Genes & Genetic Diseases - PDF

Hello, everyone, this lecture covers genes, so we got in chapter three of the multiple lectures for this module, for this module two. We're going to cover Guytons Chapter three mechanic check or four or five and six. The learning objectives are describe how genes influence all aspects of body struct...

Hello, everyone, this lecture covers genes, so we got in chapter three of the multiple lectures for this module, for this module two. We're going to cover Guytons Chapter three mechanic check or four or five and six. The learning objectives are describe how genes influence all aspects of body structure and function. Compare how defects in genes can lead to recognizable genetic diseases. In this lecture, we're going to cover in Chapter three. So first, we're going to talk about how genes control protein synthesis in the nucleus and the cell nucleus. Large numbers of genes are attached and done in an extremely long double standard helical molecules that have a molecular weight in the billions. Everyone's seen the double helix molecule now building blocks of DNA phosphoric acid deoxy Ribot's and for nitrogen basis anying guanine and two, pyramiding, timing and cytosine. So first, we'll start with DNA structure. The backbone is composed of alternating phosphoric acids and deoxy robust molecules, pierini pureeing and pyramiding bases are attached to deoxy robust molecules appearing base. Adnen always bonds with the period editing bay stimming appearing based guanine always bonds with the period of Maddin based cytosine. The genetic code consists of successful successive triplet bases. Each three successive bases is a code word. The triplets eventually control the sequence of amino acids in the protein molecule. Transcription, so is the process in which the code is transferred to the RNA, the RNA that diffuses from the nucleus through nuclear pores into the cytoplasm compartment, so the DNA actually does stays in the nucleus. The RNA is transcribed and then diffuses. There are several different types of RNA. They perform several different functions, including splicing, messenger transfer, ribosomal proteins are are formed in the cytoplasm of the cell, but not in the cell nucleus. So that's important because the nucleus does not contain mature ribosomes. The ribosome acts as a manufacturing plant, which protein molecules are formed. So we discussed ribosomes in the previous module and previous chapters. Translation is the formation of proteins in the ribosome. It's red in much the same way. It's passing through the head of a tape recorder. And you can see in the graph or figure here you have the messenger RNA that's moving this direction. The ribosome is reading it and then producing the proteins. A single messenger RNA molecule. Can form protein molecules in several different ribosomes at the same time, ribosomes attach to the in the past reticulum and give a grain of appearance. We discussed that previously. The Rough ER were proteins are being formed. These proteins then pass into the matrix of the reticulum. So then we synthesize other substances in the cell, so many thousand protein enzymes are formed in the manner just described, and they control essentially all other chemical reactions that take place in the cell. They promote synthesis of lipids, glycogen, Pyrenees proteins and hundreds of other substances. Genetic regulation or the regulation of gene expression covers the entire process from transcription in the nucleus to formation of proteins in the cytoplasm. For example, a cardiac Mossi contains the same genetic code as a real tubular epithelial cell. But many genes are expressed differently and will cover more than just a little bit. Enzyme regulation is some chemical substances have inhibitors or activators of enzyme systems that synthesized the chemical substance. It's a negative feedback loop. So the the more of that chemical substances present than it inhibits creation, more substance. So the control of cellular constituents. So to sum up kind of what we were just saying, there are two principal mechanisms that cells use to control the proper quantities and proportions. Genetic regulation and enzyme regulation genes can be activated or inhibited and enzyme systems can be activated for both. Those systems can be turned on or off. Substances from outside the cell also control intracellular biochemical reactions by activating or inhibiting one of the more of those control systems, a very big example of what would activate or inhibit our hormones. Cell reproduction, so genes in their regulatory mechanisms determine cell growth and when or whether cells will divide the form new cells. When Mimili million cells are not inhibited and reproducing as rapidly as they can, the life cycle can be anywhere from 10 to 30 hours. So basically the life cycle can be as short as 10 to 30 hours or so. It's terminated by mitosis, which is cell division of the cell into two new daughter cells. There are inhibitory factors that are almost always slow or stop the