Human Genetics 12th Edition-66-161.pdf

replication, followed by the double division of meiosis, halves the chromosome number....

replication, followed by the double division of meiosis, halves the chromosome number. Prophase II marks the start of the second meiotic division (figure 3.7). The chromosomes are again condensed and vis- Metaphase I ible. In metaphase II, the replicated chromosomes align down the center of the cell. In anaphase II, the centromeres part, and the newly formed chromosomes, each now in the unreplicated form, move to opposite poles. In telophase II, nuclear envelopes MEIOSIS II form around the four nuclei, which then separate into individ- ual cells. The net result of meiosis is four haploid cells, each carrying a new assortment of genes and chromosomes that hold a single copy of the genome. Meiosis generates astounding genetic variety. Any of a person’s more than 8 million possible combinations of Haploid daughter cells ­chromosomes can meet with any of the more than 8 million Figure 3.6 Independent assortment. The pattern combinations of a partner, raising potential variability to more in which homologs randomly align during metaphase I than 70 trillion (8,388,6082) genetically unique individuals! determines the combination of maternally and paternally Crossing over contributes almost limitless genetic diversity. derived chromosomes in the daughter cells. Two pairs of chromosomes can align in two ways to produce four possibilities in the daughter cells. The potential variability that Key Concepts Questions 3.2 meiosis generates for all 23 chromosome pairs, especially considering crossing over, is great. 1. Distinguish between haploid and diploid. 2. Explain how meiosis maintains the chromosome of still-replicated chromosomes at each end of the stretched- number over generations and mixes gene combinations. out cell. Unlike in mitosis, the centromeres of each homolog in meiosis I remain together. During a second interphase, chro- 3. Discuss the two mechanisms that generate genotypic mosomes unfold into thin threads. Proteins are manufactured, diversity. but DNA is not replicated a second time. The single DNA MEIOSIS II Prophase II Metaphase II Anaphase II Telophase II Four nonidentical Nuclear envelope Chromosomes align along Sister chromatids separate Nuclear envelopes assemble haploid daughter fragments. Spindle equator of cell. to opposite poles of cell. around two daughter nuclei. cells forms and fibers Chromosomes decondense. attach to both Spindle disappears. chromosomes. Cytokinesis divides cells. Figure 3.7 Meiosis II. The equational division of meiosis II pulls apart the replicated chromosomes, producing 46 chromo­ somes in the unreplicated form. (This figure depicts two representative chromosome types.) Chapter 3 Meiosis, Development, and Aging 45  The base of the tail has many mitochondria, which will split ATP 3.3 Gametes Mature molecules to release energy that will propel the sperm inside the female reproductive tract. After spermatid differentiation, some Meiosis happens in both sexes, but further steps elaborate the of the cytoplasm connecting the cells falls away, leaving mature, very different-looking sperm and oocyte. Different distribu- tadpole-shaped spermatozoa (singular, spermatozoon), or sperm. tions of cell components create the distinctions between sperm Figure 3.9 presents an anatomical view showing the stages of and oocytes. The forming gametes of the maturing male and spermatogenesis within the seminiferous tubules. female proceed through similar stages, but with sex-specific A sperm, which is a mere 0.006 centimeter (0.0023 inch) terminology and vastly different timetables. A male begins long, must travel about 18 centimeters (7 inches) to reach an manufacturing sperm at puberty and continues throughout life, oocyte. Each sperm cell consists of a tail, body or midpiece, whereas a female begins meiosis when she is a fetus. Meiosis in and a head region (figure 3.10). A membrane-covered area on the female completes only if a sperm fertilizes an oocyte. Sperm Form A GLIMPSE OF HISTORY Spermatogenesis, the formation of sperm cells, begins in a diploid stem cell called a spermatogonium (figure 3.8). This Sperm have fascinated biologists for centuries. Antonie van cell divides mitotically, yielding two daughter cells. One cell Leeuwenhoek was the first to view human sperm under a microscope, in 1678, concluding that they continues to specialize into a mature sperm. The other daugh- were parasites in semen. By 1685, he had ter cell remains a stem cell, able to self-renew and continually modified his view, writing that sperm contain produce more sperm. a preformed human, called a homunculus, Bridges of cytoplasm attach several spermatogonia, and and are seeds requiring nurturing in a their daughter cells enter meiosis together. As these spermato- female to start a new life. The illustration in gonia mature, they accumulate cytoplasm and replicate their figure 3A was drawn by Dutch histologist DNA, becoming primary spermatocytes. Niklaas Hartsoeker in 1694 and represents During reduction division (meiosis I), each primary sper- the once-popular homunculus hypothesis. matocyte divides, forming two equal-sized haploid cells called secondary spermatocytes. In meiosis II, each secondary sper- Figure 3A A sperm cell was once thought to house a tiny human. Illustration by Nicolaas matocyte divides to yield two equal-sized spermatids. Each sper- Hartsoeker, from Essai de Dioptrique, 1695. matid then develops the characteristic sperm tail, or flagellum. Maturation a X a X Autosomes Sex chromosomes a a X X X A Mitosis Meiosis I Meiosis II a Y Y A A Y A Y A Y Spermatogonium Primary Secondary Spermatid Sperm (diploid) spermatocyte spermatocyte (haploid) (haploid) (diploid) (haploid) Figure 3.8 Sperm formation (spermatogenesis). Primary spermatocytes have the normal diploid number of 23 chromosome pairs. The large pair of chromosomes represents autosomes (non-sex chromosomes). The X and Y chromosomes are sex chromosomes. 46 Part 1 Introduction  Meiosis Meiosis Mitosis I II Tubule wall Penis Testis Seminiferous Diploid Primary Secondary Developing Sperm cells tubule cell spermatocyte spermatocyte sperm cell (haploid) (diploid) (haploid) (haploid) Figure 3.9 Meiosis and maturation produce sperm cells. Diploid cells divide through mitosis in the linings of the seminiferous tubules. Some daughter cells then undergo meiosis, producing haploid secondary spermatocytes, which differentiate into mature sperm cells. the front end, the acrosome, contains enzymes that help the Oocytes Form sperm cell penetrate the protective layers around the oocyte. Meiosis in the female, called oogenesis (egg making), begins Within the large sperm head, DNA wraps around proteins. The with a diploid cell, an oogonium. Unlike male cells, oogonia sperm’s DNA at this time is genetically inactive. A male manu- are not attached to each other. Instead, follicle cells surround factures trillions of sperm in his lifetime. Although many of each oogonium. As each oogonium grows, cytoplasm accumu- these will come close to an oocyte, few will actually touch one. lates, DNA replicates, and the cell becomes a primary oocyte. Meiosis in the male has built-in protections that help The ensuing meiotic division in oogenesis, unlike the male prevent sperm from causing some birth defects. Spermatogo- pathway, produces cells of different sizes. nia that are exposed to toxins tend to be so damaged that they In meiosis I, the primary oocyte divides into two cells: a never mature into sperm. More mature sperm cells exposed to small cell with very little cytoplasm, called a first polar body, toxins are often so damaged that they cannot swim. and a much larger cell called a secondary oocyte (figure 3.11). Each cell is haploid, with the chromosomes in replicated form. In meiosis