Regulation of Gene Expression Lecture Outline Overview: Differential Expression of Genes • Both prokaryotes and eukaryotes alter their patterns of gene expression in response to changes in environmental conditions. • Multicellular eukaryotes also develop and maintain multiple cell types. ○ Each cell type contains the same genome but expresses a different subset of genes. ○ During development, gene expression must be carefully regulated to ensure that the right genes are expressed only at the correct time and in the correct place. • Gene expression in eukaryotes and bacteria is often regulated at the transcription stage. ○ Control of other levels of gene expression is also important. • RNA molecules play many roles in regulating eukaryotic gene expressions. • Disruptions in gene regulation may lead to cancer. Concept 18.1 Bacteria often respond to environmental change by regulating transcription • Natural selection favors bacteria that express only those genes whose products are needed by the cell. ○ A bacterium in a tryptophan-rich environment that stops producing tryptophan conserves its resources. • Metabolic control occurs on two levels. • First, cells can adjust the activity of enzymes already present. ○ This may happen by feedback inhibition, in which the activity of the first enzyme in a pathway is inhibited by the pathway’s end product. ○ Feedback inhibition, typical of anabolic (biosynthetic) pathways, allows a cell to adapt to short-term fluctuations in the supply of a needed substance. • Second, cells can vary the number of specific enzyme molecules they make by regulating gene expression. ○ The control of enzyme production occurs at the level of transcription, the synthesis of messenger RNA coding for these enzymes. ○ Genes of the bacterial genome may be switched on or off by changes in the metabolic status of the cell. • The basic mechanism for the control of gene expression in bacteria, known as the operon model, was described by Francois Jacob and Jacques Monod in 1961. The operon model controls tryptophan synthesis. • Escherichia coli synthesizes tryptophan from a precursor molecule in a series of steps, with each reaction catalyzed by a specific enzyme. • The five genes coding for the subunits of these enzymes are clustered together on the bacterial chromosome as a transcription unit, served by a single promoter. • Transcription gives rise to one long mRNA molecule that codes for all five polypeptides in the tryptophan pathway. • The mRNA is punctuated with start and stop codons that signal where the coding sequence for each polypeptide begins and ends. • A key advantage of grouping genes with related functions into one transcription unit is that a single on-off switch can control a cluster of functionally related genes. ○ In other words, these genes are coordinately controlled. • When an E. coli cell must make tryptophan for itself, all the enzymes are synthesized at one time. • The switch is a segment of DNA called an operator. • The operator, located within the promoter or between the promoter and the enzyme-coding genes, controls the access of RNA polymerase to the genes. • The operator, the promoter, and the genes they control constitute an operon. ○ The trp operon (trp for tryptophan) is one of many operons in the E. coli genome. • By itself, an operon is turned on: RNA polymerase can bind to the promoter and transcribe the genes of the operon. • The operon can be switched off by a protein called the trp repressor. ○ The repressor binds to the operator, blocks attachment of RNA polymerase to the promoter, and prevents transcription of the operon’s genes. • Each repressor protein recognizes and binds only to the operator of a particular operon. • The trp repressor is the protein product of a regulatory gene called trpR, which is located at some distance from the operon it controls and has its own promoter. • Regulatory genes are transcribed continuously at slow rates, and a few trp repressor molecules are always present in an E. coli cell. • Why is the trp operon not switched off permanently? • First, binding by the repressor to the operator is reversible. ○ An operator vacillates between two states, with and without a repressor bound to it. ○ The relative duration of each state depends on the number of active repressor molecules around. • Second, repressors contain allosteric sites that change shape depending on the binding of other molecules. ○ The trp repressor has two shapes: active and inactive. ○ The trp repressor is synthesized in an inactive form with little affinity for the trp operator. ○ Only if tryptophan binds to the trp repressor at an allosteric site does the repressor protein change to the active form that can attach to the operator, turning the operon off. • Tryptophan functions in the trp operon as a corepressor, a small molecule that cooperates with a repressor protein to switch an operon off. • When concentrations of tryptophan in the cell are high, more tryptophan molecules bind with trp repressor molecules, activating them. ○ The active repressors bind to the trp operator and turn the operon off. • At low levels of tryptophan, most of the repressors are inactive, and transcription of the operon’s genes resumes. There are two types of operons: repressible and inducible. • The trp operon is an example of a repressible operon, one that is inhibited when a specific small molecule (tryptophan) binds allosterically to a regulatory protein. • In contrast, an inducible operon is stimulated (induced) when a specific small molecule interacts with a regulatory protein. • The classic example of an inducible operon is the lac operon (lac for lactose). • Lactose (milk sugar) is available to E. coli in the human colon if the host drinks milk. ○ Lactose metabolism begins with hydrolysis of lactose into its component monosaccharides, glucose and galactose. ○ This reaction is catalyzed by the enzyme ß-galactosidase. • Only a few molecules of b-galactosidase are present in an E. coli cell grown in the absence of lactose. ○ If lactose is added to the bacterium’s environment, the number of ß-galactosidase molecules increases by a thousandfold within 15 minutes. • The gene for ß-galactosidase is part of the lac operon, which includes two other genes coding for enzymes that function in lactose metabolism. • The regulatory gene, lacI, located outside the operon, codes for an allosteric repressor protein that can switch off the lac operon by binding to the operator. • Unlike the trp operon, the lac repressor is active all by itself, binding to the operator and switching the lac operon off. ○ An inducer inactivates the repressor. ○ When lactose is present in the cell, allolactose, an isomer of lactose, binds to the repressor. ○ This inactivates the repressor, and the lac operon can be transcribed. • Repressible enzymes generally function in anabolic pathways, synthesizing end products from raw materials. ○ When the end product is present in sufficient quantities, the cell can allocate its resources to other uses. • Inducible enzymes usually function in catabolic pathways, digesting nutrients to simpler molecules. ○ By producing the appropriate enzymes only when the nutrient is available, the cell avoids making proteins that are not needed. • Both repressible and inducible operons demonstrate negative control of genes because active repressors switch off the active form of the repressor protein. ○ It may be easier to see this for the trp operon, but it is also true for the lac operon. ○ Allolactose induces enzyme synthesis not by acting directly on the genome, but by freeing the lac operon from the negative effect of the repressor. Some gene regulation is positive. • Positive gene control occurs when a protein molecule interacts directly with the genome to switch transcription on. • The lac operon is an example of positive gene regulation. • When glucose and lactose are both present, E. coli preferentially uses glucose. ○ The enzymes for glucose breakdown in glycolysis are always present in the cell. • Only when lactose is present and glucose is in short supply does E. coli use lactose as an energy source and synthesize the enzymes for lactose breakdown. • When glucose levels are low, cyclic AMP (cAMP) accumulates in the cell. • The regulatory protein catabolite activator protein (CAP) is an activator of transcription. • When cAMP is abundant, it binds to CAP, and the regulatory protein assumes its active shape and can bind to a specific site at the upstream end of the lac promoter. ○ The attachment of CAP to the promoter increases the affinity of RNA polymerase for the promoter, directly increasing the rate of transcription. ○ Thus, this mechanism qualifies as positive regulation. • If glucose levels in the cell rise, cAMP levels fall. ○ Without cAMP, CAP detaches from the operon and lac operon is transcribed only at a low level. • The lac operon is under dual control: negative control by the lac repressor and positive control by CAP. ○ The state of the lac repressor (with or without bound allolactose) determines whether or not the lac operon’s genes are transcribed. ○ The state of CAP (with or without bound cAMP) controls the rate of transcription if the operon is repressor-free. ○ The operon has both an on-off switch and a volume control. • CAP works on several operons that encode enzymes used in catabolic pathways. It affects the expression of more than 100 E. coli genes. ○ If glucose is present and CAP is inactive, then the synthesis of enzymes that catabolize other compounds is slowed. ○ If glucose levels are low and CAP is active, then the genes that produce enzymes that catabolize whichever other fuel is present are transcribed at high levels. Concept 18.2 Eukaryotic gene expression is regulated at many stages • Like unicellular organisms, the tens of thousands of genes in the cells of multicellular eukaryotes turn on and off in response to signals from their internal and external environments. • Gene expression must be controlled on a long-term basis during cellular differentiation. Differential gene expression is the expression of different genes by cells with the same genome. • A typical human cell probably expresses about 20% of its genes at any given time. ○ Highly specialized cells, such as nerves or muscles, express a tiny fraction of their genes. ○ Although all the cells in an organism contain an identical genome, the subset of genes expressed in the cells of each type is unique. • The differences between cell types are due to differential gene expression, the expression of different genes by cells with the same genome. • The function of any cell, whether a single-celled eukaryote or a particular cell type in a