Encyclopedia of
Genetics
Revised Edition
Alphabetical List of Contents
Volume 1
Aggression . . . . . . . . . . . . . . . . . . 1
Aging . . . . . . . . . . . . . . . . . . . . . 3
Albinism . . . . . . . . . . . . . . . . . . . 9
Alcoholism. . . . . . . . . . . . . . . . . . 11
Allergies . . . . . . . . . . . . . . . . . . . 13
Altruism . . . . . . . . . . . . . . . . . . . 16
Alzheimer’s Disease . . . . . . . . . . . . . 19
Amniocentesis and Chorionic
Villus Sampling. . . . . . . . . . . . . . 23
Ancient DNA . . . . . . . . . . . . . . . . 27
Animal Cloning . . . . . . . . . . . . . . . 31
Anthrax . . . . . . . . . . . . . . . . . . . 35
Antibodies . . . . . . . . . . . . . . . . . . 38
Antisense RNA . . . . . . . . . . . . . . . 42
Archaea . . . . . . . . . . . . . . . . . . . 45
Artificial Selection . . . . . . . . . . . . . 48
Autoimmune Disorders . . . . . . . . . . . 51
Central Dogma of Molecular
Biology . . . . . . . . . . . . . .
Chemical Mutagens . . . . . . . . .
Chloroplast Genes . . . . . . . . . .
Cholera . . . . . . . . . . . . . . . .
Chromatin Packaging . . . . . . . .
Chromosome Mutation . . . . . . .
Chromosome Structure . . . . . . .
Chromosome Theory of Heredity .
Chromosome Walking and
Jumping . . . . . . . . . . . . . .
Classical Transmission Genetics. . .
Cloning. . . . . . . . . . . . . . . .
Cloning: Ethical Issues . . . . . . .
Cloning Vectors . . . . . . . . . . .
Color Blindness . . . . . . . . . . .
Complementation Testing. . . . . .
Complete Dominance . . . . . . . .
Congenital Defects. . . . . . . . . .
Consanguinity and Genetic Disease
Criminality . . . . . . . . . . . . . .
Cystic Fibrosis . . . . . . . . . . . .
Cytokinesis . . . . . . . . . . . . . .
Bacterial Genetics and Cell
Structure . . . . . . . . . . . . . . . . . 54
Bacterial Resistance and Super
Bacteria . . . . . . . . . . . . . . . . . . 61
Behavior . . . . . . . . . . . . . . . . . . . 65
Biochemical Mutations . . . . . . . . . . . 70
Bioethics . . . . . . . . . . . . . . . . . . . 73
Biofertilizers . . . . . . . . . . . . . . . . . 77
Bioinformatics. . . . . . . . . . . . . . . . 79
Biological Clocks . . . . . . . . . . . . . . 83
Biological Determinism. . . . . . . . . . . 86
Biological Weapons . . . . . . . . . . . . . 88
Biopesticides . . . . . . . . . . . . . . . . 92
Biopharmaceuticals . . . . . . . . . . . . . 96
Blotting: Southern, Northern,
and Western . . . . . . . . . . . . . . . 98
Breast Cancer . . . . . . . . . . . . . . . 101
Burkitt’s Lymphoma . . . . . . . . . . . . 106
Cancer . . . . . . . . . . .
cDNA Libraries . . . . . .
Cell Culture: Animal Cells.
Cell Culture: Plant Cells . .
The Cell Cycle . . . . . . .
Cell Division . . . . . . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Developmental Genetics . . .
Diabetes . . . . . . . . . . . .
Dihybrid Inheritance . . . . .
Diphtheria . . . . . . . . . . .
DNA Fingerprinting . . . . . .
DNA Isolation . . . . . . . . .
DNA Repair . . . . . . . . . .
DNA Replication. . . . . . . .
DNA Sequencing Technology.
DNA Structure and Function .
Down Syndrome . . . . . . . .
Dwarfism . . . . . . . . . . . .
109
115
117
120
122
125
xix
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
128
131
133
137
140
144
147
152
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
158
160
166
170
174
179
181
184
187
191
193
195
198
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
201
207
210
214
216
220
223
227
233
237
244
248
Emerging Diseases . . . . . . . .
Epistasis . . . . . . . . . . . . .
Eugenics . . . . . . . . . . . . .
Eugenics: Nazi Germany . . . .
Evolutionary Biology . . . . . .
Extrachromosomal Inheritance.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
252
255
259
264
267
274
Encyclopedia of Genetics, Revised Edition
Forensic Genetics . . . . . . . . . . . . . 279
Fragile X Syndrome . . . . . . . . . . . . 282
Gel Electrophoresis . . . . . . . .
Gender Identity . . . . . . . . . .
Gene Families . . . . . . . . . . .
Gene Regulation: Bacteria . . . .
Gene Regulation: Eukaryotes . . .
Gene Regulation: Lac Operon . .
Gene Regulation: Viruses . . . . .
Gene Therapy . . . . . . . . . . .
