Gene Environment Interactions: Nature and Nurture in the Twenty-first Century

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Gene Environment Interactions : Nature and Nurture in theTwenty-first Century
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Acknowledgments
Epigraph
1
Interacting with the environment receiving and interpreting signals
	Sensory receptors
		General factors
		Touch sensation
		Nociceptors
		Sodium ion channels
		Therapeutic agents to treat pain specific that act on ion channels.
		Neuropathic pain
		Transient receptor potential (TRP) channels
		Potassium channels
	Hearing
		Gap junctions
		Fluid filled cavities of the inner ear
		Hair cells
		Sound waves and the inner ear
		The vestibular system
		Vestibular disorders
		Congenital hearing loss
		Potassium ion channel KCNQ1
	Hearing impairment and deafness
		Epidemiology
		Genetic etiology of deafness
		Deafness due to environmental factors in the perinatal period
		Newborn screening for deafness
		Electrophysiological exploration of hearing
		Auditory brain response test (ABR)
		Benefits of newborn screening and early detection of hearing loss
		Treatment options for hearing impairment
		Public health and pediatric hearing impairment
		Hearing loss in adults
		Cochlear implants, vestibular implants
		Advances in the treatment of hearing defects
		Auditory neuropathy Spectrum disorder
	Usher syndrome
	Vision and the retina
		Regions of the retina
		Retinal pigment epithelium
		Melanin in the retinal pigment epithelium
	The visual cycle, retinal pigmentary epithelium and photoreceptor interactions
		Retinal dystrophies
		Retinitis pigmentosa
			Clinical manifestations
		Leber’s congenital amaurosis
		Mitochondrial functional defects leading to visual impairment
		Age related macular dystrophy (AMD)
	Newborn eye screening and retinopathy of prematurity
		Blindness in children
		Retinopathy of prematurity
	References
2
Environment as provider
	Introduction
	Nutrients
		Nutrient production food security and environmental sustainability
		Ecosystems and food security
		Pollinator services
		Agroecology
		Nutrition and ecology
		Food production trends
		Nutritional deficiencies
		Vitamin A
	Nutrition and growth
		Undergrowth
		Genetic factors and height
		Overall increase in population height
	Requirement for specific minerals
		Zinc and zinc deficiency
		Iron
		Uptake of iron into cells
		Iron homeostasis
		Hemochromatosis
		Gene discoveries and identification of key functional proteins in iron metabolism
		Dietary iron overload
		Iron deficiency
		Calcium and vitamin D
		Insights gained into bone formation through studies in osteogenesis imperfecta
		Hypophosphatasia and alkaline phosphatase
		Rickets/osteomalacia due to genetic defects
			Autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemic rickets
		Iodine and thyroid function
		Congenital hypothyroidism
		Iodine deficiency goiter, hypothyroidism
		Requirement of other minerals present in soil
	Water
		Water pollution
		Pesticides
	Air and oxygen
		Central nervous system and air pollution
	References
3
Evolution
	Connections between paleoclimate and evolution
	Modern humans and their relationship to archaic humans
		Archaic genomes
		Genomic sequencing
		Introgression from of archaic sequences into genomes of modern humans
	Population migrations
		The ice-age and its impact on populations
		Minoans and Myceneans
		Africa
	Brain evolution: Primate and human divergence
		The DUF1220/NBPF domain also known as the Olduvai domain
		Documenting gene, metabolite differences and brain differences between primates and humans
		Foxp2
		Trajectory of brain evolution
		Products expressed primarily in excitatory neurons
		Products expressed primarily in inhibitory neurons
		Genomes, gene expression, evolution, intellect
		NOTCH2 gene expansion and impact on cortical neurogenesis
		Brain development, genes and environment
	The advantages and disadvantages of extra-copies of genomic segments
		Structural variants and adaptation
		Segmental duplications
		Whole genome sequencing and segmental duplications
		Comprehensive population studies of segmental duplications
	Phenotypic plasticity and evolution
	Mitochondrial DNA variations and population divergence
	Nutritional factors and genomic adaptations
	Polygenic adaptations to changing environments
		Studies on expression quantitative trait loci (eQTLs)
	References
4
Gene and environment interactions and phenotypes
	Introduction
	Skin pigmentation
		Oculocutaneous albinism
		Syndromic albinism
		Melanocytes and melanin
		Melanin and melanosome transcription factors
		Hyper pigmentation disorders
		Congenital hypopigmentation disorders
		Population studies on skin pigmentation