multicellular organism, depends on the appropriate set of genes being expressed. ○ Problems with gene expression and control can lead to imbalance and disease, including cancer. • Our understanding of the mechanisms that control gene expression in eukaryotes has been enhanced by new research methods, including advances in DNA technology. • In all organisms, a common control point for gene expression is at transcription, often in response to signals coming from outside the cell. ○ For this reason, the term gene expression is often equated with transcription. • With their greater complexity, eukaryotes have opportunities for controlling gene expression at additional stages. Chromatin modifications affect the availability of genes for transcription. • The DNA of eukaryotic cells is packaged with proteins in a complex called chromatin. ○ The basic unit of chromatin is the nucleosome. • The location of a gene’s promoter relative to nucleosomes and to the sites where the DNA attaches to the chromosome scaffold or nuclear lamina affect whether the gene is transcribed. • Genes of densely condensed heterochromatin are usually not expressed. • Chemical modifications of the histone proteins and DNA of chromatin play a key role in chromatin structure and gene expression. • The N-terminus of each histone molecule in a nucleosome protrudes outward from the nucleosome. ○ These histone tails are accessible to various modifying enzymes, which catalyze the addition or removal of specific chemical groups. • Histone acetylation (addition of an acetyl group, —COCH3) and deacetylation of lysines in histone tails appear to play a direct role in the regulation of gene transcription. • Acetylation of lysines neutralizes their positive charges and reduces the binding of histone tails to neighboring nucleosomes, easing access for transcription proteins. ○ Some of the enzymes responsible for acetylation or deacetylation are associated with or are components of transcription factors that bind to promoters. • Thus, histone acetylation enzymes may promote the initiation of transcription not only by modifying chromatin structure but also by binding to and recruiting components of the transcription machinery. • Other chemical groups, such as methyl and phosphate groups, can be reversibly attached to amino acids in histone tails. ○ The attachment of methyl groups (—CH3) to histone tails leads to condensation of chromatin. ○ The addition of a phosphate group (phosphorylation) to an amino acid next to a methylated amino acid has the opposite effect. • The recent discovery that modifications to histone tails can affect chromatin structure and gene expression has led to the histone code hypothesis. ○ This hypothesis proposes that specific combinations of modifications, as well as the order in which they have occurred, determine chromatin configuration. ○ Chromatin configuration in turn influences transcription. DNA methylation reduces gene expression. • While some enzymes methylate the tails of histone proteins, other enzymes methylate certain bases in DNA itself, usually cytosine. ○ DNA methylation occurs in most plants, animals, and fungi. • Inactive DNA is generally more highly methylated than actively transcribed regions. ○ For example, the inactivated mammalian X chromosome is heavily methylated. ○ Individual genes are usually more heavily methylated in cells where they are not expressed. Removal of extra methyl groups can turn on some of these genes. • In some species, DNA methylation is responsible for the long-term inactivation of genes during cellular differentiation. ○ Deficient DNA methylation leads to abnormal embryonic development in organisms as different as mice and the plant Arabidopsis. • Once methylated, genes usually stay that way through successive cell divisions in a given individual. • Methylation enzymes recognize sites on one strand that are already methylated and correctly methylate the daughter strand after each round of DNA replication. • This methylation pattern accounts for genomic imprinting, in which methylation turns off either the maternal or paternal alleles of certain mammalian genes at the start of development. • The chromatin modifications just discussed do not alter the DNA sequence, and yet they may be passed along to future generations of cells. • Inheritance of traits by mechanisms not directly involving the nucleotide sequence is called epigenetic inheritance. • The molecular systems for chromatin modification may well interact with each other in a regulated way. ○ In Drosophila, experiments suggest that a particular histone-modifying enzyme recruits a DNA methylation enzyme to one region and that the two enzymes collaborate to silence a particular set of genes. ○ Working in the opposite order, proteins have also been found that bind to methylated DNA and then recruit histone deacetylation enzymes. ○ Thus, a dual mechanism, involving both DNA methylation and histone deacetylation, can repress transcription. • Researchers are amassing more and more evidence for the importance of epigenetic information in the regulation of gene expression. ○ Epigenetic variations may explain why one identical twin acquires a genetically based disease, such as schizophrenia, while another does not, despite their identical genomes. ○ Alterations in normal patterns of DNA methylation are seen in some cancers, where they are associated with inappropriate gene expression. • Enzymes that modify chromatin structure are integral parts of the cell’s machinery for regulating transcription. Transcription initiation is controlled by proteins that interact with DNA and with each other. • Chromatin-modifying enzymes provide initial control of gene expression by making a region of DNA more available or less available for transcription. • A cluster of proteins called a transcription initiation complex assembles on the promoter sequence at the upstream end of the gene. ○ One component, RNA polymerase II, transcribes the gene, synthesizing a primary RNA transcript or pre-mRNA. ○ RNA processing includes enzymatic addition of a 5¢ cap and a poly-A tail, as well as splicing out of introns to yield a mature mRNA. • Multiple control elements are associated with most eukaryotic genes. ○ Control elements are noncoding DNA segments that serve as binding sites for protein transcription factors. ○ Control elements and the transcription factors they bind are critical to the precise regulation of gene expression in different cell types. • To initiate transcription, eukaryotic RNA polymerase requires the assistance of proteins called transcription factors. • General transcription factors are essential for the transcription of all protein-coding genes. ○ Only a few general transcription factors independently bind a DNA sequence such as the TATA box within the promoter. ○ Others are involved in protein-protein interactions, binding each other and RNA polymerase II. • Only when the complete initiation complex has been assembled can the polymerase begin to move along the DNA template strand to produce a complementary strand of RNA. • The interaction of general transcription factors and RNA polymerase II with a promoter usually leads to only a slow rate of initiation and the production of few RNA transcripts. • In eukaryotes, high levels of transcription of particular genes depend on the interaction of control elements with specific transcription factors. • Some control elements, named proximal control elements, are located close to the promoter. • Distal control elements, grouped as enhancers, may be thousands of nucleotides away from the promoter or even downstream of the gene or within an intron. • A given gene may have multiple enhancers, each active at a different time or in a different cell type or location in the organism. ○ Eukaryotic gene expression can be altered by the binding of specific transcription factors, either activators or repressors, to the control elements of enhancers. • Two structural elements are common to many activator proteins: a DNA-binding domain and one or more activation domains. ○ Activation domains bind other regulatory proteins or components of the transcription machinery to facilitate transcription. • Protein-mediated bending of DNA brings bound activators in contact with a group of mediator proteins that interact with proteins at the promoter. ○ These interactions help assemble and position the initiation complex on the promoter. • Eukaryotic repressors can inhibit gene expression by blocking the binding of activators to their control elements or to components of the transcription machinery. ○ Other repressors bind directly to control-element DNA, turning off transcription even in the presence of activators. • Some activators and repressors act indirectly to influence chromatin structure. ○ Some activators recruit proteins that acetylate histones near the promoters of specific genes, promoting transcription. ○ Some repressors recruit proteins that deacetylate histones, reducing transcription or silencing the gene. • Recruitment of chromatin-modifying proteins seems to be the most common mechanism of repression in eukaryotes. The control of transcription in eukaryotes depends on the binding of activators to DNA control elements. • The number of different nucleotide sequences found in control elements is surprisingly small: about a dozen. • On average, each enhancer is composed of about ten control elements, each of which can bind to only one or two specific transcription factors. ○ The particular combination of control elements in an enhancer may be more important than the presence of a unique control element in regulating transcription of the gene. • Even with only a dozen control element sequences, a large number of combinations are possible. • A particular combination of control elements is able to activate transcription only when the appropriate activator proteins are present, at a precise time during development or in a particular cell type. • The use of different combinations of control elements allows fine regulation of transcription with a small set of control elements. • In prokaryotes, coordinately controlled genes are often clustered into an operon with a single promoter and other control elements upstream. ○ The genes of the operon are transcribed into a single mRNA and translated together. • In contrast, very few eukaryotic genes are organized this way. • More commonly, co-expressed genes coding for the enzymes of a metabolic pathway are scattered over different chromosomes. ○ Coordinate gene expression depends on the association of a specific control element or combination of control elements with every gene of a dispersed group. ○ A common group of