Gene Therapy: Ethical and
Economic Issues . . . . . . . .
Genetic Code . . . . . . . . . . .
Genetic Code, Cracking of . . . .
Genetic Counseling . . . . . . . .
Genetic Engineering . . . . . . .
Genetic Engineering: Agricultural
Applications . . . . . . . . . . .
Genetic Engineering: Historical
Development . . . . . . . . . .
Genetic Engineering: Industrial
Applications . . . . . . . . . . .
Genetic Engineering: Medical
Applications . . . . . . . . . . .
Genetic Engineering: Risks . . . .
Genetic Engineering: Social
and Ethical Issues . . . . . . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
285
287
289
291
295
298
301
304
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
309
313
319
321
326
. . . . 332
. . . . 335
. . . . 339
. . . . 343
. . . . 347
. . . . 351
Genetic Load. . . . . . . . . . . .
Genetic Screening . . . . . . . . .
Genetic Testing . . . . . . . . . .
Genetic Testing: Ethical and
Economic Issues . . . . . . . .
Genetically Modified (GM)
Foods . . . . . . . . . . . . . .
Genetics, Historical Development
of. . . . . . . . . . . . . . . . .
Genetics in Television and Films .
Genome Size . . . . . . . . . . . .
Genomic Libraries . . . . . . . . .
Genomics. . . . . . . . . . . . . .
. . . . 354
. . . . 357
. . . . 360
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
370
376
378
380
384
Hardy-Weinberg Law . . . . . .
Heart Disease . . . . . . . . . .
Hemophilia . . . . . . . . . . .
Hereditary Diseases . . . . . . .
Heredity and Environment . . .
Hermaphrodites . . . . . . . . .
High-Yield Crops. . . . . . . . .
Homeotic Genes . . . . . . . . .
Homosexuality . . . . . . . . . .
Human Genetics . . . . . . . . .
Human Genome Project . . . .
Human Growth Hormone . . .
Huntington’s Disease . . . . . .
Hybridization and Introgression
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
389
392
396
399
406
411
413
416
419
421
428
432
434
437
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
484
485
489
491
. . . . 364
. . . . 366
Volume 2
Hybridomas and Monoclonal
Antibodies . . . . . . . . . . . . . . . . 441
Hypercholesterolemia . . . . . . . . . . . 445
Icelandic Genetic Database . . . . .
Immunogenetics . . . . . . . . . . .
In Vitro Fertilization and Embryo
Transfer . . . . . . . . . . . . . .
Inborn Errors of Metabolism . . . .
Inbreeding and Assortative Mating .
Incomplete Dominance . . . . . . .
Infertility . . . . . . . . . . . . . . .
Insurance. . . . . . . . . . . . . . .
Intelligence . . . . . . . . . . . . .
Lactose Intolerance . .
Lamarckianism. . . . .
Lateral Gene Transfer .
Linkage Maps . . . . .
. . . 447
. . . 449
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Mendelian Genetics . . . . .
Metafemales . . . . . . . . .
Miscegenation and
Antimiscegenation Laws .
Mitochondrial Diseases . . .
Mitochondrial Genes . . . .
Mitosis and Meiosis . . . . .
Model Organism:
Arabidopsis thaliana . . . .
Model Organism:
Caenorhabditis elegans . . .
Model Organism:
Chlamydomonas reinhardtii .
454
458
461
465
468
471
474
Klinefelter Syndrome . . . . . . . . . . . 479
Knockout Genetics and Knockout
Mice . . . . . . . . . . . . . . . . . . . 481
xx
.
.
.
.
.
.
.
.
. . . . . . . 494
. . . . . . . 499
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
501
503
505
509
. . . . . . . 513
. . . . . . . 516
. . . . . . . 520
Alphabetical List of Contents
Model Organism:
Drosophila melanogaster . .
Model Organism:
Escherichia coli . . . . . . .
Model Organism:
Mus musculus . . . . . . .
Model Organism:
Neurospora crassa. . . . . .
Model Organism:
Saccharomyces cerevisiae. . .
Model Organism:
Xenopus laevis . . . . . . .
Model Organisms . . . . . .
Molecular Clock Hypothesis
Molecular Genetics . . . . .
Monohybrid Inheritance . .
Multiple Alleles . . . . . . .
Mutation and Mutagenesis .
Natural Selection . . . . . .
Neural Tube Defects . . . . .
Noncoding RNA Molecules .
Nondisjunction and
Aneuploidy . . . . . . . .
Pseudogenes . . . . . . . . . . . . . . . . 646
Pseudohermaphrodites . . . . . . . . . . 648
Punctuated Equilibrium. . . . . . . . . . 650
. . . . . . . 522
. . . . . . . 527
Quantitative Inheritance . . . . . . . . . 654
. . . . . . . 533
. . . . . . . 536
. . . . . . . 539
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
542
545
547
549
555
559
561
. . . . . . . 568
. . . . . . . 572
. . . . . . . 575
. . . . . . . 579
Oncogenes . . . . . . . . . . . . . . . . . 583
One Gene-One Enzyme
Hypothesis. . . . . . . . . . . . . . . . 586
Organ Transplants and HLA
Genes . . . . . . . . . . . . . . . . . . 588
Parthenogenesis . . . . . . . .