II, the tiny first polar body may divide to yield two Acrosome polar bodies of equal size, with unreplicated chromosomes, or Head Nucleus Spiral mitochondria Midpiece Tail Secondary oocyte Polar body Figure 3.11 Meiosis in a female produces a secondary oocyte and a polar body. Unequal division and apportioning of cell parts enable the cell destined to become a fertilized ovum to accumulate most of the cytoplasm and organelles from the primary oocyte, but with only one genome copy. The Figure 3.10 Sperm. A sperm has oocyte receives most of the cytoplasm that would have gone into the meiotic distinct regions that assist in delivering DNA product that became the polar body if the division had been equal. © Prof. P.M. to an oocyte. Motta/Univ. “La Sapienza”, Rome/Photo Researchers/Science Source Chapter 3 Meiosis, Development, and Aging 47 the first polar body may decompose. The secondary oocyte, so rare. Furthermore, only one in three of the oocytes that do however, divides unequally in meiosis II to produce another meet and merge with a sperm cell will continue to grow, divide, small polar body, with unreplicated chromosomes, and the and specialize to eventually form a new individual. mature egg cell, or ovum, which contains a large volume of The diminishing number of oocytes present as a female cytoplasm. Figure 3.12 summarizes meiosis in the female, and ages was thought to be due to a dwindling original supply of figure 3.13 provides an anatomical view of the process. the cells. However, researchers have discovered that human Most of the cytoplasm among the four meiotic products ovaries contain oocyte-producing stem cells, so it is not clear in the female ends up in only one cell, the ovum. The woman’s why the number falls. body absorbs the polar bodies, which normally play no further role in development. Rarely, a sperm fertilizes a polar body. Meiosis and Mutations When this happens, the woman’s hormones respond as if she is pregnant, but a disorganized clump of cells that is not an embryo The gametes of older people are more likely to have new muta- grows for a few weeks, and then leaves the woman’s body. This tions (that is, not inherited mutations) than the gametes of event is a type of miscarriage called a “blighted ovum.” younger people. Older women are at higher risk of producing Before birth, a female has a million or so oocytes arrested oocytes that have an extra or missing chromosome. If fertil- in prophase I. (This means that when your grandmother was ized, such oocytes lead to offspring with the chromosomal con- pregnant with your mother, the oocyte that would be fertilized ditions described in chapter 13. Older men are also more likely and eventually become you was already there.) By puberty, to produce gametes that have genetic errors, but sperm tend about 400,000 oocytes remain. After puberty, meiosis I con- to have single-gene mutations rather than chromosome-level tinues in one or several oocytes each month, but halts again changes. The “paternal age effect” usually causes dominant at metaphase II. In response to specific hormonal cues each single-gene diseases. That is, only one copy of the mutant gene month, one ovary releases a secondary oocyte; this event is causes the condition. ovulation. The oocyte drops into a uterine tube, where waving The different timetables of meiosis explain why sperm cilia move it toward the uterus. Along the way, if a sperm pen- introduce single-gene conditions whereas oocytes originate etrates the oocyte membrane, then female meiosis completes, chromosome imbalances. In females, oocytes exist on the brink and a fertilized ovum forms. If the secondary oocyte is not of meiosis I for years, and the cells complete meiosis II only if fertilized, it degenerates and leaves the body in the menstrual they are fertilized. Mistakes occur when gametes are active, flow, without meiosis completed. and that is when they are distributing their chromosomes. If a A female ovulates about 400 oocytes between puberty homologous pair doesn’t separate, the result could be an oocyte and menopause. Most oocytes degrade, because fertilization is with an extra or missing chromosome. First polar body may divide a (haploid) a X Polar bodies die X a X a X Mitosis Meiosis I Meiosis II (if fertilization A X A occurs) Oogonium (diploid) X Primary oocyte (diploid) Ovum (egg) A X A Mature egg Secondary oocyte X (haploid) Second polar body (haploid) Figure 3.12 Ovum formation (oogenesis). Primary oocytes have the diploid number of 23 chromosome pairs. Meiosis in females concentrates most of the cytoplasm into one large cell called an oocyte (or egg). The other products of meiosis, called polar bodies, contain the other three sets of chromosomes and normally degenerate. 48 Part 1 Introduction  Maturing oocytes Uterine tube Primary oocyte Developing follicle Fertilization and meiosis II Meiosis I Secondary Ovary oocyte Ovulation Ovum (egg) Figure 3.13 The making of oocytes. Oocytes develop within the ovary in follicles. An ovary contains many oocytes in various stages of maturation. After puberty, the most mature oocyte in one ovary bursts out each month, in an event called ovulation. Sperm develop in only 74 days. “Paternal age effect” tended to be the youngest children in large families. The pater- conditions arise from stem cells in the testis that divide every nal age effect has only recently been recognized. Researchers 16 days, from puberty on, offering many opportunities for examined testes from elderly men who had died and donated DNA replication (discussed in chapter 9) to make a mistake, their bodies to science. Each testis was divided into 6 slices generating a dominant mutation. Table 3.2 describes some of 32 pieces, and probed for mutations that cause multiple paternal age effect conditions. They occur in genes of the endocrine neoplasia (an inherited cancer syndrome). Mutations fibroblast growth factor receptor (FGFR) family and affect were found in discrete sections of the testes, indicating that skeletal growth. Mutations in FGFR genes that arise in the stem cells perpetuated the mutation as they divided. The older testicles as a man ages skew meiosis so that more spermatogo- the man at death, the more testis cells had the mutations. nia give rise to cells with the mutation than to cells without it. The result is a mosaic cell population, or what has been called a “testicular time bomb.” Key Concepts Questions 3.3 The maternal age effect in causing chromosomal imbal- ances has been recognized since the nineteenth century, when 1. Explain the steps of sperm and oocyte formation and physicians noticed that babies with trisomy 21 Down syndrome specialization. 2. Describe how the timetables of spermatogenesis and oogenesis differ. 