1: Genes and development - Biology

  • 1.1: Genetics Review
    For the most part when we think about Molecular Genetics we are thinking about making functional proteins from a gene encoded in DNA, though some RNA is functional on its own. This happens via two highly-regulated processes: Transcription uses RNA polymerase to make a single stranded mRNA molecule from one strand of a double stranded DNA molecule. Translation uses the ribosome to make a peptide (part or all of a protein) from the mRNA .
  • 1.2: Development depends on signaling pathways
    A signaling pathway allows cells to communicate with their external environment. In Developmental Biology, this is usually cell-cell interactions. These kinds of interactions are incredibly important because each cell needs to follow its own developmental trajectory in coordination with all the cells around it. For example, imagine a growing mammalian limb bud. Each cell in the limb bud needs to know if it is on the thumb or pinky side of the limb and how close to the body it is.
  • 1.3: Major signaling pathways in developmental biology
  • 1.4: What's in a developmental biologist's "toolbox"?

Instructions to Authors

SCOPE: Genes & Development publishes high-quality research papers of general interest and biological significance. Papers should contain results that provide a novel advance and/or well-elucidated new mechanistic insight into a significant biological question. General areas of interest include, but are not limited to: Molecular Biology, Developmental Biology, Cancer and Disease Models, Stem Cells, Metabolism, Chromatin and Epigenetics, Cell Biology, Plant Biology, Genetics, Neurobiology, Systems Biology, Structural Biology, Genomics, Bacteriology and Virology.

Genes & Development publishes three research manuscript formats: Research Papers, Research Communications and Resource/Methodology papers, in addition to commissioned Review and Outlook articles. For detailed manuscript preparation guidelines in each of the manuscript formats please refer to the link below on 'Manuscript Preparation'. If an author has a query regarding whether their work is appropriate for submission to Genes & Development, they are welcome to submit a Pre-Submission Inquiry with Title Page and Abstract to the Editor ([email protected]).

To ensure a rapid review process, all Research Papers and Research Communications are evaluated by the Editors, often in consultation with members of the Editorial Board. Articles deemed not suitable for publication in Genes & Development will be returned to the author without review. Other manuscripts will be sent for a full review to experts in the field and members of the Editorial Board. Publication time from acceptance of manuscript is between one and three months. For papers accepted subject to revision, only one revised version will be considered it must be submitted within two months of the provisional acceptance.


Think of these influences as building blocks. While most people tend to have the same basic building blocks, these components can be put together in an infinite number of ways. Consider your own overall personality. How much of who you are today was shaped by your genetic background and how much is a result of your lifetime of experiences?

This question has puzzled philosophers, psychologists, and educators for hundreds of years and is frequently referred to as the nature versus nurture debate. Are we the result of nature (our genetic background) or nurture (our environment)? Today, most researchers agree that child development involves a complex interaction of both nature and nurture.  

Genetics, Genomics & Development

The Genetics, Genomics, and Development (GGD) emphasis is dedicated to preparing students for the revolution in biology that is fueled by the genome sequences of an ever-increasing spectrum of life. The GGD emphasis explores how the information in these genomes program the development of diverse organisms including humans, classical model organisms, and species that represent pivotal nodes in evolution. In the GGD emphasis, you will explore how different sequences lead to phenotypic variation among individuals, and how these differences are inherited and fixed by natural selection. You will also learn how sequence diversity influences human phenotypes, from how we appear to how we behave. These differences also have a major influence on health and disease, and you will learn how the study of human genomes has revolutionized modern medicine.

The GGD emphasis also focuses on how genetic, molecular genetic and genomics tools are used to understand various aspects of biology, ranging from how cells with the same genetic information express different sets of genes and exhibit distinct phenotypes, to how pattern develops in metazoans, to how organisms sense and respond to their environment, and to how cell divisions are orchestrated to ensure proper chromosome integrity and segregation during formation of egg and sperm and the multitude of cell divisions of the developing organism.

Upper Division Requirements

Genetics, Genomics, & Development
Track 1: Genetics, Genomics & Development Track 2: Developmental Genetics
MCB C100A: Biophysical Chemistry (Fa, Sp 4 un) MCB 102: Survey of Biochem & Molecular Biology
MCB 110: Molecular Biology (Fa, Sp 4 un) MCB 104: Genetics, Genomics & Cell Biology (Fa,Sp 4 un) OR MCB 140: General Genetics (Fa, Sp 4 un)
MCB 140: General Genetics MCB 141: Developmental Biology (Sp 4 un)
MCB 140L: Genetics Lab (Sp 4 un) MCB 140L: Genetics Lab (Sp 4 un)
GGD Elective A or B (see lists below) GGD Elective A or B (see lists below)
GGD Elective B (see list below) GGD Elective B (see list below)

Petitioning to Substitute MCB 140L with Research Units

Students may petition to substitute the lab course with equivalent knowledge and units obtained through independent research experience (such as 199 or H196 research), as determined by the Head Faculty Advisor of their major emphasis. Careful consideration and discussion with your faculty advisor are important when making the decision whether to use independent research to substitute the lab, as MCB labs expose students to many biological approaches not always encountered during these research projects. For more information on the approval process see Petition to Substitute MCB Lab Course.

Sample 4-yr Plans

These are just examples, for more sample schedules including spring start and transfer see or meet with an advisor to explore your options. It is recommended by MCB advisors and faculty to take the upper division lab as early as you can if you are interested in research and/or honors research.

Track 1: Genetics, Genomics & Development Track 2: Developmental Genetics
Year 1 Year 1
Fall Un Spring Un Fall Un Spring Un
Math 10A 4 Math 10B 4 Math 10A 4 Math 10B 4
Chem 1A/1AL 4 Chem 3A/3AL 5 Chem 1A/1AL 4 Chem 3A/3AL 5
Year 2 Year 2
Fall Un Spring Un Fall Un Spring Un
Chem 3B/3BL 5 Biology 1A/1AL 5 Chem 3B/3BL 5 Biology 1A/1AL 5
Physics 8A 4 Physics 8B 4 Physics 8A 4 Physics 8B 4
Year 3 Year 3
Fall Un Spring Un Fall Un Spring Un
MCB C100A 4 MCB 140 4 MCB 102 4 MCB 104 or 140 4
Biology 1B 4 Elective A or B 3-4 Biology 1B 4 Elective A or B 3-4
Year 4 Year 4
Fall Un Spring Un Fall Un Spring Un
MCB 110 4 MCB 140L 4 Elective B 3-4 MCB 140L 4
Elective B 3-4 MCB 141 4

GGD Approved Electives Lists

GGD Elective List A

GGD Elective List B

  • 100B Biochemistry: Pathways, Mechanisms, and Regulation (Sp 4 units)
  • C103 Bacterial Pathogenesis (Sp 3 units)
  • C112 General Microbiology (F 4 units)
  • C114 Intro to Comparative Virology (Sp 4 units)
  • C116 Microbial Diversity (F 3 units)
  • 130 Cell & Systems Biology (Sp 4 units)
  • 135A Molecular Endocrinology (F 3 units)
  • 136 Physiology (F, Sp 4 units)
  • 150 Molecular Immunology (F, Sp 4 units)
  • 153 Molecular Therapeutics (F, 4 units)
  • 160 Cellular and Molecular Neurobiology (F 4 units)
  • 161 Circuit, Systems and Behavioral Neuroscience (Sp 4 units)*MCB 160 is a prerequisite*
  • 165 Neurobiology of Disease (Sp 3 units)
  • 166 Biophysical Neurobiology (F 3 units)
  • 113 Advanced Mechanistic Organic Chemistry (F 3 units)
  • 115 Organic Chemistry - Advanced Lab Methods (F, Sp 4 units)
  • 130B Biophysical Chemistry (Sp 3 units)