uninhibited life cycle. The cell life cycle of different cells in the body can vary anywhere from 10 hours for bone marrow cells to an entire lifetime for nerve cells. Cell replication is the first step of cell replication is replication of the DNA that's takes anywhere from four to eight hours and reproduces to exact replicas of all DNA in the chromosomes. That's replicated in much the same way that RNA is transcribed from DNA. The process is described as CIMIC conservative. So there's two DNA molecules are produced, each one with a strand of the DNA. Half the chain is part of the original DNA molecule and half is brand new. And then you go to a proofreading and mutation between replication and the beginning of mitosis, there's a period of proofreading. So this is whenever an appropriate DNA nucleotides are found, special enzymes, enzymes, cut out those defective areas and replace them. Mistakes are rarely made in the DNA replication process, but when they are, it's called a mutation. So mistakes are rarely made because of this proofreading process when mistakes are made. It's called mutation. Reproduction and growth, so this is the mitosis, it's a multi-stage process whereby the cell splits into new cells, some cells grow and reproduce all the time, but many cells may not reproduce for many years. And then there are a few cells that don't reproduce for the entire life of a person. Talk about that. Bone marrow is an example of a cell that reproduces rapidly. Smooth muscle cells may not reproduce for many years. Neurons and most striated muscle cells won't reproduce for an entire lifetime. Cell size is determined almost entirely by the amount of functioning DNA in the nucleus also carry all the necessary genetic information for development of all structures. So it's an example of cell differentiation results from selective repression of different gene promoters. So this is they took mucosal cells from the stomach of a frog and put them in another portion and they grew the proper cells for the place where they were implanted. This is an example of they have all the genes they need, but the different repression or promotion creates them, making the different cells. So apoptosis is the societal programming cell death, the opprobrium that it cascade. So the cell shrinks and condenses disassembles it cytoskeleton and alters its cellular surface so that neighboring figure Sediq cells can attach the cell and digest it. It's a direct contrast to cells that die as a result of injury. Cells it drives as a result of injury usually swell and bursts due to loss of cellular membrane integrity. Once again, we talk about that in the last lecture that's called necrosis. Even adult human billions of cells die each hour and replaced by new cells. Programmed cell death is normally balanced by the formation of new cells, otherwise the body tissues would shrink or grow excessively. So, of course, if we're talking about cell reproduction and mitosis in a pathophysiology class, we're going to talk about cancer. So cancer may be caused by the mutation or by some other abnormal activation of cellular genes that control cell growth and cell mitosis. Only a minor fraction of the cells that mutate in the body actually ever lead to cancer. For these four reasons, most mutated cells have less survivable capability and simply die. Only a few of them mutate. Mutated cells that survive become cancerous because most mutated cells still have normal feedback controls that prevent excessive growth. The potentially cancerous cells are often destroyed by the body's immune system due to most mutated cells form abnormal proteins, which activates the body's immune system in people whose immune system has been suppressed. The probability that a cancer will develop is multiplied as much as five fold. And lastly, several different genes must be present simultaneously. This is something very interesting. One gene that might promote rapid reproduction. But cancer wasn't developed because the gene, the form, the need of blood vessel supplies is present. So you have to have the gene that forms the rapid reproduction and the gene that causes the blood vessels to be present. So based on those factors, we will say that chance alone is all that is required for mutations to take place. We can suppose that a large number of cancers are merely the result of a lucky occurrence, the probability of mutations, although it can be greatly increased when a person is exposed to certain chemical, physical and biological factors, half of them ionizing radiation ions form in tissue cells under the influence of radiation can rupture DNA strands and cause mutations. Chemical substances, which are called carcinogens. Cigarette smoke causes the greatest number of deaths out of all the carcinogens. Physical irritants can be something like abrasions to the intestinal tract caused by certain types of foods, hereditary tendency. So it's present one or more cancerous gene is already mutated in the inherited genome and therefore fewer additional mutations