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• Cover
• HalfTitle Page
• Title Page
• Copyright Page
• Preface
• Acknowledgments
• Table of Contents
• Detailed Contents
• Chapter 1: An Introduction to Human Evolutionary Genetics
• 1.1 What is human evolutionary genetics?
• 1.2 Insights into phenotypes and diseases
• A shared evolutionary history underpins our understanding of biology
• Understanding evolutionary history is essential to understanding human biology today
• Understanding evolutionary history shapes our expectations about the future
• 1.3 Complementary records of the human past
• Understanding chronology allows comparison of evidence from different scientific approaches
• It is important to synthesize different records of the past
• None of the different records represents an unbiased picture of the past
• 1.4 What can we know about the past?
• 1.5 The ethics of studying human populations
• Summary
• References
• Section 1: How do we study genome diversity?
• Chapter 2: Organization and inheritance of the human genome
• 2.1 The Big Picture: An Overview of the human genome
• 2.2 Structure of DNA
• 2.3 Genes, Transcription, and Translation
• Genes are made up of introns and exons, and include elements to initiate and regulate transcription
• The genetic code allows nucleotide sequences to be translated into amino acid sequences
• Gene expression is highly regulated in time and space
• 2.4 Noncoding DNA
• Some DNA sequences in the genome are repeated in multiple copies
• 2.5 Human chromosomes and the human karyotype
• The human genome is divided into 46 chromosomes
• Size, centromere position, and staining methods allow chromosomes to be distinguished
• 2.6 Mitosis, meiosis, and the inheritance of the genome
• 2.7 Recombination—the great reshuffler
• 2.8 Nonrecombining segments of the genome
• The male-specific Y chromosome escapes crossing over for most of its length
• Maternally inherited mtDNA escapes from recombination
• Summary
• Questions
• References
• Chapter 3: Human genome variation
• 3.1 Genetic Variation and the Phenotype
• Some DNA sequence variation causes Mendelian genetic disease
• The relationship between genotype and phenotype is usually complex
• Mutations are diverse and have different rates and mechanisms
• 3.2 Single Nucleotide Polymorphisms (Snps) in the Nuclear Genome
• Base substitutions can occur through base misincorporation during DNA replication
• Base substitutions can be caused by chemical and physical mutagens
• Sophisticated DNA repair processes can fix much genome damage
• The rate of base substitution can be estimated indirectly or directly
• Because of their low mutation rate, SNPs usually show identity by descent
• The CpG dinucleotide is a hotspot for mutation
• Base substitutions and indels can affect the functions of genes
• Synonymous base substitutions
• Nonsynonymous base substitutions
• Indels within genes
• Base substitutions outside ORFs
• Whole-genome resequencing provides an unbiased picture of SNP diversity
• 3.3 Sequence Variation in Mitochondrial DNA
• mtDNA has a high mutation rate
• The transmission of mtDNA mutations between generations is complex
• 3.4 Variation in Tandemly Repeated DNA Sequences
• Microsatellites have short repeat units and repeat arrays, and mutate through replication slippage
• Microsatellite mutation rates and processes
• Minisatellites have longer repeat units and arrays, and mutate through recombination mechanisms
• Minisatellite diversity and mutation
• Telomeres contain specialized and functionally important repeat arrays
• Satellites are large, sometimes functionally important, repeat arrays
• 3.5 Transposable Element Insertions
• 3.6 Structural Variation in the Genome
• Some genomic disorders arise from recombination between segmental duplications
• Copy-number variation is widespread in the human genome
• Cytogenetic examination of chromosomes can reveal large-scale structural variants
• 3.7 The Effects of Age and sex on Mutation Rate
• 3.8 The effects of Recombination on Genome Variation
• Genomewide haplotype structure reveals past recombination behavior
• Recombination behavior can be revealed by direct studies in pedigrees and sperm DNA
• The process of gene conversion results in nonreciprocal exchange between DNA sequences
• Summary
• Questions
• References
• Chapter 4: Finding and assaying genome diversity
• 4.1 First, Find Your DNA
• 4.2 The polymerase chain reaction (PCR)
• 4.3 Sanger sequencing, the human reference sequence, and snp discovery
• 4.4 A Quantum Leap in variation studies: next-generation sequencing
• Illumina sequencing is a widely used NGS method
• Sequencing can be targeted to regions of specific interest or the exome
• NGS data have to be processed and interpreted
• Third-generation methods use original, unamplifiedDNA
• 4.5 SNP typing: low-, medium-, and high-throughput methods for assaying variation
• PCR-RFLP typing is a simple low-throughput method
• Primer extension and detection by mass spectrometry is a medium-throughput method
• High throughput SNP chips simultaneously analyze more than 1 million SNPs
• Whole-genome SNP chips are based on a tag SNP design
• 4.6 Databases of sequence variation
• 4.7 Discovering and assaying variation at microsatellites
• 4.8 Discovering And Assaying structural variation on different scales
• Discovering and assaying variation at minisatellites
• Discovering and assaying variation at well-defined indels, including Alu/LINE polymorphisms
• Discovering and assaying structural polymorphisms and copy-number variants
• 4.9 Phasing: from genotypes to haplotypes
• Haplotypes can be determined by physical separation
• Haplotypes can be determined by statistical methods
• 4.10 Studying genetic variation in ancient samples
• DNA is degraded after death
• Contamination is a major problem
• Application of next-generation sequencing to aDNA analysis
• Summary
• Questions
• References
• Section 2: How do we interpret genetic variation?