Environmental Science, Policy & Management

  • C148 Pesticide Chemistry and Toxicology (Sp 3 units)
  • 162 Bioethics & Society (Sp 4 units)
  • 160 Evolution (F 4 units)
  • 110 Linear Algebra (F, Sp, Su 4 units)

Nutritional Sciences & Toxicology

  • C114 Pesticide Chemistry & Toxicology (Sp 3 units)
  • 112 Intro to Statistical & Thermal Physics (F, Sp 4 units)

Plant & Microbial Biology

  • 135 Physiology and Biochemistry of Plants (F 3 units)
  • 150 Plant Cell Biology (F 3 units)
  • 132 Biology of Human Cancer (F 4 units)
  • C134 Chromosome Biology/Cytogenetics (Sp 3 units)
  • 137L Physical Biology of the Cell (Sp 3 units)
  • 141 Developmental Biology (Sp 3 units) (for track 1 students only)
  • C148 Microbial Genomics & Genetics (Sp 4 units)
  • 149 The Human Genome (F 3 units)


  • *131 Intro to Computational Molecular and Cell Biology (F 4 units)
  • 143: Computational Methods in Biology (F 4 units)
  • 144 Introduction to Protein Informatics (Sp 4 units)

Computational Biology

Environmental Science and Policy Management

Integrative Biology

  • 161 Population & Evolutionary Genetics (Alt Sp, 4 units)
  • 162 Ecological Genetics (Alt F, 4 units)
  • 163 Molecular & Genomic Evolution (Sp, 3 units)


Plant & Microbial Biology

  • C134 Chromosome Biology/Cytogenetics (Sp, 3 units)
  • 160 Plant Molecular Genetics (Sp, 3 units)

Public Health

  • 141 Introduction to Biostatistics (Su 5 units)
  • 142 Introduction to Probability and Statistics in Bio and Public Health (F, Sp 4 units) - Note: For students who have completed Math 10A/B, or Stat 2 or 20, this course is not accepted to meet the elective requirement.
  • 256 Human Genome, Environment and Public Health (Fa 4 units)
  • 131A Intro to Probability and Statistics for Life Scientists (F, Sp 4 units)
  • 134 Concepts of Probability (F, Sp, Su 4 units)

* These electives have pre-requisites outside of courses usually required of MCB majors. Please be sure to check for pre-requisite information.

Approved Elective Courses but NOT Regularly Offered

  • BioEng C141 Stats for Bioinformatics
  • BioEng 142 Programming & Algorithm Design for Computational Biology & Genomics Application
  • BioEng 143 Computational Methods in Biology
  • IB 165 Introduction to Quantitative Genetics
  • MCB 115 Molecular Biology of Animal Viruses
  • MCB 137 Computer Simulation in Biology (replaced by MCB 137L)
  • MCB 143 Evolution of Genomes, Cells, and Development (F 3 units)
  • MCB C145 Genomics
  • MCB C146 Topics in Computational Biology
  • PHYSICS 132 Contemporary Physics
  • Pb Hlth 143 Introduction to Statistical Methods in Computational and Genomic Biology
  • Stats C141 Stats for Bioinformatics