		Complexities in determination of pigmentation
		Milk as nutrient and lactase persistence
	Recognizing non-self: The immune system
		Innate immunity
			NOD-like receptors and Inflammasome
		Adaptive immunity
			Components and functions of the adaptive immune system
			B cells and antibody production
		Cytidine deaminases and their roles in the immune system
			APOBEC proteins
			ADAR enzymes adenosine deaminase RNA specific
			Genome diversity and protection against malaria infection
			Thalassemias
			Malaria parasite erythrocyte interactions
			Glucose-6-phosphate dehydrogenase (G6PD) variants and malaria resistance
			Malaria infestation and immune response
	Trypanosome infection and adaptations
		Selective forces of pathogens on human populations
	Immune response, pathogens and adaptations in different environments
		Natural selection and infectious diseases
		Polygenic adaptations to pathogens
	Adaptation of organisms to different environments
		Polygenic adaptation
		Evolutionary adaptations of microorganisms and their hosts
	Human adaptations to high altitude
	References
5
Signals, epigenetics, regulation of gene expression
	Conveying signals into cells to modify gene expression
		Signaling pathways
		Ion channels and transmission of signals to alter gene expression
		MTORC1 and MRNA translation
		MTORC1 and MRNA translation
		Transcription factors
		NFkappaB transcription factor complex
		Pathologies associated with defective functions of these proteins
		Nuclear receptors
		The nuclear pore complex
		Transport of mRNA from the nucleus to the cytoplasm
	Epigenetics
		Epigenetic mechanisms
		Epigenetics and aging
		Accelerated aging in down syndrome role of methylation
		Epigenetics, nutritional resources and metabolism
		DNA methylation and environmental exposures
		Epigenetic status and behavior following early childhood deprivation
		Epigenetics and cell type specificity
		Epigenetic differences in monozygotic twins
		Environmental agents and epigenetic changes
		Metabolism derived substrates and cofactors involved in epigenetic modifications
		Epigenetic states and gene expression
		Transcription factor binding to DNA and impact of epigenetic processes
		Transcription regulation and the mediator complex
		Activity dependent transcription
		Calcium dependent gene transcription
		Studies on epigenetic modifications, gene expression and memory
		Regulation of gene expression
		Alternative splicing of mRNA
		Chromatin architecture folding and modeling
		Genetic variations in regulators of gene expression
	RNA modifications
		The epitranscriptome
	References
6
Maintaining homeostasis and mitigating effects of harmful factors in the intrinsic or extrinsic environment
	Concepts of homeostasis
	Metabolism and homeostasis
		The MTOR system as sensor and as molecular integrator of cellular environmental conditions
		Energy stress
		MTOR as a major link between nutrient availability, and anabolic and catabolic processes
		Importance of TSC complex in inhibiting MTORC1 activity during endoplasmic reticulum stress
		MTOR signaling and mitochondrial function
		Sensors of specific metabolites
		Metabolism and co-factors
		Nicotinamide adenine dinucleotide (NAD)
		Molecular machinery and cholesterol homeostasis
		Sterol element binding proteins (SREBPs)
		Free fatty acid receptors and sensing
		Mitochondria and metabolism, new insights
		Reactive oxygen species and superoxide dismutases
		Nutrient sensing that impacts mitochondrial function
		Mitochondria and endoplasmic reticulum metabolism and nutrient sensing
		Metabolic flexibility and metabolic inflexibility
		Adipose tissue
		Metalloregulators factors
	Harmful damaging factors, endogenous or exogenous
		Oxidative stress and mitochondria
		Oxidative damage to molecules
		Systems to repair or remove damaged components
		Oxidative DNA damage
		Environmental agents and oxidative stress
			Bisphenol A
			Damaging metabolites
	DNA damage detection, consequences, and repair
		Gene products involved in excision repair
		Mismatch repair
		Mismatch DNA repair genes in humans
		Signaling DNA damage
		Double stranded DNA damage
		Interstrand cross-linking of DNA and the Fanconi pathway
		Exogenous and endogenous agents leading to DNA damage
		Tobacco
		DNA damage response and the cell cycle
		Heavy metal exposure
		Removal of damaged cellular material
		Cellular stress and the unfolded protein response
		Telomere shortening
		Tissue homeostasis and cell death
		Molecular mechanisms to counteract and detoxify xenobiotics
		Pharmacologic agents as xenobiotics and pharmacogenetics
		Arylhydrocarbon receptor (AHR)
	References
7
Microorganisms and microbiome
	Microorganisms in soil