Patents on Life-Forms . . . . .
Paternity Tests . . . . . . . . .
Pedigree Analysis . . . . . . .
Penetrance . . . . . . . . . . .
Phenylketonuria (PKU) . . . .
Plasmids . . . . . . . . . . . .
Polygenic Inheritance . . . . .
Polymerase Chain Reaction . .
Polyploidy . . . . . . . . . . .
Population Genetics . . . . . .
Prader-Willi and Angelman
Syndromes. . . . . . . . . .
Prenatal Diagnosis . . . . . . .
Prion Diseases: Kuru and
Creutzfeldt-Jakob Syndrome
Protein Structure . . . . . . .
Protein Synthesis. . . . . . . .
Proteomics . . . . . . . . . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Race . . . . . . . . . . . . . .
Repetitive DNA . . . . . . . .
Restriction Enzymes . . . . . .
Reverse Transcriptase . . . . .
RFLP Analysis . . . . . . . . .
RNA Isolation . . . . . . . . .
RNA Structure and Function .
RNA Transcription and mRNA
Processing . . . . . . . . . .
RNA World . . . . . . . . . . .
.
.
.
.
.
.
.
Shotgun Cloning. . .
Sickle-Cell Disease . .
Signal Transduction .
Smallpox . . . . . . .
Sociobiology . . . . .
Speciation . . . . . .
Stem Cells . . . . . .
Sterilization Laws . .
Steroid Hormones . .
Swine Flu . . . . . . .
Synthetic Antibodies.
Synthetic Genes . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Tay-Sachs Disease . . . .
Telomeres . . . . . . . .
Testicular Feminization
Syndrome . . . . . . .
Thalidomide and Other
Teratogens . . . . . .
Totipotency . . . . . . .
Transgenic Organisms. .
Transposable Elements .
Tumor-Suppressor Genes
Turner Syndrome . . . .
Twin Studies . . . . . . .
592
594
596
599
602
604
606
609
611
613
617
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
658
664
667
670
672
674
676
. . . . . . 681
. . . . . . 686
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
691
692
696
700
704
708
710
715
717
720
723
725
. . . . . . . . . 727
. . . . . . . . . 728
. . . . . . . . . 731
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
733
736
739
742
746
748
750
. . . . . . 623
. . . . . . 626
Viral Genetics . . . . . . . . . . . . . . . 754
Viroids and Virusoids . . . . . . . . . . . 756
.
.
.
.
X Chromosome Inactivation . . . . . . . 759
Xenotransplants . . . . . . . . . . . . . . 761
XYY Syndrome . . . . . . . . . . . . . . . 764
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
631
634
638
643
xxi
Encyclopedia of Genetics, Revised Edition
Appendices
Biographical Dictionary of
Important Geneticists. . . . . .
Nobel Prizes for Discoveries in
Genetics . . . . . . . . . . . . .
Time Line of Major Developments
in Genetics . . . . . . . . . . .
Glossary . . . . . . . . . . . . . .
Bibliography . . . . . . . . . . . . . . . . 832
Web Sites . . . . . . . . . . . . . . . . . . 859
. . . . 767
. . . . 780
Indexes
Category Index . . . . . . . . . . . . . . . III
Personages Index. . . . . . . . . . . . . . VII
Subject Index . . . . . . . . . . . . . . . . XI
. . . . 784
. . . . 804
xxii
Aggression
Field of study: Human genetics and social
issues
Significance: Aggression refers to behavior directed
toward causing harm to others. Aggressive antisocial behavior is highly heritable, and antisocial
behavior (ASB) during childhood is a good predictor of ASB in adulthood and crime. Physical acts
of aggression are sometimes distinguished from the
more context-sensitive “covert” ASBs, including
theft, truancy, and negative peer interactions.
Key terms
antisocial behavior (ASB): behavior that violates rules or conventions of society and/or
personal rights
impulsivity: a tendency to act quickly without
planning or a clear goal in mind
irritability: a tendency to overreact to minor
stimuli; short-temperedness or volatility
liability: the risk of exhibiting a behavior; the
higher one’s score for a measure of liability,
the greater is one’s the risk of exhibiting the
behavior
serotonin: a neurotransmitter, 5-hydroxytryptamine (5-HT), present in blood platelets,
the gastrointestinal tract, and certain regions of the brain, which plays role in initiating sleep, blood clotting, and stimulating
the heartbeat, and levels of which have been
correlated with aggressive behavior as well as
depression and panic disorder
Aggression and Related Behaviors
Aggression or agonistic behavior in animals
is usually an adaptive response to specific environmental situations during competition for
resources, as in establishing dominance and a
territory or in sexual competition. Rat and mice
studies indicate it is partly genetic, because selective breeding produces strains that differ in
levels of aggression. Human aggression can
also represent a variety of natural responses to
challenging situations. Measures of aggression
vary, but of greatest concern are antisocial behaviors (ASBs) such as crime and delinquency
and whether some individuals are more likely
to engage in these behaviors than others.