  • Preface
  • Acknowledgments
  • Part 1. Principles of development in biology
    • Chapter 1. Developmental biology: The anatomical tradition
      • The Questions of Developmental Biology
      • Anatomical Approaches to Developmental Biology
      • Comparative Embryology
        • Epigenesis and preformation
        • Naming the parts: The primary germ layers and early organs
        • The four principles of Karl Ernst von Baer
        • Fate mapping the embryo
        • Cell migration
        • Embryonic homologies
        • The mathematics of organismal growth
        • The mathematics of patterning
        • The Circle of Life: The Stages of Animal Development
        • The Frog Life Cycle
        • The Evolution of Developmental Patterns in Unicellular Protists
          • Control of developmental morphogenesis: The role of the nucleus
          • Unicellular protists and the origins of sexual reproduction
          • The Volvocaceans
          • Differentiation and Morphogenesis in Dictyostelium: Cell Adhesion
          • Diploblasts
          • Protostomes and deuterostomes
          • Environmental Developmental Biology
            • Environmental sex determination
            • Adaptation of embryos and larvae to their environments
            • Autonomous Specification
            • Conditional specification
            • Syncytial specification
            • Differential cell affinity
            • The thermodynamic model of cell interactions
            • Cadherins and cell adhesion
            • The Embryological Origins of the Gene Theory
              • Nucleus or cytoplasm: Which controls heredity?
              • The split between embryology and genetics
              • Early attempts at developmental genetics
              • Metaplasia
              • Amphibian cloning: The restriction of nuclear potency
              • Amphibian cloning: The pluripotency of somatic cells
              • Cloning mammals
              • Northern blotting
              • In situ hybridization
              • The polymerase chain reaction
              • Transgenic cells and organisms
              • Determining the function of a message: Antisense RNA
              • Differential Gene Transcription
                • Anatomy of the gene: Exons and introns
                • Anatomy of the gene: Promoters and enhancers
                • Transcription factors
                • Silencers
                • Locus control regions in globin genes
                • DNA methylation and gene activity
                • Possible mechanisms by which methylation represses gene transcription
                • Control of early development by nuclear RNA selection
                • Creating families of proteins through differential nRNA splicing
                • Differential mRNA longevity
                • Selective inhibition of mRNA translation
                • Control of RNA expression by cytoplasmic localization
                • Induction and Competence
                  • Cascades of induction: Reciprocal and sequential inductive events
                  • Instructive and permissive interactions
                  • Epithelial-mesenchymal interactions
                  • The fibroblast growth factors
                  • The Hedgehog family
                  • The Wnt family
                  • The TGF-β superfamily
                  • Other paracrine factors
                  • The RTK pathway
                  • The Smad pathway
                  • The JAK-STAT pathway
                  • The Wnt pathway
                  • The Hedgehog pathway
                  • The Notch pathway: Juxtaposed ligands and receptors
                  • The extracellular matrix as a source of critical developmental signals
                  • Direct transmission of signals through gap junctions
                  • Chapter 7. Fertilization: Beginning a new organism
                    • Structure of the Gametes
                      • Sperm
                      • The egg
                      • Sperm attraction: Action at a distance
                      • The acrosomal reaction in sea urchins
                      • Species-specific recognition in sea urchins
                      • Gamete binding and recognition in mammals
                      • Fusion of the egg and sperm plasma membranes
                      • The prevention of polyspermy
                      • Early responses
                      • Late responses
                      • Fusion of genetic material in sea urchins
                      • Fusion of genetic material in mammals
                      • Preparation for cleavage
                      • An Introduction to Early Developmental Processes
                        • Cleavage
                        • Gastrulation
                        • Axis Formation
                        • Cleavage in Sea Urchins
                        • Sea Urchin Gastrulation
                        • Cleavage in Snail Eggs
                        • Gastrulation in Snails
                        • Tunicate Cleavage
                        • Gastrulation in Tunicates
                        • Why C. elegans?
                        • Cleavage and Axis Formation in C. elegans
                        • Gastrulation in C. elegans
                        • Coda
                        • Snapshot Summary: Early Invertebrate Development
                        • Early Drosophila Development
                          • Cleavage
                          • Gastrulation
                          • The Maternal Effect Genes
                          • The Segmentation Genes
                          • The Homeotic Selector Genes
                          • The Morphogenetic Agent for Dorsal-Ventral Polarity
                          • The Translocation of Dorsal Protein
                          • Axes and Organ Primordia: The Cartesian Coordinate Model
                          • Coda
                          • Snapshot Summary: Drosophila Development and Axis Specification
                          • Early Amphibian Development
                            • Cleavage in Amphibians
                            • Amphibian Gastrulation
                            • The Progressive Determination of the Amphibian Axes
                            • Hans Spemann and Hilde Mangold: Primary Embryonic Induction
                            • The Mechanisms of Axis Formation in Amphibians
                            • The Functions of the Organizer
                            • The Regional Specificity of Induction
                            • Snapshot Summary: Early Development and Axis Formation in Amphibians
                            • Early Development in Fish
                              • Cleavage in Fish Eggs
                              • Gastrulation in Fish Embryos
                              • Axis Formation in Fish Embryos
                              • Cleavage in Bird Eggs
                              • Gastrulation of the Avian Embryo
                              • Axis Formation in the Chick Embryo
                              • Cleavage in Mammals
                              • Escape from the Zona Pellucida
                              • Gastrulation in Mammals
                              • Mammalian Anterior-Posterior Axis Formation
                              • The Dorsal-Ventral and Left-Right Axes in Mammals
                              • Snapshot Summary: The Early Development of Vertebrates
                              • Chapter 12. The central nervous system and the epidermis
                                • Formation of the Neural Tube
                                  • Primary neurulation
                                  • Secondary neurulation
                                  • The anterior-posterior axis
                                  • The dorsal-ventral axis
                                  • Spinal chord and medulla organization
                                  • Cerebellar organization
                                  • Cerebral organization
                                  • Adult neural stem cells
                                  • The dynamics of optic development
                                  • Neural retina differentiation
                                  • Lens and cornea differentiation
                                  • The origin of epidermal cells
                                  • Cutaneous appendages
                                  • Patterning of cutaneous appendages
                                  • The Neural Crest
                                    • The Trunk Neural Crest
                                    • The Cranial Neural Crest
                                    • The Cardiac Neural Crest
                                    • The Generation of Neuronal Diversity
                                    • Pattern Generation in the Nervous System
                                    • The Development of Behaviors: Constancy and Plasticity
                                    • Snapshot Summary: Neural Crest Cells and Axonal Specificity
                                    • Paraxial Mesoderm: The Somites and Their Derivatives
                                      • The initiation of somite formation
                                      • Specification and commitment of somitic cell types
                                      • Determining somitic cell fates
                                      • Specification and differentiation by the myogenic bHLH proteins
                                      • Muscle cell fusion
                                      • Intramembranous ossification
                                      • Endochondral ossification
                                      • Osteoclasts
                                      • Progression of kidney types
                                      • Reciprocal interaction of kidney tissues
                                      • The mechanisms of reciprocal induction
                                      • Lateral Plate Mesoderm
                                        • The Heart
                                        • Formation of Blood Vessels
                                        • The Development of Blood Cells
                                        • The Pharynx
                                        • The Digestive Tube and Its Derivatives
                                        • The Respiratory Tube
                                        • The Extraembryonic Membranes
                                        • Snapshot Summary: Lateral Mesoderm and Endoderm
                                        • Formation of the Limb Bud
                                          • Specification of the limb fields: Hox genes and retinoic acid
                                          • Induction of the early limb bud: Fibroblast growth factors
                                          • Specification of forelimb or hindlimb: Tbx4 and Tbx5
                                          • Induction of the apical ectodermal ridge
                                          • The apical ectodermal ridge: The ectodermal component
                                          • The progress zone: The mesodermal component
                                          • Hox genes and the specification of the proximal-distal axis
                                          • The zone of polarizing activity
                                          • Sonic hedgehog defines the ZPA
                                          • Sculpting the autopod
                                          • Forming the joints
                                          • Chromosomal Sex Determination in Mammals
                                            • Primary and secondary sex determination
                                            • The developing gonads
                                            • The mechanisms of mammalian primary sex determination
                                            • Secondary sex determination: Hormonal regulation of the sexual phenotype
                                            • The sexual development pathway
                                            • The sex-lethal gene as the pivot for sex determination
                                            • The transformer genes
                                            • Doublesex: The switch gene of sex determination
                                            • Temperature-dependent sex determination in reptiles
                                            • Location-dependent sex determination in Bonellia and Crepidula
                                            • Metamorphosis: The Hormonal Reactivation of Development
                                              • Amphibian Metamorphosis
                                              • Metamorphosis in Insects
                                              • Epimorphic Regeneration of Salamander Limbs
                                              • Compensatory Regeneration in the Mammalian Liver
                                              • Morphallactic Regeneration in Hydras
                                              • Maximum Life Span and Life Expectancy
                                              • Causes of Aging
                                              • Snapshot Summary: Metamorphosis, Regeneration, and Aging
                                              • Germ Plasm and the Determination of the Primordial Germ Cells
                                                • Germ cell determination in nematodes
                                                • Germ cell determination in insects
                                                • Germ cell determination in amphibians
                                                • Germ cell migration in amphibians
                                                • Germ cell migration in mammals
                                                • Germ cell migration in birds and reptiles
                                                • Germ cell migration in Drosophila
                                                • Spermiogenesis
                                                • Oogenic meiosis
                                                • Maturation of the oocyte in amphibians
                                                • Completion of amphibian meiosis: Progesterone and fertilization
                                                • Gene transcription in oocytes
                                                • Meroistic oogenesis in insects
                                                • Oogenesis in mammals
                                                • Chapter 20. An overview of plant development
                                                  • Plant Life Cycles
                                                  • Gamete Production in Angiosperms
                                                    • Pollen
                                                    • The ovary
                                                    • Experimental studies
                                                    • Embryogenesis
                                                    • Meristems
                                                    • Root development
                                                    • Shoot development
                                                    • Leaf development
                                                    • Environmental Regulation of Normal Development
                                                      • Environmental Cues and Normal Development
                                                      • Predictable Environmental Differences as Cues for Development
                                                      • Phenotypic Plasticity: Polyphenism and Reaction Norms
                                                      • Predator-Induced Defenses
                                                      • Mammalian Immunity as a Predator-Induced Response
                                                      • Learning: An Environmentally Adaptive Nervous System
                                                      • Teratogenic Agents
                                                      • Genetic-Environmental Interactions
                                                      • Coda
                                                      • Snapshot Summary: The Environmental Regulation of Development
                                                      • “Unity of Type” and 𠇌onditions of Existence”
                                                        • Charles Darwin's synthesis
                                                        • E. B. Wilson and F. R. Lillie
                                                        • “Life's splendid drama”
                                                        • The search for the Urbilaterian ancestor
                                                        • Changes in Hox-responsive elements of downstream genes
                                                        • Changes in Hox gene transcription patterns within a body portion
                                                        • Changes in Hox gene expression between body segments
                                                        • Changes in Hox gene number
                                                        • Instructions for forming the central nervous system
                                                        • Limb formation
                                                        • Dissociation: Heterochrony and allometry
                                                        • Duplication and divergence
                                                        • Co-option
                                                        • Correlated progression
                                                        • Coevolution of ligand and receptor
                                                        • Physical constraints
                                                        • Morphogenetic constraints
                                                        • Phyletic constraints