are needed for cancer to occur. Certain types of onco viruses, such as hepatitis B and C, as well as HIV or examples, they can increase the risk of cancer. So we could talk about the invasive characteristic of cancer and the reasons or the three reasons the cancer cell does not respond to usual cellular growth limits is often far less of his adhesive to other cells. Therefore, they tend to wander through tissues and into the bloodstream and can travel to metastasize. Some cancers produce angiogenic factors that cause new blood vessel growth into the cancer to supply new nutrients directly to the cancer y the cancer cells kill. So cancer tissues compete with normal tissue for nutrients because they continue to proliferate indefinitely. Cancer cells soon demand essentially all the nutrients available to the body. Some cancers disrupt vital organ function. This is an example of lung cancer replacing tissue to the extent the lungs cannot absorb enough oxygen anymore. Hello, everyone, this lecture is going to cover genes and genetic diseases we're going to cover once again this Model two, which covers guide, Chapter three, Meccans four, five and six. This lecture will be over. Chapter four. There are also chromosomes involved in mitosis and meiosis, two types of chromosomes, cells, germline and somatic germline mutations can be transmitted to the next generation. You see an example of a germ when cells are sperm. So the somatic chromosome cells, a deployed cell which contains 23 pairs of chromosomes, 22 of those pairs are homologous. The twenty third pair, the sex chromosomes, which consist of two homologous X chromosomes and females and a non Morgus pair of X, Y and males. So we have probably plotty chromosomal cells when a germline or somatic cell has more than a deployed number of chromosomes, which is forty six. There are several types of body tissue that have this, including the liver, bronchioles and epithelial tissue and. Triploid is when a zygote when the zygote has three copies of each chromosome chromosome, rather than into nearly all triploid conceptions, are spontaneously aborted or stillborn accounts for 10 percent of all known miscarriages. Then you have aneuploidy, chromosomal cells, these cells do not contain a multiple of 23 chromosomes, so you have monism, a dipole diploid cell, which contains only one copy of chromosome instead of the two. This is always lethal. And then you have Trisomy, which is an unemployed cell containing three copies of one chromosome. The survivable trisomies are 13, 18 and 21. This is the reason you have this trisomy is normally a result on this junction where homologous chromosome or sister chromatids fail to separate normally during meiosis and mitosis. So far, we've talked about diseases that have been caused by the loss or gain of the whole chromosome, but now we're going to talk about abnormalities of the chromosome structure. Parts of chromosomes can be lost or duplicated as gametes are formed and the rearrangement of genes on chromosomes can be altered. And different types of those are deletions. A gamete with a delete deletion unites with a normal gamae to form a zygote Y chromosome with a normal complement of genes. And one has missing is missing the genes. A example of that is tried to chat syndrome. Duplications, duplications usually have less serious consequences than deletions. A deficiency of genetic material is more harmful than excess inversions. The occurrence of two breaks on a chromosome followed by the reinsertion of the missing fragment at the original site. But in an inverted order, it's balanced. There's no loss of genetic material, but it can often have deletions and duplications. So does sometimes result in diseases. So continue with the abnormalities of the chromosome structure, translocations or the interchanging of genetic material between non homologous chromosomes, Roberts oneone translocation, the long arms of two non homologous chromosomes fused at the centimeter, forming a single chromosome. Reciprocal translocation occurs when brake's take place in two different chromosomes and the material is exchanged. Fragile sites, a number of areas and chromosomes develop what microscopically can be observed as breaks and gaps. Most have no apparent relationship to disease, although there is fragile X syndrome, a fragile site located on the long arm. The X chromosome, which has considerable clinical and genetic importance associated with cognitive impairment, affects one in four thousand males and one to eight thousand females. That makes it the second most common cause of intellectual disability after Down's syndrome. OK, and now we'll talk about some different chromosomal disorders, the first of which being Down syndrome is the most well known example of influenza chromosomal cells and 800 live births typically have a low IQ quotient. The risk of Down's syndrome greatly increases with maternal age. Approximately 97 percent are caused by non destruction during formation of the one one of the parents gametes or during