Lecture Notes continue from #3 pp 26 -35
Page 36

Central Nervous System Malformation

These effects are often associated with one another, for example, it would not be uncommon to have one child that is a hydrocephalus and another child with Spina Bifida.

Anencephaly

Absence of cranial vault - cortex of the brain is virtually absent occurs  1 in a 1000 births, greater frequency among females probably due to selective loss of males. There is a higher incidence among people in the same geographic location and similar socioeconomic groups (poor) indicating an environmental influence. This disorder is fatal.

Spina Bifida

Neural arches of the vertebrae do not fuse. Spinal cord and its linings protrude outside of vertebrae and are unprotected causing an increased risk of infection. There are different severities of Spina bifida - some are relatively mild and some are extremely severe with a great loss of the neurological tissue. The disease is often associated with anencephaly or hydrocephalus. There is a familial tendency.

Hydrocephalus

A fluid called cerebrospinal fluid (CSF) circulates through the brain and through the Spinal cord. This fluid is produced by cells that line the ventricles of the brain and is absorbed in other areas. There is continuous turnover of the fluid, and it circulates constantly through the central nervous system. Increase in CSF can be due to 1) increase production of the fluid 2) decreased absorption of the fluid and 3) a block in the circulation of the fluid.
When the fluid increases in the ventricles of the brain it exerts a pressure on the neurological tissue which results in mental deficiency and convulsions. There are different causes of hydrocephalus. Some are very well understood and are known to be inherited. As autosomal recessive, others are inherited as sex link recessive. Environmental factors are also known to be a cause of this disorder, i.e. syphilis, toxoplasmosis. Other types of hydrocephalus are not so well understood and are thought to be inherited through many genes.

Pyloric Stenosis  hypertrophy of the pyloric valve.

The pyloric valve is the muscle dividing the stomach from the small intestine. Hypertrophy can cause vomiting in the infant with subsequent malnutrition and eventual death. occurs in a 1000 live births, high incidence among males, different incidents among races, high incident in monozygotic twins most likely due to both genetic and environmental influences. Environmental Influences are indicated because 1) the disease is more common in first born 2) diet and feeding schedule seems to be an important factor in etiology of the disease. Two theories for transmission 1) a common dominant gene 2) a sex modified, multifactorial background. It is very interesting that affected females pass on this trait to their children more often than affected males do. This as well as the extremely high incidence in males indicates a sex dependent factor in the etiology of the disease. Treatment - surgical.

Page 37
 

Congenital Heart Malformations

Congenital heart malformations are quite common. Some are: ventricular septal defects, patent ductus arterlosus, arterial septal defects, stenosis, Tetralogy of Fallot. These all cause defects in circulation and lead to varying degrees of cyanosis and congestive heart failure. Congenital heart malformations are attributed to many causes such as Down's syndrome, rubella, radiation, thalidomide. Multifactorial transmission could possibly be a cause of the congenital heart defects that are not attributed to the above.

Common Diseases

Diabetes Mellitus - Etiology of Diabetes is not completely understood. In some cases insulin is present and doesn't seem to work and in other cases there is a total lack of insulin. Some types of Diabetes appear only in stress situations. Others 1) juvenile (insulin Dependent Diabetes, IDD) - occurs in person before the age of twenty and last throughout life - is severe and unstable. 2) Adult onset (Insulin Nondependent Diabetes. INDD) diabetes - develops later in life, develops more slowly and is normally milder and more stable than juvenile onset diabetes. The incidence of diabetes increases greatly with increasing age. Two percent of total population are diabetic. The etiology for diabetes is not understood. Some believe it could be 1) autosomal recessive at a single gene locus with  20% penetrance 2) autosomal dominant with incomplete penetrance and 3) a major gene with less modifying genes 4) multifactorial. It is not known whether adult and juvenile onset diabetes are two distinct diseases of the same disease. Environmental factors are extremely important. Diet, drugs, pregnancy, stress can Initiate the onset of diabetes. It is believed that these factors usually only affect people that are predisposed genetically to diabetes. People are thought to have a genetic susceptibility but the disease occurs when exposed to an environmental trigger.

