population from one generation to the next. It is
a superb starting point. However, gene frequency
change is insufficient to explain phenotype evolu-
tion. To understand some particular aspect of an
organism’s design for reproduction and survival,
such as age at first reproduction, requires ana-
lysis of how the organism’s genes produce traits
that interact with environments in contributing
to survival and reproduction. Natural selection
improves reproduction, but the route to reproduc-
tion requires allocating effort among finding food,
avoiding predators and parasites, fighting, attract-
ing mates, and caring for offspring. The variants
that selection sorts do not necessarily include the
optimal type: they simply consist of the variation
that can be produced by the current population, as
it exists. Those that persist performed better than
the others, but there is no reason to think that their
performance was the best possible.
Natural selection has several components:
individual, sexual, and kin selection
The analysis of reproductive success begins with
the factors determining the number of surviving
and reproducing offspring produced by a single

31. 10 INTRODUCTION
in the frequencies of genes whose alleles do not
correlate with reproductive success. This kind of
evolution is called ‘neutral’ because the variation
is neutral with respect to selection; no variant has
any systematic advantage over any other. It is also
called drift to reflect the lack of direction of neutral
genes drifting through the population over many
generations. Drift produces random change in both
large and small populations, but it works more
rapidly and over a broader range of conditions in
small populations.
Two processes introduce randomness into
evolution: mutations and meiosis. Two other proc-
esses accentuate it: founder events and lack of
correlation of genetic effects with reproductive
success.
Mutations are random with respect to their effects
on fitness; many are neutral or deleterious, some
give an advantage. Whether the costs or bene fits
of a particular mutation will result in a systematic
change in gene frequency depends on the number
of times those effects are tested in organisms. If
they are only tested a few times, then the random-
ness of meiosis may dominate the effects of the
gene on reproductive success.
The randomness of meiosis is like a coin flip.
It consists of the 50% chance that each copy of a
chromosome has of getting into a particular gam-
ete. Since only some gametes succeed in forming a
zygote, developing, and reproducing, the random
effects of meiosis are particularly important in
small populations. This can be seen by the limiting
case of a population of two individuals, one male
and one female, who produce just one offspring.
Consider a new mutation sitting on a chromosome
in the female. It has just a 50:50 of getting into the
egg. Thus even if a new mutation gives a huge
advantage, if the bearer has only one offspring,
there is a 50% probability that the mutation will
be lost. Most genes have effects that are not per-
fectly correlated with reproductive success. To the
degree that they are not, those genes are subject to
some influence of drift. Even advantageous genes
sometimes end up in organisms that produce no
children. It is therefore only in small populations
that drift can overcome the effects of strong selec-
tion. As population size and number of offspring
increase, so do the number of chances that genes
The gene-centered view also explains why senes-
cence is a property of the soma (an individual body),
not of the germ line. Evolution ‘cares’ about the germ
line—the genes—whereas doctors treat the soma,
which is, from the point of view of evolution, dispos-
able. The consequence has been all the degenerative
diseases associated with aging, which are becoming
the bulk of medical care. Surely we should want to
understand their evolutionary origins.
Traits do not evolve for the good of
the species
Before the 1960s, one often heard that some adapta-
tion had evolved for the good of the species, helping
it to avoid extinction. For instance, lemmings were
s a id to ju mp i nto f iord s to com m it su ic ide whe n fo o d
was scarce so the species could survive. As a general
explanation, this is incorrect. The vast majority of
traits evolve only if they improve the reproductive
success of individuals and their kin; if they benefit
the species as well, they do so only as a by-product of
their benefits to the genes of individuals. Selection
acting on species requires the standard conditions
to be effective: variation among species in repro-
ductive success (in this case determined by relative
rates of extinction and speciation), variation in traits
correlated with reproductive success, and heritabil-
ity of those traits. Genes that benefit the species at
the expense of individuals will rapidly disappear,
for selection on individuals is much stronger than
selection on groups and species. Individuals have
much shorter generation times than species, and in
the time that it takes for new species to form and
go extinct, a process spanning many thousands of
individual generations, hundreds of millions of
the individuals that form those species will have
lived and died. For that reason, selection has much
greater opportunity to sort among individuals than
it does to sort among species, and species selection
simply cannot shape adaptations (Maynard Smith
1964; Williams 1966).
Random events and neutral variation:
how neutral evolution works
Some changes in the genetic composition of popula-
tions occur through neutral evolution—fluctuations

32. INTRODUCING EVOLUTIONARY THINKING FOR MEDICINE 11
functions. ‘The neutral hypothesis, when applied
to the study of human polymorphisms, might even
have a counterproductive effect if it discourages
the search for sources of natural selection’ (Vogel
and Motulsky 1997).
Trade-offs
One of the most useful generalizations evolution
offers to medicine is a vision of the body as a bun-
dle of trade-offs. No trait is perfect. Every trait could
be better, but making it better would make some-
thing else worse. Our vision could be as acute as
that of an eagle, but the price would be a decreased
capacity to detect color, depth, and movement in
a wide field of vision. If the bones in our wrists
were thicker they would not break so readily, but
we would not be able to rotate our wrists in the
wonderful motion that makes throwing efficient. If
the stomach made less acid we would be less prone
to ulcers, but more prone to GI infections. Every
trait requires analysis of the trade-offs that limit
its perfection.
This kind of thinking is especially important as
we gain more and more ability to alter our bodies.
For instance, it seems like a good idea to need less
sleep, but natural selection has been adjusting the
length of sleep for millions of years. If we think
we can take drugs to cram more into 24 hours, we
had better think twice. How much testosterone is
optimal? Increased testosterone levels in human
males may increase strength and competitiveness,
but they also decrease ability to resist pathogens
and parasites (Chapter 7). How many menstrual
cycles per lifetime are optimal? More cycles mean
more reproductive opportunities, but they increase
cancer risk. These effects of testosterone and men-
struation exemplify the central trade-off shaping
life span and aging: the trade-off between repro-
duction and survival.
Every trait must be analyzed in terms of the
costs and benefits of the trade-offs in which it
is involved. They limit how much fitness can be
improved because every improvement in one trait
will compromise some other. And those comprom-
ises can emerge as unpleasant, costly surprises
when interventions are made in ignorance of the
trade-offs they manipulate.
have of making their way into the next generation
and having their effects on reproductive success
register, and the effects of drift diminish.
Founder events are another source of random-
ness in evolution. They occur when new popula-
tions are founded by a small and unrepresentative
sample of the ancestral population. They are
important in understanding why certain genetic
diseases are unusually frequent in the descend-
ents of the Dutch who colonized South Africa,
of the French who colonized Quebec, and of the
Bounty mutineers who settled on Pitcairn Island.
The element of randomness introduced into
evolution by founder events is precisely that of
sampling error.
Even in large populations drift acts on the neu-
tral genes whose effects are not at all correlated
with reproductive success. Completely neutral
genes drift through both small and large popula-
tions like molecules in Brownian motion; the rate
at which they are fixed determines the ticking of
the molecular clocks that record the divergence
times of species in DNA sequences. Thus drift does
not only happen in small populations.
Both random effects and selection have had
important effects on populations, but we do not
yet know what proportion of genetic variation each
accounts for. In humans, the amount of variation is
large: about 30% of human genes coding for struc-
tural proteins have more than one allele. In many
proteins only certain amino acids are critical to
their function; substitutions at other positions may
be selectively neutral or close to it. On the other
hand, the fact that no selective function is known
for most human polymorphisms does not mean that
selection has not been important: absence of evi-
dence is not evidence of absence. Modern civiliza-
tion has changed our activity patterns and our diet,
and has eliminated or reduced many pathogens
that were selective agents in the past. Furthermore,
many of the body’s mechanisms are useful only in
special circumstances. Shivering is useful only in
cold situations and certain immune responses are
useful mainly against worms that are no longer a
threat. In short, the hunt for the adaptive signifi-
cance of each gene, and of genetic variation, is just
getting underway. That drift is real and sometimes
potent should not stop us from considering possible