early embryonic development remaining three percent result from translocations. The facial appearance is distinctive, with a low nasal bridge at the kanthal fold large protruding calm and low, flat, low citius. Congenital heart defects affect about one third to one half. By 40 years old, almost all always developed symptoms of early Alzheimer's disease. One of the genes that can cause Alzheimer's is located on chromosome 21. Turner Syndrome is one of the most common single chromosomal aberrations, 15 to 20 percent of spontaneous abortions are due to Turner Syndrome. One in 2500 newborn females is affected. It's the presence of a single X chromosome results in a total of 45 chromosomes and no homologous X or Y chromosome. Since they have no Y chromosomes, they're always female, but usually sterile. Physical characteristics are short in stature, webbing of the neck, widely spaced nipples, cooptation the aorta, dema the feet and newborns and sparks body hair. Next to talk about Klinefelter's syndrome, which is two X chromosomes, and why do the presence of the Y chromosome, they always have a male appearance, but usually sterile. The physical characteristics are 50 percent of them developed gynecomastia. The testes are small and body hair is sparse. Statues are elevated, voice is somewhat high pitched in. A moderate degree of mental impairment is often present to about one in a thousand male birth. Now we're just going to discuss some elements of formal genetics, vastly different definitions, locus is the location each gene occupies on a chromosome. Belial genes that a particular locust can take different forms can determine the difference between hemoglobin s and hemoglobin. A hemoglobin s is what creates sickle cell disease. The polymorphic when two or more Leal's each occur with appreciable frequencies in a population, then you have a genotype. The composition of genes that a given locus phenotype, the results of both genotype and environment, the dominant gene, which is the aleo whose affects mask and other heterozygous recessive to be expressed, must exist in homozygous form. Carrier is an individual as a disease causing aleo but is phenotypically normal. So now we'll talk about the transmission of genetic diseases. Mode of inheritance is the pattern in which the disease is inherited through the generations of a family. Once this is known, much can be learned about the gene causing the disease. This was systematically studied by Gregor Mendel, who devised the medallion trait's principle of segregation, the homologous gene separate from one another during reproduction in each reproductive cell carries on one of the mortgage genes. Principle of independent assortment of hereditary transmission of one gene has no effect on the transmission of another. The known single gene diseases can be classified into four major modes of inheritance horizontal, most dominant or recessive, excellent dominant XLE recessive. There's only a few genes that cause diseases which are found on the Y chromosome, and those primarily affect male fertility. Now we're talk about a pedigree chart. It's important in the analysis of the modes of inheritance, summarises family relationships and shows which family members are affected by a genetic disease. The problem is the individual affected by genetic disease compositors is the male perpetrator is the female the first person in the family diagnosed or seen in a clinic. That's a key for category chart. And then the bottom right is the pedigree chart. That's illustrated in Achondroplasia. So first, we'll talk about autosomal dominant inheritance, some key characteristics, both sexes exhibit the trait and equal proportion. No skipping generations affected. Heterozygous individuals transmit the trait to approximately 50 percent of their children. So based on statistics, they could transmit to zero percent of their children or 100 percent of their children. Those are just rare in large population studies, 50 percent of the children commonly affected. It's uncommon for two individuals, both affected by the same autosomal dominant seeds to produce offspring together. So these are relatively rare diseases. One in 500 people are affected. So for two individuals that are both affected by disease. To meet and produce offspring is relatively rare. More common affected offspring are produced by the union of a normal parent with an affected heterozygous. So here is the punnet square for the normal parent with the affected parent and makes a heterozygous effective. And here's the planet square. For an affected parent and an affected parent, the one difference, obviously, being you can get homozygous affected parent with two affected parents. You cannot get that with Enda's, I guess, affected parents. So goes through some genetic disease characteristics, recurrence risk is the chance that a child will have the disease when one parent is heterozygous affected and the other is unaffected, recurrence risk for the child is 50 percent. It's important to remember that each birth