STEM CELLS
I. Introduction: What are stem cells and why are they important?
Stem cells have the remarkable potential to develop into many different cell types in the body during
early life and growth. In addition, in many tissues they serve as a sort of internal repair system, dividing
essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem
cell divides, each new cell has the potential either to remain a stem cell or become another type of cell
with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell.
Stem cells are distinguished from other cell types by two important characteristics. First, they are
unspecialized cells capable of renewing themselves through cell division, sometimes after long periods of
inactivity. Second, under certain physiologic or experimental conditions, they can be induced to become
tissue- or organ-specific cells with special functions. In some organs, such as the gut and bone marrow,
stem cells regularly divide to repair and replace worn out or damaged tissues. In other organs, however,
such as the pancreas and the heart, stem cells only divide under special conditions.
Until recently, scientists primarily worked with two kinds of stem cells from animals and humans:
embryonic stem cells and non-embryonic "somatic" or "adult" stem cells. The functions and
characteristics of these cells will be explained in this document. Scientists discovered ways to derive
embryonic stem cells from early mouse embryos nearly 30 years ago, in 1981. The detailed study of the
biology of mouse stem cells led to the discovery, in 1998, of a method to derive stem cells from human
embryos and grow the cells in the laboratory. These cells are called human embryonic stem cells. The
embryos used in these studies were created for reproductive purposes through in vitro fertilization
procedures. When they were no longer needed for that purpose, they were donated for research with the
informed consent of the donor. In 2006, researchers made another breakthrough by identifying conditions
that would allow some specialized adult cells to be "reprogrammed" genetically to assume a stem cell-like
state. This new type of stem cell, called induced pluripotent stem cells (iPSCs), will be discussed in a
later section of this document.
Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a
blastocyst, the inner cells give rise to the entire body of the organism, including all of the many
specialized cell types and organs such as the heart, lung, skin, sperm, eggs and other tissues. In some
adult tissues, such as bone marrow, muscle, and brain, discrete populations of adult stem cells generate
replacements for cells that are lost through normal wear and tear, injury, or disease.
Given their unique regenerative abilities, stem cells offer new potentials for treating diseases such as
diabetes, and heart disease. However, much work remains to be done in the laboratory and the clinic to
understand how to use these cells for cell-based therapies to treat disease, which is also referred to as
regenerative or reparative medicine.
Laboratory studies of stem cells enable scientists to learn about the cells’ essential properties and what
makes them different from specialized cell types. Scientists are already using stem cells in the laboratory
to screen new drugs and to develop model systems to study normal growth and identify the causes of birth
defects.
Research on stem cells continues to advance knowledge about how an organism develops from a single
cell and how healthy cells replace damaged cells in adult organisms. Stem cell research is one of the most
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fascinating areas of contemporary biology, but, as with many expanding fields of scientific inquiry,
research on stem cells raises scientific questions as rapidly as it generates new discoveries.
II. What are the unique properties of all stem cells?
Stem cells differ from other kinds of cells in the body. All stem cells—regardless of their source—have
three general properties: they are capable of dividing and renewing themselves for long periods; they are
unspecialized; and they can give rise to specialized cell types.
Stem cells are capable of dividing and renewing themselves for long periods. Unlike muscle cells, blood
cells, or nerve cells—which do not normally replicate themselves—stem cells may replicate many times,
or proliferate. A starting population of stem cells that proliferates for many months in the laboratory can
yield millions of cells. If the resulting cells continue to be unspecialized, like the parent stem cells, the
cells are said to be capable of long-term self-renewal.
Stem cells are unspecialized. One of the fundamental properties of a stem cell is that it does not have any
tissue-specific structures that allow it to perform specialized functions. For example, a stem cell cannot
work with its neighbors to pump blood through the body (like a heart muscle cell), and it cannot carry
oxygen molecules through the bloodstream (like a red blood cell). However, unspecialized stem cells can
give rise to specialized cells, including heart muscle cells, blood cells, or nerve cells.
Stem cells can give rise to specialized cells. When unspecialized stem cells give rise to specialized cells,
the process is called differentiation. While differentiating, the cell usually goes through several stages,
becoming more specialized at each step. Scientists are just beginning to understand the signals inside and
outside cells that trigger each stem of the differentiation process. The internal signals are controlled by a
cell's genes, which are interspersed across long strands of DNA, and carry coded instructions for all
cellular structures and functions. The external signals for cell differentiation include chemicals secreted
by other cells, physical contact with neighboring cells, and certain molecules in the microenvironment.
III. What are adult stem cells?
An adult stem cell is thought to be an undifferentiated cell, found among differentiated cells in a tissue
or organ that can renew itself and ca n differentiate to yield some or all of the major specialized cell types
of the tissue or organ.
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Hematopoietic stem cells give rise to all
the types of blood cells: red blood cells,
B lymphocytes, T lymphocytes, natural
killer cells, neutrophils, basophils,
eosinophils, monocytes, and
macrophages.
Mesenchymal stem cells give rise to a
variety of cell types: bone cells
(osteocytes), cartilage cells
(chondrocytes), fat cells (adipocytes),
and other kinds of connective tissue
cells such as those in tendons.
Neural stem cells in the brain give rise
to its nerve cells (neurons)
Skin stem cells occur in the basal layer
of the epidermis and at the base of hair
follicles. The epidermal stem cells give
rise to keratinocytes, which migrate to
the surface of the skin and form a
protective layer. The follicular stem
cells can give rise to both the hair
follicle and to the epidermis.
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IV. What are embryonic stem cells?
Embryonic stem cells, as their name suggests, are derived from embryos. Most embryonic stem cells are
derived from embryos that develop from eggs that have been fertilized in vitro—in an in vitro
fertilization clinic—and then donated for research purposes with informed consent of the donors. They
are not derived from eggs fertilized in a woman's body.
V. What are the similarities and differences between embryonic and adult stem cells?
One major difference between adult and embryonic stem cells is their different abilities in the number and
type of differentiated cell types they can become. Embryonic stem cells can become all cell types of the
body because they are pluripotent. Adult stem cells are thought to be limited to differentiating into
different cell types of their tissue of origin.
Embryonic stem cells can be grown relatively easily in culture. Adult stem cells are rare in mature tissues,
so isolating these cells from an adult tissue is challenging, and methods to expand their numbers in cell
culture have not yet been worked out. This is an important distinction, as large numbers of cells are
needed for stem cell replacement therapies.
Scientists believe that tissues derived from embryonic and adult stem cells may differ in the likelihood of
being rejected after transplantation. We don't yet know whether tissues derived from embryonic stem cells
would cause transplant rejection, because testing has only just recently been approved by the FDA.
Adult stem cells, and tissues derived from them, are currently believed less likely to initiate rejection after
transplantation. This is because a patient's own cells could be expanded in culture, coaxed into assuming a
specific cell type (differentiation), and then reintroduced into the patient. The use of adult stem cells and
tissues derived from the patient's own adult stem cells would mean that the cells are less likely to be
rejected by the immune system. This represents a significant advantage, as immune rejection can be
circumvented only by continuous administration of immunosuppressive drugs, and the drugs themselves
may cause deleterious side effects
VI. What are induced pluripotent stem cells?
Induced pluripotent stem cells (iPSCs) are adult cells that have been genetically reprogrammed to an
embryonic stem cell–like state by being forced to express genes and factors important for maintaining the
defining properties of embryonic stem cells. Although these cells meet the defining criteria for pluripotent
stem cells, it is not known if iPSCs and embryonic stem cells differ in clinically significant ways. Mouse
iPSCs were first reported in 2006, and human iPSCs were first reported in late 2007.
Viruses are currently used to introduce the reprogramming factors into adult cells, and this process must
be carefully controlled and tested before the technique can lead to useful treatments for humans. In animal
studies, the virus used to introduce the stem cell factors sometimes causes cancers. Researchers are
currently investigating non-viral delivery strategies. In any case, this breakthrough discovery has created
a powerful new way to "de-differentiate" cells whose developmental fates had been previously assumed
to be determined.
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Gamete Formation
Primordial germ cells
Mature male and female germ cells are direct descendants of primordial germ cells, which in human
embryos appear in the wall of the yolk sac at the end of the 3rd week of development. These cells will
develop in the developing gonads (primitive sex glands) where they arrive at the end of the 4th week.
Oogenesis
Once primordial germ cells have arrived at the developing gonads of female embryo, they will
differentiate into oogonia (Figure 1.8 A and B). These cells undergo mitotic divisions and by the end of
the 3rd month, become arranged in clusters, surrounded by a layer of flat epithelial cells (Fig 1.9A). Some
oogonia will differentiate in primary oocytes (which will go directly into the process of Meiosis I). During
the next few months the number rapidly increases up to the 5th month which you hit the maximum
number of about 7 million germ cells. At this time cell death occurs. By the 7th month the majority of
oogonia have died and only those closest to the surface of the ovary have survived. The primary oocyte,
together with its surrounding flat epithelial cells is known as a primordial follicle.
Postnatal Maturation
Near birth, all primary oocytes have started prophase but will stop there. They enter a resting
stage known as the diplotene stage. At birth there are between 700,000 and 2 million oocytes which
continue to die until puberty. Around 400,000 remain at that point, only 500 will be ovulated though in
a lifetime.
Realize that some primary oocytes will stay in the diplotene stage for almost 40 years, which
makes scientists assume that this is a necessary rest in the evolution of human species. But, it is also
known that the later in life a woman gives birth there is a increased risk of having a child with a
chromosomal disorder. If this is the case, it suggests that the oocyte is at risk for damage during the
diplotene stage
With the onset of puberty 5-15 primordial follicles begin to mature with each ovarian cycle. The
primary oocyte begins to increase in size while the epithelial cells changes from flat to cuboidal. The
primordial follicle is now called the primary follicle. The oocyte will secrete a layer of protein that will
cover the outside of the oocyte (not the follicle)…it is known as the zona pellucia. (Fig 1.11). The follicle
begins to grow in size and fill with fluid in a space called the Antrum. It is now considered to be a
secondary follicle. The final stage of follicle development is when the size reaches approx 10 mm in
diameter (Tertiary or Graafian follicle)
With each ovarian cycle a number develop but only one reaches full maturity. The other
degenerate. As soon as the follicle is mature, the primary oocyte resumes its 1st meiotic division leading
to the formation of the secondary oocyte and one polar body. The much smaller polar body is necessary
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for the removal of DNA during the process of Meiosis. It is imperative that the final products of meiosis
are in a haploid state, therefore, the extra copies of the DNA that were created in the process of meiosis
can be removed with the formation of a polar body. The majority of the cytoplasm from the primary
oocyte stays within the secondary oocyte. This creates the major size difference between the secondary
oocyte and the polar body.