The earliest evidence for a genetic contribution to these complex behaviors comes from
twin and adoptee studies. Genes also increase
the liability for many clinical conditions that include aggressive behaviors, such as conduct disorder (physically aggressive acts such as bullying or forced sexual activity) and antisocial
personality disorder (persistent violation of social norms, including criminal behavior) and
for personality traits that often accompany aggression, such as impulsivity and irritability.
Differences in measuring ASBs partly account
for the variability in heritability estimates, which
range from 7 to 81 percent, but many studies
indicate a heritability for genetic influences of
0.40-0.50, a minor influence of shared environment, and a much more significant influence of
nonshared environment (environment unique
to the individual).
Aggression and Human Development
Aggressive behavior develops in children
through a complex interaction of many environmental and biological factors. Also increasing liability for aggression and perhaps criminality are such factors as low socioeconomic
status and parental psychopathology. A consistent finding is that the measure of the activity of
the central nervous system’s serotonin correlates inversely with levels of lifetime aggression,
tendency to physically assault, irritability, and
impulsivity. Some of the implicated genes regulate serotonin synthesis, release, and reuptake
as well as metabolism and receptor activation,
and vary from individual to individual. Serotonergic dysfunction is also noted in alcoholism
with aggression and in suicide attempters and
completers. Brain injuries can also exacerbate
tendencies to exhibit ASBs.
Some aggression, however, is a normal part
of development. Thus, Terrie Moffitt and colleagues distinguish between “adolescent-limited
aggression”—times when most adolescents are
rebelling against adult authority—and “lifecourse persistent” ASB, which likely reflects
neuropsychological deficits and specific temperaments that are often exacerbated in unsupportive family settings. Genetic factors play
2
Aggression
a smaller role in adolescent delinquency and
are consistent with aggression at this age as a
developmental response to social context.
Sex Differences
A significant feature of ASB is a marked difference between the sexes. Males exhibit higher
levels of physical aggression and violence at every age in all situations except in the context of
partner violence (where females exceed males).
More males than females are diagnosed with
conduct disorder at every age. More males than
females begin acts of theft and violence at every
age. Males also exhibit higher rates of risk factors, such as impaired neurocognitive status, increased hyperactivity, and difficulties with peers.
Females are rarely identified with the life-course
persistent form of ASB; the male:female sex ratio is 10:1. Antisocial male and female adolescents tend to associate and often marry and
reproduce at younger ages. The role that hormones, particularly testosterone, may play in
these differences is not clear.
Social Significance
There is much controversy surrounding the
efforts to identify genes associated with aggression or crime, especially now that genome sequencing is easier than ever. Many demand
that the privacy of individuals be protected because the presence of specific genes does not
dictate behavioral outcomes: Genes do not determine socially defined behaviors but only act
on physiological systems. In addition, what constitutes acceptable or unacceptable behavior
for individuals is culturally defined. Biological
and environmental risk factors may increase an
individual’s liability to commit an act of aggression or crime, but the behavior must be interpreted within its specific context. Criminal law
presumes that behavior is a function of free
will, and most attempts to use genes as a mitigating factor in the courtroom have been unsuccessful. Efforts to prevent crime and violence must include consideration of all factors.
Family milieu and parental competence are
just as important as impaired cognitive mechanisms such as reduced serotonin activity. An imbalance in brain chemistry leading to impulsivity or aggression may be ameliorated by a
supportive home setting, by medication, or by
adequate nutrition.
—Joan C. Stevenson
See also: Aging; Behavior; Biological Determinism; Criminality; DNA Fingerprinting;
Forensic Genetics; Sociobiology; Steroid Hormones; XYY Syndrome.
Further Reading
Bock, Gregory R., and Jamie A. Goode. Genetics
of Criminal and Antisocial Behaviour. New York:
John Wiley & Sons, 1996. This symposium
was held at the Ciba Foundation in London
in 1995 and includes a representative sample of the research foci in this arena, followed by discussions.
Fishbein, Diana H., ed. The Science, Treatment,
and Prevention of Antisocial Behaviors: Application to the Criminal Justice System. Kingston,
N.J.: Civic Research Institute, 2000. An excellent set of reviews on aggression and the
many associated behaviors and mental disorders.
Lesch, Klaus Peter, and Ursula Merschdorf.
“Impulsivity, Aggression, and Serotonin: A
Molecular Psychobiological Perspective.” Behavioral Sciences and the Law 18, no. 5 (2000):
581-604. A wonderful review of all the interacting factors, including all the elements of
the serotonin system.
Moffitt, Terrie E., Avshalom Caspi, Michael
Rutter, and Phil A. Silva. Sex Differences in Antisocial Behaviour: Conduct Disorder, Delinquency,
and Violence in the Dunedin Longitudinal Study.