                                                        With a chapter on Plant Development by Susan R Singer, Carleton College

                                                        By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

                                                        Developmental Biology and Genetics

                                                        The broad fields of Developmental Biology and Genetics are highly interdisciplinary with a presence in all basic medical-science areas, as well as animal and plant biology. Understanding how organisms develop requires a systems-level understanding of how cells achieve different fates, and what combinations of intercellular signaling and intracellular regulatory circuits generate spatially and temporally encoded patterns along the body axis. With the unprecedented expansion of techniques in genomics, molecular biology, and biochemistry, studies in developmental biology require an integrative perspective, applying a "systems" level approach that combines computational and genomic approaches with cell and molecular biology techniques to study developmental phenomena. In particular, many key insights into development are enabled by genetic approaches to understand how genes control the differentiation of cells and the formation of patterns. With regards to our educational mission, we are deeply committed to training outstanding researchers who are well prepared to tackle the exciting challenges that await them in this burgeoning area.

                                                        Developmental Biology

                                                        Laboratories that work in this area seek to understand how a multicellular organism arises from a single cell, the fertilized egg. Research in this area spans a broad range of topics, approaches, and experimental systems, including sea urchin development, muscle specification in mice, neural crest development in vertebrates, postembryonic nematode development, Arabidopsis development, mouse T-cell development, Drosophila mesoderm development, Xenopus signaling pathways, stem cell regulatory circuits, genomics and bioinformatics of stem cells, and evolution of development.

                                                        Genetics underlies all of biology and much biological inquiry. We build on our rich history in genetics, in which Caltech geneticists such as Morgan, Beadle, Delbruck, Benzer, Wood, Lewis and Hood laid down the foundations of our understanding of genes, gene function, genetic pathways, and genome sequences. Current research on Genetics at Caltech includes modern developmental and behavioral genetics using flies, worms, mice, yeast, Arabidopsis, and zebrafish to elucidate the genetic control of development, physiology, and behavior.

                                                        Developmental and Stem Cell Biology

                                                        Laboratories working in the area of stem cell biology are focusing on cell lineage decisions in the early embryo and what drives cells from a pluripotent to more restricted state, eventually leading to differentiation into defined cell types. To achieve these goals, we utilize a variety of approaches including high resolution live imaging, lineage tracing, genomic and epigenomic profiling on the whole embryo and single cell level coupled with perturbation approaches.

                                                        5. Development and Evolution

                                                        The relationships that obtain between development and evolution are complicated and under ongoing investigation (for a review, see Love 2015). Two main axes dominate within a loose conglomeration of research programs (Raff 2000 Müller 2007): (a) the evolution of development, or inquiry into the pattern and processes of how ontogeny varies and changes over time and, (b) the developmental basis of evolution, or inquiry into the causal impact of ontogenetic processes on evolutionary trajectories&mdashboth in terms of constraint and facilitation. Two examples where the concepts and practices of developmental and evolutionary biology intersect are treated here: the problematic appeal to functional homology in developmental genetics that is meant to underwrite evolutionary generalizations about ontogeny (Section 5.1) and the tension between using normal stages for developmental investigation and determining the evolutionary significance of phenotypic plasticity (Section 5.2). These cases expose some of the philosophical issues inherent in how development and evolution can be related to one another.

                                                        5.1 Functional Homology in Developmental Genetics

                                                        The conserved role of Hox genes in axial patterning is referred to as functionally homologous across animals (Manak and Scott 1994), over and above the relation of structural homology that obtains between DNA sequences. And yet &ldquofunctional homology&rdquo is a contradiction in terms (Abouheif et al. 1997) because the definition of a homologue is &ldquothe same organ in different animals under every variety of form and function&rdquo (Owen 1843: 379)&mdashthe descendant, evolutionary distinction between homology (structure) and analogy (function) is founded on this recognition. Therefore, the idea of functional homology appears theoretically confused and there is a conceptual tension in its use by molecular developmental biologists.

                                                        Figure 6: Vertebrate wings are homologous as forelimbs they are derived by common descent from the same structure. The function of vertebrate wings (i.e., flight) is analogous although the wings fulfill similar functions, their role in flight has evolved separately.

                                                        The reference to &ldquoorgan&rdquo in Owen&rsquos definition is indicative of a structure (an entity) found in an organism that may vary in its shape and composition (form) or what it is for (function) in the species where it occurs. Translated into an evolutionary context, sameness is cashed out by reference to common ancestry. Since structures also can be similar by virtue of natural selection operating in similar environments, homology is contrasted with analogy. Homologous structures are the same by virtue of descent from a common ancestor, regardless of what functions these structures are involved in, whereas analogous structures are similar by virtue of selection processes favoring comparable functional outcomes, regardless of common descent (Figure 6).

                                                        This is what makes similarity of function an especially problematic criterion of homology (Abouheif et al. 1997). Because functional similarity is the appropriate relation for analogy, it is not necessary for analogues to have the same function as a consequence of common ancestry&mdashsimilarity despite different origins suffices (Ghiselin 2005). Classic cases of analogy involve taxa that do not share a recent common ancestor that exhibits the structure, such as the external body morphology of dolphins and tuna (Pabst 2000). Thus, functional homology seems to be a category error because what a structure does should not enter into an evaluation of homologue correspondence and similarity of function is often the result of adaptation via natural selection to common environmental demands, not common ancestry.

                                                        Although we might be inclined to simply prohibit the terminology of functional homology, its widespread use in molecular and developmental biology should at least make us pause. [18] While it is important to recognize this pervasive practice, some occurrences may be illicit. Swapping structurally homologous genes between species to rescue mutant or null phenotypes is not a genuine criterion of functional homology, especially when there is little or no attention to establishing a phylogenetic context. This makes a number of claims of functional homology suspect. To not run afoul of the conceptual tension, explicit attention must be given to the meaning of &ldquofunction.&rdquo Biological practice harbors at least four separate meanings of function (Wouters 2003, 2005): activity (what something does), causal role (contribution to a capacity), fitness advantage or viability (value of having something), and selected effect or etiology (origination and maintenance via natural selection). Debate has raged about which of them (if any) is most appropriate for different aspects of biological and psychological reasoning or most general in scope (i.e., what makes them all function concepts?) (see discussion in Garson 2016). Here the issue is whether we can identify a legitimate concept of homology of function.