33. 12 INTRODUCTION
the ground up. You cannot change the basic design
of a car while the car is being driven. We illustrate
constraint with two examples.
The first concerns the vertebrate eye, often cited
for its astonishing precision and complexity. It
contains, however, a basic flaw (Goldsmith 1990).
The nerves and blood vessels of vertebrate eyes
lie between the photosensitive cells and the light
source, a design that no engineer would recom-
mend, for it obscures the passage of light into the
photosensitive cells. Hundreds of millions of years
ago, vertebrate ancestors had simple, cup-shaped
eyes that detected only the direction of light and
dark, not images. These simple eyes developed
as an out-pocketing of the brain, and the posi-
tion of the light-sensitive tissue layers happened
to be beneath the layers that contained nerves
and blood vessels. Once such a developmental
sequence evolved, it could not be changed without
intermed iate forms that would be almost useless.
Thus, natural selection cannot start from scratch to
make the vertebrate eye more ‘rationally designed.’
The proof that the eye’s substandard design is not
neces sary is found in the octopus eye, which has
no blind spot because the vessels and nerves run
on the outside of the eyeball, penetrating only
where they are needed.
The second example concerns the length and
location of the tubes connecting the testicles to the
penis in mammals (Williams 1992). In the adult
ancestors of primates and their relatives, and in
present day primate embryos, the testes lie in the
body cavity, near the kidneys, like the ovaries in
the adult female. For reasons still unknown, the
sperm of many mammals develop better at tem-
peratures lower than those in the body core. This
selection force moved the testes out of the high-
temperature body core into the lower-temperature
periphery and eventually into the scrotum (in
some species they only drop into the scrotum dur-
ing breeding season). This evolutionary progres-
sion in adults is replayed in the development of the
testes. As they move from the body cavity towards
the scrotum, the vas deferens does not take any-
thing like the most direct route. Instead, it wraps
around the ureters like a person watering the lawn
who gets the hose caught on a tree. If it were not Macroevolution
Relationships and fossils reveal history
The type of explanation provided by macroevo-
lution is essentially historical: things are now the
way they are because they had a particular evo-
lutionary history. Explaining the human pelvis,
for example, begins with figuring out both how its
shape changed over evolutionary time, and why
it changed. To understand that history, evolution-
ary biologists use two methods, paleontology—the
study of fossils—and the comparative method—
comparisons of living species. Often they are used
together.
For traits that do not fossilize, the comparative
method is the only way to reconstruct the history.
The first step in the comparative method is always
to locate the species on the Tree of Life, to identify
its relationships with other species. Those relation-
ships are now often more precisely understood
thanks to a great deal of research that has been strik-
ingly improved by better logic and the avail ability
of cheap DNA sequences. Many relationships are
being revised because of those developments.
Given the location of the species in the evolution-
ary tree, one can map variations in the trait on the
historical sequence of species to determine when
the trait arose and how it changed in different lin-
eages. Ancestral states can then be inferred by using
several methods to search for correlated changes
among traits over the portion of time, space, and
biodiversity represented by the phylogeny (e.g.,
Felsenstein 1985; Pagel 1994). The evolutionary his-
tories of menopause and the pelvis exemplify the
power of the method; the appendix illustrates the
challenges (Fisher 2000).
Constraints: eyes and tubes
Organisms are not soft clay from which nat-
ural selection can sculpt arbitrary forms. Natural
selection can only modify the variation currently
present in the population, and that variation is con-
strained by history, development, physiology, and
the laws of physics and chemistry. Natural selec-
tion cannot anticipate future problems, nor can it
redesign existing mechanisms and structures from

34. INTRODUCING EVOLUTIONARY THINKING FOR MEDICINE 13
Human diversity
Medicine and evolutionary biology have different
approaches to variation. Medicine tends to be nor-
mative: some states (health) are better than other
states (disease). Evolutionary biology is similarly
concerned with the causes and consequences of
variation, but particular states are not intrinsically
more valuable or desirable than others. Differential
reproduction is a consequence of interest but not a
measure of value. Despite a common misconcep-
tion, evolutionary biology is concerned with envir-
onmental as well as genetic sources of variation.
Evolutionary biologists are fascinated by whether
plastic human responses to different environ-
ments enhance genetic fitness and whether these
responses have an evolved component (see Chapter
19). But whether a particular response is adaptive or
non-adaptive (in the evolutionary sense) says noth-
ing about the desirability of the response. The idea
that some variation is ‘normal’ and some ‘abnor-
mal’ has no place within evolutionary theory.
Critics often object to the application of evolution-
ary theory to our own species because they fear
that the theory has normative implications, or will
be perceived as having such implications. However,
normative questions are not the province of evolu-
tionary biology. If it were convincingly shown that
some men have a genetic predisposition to homo-
sexuality, then the discovery would raise interesting
evolutionary questions but there would be no rea-
son to treat sexual orientation as a medical problem,
just as few people would now see left-handedness as
a problem needing correction. On the other hand, if
it could be shown that variation in growth between
human populations is an adaptive response to dif-
ferent levels of nutrition the response would be of
evolutionary interest but its existence would not
absolve us of asking why some people should have
more food than others.
Evolutionary biology is not going to provide easy
answers to medical dilemmas, nor provide a simple
guide for intervention, but a dialogue between evo-
lutionary biology and medicine should nevertheless
be of benefit to both disciplines. Most immediately,
the vast database of medicine provides unparal-
leled opportunities to test evolutionary theory
and suggest new avenues of evolutionary research.
for the constraints of history and development, the
vas deferens would be much shorter and perhaps
function better. Many other examples of subopti-
mal design are described in William Paley’s book,
Natural Theology, where they are explained as
results of the Creator’s intent to puzzle scientists
(Paley 1970 [1802]).
Conclusion
Health, fitness, and the pursuit of happiness
Shorter interbirth intervals are associated with
increased childhood mortality. Nevertheless,
Hobcraft et al. (1983) observed: ‘For what it is worth,
we note that any family trying to achieve maximal
numbers of surviving children at any cost would,
in the light of these results, continue to bear chil-
dren at the most rapid rate possible. The dramatic
excess mortality is not enough to negate the extra
births. However, it is hard to recommend a pat-
tern with such disastrous human consequences.’
This quotation illustrates two important distinc-
tions. First, maximizing the fitness of a parent need
not maximize the fitness of individual offspring.
Second, health and fitness are not synonyms when
fitness is understood in its genetic sense. Where
there is a conflict between the self-defined inter-
ests of human individuals and the interests of their
genes, medicine should serve the former. However,
what individuals will choose for themselves does
not bear any simple relation to health or fitness.
Our choices sometimes promote health over fitness
and sometimes fitness over health. When a woman
chooses to be pregnant, she takes an action that
enhances her fitness but has risks for her health.
When she uses contraception, her choice may be
good for her health but reduce her fitness.
Our evolved natures should be treated with
respect, but not with deference. We did not evolve
to be happy: rather we evolved to be happy, sad,
miserable, angry, anxious, and depressed, as the
mood takes us. We evolved to love and to hate, and
to care and be callous. Our emotions are the car-
rots and sticks that our genes use to persuade us
to achieve their ends. But their ends need not be
our ends. Goodness and happiness may be goals
attainable only by hoodwinking our genes.