New York: Cambridge University Press, 2001.
Sex differences are documented as children
grow up.
Roush, Wade. “Conflict Marks Crime Conference.” Science 269, no. 5232 (1995): 18081809. An excellent description of the pros
and cons of genetic research on ASB.
Web Site of Interest
National Institutes of Health, National Institute of Mental Health. http://www.nimh.nih
.gov/publicat/violenceresfact.cfm. Provides
information on child and adolescent violence and antisocial behavior, including research into the possible genetic factors of aggression.
Aging
Aging
Field of study: Human genetics and social
issues
Significance: In the light of modern science and
medicine, it has become apparent that the roots of
aging lie in genes; therefore, the genetic changes
that take place during aging are the source of the
major theories of aging currently being proposed.
Key terms
antioxidant: a molecule that preferentially
reacts with free radicals, thus keeping them
from reacting with other molecules that
might cause cellular damage
free radical: a highly reactive form of oxygen
in which a single oxygen atom has a free, unpaired electron; free radicals are common
by-products of chemical reactions
mitochondrial DNA (mtDNA): the genome
of the mitochondria, which contain many of
the genes required for mitochondrial function
pleiotropy: a form of genetic expression in
which a gene has multiple effects; for example, the mutant gene responsible for cystic fibrosis causes clogging of the lungs, sterility,
and excessive salt in perspiration, among
other symptoms
Why Study Aging?
Biologists have long suspected that the mechanisms of aging would never be understood
fully until a better understanding of genetics
was obtained. As genetic information has exploded, a number of theories of aging have
emerged. Each of these theories has focused
on a different aspect of the genetic changes observed in aging cells and organisms. Animal
models, from simple organisms such as Tetrahymena (a single-celled, ciliated protozoan) and
Caenorhabditis (a nematode worm) to more complex organisms like Drosophila (fruit fly) and
mice, have been used extensively in efforts to
understand the genetics of aging. The study of
mammalian cells in culture and the genetic
analysis of human progeroid syndromes (that is,
premature aging syndromes) such as Werner’s
syndrome and diseases of old age such as Alz-
3
heimer’s disease have also improved the understanding of aging. From these data, several theories of aging have been proposed.
Genetic Changes Observed in Aging Cells
Most of the changes thus far observed represent some kind of degeneration or loss of function. Many comparisons between cells from
younger and older individuals have shown that
more mutations are consistently present in
older cells. In fact, older cells seem to show
greater genetic instability in general, leading to
chromosome deletions, inversions, and other
defects. As these errors accumulate, the cell cycle slows down, decreasing the ability of cells to
proliferate rapidly. These genetic problems are
partly a result of a gradual accumulation of mutations, but the appearance of new mutations
seems to accelerate with age due to an apparent
reduced effectiveness of DNA repair mechanisms.
Cells that are artificially cultured have been
shown to undergo a predictable number of cell
divisions before finally becoming senescent, a
state where the cells simply persist and cease dividing. This phenomenon was first established
by Leonard Hayflick in the early 1960’s when
he found that human fibroblast cells would divide up to about fifty times and no more. This
phenomenon is now called the Hayflick limit.
The number of divisions possible varies depending on the type of cell, the original age of the
cell, and the species of organism from which
the original cell was derived. It is particularly
relevant that a fibroblast cell from a fetus will
easily approach the fifty-division limit, whereas
a fibroblast cell from an adult over age fifty may
be capable of only a few divisions before reaching senescence.
The underlying genetic explanation for the
Hayflick limit appears to involve regions near
the ends of chromosomes called telomeres.
Telomeres are composed of thousands of copies of a repetitive DNA sequence and are a required part of the ends of chromosomes due to
certain limitations in the process of DNA replication. Each time a cell divides, it must replicate all of the chromosomes. The process of
replication inevitably leads to loss of a portion
of each telomere, so that with each new cell di-
4
Aging
vision the telomeres get shorter. When the
telomeres get to a certain critical length, DNA
replication seems to no longer be possible, and
the cell enters senescence. Although the process discussed above is fairly consistent with
most studies, the mechanism whereby a cell
knows it has reached the limit is unknown.
A result of these genetic changes in aging humans is that illnesses of all kinds are more common, partly because the immune system seems
to function more slowly and less efficiently with
age. Other diseases, like cancer, are a direct result of the relentless accumulation of mutations.
Cancers generally develop after a series of mutations or chromosomal rearrangements have
occurred that cause the mutation of or inappropriate expression of proto-oncogenes. Protooncogenes are normal genes that are involved
in regulating the cell cycle and often are responsible for moving the cell forward toward mitosis
(cell division). Mutations in proto-oncogenes
transform them into oncogenes (cancer genes),
which results in uncontrolled cell division,
along with the other traits displayed by cancer
cells.