• Chapter 5: Processes shaping diversity
• 5.1 Basic concepts in population genetics
• Why do we need evolutionary models?
• The Hardy–Weinberg equilibrium is a simple model in population genetics
• 5.2 Generating diversity by mutation and recombination
• Mutation changes allele frequencies
• Mutation can be modeled in different ways
• Meiotic recombination generates new combinations of alleles
• Linkage disequilibrium is a measure of recombination at the population level
• Recombination results in either crossing over or gene conversion, and is not uniform across the genome
• 5.3 Eliminating diversity by genetic drift
• The effective population size is a key concept in population genetics
• Different parts of the genome have different effective population sizes
• Genetic drift causes the fixation and elimination of new alleles
• Variation in census population size and reproductive success influence effective population size
• Population subdivision can influence effective population size
• Mate choice can influence effective population size
• Genetic drift influences the disease heritages of isolated populations
• 5.4 The effect of selection on diversity
• Mate choice can affect allele frequencies by sexual selection
• 5.5 Migration
• There are several models of migration
• There can be sex-specific differences in migration
• 5.6 Interplay among the different forces of evolution
• There are important equilibria in population genetics
• Mutation–drift balance
• Recombination–drift balance
• Mutation–selection balance
• Does selection or drift determine the future of an allele?
• 5.7 The neutral theory of molecular evolution
• The molecular clock assumes a constant rate of mutation and can allow dating of speciation
• There are problems with the assumptions of the molecular clock
• Summary
• Questions
• References
• Chapter 6: Making inferences from diversity
• 6.1 What data can we use?
• 6.2 Summarizing genetic variation
• Heterozygosity is commonly used to measure genetic diversity
• Nucleotide diversity can be measured using the population mutation parameter theta (θ)
• The mismatch distribution can be used to represent genetic diversity
• 6.3 Measuring genetic distance
• Genetic distances between populations can be measured using FST or Nei’s D statistics
• Distances between alleles can be calculated using models of mutation
• Genomewide data allow calculation of genetic distances between individuals
• Complex population structure can be analyzed statistically
• Population structure can be analyzed using genomic data
• Genetic distance and population structure can be represented using multivariate analyses
• 6.4 Phylogenetics
• Phylogenetic trees have their own distinctive terminology
• There are several different ways to reconstruct phylogenies
• Trees can be constructed from matrices of genetic distances
• Trees can be generated using character-based methods
• How confident can we be of a particular phylogenetic tree?
• Networks are methods for displaying multiple equivalent trees
• 6.5 Coalescent approaches to reconstructing population history
• The genealogy of a DNA sequence can be described mathematically
• Neutral mutations can be modeled on the gene genealogy using Poisson statistics
• Coalescent analysis can be a simulation tool for hypothesis testing
• Coalescent analysis uses ancestral graphs to model selection and recombination
• Coalescent models of large datasets are approximate
• 6.6 Dating evolutionary events using genetic data
• Dating population splits using FST and Nei’s D statistics is possible, but requires a naive view of human evolution
• Evolutionary models can include the timing of evolutionary events as parameters
• Evolutionary models and effective population size
• An allele can be dated using diversity at linked loci
• Interpreting TMRCA
• Estimations of mutation rate can be derived from direct measurements in families or indirect comparisons of species
• An estimate of generation time is required to convert some genetic date estimates into years
• 6.7 Has selection been acting?