Essential Hypertension

Cause is unknown - two genetic theories, 1) multifactorial - high blood pressure Is the result of many factors, elasticity of blood vessels, pulse rate, cardiac output, etc. These are all controlled by different genes. There is filial regression in blood pressure (the blood pressure of a sibling from a parent with high blood pressure is higher than normal but lower than the parent). 2) Single gene etiology - blood pressure in a population shows continuous variation. When the same group of persons are classified according to longevity of parents, people with high blood pressure fall together at one end of the curve. The shorter the life span of the parent the higher the blood pressure of the sibling. Some people feel that this trait is dominant and that in the homozygous state a person has a high blood pressure and in the heterozygous state a moderately high blood pressure further proof of this is the presence of high and low blood pressure strains of rats. If high blood pressure is due to a single gone there should be a biochemical defect. This has not yet been demonstrated, Environmental effects are extremely important in the etiology of the disease. A disease like hypertension can have many causes.

Page 38

Peptic Ulcer

Incidents in monozygotic twins are twice as high as dizygotic twins. Higher incidence in people with type 0 blood. Higher incidence in people who are nonsecreters. Group 0 blood type secretes more gastric juices. Nonsecreters have less protection of mucus membrane. Higher incidence in males may be due to protective influence of female hormones. Environmental factors important - Stress. H-pylori is a proven bacterial cause, but many people affected with H-pylori do not got ulcers.

Ischemic Heart Disease

Coronary artery disease - increased Incidence with hyperlipemia, diabetes and hypertension - all of which thought to have a genetic etiology. Familial incidence - higher incidence in males. Environmental factors important - dietary - smoking - obesity exercise. Racial differences often change when changed when subjected to now environment.

Epilepsy

Many types, have no etiology. Idiopathic epilepsy might be due to genetic etiology. Familial Incidence, abnormal EEG's among parents and siblings of affected persons. One rare variety has definitely been traced to a dominant gene with a high degree of penetrance. Environmental factors have been known to cause epilepsy.

Page 39

Genetic Equilibrium - Population Genetics

Study of population as a whole - individuals within a population are of little significance - except in relation to the whole population. Population genetics is the basis of evolution. Important factors to consider in this study are: size of population, migration, mating regulation, fitness (genetic disease - i.e., Huntington's Chorea), mutations, degree of isolation (very primitive tribes in wilderness have been able to maintain their homogenous character).

Gene Frequencies:

population - individuals that are able to breed with each other.

deme - local population where everyone has the opportunity to breed with each other. Demography is the study of populations.

gene pool - genetic information of the group. The smaller the population, the smaller the gene pool resulting in a smaller number of genotypes (i.e., Amish).

The gene pool remains constant unless modified by mutation or migration.

Hardy-Weinberg Principle:

There is a stable, predictable number of heterozygotes and homozygotes individuals present in a population at all times as long as mating is random (no inbreeding - like inbred dogs) and migration doesn't take place.

The way to figure out what the rates of homozygous dominant, homozygous; recessive and heterozygotes in the population is to use this formula:

 p 2 + 2pq + q 2

Frequencies of rare genes:

The Hardy-Weinberg formula allows one to figure out the frequency of heterozygous individuals in a population (i.e., ss for sickle cell).

Since it is impossible to tell homozygous dominant from heterozygous, the frequency of heterozygotes are determined from the frequency of homozygotes.

Problems:

If 1 in every 400 persons had sickle cell what would be the frequency of heterozygotes?

If one in every 30 persons in a community developed Huntington's Chorea what would be the frequency of the heterozygote?

Factors of Disturbance - Nonrandom meeting, genetic drift, migration, mutation, selection.

Nonrandom Mating - in large populations mating is usually random. Nonrandom rating  is when a person shows a preference for a particular genotype (race, religion, socioeconomic,height, etc.). Nonrandom or assortive mating increases the number of homozygotes in the population.

Genetic Drift - small isolated groups that have remained in such a state for thousands of years tend to share the same number of genes due to the high frequency of inbreeding. Genetic drift is when small groups have the main population to form new communities of their own. When this occurs there is a limited number of people and genotypes in the new population. As the new population interbreeds, one gene allele drifts away (from the original population) or is fixed (a very high frequency) from the population so that only one genotype for a trait exists. (ie., Dunkers & German population with blood type and Amis with Ellis-Van Creveld Syndrome).