transcription factors binds to all the genes in the group, promoting simultaneous gene transcription. • For example, a steroid hormone enters a cell and binds to a specific receptor protein in the cytoplasm or nucleus, forming a hormone–receptor complex that serves as a transcription activator. ○ Every gene whose transcription is stimulated by that steroid hormone has a control element recognized by that hormone–receptor complex. • Other signal molecules control gene expression indirectly by triggering signal-transduction pathways that lead to activation of transcription. ○ The principle of coordinate regulation is the same: Genes with the same control elements are activated by the same chemical signals. • Systems for coordinating gene regulation probably arose early in evolutionary history. • The nucleus has a defined architecture and regulated movements of chromatin. • Recent techniques allow researchers to cross-link and identify regions of chromosomes that associate with each other during interphase. • Loops of chromatin extend from individual chromosomal territories into specific sites in the nucleus. ○ Different loops from the same chromosome and loops from other chromosomes congregate in such sites, some of which are rich in RNA polymerases and other transcription-associated proteins. ○ These sites are likely areas specialized for a common function or transcription factories. Post-transcriptional mechanisms play supporting roles in the control of gene expression. • Regulatory mechanisms that operate after transcription allow a cell to rapidly fine-tune gene expression in response to environmental changes, without altering its transcriptional patterns. ○ RNA processing in the nucleus and the export of mRNA to the cytoplasm provide opportunities for gene regulation that are not available in prokaryotes. • In alternative RNA splicing, different mRNA molecules are produced from the same primary transcript, depending on which RNA segments are treated as exons and which as introns. ○ Regulatory proteins specific to a cell type control intron-exon choices by binding to regulatory sequences within the primary transcript. • Alternative RNA splicing significantly expands the repertoire of a set of genes. ○ It may explain the surprisingly low number of human genes: similar to those of a soil worm, a mustard plant, or a sea anemone. ○ Between 75% and 100% of human genes that have multiple exons probably undergo alternative splicing. ○ The extent of alternative splicing increases the number of possible human proteins, likely correlated with complexity of form. • The life span of an mRNA molecule is an important factor in determining the pattern of protein synthesis. ○ Prokaryotic mRNA molecules are typically degraded after only a few minutes, while eukaryotic mRNAs typically last for hours, days, or weeks. ○ In red blood cells, mRNAs for hemoglobin polypeptides are unusually stable and are translated repeatedly. • Nucleotide sequences in the untranslated trailer region (UTR) at the 3¢ end affect mRNA stability. ○ Transferring such a sequence from a short-lived mRNA to a normally stable mRNA results in quick mRNA degradation. Translation presents an opportunity for the regulation of gene expression. • The initiation of translation of an mRNA can be blocked by regulatory proteins that bind to specific sequences within the 5¢ or 3¢ UTR of the mRNA, preventing ribosome attachment. • The mRNAs present in the eggs of many organisms lack poly-A tails of sufficient length to allow initiation of translation. ○ During embryonic development, a cytoplasmic enzyme adds more adenine nucleotides so that translation can begin at the appropriate time. • Translation of all the mRNAs in a eukaryotic cell may be regulated simultaneously by the activation or inactivation of the protein factors required to initiate translation. ○ This mechanism starts the translation of mRNAs that are stored in eggs. ○ Just after fertilization, translation is triggered by the sudden activation of translation initiation factors, resulting in a burst of protein synthesis. • Some plants and algae store mRNAs during periods of darkness. Light triggers the reactivation of the translational apparatus. The final opportunities for controlling gene expression occur after translation. • Often, eukaryotic polypeptides are processed to yield functional proteins. ○ For example, cleavage of pro-insulin forms the active hormone. • Many proteins must undergo chemical modifications before they are functional. ○ Regulatory proteins may be activated or inactivated by the reversible addition of phosphate groups. ○ Proteins destined for the surface of animal cells acquire sugars. • Regulation may occur at any of the steps involved in modifying or transporting a protein. • The length of time a protein functions before it is degraded is strictly regulated. ○ Proteins such as the cyclins that regulate the cell cycle must be relatively short-lived. • To mark a protein for destruction, the cell attaches a small protein called ubiquitin to it. ○ Giant protein complexes called proteasomes recognize and degrade the tagged proteins. • Mutations making specific cell cycle proteins impervious to proteasome degradation can lead to cancer. • The scientists worked out the regulated process of protein degradation won the 2004 Nobel Prize in Chemistry. Concept 18.3 Noncoding RNAs play multiple roles in controlling gene expression • Only 1.5% of the human genome codes for proteins. Of the remainder, only a very small fraction consists of genes for ribosomal RNA and transfer RNA. • Until recently, it was assumed that most of the rest of the DNA was untranscribed. Recent data have challenged that assumption, however. ○ Study of a region comprising 1% of the human genome found that over 90% of the region was transcribed. ○ Introns accounted for only a fraction of this transcribed, nontranslated RNA. • A significant amount of the genome may be transcribed into non–protein-coding RNAs (or noncoding RNAs or ncRNAs), including a variety of small RNAs. • A large, diverse population of RNA molecules may play crucial roles in regulating gene expression in the cell. MicroRNAs can bind to complementary sequences in mRNA molecules. • In the past few years, researchers have found small, single-stranded RNA molecules called microRNAs (miRNAs) that bind to complementary sequences in mRNA molecules. • miRNAs are formed from longer RNA precursors that fold back on themselves to form one or more short, double-stranded hairpin structures stabilized by hydrogen bonding. • An enzyme called Dicer cuts each hairpin into a short, double-stranded fragment of about 22 nucleotide pairs. • One of the two strands is degraded. The other strand (miRNA) associates with a protein complex and directs the complex to any mRNA molecules that have a complementary sequence of 7-8 nucleotides. • The miRNA–protein complex either degrades the target mRNA or blocks its translation. • Expression of up to one-half of all human genes may be regulated by miRNAs. • The phenomenon of inhibition of gene expression by RNA molecules is called RNA interference (RNAi). • Injecting double-stranded RNA molecules into a cell somehow turns off expression of a gene with the same sequence as the RNA. ○ This RNA interference is due to small interfering RNAs (siRNAs), similar in size and function to miRNAs and are generated by similar mechanisms in eukaryotic cells. • Both miRNAs and siRNAs can associate with the same proteins, with similar results. ○ The distinction between these molecules is the nature of the precursor molecules from which they are formed. ○ Each miRNA forms from a single hairpin in the precursor RNA, while multiple siRNAs form from a longer, double-stranded RNA molecule. • Cellular RNAi pathways lead to the destruction of RNAs and may have originated as a natural defense against infection by double-stranded RNA viruses. ○ The fact that the RNAi pathway can also affect the expression of nonviral cellular genes may reflect a different evolutionary origin for the RNAi pathway. • Many species, including mammals, possess long, double-stranded precursors to small RNAs that interfere with various steps in gene expression. Small RNAs can remodel chromatin and silence transcription. • Small RNAs can cause remodeling of chromatin structure. ○ In yeast, siRNAs are necessary for the formation of heterochromatin at the centromeres of chromosomes. • An RNA transcript produced from DNA in the centromeric region of the chromosome is copied into double-stranded RNA by a yeast enzyme and then processed into siRNAs. ○ The siRNAs associate with a protein complex, targeting the complex back to the RNA sequences made from the centromeric sequences of DNA. ○ The proteins in the complex recruit enzymes to modify the chromatin, turning it into the highly condensed centromeric heterochromatin. • A newly discovered class of small ncRNAs, called piwi-associated RNAs (piRNAs) also induce formation of heterochromatin, blocking expression of parasitic DNA elements in the genome known as transposons. ○ piRNAs, 24–31 nucleotides in length, are processed from single-stranded RNA precursors. ○ In germ cells of many animal species, piRNAs help re-establish appropriate methylation patterns in the genome during gamete formation. • Chromatin remodeling not only blocks expression of large regions of the chromosome; RNA-based mechanisms may also block the transcription of specific genes. ○ Some plant miRNAs have sequences that bind to gene promoters and can repress transcription; piRNAs can also block expression of specific genes. ○ In some cases, miRNAs and piRNAs activate gene expression. • Small ncRNAs regulate gene expression at multiple steps and in many ways. ○ Extra levels of gene regulation may allow evolution of a higher degree of complexity of form. ○ An increase in the number of miRNAs encoded in the genomes of species may have allowed morphological complexity to increase over evolutionary time. • A survey of species suggests that siRNAs evolved first, followed by miRNAs and later piRNAs, which are found only in animals. ○ While there are hundreds of types of miRNA, there appear to be many thousands of types of piRNAs, allowing the potential for very sophisticated gene regulation by piRNAs. • Many ncRNAs play important roles in embryonic development, the ultimate example of an elaborate program of regulated gene expression. Concept 18.4 A program of differential gene expression leads to the different cell types in a multicellular organism • In the development of most multicellular organisms, a single-celled zygote gives rise to cells of many different types. ○ Each type has a different structure and