                                                        If we are to avoid mixing homology and analogy, then the appropriate notion of function cannot be based on selection history, which is allied with the concept of analogy and concerns a particular variety of function. Similarly, viability interpretations concentrate on features where the variety of function is critical because of conferred survival advantages. Any interpretation of function that relies on a particular variety of function (because it was selected or because it confers viability) clashes with the demand that homology concern something &ldquounder every variety of form and function.&rdquo A causal role interpretation emphasizes a systemic capacity to which a function makes a contribution. It too focuses on a particular variety of function, though in a way different from either selected effect or viability interpretations. Only an activity interpretation (&lsquowhat something does&rsquo) accents the function itself, apart from its specific contribution to a systemic capacity and position in a larger context. Therefore, the most appropriate meaning to incorporate into homology of function is &ldquoactivity-function&rdquo because it is at least possible for activity-functions to remain constant under every variety. An evaluation of sameness due to common ancestry is made separately from the role the function plays (or its use), whether understood in terms of a causal role, a fitness advantage, or a history of selection. [19] Activity-functions can be put to different uses while being shared via common descent (i.e., homologous). More precisely, homology of function can be defined as the same activity-function in different animals under every variety of form and use-function (Love 2007). This unambiguously removes the tension that plagued functional homology.

                                                        Careful discussions of regulatory gene function in development and evolution recognize something akin to the distinction between activity- and use-function (i.e., between what a gene does and what it is for in some process within the organism).

                                                        When studying the molecular evolution of regulatory genes, their biochemical and developmental function must be considered separately. The biochemical function of PAX-6 and eyeless are as general transcription factors (which bind and activate downstream genes), but their developmental function is their specific involvement in eye morphogenesis (Abouheif 1997: 407).

                                                        The biochemical function is the activity-function and the developmental function is the use-function. This distinction helps to discriminate between divergent evolutionary trajectories. Biochemical (activity-functions) of genes are often conserved (i.e., homologous), while simultaneously being available for co-option to make causal role contributions (use-functions) to distinct developmental processes. The same regulatory genes are evolutionarily stable in terms of activity-function and evolutionarily labile in terms of use-function. [20] By implication, claims about use-function homology for genes qua developmental function are suspect compared to those concerning activity-function homology for genes qua biochemical function because developmental functions are more likely to have changed as phylogenetic distance increases.

                                                        The distinction between biochemical (activity) function and developmental (use) function is reinforced by the hierarchical aspects of homology (Hall 1994). A capacity defining the use-function of a regulatory gene at one level of organization, such as axial patterning, must be considered as an activity-function itself at another level of organization, such as the differentiation of serially repeated elements along a body axis. (Note that &ldquolevel of organization&rdquo need not be compositional and thus the language of &ldquohigher&rdquo and &ldquolower&rdquo levels may be inappropriate.) The developmental roles of Hox genes in axial patterning may be conserved by virtue of their biochemical activity-function homologies but Hox genes are not use-function homologues because of these developmental roles. Instead of focusing on the activity of a gene component and its causal role in axial patterning, we shift to the activity of axial patterning and its causal role elsewhere (or elsewhen) in embryonic development.

                                                        Introducing a conceptually legitimate idea of homology of activity-function is not about keeping the ideas of developmental biology tidy. It assists in the interpretation of evidence and circumscribes the inferences drawn. For example, NK-2 genes are involved in mesoderm specification, which underlies muscle morphogenesis. In Drosophila, the expression of a particular NK-2 gene (tinman) is critical for both cardiac and visceral mesoderm development. If tinman is knocked out and transgenically replaced with its vertebrate orthologue, Nkx2-5, only visceral mesoderm specification is rescued the regulation of cardiac mesoderm is not (Ranganayakulu et al. 1998). A region of the vertebrate protein near the 5&prime end of the polypeptide differs enough to prevent appropriate regulation in cardiac morphogenesis. The homeodomains (stretches of sequence that confer DNA binding) for vertebrate Nkx2-5 and Drosophila tinman are interchangeable. The inability of Nkx2-5 to rescue cardiac mesoderm specification is not related to the activity-function of differential DNA binding. One component of the orthologous (homologous) proteins in both species retains an activity-function homology related to visceral mesoderm specification but another component (not the homeodomain) has diverged. This homeobox gene does not have a single use-function (as expected), but it also does not have a single activity-function. Any adequate evaluation of these cases must recognize a more fine-grained decomposition of genes into working units to capture genuine activity-function conservation. We can link activity-function homologues directly to structural motifs within a gene, but there is not necessarily a single activity-function for an entire open reading frame.

                                                        Defusing the conceptual tensions between developmental and evolutionary biology with respect to homology of function has a direct impact on the causal generalizations and inferences made from model organisms (Section 4). Activity-function homology directs our attention to the stability or conservation of activities. This conservation is indicative of when the study of mechanisms in model organisms will produce robust and stable generalizations (Section 1.3). The widespread use of functional homology in developmental biology is aimed at exactly this kind of question, which explains its persistence in experimental biology despite conceptual ambiguities. Generalizations concerning molecular signaling cascades are underwritten by the coordinated biochemical activities in view, not the developmental roles (though sometimes they may coincide). Thus, activity-function details about a signaling cascade gleaned from a model organism can be generalized via homology to other unstudied organisms even if the developmental role varies for the activity-function in other species.

                                                        5.2 Normal Stages and Phenotypic Plasticity

                                                        All reasoning strategies combine distinctive strengths alongside of latent weaknesses. For example, decomposing a system into its constituents to understand the features manifested by the system promotes a dissection of the causal interactions of the localized constituents, while downplaying interactions with elements external to the system (Wimsatt 1980 Bechtel and Richardson 1993). Sometimes the descriptive and explanatory practices of the sciences are successful precisely because they intentionally ignore aspects of natural phenomena or use a variety of approximation techniques. Idealization is one type of reasoning strategy that scientists use to describe, model, and explain that purposefully departs from features known to be present in nature. For example, the interior space of a cell is often depicted as relatively empty even though intracellular space is known to be crowded (Ellis 2001) the variable of cellular volume takes on a value that is known to be false (i.e., relatively empty). Idealizations involve knowingly ignoring variations in properties or excluding particular values for variables, in a variety of different ways, for descriptive and explanatory purposes (Jones 2005 Weisberg 2007).

                                                        &ldquoNormal development&rdquo is conceptualized through strategies of abstraction that manage variation inherent within and across developing organisms (Lowe 2015, 2016). The study of ontogeny in model organisms (Section 4) is usually executed by establishing a set of normal stages for embryonic development (see Other Internet Resources). A developmental trajectory from fertilized zygote to fully-formed adult is broken down into distinct temporal periods by reference to the occurrence of major events, such as fertilization, gastrulation, or metamorphosis (Minelli 2003: ch. 4 see Section 1.2). This enables researchers in different laboratory contexts to have standardized comparisons of experimental results (Hopwood 2005, 2007). They are critical to large communities of developmental biologists working on well-established models, such as chick (Hamburger and Hamilton 1951) or zebrafish (Kimmel et al. 1995): &ldquoEmbryological research is now unimaginable without such standard series&rdquo (Hopwood 2005: 239). These normal stages are a form of idealization because they intentionally ignore kinds of variation in development, including variation associated with environmental variables. While facilitating the study of particular causal relationships, this means that specific kinds of variation in developmental features that might be relevant to evolution are minimized in the process of rendering ontogeny experimentally tractable (Love 2010).