35. 14 INTRODUCTION
to describe, with examples, how natural selection
explains why organisms are the way they are. The
body is not a machine designed from first prin-
ciples by an omniscient engineer. Evolution has
assembled it by tinkering with the variants avail-
able, every step of the way.
Trade-offs and constraints are ubiquitous— 2.
Because selection has pushed the design of organ-
isms to limits determined by trade-offs and
constraints, improving one thing often makes
something else worse. Because some trade-offs
are not obvious, unpleasant surprises are possible.
Because constraints are real, the optimal has often
not been attained.
The distinction between proximate and evo-3.
lutionary explanations and how they combine to
explain traits—Those who do not understand this
distinction will waste time on futile arguments
and will not grasp the importance of evolution-
ary explanations. For instance, those who think
that type I diabetes is caused only by genes and
autoimmune reactions have often not considered
why those genes persist and why the autoimmune
reactions evolved as they have.
The distinction between micro- and macroevo-4.
lution—Some think that evolution is only about
anthropological studies of bones and primates
and confuse that with studies of changes in gene
frequencies.
The distinction between evolution and nat ural 5.
selection—Evolution is more than just natural
selection. It includes gene drift, gene flow, founder
events, speciation, and all of their consequences.
Group selection is weak—Many who do not 6.
know this is a problem offer explanations for traits
such as aging that are inconsistent with evolution-
ary mechanisms. The correct explanation of aging
follows as an example of explanations based on
individual selection.
Aging is a by-product of selection operating 7.
on the whole life cycle, from birth to maturity to
death—Selection pressures drop with age and dis-
appear in post-reproductive individuals, and up
to a point more fitness can be gained by investing
in reproduction than in maintenance that would
improve survival. Therefore all organisms must
evolve senescence. By understanding why we
age, we can better appreciate the consequences of
We hope that evolutionary biology will be able to
repay some of this debt by providing medicine
with new hypotheses for answering old questions.
Implications for medical practice, research,
and education
Clinicians can profit from viewing infection from
the pathogen’s point of view and being able to
anticipate the evolutionary responses of patho-
gens to treatments with antibiotics and vaccines.
The coevolution of pathogens with our bodies,
our behaviors, our interventions, and our drug
industries is ongoing, incessant, and inescapable
(Chapters 10–17). The evolutionary view helps clin-
icians dealing with reproductive medicine, cancer,
and autoimmune disease to understand how our
bodies are mismatched to modernity and how far
biological adaptation lags behind cultural change.
The diseases of civilization include significant
proportions of cancers, allergies, asthma, obesity,
diabetes, and cardiovascular disease (Chapters 8,
9, 19–23).
For medical researchers evolution provides a
continuing supply of a key limiting resource: new
questions posed from a different point of view
leading to alternative explanations that suggest
new lines of research on tough problems. We rec-
ommend considering graduate research programs
that bridge medical school departments with
departments doing basic research in evolutionary
biology.
For medical education, the engagement with evo-
lution does not necessarily imply any new courses
or any fundamental restructuring of the premed-
ical or medical school curricula. Both are already
packed with useful information that would be a
mistake to discard. Instead, we suggest fitting evo-
lutionary material into roughly 10% of that subset
of courses where such material is relevant and
clearly beneficial.
What doctors need to know about
evolution and why
How natural selection works—By this we mean 1.
not just memorizing ‘variation, inheritance, and
differential reproductive success’ but being able

36. INTRODUCING EVOLUTIONARY THINKING FOR MEDICINE 15
measures such as vaccination all cause virulence
to evolve, for better or for worse (Chapters 11, 12,
16, and 17).
The evolutionary analysis of genetic conflicts 11.
tell us why both the placenta and the ovary make
high concentrations of reproductive hormones
during pregnancy and why some fetal proteins are
derived only from the father’s genes while others
are derived only from mother’s (Chapter 6).
Selection is everywhere in everyday life, includ-12.
ing what drugs physicians use, which patients
keep coming for treatment, and which insurance
compan ies stay in business—Understanding selec-
tion in general is the foundation for understanding
natural selection. Doctors need to understand this
to help explain evolution to their patients.
treating the symptoms of aging and attempting to
prolong life (Chapters 18, 23).
Each human individual has had a slightly differ-8.
ent evolutionary history, and each has a different
genetic makeup—This leads to important differ-
ences in the way that different human individ uals
react to drugs and to diseases (Chapters 2, 3, 4,
and 5).
Microorganisms and cancer cells rapidly evolve 9.
resistance to drugs—This has important implica-
tions for drug design and the management of treat-
ment (Chapters 10, 21, and 22).
Evolutionary theory tells us why virulence 10.
evolves to a certain level and no further and what
measures could be taken to reduce it—Changes
in our lifestyle, in treatment, and in public health