3. Explain how paternal and maternal age effect Table 3.2 Paternal Age Effect Conditions conditions differ. Disease Phenotype Achondroplasia Short-limbed dwarfism (see figure 5.1a) Crouzan syndrome Premature fusion of skull bones in infancy, causing wide-spaced and bulging eyes, 3.4 Prenatal Development beaked nose, short upper lip, small upper jaw, and jutting lower jaw A prenatal human is considered an embryo for the first 8 weeks, when rudiments of all body parts form. During the Multiple Cancers of thyroid, parathyroid, and adrenal endocrine glands first week, the embryo is in a “preimplantation” stage because neoplasia 2 it has not yet settled into the uterine lining. Some biologists consider a prenatal human to be an embryo when it begins to Pfeiffer Premature fusion of skull bones in infancy, develop tissue layers, at about 2 weeks. syndrome short and fused fingers and toes Prenatal development after the eighth week is the fetal Thanatophoric Severe short-limbed dwarfism period, when structures grow and specialize. From the start dysplasia of the ninth week until birth, the prenatal human organism is a fetus. Chapter 3 Meiosis, Development, and Aging 49  Bioethics Why a Clone Is Not an Exact Duplicate Cloning creates a genetic replica of an individual. In contrast, because X inactivation normally occurs in the embryo, not normal reproduction and development combine genetic material in the first cell (see section 6.4). from two individuals. In fiction, scientists have cloned Nazis, Mitochondrial DNA. A clone’s mitochondria descend from politicians, dinosaurs, children, and organ donors. Real scientists the recipient oocyte, not from the donor cell, because have cloned sheep, mice, cats, pigs, dogs, monkeys, and mitochondria are in the cytoplasm, not the nucleus (see amphibians. figure 5.10). Identical multiples, such as twins and triplets, are natural clones. Armadillos naturally always give birth to identical The environment is another powerful factor in why a clone quadruplets (figure 3B). A technique called “somatic cell nuclear isn’t an identical copy. For example, coat color patterns differ transfer,” or just “nuclear transfer,” is used to create clones. It in cloned calves and cats. When the animals were embryos, transfers a nucleus from a somatic cell into an oocyte whose cells destined to produce pigment moved in a unique way in nucleus has been removed. each individual, producing different color patterns. In humans, Cloning cannot produce an exact replica of a person, for experience, nutrition, stress, exposure to infectious disease, and several reasons: many other factors join our genes in molding who we are. Premature cellular aging. In some species, telomeres of Questions for Discussion chromosomes in the donor nucleus are shorter than those in the recipient cell (see figure 2.16). 1. Which of your characteristics do you think could not be Altered gene expression. In normal development, for duplicated in a clone, and why? some genes, one copy is turned off, depending upon which 2. What might be a reason to clone humans? parent transmits it. This phenomenon is called genomic 3. What are potential dangers of cloning humans? Of cloning imprinting (see section 6.5). In cloning, genes in a donor pets? nucleus skip passing through a sperm or oocyte, and thus 4. Do human clones exist naturally? are not imprinted. Lack of imprinting causes cloned animals to be unusually large. More mutations. DNA from a donor cell has had years to accumulate mutations. A mutation might not be noticeable in one of millions of somatic cells in a body but it could be devastating if that nucleus is used to program development of a new individual. X inactivation. At a certain time in early prenatal development in female mammals, one X chromosome is inactivated. Whether that X chromosome is from the mother or the father occurs at random in each cell, creating Figure 3B Armadillos are clones. These armored an overall mosaic pattern of expression for genes on the mammals always give birth to four genetically identical X chromosome. The pattern of X inactivation of a female offspring—that is, quadruplet clones. © Bianca Lavies/National clone would probably not match that of her nucleus donor, Geographic Creative A sperm first contacts a covering of follicle cells, called Sperm and Oocyte Meet at Fertilization the corona radiata, that guards a secondary oocyte. The Hundreds of millions of sperm cells are deposited in the vagina sperm’s acrosome then bursts, releasing enzymes that bore during sexual intercourse. A sperm cell can survive in a wom- through a protective layer of glycoprotein (the zona pellucida) an’s body for up to 3 days, but the oocyte can only be fertilized beneath the corona radiata. Fertilization, or conception, begins in the 12 to 24 hours after ovulation. when the outer membranes of the sperm and secondary oocyte The woman’s body helps sperm reach an oocyte. A pro- meet and a protein on the sperm head contacts a different type cess in the female called capacitation chemically activates of protein on the oocyte (figure 3.14). A wave of electricity sperm, and the oocyte secretes a chemical that attracts sperm. spreads physical and chemical changes across the oocyte sur- Contractions of the female’s muscles and moving of sperm face, which keep other sperm out. More than one sperm can tails propel the sperm. Still, only 200 or so sperm get near the enter an oocyte, but the resulting cell has too much genetic oocyte. material for development to follow. 50 Part 1 Introduction  Corona radiata Polar body Second meiotic spindle Cytoplasm of ovum Zona pellucida Plasma membrane Sperm of ovum Figure 3.14 Fertilization. Fertilization by a sperm cell induces the oocyte (arrested in metaphase II) to complete meiosis. Before fertilization occurs, the sperm’s acrosome bursts, spilling enzymes that help the sperm’s nucleus enter the oocyte. Usually only the sperm’s head enters the oocyte. Within 12 hours of the sperm’s penetration, the ovum’s nuclear mem- A GLIMPSE OF HISTORY brane disassembles, and the two sets of chromosomes, called pronuclei, approach one another. Within each pronucleus, DNA Today’s home tests for the pregnancy hormone hCG replicates. Fertilization completes when the two genetic pack- cap a long legacy of ways to tell if a woman was expecting. Etchings on an Egyptian papyrus from 1350 ages meet and merge, forming the genetic instructions for a B.C.E. show a woman whose menstrual period was late new individual. The fertilized ovum is called a zygote. The urinating on wheat and barley seeds. If wheat sprouted Bioethics reading discusses cloning, which is a way to start it would be a girl, if barley grew it was a boy, and if development without a fertilized egg. nothing happened, then the woman wasn’t with child. The effect on seeds might have been due to estrogens in the urine. In the ensuing centuries, “piss prophets” The Embryo Cleaves and Implants attempted to divine the pregnant state from the shades A day after fertilization, the zygote divides by mitosis, and textures of urine. beginning a period of frequent cell division called cleavage (figure 3.15). The resulting early cells are called blastomeres. In the early twentieth century, researchers seeking ways When the blastomeres form a solid ball of sixteen or more cells, to confirm pregnancy measured levels of the hormones that wax and wane during the menstrual cycle and the the embryo is called a morula (Latin for “mulberry,” which it body parts that they affect. They injected the urine of resembles). possibly pregnant women into rabbits, rats, mice, or frogs, During cleavage, organelles and molecules from the sec- leading to the once-famous announcement of impending ondary oocyte’s cytoplasm still control cellular activities, but parenthood, “The rabbit died!” Actually, all the rabbits some of the embryo’s genes begin to function. The ball of cells injected with human urine died, as doctors probed the hollows out, and its center fills with fluid, creating a b ­ lastocyst. ovaries for the swelling that would indicate presence of (The term “cyst” refers to the fluid-filled center.) Some of the the telltale human pregnancy hormone. cells form a clump on the inside lining called the inner cell mass. Its formation is the first event that distinguishes cells In the 1970s, increasing interest in women’s health sped development of a pregnancy test for the active part of from each other by their relative positions. The inner cell mass the hCG molecule using chemicals in a test tube, rather continues developing, forming the embryo. than sacrificing rabbits. At first doctors sent urine to labs A week after conception, the blastocyst nestles into the for analysis. Then in 1978 came the first at-home “early uterine lining. This event, called implantation, takes about a pregnancy test,” sold at drug stores and revolutionary at week. As implantation begins, the outermost cells of the blasto- the time. The thin