At the completion of the first division, but before the nucleus of the secondary oocyte has returned to
the uncoiled (chromatin) state, the cell enters the second round of division. The moment the secondary
oocyte shows spindle formation with chromosomes aligned on the metaphase plate, ovulation occurs,
and the oocyte is shed from the ovary. Anaphase will only continue IF the oocyte is fertilized by a
sperm. If an oocyte is not fertilized the cell will degenerate approximately 24 hours after ovulation.
Whether or not the 1st polar body will continue into the second division is uncertain, but fertilized eggs
accompanied by three polar bodies have been observed.
Spermatogenesis
Includes all of the events by which spermatogonia are transformed into spermatozoa. In the male,
differentiation of primordial germ cells begins at puberty as compared to females when it begins in
utero.
In males, at puberty the primordial germ cells give rize to spermatogonia: which consist of two types:
Type A and Type B. Type A will divide by mitosis to provide a continuous reserve of stem cells, while
Type B will give rise to primary spermatocytes. In progression, some type A cells leave the stem cell
population and give rise to successive gernatiosn of spermatogonia.
Type B spermatogonia subsequently undergo mitosis to give rise to primary spermatocytes. Primary
spermatocytes then enter a prolonged prophase (22 days) followed by a rapid completion of Meiosis I
and formation of the secondary spermatocytes. These cells begin immediately to form spermatids
during the 2nd meiotic division.
Spermiogenesis – the series of changes resulting in the transformation of spermatids into spermatozoa.
These changes include:
A.)
B.)
C.)
D.)
Formation of the acrosome
Condensation of the nucleus
Formation of the neck, middle piece, and tail
Shedding of most of the cytoplasm
The time it takes to complete this process is 64 days.
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When fully formed the spermatozoa enter the lumen of the seminiferous tubules. From there, they are
pushed toward the epididymis by contractile motions in the tubules. Full motility of a sperm does not
occur until the epididymis.
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Ovulation to Implantation
Ovarian Cycle – At puberty, the female begins to undergo regular monthly cycles. These cycles are
controlled by the hypothalamus. Gonadotropin-releasing hormone (GnRH) produced by the
hypothalamus acts on cells in the pituitary gland which in turn release gonadotropins. These hormones,
follicle stimulating hormone (FSH) and luteinizing hormone (LH) stimulate and control cyclic changes in
the ovary.
Ovulation
In the days immediately preceding ovulation, the graafian follicle increase rapidly in size under the
influence of the FSH and LH and expands to a diameter of 15 mm. Coinciding with this change, the
primary oocyte which has remained in the diplotene stage resumes meiosis I. In the meantime, the
surface of the ovary beings to bulge. As a result of local weakening and degeneration of the ovarian
surface, increasing intrafollicular pressure, and muscular contraction in the ovarian wall, the oocyte is
extruded. The oocyte is still surrounded by the zona pellucida and other supporting cells. At the moment
the oocyte is discharged, the 1st meiotic division is complete and the secondary oozyte has started its 2nd
meiotic division.
Following ovulation, the cells that bordered the graafian follicle (which is now ruptured) become
vascularized by surrounded vessels. LH will influence these cells to change to a yellowish pigment and to
produced a hormone known as progesterone. This hormone, together with estrogen causes the uterine
mucosa to enter the secretory stage in preparation for implantation of the embryo. (Known as the
corpus luteum)
If fertilization does not occur, the maximum development of these cells will occur about 9 days after
ovulation. Subsequently the corpus luteum decreases in size through degeneration of luteal cells and
forms a mass of scar tissue known as the corpus albicans. Simultaneous progesterone production
decreases, thus precipitating menstrual bleeding.
Oocyte transport.
Shortly before ovulation, fimbriae (finger like projections) of the oviduct cover the surface of the ovary.
Once the oocyte is released the contractions of the muscular wall cause the oocyte to travel up the
uterine tube. The rate of transport is about 3 – 4 days.
Corpus Albicans
If fertilization fails to occur, the corpus luteum reaches maximum development about 9 days after
ovulation. It can be recognized as a yellowish projection on the surface of the ovary. Subsequently, the
corpus luteum decreases in size through degeneration of luteal cells and forms a mass of fibrotic scar
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tissue, known as the corpus albicans. Simultaneously, progesterone production decreases, thus causing
menstrual bleeding.
If fertilization occurs, the degeneration of the corpus luteum is prevented by hCG (a hormone secreted
by the trophoblast of the developing embryo). The corpus luteum continues to grow and form the
corpus luteum of pregnancy.
Fertilization
Fertilization, the process by which male and female gametes fuse, occurs in the ampullary regions of the
uterine tube. This is the widest part of the tube and is located close to the ovary. Spermatozoa and the
oocyte can remain viable in the uterine tube for approximately 24 hours.
Spermatozoa can move rapidly from the vagina into the uterus and subsequently into the uterine tube.
This is caused by the contractions of the muscles in the uterus and the tube. Be aware that the sperm
deposited in the uterine tube CAN NOT fertilize the egg as is! In order to be a viable sperm, it must
under two reactions: a.) capacitation and b.) the acrosome reaction
Capacitation is the preparation period in the female reproductive tract. This process can take up to
seven hours to complete. During this time, a layer of glycoprotein and several proteins are removed
from the plasma membrane that covers the acrosomal region on the spermatozoa. Only capacitated
sperm are able to penetrate the corona cells and under the acrosome reaction.
The acrosome reaction occurs after binding to the zona pellucida. This reaction ends with the release of
special enzymes necessary to penetrate the zona pellucid. The phases of fertilization include:
penetration of the corona radiata, penetration of the zona pellucida, and fusion of the oocyte and the
sperm cell membranes
Phase 1: Penetration of the cornona radiata
Of the 200-300 million spermatozoa that are deposited into the female genital tract, only 300-500 reach
the site of fertilization. (Apparently several of them got lost along the way and did not have the ability to
ask for directions…typical man!) Only one sperm is obviously necessary to fertilize the egg. It is thought
that the others aid in the fertilizing sperm in penetrating the barriers of the female gamete. They kind of
act as the wing men for the sperm.
Phase 2: Penetration of the Zona Pellucida
The zona pellucida has a glycoprotein shell surrounding the egg that will help in the binding of the sperm
to the egg. It is also responsible for the acrosome reaction (which is a necessary process for the sperm to
become viable) Release of the acrosomal enzymes allows sperm to pass through the zona, thereby
allowing contact of the sperm and the plasma membrane of the oocyte. Once a sperm has entered the
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area beyond the zona pellucida, a chemical reaction will take place on the zona pellucida’s surface which
will prevent any more sperm from entering.
Phase 3: Fusion of the oocyte and sperm cell membranes
As soon as the spermatozoa comes in contact with the oocyte cell membrane, the two plasma
membranes will fuse. Since the plasma membrane that was covering the tip of the sperm was removed
in the process of capacitation, the plasma membrane of the oocyte will fuse with the cell membrane on
the posterior side of the sperm.
Once the spermatozoa has entered the oocyte, the egg responds in three different ways:
1. Zona Reactions: the chemical alteration of the zona pellucida will prevents the entering of
any more spermatozoa
2. Resumption of the 2nd meiotic division: Recall that the oocyte was released from the follicle
in the middle of metaphase II of meiosis. It stayed in that phase and would only continue IF
the sperm were present. The final nucleus that is formed is known as the female pronucleus
3. Activation of the egg: It is hypothesized that the factor that activates the egg is actually
carried in the sperm.
The spermatozoan, meanwhile, moves forward until it lies in close proximity to the female pronucleus.
Its own nucleus will become swollen and forms the male pronucleus while the tail detaches and then
degenerates. By their looks, the male and female pronucleus are indistinguishable from one another.
Eventually the two pronuclei will come in close contact and lose their nuclear membranes. During the
process of growth in the male and female pronuclei, the DNA must replicate. Once the pronuclei fuse
they will immediately enter into mitosis. They need to have their DNA replicated at that point or the first
two cells would not be a diploid cell.
Cleavage
Once the zygote has reached the two-cell stage, it undergoes a series of mitotic divisions, resulting in an
increase in cell number. Normally the cells will have a chance to go through interphase, allowing growth
of the cell. Initial cells do not enter the Gap phases, therefore the cells become smaller and smaller with
each division. These cells are known as blastomeres, and until the eight-cell stage form a loosely
arranged clump. However after the 3rd cell division, blastomeres will maximize their contact with each
other, forming a compact ball of cells held together by their adjacent cell membranes. About three days
after fertilization cells of the compacted embryo divide again to form a 16-cell morula. Inner cells of the
morula are known as the inner cell mass, while surrounding cells compose the outer cell mass. The inner
cell mass will eventually give rise to the developing embryo while the outer cell mass (trophoblast) will
contribute to the formation of the placenta.
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Blastocyst Formation
About the time the morula enters the utuerine cavity, fluid begins to penetrate through the zona
pellucid into the intercellular spaces of the inner cell mass. At this time the embryo is known as a
blastocyst. Cells of the inner cell mass, no referred to as the embryoblast, are located on one pole, while
those of the outer cell mass, or trophoblast, flatten and form the epithelial wall of the blastocyst. The
zona pellucia has now disappeared, allowing implantation to being.
In the human, trophoblastic cells over the embryoblast pole being to penetrate between the epithelial
cells of the uterine mucosa at about the 6th day.
Uterus at Time of implantation
The wall of the uterus consists of three layers: (a). endometrium or mucosa lining of the inside wall, (b)
mymeterium, a thick layer of smooth muscle; and (c) perimetrium, the peritoneal covering lining the
outside wall. From puberty until menopause, the endometrium undergoes cyclical changes that occur
approximately every 28 days and are under hormonal control by the ovary. During the menstrual cycle,
the uterine endometrium passes through three stages, which consist of follicular or proliferative phase,
the secretory or pregestational phase, and the menstrual phase.
The proliferative phase begins at the end of the menstrual phase, is under the influence of
estrogen, and parallels growth of the ovarian follicles. The secretory phase begins approximately 2-3
days after ovulation in response to progesterone produced by the corpus luteum. If fertilization does not
take place, the shedding of the endometrium (compact and spongy layers) begins, marking the initiation
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of the menstrual phase. If fertilization does occur, then the endometrium assists in the implantation and
contributes to the formation of the placenta. When the menstrual phase begins, blood escapes from the
outermost arteries and small pieces of stroma and glands break away. During the following 3 or 4 days,
the compact and spongy layers are expelled from the uterus and the basal layer is the only part that is
retained. This layer is supplied by its own arteries, the basal arteries, and functions as the regenerative
layer in the rebuilding of glands and arteries in the proliferative phase.