corresponding function. ○ Cells of different types are organized into tissues, tissues into organs, organs into organ systems, and organ systems into the whole organism. • Thus, the process of embryonic development must give rise not only to cells of different types but also to higher-level structures arranged in a particular way in three dimensions. A genetic program is expressed during embryonic development. • As a zygote develops into an adult organism, its transformation results from three interrelated processes: cell division, cell differentiation, and morphogenesis. • Through a succession of mitotic cell divisions, the zygote gives rise to many cells. ○ Cell division alone would produce only a great ball of identical cells. • During development, cells become specialized in structure and function, undergoing cell differentiation. • Different kinds of cells are organized into tissues and organs. • The physical processes that give an organism its shape constitute morphogenesis, the “creation of form.” • Cell division, cell differentiation, and morphogenesis have their basis in cellular behavior. ○ Morphogenesis can be traced back to changes in the shape and motility of cells in the various embryonic regions. ○ The activities of a cell depend on the genes it expresses and the proteins it produces. ○ Because almost all cells in an organism have the same genome, differential gene expression results from differential gene regulation in different cell types. • Why are different sets of activators present in different cell types? • One important source of information early in development is the egg’s cytoplasm, which contains both RNA and proteins encoded by the mother’s DNA, distributed unevenly in the unfertilized egg. • Maternal substances that influence the course of early development are called cytoplasmic determinants. ○ These substances regulate the expression of genes that affect the developmental fate of the cell. ○ After fertilization, the cell nuclei resulting from mitotic division of the zygote are exposed to different cytoplasmic environments. ○ The set of cytoplasmic determinants a particular cell receives helps determine its developmental fate by regulating expression of the cell’s genes during cell differentiation. • The other important source of developmental information is the environment around the cell, especially signals impinging on an embryonic cell from nearby cells. ○ In animals, these signals include contact with cell-surface molecules on neighboring cells and the binding of growth factors secreted by neighboring cells. • These signals cause changes in the target cells, a process called induction. ○ The molecules conveying these signals within the target cells are cell-surface receptors and other proteins expressed by the embryo’s own genes. ○ The signal molecules send a cell down a specific developmental path by causing a change in its gene expression that eventually results in observable cellular changes. Cell differentiation is due to the sequential regulation of gene expression. • During embryonic development, cells become visibly different in structure and function as they differentiate. • The earliest changes that set a cell on a path to specialization show up only at the molecular level. ○ Molecular changes in the embryo drive the process, called determination, which leads to the observable differentiation of a cell. • Once it has undergone determination, an embryonic cell is irreversibly committed to its final fate. ○ If a determined cell is experimentally placed in another location in the embryo, it will differentiate as if it were in its original position. • The outcome of determination—observable cell differentiation—is caused by the expression of genes that encode tissue-specific proteins. ○ These proteins give a cell its characteristic structure and function. • Differentiation begins with the appearance of cell-specific mRNAs and is eventually observable in the microscope as changes in cellular structure. • In most cases, the pattern of gene expression in a differentiated cell is controlled at the level of transcription. • Cells produce the proteins that allow them to carry out their specialized roles in the organism. ○ For example, liver cells specialize in making albumin, while lens cells specialize in making crystalline. ○ Skeletal muscle cells have high concentrations of proteins specific to muscle tissues, such as a muscle-specific version of the contractile proteins myosin and actin, as well as membrane receptor proteins that detect signals from nerve cells. • Muscle cells develop from embryonic precursors that have the potential to develop into a number of alternative cell types. ○ Although the committed cells are unchanged, they are now myoblasts. ○ Eventually, myoblasts begin to synthesize muscle-specific proteins and fuse to form mature, elongated, multinucleate skeletal muscle cells. • Researchers have worked out the events at the molecular level that lead to muscle cell determination by growing myoblasts in culture and analyzing them with molecular biology techniques. ○ Researchers isolated different genes, caused each to be expressed in a separate embryonic precursor cell, and looked for differentiation into myoblasts and muscle cells. ○ They identified several “master regulatory genes” that, when transcribed and translated, commit the cells to become skeletal muscle. • One of these master regulatory genes is called myoD. ○ myoD encodes MyoD protein, a transcription factor that binds to specific control elements in the enhancers of various target genes and stimulates their expression. ○ Some target genes for MyoD encode for other muscle-specific transcription factors. ○ MyoD also stimulates expression of the myoD gene itself, helping to maintain the cell’s differentiated state. • All the genes activated by MyoD have enhancer control elements recognized by MyoD and are thus coordinately controlled. • The secondary transcription factors activate the genes for proteins such as myosin and actin to confer the unique properties of skeletal muscle cells. • The MyoD protein is capable of changing fully differentiated fat and liver cells into muscle cells. • Not all cells can be transformed by MyoD, however. ○ Nontransforming cells may lack a combination of regulatory proteins in addition to MyoD. Pattern formation sets up the embryo’s body plan. • Cytoplasmic determinants and inductive signals contribute to pattern formation, the development of spatial organization in which the tissues and organs of an organism are all in their characteristic places. • Pattern formation begins in the early embryo, when the major axes of an animal are established. • Before specialized tissues and organs form, the relative positions of a bilaterally symmetrical animal’s three major body axes (anterior-posterior, dorsal-ventral, right-left) are established. • The molecular cues that control pattern formation, positional information, are provided by cytoplasmic determinants and inductive signals. ○ These signals tell a cell its location relative to the body axes and to neighboring cells and determine how the cell and its progeny will respond to future molecular signals. • Studies of pattern formation in Drosophila melanogaster have established that genes control development and have identified the key roles of specific molecules in defining position and directing differentiation. • Combining anatomical, genetic, and biochemical approaches in the study of Drosophila development, researchers have discovered developmental principles common to many other species, including humans. • Fruit flies and other arthropods have a modular construction. ○ An ordered series of segments make up the three major body parts: the head, thorax (with wings and legs), and abdomen. • Cytoplasmic determinants in the unfertilized egg provide positional information for two developmental axes (anterior-posterior and dorsal-ventral axis) before fertilization. • The Drosophila egg develops in the female’s ovary, surrounded by ovarian cells called nurse cells and follicle cells that supply the egg cell with nutrients, mRNAs, and other substances. • During fruit fly development, the egg forms a segmented larva, which goes through three larval stages. ○ The fly larva forms a pupal cocoon within which it metamorphoses into an adult fly. • In the 1940s, Edward B. Lewis used mutants to investigate Drosophila development. ○ Bizarre developmental mutations were on the fly’s genetic map, providing the first concrete evidence that genes somehow direct the developmental process. ○ These homeotic genes control pattern formation in the late embryo, larva, and adult. • In the late 1970s, Christiane Nüsslein-Volhard and Eric Weischaus set out to identify all the genes that affect segmentation in Drosophila. They faced three problems. • First, because Drosophila has about 13,700 genes, there could be either only a few genes affecting segmentation or so many that the pattern would be impossible to discern. • Second, mutations that affect segmentation are likely to be embryonic lethals, leading to death at the embryonic or larval stage. ○ Flies with embryonic lethal mutations never reproduce, and cannot be bred for study. ○ Nüsslein-Volhard and Wieschaus focused on recessive mutations that could be propagated in heterozygous flies. • Third, because of maternal effects on axis formation in the egg, the researchers also needed to study maternal genes. • After exposing flies to mutagenic chemicals, Nüsslein-Volhard and Wieschaus looked for dead embryos and larvae with abnormal segmentation. ○ Through appropriate crosses, they found heterozygotes carrying embryonic lethal mutations. • Nüsslein-Volhard and Wieschaus identified 1,200 genes essential for embryonic development. ○ About 120 of these were essential for normal segmentation. • The researchers grouped the genes by general function, mapped them, and cloned many of them. • In 1995, Nüsslein-Volhard, Wieschaus, and Lewis were awarded a Nobel Prize. Gradients of maternal molecules in the early Drosophila embryo control axis formation. • Cytoplasmic determinants produced under the direction of maternal effect genes are deposited in the unfertilized egg. • A maternal effect gene is a gene that, when mutant in the mother, results in a mutant phenotype in the offspring, regardless of the offspring’s own genotype. ○ In fruit fly development, maternal effect genes encode proteins or mRNA that are placed in the egg while it is still in the ovary. ○ When the mother has a mutation in a maternal effect gene, she makes a defective gene product (or none at all) and her eggs will not develop properly when fertilized. • Maternal effect genes are also called egg-polarity genes because they control the orientation of the egg and consequently the fly. ○ One group of genes sets up the anterior-posterior axis, while a second group establishes the dorsal-ventral axis. • One gene called bicoid affects the front half of the body. • An embryo whose mother has a mutant bicoid gene lacks the front half of its body and has duplicate posterior structures at both ends. ○ This suggests that the product of the mother’s bicoid gene is essential for setting up the anterior end of the fly and might be concentrated at the future anterior end. • This is a specific version of the morphogen gradient hypothesis, in which gradients of morphogens establish an embryo’s axes and other features. • Using DNA technology and biochemical methods, researchers were able to clone the bicoid gene and use it as a probe for bicoid mRNA in the egg. ○ As predicted, the bicoid mRNA is concentrated at the extreme anterior end of the egg cell. • After the egg is fertilized, bicoid mRNA is transcribed into protein, which diffuses from the anterior end toward the posterior, resulting in a gradient of proteins in the early embryo. ○ Injections of pure bicoid mRNA into various regions of early embryos resulted in the formation of anterior structures at the injection sites. • The bicoid research is important for three reasons. 