Progeroid Syndromes as Models of Aging
Several progeroid syndromes have been
studied closely in hopes of finding clues to the
underlying genetic mechanisms of aging. Although such studies are useful, they are limited
in the sense that they display only some of the
characteristics of aging. Also, because they are
typically due to a single mutant gene, they represent a gross simplification of the aging process. Recent genetic analyses have identified
the specific genetic defects for some of the
progeroid syndromes, but often this has only
led to more questions.
Down syndrome is the most common
progeroid syndrome and is usually caused by
possession of an extra copy of chromosome 21
(also called trisomy 21). Affected individuals
display rapid aging for a number of traits such
as atherosclerosis and cataracts, although the
severity of the effects varies greatly. The most
notable progeroid symptom is the development
of Alzheimer’s disease-like changes in the brain
such as senile plaques and neurofibrillary tangles. One of the genes sometimes involved in
Alzheimer’s disease is located on chromosome
21, possibly accounting for the common symptoms.
Werner’s syndrome is a very rare autosomal
recessive disease. The primary symptoms are
severe atherosclerosis and a high incidence of
cancer, including some unusual sarcomas and
connective tissue cancers. Other degenerative
changes include premature graying, muscle atrophy, osteoporosis, cataracts, and calcification
of heart valves and soft tissues. Death, usually by
atherosclerosis, often occurs by fifty or sixty
years of age. The gene responsible for Werner’s
syndrome has been isolated and encodes a
DNA helicase (called WRN DNA helicase), an
enzyme that is involved in helping DNA strands
to separate during the process of replication.
The faulty enzyme is believed to cause the process of replication to stall at the replication
fork, the place where DNA replication is actively taking place, which leads to a higherthan-normal mutation rate in the DNA, although more work is needed to be sure of its
mechanism.
Hutchinson-Gilford progeria shows even
more rapid and pronounced premature aging.
Effects begin even in early childhood with balding, loss of subcutaneous fat, and skin wrinkling, especially noticeable in the facial features.
Later, bone loss and atherosclerosis appear,
and most affected individuals die before the
age of twenty-five. The genetic inheritance pattern for Hutchinson-Gilford progeria is still debated, but evidence suggests it may be due to a
very rare autosomal dominant gene, which may
represent a defect in a DNA repair system.
Cockayne syndrome, another very rare autosomal recessive defect, displays loss of subcutaneous fat, skin photosensitivity (especially to ultraviolet, or UV, light), and neurodegeneration.
Age of death can vary but seems to center
around forty years of age. The specific genetic
defect is known and involves the action of a few
different proteins. At the molecular level, the
major problems all relate to some aspect of
transcription, the making of messenger RNA
(mRNA) from the DNA template, which can
also affect some aspects of DNA repair.
Another, somewhat less rare, autosomal recessive defect is ataxia telangiectasia. It displays
Aging
5
In April, 2003, fifteen-year-old John Tacket announced the discovery of a gene that causes the disease he suffers from, progeria, a
syndrome that accelerates aging. (AP/Wide World Photos)
a whole suite of premature aging symptoms,
including neurodegeneration, immunodeficiency, graying, skin wrinkling, and cancers, especially leukemias and lymphomas. Death usually occurs between forty and fifty years of age.
The specific defect is known to be loss of a protein kinase, an enzyme that normally adds phosphate groups to other proteins. In this case, the
kinase appears to be involved in regulating the
cell cycle, and its loss causes shortening of
telomeres and defects in the repair of doublestranded breaks in DNA. One of the proteins
it appears to normally phosphorylate is p53, a
tumor-suppressor gene whose loss is often associated with various forms of cancer.
Although the genes involved in the various
progeroid syndromes are varied, they do seem
to fall into some common functional types.
Most have something to do with DNA replication, transcription, or repair. Other genes are
involved in control of some part of the cell cycle. Although many other genes remain to be
discovered, they will likely also be involved with
DNA or the cell cycle in some way. Based on
many of the common symptoms of aging, these
findings are not too surprising.
Genetic Models of Aging
The increasing understanding of molecular
genetics has prompted biologists to propose a
number of models of aging. Each of the models
is consistent with some aspect of cellular genetics, but none of the models, as yet, is consistent
with all evidence. Some biologists have suggested that a combination of several models
may be required to adequately explain the process of aging. In many ways, understanding of
the genetic causes of aging is in its infancy, and
geneticists are still unable to agree on even the
probable number of genes involved in aging.
Even the extent to which genes control aging at
all has been debated. Early studies based on
correlations between time of death of parents
and offspring or on the age of death of twins
6
Aging
suggested that genes accounted for 40 to 70
percent of the heritability of longevity. More recent research on twins has suggested that genes
may only account for 35 percent or less of the
observed variability in longevity, and for twins
reared apart the genetic effects appear to be
even less.
Genetic theories of aging can be classified
as either genome-based or mutation-based. Genome-based theories include the classic idea that
longevity is programmed, as well as some evolution-based theories such as antagonistic pleiotropy, first proposed by George C. Williams,
and the disposable soma theory. Mutationbased theories are based on the simple concept
that genetic systems gradually fall apart from
“wear and tear.” The differences among mutation-based theories generally involve the causes
of the mutations and the particular genetic systems involved. Even though genome-based and
mutation-based theories seem to be distinct,
there is actually some overlap. For example,
the antagonistic pleiotropy theory (a genomebased theory) predicts that selection will “weed
out” lethal mutations whose effects are felt during the reproductive years, but that later in life
lethal mutations will accumulate (a mutationbased theory) because selection has no effect
after the reproductive years.