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
Caudal (Latin - cauda, tail): of, at, or near the tail or the posterior end of the body. In the
human case, towards the bottom of the feet (also the "tail" of the spinal cord, and body).
Second Week of Development
8th Day of Development
At the 8th day of development, the blastocyst is partially embedded in the endometrial stroma. In the
area over the embryoblast, the trophoblast has differentiated into two layers (a). an inner layer of single
nucleated cells and (b.) and outer multinucleated zone without distinct cell boundaries
The cells of inner cell mass also differentiate into two layers: (a.) – a layer small cuboidal cells known as
the hypoblast layer and (b) – a layer of high columnar cells known as the epiblast layer. The two layers of
cells together are known as the bilaminar germ disc.
As the epiblast and hypoblast are forming there, are two spaces developing within the trophoblast
membrane. The area between the epiblast and the trophoblast is the amniotic cavity, while the area
between the trophoblast and the hypoblast is called the exocoelomic cavity (or the primitive yolk sac).
Initially the amniotic cavity is found in one distinct area, but as the embryo develops the amniotic area
will grow and surround the entire embryo, creating a cavity that fills with fluid. Early on, this fluid,
amniotic fluid, is derived from the filtered portion of the maternal blood, but later, the fetus contributes
by excreting urine that adds to the fluid. This fluid serves as a shock absorber, regulates fetal body
temperature, prevents drying out, and prevents adhesion between fetal skin and the surrounding
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tissues. During development, fetal skin cells will be slough off, the can be collected and examined via
amniocentesis. Just before birth, the amniotic cavity will rupture causing a woman’s “water to break. ”
The primitive yolk sac is small, shrunken and empty since the embryo gets its nutrients from the mother.
But, it is necessary in early development because the placenta does not form immediately; therefore
some nutrients are needed to be transported.
9th day of development
The blastocyst is deeply embedded in the endometrium, and the hole in the surface lining due to the
implantation is closed with fibrin coagulum. The multinucleated trophoblast layer becomes larger and
begins to be filled with vacuoles
11th – 12th day
The trophoblast starts to erode the maternal arteries which cause blood to fill into the vacuole spaces
within the trophoblast. This flow begins the establishment of the uteroplacental circulation.
13th day
The surface defect in the endometrium has usually healed. Occasionally bleeding may occur at the
implantation site as a result of increased blood flow into the vacuoles. Since this bleeding occurs near
the 28th day of the menstrual cycle, it may be confused with normal bleeding.
The outermost trophoblast is responsible for hormone production including human chorionic
gonadotropin (hCG). By the end of the 2nd week, sufficient quantities of this hormone are produced and
can be detected by pregnancy tests. Because 50% of the implanting embryo’s genome is paternally
derived, it represents a foreign body that, potentially, should be rejected by the maternal system.
Theories exist as to why the female body does not reject the developing embryo. They believe the
trophoblast lining lacks antigens, which would cause the embryo to go unnoticed in female immune
system. In order to warrant an immune response the body must recognize a foreign antigen. In
response, your system will develop antibodies to attack the foreign substance. If the substance lacks
antigens, the immune system cannot be triggered to start.
Abnormal implantation sites sometimes occur even within the uterus. Normally the human blastocyst
implants along the posterior or anterior wall of the uterus. Implantation that takes place in abnormal
locations is termed “extrauterine or ectopic pregnancy” Ectopic pregnancies may occur at any place in
the abdominal cavity, ovary, or uterine tube. However, 95% of the ectopic pregnancies occur in the
uterine tube, and most of these are located in the ampulla.
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Third Week of Development
The most characteristic event occurring during the third week of development is known as gastrulation.
This is the process by which all three germ layers will become established in the embryo. The three
different germ layers are ectoderm, mesoderm, and the endoderm. But, the actual formation of these
layers begins with the formation of the primitive streak which takes place on the surface of the epiblast.
It begins as a faint streak, but by days 15 or 16 a clear groove is visible. On each side of the groove there
will be a slight bulge seen. At the end of the streak, a primitive node forms. The primitive streak clearly
establishes the head and tail ends and the right and left.
This node consists of a slightly elevated area that is formed by a group of flask like cells developing
between the epiblast and the hypoblast. Recall that the two germ layers that formed in the first week
were the epiblast and hypoblast. Cells of the epiblast begin to migrate towards the primitive streak.
Some will detach from one another forming a wedge between the hypoblast. These cells will become
the embryonic endoderm, while others will squeeze between the epiblast and the hypoblast. These cells
will become part of the mesoderm. The remaining epiblast will develop into the embryonic ectoderm.
This endoderm will eventually give rise to the epithelial lining of the gastrointestinal tract as well as the
respiratory tract. The mesoderm will differentiate into such cell as the muscle, bone, different types of
connective tissue, as well as the dermis of the skin. The ectoderm will develop into the epidermis and
the nervous system.
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Along with the development of the three germ layers, the notochord develops. This structure begins
forming around the 16th day of development. The mesoderm cells from the node will migrate toward
the head and form a hollow tube called the notochord. By the 24th day, this hollow tube will become a
solid cylinder. The notochord will serve as the midline axis by which the skeleton will form. The
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notochord is a characteristic of any organism found in the phylum chordata. The notochord is not to be
confused with the spinal cord. The notochord is an embryonic structure that will guide other cells in the
developing embryo into the specialized type they are meant to be turned into. The notochord will
disappear later in development.
Gastrulation, the primary process of the third week of development has three key roles in embryology:
1. Bringing cell populations close together so they can induce each other
2. Establishing the axis of the body
3. Forming 3 germ layers from 2
Common defects that occur due to improper gastrulation include: Sirenomelia, Spina Bifida,
Sarcoccygeal teratoma.
The stages of human gastrulation are very difficult to study due to the fact that it is unethical science to
work with human embryos. Therefore the process of gastrulation has to be studied in other organisms
such as frogs or chickens. Humans are in a category of gastrulation known as deuterostomes which
translates to “second mouth”. During embryonic development the hollow stage will begin to pinch in
and form the blastopore. This blastopore will develop into the anus. Other organisms can be classified
as protostomes (“first mouth”). In protostomes, blastopores will develop into the mouth of the
organism. Later in development, the other anus will form just as in deuterostomes the mouth will form
eventually.
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Week Four Events
The spinal cord precursor is known as the neural tube. The process of forming the neural tube is called
neuralation, which will occur starting in the fourth week of development. The neural tube forms from
the folding of the flattened 3-germ layer embryo. As the notochord is forming, the midline of the
embryo begins to invaginate (sink in). As the midline is depressing, the outer edges of the embryo begin
to fold up and attach to each other. Once a connection between the two sides is established, you are
now starting the formation of the tube. While the neural tube is forming, small bumps along the tube
will be visible. These structures are known as somites, which are precursors to the vertebrae of the
organism. Age of the embryo can be determined based upon the number of somites present.
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Neural tube defects are caused by the arrest of normal development and the closure of the actual
neural tube. Anencephaly is a cephalic disorder that results from a neural tube defect that occurs when
the cephalic (head) end of the neural tube fails to close, usually between the 23rd and 26th day of
pregnancy, resulting in the absence of a major portion of the brain, skull, and scalp. Children with this
disorder are born without a forebrain, the largest part of the brain consisting mainly of the cerebral
hemispheres (which include the neocortex, which is responsible for higher-level cognition, i.e., thinking).
The remaining brain tissue is often exposed—not covered by bone or skin. Most babies with this genetic
disorder do not survive birth.
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Placenta formation
Many people have mistaken ideas about how a growing embryo eats and breathes in the uterus.
From the earliest stages of its development, the growing embryo requires nutrition and oxygen, and a
disposal system for the waste products of its own metabolism. All of this is accomplished by the
placenta, which allows the growing embryo to eat and breathe while in the mother’s uterus.
To get some perspective on how the placenta began, let’s go back to Day 8. This hollow ball of cells
moving through the uterus is the blastocyst, searching for an implantation site. The blastocyst will
implant itself into the uterine lining in search of blood vessels that will help nourish the embryo through
the pregnancy. As it went deeper, a single layer of cells from the mother’s uterine lining surrounded it,
so that it would be protected from harm. On Day 9, as it grew larger and more complex, the blastocyst
became an embryo. At this point the embryo is the size of a pinhead.
Also on Day 9, the outer layer of the embryo developed spaces called lacunae which were tiny vacuolelike spaces. This lacunae formed from the multinucleated trophoblast. The lacunae filled up with blood
from the mother’s uterine lining.
On Day 13, small projections from the embryo’s chorionic layer reached out into the uterine lining. The
chorionic layer is one of the membranes that surround the embryo and help it implant.
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On Days 15 through 21, blood vessels began to form beneath this chorionic layer.
Around Day 21, the embryo’s blood stream and the mother’s blood stream were in such close contact
that nutrients and oxygen could cross from mother to embryo. This was how the embryo first got its
food and air from the mother, and technically this is when the placenta began to function.
Here you see a vein and an artery from the embryo in close contact with the blood in the mother’s
uterine lining. Inside the blood vessels, you can also see red blood cells, which carry oxygen.
The two blood streams are separated by a thin collection of tissues in the placenta called the blood
barrier. This barrier permits small particles like nutrients and oxygen to pass from the mother to the
embryo, and allows waste products to pass from the embryo back to the mother. The blood barrier also
prevents many large or potentially harmful particles from entering the embryo’s blood stream. Notice
that the red blood cells do not cross from the mother’s blood stream to the embryo’s.
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You may be wondering how a mother’s blood cells could be harmful to her growing baby, and why it’s
important to keep the two blood streams separate. If the mother’s blood type is RH negative, and her
embryo’s blood type is RH positive, then the mother’s antibodies would treat the embryo as an invading
foreign organism, and try to destroy it.
Now you can see why the placenta and its blood barrier are important for supplying the growing embryo
with nutrition and oxygen, removing its waste products, and preventing harmful substances from
getting into its blood stream. The placenta does not block everything from passing from mother to child.
For instance, sexual transmitted diseases and other viruses can be passed via the placenta. Toxins, such
as those found in alcohol can be diffused across the membrane as well.
Upon delivery of the child, the placenta will be pushed out by contractions of the uterus. A doctor may
push on the abdomen to hurry the process along. The removal of the placenta is known as the
“afterbirth.”