Page 40

Gene Flow or Migration - slow, gradual change. New genes are added to the population, interchange of genes between groups, within close proximity. 30% of alleles carried by Afro-Americans are Caucasian, suggesting a gene flow of about 3% per generation (i.e., Rh factor in black).

Mutation - sudden change in genetic material. Can be change of one or more genes. If a mutation is beneficial it might survive. If a gene is detrimental before reproduction its chances of survival are diminished. Most mutations are not beneficial. Why do you think that would be? If mutation occurs after reproduction, it will not be transmitted to offspring.

Genetic Load - genes a person carried that would be lethal in the homozygous state. Each person usually carries 3 to 8 such genes. Mutation rate is about 1 in 25,000 to 1 in 1,000,000 per locus per gamete.

Mutations are usually spontaneous but may be caused by a mutagens such as temperature (increased temperature increases mutation rate), chemicals (carcinogenic - not thought to come in contact with germ cells), ionizing radiation (more important, mutations are proportional to amount received regardless of what radiation has the greater effect on rapidly dividing cells). Effect on germ cells is what's important to genetics - why? Sources - background - cosmic rays, etc., diagnostic, fallout from nuclear explosion and atomic wastes - low. Units of measurement - roetgen (r) = unit of exposure; rad (R) = unit absorbed.

Selection - when a mutation is advantageous it will become prevalent through selection. Very important in the evolutionary process. Fitness = ability to transmit genes, increased survival, increased fertily. Selection must operate before the end of the reproductive period. If a dominant mutation is lethal or causes sterility it will be quickly eliminated from the gene pool whereas a recessive gene will not. Why isn't Huntington's Chorea eliminated.

Many genes are not lethal but reduce fitness. If reduced fitness causes few offspring the gene will eventually disappear.

Some mutant genes increase fitness - i.e., sickle cell anemia, perhaps cystic fibrosis.

Balance polymorphism - superior fitness of heterozygote. In sickle cell, when malaria is removed from the environment, the balanced polymorphism is lost. The heterzygote no longer demonstrates increased fitness. The heterzygote no longer demonstrates increased fitness.

Cystic Fibrosis - high rate of carrier, 1 in 20, perhaps some selective advantage, since parent of CF children often have more offspring perhaps gene increases fertility.

Mutation - selection equilibrium
Detrimental genes eliminated by selection.
Detrimental genes added by mutation.
This represents EQUILIBRIUM.
For example, if every time one gene for cystic fibrosis is eliminated a new one arises by mutation, we are in a state of equilibrium and the gene is maintained at a constant level in the population.

Evolution - organisms must adapt to their environment. The environment is always changing. Evolutionary process is still under-way.

Anything that alters gene frequency will effect the course of evolution.

Page 41

Genetic and Environmental Influences on
Differentiation and Development

Regulation of all body functions are controlled by gene action. Environmental effects also influences development, in particular, during critical times of differentiation.

Embryogenesis:

The fertilized egg, zygote, starts dividing in the fallopian tube. The cells keep dividing exponentially until they form a morual The morual is a solid ball of cells, which is about the same size a., the zygote. The reason this occurs is as they divide, the cells become smaller and smaller. It should be remembered that the zygote is a very large cell. Identical twinning occurs when there is complete division between cells before the cells start to differentiate. As division progresses, the cells become unequal in size and configuration. The next noticeable stage is called the blastocyst - includes an inner cells mass and a fluid-filled ball, indicates that differentiation has begun. At this stage, there are about 108 cells, and only about 8 of these cells will develop into the embryo. The remaining cells will form the placenta, embryonic, chorion, and umbilical cord. At about 7 days, some of the cells from the conceptus starts producing chorionic gonadopropin. This maintains the corpus luteum, thus maintaining pregnancy. The 8 cells that will become the embryo are called the formative laver. The embryo is derived from two layer of cells.

ectoderin (ecto-outer, derm skin) - to develop into brain neurological tissue, sense organ

endoderm (endo means inner) - this layer differentiates into digestive tract, pancreas, bladder, lungs (Tumors arising from these two layers are termed carcinomas.)

mesoderm (middle) - primitive layer that appears between the ectoderm and endoderm differentiates into bone, muscles, blood vessels, connective tissues. (Tumors arising from mesoderm are called sarcomas.)