• Differences in gene sequences between species can be used to detect selection
• Comparing variation between species with variation within a species can detect selection
• Selection tests can be based on the analysis of allele frequencies at variant sites
• Comparing haplotype frequency and haplotype diversity can reveal positive selection
• Analysis of frequency differences between populations can indicate positive selection
• Other methods can be used to detect ongoing or very recent positive selection
• How can we combine information from different statistical tests?
• Tests for positive selection have severe limitations
• 6.8 Analyzing genetic data in a geographical context
• Genetic data can be displayed on maps
• Genetic boundary analysis identifies the zones of greatest allele frequency change within a genetic landscape
• Spatial autocorrelation quantifies the relationship of allele frequency with geography
• Mantel testing is an alternative approach to examining a relationship between genetic distance and other distance measures
• Summary
• Questions
• References
• Section 3: Where and when did humans originate?
• Chapter 7: Humans as apes
• Which nonhuman animals are the closest living relatives of humans?
• Are humans typical apes?
• 7.1 Evidence from morphology
• Primates are an Order of mammals
• Hominoids share a number of phenotypic features with other anthropoids
• Ancestral relationships of hominoids are difficult to resolve on morphological evidence
• 7.2 Evidence from chromosomes
• Human and great ape karyotypes look similar, but not identical
• Molecular cytogenetic analyses support the picture from karyotype comparisons
• 7.3 Evidence from molecules
• Molecular data support a recent date of the ape–human divergence
• Genetic data have resolved the gorilla–chimpanzee–human trichotomy
• Sequence divergence is different among great apes across genetic loci
• Great apes differ by gains and losses of genetic material
• The DNA sequence divergence rates differ in hominoid lineages
• 7.4 Genetic diversity among the great apes
• How many genera, species, and subspecies are there?
• Intraspecific diversity in great apes is greater than in humans
• Signatures of lineage-specific selection can be detected in ape genomes
• Summary
• Questions
• References
• Chapter 8: What Genetic Changes Have Made us Human?
• 8.1 Morphological and behavioral changes en route to homo sapiens
• some human traits evolved early in hominin history
• The human mind is unique
• Only a few phenotypes are unique to modern humans
• 8.2 Genetic uniqueness of humans and hominins
• The sequence and structural differences between humans and other great apes can be cataloged
• Humans have gained and lost a few genes compared with other great apes
• Humans differ in the sequence of genes compared with other great apes
• Humans differ from other apes in the expression levels of genes
• Genome sequencing has revealed a small number of fixed genetic differences between humans and both Neanderthals and Denisovans
• 8.3 Genetic basis of phenotypic differences between apes and humans
• Mutations causing neoteny have contributed to the evolution of the human brain
• The genetic basis for laterality and language remains unclear
• What next?
• Summary
• Questions
• References
• Chapter 9: Origins of Modern Humans
• 9.1 Evidence from fossils and morphology
• Some fossils that may represent early hominins from 4–7 MYA are known from Africa
• Fossils of australopithecines and their contemporaries are known from Africa
• The genus Homo arose in Africa
• The earliest anatomically modern human fossils are found in Africa
• The morphology of current populations suggests an origin in Africa
• 9.2 Evidence from archaeology and linguistics
• Paleolithic archaeology has been studied extensively
• Evidence from linguistics suggests an origin of language in Africa
• 9.3 Hypotheses to explain the origin of modern humans
• 9.4 Evidence from the genetics of present-day populations
• Genetic diversity is highest in Africa
• Genetic phylogenies mostly root in Africa
• Mitochondrial DNA phylogeny
• Y-chromosomal phylogeny
• Other phylogenies
• Insights can be obtained from demographic models
• 9.5 Evidence from ancient dna
• Ancient mtDNA sequences of Neanderthals and Denisovans are distinct from modern human variation
• A Neanderthal draft genome sequence has been generated
• A Denisovan genome sequence has been generated
• Summary
• Questions
• References
• Section 4: How did humans colonize the world?