1. It identified a specific protein required for some of the earliest steps in pattern formation. 2. It increased our understanding of the mother’s role in the development of an embryo. 3. It demonstrated a key developmental principle: a gradient of molecules can determine polarity and position in the embryo. • Maternal mRNAs are crucial during development of many species. ○ In Drosophila, gradients of specific proteins encoded by maternal mRNAs determine the posterior and anterior ends and establish the dorsal-ventral axis. • Later, positional information encoded by the embryo’s genes establishes a specific number of correctly oriented segments and triggers the formation of each segment’s characteristic structures. Concept 18.5 Cancer results from genetic changes that affect cell cycle control • Cancer is a set of diseases in which cells escape the control mechanisms that normally regulate cell growth and division. ○ The gene regulation systems that go wrong during cancer are the systems that play important roles in embryonic development and immune response. • The genes that normally regulate cell growth and division during the cell cycle include genes for growth factors, their receptors, and the intracellular molecules of signaling pathways. ○ Mutations altering any of these genes in somatic cells can lead to cancer. ○ The agent of such changes can be random spontaneous mutations or environmental influences such as chemical carcinogens, X-rays, and some viruses. Proto-oncogenes can become oncogenes, contributing to the development of cancer. • Cancer-causing genes, oncogenes, were initially discovered in viruses. ○ Close counterparts have been found in the genomes of humans and other animals.å • Normal versions of cellular genes, called proto-oncogenes, code for proteins that stimulate normal cell growth and division. • A proto-oncogene becomes an oncogene following genetic changes that lead to an increase in the proto-oncogene’s protein production or in the intrinsic activity of each protein molecule. ○ These genetic changes include movement of DNA within the genome, amplification of the proto-oncogene, and point mutations in a control element or the proto-oncogene itself. • Cancer cells frequently have chromosomes that have been broken and rejoined incorrectly. ○ A fragment may be moved to a location near an active promoter or other control element. • Amplification increases the number of copies of the proto-oncogene in the cell. • A point mutation in the promoter or enhancer of a proto-oncogene may increase its expression. • A point mutation in the coding sequence may lead to translation of a protein that is more active or longer-lived. • All of these mechanisms can lead to abnormal stimulation of the cell cycle, putting the cell on the path to malignancy. Mutations to tumor-suppressor genes may contribute to cancer. • The normal products of tumor-suppressor genes inhibit cell division. • Some tumor-suppressor proteins normally repair damaged DNA, preventing the accumulation of cancer-causing mutations. • Other tumor-suppressor proteins control the adhesion of cells to each other or to an extracellular matrix, which is crucial for normal tissues and often absent in cancers. • Still others are components of cell-signaling pathways that inhibit the cell cycle. ○ Decreases in the normal activity of a tumor-suppressor protein may contribute to cancer. • The proteins encoded by many proto-oncogenes and tumor-suppressor genes are components of cell-signaling pathways. • Mutations in the products of two key genes, the ras proto-oncogene and the p53 tumor-suppressor gene, occur in 30% and over 50% of human cancers, respectively. • The Ras protein, the product of the ras gene, is a G protein that relays a growth signal from a growth factor receptor on the plasma membrane to a cascade of protein kinases. ○ At the end of the pathway is the synthesis of a protein that stimulates the cell cycle. • Many ras oncogenes have a point mutation that leads to a hyperactive version of the Ras protein that trigger the kinase cascade in the absence of growth factor, resulting in excessive cell division. • The p53 gene, named for its 53,000-dalton protein product, is a tumor-suppressor gene. ○ The p53 protein is a specific transcription factor for the synthesis of several cell cycle-inhibiting proteins. ○ The p53 gene has been called the “guardian angel of the genome.” • Once activated by DNA damage, the p53 protein functions as an activator for several genes. ○ The p53 protein can activate the p21 gene, whose product halts the cell cycle by binding to cyclin-dependent kinases, allowing time for DNA repair. ○ p53 also activates expression of a group of miRNAs, which inhibit the cell cycle. ○ The p53 protein can also turn on genes directly involved in DNA repair. ○ When DNA damage is irreparable, the p53 protein can activate “suicide genes” whose protein products cause cell death by apoptosis. • A mutation that knocks out the p53 gene can lead to excessive cell growth and cancer. Multiple mutations underlie the development of cancer. • More than one somatic mutation is generally needed to produce the changes characteristic of a full-fledged cancer cell. • If cancer results from an accumulation of mutations, and if mutations occur throughout life, then the longer we live, the more likely we are to develop cancer. • Colorectal cancer, with 140,000 new cases and 50,000 deaths in the United States each year, illustrates a multistep cancer path. ○ The first sign is often a polyp, a small benign growth in the colon lining. ○ The cells of the polyp look normal but divide unusually frequently. ○ Through gradual accumulation of mutations that activate oncogenes and knock out tumor-suppressor genes, the polyp can develop into a malignant tumor. ○ A ras oncogene and a mutated p53 tumor-suppressor gene are usually involved. • About a half dozen DNA changes must occur for a cell to become fully cancerous. • These changes usually include the appearance of at least one active oncogene and the mutation or loss of several tumor-suppressor genes. ○ Because mutant tumor-suppressor alleles are usually recessive, mutations must knock out both alleles. ○ Most oncogenes behave like dominant alleles and require only one mutation. Cancer can run in families. • The fact that multiple genetic changes are required to produce a cancer cell helps explain the predispositions to cancer that run in families. ○ An individual inheriting an oncogene or a mutant allele of a tumor-suppressor gene is one step closer to accumulating the necessary mutations for cancer to develop. • Geneticists are devoting much effort to finding inherited cancer alleles so that a predisposition to certain cancers can be detected early in life. • About 15% of colorectal cancers involve inherited mutations. • Many of these mutations affect the tumor-suppressor gene adenomatous polyposis coli or APC. ○ Normal functions of the APC gene include regulation of cell migration and adhesion. ○ Even in patients with no family history of the disease, APC is mutated in about 60% of colorectal cancers. • Between 5% and 10% of breast cancer cases show an inherited predisposition. ○ Breast cancer is the second most common type of cancer in the United States, annually striking more than 180,000 women and leading to 40,000 deaths. • Mutations in one gene, BRCA1, increase the risk of breast and ovarian cancer. ○ Mutations in BRCA1 and the related gene BRCA2 are found in at least half of inherited breast cancers. • A woman who inherits one mutant BRCA1 allele has a 60% probability of developing breast cancer before age 50 (versus a 2% probability in an individual with two normal alleles). ○ Both BRCA1 and BRCA2 are considered tumor-suppressor genes because their wild-type alleles protect against breast cancer and their mutant alleles are recessive. • BRCA1 and BRCA2 proteins function in the cell’s DNA damage repair pathway. ○ BRCA2, in association with another protein, helps repair breaks that occur in both strands of DNA. • Because DNA breakage can contribute to cancer, the risk of cancer can be lowered by minimizing exposure to DNA-damaging agents, such as ultraviolet radiation in sunlight and the chemicals found in cigarette smoke. • In addition to mutations and other genetic alterations, a number of tumor viruses can cause cancer in various animals, including humans. ○ In 1911, Peyton Rous, an American pathologist, discovered a virus that causes cancer in chickens. ○ The Epstein-Barr virus, which causes infectious mononucleosis, has been linked to several types of cancer in humans, notably Burkitt’s lymphoma. ○ Papillomaviruses are associated with cancer of the cervix, and a virus called HTLV-1 causes a type of adult leukemia. • Worldwide, viruses seem to play a role in about 15% of the cases of human cancer. • Viruses can interfere with gene regulation in several ways if they integrate their genetic material into a cell’s DNA. ○ Viral integration may donate an oncogene to the cell, disrupt a tumor-suppressor gene, or convert a proto-oncogene to an oncogene. ○ Some viruses produce proteins that inactivate p53 and other tumor-suppressor proteins, making the cell more likely to become cancerous. Lecture Outline for Reece et al., Campbell Biology, 10th Edition, Copyright © 2014 Pearson Education, Inc