The blastocyst implants into the wall of the uterus at about 9 days of age. At this stage, part of the conceptus forms villi that penetrates the uterus so that food and oxygen from the mother can nourish the embryo. The outer layer of cells develops into the chorion. Part of the chorion develops into the placenta. Within the chorion the amnion and yoke sac develop. The formative layers that will develop into the embryo lie between the amnion and the yoke sake. By the end of three months, the embryo has developed into a fetus, the amnion and chorion and placenta are fully developed. By three months, the yoke sac has shrunk to a pear-shaped remnant, which is connected to the mid-gut.

Function of the yoke sac:

1 . Transfer of nutrients to embryo during the second and third weeks until placental circulation is established.

2. Blood - developed on the walls of the yoke sack until hemopoietic activity begins in the liver during the sixth week of gestation.

3. Primitive gut - part of the yoke sack becomes part of the GI track and respiratory system.
 

4. Germ cells - appear in the wall of the yoke sac in the third week and migrate into developing gonads. In some people the yoke sac persists as Meckel's diverticulum.

About 25% of early aborted embryos have chromosome abnormalities, mostly non-disiunction. Exposure of embryo to teratogens during the first two weeks usually does not cause congential malformation.

Page 42

differentiation - the process by which cells acquire specific and characteristic properties. All cells are genotypically identical. By the process of differentiation, they become phenotypically different. In other words, most genes are turned off. For example, in the pancreas, genes that make insulin arc turned on, whereas the genes that make hemoglobin, myoglobin and cause cell contraction are turned off.

Basic Cell Differentiation

Epigenetic - development consists of successive formation of an addition of new parts through orderly development and interaction. What this means is that the development of one part will influence the development of the next part and so on, and that the various parts must interact in order for differentiation occur.

In the embryo as well as the adult organism, genes of all the cells are the same; what differs is the chemical environment surrounding the cells (interstitual) and surrounding the nucleus (intercellular). In other words, the cytoplasm of different cells is different. For example, the cytoplasm of the liver is different from the cytoplasm of a muscle cell. Not only this, but the chemical environment surrounding ic cells, the interstitual space, is different. These facts are important in understanding differentiation. The genes within a cell are what brings about the different chemical environment and cytoplasmic environment. (Remember repressor substance.) When studying neoplasia, we learn about protooncogenes and suppressor oncogens.

Tissue Interaction - one type of tissue has the ability to stimulate or repress a response in neighboring tissue.

Tissue Movement- morphogenic - tissue development begins in one area and migrates to another area. Spina bifida and cleft palate are thought to be the result of abnormal tissue movement.

Cellular Degeneration - some cells are programmed to die during the developmental process. These cells are timed to die at particular points in development; this timing is controlled by genes. Examples of tissues programmed to die are cells between the fingers and toes, cells filling up hollow organs, such as ducts, lumens, and eyelids. If the genes are defective so as to prevent normal degeneration, such anomalies as web fingers, presence of a tail, and neuroblastomas will occur.

Extrachromosomal Effect - the egg produced by the female has a great deal of cytoplasmic material whereas the sperm does not. In the cytoplasm are the various types of RNA (transfer, Ribosome) which control protein synthesis and sustains the life of the cell. The coding activity (for proteins) in the zygote remains dormant. In other words, the DNA of the zygote is just involved in cell division and does not take part in coding of messenger RNA during the early stages of embryo genesis. Because no cytoplasmic RNA is transmitted from the sperm, it stands to reason that the genetic constitution of the mother (and not the father) affects early development of the embryo. The significance of this effect is not known. The mitochondria of the egg contains DNA.

Repgulation of the Gene Action - during embryo genesis, structural genes must be turned off and turned on at particular times in order-to bring about the development of a normnal embryo. The mechanism used to bring this about is the same as that seen in the adult, the operator, regulator mechanism, which includes repressor gene and a repressor substance. Defects in the form of mutation occurring in this mechanism which would be extremely detrimental to development.
Changes in Protein during Development - it is known that during the developmental process, proteins and enzymes change. This is understood by studying various proteins. One example is LDH (Lactic Acid Dehydrogenase Isozynes) which is found in plainly different forms during the developmental process and in the adult. Another example is the development of hemoglobin. There are two types of hemoglobin: hemoglobin A which is adult hemoglobin and hemoglobin F which is fetal hemoglobin. They are both coded by different suctural genes and they have different capacities for transporting oxygen.