37. PART II
The history and variation of
human genes

38. 19
more potential vectors and led to greater exposure
to zoonotic diseases (Polgar 1964). Over this long
period, aspects of human behavior, physiology,
and genetics evolved in response to these diseases
(Armalegos and Dewey 1970; Dronamraju 2004).
We consider in this chapter three main questions
about the global distribution of infectious diseases
and their impact, in particular the impact of their
diversity, on human evolution. First, what are the
global geographical patterns of the distribution of
pathogen species, and how can we explain them?
Second, how does parasitic diversity influence the
evolution of genetic diversity and the distribution
of alleles at particular genes in humans? Third, how
has geographical variation in the distribution and
diversity of infectious disease shaped the distribu-
tion of life-history traits observed in current human
populations? We argue that while the emergence of
new diseases has been a recurrent pattern since the
origin of hominids, with the new emerging patho-
gens we now face an important epidemiological
transition that potentially influences human adap-
tation and survival. In particular, global trade and
transcontinental economic exchange and transport
will considerably alter the occurrence and distri-
bution of human infectious diseases and thus the
selection they exert on humans.
Geographical aspects of human diseases
Latitude affects the diversity and distribution of
many free-living organisms, but little is known
about large-scale patterns of the distribution of
human or animal pathogens (Finlay 2002). One
Introduction
The range of diseases to which humans have been
exposed has changed considerably from early
human populations nearly four millions years ago
through Neolithic humans c.10,000–8,000 years
ago to modern humans living today in megalop-
olises (Armalegos et al . 1996). Over this long period
humans have constantly created new ways of liv-
ing and eating, thus generating new pathways for
diseases to invade and spread into communities.
For most of their evolutionary history, humans
lived in small, sparsely settled communities with
very low population sizes and densities. Although
such human communities were too small to sup-
port endemic pathogens that were constantly
present, they were regularly infected by zoono-
ses through insect bites (e.g., sleeping sickness),
by preparation and consumption of contaminated
flesh, from wounds inflicted by animals (e.g.,
tetanus), and by direct contacts with animal res-
ervoirs (e.g., avian tuberculosis and leptospirosis
(Armalegos et al. 1996)). Moreover, the range of
earliest hominids was probably restricted to the
tropical savannah, which would have limited the
number of pathogen species. As they moved into
temperate zones, hominids escaped from some of
the tropical diseases that had plagued their ances-
tors and acquired new pathogens. When, about
10,000 years ago, the agricultural revolution pro-
duced larger, less mobile human populations,
infectious diseases such as influenza, measles,
mumps, and smallpox increased (Armalegos et al .
1996). The domestication of animals also attracted
CHAPTER 2
Global spatial patterns of infectious
diseases and human evolution
Jean-François Guégan, Franck Prugnolle,
and Frédéric Thomas

39. 20 THE HISTORY AND VARIATION OF HUMAN GENES
diseases affecting humans in the tropics (Guernier
et al. 2004). But does this distribution of modern
diseases reflect the environment of early humans?
There are indeed several reasons to expect a similar
or even stronger pattern for early human popula-
tions. First, the natural history explorations at the
beginning of the sixteenth century and more recent
large-scale dispersal due to intercontinental trade
and transport increased the geographical ranges of
diseases (McMichael 2004) and thereby weakened
spatial patterns. Second, the geographic variation
of temperature and rainfall affects disease ranges,
in particular those of vector- and reservoir-borne
diseases (Guernier et al. 2004). If, as we would
expect, the latitudinal increase in winter severity
decreases the survival of pathogens or their vec-
tors, disease diversity would decrease as we move
away from the equator. In addition, the amount of
precipitation during a growing season decreases
as we move away from the equator, which should
affect the range of diseases and vectors that are
sensitive to moisture. Finally, species richness of
the parasites of non-human hosts also decreases
with increasing latitude, in particular for metazoan
parasites of marine fish (Rohde 1999), of primates
(Nunn et al. 2005), and for parasites of some plant
hosts, e.g., soybean (Yang and Feng 2001). Even if
this rule does not apply to all microbial organisms
reason large-scale patterns of human diseases have
so rarely been studied is that their geographical dis-
tribution has probably changed substantially over
human history, with a major transition during the
late twentieth century. In particular, it is generally
thought that infection chains and intercontinen-
tal transfers of microbes would homogenize their
spatial distribution, so that no geographical pat-
terns could be detected (see Haggett 1994; Finlay
2002). However, recent studies of human microbial
pathogens identify several macroscale distribution
patterns of human diseases.
Latitude and the species diversity of
human pathogens
Disease species diversity is higher in the tropics
than in temperate areas (Fig. 2.1a) (Guernier et al .
2004). This pattern is stronger in the northern
hemisphere, where human populations are con-
centrated, than in the southern hemisphere. Most
important parasites of humans occur in tropical
and subtropical countries, and some of these spe-
cies, mainly zoonotic and vector-borne diseases, are
restricted to those regions because of the restricted
geographical distribution of their hosts (Woolhouse
and Gowtage-Sequeria 2005). Humans in temper-
ate regions suffer from only a small subset of the
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
4
4
4
4
4
5
5
5
6
Disease diversity Disease composition
Latitudinal distribution
range
Equator line
Latitude
Latitude
Latitude
(a) (b) (c)
Figure 2.1 At a global scale, three macroscopic patterns for human diseases emerge: (a) the relationship between human disease species
diversity and latitude; (b) the relationship between latitude and disease species composition, where disease species comprising smaller
assemblages at high latitudes constitute a subset of the species in richer tropical areas (nested pattern); numbers indicate different parasite
species; (c) the relationship between latitudinal geographic range of human diseases and latitudinal centroids of diseases (Rapoport’s rule).