		Horizontal gene transfer between microorganisms
		Efforts to restore degraded soils
		Plant root exudates
		Climate change and microorganisms
		Agroecosystems
	Antibiotic resistance
		Mechanisms by which microorganisms develop antibiotic resistance
		Antibiotic resistance in Gram negative organisms
		Antibiotic tolerant persisters and microfilms
		Antibiotic use in animal food production
		Antibiotic stewardship programs
		Mycobacterium tuberculosis (M. Tb) and antibiotic resistance
		Point of care diagnostics
		M. Tb drug susceptibility testing
		Diagnostic tests for tuberculosis
	New techniques for identifying anti-microbial agents
		Diffusion chambers and I-chip techniques
		Nucleotide analyses and identification of anti-bacterial products
	The search for anti-microbial medicines in plants
	Phage therapy
		Implication of bacteriophage therapies for clinical laboratories
	Microbiome
		Comprehensive microbiome analyses
		The microbiome in early post-natal life
		Breast feeding
		Microbiome, intestinal function and health
		Short chain fatty acids
		Low density lipoproteins
		Amino acids
		Bile components secreted into the intestine
		Microbiota and the immune system development
		Gut microbiota, diet and health
		Microbiome related disorders and antibiotic usage
		The microbiome in malnutrition
			Kwashiorkor
		Interaction of the human genome and the gut microbiome
		Gut microbiome and colorectal cancer
		Gut/brain axis and the intestinal microbiome
		The lung microbiome
		Respiratory diseases
		Skin microbiome
		Allergic responses and gene environment interactions
		The skin disease psoriasis
		Microorganisms environmental influences. Host factors and auto-immune diseases
		Auto-immunity and molecular mimicry
	References
8
Genomic changes and environmental factors in causation of birth defects and neurodevelopmental disorders
	Birth defects
		Introduction
		Mosaicism
		Holoprosencephaly
		Ethanol as holoprosencephaly inducing teratogen
		Holoprosencephaly in cases where definitively classified pathogenic mutations SHH pathways genes were not identified
		Cleft lip and palate: Gene variants and environmental pathways
		Studies in multi-generational families each with multiple cases of cleft lip and palate
	Neurodevelopmental disorders: Genetic and environmental factors
		Introduction
		Genomic and genetic factors in neurodevelopment
		Concepts relevant to neurodevelopmental disorders
	Infant and child development, environment, genes and their interactions
		Developmental trajectories of neuronal circuits and networks
		Key factors in child development
		Autism
		Syndromic autism
		Autism epidemiology
		Possible causative environmental factors in autism
		Epigenetics and autism
		Non-syndrome autism and common risk variants
		Genome-wide analyses of de novo variants in autism
		Functional magnetic neuroimaging in autism
	Epilepsy
		Epilepsy due to rare genomic changes of major effect
		Common epilepsy (idiopathic generalized epilepsy)
		Genomic and genetic mosaicism in epilepsy
	References
9A
Personalized precision medicine—Part A: Concepts and relevance in Mendelian disorders
	Concepts
		Precision medicine goals
		Important definitions related to precision medicine studies
		The UK Biobank: An example of connecting genomic and phenotypic data and health
		Studies that have utilized data from UK Biobank
		UK Biobank data and calcific aortic stenosis
		Factors to take into account in connecting genotype and phenotype: Variable penetrance
		Allelic exclusion
		Segmental genomic copy number variants and disease manifestations
		Modifier genes and networks
		Modes of effects of modifier genes
		Modifiers of complex traits
		Disorders that can result from environmental factors, single rare gene defects or common gene variants
			Nephrotic syndrome
			The continuum of rare and common diseases
	Personalized precision medicine in individuals with Mendelian disorders
		Definitive diagnoses of Mendelian disorders and inborn errors of metabolism
		Discovery of genes that harbored variants that cause rare diseases
			Problems in exome sequencing
		Databases with information on human genes, mutations and disease relevance
			The ClinGen endeavor
			Functional validation of genetic variants in cases with inborn errors of metabolism (IEM)
		Mosaicism
		RNA analyses to improve diagnosis
		Multidisciplinary precision medicine
			Enzyme assays in inborn errors of metabolism
			Next-generation sequencing for diagnosis of genetic diseases
			Additional factors to be taken into account following molecular diagnosis of Mendelian disease
			Modifier genes
		International collaborations on rare disease research