blue line that indicated pregnancy took cyst, called the trophoblast, secrete human chorionic gonadotro- much of the mystery and anxiety out of confirming what a pin (hCG), a hormone that prevents menstruation. This hormone woman may have already strongly suspected. detected in a woman’s urine or blood is one sign of pregnancy. Chapter 3 Meiosis, Development, and Aging 51  Uterus Day 2 Day 3 Day 4 Day 1 Uterine tube 2 cells 4 cells Morula Inner Blastocyst Zygote cell mass implants Day 7 Fertilization Embryo Day 0 Ovulated Muscle layer secondary oocyte Endometrium Ovary Figure 3.15 Cleavage: From ovulation to implantation. The zygote forms in the uterine tube when a sperm nucleus fuses with the nucleus of an oocyte. The first divisions proceed while the zygote moves toward the uterus. By day 7, the zygote, now called a blastocyst, begins to implant in the uterine lining. (left): © Petit Format/Nestle/Photo Researchers/Science Source; (middle): © P.M. Motta & J. Van Blerkom/SPL/Science Source; (right): © Petit Format/Nestle/Photo Researchers/Science Source methyls bind to and silence specific sets of genes. The pattern The Embryo Forms of methyl group binding that guides the specialization of the During the second week of prenatal development, a space embryo establishes the epigenome. The term epigenetic refers called the amniotic cavity forms between the inner cell mass to changes to DNA expression, not to DNA nucleotide base and the outer cells anchored to the uterine lining. Then the sequence. Each layer of the embryo retains stem cells as the inner cell mass flattens into a two-layered embryonic disc. organism develops. Under certain conditions, stem cells may The layer nearest the amniotic cavity is the ectoderm; the produce daughter cells that can specialize as many cell types. inner layer, closer to the blastocyst cavity, is the endoderm. Each primary germ layer gives rise to certain structures. Shortly after, a third layer, the mesoderm, forms in the middle. Cells in the ectoderm become skin, nervous tissue, or parts This three-layered, curved, sandwich-like structure is called of certain glands. Endoderm cells form parts of the liver and the primordial embryo, or the gastrula (figure 3.16). pancreas and the linings of many organs. The middle layer of The cells that form the layers of the primordial embryo, the embryo, the mesoderm, forms many structures, including called primary germ layers, become “determined,” or fated, muscle, connective tissues, the reproductive organs, and the to develop as specific cell types. The cells specialize by the kidneys. progressive switching off of the expression of genes impor- Genes called homeotics control how the embryo devel- tant and active in the early embryo as other genes begin to be ops parts in the right places. Mutations in these genes cause expressed. Gene expression shuts off when a small molecule some very interesting conditions, including forms of intellec- called a methyl (CH3; a carbon bonded to three hydrogen atoms) tual disability, autism, blood cancer, and blindness. Clinical binds certain genes and proteins. In the early embryo, methyls Connection 3.1 describes a human disease that results from bind the proteins (histones) that hold the long DNA molecules mutations in homeotic genes. Table 3.3 summarizes the stages in a coil (see figure 9.13 and figure 11.5). In the later embryo, of early human prenatal development. 52 Part 1 Introduction  Supportive Structures Digestive tract Form Skin As an embryo develops, structures Amnion Spinal cord form that support and protect it. Amniotic fluid These include chorionic villi, the pla- Heart centa, the yolk sac, the allantois, the umbilical cord, and the amniotic sac. Chorion By the third week after con- Tail end ception, fingerlike outgrowths called chorionic villi extend from the area Body stalk with umbilical of the embryonic disc close to the blood vessels uterine wall. The villi project into pools of the woman’s blood. Her Trophoblast blood system and the embryo’s are separate, but nutrients and oxygen Brain diffuse across the chorionic villi from her circulation to the embryo. Wastes leave the embryo’s circula- Yolk sac tion and enter the woman’s circula- tion, to be excreted. By 10 weeks, the placenta is fully formed from the chorionic villi. The placenta links the woman and her fetus for the rest of the pregnancy. It secretes hormones that maintain pregnancy and sends nutrients to the fetus. Endoderm Other structures nurture the Mesoderm Epithelium of pharynx, developing embryo. The yolk sac auditory canal, tonsils, manufactures blood cells, as does Ectoderm Muscle thyroid, parathyroid, Connective tissue: thymus, larynx, trachea, the allantois, a membrane surround- Epidermis of skin and epidermal cartilage, bone, blood lungs, digestive tract, ing the embryo that gives rise to the derivatives: hair, nails, glands Dermis of skin; dentin of teeth urinary bladder and of the skin; linings of cavities Epithelium of blood vessels, umbilical blood vessels. The umbili- urethra, vagina Nervous tissue; sensory organs lymphatic vessels, cavities Liver and pancreas cal cord forms around these vessels Lens of eye; tooth enamel Internal reproductive organs and attaches to the center of the pla- Pituitary gland Kidneys and ureters Adrenal medulla Adrenal cortex centa. Toward the end of the embry- onic period, the yolk sac shrinks, as the amniotic sac swells with fluid Figure 3.16 The primordial embryo. When the three primary germ layers of the embryo form at gastrulation, many cells become “fated” to follow a specific developmental that cushions the embryo and main- pathway. tains a constant temperature and pressure. The amniotic fluid con- tains fetal urine and a few fetal cells. Table 3.3 Stages and Events of Early Human Prenatal Development Two of the supportive struc- tures that develop during preg- Stage Time Period Principal Events nancy provide material for prenatal Fertilized 12 to 24 hours following Oocyte fertilized; zygote has 23 pairs of tests, discussed in chapters 13 and ovum ovulation chromosomes and is genetically distinct 20. Chorionic villus sampling examines chromosomes from cells Cleavage 30 hours to third day Mitosis increases cell number snipped off the chorionic villi at 10 Morula Third to fourth day Solid ball of cells weeks. Because the villi cells and the embryo’s cells come from the same Blastocyst Fifth day through Hollowed fluid-filled ball forms trophoblast fertilized ovum, an abnormal chro- second week (outside) and inner cell mass, which implants mosome in villi cells should also be and flattens to form embryonic disc in the embryo. In amniocentesis, Gastrula End of second week Primary germ layers form a sample of amniotic fluid is taken and fetal cells in it are examined for Chapter 3 Meiosis, Development, and Aging 53 biochemical, genetic, and chromosomal anomalies. However, Multiples chorionic villus sampling and amniocentesis may be replaced Twins and other multiples arise early in development. Frater- with collection and analysis of fetal DNA that is in the pregnant nal, or dizygotic (DZ), twins result when two sperm fertilize woman’s bloodstream. This DNA is “cell free”—that is, outside two oocytes. This can happen if ovulation occurs in two ova- blood cells, in the liquid part of the blood. Eight weeks after ries in the same month, or if two oocytes leave the same ovary conception, about 10 percent of the cell-free DNA in the mater- and are both fertilized. DZ twins are no more alike than any nal circulation comes from the fetus or the placenta. two siblings, although they share a very early environment in The umbilical cord is another prenatal structure that has the uterus. The tendency to ovulate two oocytes in a month, medical applications. In addition to blood stem cells mentioned leading to conception of DZ twins, can run