is an independent event. So much like the flip of a coin, one birth does not affect the other one. Flip a coin does not affect the next so normal parent affected parent 50 percent chance of being affected, 50 percent chance of being normal. If a child has been born with autism or dominant disease, there's and there's no history of the disease in the family, child is probably the product of the new gene mutation. So penetrates is the percentage of individuals with a genotype who also exhibit the expected phenotype. So incomplete penetrance, the individuals who have a disease causing bit may not exhibit the disease phenotype at all. In other words, they have the disease, but they don't exhibit any symptoms. The illegal and the associated disease may be transmitted to the next generation in which you would have at the bottom here the opposite carrier. So this is the person whose parent is affected, their child is affected, and therefore they must themselves be the carrier must carry the illegal, but they are not affected by the disease. And then also, you have aged dependent pensions, so symptoms of the disease are not seen until 40 years of age or later. So multiple diseases are common breast cancer, colon cancer, haemochromatosis and polycystic kidney disease. So these people are left with the question with any of these, should I have children knowing there's a 50/50 chance they will have this disease? So should I have children knowing I can pass this gene to them and may not either be symptomatic yet or may not ever be symptomatic? So we talk about autosomal dominant and now we'll talk about autosomal recessive diseases caused by autosomal recessive illegals are rare, just like others on the dominant frequency of carriers can be high. Individuals must be homozygous for recessive illegals to express the disease carriers or phenotypically normal, they can be characterized by incomplete. Penetrance age dependent insurance, as well as variable aggressivity, the same as the others. Some of the diseases are the most common. Lethal disease is in children with cystic fibrosis, which occurs in about one in twenty five hundred births, which is a defective chloride transporter, which leads to a salt imbalance resulting in abnormally thick, dehydrated mucus secretions. Death from lung disease or heart failure can occur about 40 years on average. So here we have the punnet square. So we have. Homozygous, normal, so dominant, you have the heterozygous carrier and the head is like a carrier, so you have to homozygous affected. So this is why your carrier percentage is high. An important concept, an autosomal recessive inheritance is continuity, the marriage, which is the marriage between related individuals. It's often a factor in producing recessive disease related individuals are more likely to share the same recessive disease, causing appeals for important criteria for discerning autism and inheritance. Males and females are affected in equal proportions consensually is sometimes present. The disease is seen in siblings, but not usually in their parents. On average, a quarter of the offspring of carrier parents will be affected. Actually, inheritance. So the Y chromosome contains only a few dozen genes, so most sex linked traits are located on the X chromosome with the exception of Fragile X syndrome. Females receive two X chromosomes and therefore can be homozygous for disease, homozygous for the normal leel or heterozygous. A male who inherits a recessive disease on the X chromosome will be affected by that disease because the X chromosome does not carry normal illegal to counteract the effects of the disease causing a will. Therefore, males were more frequently affected by excellent recessive diseases characteristics of X linked recessive conditions. The trait will be seen much more often in males. Females must adhere to copies of the recessive illegal to express the disease. Males need only inherit one recessive atleo from their mother. It's never transmitted from father to son. Sons only receive the Y chromosome from their father. The gene can be transmitted through a series of carrier females, causing the appearance of skip generations. Affected fathers will transmit to all daughters who then will be phenotypically normal carriers, transmitting the gene to approximately half of their sons who will be affected. The most common and severe of all excellent recessive disorders is to change muscular dystrophy, which affects approximately one in thirty five hundred males. So excellent recurrence risk. The most common mating type is the combination of female carrier and a normal male. The mother will transmit the disease, causing real to half of their offspring. Half the daughters will be carriers. Half will be normal. Half the sons will be normal. Half of them will have the disease. Sex determination begins during the sixth week of gestation. One Y chromosome is sufficient to initiate the process of gonadal differentiation. The number of X chromosomes does not alter this process, and an