40. GLOBAL SPATIAL PATTERNS OF INFECTIOUS DISEASES 21
requirements of their hosts restrict the range
of many of these pathogens to tropical regions.
According to Woolhouse and Gowtage-Sequeria
(2005), 58% of 1,407 recognized species of human
pathogens are zoonotic and thus constrained by the
animal host’s spatial range. Because many of these
animal hosts are tropical, most actual and potential
human pathogens are endemic to tropical zones.
Latitude and the geographical range of
human pathogens
According to Rapoport’s rule, species whose geo-
graphical ranges are centered at higher latitude
tend to be distributed over a larger latitudinal
range (Gaston and Blackburn 2000). This rule is
valid for some human pathogens, for mean latitude
and disease ranges (Fig. 2.1c) are positively corre-
lated for five of the six pathogen categories consid-
ered, namely protozoa, fungi, bacteria, helminthes,
and vector-transmitted viruses (Guernier and
Guégan, submitted). The exceptions to the rule
are directly transmitted viruses. Despite previous
doubts about the existence of Rapoport’s rule for
the southern hemisphere (see Rohde 1999) and its
generality as a common pattern in macroecology
(Gaston and Blackburn 2000), the spatial trend for
the five groups of human pathogens is also sup-
ported in the southern hemisphere. Moreover, this
pattern also occurs in the tropics, although several
previous studies suggested that it is limited to the
Palearctic and Neartic above latitudes of 40–50°N
(Chown et al. 2004). Thus human diseases centered
at higher latitudes have wider geographical ranges
than what it is generally observed for diseases
endemic to the intertropical belt.
Geographical area and the species diversity
of human pathogens
Perhaps more than any other ecological pattern,
the species–area relationship has influenced
the development of ecology. Smith and collabor-
ators (2007) identified three distinct categories of
species–area relationships for human diseases
(Fig. 2.2). First, directly transmitted diseases, such
as measles and pertussis, do not show a significant
species–area relationship (Fig. 2.2). In other words,
(see Finlay 2002), the similarity of the effect of lati-
tude in these examples is striking.
Longitude and the species diversity of
human pathogens
In contrast to the latitudinal gradient of species
richness, the tendency for richness to vary with
longitude has been largely ignored (Gaston and
Blackburn 2000). Yet, the diversity of human dis-
eases is generally highest in continental Africa and
is lower in both southern America and southeast
Asia (unpublished data). This spatial pattern prob-
ably reflects in part the long-distance dispersal of
diseases by humans during their history of expan-
sion and migration, as in the example of fungal
pathogens that followed the American migration
of humans from the north to the south (Fisher et al.
2001). Inevitably, increasing global travel, trade,
and migration (Wilson 1995) will weaken this
spatial trend.
Latitude and the nested pattern of
human pathogens
As in animal and plant communities, human
patho gens are distributed in a nested species struc-
ture (Guernier et al. 2004): some species are widely
distributed and occur in many local communities,
whereas others have more restricted distributions
and occur only in a subset of the richest local com-
munities (Fig. 2.1b). Together with the latitudinal
gradient mentioned above, this means that some
parasites only occur in tropical regions, others
occur everywhere, but very few (e.g., Lyme dis-
ease) occur only in temperate areas (see Guernier
et al. 2004). Pathogens that occur in tropical and
temperate zones are generally directly transmitted
viruses, bacteria and fungi, which are internal to the
host and therefore little affected by environmental
variability. This category of disease agents repre-
sents around 36% of 332 pathogen species described
by Smith et al . (2007); their dispersal is primarily
drive by contagion (Guernier et al. 2004). In contrast,
pathogens with external stages (helminth worms,
vector-transmitted pathogens, and reservoir-borne
diseases) are more strongly influenced by environ-
mental conditions; the ranges and environmental

41. 22 THE HISTORY AND VARIATION OF HUMAN GENES
In summary, geographical barriers rarely
restrict the large-scale dispersal of directly trans-
mitted pathogens. The local diversity of these
pathogens—to which human populations are
exposed—is large and probably a significant pro-
portion of global diversity (Fig. 2.2). At the other
extreme, the ranges of multihost reservoir diseases
and zoonotic diseases do not differ markedly from
the ranges of their macroscopic hosts, and they
show some well-known biogeographical patterns:
species richness and species composition gradients
with latitude and longitude, range size with lati-
tude, species richness–area curves. Within these
two groups of pathogens, many novel, endemic
pathogen species probably exist with spatial dis-
tributions largely driven by that of their reservoir
species and with high species diversity in the trop-
ics. New emerging diseases will likely originate
from animal reservoirs, especially those in the
tropics. International exotic animal trade may be
an excellent pathway for disseminating such emer-
ging diseases into ‘microbe-free’ regions around
the globe (Di Giulio and Eckburg 2004).
Historical patterns of the distribution
of disease
It is unlikely that early modern humans faced the
pathogen species diversity that we know today, for
many diseases—e.g., coccidioidomycosis (Fisher
the species diversity within a local community
does not differ statistically from that observed at
the largest scale (Fig. 2.2), and communities from
adjacent sites are not more similar to each other
than they are to those from more distant sites.
This suggests that such parasites disperse rapidly
over large distances, thus maintaining their global
distribution.
Second, multihost diseases such as trypano-
somiasis, with human hosts and non-human reser-
voirs or vectors, have a positive species–area curve
(Fig. 2.2). For these diseases, increasing the size of
the sampling area increases the number of patho-
gen species, which suggests that they are to some
extent endemic to certain localities, as discussed
earlier.
Third, reservoir host diseases, such as monkey-
pox virus or Ebola virus, which require an animal
to spread, follow a positive species–area curve
(Fig. 2.2). For this category of diseases, for which
transmission from person to person is impossible
or extremely rare and humans are unusual, acci-
dental hosts and not part of the normal life cycle,
pathogen communities from distant localities are
composed of distinct pathogen species, for many
zoonotic parasites are restricted to locally distrib-
uted reservoir species, such as tropical rodents.
Therefore it is likely that with increasing sampling
effort more zoonotic pathogen microbes will be
discovered in the future.
Surface area (in Log)
Species diversity ( in Log)
2
1.5
1
Figure 2.2 Areal species richness diversity and surface area size (double-logarithmic transformations) for three categories of human
pathogens: contagious diseases (black squares), zoonotic diseases (open triangles), and multihost diseases (black circles). Each point represents
a pathogen species. Modified from Smith
et al. (2007).

42. GLOBAL SPATIAL PATTERNS OF INFECTIOUS DISEASES 23
Pathogen distribution and human genetic
evolution: the case of sickle cell disease
Hemoglobin and sickle cell disease
Sickle cell disease is caused by a change in the
hemoglobin protein (Pauling et al. 1949). Individuals
with two copies of the Hb S variant of the π-globin
(homozygous Hb SS) develop stiff, distorted red
blood cells that have difficulty passing through
the body’s blood capillaries. Tissues with reduced
blood flow become damaged. Eventually, the dis-
order causes anemia, joint pain, a swollen spleen,
and often severe infections that lead to death.
Homozygous individuals have a short life expect-
ancy and rarely reproduce. Heterozygotes for this
variant (individuals that present the ‘normal’ vari-
ant Hb A and the ‘abnormal’ one Hb S) produce
both sickle-shaped red cells and normal ones but
rarely develop any symptoms (Ashley-Koch et al.
2000). Because persons homozygous for the sickle
cell gene very rarely reproduce, the sickle cell allele
(Hb S) should decline in every generation within
populations and should therefore be observed only
at very low frequencies if at all. This, however, is
not the case everywhere.
Sickle cell trait distribution
High frequencies of more than 20% of the sickle cell
trait are found in populations across a broad belt of
tropical Africa (Allison 1954a,b) (Fig. 2.3). Elevated
frequencies are also found in Greece, Turkey, and
India (Singer 1953). Intermediate frequencies are
found in, for example, Sicily, Algeria, Tunisia, Yemen,
Palestine, and Kuwait. The sickle cell gene is thus
found in a large and nearly continuous region of the
Old World (and in populations that have recently
emigrated from there), whereas the trait is almost
completely absent from northern Europe, Australia,
and North America (Singer 1953). Two main hypoth-
eses have been proposed to explain the observed
high frequencies within certain populations (Neel
1951) despite its highly deleterious effects: either
the sickle cell allele frequently arises by recurrent
mutation within populations, or the heterozygous
individuals for the sickle cell allele (Hb AS) have a
selective advantage (i.e., overdominance) over both
the ‘normal’ homozygotes (Hb AA) and the sickle
cell ones (Hb SS). Overdominance would enable
et al. 2001), smallpox (Oldstone 1998), the plague
(Scott and Duncan 2001), leprosy (Monot et al. 2005),
and many zoonotic diseases (Oldstone 1998)—
emerged only a few thousand years ago. Leprosy,
for instance, originated in Eastern Africa or the Near
East and was introduced into the Americas within
the past 500 years (Monot et al. 2005). Similarly,
the fungal disease Coccidioides immitis probably
appeared in South America within the past 10,000
years via human migrations (Fisher et al . 2001).
Although current macroscopic patterns of disease
distribution and occurrence cannot precisely mir-
ror the situation of early human populations, the
broad macroecological patterns of diseases dis-
cussed earlier are likely to have been similar.
To summarize this section: large-scale human-
pathogen interactions show two general spatial
trends: (a) globally distributed pathogens selected
throughout history as strains adapted to human
populations, and (b) endemic pathogens, primarily
zoonoses, whose species diversity is highest in the
tropics.
Pathogen distribution and human
genetic evolution
Did differences in levels of exposure to certain
patho gens or groups of pathogens differentially
affect the genetic evolution of human populations?
The answer is yes! Of several good examples,
we focus here on two. The first concerns the gene
that codes for the π-globin found in hemoglobin.
Some mutants of this gene have been maintained at
high frequencies in certain human populations—
despite their obvious deleterious effects—because
they confer resistance against particular patho-
gens. The second concerns a group of genes with
immune function, the HLA (human leucocyte anti-
gen) genes also known as major histocompatibility
complex (MHC). Human populations exposed to a
higher diversity of disease agents display higher
genetic diversity at HLA genes than is expected
under a simple neutral model. While genetic drift
and demographic history have also been important
in shaping their patterns of diversity, we argue that
selection exerted by local pathogen communities
has influenced the local evolution of these human
genes.