                                                        Phenotypic plasticity is a ubiquitous biological phenomenon. It involves the capacity of a particular genotype to generate phenotypic variation, often in the guise of qualitatively distinct phenotypes, in response to differential environmental cues (Pigliucci 2001 DeWitt and Scheiner 2004 Kaplan 2008 Gilbert and Epel 2009). One familiar example is seasonal caterpillar morphs that depend on different nutritional sources (Greene 1989). Some of the relevant environmental variables include temperature, nutrition, pressure/gravity, light, predators or stressful conditions, and population density (Gilbert and Epel 2009). The reaction norm is a summary of the range of phenotypes, whether quantitatively or qualitatively varying, exhibited by organisms of a given genotype for different environmental conditions. When the reaction norm exhibits discontinuous variation or bivalent phenotypes (rather than quantitative, continuous variation), it is often labeled a polyphenism (Figure 7).

                                                        Figure 7: A color polyphenism in American Peppered Moth caterpillars that represents an example of phenotypic plasticity.

                                                        Phenotypic plasticity has been of recurring interest to biological researchers and controversial in evolutionary theory. Extensive study of phenotypic plasticity has occurred in the context of quantitative genetic methods and phenotypic selection analyses, where the extent of plasticity in natural populations has been demonstrated and operational measures delineated for its detection (Scheiner 1993 Pigliucci 2001). Other aspects of plasticity require different investigative methods to ascertain the sources of plasticity during ontogeny, the molecular genetic mechanisms that encourage plasticity, and the kinds of mapping functions that exist between the genotype and phenotype (Pigliucci 2001 Kirschner and Gerhart 2005: ch. 5). These latter aspects, the origin of phenotypic variation during and after ontogeny, are in view at the intersection of development and evolution: How do molecular genetic mechanisms produce (or reduce) plasticity? What genotype-phenotype mapping functions are prevalent or rare? Does plasticity contribute to the origination of evolutionary novelties (Moczek et al. 2011 West-Eberhard 2003)?

                                                        In order to evaluate these questions experimentally, researchers need to alter development through the manipulation of environmental variables and observe how a novel phenotype can be established within the existing plasticity of an organism (Kirschner and Gerhart 2005: ch. 5). This manipulation could allow for the identification of patterns of variation through the reliable replication of particular experimental alterations within different environmental regimes. However, without measuring variation across different environmental regimes, you cannot observe phenotypic plasticity. These measurements are required to document the degree of plasticity and its patterns for a particular trait, such as qualitatively distinct morphs. An evaluation of the significance of phenotypic plasticity for evolution requires answers to questions about where plasticity emerges, how molecular genetic mechanisms are involved in the plasticity, and what genotype-phenotype relations obtain.

                                                        Developmental stages intentionally ignore variation associated with phenotypic plasticity. Animals and plants are raised under stable environmental conditions so that stages can be reproduced in different laboratory settings and variation is often viewed as noise that must be reduced or eliminated if one is to understand how development works (Frankino and Raff 2004). This practice also encourages the selection of model organisms that exhibit less plasticity (Bolker 1995). The laboratory domestication of a model organism may also reduce the amount or type of observable phenotypic variation (Gu et al. 2005), though laboratory domestication also can increase variation (e.g., via inbreeding). Despite attempts to reduce variation by controlling environmental factors, some of it always remains (Lowe 2015) and is displayed by the fact that absolute chronology is not a reliable measure of time in ontogeny, and neither is the initiation or completion of its different parts (Mabee et al. 2000 Sheil and Greenbaum 2005). Developmental stages allow this recalcitrant variation to be effectively ignored by judgments of embryonic typicality. Normal stages also involve assumptions about the causal connections between different processes across sequences of stages (Minelli 2003: ch. 4). Once these stages have been constructed, it is possible to use them as a visual standard against which to recognize and describe variation as a deviation from the norm (DiTeresi 2010 Lowe 2016). But, more typically, variation ignored in the construction of these stages is also ignored in the routine consultation of the stages in day-to-day research contexts (Frankino and Raff 2004).

                                                        Normal stages fulfill a number of goals related to descriptive and explanatory endeavors that developmental biologists engage in (Kimmel et al. 1995). They yield a way to measure experimental replication, enable consistent and unambiguous communication among researchers, especially if stages are founded on commonly observable morphological features, facilitate accurate predictions of developmental phenomena, and aid in making comparisons or generalizations across species. As idealizations of ontogeny, normal stages allow for a classification of developmental events that is comprehensive with suitably sized and relatively homogeneous stages, reasonably sharp boundaries between stages, and stability under different investigative conditions (Dupré 2001), which encourages more precise explanations within particular disciplinary approaches (Griesemer 1996). Idealizations also can facilitate abstraction and generalization, both of which are a part of extrapolating findings from the investigative context of a model organism to other domains (Steel 2008 see Section 4 and 5.1).

                                                        There are various weaknesses associated with normal stages that accompany the fulfillment of these investigative and explanatory goals. Key morphological indicators sometimes overlap stages, terminology that is useful for one purpose may be misleading for another, particular terms can be misleading in cross-species comparisons, and manipulation of the embryo for continued observation can have a causal impact on ontogeny. Avoiding variability in stage indicators can encourage overlooking the significance of this variation, or at least provide a reason to favor its minimization.

                                                        Thus, there are good reasons for adopting normal stages to periodize model organism ontogeny, and these reasons help to explain why their continued use yields empirical success. However, similar to other standard (successful) practices in science, normal stages are often taken for granted, which means their biasing effects are neglected (Wimsatt 1980), some of which are relevant to evolutionary questions (e.g., systematically underestimating the extent of variation in a population). This is critical to recognize because the success of a periodization is not a function of the eventual ability to relax the idealizations periodizations are not slowly corrected so that they become less idealized. Instead, new periodizations are constructed and used alongside the existing ones because different idealizations involve different judgments of typicality that serve diverse descriptive and explanatory aims. In addition to the systematic biases involved in developmental staging, most model organisms are poorly suited to inform us about how environmental effects modulate or combine with genetic or other factors in development&mdashthey make it difficult to discover details about mechanisms underlying reaction norms. Short generation times and rapid development are tightly correlated with insensitivity to environmental conditions through various mechanisms such as prepatterning (Bolker 1995).

                                                        The tension between the specific practice of developmental staging in model organisms and uncovering the relevance of variation due to phenotypic plasticity for evolution can be reconstructed as an argument.

                                                        1. Variation due to phenotypic plasticity is a normal feature of ontogeny.
                                                        2. The developmental staging of model organisms intentionally downplays variation in ontogeny associated with the effects of environmental variables (e.g., phenotypic plasticity) by strictly limiting the range of values for environmental variables and by removing variation in characters utilized to establish the comprehensive periodization.
                                                        3. Therefore, using model organisms with specified developmental stages will make it difficult, if not impossible, to observe patterns of variation due to phenotypic plasticity.