• Chapter 10: The Distribution of Diversity
• 10.1 Studying human diversity
• The history and ethics of studying diversity are complex
• Linnaeus’ classification of human diversity
• Galton’s “Comparative worth of different races”
• Modern attitudes to studying diversity
• Who should be studied?
• A few large-scale studies of human genetic variation have made major contributions to human evolutionary genetics
• What is a population?
• How many people should be analyzed?
• 10.2 Apportionment of human diversity
• The apportionment of diversity shows that most variation is found within populations
• The apportionment of diversity can differ between segments of the genome
• Patterns of diversity generally change gradually from place to place
• The origin of an individual can be determined surprisingly precisely from their genotype
• The distribution of rare variants differs from that of common variants
• 10.3 The influence of selection on the apportionment of diversity
• The distribution of levels of differentiation has been studied empirically
• Low differentiation can result from balancing selection
• High differentiation can result from directional selection
• Positive selection at EDAR
• Summary
• Questions
• References
• Chapter 11: The colonization of the old world and australia
• 11.1 A Colder and more variable environment 15–100 Kya
• 100–70 Kya
• Glacial maximum,70–55 Kya
• 55–25 Kya
• Last glacial maximum (LGM),23–14 Kya
• Holocene, 12 KYA to present
• 11.2 Fossil and archaeological evidence for two expansions of anatomically modern humans out of africa in the last ∼130 KY
• Anatomically modern, behaviorally pre-modern humans expanded transiently into the Middle East ∼90–120 KYA
• Modern human behavior first appeared in Africa after 100 KYA
• Fully modern humans expanded into the Old World and Australia ∼50–70 KYA
• Modern human fossils in Asia, Australia, and Europe
• Initial colonization of Australia
• Upper Paleolithic transition in Europe and Asia
• 11.3 A single major migration out of africa 50–70 KYA
• Populations outside Africa carry a shared subset of African genetic diversity with minor Neanderthal admixture
• mtDNA and Y-chromosomal studies show the descent of all non-African lineages from a single ancestor for each who lived 55–75 KYA
• 11.4 Early population divergence between australians and eurasians
• Summary
• Questions
• References
• Chapter 12: Agricultural expansions
• 12.1 Defining agriculture
• 12.2 The where, when, and why of agriculture
• Where and when did agriculture develop?
• Why did agriculture develop?
• Which domesticates were chosen?
• 12.3 Outcomes of agriculture
• Agriculture had major impacts on demography and disease
• Rapid demographic growth
• Malnutrition and infectious disease
• Agriculture led to major societal changes
• 12.4 The farming–language co-dispersal hypothesis
• Some language families have spread widely and rapidly
• Linguistic dating and construction of proto-languages have been used to test the hypothesis
• What are the genetic implications of language spreads?
• 12.5 Out of the near east into europe
• Nongenetic evidence provides dates for the European Neolithic
• Different models of expansion give different expectations for genetic patterns
• Models are oversimplifications of reality
• Principal component analysis of classical genetic polymorphisms was influential
• Interpreting synthetic maps
• mtDNA evidence has been controversial, but ancient DNA data are transforming the field
• Data from ancient mtDNA
• Y-chromosomal data show strong clines in Europe
• New developments for the Y chromosome
• Biparentally inherited nuclear DNA has not yet contributed much, but important ancient DNA data are now emerging
• Ancient DNA data
• What developments will shape debate in the future?
• 12.6 Out of tropical west africa into sub-equatorial africa
• There is broad agreement on the background to African agricultural expansion
• Rapid spread of farming economies
• Bantu languages spread far and rapidly
• Genetic evidence is broadly consistent, though ancient DNA data are lacking
• Genomewide evidence
• Evidence from mtDNA and the Y chromosome
• 12.7 Genetic analysis of domesticated animals and plants
• Selective regimes had a massive impact on phenotypes and genetic diversity
• Key domestication changes in crops
• Effects on crop genetic diversity
• Phenotypic and genetic change in animals
• How have the origins of domesticated plants been identified?
• How have the origins of domesticated animals been identified?
• Cattle domestication
• Summary
• Questions
• References
• Chapter 13: Into New-Found Lands
• 13.1 Settlement of the new territories
• Sea levels have changed since the out-of-Africa migration
• What drives new settlement of uninhabited lands?