43. 24 THE HISTORY AND VARIATION OF HUMAN GENES
cell heterozygotes to malaria. Resistance can be
mediated by the reduced ability of parasites to
grow and multiply in Hb AS red cells (Friedman
1978) or by their early removal from circulation
(Luzzatto et al. 1970). Thus, parasite-infected Hb
AS erythrocytes sickle more than non-parasitized
Hb AS cells, which may lead to the parasites’
intracellular death (Friedman et al. 1979) or their
removal by the immune system (Luzzatto et al.
1970). Although the latter may be largely the
result of innate immunity, recent data suggest
that acquired immunity may also be involved
(Williams 2006). The contributions of these proc-
esses to protection against malaria in vivo are still
largely undetermined.
Malaria and other red cell polymorphisms
The Hb S variant is not the only polymorphism
of red cell proteins that has been selected for pro-
tection against malaria (Table 2.1). As shown in
Fig. 2.3, the distribution of these variants is simi-
lar to the geographical distribution of malaria.
However, human double heterozygotes for some of
these variants, such as Hb S and π-thalassemia, or
Hb S and Hb C, also suffer from a type of sickle cell
disease (as do homozygotes) that reduces their fit-
ness, so that these variant alleles tend to be mutu-
ally exclusive in human populations (Allison 1964).
By comparison, other combinations of variants, for
which there is no negative interaction between
mutants, can be found at high frequencies (as is
the case for G6PD deficiency and the Hb S variant;
Fig. 2.3).
the deleterious allele to be maintained at a stable
polymorphism.
For the first hypothesis, the mutation rate would
have to be very high and confined to certain human
populations. Vandepitte et al. (1955) demonstrated
that the mutation rate in hemoglobin was not high
enough to maintain the observed frequencies of
the sickle cell allele within populations. Therefore
selection in favour of heterozygous individuals
seems the best explanation. Why, then, had the
gene become common in some parts of the world
but not in others? Why did human heterozygotes
have an advantage only in certain communities?
Malaria and the sickle cell trait: the advantage of
heterozygotes
Allison et al. (1952) proposed that malaria could
be the selective agent behind this process by not-
ing that the geographical distribution of the gene
for hemoglobin S and the distribution of malaria
in Africa virtually overlapped (see Fig. 2.3). And
indeed, Allison (1954a,b) later demonstrated that
the prevalence and intensity of the infectious dis-
ease were lower in Hb AS heterozygote individuals
than in Hb AA homozygous individuals. Hb AS
children are more likely to survive than Hb AA
children in highly malaria endemic areas (Aidoo
et al. 2002).
Mechanisms of resistance: an intimate association
between malaria and red cells
Several factors are likely to contribute in vary-
ing degrees to the partial resistance of sickle
Endemic
malaria 2-4
7D-9.9
G6PD
deficiency
1DD-14.9
215
4-6
6-3
3-1D
1D-12
12-14
214
Figure 2.3 Maps showing the relation between (a) the geographic presence of malaria before 1920, (b) the frequencies (%) of the Hb S
allele, and (c) the frequencies (%) of the G6PD deficiency in males in Africa, southern Europe, and west Asia. For G6PD, only the frequencies
higher than 7% are reported. In many regions where malaria is prevalent but not the Hb S or the G6PD deficiency, other mutant hemoglobins
may be found. Data mapping compilation from different sources by one of the authors (FP).