			Genetic disorders in which causation cannot be easily resolved by genomic studies
		Gene environment interactions in causation of congenital malformation
			Importance of genome studies in providing insight into underlying gene mechanisms
			Rare diseases and development of therapies
			Predicting phenotype from genotype
			Hemochromatosis, rare and common gene variants and gene-environment interactions
			Gene defects with low penetrance except under specific environmental conditions
				Porphyrias
				Acute intermittent porphyria (AIP)
				Coproporphyria
	References
9B
Personalized medicine. Precision medicine: PART B multifactorial diseases, genes, environments, interactions
	Cardiac conditions
		Long QT syndrome
			Founder mutations and the study genetic and environmental modifiers
		Dilated cardiomyopathy
		Lamin mutations
		Testing of family members of patients with cardiomyopathy inducing variants
	Cardio-vascular diseases and precision medicine
		Rare genetic variants in familial hypercholesterolemia
		Studies of genetic variants associated with common disease and polygenic risk scores
	Age related macular degeneration: Gene variants and environmental interactions
		Environmental factors in macular degeneration
		Specific AMD risk variants
	Age related neurodegenerative disorders
		Alzheimer’s disease
			Different forms of Alzheimer’s disease
			Late onset Alzheimer’s disease (LOAD) and APOE4
			Analyses of gene variants in Alzheimer’s disease
	Amyotrophic lateral sclerosis also known as Lou Gehrig disease, motor neuron disease
		Evidence for RNA dysregulation in amyotrophic lateral sclerosis
		Gene-time-environment models
	Parkinson’s disease ( PD)
		Exome sequencing in Parkinson’s disease
		Environmental factors and Parkinson’s disease
	Traumatic brain injury and consequences
	Psychiatric disorders
	Personalized medicine and Cancer prevention
		Germline mutations in cancer risk genes
			Cancer gene panels
			Classification of cancer risk genes
			Pathogenic BRCA mutations and incomplete penetrance
		Cancer risk genes and genetic testing
		Lynch syndrome
		Molecular pathogenesis of Lynch syndrome
	DNA mismatch repair and its role in cancer
		Mismatch DNA repair gene defects in tumors and immunotherapy
		Identifying cancer risk mutations
		Microbiome and colorectal cancer
		Multiple endocrine neoplasia syndromes
		Melanoma
	References
10
Integrating Genetic, Epigenetic And Environmental Information To Improve Health And Well-Being
	Integrating information on genetic variants and environmental factors in analyses of disease risk factors
		Expression quantitative trait loci
		Aspects of hypertension
			Systolic hypertension
			Carotid artery intima and media thickness and carotid plaque
			Monogenic factors in hypertension
			Monogenic forms of endocrine related hypertension: Adrenocortical hormones
			Cushing syndrome arising from excess adrenocortical function
			Blood pressure abnormalities due to mutations in ion channels
			Sympathetic and central nervous systems in hypertension
		Renal factors involved in blood pressure control
			Kidney disease and hypertension
		Epigenetics and hypertension
		High blood pressure predisposition, polygenic and environmental effects
		Stroke
			Polygenic factors life-style factors and stroke
			Single gene defects, small vessel disease and stroke
			Cadasil
			Cerebral amyloid angiopathy
		Coagulation and atherothrombosis
			Environmental factors and stroke
		Coronary heart disease (CAD)
			Heritability of coronary artery disease
			Treatment of broadly relevant causes and specific drivers of coronary heart disease
			Polygenic risk scores
			Core genes and peripheral genes in complex common diseases
			Modifiable risk factors in coronary heart disease
			Hypercholesterolemia
		Polygenic risk studies and complex common diseases
		Gene interactions
		Regulation of gene expression
			Regulatory element variations
			Transcription analyses
			Transcriptome wide association studies
		Genome wide studies in common metabolic diseases
			Interactions between allelic variants and the environment
	Rare genetic defects that increase the impact of specific environmental factors
		Infectious agents
			Parvovirus B19
			Cystic fibrosis
	Adjusting the environment particularly nutrition to compensate for inborn errors of metabolism
		Metabolic studies
		Sequence analysis
		Transcriptome studies
		Protein complex profiling
		Inborn errors of metabolism due to defects in mitochondrial function
		Emergence of the phenotype in a specific metabolic disease
		Compensatory mechanisms that can reduce the impact of specific gene mutations
		Mitochondrial related disorders and compensatory mechanisms
		Treatment of inborn errors of metabolism