• 13.2 Peopling of the americas
• The changing environment has provided several opportunities for the peopling of the New World
• Fossil and archaeological evidence provide a range of dates for the settlement of the New World
• Fossils
• Archaeological remains
• Clovis and the Paleoindians
• Pre-Clovis sites
• Unresolved issues
• Did the first settlers go extinct?
• A three-migration hypothesis has been suggested on linguistic grounds
• Genetic evidence has been used to test the single- and the three-wave migration scenarios
• Mitochondrial DNA evidence
• Interpretation of the mtDNA data
• Evidence from the Y chromosome
• Evidence from the autosomes
• Conclusions from the genetic data
• 13.3 Peopling of the pacific
• Fossil and archaeological evidence suggest that Remote Oceania was settled more recently than Near Oceania
• Two groups of languages are spoken in Oceania
• Several models have been proposed to explain the spread of Austronesian speakers
• Austronesian dispersal models have been tested with genetic evidence
• Classical polymorphisms
• Globin gene mutations
• Mitochondrial DNA
• The Y chromosome
• Autosomal evidence
• Evidence from other species has been used to test the Austronesian dispersal models
• Summary
• Questions
• References
• Chapter 14: What Happens when Populations Meet
• 14.1 What is genetic admixture?
• Admixture has distinct effects on genetic diversity
• 14.2 The impact of admixture
• Dierent sources of evidence can inform us about admixture
• Consequences of admixture for language
• Archaeological evidence for admixture
• The biological impact of admixture
• 14.3 Detecting admixture
• Methods based on allele frequency can be used to detect admixture
• Admixture proportions vary among individuals and populations
• Calculating individual admixture levels using multiple loci
• Calculating individual admixture levels using genomewide data
• Calculating admixture levels from estimated ancestry components
• Problems of measuring admixture
• Natural selection can affect the admixture proportions of individual genes
• 14.4 Local admixture and linkage disequilibrium
• How does admixture generate linkage disequilibrium?
• Admixture mapping
• Admixture dating
• 14.5 Sex-Biased admixture
• What is sex-biased admixture?
• Detecting sex-biased admixture
• Sex-biased admixture resulting from directional mating
• The effect of admixture on our genealogical ancestry
• 14.6 Transnational isolates
• Roma and Jews are examples of widely spread transnational isolates
• European Roma
• The Jews
• Summary
• Questions
• References
• Section 5: How is an evolutionary perspective useful?
• Chapter 15: Understanding the past, present, and future of phenotypic variation
• 15.1 Normal and pathogenic variation in an evolutionary context
• 15.2 Known variation in human phenotypes
• What is known about human phenotypic variation?
• Morphology and temperature adaptation
• Facial features
• Tooth morphology and cranial proportions
• Behavioral differences
• How do we uncover genotypes underlying phenotypes?
• What have we discovered about genotypes underlying phenotypes?
• 15.3 Skin pigmentation as an adaptation to ultraviolet light
• Melanin is the most important pigment influencing skin color
• Variable ultraviolet light exposure is an adaptive explanation for skin color variation
• Short-term UVR exposure causes sunburn
• Long-term UVR exposure causes cancers
• UVR causes nutrient photodegradation in the skin
• Several genes that affect human pigmentation are known
• Genetic variation in human pigmentation genes is consistent with natural selection
• Does sexual selection have a role in human phenotypic variation?
• 15.4 Life at high altitude and adaptation to hypoxia
• Natural selection has influenced the overproduction of red blood cells
• High-altitude populations differ in their adaptation to altitude
• 15.5 Variation in the sense of taste
• Variation in tasting phenylthiocarbamide is mostly due to alleles of the TAS2R38 gene
• There is extensive diversity of bitter taste receptors in humans
• Sweet, umami, and sour tastes may show genetic polymorphism
• 15.6 Adapting to a changing diet by digesting milk and starch
• There are several adaptive hypotheses to explain lactase persistence
• Lactase persistence is caused by SNPs within an enhancer of the lactase gene
• Increased copy number of the amylase gene reflects an adaptation to a high-starch diet
• 15.7 The future of human evolution
• Have we stopped evolving?
• Natural selection acts on modern humans
• Can we predict the role of natural selection in the future?