Umbilical Cord
The umbilical cord develops from and contains remnants of the yolk sac and allantois (and is therefore
derived from the same zygote as the fetus). It forms by the fifth week of fetal development, replacing
the yolk sac as the source of nutrients for the fetus. The cord is not directly connected to the mother's
circulatory system, but instead joins the placenta, which transfers materials to and from the mother's
blood without allowing direct mixing. The length of the umbilical cord is approximately equal to the
crown-rump length of the fetus throughout pregnancy. The umbilical cord in a full term neonate is
usually about 50 centimeters (20 in) long and about 2 centimeters (0.75 in) in diameter. This diameter
decreases rapidly within the placenta. The fully-patent umbilical artery has two main layers: an outer
layer consisting of circularly arranged smooth muscle cells and an inner layer which shows rather
irregularly and loosely arranged cells. The two umbilical arteries take deoxygenated blood and wastes to
the placenta from the fetus, while the one umbilical vein brings oxygen and nutrients to the fetus. The
supporting tissue around these veins and arterties is called wharton’s jelly. Upon birth, the umbilical
cord can be cut and tied about 1 inch remaining. Withing a 12-15 day period, this piece will fall off and
leave a scar where it was attached called the umbilicus or navel. The blood cells found within the
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umbilical cord/placenta can be frozen to provide a source of pleuripotent stem cells in case the child
needs them for later.
Notice a fourth tube running through the umbilical cord. The allantois is a sac-like structure is primarily
involved in nutrition and excretion, and is webbed with blood vessels. The function of the allantois is to
collect liquid waste from the embryo, as well as to exchange gases used by the embryo.
Organogenesis – The development of organs.
All organs will be derived from the differentiation of tissue types that were once a part of the primary
germ layers. In the image, you can see some example of the organs/types of tissues these germ layers
will develop. It will take several weeks for many of the organs to develop and become functional.
Organogenesis can begin as early as the 4th week, which is when the first heart beats will happen, but
other organs will not be starting their development until the 8th week. It is during this fourth week when
major changes are occurring. The size of the embryo will triple in size and change from a flattened 2-D
disc, into a more 3-D cylinder, in large part due to the process of neurulation. This cylinder has arranged
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itself so that the primary germ layers are in their respective locations to help produce the more specific
cell types. For example, the cylindrical embryo has arranged the endoderm on the inside of the cylinder,
which is referred to as the “gut”, while the ectoderm which gives rises to the epidermis is now found on
the outside of the embryo. The mesoderm, primarily responsible for development of muscle tissue helps
to form the upper limbs during this fourth week of development. These “buds” will grow from the
mesoderm, but will be covered by the ectodermal layer. It will not be long before the lower limbs start
to also develop. This is a matter of beginning of the fourth week versus the end of the fourth week. One
link to the evolutionary past of all organisms is the presence of a tail during development. Even though
the human species will eventually have the tail disappear, a visible tail is present by the end of the 4th
week as well.
Fifth week
The fifth week is most notably recorded as the time of brain development. With the rapid growth of the
brain during this period, the head of the embryo will also need to enlarge at a fast rate.
Sixth week
With further development of the brain, the head becomes much larger than the rest of the limbs and
trunk of the embryo. The neck and trunk will begin to straight out as opposed to the curved nature that
the embryo has taken to this point. In the two weeks since its first heart beat, the development of the
heart has reached the point where it is now a 4-chambered organ.
Seventh Week
The limbs that formed during the fourth week will begin to develop individual digits.
Eighth Week
The digits on each hand are now short and webbed. The tail that was present a few weeks ago is also
still present, but it is much shorter relative to the body. The eyes are now open and the auricles of the
ears are also now visible.
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In embryology, Carnegie stages are a standardized system of 23 stages used to provide a
unified developmental chronology of the vertebrate embryo.
The stages are delineated through the development of structures, not by size or the number of
days of development, and so the chronology can vary between species, and to a certain extent
between embryos. It only covers the first 60 days of development; at that point the term
embryo is usually replaced with the term fetus.
It was based on work by Streeter (1942) and O'Rahilly and Müller (1987). The name "Carnegie
stages" comes from the Carnegie Institution of Washington.
Stage
Days
(approx)
Size
(mm)
Images
(not to scale)
Events
1
1
0.1 - 0.15
fertilized oocyte, zygote, pronuclei
(week 1)
2
2-3
0.1 - 0.2
morula cell division with reduction in cytoplasmic
volume, blastocyst formation of inner and outer cell
mass
3
4-5
0.1 - 0.2
loss of zona pellucida, free blastocyst
4
5-6
0.1 - 0.2
attaching blastocyst
5
7 - 12
(week 2)
0.1 - 0.2
implantation
6
13 - 15
0.2
extraembryonic mesoderm, primitive streak,
gastrulation
0.4
gastrulation, notochordal process
15 - 17
7
(week 3)
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8
17 - 19
1.0 - 1.5
primitive pit, notochordal canal
9
19 - 21
1.5 - 2.5
Somitogenesis Somite Number 1 - 3 neural folds,
cardiac primordium, head fold
22 - 23
10
2 - 3.5
Somite Number 4 - 12 neural fold fuses
(week 4)
11
23 - 26
2.5 - 4.5
Somite Number 13 - 20 rostral neuropore closes
12
26 - 30
3-5
Somite Number 21 - 29 caudal neuropore closes
4-6
Somite Number 30 leg buds, lens placode, pharyngeal
arches
28 - 32
13
(week 5)
14
31 - 35
5-7
lens pit, optic cup
15
35 - 38
7-9
lens vesicle, nasal pit, hand plate
8 - 11
nasal pits moved ventrally, auricular hillocks, foot plate
11 - 14
finger rays
13 - 17
ossification commences
16 - 18
straightening of trunk
37 - 42
16
(week 6)
17
42 - 44
44 - 48
18
(week 7)
19
48 - 51
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51 - 53
20
18 - 22
upper limbs longer and bent at elbow
(week 8)
21
53 - 54
22 - 24
hands and feet turned inward
22
54 - 56
23 - 28
eyelids, external ears
23
56 - 60
27 - 31
rounded head, body and limbs
Congenital Malformations
Congential malformations, congential anomalies, and birth defects are synonymous terms used to
describe structural, behavioral, functional, and metabolic disorders present at birth. The science that
studies the causes of these disorders is known as teratology. “Teratos” comes from Greek meaning
monster. Birth defects are the leading cause of infant mortality, accounting for approximately 21% of all
infant deaths.
In 40%-60% of all birth defects, the cause is unknown. Malformations occur during the formation of
structures, which primarily take place during the 3rd – 8th week of development.
Environmental Factors
Until the early 1940’s, it was assumed that congenital defects were caused primarily by hereditary
factors. With the discovery by Gregg that German measles affecting a mother during early pregnancy
caused abnormalities in the child, it suddenly became evident that malformations in humans can also be
caused by the environment.
Infectious Agents
Rubella (German Measles) – Currently we know that the rubella virus has the ability to cause
malformations of the eye, internal ear, heart, and occasionally teeth. The type of malformation that the
child would receive depended upon the timing of the virus. For example, cataracts would occur if the
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infection occurred during the 6th week, while deafness would happen if the mother was affected during
her 9th week.
Herpes Simplex Virus – In most cases the child receives the infection from the mother at birth as a
venereal disease
Chickenpox – There is approximately a 20% chance of congential anomalies occurring following a
mother’s infection during the first trimester. Defects include limb hypoplasia, mental retardation, and
muscle atrophy.
Alcohol – Defects include craniofacial abnormalities, limb deformities, and cardiovascular defects.
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System Development
I.
Skeletal System
Cells from the mesoderm germ layer, termed mesenchymal cells, migrate into areas where bones will
form. These cells are still not totally specialized, so therefore they will differentiate into more specific
types of cells. Some of the mesenchymal cells will develop in chondroblasts that will be the cells that
make up the cartilage portion of your skeleton. The other cells will differentiate into osteoblasts which
are the ones that form bone. Think of terms such as osteoporosis, which is a weakening of the bones.
As covered in the previous section, the limbs (which are a part of your skeleton) will form in the fourth
week. The upper limbs will appear in the early portion of the fourth week while the lower limbs will start
to protrude closer to the end of the week. Each bud which developed from the mesoderm has a layer of
ectoderm surrounding it, which will eventually be the epidermal layer that protects the skeleton. Some
of the mesoderm surrounding the developing bone will also differentiate into skeletal muscle. By the 6th
week, the limbs and buds that have been growing will begin to constrict and as a result will form what
are known as hand and foot plates. By this time, a skeleton that is primarily composed of cartilage is
present. The remaining pieces to the skeleton begin forming in the 7th week: Arm, Forearm, Hand as well
as Thigh , Legs, and Feet. During this time, ossification (the process of becoming mature bone cells has
begun).
In the next week, the areas that are more join oriented begin their development – shoulder, wrist, and
elbow. Recall that an important piece of the embryo, the notochord, is responsible for stimulating
change in cells around it. It was very early on, days 22 – 24 where the notochord formed and from then
on it was producing change by inducing unspecialized cells to differentiate into specialized tissues that
would help form the vertebral column, the final piece to the skeleton.
Clinical Correlations
In some rare cases, the neurospore fails to close and therefore an opening is present for the nervous
tissue to grow beyond the skeleton. The brain tissue is exposed directly to the amniotic fluid around the
fetus and it will begin to degenerate. This is known as anencephaly.
In other cases the brain can fail to grow to its maximum size, as well as the skull fails to reach its
potential as well. Microencephaly will most likely cause severe mental retardation in the child.
Defects are not limited to the brain and skull, but also to the limbs. Meromelia (partial) or Amelia (Total)
absence of the limbs can occur. Sometimes the long bones of the skeleton fail to form, but the hand and
feet plates do develop. This genetic condition is referred to as phocomelia.
Some defects may not technically be defects, but genes actually control the growth of the limbs.
Polydactyly individuals have more than 5 digits on their hands and feet. Some classify this as a defect
because the sixth digit does not have the same agility as the other five digits. It may lack the
musculature that the others have developed. Other times, the digits may fail to actually separate from
other another. This is known as syndactyly.
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II. Muscular System
Except for the muscles that help contract your pupils or the muscles that help your hair follicles stand on
end, all muscles are formed from the mesoderm as well. As the mesoderm develops, part of it becomes
arranged in dense columns on either side of the developing nervous system (neural crest). As the neural
crest is folded onto itself, it will undergo segmentation into block-like masses known as somites. The
first of the somites appear around day 17 with 21-22 pairs forming by the end of the 5th week. Recall
that the age of the embryo can be determined based upon the number of somites formed at any
moment.