44. GLOBAL SPATIAL PATTERNS OF INFECTIOUS DISEASES 25
the human genome and in the genome of other
vertebrates. For instance, more than 350 alleles are
known for the Class I HLA B gene alone (Robinson
et al. 2001).
Several pieces of evidence suggest that this
extreme polymorphism is, at least in part,
maintained by balancing selection (Meyer and
Thomson 2001). Thus, within human populations,
the number of HLA alleles is far higher than the
number expected under neutrality. Furthermore,
when alleles do not differ in their selective effect
(Potts and Wakeland 1993), they are generally
more evenly distributed within populations than
expected under a pure neutral model of evolution
(Hedrick and Thomson 1983), and heterozygote
excesses are observed more often than predicted
by Hardy-Weinberg expectations (see Markow
et al. 1993).
Several hypotheses have been proposed to
explain selection operating on HLA genes within
populations, including MHC-dependent mate
choice (Penn et al. 2002), spontaneous abortion
(Thomas et al. 1985), and the selection imposed
by the various species or strains of pathogens
infecting human populations (Klein and Ohuigin
1994). This latter kind of selection, generally called
‘pathogen-driven balancing selection,’ is expected
to operate when different alleles are selected
Malaria and human gene evolution
Malaria has been a major determinant in the evo-
lution of several human genes, especially those
involved in the constitution of red blood cells. It
has in fact been suggested that malaria was (and
still is) one of the most powerful forces of selection
operating on humans. Despite the widespread use
of drugs, malaria is still responsible for between
1.5 and 2.7 million deaths each year, primarily of
children under the age of five years (Phillips 2001),
and as such still has a major impact on human fit-
ness in many populations. This infectious disease
has shaped the evolution of several human genes.
Variations in pathogen diversity and human
genetic evolution: the HLA genes
HLA is a complex of genes with a major role in the
recognition and presentation of non-self (antigens)
to the effector cells of the immune system (T-cells)
(Zinkernagel and Doherty 1974). Class I genes (A, B,
and C), which are expressed in almost all cells, are
involved in the recognition of intracellular non-
self (e.g., viruses); class II genes (DP, DQ, and DR),
which are only expressed in the antigen present-
ing cells, are mainly involved in the recognition of
extracellular pathogens (or non-self). HLA genes
are among the most polymorphic genes, both in
Table 2.1 Examples of red cell genes involved in malaria resistance, and which polymorphism worldwide may have been partly determined by the
presence/absence of malaria
Cell component Variant Gene Protein and function Effect on malaria Main distribution
Hemoglobin Hb S HBBπ-globin (hemoglobin component)Protects against severe malaria Africa, Middle East,
India, Mediterranean
Hb C HBBπ-globin (hemoglobin component)Protects against severe malaria Africa
Hb E HBBπ-globin (hemoglobin component)Reduces parasite invasion Southeast Asia
≥-thalassemiaHBAπ-globin (hemoglobin component)Protects against severe malaria Africa, Mediterranean
India, Southeast Asia
π-thalassemiaHBB≥-globin (hemoglobin component)Protects against severe malaria Africa, Mediterranean,
India, Southeast Asia,
Melanesia
Red cell enzymes G6PD deficiency G6PD Glucose-6-phosphate dehydrogenase
(protects against oxidative stress)
Protects against severe malaria Africa, Mediterranean,
India, Southeast Asia
Red cell membrane FY*O FY Duffy antigen (Chemokine receptor) Protects against
Plasmodium
vivax
a
Africa
a
Plasmodium vivax is one of the agents of the human malaria. The others are Plasmodium falciparum, Plasmodium malariae, and Plasmodium ovale.
The deadliest is
P. falciparum.

45. 26 THE HISTORY AND VARIATION OF HUMAN GENES
intracellular stage). The relationship is stronger for
HLA B than for HLA A, suggesting that the HLA
B gene might be under stronger balancing selec-
tion than the other Class I genes. This finding is in
good agreement with other genetic and immuno-
logical studies, which have shown a stronger
involvement of HLA B than of HLA A in the recog-
nition of non-self (Kiepiela et al . 2004). Subdividing
the intracellular pathogens into viruses, bacteria,
and protozoans shows that HLA class I diversity
is mainly correlated with virus species richness,
suggesting that virus diversity, which is higher
in the tropics, might exert stronger selective pres-
sure on immune genes than any other category of
pathogens.
Pathogens are not distributed evenly in space
(see above). They form an ecologically heterogene-
ous landscape in which spatially separated human
populations have been submitted to different
selected regimes, leading populations to adapt to
their local parasitic conditions. Today, the traces of
these different evolutionary histories may be found
in the genomes of human populations.
Infectious diseases and human
life-history traits
Human populations differ in life-history traits such
as survival, fertility, age at first menstruation, and
age at menarche (Thomas et al. 2001; Barret et al .
2002). Social scientists and demographers have tra-
ditionally assumed that socioeconomic variables—
such as development, modernization, culture,
and family planning programs—predominate in
determining these differences. Variation in human
life-history traits, however, might also have evo-
lutionary explanations that rely on differences in
characteristics of the environment, including biotic
interactions (Stearns 1992). For instance, in many
plant and animal species, parasites play an import-
ant role in the evolution of host life-history traits (see,
e.g., Kris and Lively 1998; Fredensborg and Poulkin
2006). Parasites use resources that the host could
otherwise use for its own growth, maintenance, or
reproduction. Direct costs of this exploitation lead
to variation in life-history traits among individu-
als and populations. Alternatively, changes in host
life-history traits may be an adaptive response to
because of their ability to provide higher resis-
tance against certain species of pathogens or certain
strains, and is supported by several pieces of evi-
dence. Thus, certain alleles confer more resistance
against certain pathogens (e.g., against malaria or
HIV) and individuals heterozygous for HLA genes
are more resistant to some infectious diseases than
homozygous individuals (overdominant selection)
(see Penn 2002).
There is therefore little doubt that the evolution
of HLA in humans is linked to pathogens. But can
this link explain why HLA diversity varies among
human populations worldwide? In other words,
might pathogenic species richness and compos-
ition have influenced the local evolution of these
immune genes in modern humans?
HLA genetic diversity and pathogen-driven selection
Across 61 populations (Fig. 2.4), there is a strong
positive correlation between HLA class I diver-
sity and pathogen species diversity, especially for
genes A and B after accounting for the effect of
human demography on HLA diversity (for details
see Prugnolle et al . 2005). Note that, as HLA class I
genes (A, B, C) are mainly involved in the presen-
tation and recognition of intracellular pathogens,
the analysis considered only intracellular disease
agents (viruses, obligate and facultative intracel-
lular bacteria, and protozoans with at least one
30
μ0.4
μ0.2
0.0
0.2
0.4
0.6
35 40 45
Virus species richness
Partials of Hs
HLA*
/distance
from Africa
50 55 60
Figure 2.4 Partial residuals (after having taken into account
the effect of demography) of Hs
HLA
*( = log[Hs/(1-Hs)]) against
virus species diversity for the HLA B gene. For details refer to
Prugnolle
et al. (2005). Hs is the HLA genetic diversity. Dot size
is inversely proportional to the number of human populations
coming from the same region in order to avoid statistical bias due
to over-representation of some human communities. Modified from
Prugnolle
et al. (2005).