Genome-Based Theories of Aging
The oldest genome-based theory of aging,
sometimes called programmed senescence, suggested that life span is genetically determined.
In other words, cells (and by extrapolation, the
entire organism) live for a genetically predetermined length of time. The passing of time is
measured by some kind of cellular clock and
when the predetermined time is reached, cells
go into a self-destruct sequence that eventually
causes the death of the organism. Evidence for
this model comes from the discovery that animal cells, when grown in culture, are only able
to divide a limited number of times, the socalled Hayflick limit discussed above, and then
they senesce and eventually die. Further evidence comes from developmental studies where
it has been discovered that some cells die spontaneously in a process called apoptosis. A process similar to apoptosis could be responsible
for cell death at old age. The existence of a cellular clock is consistent with the discovery that
telomeres shorten as cells age.
In spite of the consistency of the experimental evidence, this model fails on theoretical
grounds. Programmed senescence, like any
complex biological process, would be required
to have evolved by natural selection, but natural selection can only act on traits that are expressed during the reproductive years. Because
senescence happens after the reproductive
years, it cannot have developed by natural selection. In addition, even if natural selection
could have been involved, what advantage
would programmed senescence have for a species?
Because of the hurdles presented by natural
selection, the preferred alternative genomebased theory is called antagonistic pleiotropy.
Genes that increase the chances of survival before and during the reproductive years are detrimental in the postreproductive years. Because
natural selection has no effect on genes after
reproduction, these detrimental effects are not
“weeded” out of the population. There is some
physiological support for this in that sex hormones, which are required for reproduction
earlier in life, cause negative effects later in life,
such as osteoporosis in women and increased
cancer risks in both sexes.
The disposable soma theory is similar but is
based on a broader physiological base. It has
been noted that there is a strong negative correlation among a broad range of species between
metabolic rate and longevity. In general, the
higher the average metabolic rate, the shorter
lived the species. In addition, the need to reproduce usually results in a higher metabolic
rate during the reproductive years than in later
years. The price for this high early metabolic
rate is that systems burn out sooner. This theory is not entirely genome-based, but also has a
mutation-based component. Data on mutation
rates seem to show a high correlation between
high metabolic rate and high mutation rates.
One of the by-products of metabolism is the
production of free oxygen radicals, single oxygen atoms with an unpaired electron. These
free radicals are highly reactive and not only
cause destruction of proteins and other mole-
Aging
cules, but also cause mutations in DNA. So the
high metabolic rate during the reproductive
years causes a high incidence of damaging DNA
mutations which lead to many of the diseases of
old age. After reproduction, natural selection
no longer has use for the body, so it gradually
falls apart as the mutations build up. Unfortunately, all attempts so far to assay the extent of
the mutations produced have led to the conclusion that not enough mutations exist to be the
sole cause of the changes observed in aging.
Mutation-Based Theories of Aging
The basic premise of all the mutation-based
theories of aging is that the buildup of mutations eventually leads to senescence and death,
the ultimate cause being cancer or the breakdown of a critical system. The major support for
these kinds of theories comes from a number of
recent studies that have found a larger number
of genetic mutations in elderly individuals than
in younger individuals, the same pattern being
observed even when the same individual is assayed at different ages. The differences among
the various mutation-based theories have to do
with what causes the mutations and what kinds
of DNA are primarily affected. As mentioned
above, the disposable soma theory also relies,
in part, on mutation-based theories.
The most general mutation-based theory is
the somatic mutation/DNA damage theory,
which relies on background radiation and other
mutagens in the environment as the cause of
mutations. Over time, the buildup of these mutations begins to cause failure of critical biochemical pathways and eventually causes death.
This theory is consistent with experimental evidence from the irradiation of laboratory animals. Irradiation causes DNA damage, which, if
not repaired, leads to mutations. The higher
the dose of radiation, the more mutations result. It has also been noted that there is some
correlation between the efficiency of DNA repair and life span. Further support comes from
observations of individuals with more serious
DNA repair deficiencies, such as those affected
by xeroderma pigmentosum. Individuals with
xeroderma pigmentosum have almost no ability to repair the type of DNA damage caused by
exposure to UV light, and as a result they de-
7
velop skin cancer very easily, which typically
leads to death.
The major flaw in this theory is that it predicts that senescence should be a random process, which it is not. A related theory called error catastrophe also predicts that mutations
will build up over time, eventually leading to
death, but it suffers from the same flaw. Elderly
individuals do seem to possess greater amounts
of abnormal proteins, but that does not mean
that these must be the ultimate cause of death.