Again, with the exception of the skeletal muscles of the head and limbs, the skeletal muscles develop
from the mesoderm of the SOMITES. The skeletal muscles of the limbs will develop from mesoderm that
surrounds the developing bone (not from the somites). Keep in mind that in a developing embryo, cells
are constantly migrating from one place to another. Especially early on in development, these cells need
to migrate to their relative locations so the future cells they will differentiate into are there, such as
cardiac muscle. Cardiac muscle develops from mesodermal cells that migrate to primitive heart tube,
realizing that eventually this heart tube will become a four chambered heart that must need the muscle
cells to help contract the organ. Smooth muscle cells will also migrate to the developing gastrointestinal
tract.
Defects to the muscular system can result in a partial or complete absence of one or more muscles.
These defects are rather common. One of the most common is the lack of muscle formation on the
pectoralis major. Absence of the abdominal musculature can result in a “prune belly” syndrome – the
abdominal wall is so think the organs can be seen.
One of the most talked about and recognizable genetic disorders that affects the muscular system is
known as muscular dystrophy. This is a group of inherited muscle destroying diseases that cause
progressive degeneration of the skeletal muscle fibers. Enough studies have been done to link this gene
to the X-chromosome, so therefore many parents are aware if they indeed are carriers for the disease,
since a pattern can be established.
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III. Cardiovascular System
The heart is derived from the mesoderm and begins developing in the third week in the ventral
region of the foregut. It will develop from a group of cells called the cardiogenic area. The next step is
the formation of a pair of tubes , the endocardial tubes. These tubes will connect to from a common
tube known as the primitive heart tube.
The mesoderm adjacent to the fused tube will gradually thicken and form three layers of the heart tube:
1. Endocardium – forms the internal lining of the heart
2. Myocardium – forms the muscular wall
3. Epicardium – forms the outer covering
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The image above is to show you the eventual end result of the three layers. We still have not
progressed past the heart tube. 
The primitive heart tube develops five distinct regions:
1. Truncus Arteriosus
2. Bulbus Cordis
3. Ventricle
4. Atrium
5. Sinus Venosus
The rate at which the different sections of the primitive heart tube grow is not equal. For instance, the
bulbus cordis and ventricle grow most rapidly and because the heart enlarges more rapidly than its
upper and lower attachments, the heart assumes a U shape and then an S – shape.
In a complex series of folds, the heart develops into a four chambered organ, with two ventricles and
two atria.
Embryonic
Dilatation
Sinus venosus
Primitive
atrium
Primitive
ventricle
Bulbis cordis
Truncus
arteriosus
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Adult Structure
Smooth part of right atrium (sinus venarum),
coronary sinus, oblique vein of left atrium
Trabeculated parts of right and left atria
Trabeculated parts of right and left ventricles
Smooth part of right ventricle (conus arteriosus),
smooth part of left ventricle (aortic vestibule)
Aorta, pulmonary trunk
Development of Blood Vessels
Blood vessel formation (angiogenesis) starts at the beginning of the third week. Blood vessels
first start to develop in the extraembryonic mesoderm of the yolk sac, connecting stalk, and
chorion. Blood vessels begin to develop in the embryo about two days later.
Production of Blood
Production of blood (hemopoiesis or hematopoiesis) begins first in the yolk sac wall about the
third week of development. Erythrocytes produced in the yolk sac have nuclei. Blood
formation does not begin inside the embryo until about the fifth week. Erythrocytes produced
in the embryo do not have nuclei (eunucleated). Hematopoiesis inside in the embryo occurs
first in the liver, then later in the spleen, thymus, and bone marrow.
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IV. Respiratory System
Lower Respiratory System
The primordium of the lower respiratory system develops in about the fourth week. The
laryngotracheal diverticulum arises from endoderm on the ventral wall of the foregut.
Tracheoesophageal folds develop on either side and join to form a tracheoesophageal septum
that separates it from the rest of the foregut. This divides the foregut into the laryngotracheal
tube (ventral) and the esophagus (dorsal). The caudal end of the laryngotracheal diverticulum
enlarges to form the lung bud, which is surrounded by splanchnic mesenchyme.
Bronchi
At the end of the fourth week the lung bud divides into two bronchial buds, which enlarge to
form the primary bronchi. The right bronchus is larger and more vertically oriented than the
left one, and this relationship persists throughout life. In the fifth week, each bronchial bud
divides into secondary bronchi. In the eighth week the secondary bronchi divide to form the
segmental bronchi (tertiary bronchi), ten in the right lung and eight in the left. Each segmental
bronchus becomes a bronchopulmonary segment (segment in a lung). The smooth muscle,
connective tissue, and cartilaginous plates in the bronchi are derived from splanchnic
mesenchyme.
Time period
Weeks
5 – 17
Notes
Developing lungs resemble an exocrine gland. Respiration is not possible.
Fetuses born during this period cannot survive.
Weeks
16 – 25
Terminal bronchioles divide and primitive alveolar sacs (terminal sacs) develop.
Some respiration may be possible towards the end of this stage. Fetuses born
towards the end of this period (weeks 22-25) can survive if given intensive care
but often die anyway.
Week 24 –
birth
Many more alveoli develop, and the epithelium lining the terminal sacs become
thin enough to allow respiration. Type I and Type II pneumocytes develop. Type
II pneumocytes begin producing pulmonary surfactant, which counteracts
surface tension and facilitates expansion of the terminal sacs at birth. Fetuses
born after 24 weeks may survive, and those born after 32 weeks have a good
chance of survival.
Birth –
year 8
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Respiratory bronchioles, terminals, alveolar ducts continue to increase in
number
V. Reproductive System
Determination of Gender
Although genetic sex (XX or XY) is determined at fertilization, the embryo’s gender is not distinguishable
for the first six weeks of development; this is known as the indifferent period of development.
Characteristics of either male or female genitalia can often be recognized by week twelve of
development.
Development of External Genitalia
In both sexes about the fourth week of development an indifferent genital tubercle develops
near the cloaca and elongates to form a phallus. In a male embryo, androgens secreted by the
testes cause the phallus to elongate into the penis and the urogenital folds to fuse and form
the spongy urethra. Without influence of androgens, the phallus becomes the clitoris, the
urogenital folds become the labia minora, and the labioscrotal swellings become the labia
majora. The external genital organs are not fully differentiated until about the twelfth week of
development.
Development of Genital Ducts
During indifferent development both pairs of genital ducts are present. In female embryos the
paramesonephric ducts (müllerian ducts) develop into most of the female genital tract, including the
uterine tubes, uterus, and part of the vaginal canal. In male embryos the testes secrete müllerian
inhibiting substance, which suppresses development of the paramesonephric ducts. Instead the
mesonephric ducts develops into the epididymis, ductus deferens, and ejaculatory duct.
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Descent of the Ovaries and Testes
The ovaries and testes develop in the abdomen and descend to their adult anatomical positions before
birth. In the male the testes descend from the abdomen into the scrotum about the twenty-eighth
week of development.
Clinical Correlations
Hypospadias
Incomplete fusion of the urogenital folds creates abnormal openings of the urethra on the
ventral aspect of the penis. This malformation occurs in about 1/300 infants.
Malformations of the Uterus and Vagina
If the two paramesonephric ducts fail to fuse correctly, it can result in duplication of the uterus and
vagina (double uterus and double vagina). If one paramesonephric duct fails to develop it results in
formation of a single uterine tube and single horn of the uterus (unicornuate uterus).
A-double uterus & vagina
B- double uterus, single vagina
C- Bicornuate uterus
D- Septate uterus
E- Unicornuate uterus
F- Atresia of the cervix
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Cyrptorchidism
Failure of the testes to descend into the scrotum (cryptorchidism) is the most common malformation of
the male genital system, resulting in infertility and an increased risk of testicular cancer. The testes may
remain anywhere between the abdomen and the scrotum.
Intersexuality
Rare true hermaphrodites have both ovarian and testicular tissues, usually possessing a 46,XX
karyotype. The internal and external and external genitalia are variable. Female
pseudohermaphrodites are more common, possessing a 46, XX karyotype, and typically result from
exposure to excess androgens during embryologic development (as in congenital virilizing adrenal
hyperplasia). Male pseudohermaphrodites have testes and a 46, XY karyotype. This condition results
from an inadequate production of androgens by the testes, or when embryonic genital tissues lack a
specific receptor needed to respond to normal levels of the hormone.
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VI. Urogenital System
The urogenital system arises during the fourth week of development from urogenital ridges in
the intermediate mesoderm on each side of the primitive aorta. The nephrogenic ridge is the
part of the urogenital ridge that forms the urinary system. Three sets of kidneys develop
sequentially in the embryo: The pronephros is rudimentary and nonfunctional, and regresses
completely. The mesonephros is functional for only a short period of time, and remains as the
mesonephric (Wolffian) duct. The metanephros remains as the permanent adult kidney. It
develops from the uteric bud, an outgrowth of the mesonephric duct, and the metanephric
mesoderm, derived from the caudal part of the nephrogenic ridge.
Urine excreted into the amniotic cavity by the fetus forms a major component of the amniotic
fluid. Urine formation begins towards the end of the first trimester (weeks 11 to 12) and
continues throughout fetal life.
The kidneys develop in the pelvis and ascend during development to their adult anatomical
location at T12-L3. This normally happens by the ninth week.
Table Error! Bookmark not defined. - Adult Derivatives of Embryonic Kidney Structures
Embryonic Structure
Ureteric bud (metanephric
diverticulum)
Adult Derivative
Ureter
Renal pelvis
Major and minor calyces
Metanephric mesoderm
Collecting tubules
Renal glomerulus +
capillaries
Bowman’s capsule
Proximal convoluted tubule
Loop of Henle
Distal convoluted tubule
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Suprarenal Gland
The adrenal medulla forms from neural crest cells that migrate into the fetal cortex and differentiate
into chromaffin cells.
Urinary Bladder
The urinary bladder develops from the upper end of the urogenital sinus, which is continuous
with the allantois. It is lined with endoderm. The lower ends of the metanephric ducts are
incorporated into the wall of the urogenital sinus and form the trigone of the bladder. The
connective tissue and smooth muscle surrounding the bladder are derived from adjacent
splanchnic mesoderm.
The allantois degenerates and remains in the adult as a fibrous cord called the urachus
(median umbilical ligament).