46. GLOBAL SPATIAL PATTERNS OF INFECTIOUS DISEASES 27
infants with a low birthweight are at a higher risk
of expressing chronic diseases later in life (e.g.,
cardiovascular diseases, diabetes, certain cancers,
impairment of hearing and vision; cf. Chapter 19),
selection in these environments is expected to
favour individuals producing larger children. Even
if some of these somatic diseases occur late in life
(i.e., after reproduction), they are likely to be detri-
mental to an individual’s fitness, for they reduce its
capacity to deliver grandparental care.
In countries where the risks of parasitic infec-
tions are high (i.e., numerous developing coun-
tries), women are, other things being equal, also
expected to deliver infants with a high birthweight.
Indeed, infants with low birthweight generally
have an increased vulnerability to infectious dis-
eases because of impaired immune function (e.g.,
Moore et al. 1999). Given that offspring mortality
(due to infections), more than fertility, is likely to
be the primary determinant of fitness variation
between reproducing females, mothers in parasite-
rich envir onments will have a particular repro-
ductive interest in producing larger, more resistant,
children. The study by Thomas et al. (2004) also
predicts that once a threshold in infection risk is
reached, birthweights significantly increase with
the number of diseases present.
Finally, in environments where adverse envir-
onmental conditions—famine, drought, or
accidents—are frequent, selective pressures for
producing large offspring are likely to be relaxed
because the negative impacts of environmental fac-
tors on individual fitness are largely independent
of birthweight. Instead, the fitness costs incurred
by the mothers when producing large children
(e.g., reduced survival, lower probability of subse-
quent reproduction, cf Bereczkei et al. 2000) are less
well compensated by reproductive advantages, so
that natural selection should favor individuals pro-
ducing smaller babies.
Human behavior and culture, and the species
diversity of human pathogens
Can infectious diseases also alter human culture?
One example is the protozoan Toxoplasma gon-
dii (see Lafferty 2006), which lives in the nervous
system. Cats are the final hosts of T. gondii, and
parasitism. One solution developed by many ani-
mal species against parasites is the adjustment of
life-history traits to compensate for their negative
effects on fitness. By analogy, we here suggest that
parasitic and infectious diseases have also affected
human life-history traits.
Human fertility and the species diversity of
human pathogens
Guégan et al. (2001) performed a comparative ana-
lysis on 150 countries to explore the relationship
between the diversity of infectious disease agent
species and human fertility. The prediction was
that humans in countries with high quantities
and diversity of virulent parasites should compen-
sate for the high offspring mortality by increasing
their reproductive investment. In agreement with
this prediction, human fertility was positively
related to the diversity of disease types encoun-
tered by local human communities. The correla-
tive nature of this study prohibits any conclusions
about the causal mechanisms relating diseases
and fertility. One important finding was that a
set of co-occurring diseases rather than a unique
infectious disease is the key to understanding
the link between parasitism and human life-his-
tory traits.
Human birthweight and the species diversity
of human pathogens
Human populations differ in birthweight (Vangen
et al. 2002). Many variables influence prenatal
growth and birthweight in humans, e.g., maternal
energy supply, maternal stature, physical work,
stress, temperature, disease status, smoking status,
gestation length, and altitude (see Koupilova et al.
2000; Wells 2002). Thomas et al. (2004) present a the-
oretical model to suggest that a significant part of
the variability in human birthweight results from
adaptive responses among which the risk of fitness
reduction predominates (this idea has not yet been
formally tested). In stable, well-resourced, low-par-
asite environments (i.e., most modern industrial-
ized countries), somatic (i.e., non communicable)
diseases are likely to be an important source of
fitness variation among individuals. Because

47. 28 THE HISTORY AND VARIATION OF HUMAN GENES
also score higher in the ‘neurotic’ cultural dimen-
sions of uncertainty avoidance and of masculine
sex roles (Fig. 2.5). Many infectious agents may
play a role in some neuropsychiatric disorders
(McSweegan 1998), and a recent study has pointed
out that nearly half (49%) of all emerging viruses
today are characterized by encephalitis or serious
neurological clinical symptoms in humans (Olival
and Daszak 2005), highlighting the importance of
neurotropic disease agents in medicine and social
culture. Recent investigations have illuminated the
molecular mechanisms that enable neurotropic
viruses to alter brain function and lead to neurobe-
havioural disorders (Volmer et al . 2006).
Although parasitic and infectious diseases have
had a major impact on human population demog-
raphy around the world, relatively few attempts
have been made to investigate how disease- causing
agents have affected human biology. The few stud-
ies above suggest that their influence might be
substantial. The importance of parasites as a deter-
minant of human life histories as compared to
other factors remains to be assessed.
Summary
Human infectious diseases are not distributed 1.
at random: contagious diseases are everywhere;
zoonotic pathogens are more locally concentrated
in the tropics.
Therefore, human communities are not all 2.
equally exposed to disease; populations in the
tropics have suffered, and are still suffering, from
a greater diversity of pathogens.
Pathogens have exerted strong selective pres-3.
sures on modern humans, which in turn have
evolved resistant genotypes. Results of this evolu-
tion may be observed in the genomes of current
human populations.
Because pathogens are not distributed homoge-4.
neously, human populations have been submitted
to qualitatively and quantitatively different selec-
tive pressures. Therefore, different human popu-
lations may have followed different evolutionary
pathways.
An allele that confers resistance against a patho-5.
gen may reduce fitness in the absence of the patho-
gen. The evolution of an allele conferring resistance
rodents are its normal intermediate hosts, but the
parasite also develops well in humans. The parasite
induces behavioral alterations in rodents that lead
to an increased risk of predation by cats (Berdoy
et al. 2000). In humans, Toxoplasma infections result
in slight personality changes, for example guilt
proneness, a form of neuroticism, and reduced
psychomotor performance (Havlicek et al. 2001).
Because cats do not normally prey on humans,
these behavioral changes are of no apparent value
to the parasite. They could be manifestations of
mechanisms evolved in the past to manipulate the
normal rodent hosts, or they may be mere coin-
cidental pathology. Whatever the cause of such
changes, Lafferty’s results suggest that Toxoplasma
could affect specific elements of human culture.
He found that countries with high Toxoplasma
prevalence have a higher aggregate neuroticism
score, and Western nations with high prevalence
0
0
0
20
40
60
80
20
40
60
Uncertainty avoidance
80
100
(a)
10 20 30 40 50 60 70
0
‘ Masculine’ sex roles
(b)
10 20 30
National prevalence of T. gondil (Western nations)
40 50 60 70
Figure 2.5 Association between (a) the cultural dimension of
uncertainty avoidance and the prevalence of
Toxoplasma gondii in
Western nations, and (b) the cultural dimension of masculine sex
roles avoidance and the prevalence of
T. gondii in Western nations.
From Lafferty (2006).

48. GLOBAL SPATIAL PATTERNS OF INFECTIOUS DISEASES 29
Which kinds of pathogens are most likely to spread
in human populations in the future (cf. Chapter 16
To what extent will the homogenization of zoonotic
diseases interfere with human adaptation and evo-
lution? If pathogen pressure maintains much human
polymorphism, what will be the effects of disease
control and eradication on our own evolution?
Acknowledgments
The authors thank the Institut de Recherche pour le
Développement and the Centre National de la Recherche
Scientifique for financial support. The authors are
also grateful to Professors Steve Stearns and Jacob
Koella for their judicious comments on an early
draft and for inviting us to write this chapter.
Finally, thanks are due to Marc Choisy for improv-
ing our English.
against a pathogen is often the result of a complex
balance between costs and benefits.
The life-history traits of early humans (like 6.
those of many animals) were shaped by inter-
actions with parasites, but to what extent those of
modern humans result from selection by disease is
a matter of debate. Better comparative statistics on
life-history traits in humans (in addition to traits
usually surveyed by anthropologists) are needed
to explore this important issue.
Given the current epidemiological transition into 7.
which modern societies have entered (less parsitic
load), analyses of the connections between life-
history traits and disease biology can also help us
to understand evolutionary responses in fertility,
sexual dimorphism, and life span (cf. Chapter 7).
These considerations stimulate important ques-8.
tions about the role of parasites in our evolution:

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