in families. in Bioethics in chapter 2, the cord yields bone, fat, nerve, and Identical, or monozygotic (MZ), twins descend from a cartilage cells. Stem cells from the cord itself are used to treat a single fertilized ovum and therefore are genetically identical. respiratory disease of newborns. The stem cells give rise to lung They are natural clones. Three types of MZ twins can form, cells that secrete surfactant, which is the chemical that inflates depending upon when the fertilized ovum or very early embryo the microscopic air sacs, and the cell type that exchanges oxy- splits (figure 3.17). This difference in timing determines which gen for carbon dioxide. Stem cells from umbilical cords are supportive structures the twins share. About a third of all MZ abundant, easy to obtain and manipulate, and can give rise to twins have completely separate chorions and amnions, and almost any cell type. Two-cell stage Embryos Embryos Embryos Chorion Chorion Chorion Chorion Chorion Chorion Amniotic Chorion sac Amniotic sac Amniotic Amniotic Amniotic sac sac sac Identical twins with separate Identical twins that share an Identical twins that share a chorion amnions and chorions amnion and chorion but have separate amnions (a) (b) (c) Figure 3.17 Types of identical twins. Identical (MZ) twins originate at three points in development. (a) In about one-third of identical twins, separation of cells into two groups occurs before the trophoblast forms on day 5. These twins have separate chorions and amnions. (b) About 1 percent of identical twins share a single amnion and chorion, because the tissue splits into two groups after these structures have already formed. (c) In about two-thirds of identical twins, the split occurs after day 5 but before day 9. These twins share a chorion but have separate amnions. Fraternal (DZ) twins result from two sperm fertilizing two secondary oocytes. These twins develop their own amniotic sacs, yolk sacs, allantois, placentas, and umbilical cords. 54 Part 1 Introduction  Clinical Connection 3.1 When an Arm Is Really a Leg: Homeotic Mutations Flipping the X ray showed Stefan Mundlos, MD, that his hunch was its head. Extra and fused fingers and various bony alterations also correct—the patient’s arms were odd-looking and stiff because stem from homeotic mutations. the elbows were actually knees! The condition, Liebenberg The search for the mutation behind the arm-to-leg syndrome, had been described in 1973 among members of a Liebenberg phenotype began with abnormal chromosomes. five-generation white South African family (figure 3C). Four males Affected members of the three known families were each missing and six females had stiff elbows and wrists and short fingers 134 DNA bases in the same part of the fifth largest chromosome. that looked misplaced. A trait that affects both sexes in every The researchers identified a gene called PITX1 that controls other generation is autosomal dominant inheritance—each child of a genes that oversee limb development. In the Liebenberg families, person with the unusual limbs has a 50:50 chance of having the the missing DNA places an “enhancer” gene near PITX1, altering condition, too. its expression in a way that mixes up developmental signals so that In 2000, a medical journal described a second family the forming arm instead becomes a leg. with Liebenberg syndrome. Several members had restricted movements because they couldn’t bend their misshapen elbows. Then in 2010, a report appeared on identical twin girls with stiff Questions for Discussion elbows and long arms, with fingers that looked like toes. 1. What is the genotype and phenotype of Liebenberg In 2012, Dr. Mundlos noted that the muscles and tendons of syndrome? the elbows, as well as the bones of the arms, weren’t quite right in 2. How can homeotic mutations be seen in such different his patient. The doctor, an expert in the comparative anatomy of species as humans, mice, fruit flies, and flowering limb bones of different animals, realized that the stiff elbows were plants? acting like knees. The human elbow joint hinges and rotates, but 3. Explain the molecular basis of a homeotic mutation and the the knee extends the lower leg straight out. Then an X-ray scan resulting phenotype. of the patient’s arm fell to the floor. He suddenly realized that the 4. Describe a human disease other than Liebenberg syndrome entire limb looked like a leg. that results from a homeotic mutation. Genes that switch body parts are termed homeotic. They are well studied in organisms as evolutionarily diverse as fruit flies, flowering plants, and mice, affecting the positions of larval segments, petals, legs, and much more. Assignment of body parts begins in the early embryo, when cells look alike but are already fated to become specific structures. Gradients (increasing or decreasing concentrations) of “morphogen” proteins in an embryo program a particular region to develop a certain way. Mix up the messages, and an antenna becomes a leg, or an elbow a knee. Homeotic genes include a 180-base-long DNA sequence, called the homeobox, which enables the encoded protein to bind other proteins that turn on sets of other genes, crafting an embryo, section by section. Homeotic genes line up on their chromosomes in the precise order in which they’re deployed in development, like chapters in an instruction manual to build a body. The human genome has four clusters of homeotic genes, and mutations in them cause disease. In certain lymphomas, a homeotic mutation sends white blood cells along the wrong developmental pathway, resulting in too many of some blood cell types and too few of others. The abnormal ears, nose, mouth, Figure 3C The hands of a person with Liebenberg and throat of DiGeorge (22q11.2 deletion) syndrome echo the syndrome resemble feet; arms resemble legs. Photo abnormalities in Antennapedia, a fruit fly mutant that has legs on courtesy of Dr. Malte Spielmann Chapter 3 Meiosis, Development, and Aging 55 about two-thirds share a chorion but have separate amnions. birth Abigail and Brittany were strong and healthy, doctors Slightly fewer than 1 percent of MZ twins share both amnion suggested surgery to separate them. But their parents, aware of and chorion. These differences may expose the different types other cases where only one child survived separation, declined of MZ twins to slightly different uterine environments. For surgery. example, if one chorion develops more attachment sites to the The Hensel twins have learned to work together, from maternal circulation, one twin may receive more nutrients and crawling as babies to biking and driving a car today. As teens, gain more weight than the other. Abigail and Brittany enjoyed kickball, volleyball, and basket- In 1 in 50,000 to 100,000 pregnancies, an embryo divides ball, and developed distinctive tastes in clothing and in food. into twins after the point at which the two groups of cells can They graduated from college and had their own reality TV develop as two individuals, between days 13 and 15. The result series. Today they are elementary school teachers. is conjoined or “Siamese” twins. The latter name comes from MZ twins occur in 3 to 4 pregnancies per 1,000 births Chang and Eng Bunker, who were born in Thailand, then worldwide. In North America, twins occur in about 1 in 81 called Siam, in 1811. They were joined by a band of tissue pregnancies, which means that 1 in 40 of us is a twin. However, from the navel to the breastbone, and could easily have been not all twins survive to be born. One study of twins detected separated today. Chang and Eng lived for 63 years, attached. early in pregnancy showed that up to 70 percent of the eventual They fathered 22 children and divided each week between their births are of a single child. This is called the “vanishing twin” wives. phenomenon. For Abigail and