                                                        Although this tension obtains even if the focus is not on evolutionary questions, sometimes encouraging developmental biologists to interpret absence of evidence as evidence of the developmental insignificance of phenotypic plasticity, it is exacerbated for evolutionary researchers. The documentation of patterns of variation is precisely what is required to gauge the evolutionary significance of phenotypic plasticity. Practices of developmental staging in model organisms can retard our ability to make either a positive or negative assessment. Developmental staging, in conjunction with the properties of model organisms, tends to encourage a negative assessment of the evolutionary importance of phenotypic plasticity because the variation is not manifested and documented, and therefore is unlikely to be reckoned as substantive. Idealizations involving normal stages discourage a robust experimental probing of phenotypic plasticity, which is an obstacle to determining its evolutionary significance.

                                                        The consequences of this tension for the intersection of development and evolution are two-fold. First, the most powerful experimental systems for studying development are set up to minimize variation that may be critical to comprehending how evolutionary processes occur in nature. Second, if evolutionary investigations revolve around a character that was assessed for typicality to underwrite the temporal partitions that we call stages, then much of the variation in this character was conceptually removed as a part of rendering the model organism experimentally tractable. [21]

                                                        The identification of drawbacks that accompany strategies of idealization used to study development invites consideration of ways to address the liabilities identified (Love 2006). We can construct a principled perspective on how to address these liabilities by adding three further premises:

                                                        1. Reasoning strategies involving idealization, such as (2), are necessary to the successful prosecution of biological investigations of ontogeny.
                                                        2. Therefore, compensatory tactics should be chosen in such a way as to specifically redress the blind spots arising from the kind of idealizations utilized.
                                                        3. Given (1)&ndash(3), compensatory tactics must be related to the effects of ignoring variation due to phenotypic plasticity that result from the developmental staging of model organisms.

                                                        At least two compensatory tactics can promote observations of variation due to phenotypic plasticity that is ignored when developmental stages are constructed for model organisms: the employment of diverse model organisms and the adoption of alternate periodizations.

                                                        Variation often will be observable in non-standard model organisms because experimental organisms that do not have large communities built around them are less likely to have had their embryonic development formally staged, and thus the effects of idealization on phenotypic plasticity are not operative. In turn, researchers are sensitized to the ways in which these kinds of variation are being muted in the study of standard models. Stages can be used then as visual standards to identify variation as deviations from a norm and thereby characterize patterns of variability. [22]

                                                        A second compensatory tactic is the adoption of alternative periodizations. This involves choosing different characters to construct new temporal partitions, thereby facilitating the observation of variation with respect to characteristics previously stabilized in the normal stage periodization. These alternative periodizations often divide a subset of developmental events according to processes or landmarks that differ from those used to construct the normal stages, and they may not map one-one onto the existing normal stages, especially if they encompass events beyond the trajectory from fertilization to a sexually mature adult. This lack of isomorphism between periodizations also will be manifested if different measures of time are utilized, whether sequence (event ordering) or duration (succession of defined intervals), and whether sequences or durations are measured relative to one another or against an external standard, such as absolute chronology (Reiss 2003 Colbert and Rowe 2008). These incompatibilities prevent assimilating the alternative periodizations into a single, overarching staging scheme. In all of these cases, idealization is involved and therefore each new periodization is subject to the liabilities of ignoring kinds of variation. However, alternative periodizations require choosing different characters to stabilize and typify when defining its temporal partitions, which means different kinds of variation will be exposed than were previously observable. [23]

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                                                        B1.1 What are genes and how do they affect the way that organisms develop?

                                                        A GENE is a short section of DNA. Genes carry instructions that control how you develop and function – they are long molecules of a molecule called DNA. Each gene codes for a specific protein by specifying the order in which AMINO ACIDS must be joined together.

                                                        STRUCTURAL PROTEIN: Gives the body structure, rigidity and strength E.g. Skin, Hair, Muscles etc

                                                        FUNCTIONAL PROTEIN: Enables the body to function E.g. Enzymes, Antibodies etc.

                                                        The differences between individuals of the same species are described as VARIATIONS.

                                                        • GENOTYPE – The genetic makeup of an organism. The different characteristics that an individual inherits, E.g. whether you have dimples or not.
                                                        • PHENOTYPE – The observable characteristics the organism has. How the environment changes an individual, E.g. cutting the skin may cause a scar.

                                                        IDENTICAL TWINS have the same set of genotype however any differences between them is because of environment.

                                                        Content of the Special Issue

                                                        The series of papers comprising this special PNAS issue advances an agenda for future research on “genes and environment, development and time” and reflects recent discoveries by contributors to this volume. These include: 1) A debunking of two assumed truths about critical periods in development, namely, that they are fixed within chronological windows and irreversible 2) a shift in research on G–E interplay from an initial assumption that epigenomic variation is largely sculpted by the “environment” to a more sophisticated model in which gene expression and epigenetic modification are dependent upon genomic context (DNA sequence) 3) a higher resolution picture of the environments that influence biological embedding and the emergent genes and pathways involved 4) evidence that past experiences prime the genomic response to future experiences 5) increased reliance on the network concept, at different time scales of operation and 6) the successes in translating research insights bidirectionally between animal and human.

                                                        Furthermore, the set of papers yield direct insight, explicitly or implicitly, into the operation of time and timing in the context of G–E interplay. Collectively, the papers argue—we believe persuasively—that G–E interplay research must now incorporate time at multiple scales (38). Timing increasingly emerges as a fundamental element in the epigenesis of developmental events, and each of the assembled papers recapitulates and illustrates this reality in some manner. The volume contains four perspective papers and eight original research papers, which are highlighted below.

                                                        Reh et al. (45) discuss processes involved in the onset and closure of critical periods of brain plasticity across multiple timescales. Their paper describes the central role of the network of parvalbumin-positive, inhibitory interneurons that shape excitatory–inhibitory balances within successive regions of cortical circuitry. The molecular events determining the timing of critical periods and the perturbations of development attending various exposures span multiple temporal scales, ranging from milliseconds in the case of neuronal oscillations to generational or even intergenerational lifespans in the case of epigenetic processes. The Reh et al. paper discusses how critical periods, although conventionally viewed as static and unchanging in time, can be altered by experience-dependent epigenetic processes and by pharmacologic agents and genetic manipulations. Understanding the normative development and function of these parvalbumin-positive, inhibitory interneuron-mediated processes can provide insight into mental illness and brain injury.

                                                        Clayton et al. (30) discuss how dynamic patterns of gene expression play a role in the encoding of experience. They update the concept of the genomic action potential (gAP), analogous to the familiar electrophysiological action potential, which occurs in milliseconds (68). In contrast, the gAP occurs over minutes and is measured as an array of immediate early genes (IEGs) becoming responsive to salient experiential events. Clayton et al. (30) discuss the gAP from the perspective of molecular elements within a brain cell, neural contexts, the encoding of engrams, and cellular proliferation. An example of the gAP at the organismal level is also provided from the perspective of stress responses.