		Newborn screening and inborn errors of metabolism
			Analyzing utility of nutritional interventions
		Interactions
			Integrating gene expression and environmental nutrient conditions
			Gene product modifications
		Mitochondrial functions and adaptations
			Homeostasis cofactors and their relationship to vitamins
		Sunlight
			Genetic disorders where individuals have increased sensitivity to sunlight and UVB
			Porphyrias
	Genes, networks, society and patients
		Systems perspectives
			Genes networks, society and patients
			Health disease and society
	References
11
Environments, resources, and health
	Green-house gas production and climate change problems and potential solutions
		Ozone
			Countries with highest energy use and percentage of energy generated from renewable resources
		Renewable energy resources
			Rockefeller Foundation Lancet Commission on planetary health report 2015 (RFLC)
		Documenting the scope and depth of problems
		Effects of climate change on waterways and marine ecosystems
		Loss of protection in coastal regions
		Loss of Behring sea ice and Arctic temperatures
		Retreat of the Antarctic ice sheet
		Invasive insects
		Downgrading of biodiversity protection areas
	Climate change, questions relating to sustainability and human health
		Climate change and human well-being
		Questions of environmental state, sustainability human interactions and human health
		Spread of disease across borders
			Population aging
		Gerontology
		Extending life and growing numbers of older individuals
		Networks and determinants of aging
		Nutrient sensing pathways
		Mitochondria
		Oxidative stress and DNA damage
		Telomeres
		Epigenetics and aging
		Sirtuins, NAD and aging
		NAD sources and availability
		DNA methylation changes in aging
		Proteins and aging
		Translation of information
			The Millennium ecosystem assessment
		Ecosystem changes
		Climate change
		World population growth
		Refugees and migrants
			Achievements in world-health
		HIV incidence
		Malaria
		Tuberculosis
		Hepatitis
		Trachoma that leads to blindness
		Vaccines
		Emerging diseases and vaccines
		Vaccine availability
		GAVI the global alliance for vaccines and immunization
		Vaccine shortages
			Non-Communicable cases of death
		Obesity
		Malnutrition
		Family planning
		Ecosystem services
			The one health concept
		Additional approaches to health: The one health concept
			Ecosystem dynamics
		Ecotoxicology
			Child development and nurture
		Environmental agent exposures and child development
		Child development, physical environment and green space
		Social ecology and health
		Health and employment
			Sustainable development goals
			The WHO comprehensive Mental Health Action plan 2013–2020 64
		Mental health and sustainable development
		Reframing mental health
		Limitations in diagnosing mental disorders
		Genomic studies of value in certain neurodevelopmental disorders in childhood
			Importance for human health of contact with nature
		The Biophilia hypothesis
			Partnerships and interconnections in dealing with challenges
	Efforts to counteract climate change and associated devastations
		Striving toward solutions
			Dietary changes to benefit health and mitigate climate change
			Proposed transformative changes in energy generation
		Physiological adaptations
			The heat shock response and heat-shock proteins
		Documenting problems and sometimes proposing solutions
			Loss of large carnivores and consequences
			Rewilding
			Perspectives on limitations
		Efforts to counteract climate change and associated devastations
			Drawdown
	Celebrations of nature in human endeavors
	References
12
Summary chapter epilogue
	Chapter 1 Interacting with the environment receiving and interpreting signals
	Chapter 2 Environment as provider
	Chapter 3 Evolution
	Chapter 4 Gene and environment interactions and phenotypes
	Chapter 5 Signals, epigenetics, regulation of gene expression
	Chapter 6 Maintaining homeostasis and mitigating effects of harmful factors in the intrinsic or extrinsic environment
	Chapter 7 Microorganisms and microbiome
	Chapter 9 Precision medicine and personalized medicine
		Personalized medicine in Mendelian disorders
		Personalized precision medicine in multifactorial diseases
	Chapter 10 Integrating genetic, epigenetic and environmental information to improve health and well-being
		Rare genetic defects and approaches to management
		Adjusting environments to compensate for inborn errors of metabolism
		Networks and gene interactions
	Chapter 11 Environments, resources, and health
		Greenhouse gas production climate change and potential solutions
		The one health concept
Index
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