Brittany Hensel, shown in figure 3.18, the separation occurred after day 9 of development, but before The Embryo Develops day 14. Biologists know this because the shared organs have derivatives of ectoderm, mesoderm, and endoderm; that is, As prenatal development proceeds, different rates of cell divi- when the early embryo divided incompletely, the three primary sion in different parts of the embryo fold the forming tissues germ layers had not yet fully sorted themselves out into two into intricate patterns. In a process called embryonic induction, bodies. The Hensels are extremely rare “incomplete twins.” the specialization of one group of cells causes adjacent groups They are “dicephalic,” which means that they have two heads. of cells to specialize. Gradually, these changes mold the three Despite the fact that anatomically they are not as distinct as primary germ layers into organs and organ systems. Organo- Chang and Eng were from each other, the two young women genesis is the transformation of the simple three layers of the are very much individuals. embryo into distinct organs. During these weeks, the embryo Each twin has her own neck, head, heart, stomach, gall- is sensitive to environmental influences, such as exposure to bladder, and lungs. Each has one leg and one arm, and a third toxins and viruses. arm between their heads was surgically removed. Each twin During the third week of prenatal development, a band also has her own nervous system. The twins share a large liver, called the primitive streak appears along the back of the a single bloodstream, a large ribcage and diaphragm muscle, embryo. Some nations designate day 14 of prenatal develop- and all organs below the navel (colon, bladder, pelvis, and ment and primitive streak formation as the point beyond which reproductive organs). They have three kidneys. Because at they ban research on the human embryo. The reasoning is that the primitive streak is the first sign of a nervous system and day 14 is when implantation completes. The primitive streak gradually elongates to form an axis that other structures organize around as they develop. The primitive streak eventually gives rise to connective tissue pro- genitor cells and the notochord, which is a structure that forms the basic framework of the skeleton. The notochord induces a sheet of overlying ectoderm to fold into the hollow neural tube, which develops into the brain and spinal cord (central nervous system). If the neural tube does not completely close by day 28, a neural tube defect (NTD) occurs, in which parts of the brain or spinal cord protrude from the open head or spine, and body parts below the defect cannot move. Surgery can correct some NTDs. Lack of the B vitamin folic acid can cause NTDs in embryos with a genetic susceptibility. For this reason, the U.S. government adds the vitamin to grains, and pregnant women take supplements. A blood test during the fifteenth week of pregnancy detects a substance from the fetus’s liver called Figure 3.18 Conjoined twins. Abigail and Brittany Hensel alpha fetoprotein (AFP) that moves at an abnormally rapid rate are the result of incomplete twinning during the first 2 weeks into the woman’s circulation if there is an open NTD. Using of prenatal development. Courtesy of Brittany and Abigail Hensel hints from more than 200 genes associated with NTDs in other 56 Part 1 Introduction vertebrates, investigators are searching the genome sequences of people with NTDs to identify patterns of gene variants that could contribute to risk for or cause these conditions. Appearance of the neural tube marks the beginning of organ development. Shortly after, a reddish bulge containing the heart appears. The heart begins to beat around day 18, and this is easily detectable by day 22. Soon the central nervous system starts to form. The fourth week of embryonic existence is one of spec- tacularly rapid growth and differentiation (figure 3.19). Arms and legs begin to extend from small buds on the torso. Blood cells form and fill primitive blood vessels. Immature lungs and kidneys begin to develop. By the fifth and sixth weeks, the embryo’s head appears too large for the rest of its body. Limbs end in platelike struc- 28 days 49 days tures with tiny ridges, and gradually apoptosis sculpts the (a) 4 – 6 mm 13–22 mm (b) fingers and toes. The eyes are open, but they do not yet have lids or irises. By the seventh and eighth weeks, a skeleton com- Figure 3.19 Human embryos at (a) 28 days and posed of cartilage forms. The embryo is now about the length (b) 49 days. (a): © Petit Format/Nestle/Photo Researchers/Science Source; (b): © Petit Format/SPL/Photo Researchers/Science Source and weight of a paper clip. At the end of 8 weeks of gestation, the prenatal human has tiny versions of all structures that will be present at birth. It is now a fetus. The Fetus Grows During the fetal period, body proportions approach those of a newborn. Initially, the ears lie low and the eyes are widely spaced. Bone begins to replace the softer cartilage. As nerve and muscle functions become coordinated, the fetus moves. Sex is determined at conception, when a sperm bear- ing an X or Y chromosome meets an oocyte, which always carries an X chromosome. An individual with two X chromo- somes is a female, and one with an X and a Y is a male. A gene on the Y chromosome, called SRY (for “sex-determining region of the Y”), determines maleness. Anatomical differences between the sexes appear at week 6, after the SRY gene is expressed in males. Male hor- mones stimulate male reproductive organs and glands to dif- ferentiate from existing, indifferent structures. In a female, the Figure 3.20 A 16-week fetus. A fetus at this stage has indifferent structures of the early embryo develop as female hair, eyebrows, lashes, and other features that look human. organs and glands, under the control of other genes. Differ- © Nestle/Petit Format/Science Source ences may be noticeable on ultrasound scans by 12 to 15 weeks. Chapter 6 discusses sexual development further. By week 12, the fetus sucks its thumb, kicks, makes fists In the final trimester, fetal brain cells rapidly link into and faces, and has the beginnings of teeth. It breathes amniotic networks as organs elaborate and grow. A layer of fat forms fluid in and out, and urinates and defecates into it. The first beneath the skin. The digestive and respiratory systems mature trimester (3 months) of pregnancy ends. last, which is why infants born prematurely often have diffi- By the fourth month, the fetus has hair, eyebrows, lashes, culty digesting milk and breathing. Approximately 266 days nipples, and nails (figure 3.20). By 18 weeks, the vocal cords after a single sperm burrowed its way into an oocyte, a baby is have formed, but the fetus makes no sound because it doesn’t ready to be born. breathe air. By the end of the fifth month, the fetus curls into The birth of a healthy baby is against the odds. Of every a head-to-knees position. It weighs about 454 grams (1 pound). 