• Climate change
• Dietary change
• Infectious disease
• What will be the effects of future demographic changes?
• Increasing population size
• Increased mobility
• differential fertility
• differential generation time
• Will the mutation rate change?
• Summary
• Questions
• References
• Chapter 16: Evolutionary Insights into Simple Genetic Diseases
• 16.1 Genetic disease and mutation–selection balance
• Variation in the strength of purifying selection can affect incidence of genetic disease
• Variation in the deleterious mutation rate can affect incidence of genetic disease
• 16.2 Genetic drift, founder effects, and consanguinity
• Jewish populations have a particular disease heritage
• Finns have a disease heritage very distinct from other Europeans
• Consanguinity can lead to increased rates of genetic disease
• 16.3 Evolutionary causes of genomic disorders
• Segmental duplications allow genomic rearrangements with disease consequences
• Duplications accumulated in ancestral primates
• 16.4 Genetic diseases and selection by malaria
• Sickle-cell anemia is frequent in certain populations due to balancing selection
• α-Thalassemias are frequent in certain populations due to balancing selection
• Glucose-6-phosphate dehydrogenase deficiency alleles are maintained at high frequency in malaria-endemic populations
• What can these examples tell us about natural selection?
• Summary
• Questions
• References
• Chapter 17: Evolution and Complex Diseases
• 17.1 Defining complex disease
• The genetic contribution to variation in disease risk varies between diseases
• Infectious diseases are complex diseases
• 17.2 The global distribution of complex diseases
• Is diabetes a consequence of a post-agricultural change in diet?
• The drifty gene hypothesis
• Evidence from genomewide studies
• The thrifty phenotype hypothesis
• 17.3 Identifying alleles involved in complex disease
• Genetic association studies are more powerful than linkage studies for detecting small genetic effects
• Candidate gene association studies have not generally been successful in identifying susceptibility alleles for complex disease
• Genomewide association studies can reliably identify susceptibility alleles to complex disease
• GWAS data have been used for evolutionary genetic analysis
• 17.4 What complex disease alleles do we expect to find in the population?
• Negative selection acts on disease susceptibility alleles
• Positive selection acts on disease resistance alleles
• Severe sepsis and CASP12
• Malaria and the Duffy antigen
• HIV-1 and CCR5Δ32
• Unexpectedly, some disease susceptibility alleles with large effects are observed at high frequency
• Susceptibility to kidney disease, APOL1, and resistance to sleeping sickness
• Implications for other GWAS results
• 17.5 Genetic influence on variable response to drugs
• Population differences in drug-response genes exist, but are not well understood
• Summary
• Questions
• References
• Chapter 18: Identity and identification
• 18.1 Individual Identification
• The first DNA fingerprinting and profiling methods relied on mini satellites
• PCR-based microsatellite profiling superseded minisatellite analysis
• How do we interpret matching DNA profiles?
• Complications from related individuals, and DNA mixtures
• Large forensic identification databases are powerful tools in crime-fighting
• Controversial aspects of identification databases
• The Y chromosome and mtDNA are useful in specialized cases
• Y chromosomes in individual identification
• mtDNA in individual identification
• 18.2 What dna can tell us about john or jane doe
• DNA-based sex testing is widely used and generally reliable
• Sex reversal
• Deletions of the AMELY locus in normal males
• Some other phenotypic characteristics are predictable from DNA
• Reliability of predicting population of origin depends on what DNA variants are analyzed
• Prediction from forensic microsatellite multiplexes
• Prediction from other systems
• The problem of admixed populations
• 18.3 Deducing family and genealogical relationships
• The probability of paternity can be estimated confidently
• Other aspects of kinship analysis
• The Y chromosome and mtDNA are useful in genealogical studies
• The Thomas Jefferson paternity case
• DNA-based identification of the Romanovs
• Y-chromosomal DNA has been used to trace modern diasporas
• Y-chromosomal haplotypes tend to correlate with patrilineal surnames
• 18.4 The personal genomics revolution
• The first personal genetic analysis involved the Y chromosome and mtDNA
• Personal genomewide SNP analysis is used for ancestry and health testing
• Personal genome sequencing provides the ultimate resolution
• Personal genomics offers both promise and problems
• Summary
• Questions
• References
• Appendix
• Glossary
• Index