Clinical Correlations
Renal agenesis
Absence of a kidney results when the ureteric bud fails to develop or regresses after
development. If both kidneys are absent (bilateral renal agenesis) the fetus cannot urinate and
amniotic fluid is deficient (< 400ml) resulting in oligohydramnios and characteristic physical
deformations known as Potter facies (flattened nose, low-set ears, thickened, tapering fingers).
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Congenital Polycystic Disease of the Kidneys
An autosomal recessive condition manifested by the presence of many heterogeneous cysts within the
parenchyma of the kidney. The cause and pathogenesis is unknown.
Horseshoe Kidney
Horseshoe kidney occurs when the inferior poles of the kidneys fuse together. The combined kidney is
not able to ascend to its adult physiological location because it gets “hung up” on the inferior
mesenteric artery.
Pelvic Kidney
A pelvic kidney is one that has failed to migrate to its adult anatomical location. In crossed ectopia one
kidney and its associated ureter migrate to the opposite side of the body.
Urachial Fistula
If the lumen of the allantois persists as the urachus forms it may give rise to an abnormal
communication between the urinary bladder and the umbilicus known as an urachal fistula. Often with
this condition urine will dribble from the umbilicus when the baby cries. A blind-ending communication
that will not drain urine is known as an urachal sinus.
VII. DIGESTIVE SYSTEM
Primitive Gut Tube
The primitive gut tube is derived from the dorsal part of the yolk sac, which is incorporated
into the body of the embryo during folding of the embryo during the fourth week. The
primitive gut tube is divided into three sections.
Table Error! Bookmark not defined. - Sections of the Gut Tube
Section
Foregut
Blood supply
Celiac artery
Midgut
Superior
mesenteric artery
Hindgut Inferior
mesenteric artery
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Adult derivatives
Pharynx, lower respiratory system, esophagus, stomach, proximal
half of duodenum, liver and pancreas, biliary apparatus
Small intestine, distal half of duodenum, cecum and vermiform
appendix, ascending colon, most of the transverse colon
Left part of transverse colon, descending colon, sigmoid colon,
rectum, superior part of anal canal, epithelium of urinary bladder,
most of the urethra
The epithelium of and the parenchyma of glands associated with the digestive tract (e.g., liver
and pancreas) are derived from endoderm. The muscular walls of the digestive tract are
derived from splanchnic mesoderm.
During the solid stage of development the endoderm of the gut tube proliferates until the gut is
a solid tube. A process of recanalization restores the lumen.
Proctodeum and Stomodeum
The proctodeum (anal pit) is the primordial anus, and the stomodeum is the primordial mouth. In both
of these areas ectoderm is in direct contact with endoderm without intervening mesoderm, eventually
leading to degeneration of both tissue layers.
Foregut
Esophagus
The tracheoesophageal septum divides the foregut into the esophagus and trachea. See the
chapter on Respiratory system for more information.
Stomach
The primordium of the primitive stomach is visible about the end of the fourth week. It is
initially oriented in the median plane and suspended from the dorsal wall of the abdominal
cavity by the dorsal mesentery or mesogastrium. During development the stomach rotates 90
in a clockwise direction along its longitudinal axis, placing the left vagus nerve along its anterior
side and the right vagus nerve along its posterior side. Rotation of the stomach creates the
omental bursa or lesser peritoneal sac.
Duodenum
The duodenum acquires its C-shaped loop as the stomach rotates. Because of its location at
the junction of the foregut and the midgut, branches of both the celiac trunk and the superior
mesenteric artery supply the duodenum.
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Pancreas
The pancreas develops from two outgrowths of the endodermal epithelium, the dorsal
pancreatic bud and the ventral pancreatic bud. During rotation of the gut these primordial
come together to form a single pancreas. The ventral pancreatic bud forms the uncinate
process and part of the head, while the dorsal pancreatic bud forms the remainder of the head,
body, and tail of the pancreas. The ducts of the pancreatic buds join together to form the main
pancreatic duct, but the proximal part of the duct of the dorsal pancreatic bud may persist as
an accessory pancreatic duct.
Liver and Biliary Apparatus
The liver develops from endodermal cells that form the hepatic diverticulum. The liver grows
in close association with the septum transversum, which later forms part of the diaphragm. As
it grows the hepatic diverticulum divides into a cranial part, which forms the parenchyma of
the liver, and the caudal part, which gives rise to the gallbladder and cystic duct. The
hemopoietic cells, Kupffer cells, and connective tissue of the liver are derived from
mesenchyme in the septum transversum. The embryonic liver is large and fills much of the
abdominal cavity during the seventh through ninth weeks of development.
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Blood formation (hemopoiesis) begins in the liver during the sixth week of development, and
bile formation begins in the twelfth week.
Spleen
The spleen develops from mesenchymal cells located between layers of the dorsal
mesogastrium.
Midgut
The midgut communicates with the yolk sac via the yolk stalk. As the midgut forms, it
elongates into a U-shaped loop (midgut loop) that temporarily projects into the umbilical cord
(physiological umbilical herniation). The cranial limb of the midgut elongates rapidly during
development and forms the jejunum and cranial portion of the ileum. The caudal limb forms
the cecum, appendix, caudal portion of the ileum, ascending colon, and proximal two-thirds
of the transverse colon. The caudal limb is easily recognized during development because of
the presence of the cecal diverticulum.
The midgut loop rotates 270 counterclockwise around the superior mesenteric artery as it
retracts into the abdominal cavity during the tenth week of development.
Hindgut
The hindgut is defined to begin where the blood supply changes from the superior mesenteric
artery to the inferior mesenteric artery, i.e. at the distal third of the transverse colon.
Partitioning of the Cloaca
The cloaca is the endodermally lined cavity at the end of the gut tube. It has a diverticulum into
the body stalk called the allantois. The cloacal membrane separates the cloaca from the
proctodeum (anal pit). During development a sheet of mesenchyme (urorectal septum)
develops to divide the cloaca into a ventral (urogenital sinus) and a dorsal portion (anorectal
canal). By week seven the urorectal septum reaches the cloacal membrane, dividing it into
ventral (urogenital membrane) and dorsal (anal membrane) portions.
Anal Canal
The epithelium of the superior two-thirds of the anal canal is derived from the endodermal
hindgut; the inferior one-third develops from the ectodermal proctodeum. The junction of
these two epithelia is indicated by the pectinate line, which also indicates the approximate
former site of the anal membrane that normally ruptures during the eighth week of
development.
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Clinical Correlations
Anorectal Agenesis
Abnormal formation of the urorectal septum causes the rectum to end as a blind sac above the
puborectalis muscle.
Anal Agenesis
Abnormal formation of the urorectal septum causes the rectum to end as a blind sac below the
puborectalis muscle.
Imperforate Anus
The anal membrane fails to break down before birth. The anus must be reconstructed surgically, with
severity depending on the thickness of the intervening tissue.
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Drosophila melanogaster
What is it and why bother about it?
Drosophila melanogaster is a fruit fly, a little insect about 3mm long, of the kind that accumulates
around spoiled fruit. It is also one of the most valuable of organisms in biological research, particularly in
genetics and developmental biology. Drosophila has been used as a model organism for research for
almost a century, and today, several thousand scientists are working on many different aspects of the
fruit fly. Its importance for human health was recognised by the award of the Nobel prize in
medicine/physiology to Ed Lewis, Christiane Nusslein-Volhard and Eric Wieschaus in 1995.
Why work with Drosophila?
Part of the reason people work on it is historical - so much is already known about it that it is easy to
handle and well-understood - and part of it is practical: it's a small animal, with a short life cycle of just
two weeks, and is cheap and easy to keep large numbers. Mutant flies, with defects in any of several
thousand genes are available, and the entire genome has recently been sequenced.
Life cycle of Drosophila
The drosophila egg is about half a millimeter long. It takes about one day after fertilization for the
embryo to develop and hatch into a worm-like larva. The larva eats and grows continuously, molting one
day, two days, and four days after hatching (first, second and third instars). After two days as a third
instar larva, it molts one more time to form an immobile pupa. Over the next four days, the body is
completely remodeled to give the adult winged form, which then hatches from the pupal case and is
fertile within about 12 hours. (Timing is for 25°C; at 18°, development takes twice as long.)
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Research on Drosophila
Drosophila is so popular, it would be almost impossible to list the number of things that are being done
with it. Originally, it was mostly used in genetics, for instance to discover that genes were related to
proteins and to study the rules of genetic inheritance. More recently, it is used mostly in developmental
biology, looking to see how a complex organism arises from a relatively simple fertilized egg. Embryonic
development is where most of the attention is concentrated, but there is also a great deal of interest in
how various adult structures develop in the pupa, mostly focused on the development of the compound
eye, but also on the wings, legs and other organs.
The Drosophila genome
Drosophila has four pairs of chromosomes: the X/Y sex chromosomes and the autosomes 2,3, and 4. The
fourth chromosome is quite tiny and rarely heard from. The size of the genome is about 165 million
bases and contains and estimated 14,000 genes (by comparison, the human genome has 3,400 million
bases and may have about 22,500 genes; yeast has about 5800 genes in 13.5 million base bases). The
genome was (almost) completely sequenced in 2000, and analysis of the data is now mostly complete.
Several other insect genomes have now been sequenced, including many Drosophila species, and the
genomes of mosquito and honey bee, and these are starting to show what is common among all insects,
and what distinguishes them from each other.
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Sexing flies: Male and female fruit flies can be distinguished from each other in three ways:
1) Only males have a sex comb, a fringe of black bristles on the forelegs.
2) The tip of the abdomen is elongate and somewhat pointed in females and more rounded in
males.
3) The abdomen of the female has seven segments, whereas that of the male has only five
segments.
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Analyzing the data of your experiment – Conducting a chi squared test
Case One:
Look at the tables you printed from Case 1. From the data presented, you can deduce that the F1
cross was between individuals heterozygous for eye color:
+se x +se (+ = red; se = sepia ). From this conclusion, you could write the following hypothesis: "If
the parents are heterozygous for eye color, there will be a 3:1 ratio of red eyes to sepia eyes in the
offspring." Do your results support this hypothesis?
The actual results of an experiment are unlikely to match the expected results precisely. But how
great a variance is significant? One way to decide is to use the chi-square (x2) test. This analytical tool
tests the validity of a null hypothesis, which states that there is no statistically significant difference
between the observed results of your experiment and the expected results. When there is little
difference between the observed results and the expected results, you obtain a very low chi-square
value; your hypothesis is supported.
Next we'll see how to calculate and interpret chi-square
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How to Calculate the Expected Value
In a cross between two heterozygous individuals, the offspring would be expected to show a 3 : 1
ratio. For example, in Case 1, three-fourths of the individuals would have red (wild-type) eyes, and
one-fourth would have sepia eyes.