                                                        Aristizabal et al. (31) provide a primer on the many molecular processes that can contribute to the biological embedding of experience. These include the methodologically accessible methylation and hydroxymethylation of DNA at cytosine-guanine dinucleotides (CpG sites), as well as structural revisions of chromatin accessibility, posttranslational modifications of nucleosomal histone proteins, noncoding- and micro-RNAs, and more than 150 varieties of RNA base modifications. Future research that takes into account DNA sequence variation, developmental timing, tissue specificity, age, and sex will be required to delineate the molecular mechanisms that function together in the biological embedding of experience. The pairing of longitudinal human cohort studies with experimental animal studies should also facilitate the transition from correlative to causal studies in this young field.

                                                        Sinha et al. (69) examine emerging insights into the spatial and temporal aspects of linkages between neural networks (NNs) and gene regulatory networks in the brain. They present a strong case for brain gene regulatory networks (bGRNs), as important substrates of behavior involving gene-expression changes in hundreds to thousands of genes within a neuron in response to the environment. NNs comprise circuits of neurons transmitting electrochemical signals from one neuron to another and integrating experiential stimuli to orchestrate an organism’s behavior. bGRNs act at different (but sometimes interacting) levels of organization than NNs and on different timescales. NNs act in milliseconds to seconds, while bGRNs affecting gene expression and epigenetic changes arise over minutes to days. A role for developmental GRNs (dGRNs) in the interplay between NN’s and bGRNs is also considered.

                                                        The aging or cellular weathering associated with the passage of time in individual lives depends on cumulative exposures to adversity. As a model for prenatal stress exposure, Provençal et al. (32) expose a human fetal hippocampal progenitor cell line to glucocorticoids. Exposure early in neurogenesis results in lasting changes in DNA methylation, altering the set point for future transcriptional responses to stress. Such early priming of neural responses with glucocorticoids exposure could contribute to individual differences in vulnerabilities to stress later in life.

                                                        Temporal response latencies figure prominently in the paper by Dason et al. (70). They focus upon the role of the foraging gene (for), which encodes a guanosine 3′,5′-cyclic monophosphate-dependent protein kinase (PKG) in nociceptive-like escape responses among Drosophila melanogaster larvae. The paper shows that nociceptive-like response latency (curling and rolling of the larva) during threat is faster in one genetic variant of for (rover) than the other (sitter). Dason et al. use optogenetics and transgenic manipulations to trace these behavioral differences to variation in gene expression from for’s pr1 promoter among neurons of the ventral cord, and show that prior activation of the pr1 circuit during development suppresses the nociceptive-like escape response.

                                                        Measures of individuality are important for trajectories of child development when reliance on population means cannot be used to predict individual susceptibilities. Nonetheless, little is known about developmental, genetic, environmental, and stochastic contributions to individuality. Honegger et al. (71) investigate the biological basis of individuality in the odor responses of D. melanogaster. They measure individual variability using repeated measures of the same olfactory response behavior over time and map neural activity in the brain. The author’s find, when comparing individual flies, that the same odor stimulus can result in different behavioral responses and different brain activities. Transgenic and pharmacological manipulations reveal that neuromodulators and sets of neurons in the fly brain’s olfactory region directly modulate behavioral variability and that this modulation is flexibly dependent on the environment.

                                                        Artoni et al. (72) develop an approach for early detection of neurodevelopmental spectrum disorders, in this case, autism spectrum disorder (ASD), by using a transfer learning experiment across species (mouse to human). Their approach is based on spontaneous arousal fluctuations combined with deep learning and is a possible breakthrough in the early detection of risk for ASD and related disorders, where late diagnosis strongly diminishes intervention efficacy. The research attends to critical periods in developmental time and illustrates the utility of methods—in this case, the use of convolutional neural networks—that allow for the detection of nonlinear functions in biological systems.

                                                        Gonzales et al. (73) investigate the cellular distribution of IEG expression after an acute exposure to cocaine in mouse striatal neurons. The induction and decay of IEG expression is used as a marker to encode recent experience. They investigate the timing and spatial distribution of IEGs in the neuronal ensembles and find spatially defined clusters characterized by consistent and robust expression of many IEGs. The authors suggest that the existence of clusters of neurons in response to acute cocaine experience may be a general principle for responses to other types of experience.

                                                        George et al. (74) show that social isolation in the highly social zebra finch affects gene expression in the brain and that this is correlated with an increase in DNA methylation of a subset of those differentially expressed genes. Hundreds of genes located in higher forebrain centers were involved in social communication when birds were isolated in a sound chamber overnight, compared to when they were paired with a same-sex partner in the chamber. Changes in circulating corticosterone levels were not sufficient to explain the genomic response.

                                                        Sanz et al. (75) show that the response of the rhesus macaque immune system is affected by current social conditions and a biological memory of past conditions. A history of social subordination in female rhesus monkeys changes the blood gene-expression responses to experimentally induced bacterial and viral challenges. Pathogen exposure, type, and social history all affect immune cell gene expression. The authors also found that a history of social subordination reduces sensitivity to present-day social conditions. Their paper provides a compelling example of the biological embedding of social experience over long timescales.

                                                        Rivenbark et al. (76) demonstrate, in a British birth cohort of mono- and dizygotic twins, how the passage of developmental time can alter associations with mental and physical health endpoints. They find evidence for a “status syndrome” at 18 y of age, in which subjective estimates of family social position in the community are significantly predictive of multiple indicators of mental health and developmental well-being, even with controls for objective socioeconomic status and family environment. The relative lack of such associations with subjective social position assessed at 12 y of age underscores the manner in which relations among social environmental and health measures can change longitudinally over developmental time.

                                                        The aging or cellular weathering associated with the passage of time in individual lives is not absolute but dependent upon cumulative exposures to adversity, and perhaps other factors. McEwen et al. (52) develop a pediatric-buccal-epigenetic (PedBE) clock tool by using the DNA methylome to measure the biological age of children ages 0 to 20 y taken from 11 distinct cohorts. They find an array of methylation scores at 94 CpG dinucleotide sites highly predictive of chronological age. Positive deviation from predicted age (suggesting more advanced weathering of cells) is associated, in a separate sample and analysis, with ASD.

                                                        Taken together, the collection of papers herein weaves together a sturdy if incomplete fabric of evidence for how time and timing are critical to developing our understanding of G–E interplay in the biological embedding of experience. Time, it increasingly appears, is an essential element in plumbing and understanding how genes and environments operate together to shape probabilistically the trajectories of individual lives. This elegance and complexity, added to the pullulating and enticing story of how human differences arise, call to mind the work and thinking of two memorable, now departed, progenitors of the Canadian Institute for Advanced Research Child and Brain Development Program: Fraser Mustard and Clyde Hertzman (77, 78). Both were convinced that the experiences and exposures of early life, and especially the timing of such events, were the elemental building blocks of human potential, for good or ill, for success or failure, for health or misfortune. It is that discerning insight that has guided and continues to mark the developmental science to which this collection of papers presents a compelling, if promissory, note.

                                                        Watch the video: μάθημα 35 Κυτταρική Διαίρεση part 1. Βιολογία Γ λυκείου, Biology maniax. (January 2022).