Haploid Gametes and Diploid Zygotes

Exam 1 - Zygote Stage

Medical Terminology - tubercul/o- to zygo- (851-900)

Development Stages from Zygote to Fetus

post zygotic isolating mechanisms

these topics one by one: 1. Conception: This is when a sperm cell successfully fertilizes an egg cell, creating a zygote. The sperm's nucleus fuses with the egg's nucleus, combining their genetic material to form a complete set of chromosomes. 2. Longitudinal Study: This is a research method where data is gathered for the same subjects repeatedly over a period of time. It can extend over years or even decades. For example, researchers might study a group of children from age 5 to age 25 to track their development. 3. Prenatal Development: This is divided into three phases: * Germinal Stage: This is the first 2 weeks after conception. The zygote divides and implants in the uterine wall. * Embryonic Stage: This is from weeks 3 to 8. Major organs and body systems begin to form. The heart starts beating, and arms, legs, and facial features develop. * Fetal Stage: This is from week 9 until birth. The fetus grows in size and its organs mature. By the end of this stage, the fetus is capable of surviving outside the womb. 4. Teratogens and Fetal Alcohol Syndrome: * Teratogens: These are substances or agents that can cause birth defects. Examples include alcohol, drugs, certain medications, and environmental toxins. * Fetal Alcohol Syndrome (FAS): This is a condition caused by prenatal alcohol exposure. It can result in physical, cognitive, and behavioral problems in the child. 5. Infant Development: * Infant Brain Development: The brain grows rapidly during infancy. Synaptic connections form at an astonishing rate, allowing for learning and development. * Face Preference Study: Studies show that infants prefer looking at faces from birth. This preference helps them learn to recognize caregivers and understand social cues. * Newborn Behaviors: Newborns have reflexes like sucking, grasping, and rooting. They spend much of their time sleeping and eating. 6. Baby's Motor Skills: * Typical Motor Skill Development: Babies develop motor skills in a predictable sequence. They first learn to lift their heads, then roll over, sit up, crawl, and eventually walk. * Walking in the U.S.: Most babies in the U.S. begin walking between 9 and 15 months of age. 7. Adolescence: * Brain Development: The brain continues to develop during adolescence, particularly the prefrontal cortex, which is responsible for decision-making and impulse control. * Social Development: Adolescents explore their identity and form relationships with peers. They may experience increased independence and conflict with parents. * Physical Development: Adolescence is marked by puberty, which includes the development of secondary sexual characteristics and rapid growth spurts