If there are 44 offspring, how many are expected to have red eyes?
We expect three-fourths to have red eyes.
If there are 44 offspring, how many are expected to have sepia eyes?
Now you are ready to calculate chi-square.
Calculating Chi-Square
The formula for chi-square is:
X2 = the sum of
where:
o = observed number of individuals
e = expected number of individuals
Using the Chi-Square Critical Values Table
The chi-square critical values table provides two values that you need to calculate chi-square:
• Degrees of freedom. This number is one less than the total number of classes of offspring in a
cross. In a monohybrid cross, such as our Case 1, there are two classes of offspring (red eyes
and sepia eyes). Therefore, there is just one degree of freedom. In a dihybrid cross, there are
four possible classes of offspring, so there are three degrees of freedom.
• Probability. The probability value (p) is the probability that a deviation as great as or greater
than each chi-square value would occur simply by chance. Many biologists agree that
deviations having a chance probability greater than 0.05 (5%) are not statistically significant.
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Therefore, when you calculate chi-square you should consult the table for the p value in the
0.05 row.
Use the critical values table here to do the problems below. *
Degrees of Freedom (df)
Probability (p)
1
2
3
4
5
0.05
3.84
5.99
7.82
9.49
11.1
0.01
6.64
9.21
11.3
13.2
15.1
0.001
10.8
13.8
16.3
18.5
20.5
1. Determine the degrees of freedom. This is the
number of categories (red eyes or sepia eyes) minus
one. For the data in Case 1, the number of degrees
of freedom is
Your answer: 1
Answer: There are 2 categories minus 1. The
degrees of freedom is therefore 1.
2. Find the probability (p) value for 1 degree of
freedom in the 0.05 row.
Your answer: 3.84
Answer: It is 3.84. Compare this to the chi-square
value you calculated earlier. If the chi-square value
calculated for your experiment is less than the value
of p = 0.05, the null hypothesis is valid. Since =
.4848, your results support the hypothesis. Although
your observed results are not precisely 3:1, there is
little variation from the expected results. The
probability of obtaining results so close to the
expected merely by chance is less than 0.05 or 5%.
The deviation in your experiment is not regarded as
statistically significant.
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Mendelian Genetics
Gregor Johann Mendel (July 20, 1822 – January 6, 1884) was an Austrian scientist and Augustinian friar
who gained posthumous fame as the founder of the new science of genetics. Mendel demonstrated that
the inheritance of certain traits in pea plants follows particular patterns, now referred to as the laws of
Mendelian inheritance. Although the significance of Mendel's work was not recognized until the turn of
the 20th century, the independent rediscovery of these laws formed the foundation of the modern
science of genetics.
The important thing to realize that not every trait is a classified as a mendelian trait. In order to be
placed into a category of mendelian, the trait must be controlled by only one gene. That one gene will
only have two variations, or alleles, and one of those variations will be dominant to the other. The pea
plants that he studies happened to have 7 distinct traits that were controlled in this manner. The words
dominant and recessive are often hard to understand at an introductory level, but we are going to try
and understand this concept in a much more conceptual manner at this point. Dominant is often
referred to as the trait that has the ability to mask the other variation, while recessive is often known as
the trait that can only be visibly shown if the dominant variation is not present. While these are true, it
is only one way of thinking about these words. Other geneticists will use the terms “loss of function”
allele and “gain of function” allele. For example, cystic fibrosis is classified as a recessive mendelian
disorder. Students believe that the reason people get cystic fibrosis is because they inherited two
recessive alleles. But, cystic fibrosis is caused by a mutation in a gene which obviously causes the
gene/protein to work improperly. If you inherit the mutation from your mother and from your father, is
there any chance that your body can produce the correct protein? If you inherit one good copy from
your father and a mutated gene from your mother, the good copy can work well enough to produce
enough of the protein for your body not to be affected by the disorder. So instead of saying that cystic
fibrosis is a recessive allele, one could say that cystic fibrosis is caused by a loss in function of a gene.
This is not to confuse you, but to make you think in a different way. Do not always associate “loss of
function” with recessive/mutated and “gain of function” with dominant/good copy.
When a student performs a punnett square, they are immediately trained to separate the alleles and
place them along the top and/or side of the punnett square. Students do this without hesitation, but
truly do not understand what they are actually doing when they complete the square. If you are given a
simple monohybrid cross: Rr x Rr, students know well enough to separate the R from the r. But, they
lose the connection to genetics as to WHY they are separating these two letters from one another. Refer
back to the process of meiosis. The act of you separating the R from the r, is reenacting the process of
anaphase I, where the homologous chromosomes separate from one other. The punnett square is just a
graphical representation of this process known as the “law of segregation”. The act of completing the
actual punnett square represents the process of fertilization. Each square in the punnett square will
represent a potential offspring that could be produced from the two parents in question. The more
often a specific pattern in the offspring is present, the more likely those parents are to have that type of
child. In this example, the punnett square will look as such:
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R
r
R
RR
Rr
r
Rr
rr
This punnett square demonstrates that there is a 50% likelihood that the offspring of these parents will
have the heterozygous genotype, while there is only a 25% chance their child will homozygous dominant
or homozygous recessive. Notice that each offspring has a diploid number of chromosomes. Each
offspring has received two copies of the “R” gene, since each square as two represented R/r’s.
Students can easily do a monohybrid cross, but have truly no idea what the cross actually means. This
usually is demonstrated when asked to show the probability of two genes being passed on to their child.
If I asked a student to complete a dihybrid cross (one in which two genes are traced from parent to
offspring), students who do not know what is going will do the following:
This punnett square shows that a student is only trained to separate letters and then place them along
the outside of the square. They cannot see that what they are doing is “genetically” incorrect. Let’s look
at WHY this is not correct:
1. The outside perimeter of the punnett square represents potential gametes from the parents.
Since both parents have identical genotypes it does not matter which one I refer to in this
example. In both cases, this student is saying that some gametes will receive a copy of the “R”
gene while other gametes will not get any “R’s”, they will get the “T” gene. So what this student
is saying is not every gamete will have the same types of genes in them. How would this cause
problems?
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2. If you begin filling in this punnett square, you would get only 2 letters in each box. Some would
have two R’s, other will have two T’s, while some will one copy of the R-gene and one copy of
the T-gene. As I mentioned before, the punnett square boxes represent potential offspring to
the parents. Would you like to be the way that genes are passed on? What if the R gene
controlled if you had attached earlobes or unattached earlobes. This student is saying that not
every offspring will be given the instructions to have either of those variations. In the case of the
offspring that even had the privilege of receiving one R-gene and one T-gene, they are choosing
to produce an offspring that is haploid. They would have half the number of chromosomes than
the parent generation.
Do not laugh at this example, because I can guarantee that over 40% of you would have
completed a dihybrid cross in this fashion if I gave you a pretest with this example cross on it.
Let’s look at how this example should have been completed.
During the process of meiosis homologous chromosomes are copied and then divided amongst
the four gametes in an equal fashion. If two genes (G and Y) are found on completely different
chromosomes, the homologous chromosomes will line up in independently from one another. If
you look at the top cell you will notice that the Y replicated chromosome lined up on the top of
the equator, therefore was inherited WITH the G replicated chromosome in the first example.
There is no rule as to HOW homologous chromosomes line up at the equator during Metaphase
I of meiosis. In the bottom example, the diagram shows that the Y replicated chromosome could
have lined up on the bottom of the equator; therefore the G replicated chromosome was paired
with the y-replicated chromosome. Notice how the lining up in Metaphase I really dictates the
outcome of the gametes in the end of meiosis. The punnett square is designed to take into
account ALL OPTIONS of independent assortment!!!
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The results on the right of the image show all the potential gametes that could be produced
from this parent. Does this mean that we would have 8 possible choices along the top of a
punnett square? If you take a closer look, there is always two of the SAME combination next to
each other because in meiosis II, separation of sister chromatids will yield the same combination
of alleles. So a closer examination shows that there are technically only four different gametes
that could be produced. Notice how EACH gamete has received one copy of a “G” allele and one
copy of the “Y” allele.
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Many students get hung up on the letters used in examples. Letters are completely arbitrary in most
cases. In the above example the full genotype would be AaBb and the possible gametes are listed as
such: aB, AB, ab, Ab. The same thing could have been given with RrTt as was done in the original
example. The set up would be the same way, and the results would be the same example the letters are
now in R’s and T’s. If I asked an introductory student to perform the following cross: AaBb x AaBb, they
would be able reach the correct answer. If I asked in the NEXT problem to cross RrTt x RrTt, they would
go through the whole process again expecting different results than they just got. Those two crosses are
the same cross. Use some logic when you solve problems!! As a quick double check, whenever you are
completing dihybrids, trihybrids, etc things will follow a pattern. For example, if you did the work for the
dihybrid cross AaBb x AaBb you will obtain a phenotypic ratio of 9 (dominant, dominant), 3 (dominant,
recessive), 3 (recessive, dominant), 1 (recessive, recessive). Other times when you do dihybrids you may
receive 2:2:2:2, or 3:3:1:1. In each of these cases, do you notice there is some sort of pattern? If you are
getting answers such as 8:4:3:1, you did something wrong. Random ratios do not happen in mendelian
genetics.
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Extensions of Mendelian Genetics
Not every gene in the living world is classified as a Mendelian trait. Some traits are caused by more than
one gene meaning that multiple genes influence each other and show a particular phenotype. Other
genes are influenced by the environment which makes it harder to predict future generations of
phenotypes. In this section will look at traits that are caused still by one gene, but they do not fit the one
variation is dominant and another is recessive.
Incomplete Dominance – Incomplete dominance is given this name for the sole reason that neither of
the alleles in the gene are dominant to one another. I tried to explain dominant and recessive in a
different way before because in this example there is no such thing as recessive or dominant. Instead
you must look at each allele as making a different type of protein, in most cases the examples used are
genes for color. Incomplete dominance traits are still only controlled by one gene with two variations,
but the tricky part is that each variation when present in the organism has the ability to work. So if you
had an example where one variation produced a “black” protein, while the other variation produced a
“white” protein and someone happened to inherit one copy of each then they have instruction in their
cell on how to make the “black” and the “white” variations, so the body does as such. The colors, when
produced, blend together though in a sort of mosaic pattern such that you cannot tell both black and
white are being made, instead you will see a blending of the two variations. In this case, a gray color
might be observed. So is gray an actual variation of the gene? No, it is a result of the two variations
coming together in the same cell. When completing a punnett square, we can no longer assign a capital
letter for one allele and a lower-case letter to the other since both alleles will make the protein.