individual can have to X chromosomes and one Y chromosome and still be a phenotypically male. The S.R. Y, which is the sex determining region on the Y, has been located on short arm the Y chromosome. It appears to act as a trigger that initiates the action of genes on the other chromosomes. So sometimes there can be some confusion between the difference in sex limiting trait in a sex influence straight. So a sex limited trait is a trait that can occur in only one of the sexes, often because of anatomic differences. Example that is breast cancer, which is 70 times more common in females than males. The sex influence trait trait that occurs much more often in one sex than the other, such as male pattern baldness. Gene identification, so locating the positions of genes on chromosomes has been one of the most important endeavors in human genetics for most genetic diseases. It is not possible to test directly for the disease causing mutation, often by sequencing the germline DNA and family members. Can you find the disease? Germline DNA is tissue derived from reproductive cells, egg or sperm that become incorporated into the DNA of every cell in the body of their offspring. As the cost of sequencing the whole human genome has declined is now common to search for diseases using common mutations in individual or family by evaluating their entire germline DNA sequence. Currently, the causes of about 4700 Madeley and conditions have been determined, enabling genetic testing, more accurate diagnosis and in some cases, more effective treatment of the disease. So now we'll talk about precision or personalized medicine, which is something that could really affect both the general practice and anaesthesia worlds coming in the near future. Each person's unique genetic and environmental risk factors are taken into account in the diagnosis and management of diseases. It's becoming increasingly common to diagnose diseases by searching for disease, causing variances in the person's entire DNA sequence. Perhaps the area in which genetics is contributing. Most significant is the guidance of therapeutic drug prescriptions. So. This is what could really have an effect on us out of. Twelve hundred drugs are approved by the FDA. 15 percent have recommendations for genetic testing to be done to guide administration dosing variants in a sea wipe 286 gene, which encodes for Cytochrome B 450 influences the metabolism of more than 25 percent of all prescribed drugs. So testing for the S.O.P to desex can reduce trial and error for estimating appropriate drug levels. So this is where in the future someone could go have genetic testing done prior to coming in for their anesthetic. And we would know exactly what their metabolism was like and whether they would be rapid metabolizes of fentanyl for persay or slow metabolism. So this is where sometimes maybe we see the variance of someone who has long term effects of something like fentanyl that we give or that we give one hundred mikes of fentanyl and there's a very Short-Lived effects or no effects. Hello, everyone, this is Jeanne's environment, lifestyle and common diseases. This is Module two, which covers Goytan Chapters three, Mcance four, five and six. As everyone knows, this lecture covers a Chapter five genes, environment, lifestyle, common diseases, as we said. So first, we'll talk about the incidence of disease in populations. The incidence rate is the number of new cases of disease reported during a specific period, typically one year. The prevalence rate is the proportion of population affected by the disease and a specific point in time. So the prevalence rate is usually higher than the incidence rate. Comparison of these two numbers depends on the length of the survival period. The prevalence rate of AIDS is larger than the incidence rate because most people, they survive for several years. These are examples of many diseases very in prevalence from one population to a next. Cystic fibrosis is common in Europeans rare occasions sickle cell disease, one in 600 American blacks, but much less frequent in whites. Colon cancer is rare in Japan, but is the second most common cancer in the United States, whereas stomach cancer is common in Japan but rare in the United States as Japanese have immigrated to the US. Epidemiologists have been able to observe what happens to the rates of stomach cancer and colon cancer, which they switched, so indicate an important role for environmental factors, environmental factors for colon and stomach cancer. So as they've integrated the rates of colon cancer in Japanese have went up and their rates of stomach cancer went down. So risk factors, relative risk is the increased rate of disease among individuals exposed, so you have individuals exposed over individuals not exposed. An example would be lung cancer. They did a study of lung cancer in physicians. So lung cancer death had a rate of one point sixty six. For those that were heavy smokers, it had zero point zero seven rate of death for among nonsmokers. So you would say