100 secondary oocytes exposed to sperm, 84 are fertilized. Of During the sixth month, the skin appears wrinkled because these 84, only 69 implant in the uterus, 42 survive 1 week or there isn’t much fat beneath it, and turns pink as capillaries fill longer, 37 survive 6 weeks or longer, and 31 are born alive. Of with blood. By the end of the second trimester, the fetus kicks the fertilized ova that do not survive, about half have chromo- and jabs and may even hiccup. It is now about 23 centimeters somal abnormalities that cause problems too severe for devel- (9 inches) long. opment to proceed. Chapter 3 Meiosis, Development, and Aging 57  Some birth defects are caused by a mutation that acts at a Key Concepts Questions 3.4 specific point in prenatal development. In a rare inherited con- dition called phocomelia, for example, a mutation halts limb 1. Describe the events of fertilization. development from the third to the fifth week of the embryonic 2. Distinguish among the zygote, morula, and blastocyst. period, severely stunting arms and legs. The risk that a geneti- 3. What happens to the inner cell mass? cally caused birth defect will affect a particular family member 4. Explain how some genes are silenced as development can be calculated. proceeds. Many birth defects are caused by toxic substances the 5. Explain the significance of the formation of primary pregnant woman encounters. These environmentally caused germ layers. problems will not affect other family members unless they, too, 6. Describe the supportive structures that enable an are exposed to the environmental trigger. Chemicals or other embryo to develop. agents that cause birth defects are called teratogens (Greek for 7. Explain how twins arise. “monster-causing”). While it is best to avoid teratogens while 8. Distinguish the embryo from the fetus. pregnant, some women may need to continue to take poten- tially teratogenic drugs to maintain their own health. 9. List the events of the embryonic and fetal periods. Teratogens Most drugs are not teratogens. Whether or not exposure to a particular drug causes birth defects may depend upon a wom- an’s genes. For example, certain variants of a gene that con- 3.5 Birth Defects trol the body’s use of an amino acid called homocysteine affect whether or not the medication valproic acid causes birth defects. Certain genetic abnormalities or toxic exposures can affect Valproic acid is used to prevent seizures and symptoms of bipo- development in an embryo or fetus, causing birth defects. Only lar disorder. Rarely, it can cause NTDs, heart defects, hernias, a genetic birth defect can be passed to future generations. and clubfoot. Women who have this gene variant (MTHFR Although development can be abnormal in many ways, 97 per- C677T) can use a different drug to treat seizures or bipolar dis- cent of newborns appear healthy at birth. order when they try to conceive. The Critical Period When physical The specific nature of a birth defect structures develop reflects the structures developing when Reproductive system the damage occurs. The time when genetic abnormalities, toxic substances, Ears or viruses can alter a specific structure Eyes is its critical period (figure 3.21). Some body parts, such as fingers and toes, are Arms and legs sensitive for short periods of time. In Heart contrast, the brain is sensitive through- Central nervous system out prenatal development, and connec- tions between nerve cells continue to Sensitivity to change throughout life. Because of the teratogens during pregnancy brain’s continuous critical period, many birth defect syndromes include learning Thalidomide disabilities or intellectual disability. About two-thirds of all birth Accutane defects arise from a disruption dur- Diethylstilbestrol ing the embryonic period. More subtle defects, such as learning disabilities, 0 1 2 3 4 5 6 7 8 9 that become noticeable only after Month infancy, are often caused by interven- Figure 3.21 Critical periods of development. The nature of a birth defect resulting tions during the fetal period. A disrup- from drug exposure depends upon which structures were developing at the time of tion in the first trimester might cause exposure. Isotretinoin (Accutane) is an acne medication that causes cleft palate and severe intellectual disability; in the eye, brain, and heart defects. Diethylstilbestrol (DES) was used in the 1950s to prevent seventh month of pregnancy, it might miscarriage. It caused vaginal cancer in some “DES daughters.” Thalidomide was used to cause difficulty in learning to read. prevent morning sickness. 58 Part 1 Introduction Thalidomide before and after birth. Teens and young adults are short and have small heads. More than 80 percent of them retain the The idea that the placenta protects the embryo and fetus was facial characteristics of a young child with FAS. tragically disproven between 1957 and 1961, when 10,000 The long-term cognitive effects of prenatal alcohol expo- children were born in Europe with what seemed, at first, to be sure are more severe than the physical vestiges. Intellectual phocomelia. This genetic disease is rare, and therefore couldn’t impairment ranges from minor learning disabilities to intellec- be the cause of the sudden problem. Instead, the mothers had tual disability. Many adults with FAS function at early grade- all taken a mild tranquilizer, thalidomide, to alleviate nausea school level. They never develop social and communication early in pregnancy, during the critical period for limb forma- skills and cannot understand the consequences of actions, form tion. Many “thalidomide babies” were born with incomplete or friendships, take initiative, and interpret social cues. A person missing legs and arms. with FAS may have the cognitive symptoms without the facial The United States was spared from the thalidomide characteristics, so considering alcohol consumption is impor- disaster because an astute government physician noted the tant for diagnosis. drug’s adverse effects on laboratory monkeys. Still, several Greek philosopher Aristotle noticed problems in chil- “thalidomide babies” were born in South America in 1994, dren of women with alcoholism more than 23 centuries ago. In where pregnant women were given the drug. In spite of its tera- the United States today, 1 to 3 of every 1,000 infants has FAS, togenic effects, thalidomide is used to treat leprosy, AIDS, and meaning 2,000 to 6,000 affected children are born each year. certain blood and bone marrow cancers. Many more children have milder “alcohol-related effects.” A fetus of a woman with active alcoholism has a 30 to 45 percent Alcohol chance of harm from alcohol exposure. A pregnant woman who has just one or two alcoholic drinks a day, or perhaps a large amount at a single crucial time, risks a Nutrients fetal alcohol spectrum disorder in her unborn child. An analy- Certain nutrients ingested in large amounts, particularly vita- sis of 1,728 people with these disorders showed that more than mins, act as drugs. The acne medicine isotretinoin (Accutane) 90 percent have behavior problems, 80 percent have commu- is a vitamin A derivative that causes spontaneous abortion nication challenges, 70 percent have abnormal cognition, and and defects of the heart, nervous system, and face in exposed about 50 percent have hyperactivity and short attention span. embryos. Another vitamin A–based drug, used to treat pso- People with fetal alcohol spectrum disorders are also more riasis, as well as excesses of vitamin A itself, also cause birth likely to have hearing and/or visual loss. defects. Vitamin A and its derivatives may accumulate enough Tests for variants of genes that encode proteins that regu- to harm embryos because they are stored in body fat for up to late alcohol metabolism may be able to identify women whose 3 years. fetuses are at elevated risk for developing fetal alcohol spec- Excess vitamin C can harm a fetus that becomes accus- trum disorders. Until these tests are validated, pregnant women tomed to the large amounts the woman takes. After birth, are advised to avoid all alcoholic beverages. when the vitamin supply suddenly plummets, the baby may The most severe manifestation of alcohol exposure before develop symptoms of vitamin C deficiency, such as bruising birth is fetal alcohol syndrome (FAS). Most children with FAS and becoming infected easily. have small heads and flat faces (figure 3.22). Growth is slow Malnutrition threatens a fetus. The opening essay to chapter 11 describes the effects of starvation on embryos during the bleak “Dutch Hunger Winter” of 1944–1945. Poor nutrition later in pregnancy affects the development of the placenta and Small head circumference