The free radical theory of aging is more
promising and is probably one of the most familiar theories to the general public. This theory has also received much more attention
from researchers. The primary culprit in this
theory is free oxygen radicals, which are highly
reactive and cause damage to proteins, DNA,
and RNA. Free radicals are a natural by-product
of many cellular reactions and most specifically
of the reactions involved in respiration. In fact,
the higher the metabolic rate, the more free
radicals will likely be produced. Although this
theory also involves a random process, it is a
more consistent and predictable process, and
through time it can potentially build on itself,
causing accelerated DNA damage with greater
age.
Significant attention has focused on mitochondrial DNA (mtDNA). Because free radicals are produced in greater abundance in respiration, which takes place primarily in the
mitochondria, mtDNA should show more mutations than nuclear DNA. In addition, as DNA
damage occurs, the biochemical pathways involved in respiration should become less efficient, which would theoretically lead to even
greater numbers of free radicals being produced, which would, in turn, cause more damage. This kind of positive feedback cycle would
eventually reach a point where the cells could
not produce enough energy to meet their needs
and they would senesce. Assays of mtDNA have
shown a greater number of mutations in the elderly, and it is a well-known phenomenon that
mitochondria are less efficient in the elderly.
Muscle weakness is one of the symptoms of
these changes.
The free radical theory has some appeal, in
the sense that ingestion of increased amounts
8
Aging
of antioxidants in the diet would be expected
to reduce the number of free radicals and thus
potentially delay aging. Although antioxidants
have been used in this way for some time, no
significant increase in life span has been observed, although it does appear that cancer incidence may be reduced.
From Theory to Practice
Many of the genetic theories of aging are intriguing and even seem to be consistent with
experimental evidence from many sources, but
none of them adequately addresses longevity
at the organismal level. Although telomeres
shorten with age in individual cells, cells continue to divide into old age, and humans do not
seem to die because all, or most, of their cells
are no longer able to divide. Cells from older
individuals do have more mutations than cells
from younger individuals, but the number of
mutations observed does not seem adequate to
account for the large suite of problems present
in old age. Mitochondria, on average, do function more poorly in older individuals and their
mtDNA does display a larger number of mutations, but many mitochondria remain high
functioning and appear to be adequate to sustain life.
Essentially, geneticists have opened a crack
in the door to a better understanding of the
causes of aging, and the theories presented
here are probably correct in part, but much
more research is needed to sharpen the understanding of this process. The hope of geneticists, and of society in general, is to learn how
to increase longevity. Presently, it seems all that
is possible is to help a larger number of people approach the practical limit of 120 years
through lifestyle modification and medical intervention. Going significantly beyond 120
years is probably a genetic problem that will not
be solved for some time.
—Bryan Ness
See also: Alzheimer’s Disease; Autoimmune
Disorders; Biochemical Mutations; Biological
Clocks; Biological Determinism; Cancer; Chemical Mutagens; Developmental Genetics; Diabetes; DNA Repair; Genetic Engineering: Medical
Applications; Heart Disease; Human Genetics;
Human Growth Hormone; Immunogenetics;
Insurance; Mitochondrial Genes; Mutation and
Mutagenesis; Oncogenes; Stem Cells; Telomeres; Tumor-Suppressor Genes.
Further Reading
Arking, Robert, ed. Biology of Aging: Observations
and Principles. 2d ed. Sunderland, Mass.:
Sinauer, 2001. A revised edition of a 1990
text that examines such topics as defining
and measuring aging, changes in populations, genetic determinants of longevity, and
aging as an intracellular process.
Austad, Steven N. Why We Age: What Science Is
Discovering About the Body’s Journey Throughout
Life. New York: John Wiley & Sons, 1997. A
review of the latest biological research and
theories of aging, including an assessment of
the oldest attainable age for humans.
Hekimi, Siegfried, ed. The Molecular Genetics of
Aging. New York: Springer, 2000. Part of the
Results and Problems in Cell Differentiation
series. Illustrated.
Macieira-Coelho, Alvaro. Biology of Aging. New
York: Springer, 2002. A solid text that includes many figures, tables, charts, and illustrations.
Manuck, Stephen B., et al., eds. Behavior, Health,
and Aging. Mahwah, N.J.: Lawrence Erlbaum,
2000. Examines a host of health care dilemmas associated with the elderly. One section
considers the basic tenets of genetic and molecular biology, including some of the methods of looking at heritable differences in
health and well-being. Illustrated.
Medina, John J. The Clock of Ages: Why We Age,
How We Age—Winding Back the Clock. New
York: Cambridge University Press, 1996. A
book written especially for the general
reader. Covers aging on a system-by-system
basis and includes a large section on the genetics of aging.
Ricklefs, Robert E., and Caleb E. Finch. Aging:
A Natural History. New York: W. H. Freeman,
1995. A good general introduction to the biology of aging by two biologists who specialize in aging research.
Rusting, Ricki L. “Why Do We Age?” Scientific
American 267 (December, 1992). Summarizes the changes that occur with aging and
the roles of oxidants and free radicals.