Zygotic patterning

3 post zygotic barriers

5 pre zygotic barriers

Early Embryology: Zygote to Neural Crest

Pregnancy: Zygote to Fetus and Maternal Hormonal Changes

The Key Concepts of Developmental Biology: From Zygote to Organism

Topic # 3: PROCESS OF CONCEPTION OVUM, SPERM CELL, AND ZYGOTE

uter-zygot

Types of Zygotic Barriers

L13: drosophila- zygotic patterning

Chapter 6: Adolescence Growth in Adolescence Puberty is a period of rapid growth and sexual maturation. These changes begin sometime l between eight and fourteen. Girls begin puberty at around ten years of age and boys begin approximately two years later. Pubertal changes take around three to four years to complete. Adolescents experience an overall physical growth spurt. The growth proceeds from the extremities toward the torso. This is referred to as distalproximal development. First the hands grow, then the arms, hand finally the torso. The overall physical growth spurt results in 10-11 inches of added height and 50 to 75 pounds of increased weight. The head begins to grow sometime after the feet have gone through their period of growth. Growth of the head is preceded by growth of the ears, nose, and lips. The difference in these patterns of growth result in adolescents appearing awkward and out-of-proportion. As the torso grows, so do the internal organs. The heart and lungs experience dramatic growth during this period. During childhood, boys and girls are quite similar in height and weight. However, gender differences become apparent during adolescence. From approximately age ten to fourteen, the average girl is taller, but not heavier, than the average boy. After that, the average boy becomes 223 both taller and heavier, although individual differences are certainly noted. As adolescents physically mature, weight differences are more noteworthy than height differences. At eighteen years of age, those that are heaviest weigh almost twice as much as the lightest, but the tallest teens are only about 10% taller than the shortest (Seifert, 2012). Both height and weight can certainly be sensitive issues for some teenagers. Most modern societies, and the teenagers in them, tend to favor relatively short women and tall men, as well as a somewhat thin body build, especially for girls and women. Yet, neither socially preferred height nor thinness is the destiny for many individuals. Being overweight, in particular, has become a common, serious problem in modern society due to the prevalence of diets high in fat and lifestyles low in activity (Tartamella et al., 2004). The educational system has, unfortunately, contributed to the problem as well by gradually restricting the number of physical education courses and classes in the past two decades. Average height and weight are also related somewhat to racial and ethnic background. In general, children of Asian background tend to be slightly shorter than children of European and North American background. The latter in turn tend to be shorter than children from African societies (Eveleth & Tanner, 1990). Body shape differs slightly as well, though the differences are not always visible until after puberty. Asian background youth tend to have arms and legs that are a bit short relative to their torsos, and African background youth tend to have relatively long arms and legs. The differences are only averages, as there are large individual differences as well. Sexual Development Typically, the growth spurt is followed by the development of sexual maturity. Sexual changes are divided into two categories: Primary sexual characteristics and secondary sexual characteristics. Primary sexual characteristics are changes in the reproductive organs. For males, this includes growth of the testes, penis, scrotum, and spermarche or first ejaculation of semen. This occurs between 11 and 15 years of age. For females, primary characteristics include growth of the uterus and menarche or the first menstrual period. The female gametes, which are stored in the ovaries, are present at birth, but are immature. Each ovary contains about 400,000 gametes, but only 500 will become mature eggs (Crooks & Baur, 2007). Beginning at puberty, one ovum ripens and is released about every 28 days during the menstrual cycle. Stress and higher percentage of body fat can bring menstruation at younger ages. Male Anatomy: Males have both internal and external genitalia that are responsible for procreation and sexual intercourse. Males produce their sperm on a cycle, and unlike the female's ovulation cycle, the male sperm production cycle is constantly producing millions of sperm daily. The main male sex organs are the penis and the testicles, the latter of which produce semen and sperm. The semen and sperm, as a result of sexual intercourse, can fertilize an ovum in the female's body; the fertilized ovum (zygote) develops into a fetus which is later born as a child. Female Anatomy: Female external genitalia is collectively known as the vulva, which includes the mons veneris, labia majora, labia minora, clitoris, vaginal opening, and urethral opening. Female internal reproductive organs consist of the vagina, uterus, fallopian tubes, and ovaries. The uterus hosts the developing fetus, produces vaginal and uterine secretions, and passes the male's sperm through to the fallopian tubes while the ovaries release the eggs. A female is born with all her eggs already produced. The vagina is attached to the uterus through the cervix, while the uterus is attached to the ovaries via the fallopian tubes. Females have a monthly reproductive cycle; at certain intervals the ovaries release an egg, which passes through the fallopian tube into the uterus. If, in this transit, it meets with sperm, the sperm might penetrate and merge with the egg, fertilizing it. If not fertilized, the egg is flushed out of the system through menstruation. Secondary sexual characteristics are visible physical changes not directly linked to reproduction but signal sexual maturity. For males this includes broader shoulders and a lower voice as the larynx grows. Hair becomes coarser and darker, and hair growth occurs in the pubic area, under the arms and on the face. For females, breast development occurs around age 10, although full development takes several years. Hips broaden, and pubic and underarm hair develops and also becomes darker and coarser. Acne: An unpleasant consequence of the hormonal changes in puberty is acne, defined as pimples on the skin due to overactive sebaceous (oil-producing) glands (Dolgin, 2011). These glands develop at a greater speed than the skin ducts that discharges the oil. Consequently, the ducts can become blocked with dead skin and acne will develop. According to the University of California at Los Angeles Medical Center (2000), approximately 85% of adolescents develop acne, and boys develop acne more than girls because of greater levels of testosterone in their systems (Dolgin, 2011). Experiencing acne can lead the adolescent to withdraw socially, especially if they are self-conscious about their skin or teased (Goodman, 2006). Effects of Pubertal Age: The age of puberty is getting younger for children throughout the world. According to Euling et al. (2008) data are sufficient to suggest a trend toward an earlier breast development onset and menarche in girls. A century ago the average age of a girl’s first period in the United States and Europe was 16, while today it is around 13. Because there is no clear marker of puberty for boys, it is harder to determine if boys are maturing earlier too. In addition to better nutrition, less positive reasons associated with early puberty for girls include increased stress, obesity, and endocrine disrupting chemicals. Cultural differences are noted with Asian-American girls, on average, developing last, while African American girls enter puberty the earliest. Hispanic girls start puberty the second earliest, while European-American girls rank third in their age of starting puberty. Although African American girls are typically the first to develop, they are less likely to experience negative consequences of early puberty when compared to European-American girls (Weir, 2016). Research has demonstrated mental health problems linked to children who begin puberty earlier than their peers. For girls, early puberty is associated with depression, substance use, eating disorders, disruptive behavior disorders, and early sexual behavior (Graber, 2013). Early maturing girls demonstrate more anxiety and less confidence in their relationships with family and friends, and they compare themselves more negatively to their peers (Weir, 2016). Problems with early puberty seem to be due to the mismatch between the child’s appearance and the way she acts and thinks. Adults especially may assume the child is more capable than she actually is, and parents might grant more freedom than the child’s age would indicate. For girls, the emphasis on physical attractiveness and sexuality is emphasized at puberty and they may lack effective coping strategies to deal with the attention they may receive. 226 Figure 6.4 Source Additionally, mental health problems are more likely to occur when the child is among the first in his or her peer group to develop. Because the preadolescent time is one of not wanting to appear different, early developing children stand out among their peer group and gravitate toward those who are older. For girls, this results in them interacting with older peers who engage in risky behaviors such as substance use and early sexual behavior (Weir, 2016). Boys also see changes in their emotional functioning at puberty. According to Mendle, Harden, Brooks-Gunn, and Graber (2010), while most boys experienced a decrease in depressive symptoms during puberty, boys who began puberty earlier and exhibited a rapid tempo, or a fast rate of change, actually increased in depressive symptoms. The effects of pubertal tempo were stronger than those of pubertal timing, suggesting that rapid pubertal change in boys may be a more important risk factor than the timing of development. In a further study to better analyze the reasons for this change, Mendle et al. (2012) found that both early maturing boys and rapidly maturing boys displayed decrements in the quality of their peer relationships as they moved into early adolescence, whereas boys with more typical timing and tempo development actually experienced improvements in peer relationships. The researchers concluded that the transition in peer relationships may be especially challenging for boys whose pubertal maturation differs significantly from those of others their age. Consequences for boys attaining early puberty were increased odds of cigarette, alcohol, or another drug use (Dudovitz, et al., 2015). Gender Role Intensification: At about the same time that puberty accentuates gender, role differences also accentuate for at least some teenagers. Some girls who excelled at math or science in elementary school, may curb their enthusiasm and displays of success at these subjects for fear of limiting their popularity or attractiveness as girls (Taylor et al/, 1995; Sadker, 2004). Some boys who were not especially interested in sports previously may begin dedicating themselves to athletics to affirm their masculinity in the eyes of others. Some boys and girls who once worked together successfully on class projects may no longer feel comfortable doing so, or alternatively may now seek to be working partners, but for social rather than academic reasons. Such changes do not affect all youngsters equally, nor affect any one youngster equally on all occasions. An individual may act like a young adult on one day, but more like a child the next. Adolescent Brain The brain undergoes dramatic changes during adolescence. Although it does not get larger, it matures by becoming more interconnected and specialized (Giedd, 2015). The myelination and 227 development of connections between neurons continues. This results in an increase in the white matter of the brain and allows the adolescent to make significant improvements in their thinking and processing skills. Different brain areas become myelinated at different times. For example, the brain’s language areas undergo myelination during the first 13 years. Completed insulation of the axons consolidates these language skills but makes it more difficult to learn a second language. With greater myelination, however, comes diminished plasticity as a myelin coating inhibits the growth of new connections (Dobbs, 2012). Even as the connections between neurons are strengthened, synaptic pruning occurs more than during childhood as the brain adapts to changes in the environment. This synaptic pruning causes the gray matter of the brain, or the cortex, to become thinner but more efficient (Dobbs, 2012). The corpus callosum, which connects the two hemispheres, continues to thicken allowing for stronger connections between brain areas. Additionally, the hippocampus becomes more strongly connected to the frontal lobes, allowing for greater integration of memory and experiences into our decision making. The limbic system, which regulates emotion and reward, is linked to the hormonal changes that occur at puberty. The limbic system is also related to novelty seeking and a shift toward interacting with peers. In contrast, the prefrontal cortex which is involved in the control of impulses, organization, planning, and making good decisions, does not fully develop until the mid-20s. According to Giedd (2015) the significant aspect of the later