Page 43

 Fetal hemoglobin will transport oxygen in a lower oxygen environment. Both types of hemoglobin are made up of four (4) chains. Each of them have 2 Alpha chains, whereas hemoglobin A has two Beta chains beginning in the developmental process Alpha chains are produced. These Alpha chains will be produced throughout life into old age. The Gamma chains are also manufactured during embryogenesis. The ability to produce Gamma chains continues throughout the developmental period and decreases and disappears at about 4 months of age, whereas the manufacture of Beta chains which are seen in adult hemoglobin begin in the latter span of fetal life and continue throughout the remainder of the organism's life span.

Male Pseudo-hermaphroditism - genotype of male (XY). External genitalia and secondary sex characteristics of females.

Testicular feminization - genotype (XY), testes might secrete estrogen, persons phenotypically female, often married and do not seek advice until amenorrhea, or a desire for children, heredity.

Female Pseudo-hermaphroditism - genotype (XX), due to increased secretion of androgen from the adrenal cortex. May be due to production of androgen by fetus or by maternal cortex with androgen reaching fetus through placenta. Progrestational agents used to prevent abortion have androgenic properties.

Congenital Malformation:

1. Can arise during any stage of development, etiology - one single gene mutant, i.e., polydactyly or deafness.

2. Chromosomal aberration, i.e., Down's Syndrome.
 

3. Interuterine environmental factors, i.e., rubella or interaction between genetic and environmental factors, i.e., club foot, dislocated hip.

Environmental Influences

The most severe effects on development occur before implantation when the embryo is rapidly dividing. During this time, most abnormal embryos are aborted. The majority of abnormalities seen in the fetus or child occur from the time of implantation until the end of the third month of gestation.

Critical Period - is a period of rapid development when the organism is vulnerable. Teratogens are agents capable of producing adverse effects during this time. A teratogen will affect an organ during its critical stage. Each organ has its own critical period and in many cases, the critical periods of organs overlap. Raditation, chemicals, and infectious agents can be teratogens. Most common infectious agent teratogen is rubella which causes most heart defects, eye defects, deafness, mental retardation and microcephaly. The type of defect is directly related to the stage of fetal development when exposure occurs. The most severe defects occur during the first trimester of pregnancy. Other infectious agents are known teratogens. Radiation is both mutagenic and teratogenic. It can affect any organ in the embryo and fetus The malformations are less severe in the later stages of pregnancy, and require higher dosage of radiation. The best known chemical is thalidomide which causes severe developmental affects in the fetus. The affect of the thalidomide normally occurs from the beginning of the second month until the end of the third month. Other minor tranquilizers such as librium and valium are also known to be teratogenic and cause the less severe symptoms of cleft palate and deafness, etc. Many other chemicals are thought to be teratogenic but no proof as yet has been established. Because of this, it is advisable to limit the use of pharmaceuticals to all women during pregnancy. There is a strong correlation between nutritional factor and development. Besides a poor diet, others things such as faculty implantation of the ovum, degeneration of the chorion, and altheration in the location of the function of the placenta can disrupt the nutrition of the developing organism.

Page 44
 
 

Phenocopes:

An environmental agent can mimic almost any phenotype. An example of this is mental retardation which can be caused by a single gene disorder, a chromosomal aberration, or a decrease of oxygen from various environmental factors such as anesthesia during labor, carbon monoxide poisoning, or it can also be due to a dietary insufficiency such as a lack of iodine. It is important to consider environmental factors before a disorder is labeled hereditary.

Abortion:

Spontaneous abortion is a common phenomenon. Probably 10 to 25 percent of human pregnancies are lost within the first three months following fertilization. Spontaneous abortion is common at the extremes of maternal age. Spontaneous abortion is usually related to lethal genes, teratogenic: effects in the early part of pregnancies, and to an unsuitable maternal environmental. There is another phenomenon called antigen antibody compatibility which is related to the ABO blood system. In his case, women with 0 blood made antibodies against A and B antigens. If the embryo happens to have A or B blood, the female might reject the fetus through the ABO system early in the pregnancy. The most cornmon cause of spontaneous abortion is chromosomal aberration.