Therefore, geneticists assign each variation their own allele. For this example, black would be given the
letter B, while the white would be given the letter W. Notice that gray is NOT given a letter because gray
is NOT a variation of the gene!!! Genotypes can be easily assigned to organisms that are experiencing an
incomplete dominant situation. The hard part for students is recognizing the trait as being incomplete
dominant. Here are a few pointers:
1. If a situation arises where there are three different phenotypes being talked about in the
example.
2. If it seems the variations are along a continuum
a. Short, Medium, Tall
b. Straight, Wavy, Curly
c. Small, Medium, Large
3. If it deals with three colors, are the colors related to one another?
a. White, Gray, Black
b. White, Pink, Red
c. Blue, Green, Yellow
Once you realize the situation is classified as incomplete dominant, assigning the alleles is the next step
students will struggle with in the process. Since there are only TWO alleles, you have to choose the two
phenotype variations that represent the genes! The extreme phenotypes are the ones that will be
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assigned the alleles. It is easiest to just give the capital letter to the each extreme. In the end, the
punnett square will look like:
2. Codominance – Codominance is a very similar situation as the incomplete dominant pattern of
inheritance. Therefore, students struggle with the idea. Yes, you will get the idea now in the moment,
but the challenge is to be able to always differentiate between them. In March, April, May, final exam
time! That will be the challenge!
Codominance is still caused by only one gene with two variations of the alleles. There is no such thing as
recessive because, again, in the case of a heterozygous individual both of the variations will show
through in the phenotype. Instead of the two alleles blending together, they will remain independent of
one another. What to look for to determine if something is inherited codominantly:
A. Look for three variations of a phenotype
B. Blending does not occur though
C. Phenotypes would look something like:
a. White, Black, Black & White
Determining which variations receive the allele letters is a bit easier in this example, since it is clear that
Black & White is the heterozygous individual. We cannot just assign a capital B to black and a W to
white because that notation is already reserved for incomplete dominance. Instead we take the concept
of the B and the W and use a notation where the actual alleles are more of an exponent. In order to
have an exponent though, you need a “base letter”. This base letter is not interpreted in any fashion in
the genotype, instead it is just a place holder so an exponent can be used.
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Notice how each of the true alleles (R and W) are attached to the F and are not removed when the
punnett square is filled in. Some students who first begin writing codominant punnett squares will write
it as FRW instead of FRFW. The latter is the correct way of writing the genotype. The square that is filled in
on this example would exhibit both phenotypes. They do not blend together. If R stood for red and W
stood for White, this organism would be both Red and White. They could be feathers or hairs, either
way you would NOT have pink feathers and/or hairs on the organism.
Multiple Alleles
In this case of extending beyond the mendelian genetics we are faced with a situation in which the
phenotype of interest is still only controlled by one gene, yet there are more than two alleles in which
someone can inherit. This DOES NOT mean that a person inherits more than two alleles for the
phenotype, it simply means there are more alleles in the pool. The premier example for human genetics
is blood typing. As you are all aware, there are four types of blood: A, B, AB, and O. As some of you many
recall from biology, this example does not only show multiple alleles, it also shows codominance as well.
From the look at the phenotypes, hopefully you can see that the alleles that must be codominant to one
another is the allele that causes the A phenotype and the allele that causes the B phenotype. Therefore,
we must use proper notation to show this relationship. Most often you are given full creativity to create
your own “base letter”. In this case you are not!! You are to use the base letter I whenever you are using
the blood typing punnett square. Since A and B are codominant to one another, their proper notation in
a genotype would then be IA and IB. So you may question where the O phenotype has come from. This is
when multiple alleles comes into play. A and B alleles are codominant to each other, yet they are both
dominant to the O allele. Thus, in our notation we will signify its “recessiveness” by using a lower case
“i”. From this explanation, make note that there are a total of three different alleles: IA, IB, i. There has
not been an instance to this point where there more than two variations of the gene.
Notice that in the example you will have cases where two of the IB alleles are paired up with one
another, while in other instances you may have IB paired with a i. Both of these genotypes will yield a
person with B-blood. To distinguish between these two genotypes, the words homozygous and
heterozygous will be used. Individuals with AB blood or O blood will not be described as such because
there is only one way in those two phenotypes could arise: IAIB or ii.
Often associated with blood typing is the concept of positive and negative. Located on your
chromosome is a gene which controls if your blood is positive or negative. This gene happens to be
inherited through the mendelian pattern of inheritance, where it is controlled by one gene that has two
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variations: one dominant and one recessive. Positive will always be dominant to negative. The problem
is some books do not notate the genotypes as easily as they do for other mendelian traits. But
remember, the letters in a mendelian punnett square are arbitrary. With that being said, you can choose
whatever letter combination you would like to represent positive and negative. Some books will use the
genotype (Rh+/Rh-) This simply means that the person is heterozygous for this gene. One must know
that the positive allele will mask that of the negative and therefore the blood would be classified as
positive. Would you be able to figure that out without that piece of information, probably not! But if I
said someone was Pp and you knew that P = positive and p= negative, could you then interpret…you
better be able to!
Epistasis
Epistasis is a genetic term to describe when one gene has an effect on the phenotypic expression of
ANOTHER gene. One of the best examples would be a gene found in the fruit fly to be “eyeless”. Yes, it
does exist, fruit flies without eyes. Yet, fruit flies also can have variations in their eye color, just like
humans. If both of these two genes exist, it is possible to see how a gene for eyelessness can actually
control if the color for eyes is actually seen. Does this mean that the eyeless fruit fly DOES NOT have
alleles for eye color? No, this simply means that the phenotypic expression of that gene is not shown.
That eyeless fruit fly can still bear offspring and those children will still receive one allele from their
father that control if they have eyes as well as the color of those eyes. Let’s look at this example in
genotypic terms:
E = eyes are present
e = eyeless
W = white eyes
w = sepia eyes
If a fruit fly has the genotype EeWw, the fruit fly will have white eyes. But if the genotype of the
offspring were to be eeWw, the second gene would not have a chance to be shown and therefore the
phenotype would just be written as eyeless. It is NOT written as eyeless, white eyes. That is just you not
thinking at all. If you truly understand epistasis you will see that you have think sometimes when writing
the actual phenotype. It is not just going to combining two genes and writing the individual phenotypes
out on the paper. For instance, if you had a gene that prevent color from being expressed, yet there was
a second gene that made someone’s hair red, would you write as a phenotype: Prevent of Color, Red
Hair? No, you would have to think, if this person inherited the phenotype “prevention of color”, what
might that do to the phenotype of the person? The thinking student would write down, most likely –
White hair.
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Epistasis is placed into two categories:
A. Dominant epistasis
B. Recessive epistasis
These two types are simply differentiated based upon the gene is that actually causing the change to the
second phenotype. In the case of the fruit fly, you can determine that is clearly the eyeless allele that is
affecting the expression of the color gene. Since the eyeless gene is the recessive allele, this would be an
example of recessive epistasis. If eyelessness was caused by the dominant allele, this would then change
to a dominant epistasis variety. To determine the possible outcomes of crosses, at a minimum, the
cross would look like a dihybrid cross. You just have to make sure you interpret each offspring correctly.
The ratios will take on a different pattern than one is used to seeing.
In the example below (or on the next page), do you think you can assign the alleles of B, b, C, c? The
phenotypic ratio given is 9:3:4. The rules of patterned ratios do not apply to epistasis. Unlike with
mendelian genetics where you can somewhat determine you interpreted results wrong when your
ratios were a hodgepodge of numbers, epistasis is a fair game for random ratios. Just double check to
make sure you took into account each genotype.
Not all extensions of mendel have to include a completion of a punnett square. I like to classify the
following as phenomena that take place in the world of genetics. It will be your responsible to read
about different disorders and place them into the correct type of phenomenon.
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Incomplete Penetrance - You have been trained to interpret every heterozygous individual as
expressing the dominant phenotype. If you were given the genotype Aa, you would immediately say
that the person would express whatever the A gene matched to, because that is all you know. This does
not happen 100% of the time. Some dominant alleles are said to be “incompletely penetrant.” This
basically means that in certain genes, when you have a heterozygous individual the dominant gene is
not always the one that shows. The premier example involves a human trait known and polydactyl.
Having 6 fingers is a dominant trait, while having only 5 fingers is a recessive trait. Given this
information along with a genotype of Aa, one would conclude that this person would have six fingers.
Unfortunately, this gene may be only 70% penetrant. This means that only 70% of the time will a person
who is heterozygous actually have the extra finger. 30% of the time the recessive phenotype WILL STILL
SHOW through. In essence, you have been taught exclusively “Completely Penetrant” examples. These
are genes that express the dominant phenotype every time the dominant allele is present.
Variable Expressivity – In this situation an organism inherits a particular phenotype but, like snowflakes,
no two individuals may have the exact same phenotype. For example, spots on a dog. If having spots is
controlled by a specific gene, no two dogs might have the same pattern of spots. Dogs that are spotted
may have the genotype Ss, but that does not guide the location and/or how many spots are seen.
Another hint to variable expressivity is often when there is a major continuum of how mild to severe a
disorder might be. Myopia might be classified as variably expressive. We all know that people can be
nearsighted to different degrees. They are all “myopic”, but the severity can be different amongst those
individuals.
Phenocopy – A phenocopy is not a type of mutation, it is an environmentally induced, non-hereditary
phenotypic modification that resembles a similar phenotype produced by a gene mutation. In laymen’s
terms it is an environmentally caused disorder/problem that may mimic that of a genetic disorder.
Thalidomide babies were a perfect example of a phenocopy. Expectant mothers in the 1950’s were
given a drug to help with morning sickness. Babies in that time period had a high incidence of
phocomelia. It was soon realized that many of these babies did not have phocomelia, instead they
suffered from a side effect of the drug thalidomide.
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Person with phocomelia
Thalidomide Baby
Genetic Heterogeneity – Sometimes a symptom of a disease can be a result of many different types of
gene mutations. This does not mean that you have to inherit the mutation from five different genes, it
means that these five gene, if mutated (independent of one another), can cause the same symptom. For
example, deafness can be a result of over 32 different mutated genes.
Pleiotropy – Pleiotropy is one of the easiest to identify. This is caused when one gene makes a protein
that is actually utilized in many different parts of the body, therefore, ALL of those parts are affected. If
many parts of the body are affected, that would then translate to mean that you will suffer from many
different types of symptoms.
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