developing prefrontal cortex and early development of the limbic system is the “mismatch” in timing between the two. The approximately ten years that separates the development of these two brain areas can result in risky behavior, poor decision making, and weak emotional control for the adolescent. When puberty begins earlier, this mismatch extends even further. Teens often take more risks than adults and according to research it is because they weigh risks and rewards differently than adults do (Dobbs, 2012). For adolescents the brain’s sensitivity to the neurotransmitter dopamine peaks, and dopamine is involved in reward circuits, so the possible rewards outweighs the risks. Adolescents respond especially strongly to social rewards during activities, and they prefer the company of others their same age. Chein et al. (2011) found that peers sensitize brain regions associated with potential rewards. For example, adolescent drivers make risky driving decisions when with friends to impress them, and teens are much more likely to commit crimes together in comparison to adults (30 and older) who commit them alone (Steinberg et al., 2017). In addition to dopamine, the adolescent brain is affected by oxytocin which facilitates bonding and makes social connections more rewarding. With both dopamine and oxytocin engaged, it is no wonder that adolescents seek peers and excitement in their lives that could end up actually harming them. 228 Because of all the changes that occur in the adolescent brain, the chances for abnormal development can occur, including mental illness. In fact, 50% of the mental illness occurs by the age 14 and 75% occurs by age 24 (Giedd, 2015). Additionally, during this period of development the adolescent brain is especially vulnerable to damage from drug exposure. For example, repeated exposure to marijuana can affect cellular activity in the endocannabinoid system. Consequently, adolescents are more sensitive to the effects of repeated marijuana exposure (Weir, 2015). However, researchers have also focused on the highly adaptive qualities of the adolescent brain which allow the adolescent to move away from the family towards the outside world (Dobbs, 2012; Giedd, 2015). Novelty seeking and risk taking can generate positive outcomes including meeting new people and seeking out new situations. Separating from the family and moving into new relationships and different experiences are actually quite adaptive for society. Adolescent Sleep According to the National Sleep Foundation (NSF) (2016), adolescents need about 8 to 10 hours of sleep each night to function best. The most recent Sleep in America poll in 2006 indicated that adolescents between sixth and twelfth grade were not getting the recommended amount of sleep. On average adolescents only received 7 ½ hours of sleep per night on school nights with younger adolescents getting more than older ones (8.4 hours for sixth graders and only 6.9 hours for those in twelfth grade). For the older adolescents, only about one in ten (9%) get an optimal amount of sleep, and they are more likely to experience negative consequences the following day. These include feeling too tired or sleepy, being cranky or irritable, falling asleep in school, having a depressed mood, and drinking caffeinated beverages (NSF, 2016). Additionally, they are at risk for substance abuse, car crashes, poor academic performance, obesity, and a weakened immune system (Weintraub, 2016). Troxel et al. (2019) found that insufficient sleep in adolescents is a predictor of risky sexual behaviors. Reasons given for this include that those adolescents who stay out late, typically without parental supervision, are more likely to engage in a variety of risky behaviors, including risky sex, such as not using birth control or using substances before/during sex. An alternative explanation for risky sexual behavior is that the lack of sleep negatively affects impulsivity and decision-making processes. Figure 6.7 Source Why do adolescents not get adequate sleep? In addition to known environmental and social factors, including work, homework, media, technology, and socializing, the adolescent brain is also a factor. As adolescent go through puberty, their circadian rhythms change and push back their sleep time until later in the evening (Weintraub, 2016). This biological change not only keeps adolescents awake at night, it makes it difficult for them to wake up. When they are awake too early, their brains do not function optimally. Impairments are noted in attention, academic achievement, and behavior while increases in tardiness and absenteeism are also seen. 229 To support adolescents’ later sleeping schedule, the Centers for Disease Control and Prevention recommended that school not begin any earlier than 8:30 a.m. Unfortunately, over 80% of American schools begin their day earlier than 8:30 a.m. with an average start time of 8:03 a.m. (Weintraub, 2016). Psychologists and other professionals have been advocating for later school times, and they have produced research demonstrating better student outcomes for later start times. More middle and high schools have changed their start times to better reflect the sleep research. However, the logistics of changing start times and bus schedules are proving too difficult for some schools leaving many adolescent vulnerable to the negative consequences of sleep deprivation. Troxel et al. (2019) cautions that adolescents should find a middle ground between sleeping too little during the school week and too much during the weekends. Keeping consistent sleep schedules of too little sleep will result in sleep deprivation but oversleeping on weekends can affect the natural biological sleep cycle making it harder to sleep on weekdays. Adolescent Sexual Activity By about age ten or eleven, most children experience increased sexual attraction to others that affects social life, both in school and out (McClintock & Herdt, 1996). By the end of high school, more than half of boys and girls report having experienced sexual intercourse at least once, though it is hard to be certain of the proportion because of the sensitivity and privacy of the information. (Center for Disease Control, 2004; Rosenbaum, 2006). Adolescent Pregnancy: As can be seen in Figure 6.8, in 2018 females aged 15–19 years experienced a birth rate (live births) of 17.4 per 1,000 women. The birth rate for teenagers has declined by 58% since 2007 and 72% since 1991, the most recent peak (Hamilton, Joyce, Martin, & Osterman, 2019). It appears that adolescents seem to be less sexually active than in previous years, and those who are sexually active seem to be using birth control (CDC, 2016). Figure 6.8 Source Risk Factors for Adolescent Pregnancy: Miller et al. (2001) found that parent/child closeness, parental supervision, and parents' values against teen intercourse (or unprotected intercourse) decreased the risk of adolescent pregnancy. In contrast, residing in disorganized/dangerous neighborhoods, living in a lower SES family, living with a single parent, having older sexually 230 active siblings or pregnant/parenting teenage sisters, early puberty, and being a victim of sexual abuse place adolescents at an increased risk of adolescent pregnancy. Consequences of Adolescent Pregnancy: After the child is born life can be difficult for a teenage mother. Only 40% of teenagers who have children before age 18 graduate from high school. Without a high school degree her job prospects are limited, and economic independence is difficult. Teen mothers are more likely to live in poverty, and more than 75% of all unmarried teen mother receive public assistance within 5 years of the birth of their first child. Approximately, 64% of children born to an unmarried teenage high-school dropout live in poverty. Further, a child born to a teenage mother is 50% more likely to repeat a grade in school and is more likely to perform poorly on standardized tests and drop out before finishing high school (March of Dimes, 2012). Research analyzing the age that men father their first child and how far they complete their education have been summarized by the Pew Research Center (2015) and reflect the research for females. Among dads ages 22 to 44, 70% of those with less than a high school diploma say they fathered their first child before the age of 25. In comparison, less than half (45%) of fathers with some college experience became dads by that age. Additionally, becoming a young father occurs much less for those with a bachelor’s degree or higher as just 14% had their first child prior to age 25. Like men, women with more education are likely to be older when they become mothers. Eating Disorders Figure 6.9 According to the DSM-5-TR (American Psychiatric Association, 2022), eating disorders are characterized by a persistent disturbance of eating or eating-related behavior that results in the altered consumption or absorption of food and that significantly impairs physical health or psychosocial functioning. Although eating disorders can occur in children and adults, they frequently appear during the teen years or young adulthood (National Institute of Mental Health (NIMH), 2016). Eating disorders affect both genders, although rates among women are 2½ times greater than among men. Similar to women who have eating disorders, men also have a distorted sense of body image, including muscle dysmorphia, which is an extreme desire to increase one’s muscularity (Bosson et al., 2019). The prevalence of eating disorders in the United States is similar among Non-Hispanic Whites, Hispanics, African-Americans, and Asians, with the exception that anorexia nervosa is more common among Non-Hispanic Whites (Hudson et al., 2007; Wade et al., 2011). Source Risk Factors for Eating Disorders: Because of the high mortality rate, researchers are looking into the etiology of the disorder and associated risk factors. Researchers are finding that eating disorders are caused by a complex interaction of genetic, biological, behavioral, psychological, and social factors (NIMH, 2016). Eating disorders appear to run in families, and researchers are working to identify DNA variations that are linked to the increased risk of developing eating 231 disorders. Researchers from King’s College London (2019) found that the genetic basis of anorexia overlaps with both metabolic and body measurement traits. The genetic factors also influence physical activity, which may explain the high activity level of those with anorexia. Further, the genetic basis of anorexia overlaps with other psychiatric disorders. Researchers have also found differences in patterns of brain activity in women with eating disorders in comparison with healthy women. The main criteria for the most common eating disorders: Anorexia nervosa, bulimia nervosa, and binge-eating disorder are described in the DSM-5-TR (American Psychiatric Association, 2022) and listed in Table 6.1. Table 6.1 DSM-5-TR Eating Disorders Anorexia Nervosa  Restriction of energy intake leading to a significantly low body weight  Intense fear of gaining weight  Disturbance in one’s self-evaluation regarding body weight Bulimia Nervosa Binge-Eating Disorder  Recurrent episodes of binge eating  Recurrent inappropriate compensatory behaviors to prevent weight gain, including purging, laxatives, fasting or excessive exercise  Self-evaluation is unduly affected by body shape and weight  Recurrent episodes of binge eating  Marked distress regarding binge eating  The binge eating is not associated with the recurrent use of inappropriate compensatory behavior Health Consequences of Eating Disorders: For those suffering from anorexia, health consequences include an abnormally slow heart rate and low blood pressure, which increases the risk for heart failure. Additionally, there is a reduction in bone density (osteoporosis), muscle loss and weakness, severe dehydration, fainting, fatigue, and overall weakness. Anorexia nervosa has the highest mortality rate of any psychiatric disorder (Arcelus et al., 2011). Individuals with this disorder may die from complications associated with starvation, while others die of suicide. In women, suicide is much more common in those with anorexia than with most other mental disorders. The binge and purging cycle of bulimia can affect the digestives system and lead to electrolyte and chemical imbalances that can affect the heart and other major organs. Frequent vomiting can cause inflammation and possible rupture of the esophagus, as well as tooth decay and staining from stomach acids. Lastly, binge eating disorder results in similar health risks to obesity, including high blood pressure, high cholesterol levels, heart disease, Type II diabetes, and gall bladder disease (National Eating Disorders Association, 2016). 232 Figure 6.10 Source Eating Disorders Treatment: To treat eating disorders, adequate nutrition and stopping inappropriate behaviors, such as purging, are the foundations of treatment. Treatment plans are tailored to individual needs and include medical care, nutritional counseling, medications (such as antidepressants), and individual, group, and/or family psychotherapy (NIMH, 2016). For example, the Maudsley Approach has parents of adolescents with anorexia nervosa be actively involved in their child’s treatment, such as assuming responsibility for feeding the child. To eliminate binge eating and purging behaviors, cognitive behavioral therapy (CBT) assists sufferers by identifying distorted thinking patterns and changing inaccurate beliefs

Zygote

post vs pre zygote isolation