can cause low birth weight, short stature, tooth decay, delayed sexual development, and learning disabilities. Low nasal bridge Eye folds Viral Infection Viruses are small enough to cross the placenta and reach a Short nose fetus. Some viruses that cause mild symptoms in an adult, such as the chickenpox virus, may devastate a fetus. Men can trans- Small midface mit viral infections to an embryo or fetus during sexual inter- Thin upper lip course. Zika virus, for example, is carried in semen. This virus Hagen was discovered in Uganda in 1947, but came to the world’s attention in 2015, after it was associated with a dramatic increase in the incidence of the birth defect microcephaly in Figure 3.22 Fetal alcohol syndrome. Some children Brazil (figure 3.23). About 11 percent of women exposed to whose mothers drank alcohol during pregnancy have the virus during the first trimester of pregnancy have a child characteristic flat faces. with microcephaly or another brain abnormality, whether or Chapter 3 Meiosis, Development, and Aging 59  Typical head size Baby with microcephaly Baby with typical head size Figure 3.23 Zika virus causes birth defects. Exposure of a fetus to Zika virus can cause an abnormally small brain (microcephaly) that has scattered calcifications, inflammation, and no characteristic infoldings. not the women had symptoms of viral infection. Mosquitoes spread Zika virus, which causes a mild illness of fever, rash, 3.6 Maturation and Aging joint pain, and red eyes in some adults. “Aging” means moving through the life cycle, despite adver- HIV can reach a fetus through the placenta or infect a tisements for products that promise to reverse the process. newborn via blood contact during birth. The risk of transmis- As we age, the limited life spans of cells are reflected in the sion is significantly reduced if a pregnant woman takes anti- waxing and waning of biological structures and functions. HIV drugs. Fetuses of HIV-infected women are at higher risk Although some aspects of our anatomy and physiology peak for low birth weight, prematurity, and stillbirth if the woman’s very early—such as the number of brain cells or hearing acuity, health is failing. which do so in childhood—age 30 seems to be a turning point German measles (rubella) is a well-known viral terato- for decline. Some researchers estimate that, after this age, gen. In the United States, in the early 1960s, an epidemic of the human body becomes functionally less efficient by about the usually mild illness caused 20,000 birth defects and 30,000 0.8 percent each year. stillbirths. Exposure during the first trimester of pregnancy Can we slow aging? In the quest to extend life, people caused cataracts, deafness, and heart defects. Exposure dur- have sampled everything from turtle soup to owl meat to ing the second or third trimester of pregnancy caused learning human blood. More recently, attention has turned to a com- disabilities, speech and hearing problems, and type 1 diabetes ponent of red wine, dark chocolate, and raspberries called res- mellitus. Incidence of these problems, called congenital rubella veratrol. It is a type of enzyme called a sirtuin that regulates syndrome, has dropped markedly since vaccination eliminated energy use in cells by altering the expression of certain sets the disease in the United States. Similar problems may emerge of genes. Through their effect on energy metabolism, the sir- among children exposed to Zika virus in the uterus as they near tuins seem to prevent or delay several diseases that are more school age. common in the aged, such as heart disease and neurodegenera- tive conditions. Levels of sirtuins are lower in brain cells from people who have died of Alzheimer disease. However, clinical trials testing synthetic sirtuins in dosages up to the equivalent Key Concepts Questions 3.5 of a thousand bottles of red wine drunk at once indicate safety, 1. What is the critical period? but had no effect on Alzheimer disease progression. Many diseases that begin in adulthood, or are associ- 2. Explain why most birth defects that develop during the ated with aging, have genetic components. These diseases tend embryonic period are more severe than problems that arise during fetal development. to be multifactorial, because it takes many years for environ- mental exposures to alter gene expression in ways that notice- 3. Define teratogen and give an example of one. ably affect health. Following is a closer look at how genes may impact health throughout life. 60 Part 1 Introduction  contain structures called neurofibrillary tangles, which con- Adult-Onset Inherited Diseases sist of a protein called tau. Tau binds to and disrupts microtu- Human prenatal development is a highly regulated program of bules in nerve cell branches, destroying the shape of the cell, genetic switches that are turned on in specific body parts at spe- impairing its ability to communicate. Clinical Connection 5.1 cific times. Environmental factors can affect how certain genes discusses Alzheimer disease further. are expressed before birth in ways that create risks that appear much later. For example, adaptations that enable a fetus to grow despite near-starvation become risk factors for certain common Disorders That Resemble Accelerated Aging conditions of adulthood, when conserving calories is no longer Genes control aging both passively (as structures break down) needed. Such diseases include coronary artery disease, obesity, and actively (by initiating new activities). A group of “prema- stroke, hypertension, schizophrenia, and type 2 diabetes mel- ture aging” inherited disorders is rare, but may hold clues to litus. A malnourished fetus has intrauterine growth retardation how genes control aging in all of us, as discussed in the chapter (IUGR), and though born on time, is quite small. Premature opener. infants, in contrast, are small but are born early, and are not Disorders that accelerate aging and shorten life, or that predisposed to conditions resulting from IUGR. make a person appear older than they are but do not affect More than 100 studies correlate low birth weight due to lifespan, are termed progeroid. The most severe such disorders IUGR with increased incidence of cardiovascular disease and are the progerias, which shorten life span. Most accelerated diabetes later in life. Much of the data come from war records aging conditions are caused by the inability of cells to ade- because enough time has elapsed to study the effects of prena- quately repair DNA, which is discussed in section 12.7. With tal malnutrition as people age. The introduction to chapter 11 poor DNA repair, mutations that would ordinarily be corrected describes how prenatal nutrient deficiency may set the stage for persist. Over time, the accumulation of mutations destabilizes later schizophrenia. the entire genomes of somatic cells, and more mutations occur. How can poor nutrition before birth cause disease Changes associated with aging ensue. decades later? Perhaps to survive, the starving fetus redirects Table 3.4 lists the more common progeroid syndromes. its circulation to protect vital organs, as muscle mass and hor- They vary in severity. People with Rothmund-Thomson syn- mone production change to conserve energy. Growth-retarded drome, for example, may have a normal life span, but develop babies have too little muscle tissue, and because muscle is the gray hair or baldness, cataracts, cancers, and osteoporosis at a primary site of insulin action, glucose metabolism changes. young age. Werner syndrome becomes apparent before age 20, Thinness at birth, and the accelerated weight gain in childhood causing death before age 50 from diseases associated with that often compensates, increases risk for coronary heart dis- aging. Young adults with Werner syndrome develop atheroscle- ease and type 2 dia