it had a twenty four fold risk of death from lung cancer for heavy smoking risk factors of developing a disease can be genetic or lifestyle related. So age, gender, diet, amount of exercise, family history can all affect or read disease smokers example of genetic causes or variants. Smokers who have a very genes that are involved in the metabolism of tobacco and tobacco smoke components are significantly increased our rate of risk of developing lung cancer. So now we get a little more complicated with multifactorial inherits polygenic his traits in which variation is thought to be caused by the combined effects of multiple genes. Multifactorial is when environmental factors are also believed to cause the variation in traits. So, for example, height is affected by more than one gene as well as environmental factors, and therefore there are many more possibilities and taulbee absorb. So it was just affected by one gene. You have taught me to make sure we all know that's not accurate. So here's an example of that. Tall, medium, short. We see if you add in just one more gene, this creates a different a little bit different distribution and a lot more possibilities, which is more accurate. And then you add in. Lifestyle, environmental factors, which can make this a lot more of a normal distribution. Blood pressure is influenced by parents blood pressure, but also environmental factors such as diet, exercise. So an example, many adult diseases, hypertension, coronary heart disease and stroke, diabetes and some other cancers are influenced. Threshold of viability, certain diseases. There doesn't seem to be a normal distribution there, either present or absence, a number of different genes, along with a number of environmental variables, variables, actors, risk or protective factors. So, for example, you have pyloric stenosis. So this is an example of pilots and osis and a distribution curve. It's more common in males and females. So you have the threshold of liability for a male being here. So it either happens, you happen to notice or you don't, or females, which are a lot less incidents of risk or incidents with females. Recurrence, risk and transmission patterns, risk estimation is difficult with multifactorial diseases for most multifactorial diseases, empirical risk has been derived. It is difficult to distinguish polygenic or multifactorial diseases from single gene diseases that reduce benefits or variable expression. These are several criteria that have been used to define multifactorial inheritance so the recurrence becomes higher if more than one family member is affected. Interestingly, this does not mean the family's risk is actually changed. It only means there's more information about the family's true risk. If the expression of disease in the band is more severe, the recurrence risk is higher, the recurrence risk is higher. If the band of the less is of the less commonly affected sex, the recurrence risk for the disease usually decreases rapidly in more remote relatives to recurrence risk for single gene diseases 50 percent for each degree of relationship, 50 percent decrease. This decreases much more quickly for multifactorial diseases. So we can discuss twin studies of twins occur about one in 100 births and white populations more common and blacks less common, and Asians monozygotic Emsley are identical when the developing embryo divides to form two separate but identical embryos. So they been fertilized and then at some later time splits or divides to form two embryos, dizygotic dezi or fraternal double ovulation, followed by fertilization of each egg by different sperm. It is possible for each twin to have a different father. M.S. twins are concerned across populations, whereas d.g twinning rates vary somewhat. Monozygotic twins are genetically identical. So any differences should be caused only by environmental factors. Dizygotic twins are genetically different, but their environment differences should be similar. Genetically, they are the same as siblings as someone who has dizygotic twins, one with blond hair, one with brunette hair. They are the same as siblings. They are just born at the same time. Incredibly interesting and then environmental factors should be extremely similar for the two, although we will see in just a little bit. Things can vary slightly. Twin studies concordant both members of the twin pair share a trait discordant if they do not share the trait. If a trait is solely determined by genes, monozygotic twins should always be concordant. The concordance rate for contagious diseases such as measles are quite similar for monozygotic and dizygotic twins because they're not caused by genetic. The concordance rate is quite dissimilar for schizophrenia and bipolar affective disorder, which shows that it has a sizable genetic component. On page 166 in cancer, there's a table on the concordance rate in my monozygotic and dizygotic twins. It's an interesting read. Twins were once thought to provide a natural, a perfect natural laboratory. But several