Twins - Type

Monozyaotic - identical - same genotype, same phenotype. Always the same sex. Always the same blood group, may share the same amnion and the same chorion. Often are mirror images of each other. Identical twins develop from the same egg and the same sperm which undergoes a complete division during early differentiation. The incidence of monozygotic twins is a rare event and occurs at the same rate in each and every race,

Dizygotic - twins - fraternal - not identical - may have the same blood types or different blood types, may be of the same sex or different sex, are genotypically and phenotypically different, occurs when two unalike ova are released simultaneously by the female and fertilized by two unalike sperm. This incidence of Dizygotic twins is different between races, the Negroid race having the highest amount - one in every twenty to thirty pregnancies; Caucasians, one in 80 pregnancies and in the Oriental races, 1 in 150 to 200 pregnancies. Dizygotic twinning increases with age and number of pregnancies. In other words, the more pregnancies a woman has the more likely she is to have Dizygotic twins. There two factors correlate independently.

The incidence of twinning is affected by heredity. There is an increased incidence of twinning in families. The incidence if prominent on the maternal side. In other words, if you are a female and there a history of twinning in your family, there is a higher than average probability that you might produce twin offspring. On the other hand, if there is a high incidence of twinning on your husband's side of the family, it will not increase your likelihood to produce twins. It is possible that your husband's sperm will pass on to any daughters that you might have, the ability to produce two ovum at ovulation (twin). This accounts for the skip in generation that is often associated with twinning. Double ovulation is increased by the production of pituitary gonadotrophin, Women with enlarged pituitary glands are more likely to produce twins. All characteristics that increase the likelihood of twins correlates with pituitary gland size.

Determination of Zygosity - the phenomenon of twinning is important medical research. It enables us t study disease processes and the influence of heredity and the environment on disease. Therefore, it is important that a distinction is made as early as possible between identical and fraternal twin. It is not always easy to make this distinction. Some criteria for determining identical and non-identical twins are as follows:
Page 45

1.  Fetal membrane - fraternal twins will never share the same membrane although identical twins  can have separate membranes.

2.  Identical twins will often be mirror images of each other. Identical twins will always have the same blood type, although fraternal twins can have the same blood type.

3.  Identical twins will accept transplants from each other, whereas fraternal twins will not. This can be tested by a simple skin graft.

4.  Today DNA testing is used.

Aging

Aging is determined by heredity. Although we do not know if there are specific genes for aging, we do know that physical changes occur at different ages for different organs. We also know that related people tend to have life spans more alike than non-related people. There is a smaller difference of life span between Monozygotic twins that Dizygotic twins. Different species age at different rates. We do not know what causes aging. We do know that as organisms get older it is more difficult to maintain homeostasis. Normal cells are mortal and can only divide a certain number of times. Cancer cells are immortal.

Sex Ratio

One hundred and six males are born to every 100 females. One hundred thirty males are conceived for every 100 females. As aging occurs, there is an increased mortality among males. By the time of reproduction, there is an equal number of males and females in the population. As aging progresses, there is increased mortality among males so that by the time of age 85 there are 85 males to every 100 females. This might be due to an x-linked recessive chromosome which would most likely show up in the male or perhaps to hybrid vigor (two X's) among the female in the population.

Sex Differentiation

For the first six weeks of life there is no sexual distinction. The embryo is neither male nor female. The embryo contains all tissues for development into either sex. Sexual development occurs during the 7th and 8th week. Development of male characteristics is determined by the genes on the Y chromosome. If there is no hormonal stimulation the embryo will differentiate into a female regardless of the genotype.

Abberant Sexual Development

May be chromosomal or non-chromosomal. Non-chromosomal is the result of hormonal or environmental influence.

Intersex  persons whose sex is ambiguous, fail to display all criteria for one sex.

Hermaphroditism - true, rare - may be genetic male or female, have both testes and ovaries, must be recognized by histological examination. Cause is unknown.
 
 
 
 
 

End of Lecture Notes
Return to Main Page