difficulties arose the assumptions that the environments are equally similar. I was one of the issues and I could say that each each sibling that's born into a family is born into a different environment, even if they're born at the same time. Things are different, whether you mean to or not. So it is not identical environment and they can be treated differently so than we can compare adoption studies. Children born to parents who have a disease but then subsequently adopted by parents lacking the disease can be studied to find out whether these children develop the disease. When such children develop disease more often than a comparative control population, it provides some evidence that genes may be involved in the causation of that disease. Eight to 10 percent of adopted children of a schizophrenic parent develop schizophrenia, whereas only one percent of parents of children who whose parents don't have schizophrenia develop schizophrenia. Showing that it has a genetic component. Caution must be exercised interpreting the results so prenatal interpreting the results of adoption studies, prenatal environmental influences could have long lasting effects on adopted child and children can be adopted after they are several years old. And sharing some of the environmental influences have been important. So what are twins in adoption studies tell us the most common diseases are not the result of either genetics or environment solely. It's a combination, and genetic and genetic factors usually interact to influence one's likelihood of developing the disease. Genetics are common diseases, so some common multifactorial disorders are present at birth. Others are seeing adolescents and adults. So unravelling the genetics of those diseases is a much more daunting task. Obviously, congenital malformations or president birth as an example, heart disease, cancer and diabetes are adolescents and adults. Coronary heart disease is the leading killer of Americans, approximately 25 percent of all deaths. The United States risk factors include obesity, cigarette smoking, hypertension, elevated cholesterol and positive family history. An individual with a positive family history is two to seven times more likely to have heart disease. Positive family history is defined as having one or more affected. First three relative. So some common criteria that we've discussed before, the criteria that are commonly used to define multifactorial inheritance, more effective affected relatives, affected relatives or relatives of females, an age of onset of the affected relative younger than 55. So those were all things we discussed, the criteria we discussed earlier. And of course, environmental factors also affect heart disease, cigarette smoking and obesity. To increase your risk, exercise and a diet low in saturated fats decrease your risk. So continue to go through some common diseases that could have genetic or environmental factors. Hypertension has a worldwide prevalence of approximately 25 to 30 percent key risk factors for heart disease, stroke and kidney disease, 20 to 40 percent of the variation in systolic and diastolic blood pressure is caused by genetic factors. This indicates that environmental factors must be an important cause of hypertension due the complexity of blood pressure regulation. Much research has now focused on very specific components, such as the Rinnan angiotensin system, Taissa dilators like nitrous oxide and iron transporter systems. And this is the renewed renin angiotensin aldosterone system just kind of going through that. So as we go through steps flow diagram. Cancer, second leading cause of death in United States, the many types of cancer cluster strongly in families caused both by genes and shared environmental factors. Tobacco use accounts for one third of all cancer cases in the United States. Different types of cancer. So breast cancer, the most common cancer among women, affecting approximately 12 percent of Americans, American women who live in to be 85 or older. There's a strong family correlation. One affected first degree relative doubles. The risk of breast cancer risk is increased if affected relative as young as a young age onset and has bilateral cancer. The BRCA one and BRCA two genes are responsible for an autosomal dominant form of breast cancer, which accounts for five to 10 percent of the cases in the US, women who inherit a mutation of that gene have a 50 to 80 percent lifetime risk of developing breast cancer. BRCA one mutations also carry a 20 to 50 percent lifetime risk of ovarian cancer. So if you have a BRCA one mutation, you would have a 50 to 80 percent risk of developing breast cancer and a 20 to 50 percent risk of developing ovarian cancer. Breast cancer. Colorectal cancer is second only to lung cancer and the number of deaths in the U.S. deaths annually. A risk is two to three times higher if there's one affected first degree relative prostate cancer, the second most commonly diagnosed cancer in men. And just as colorectal cancer, it's the risk is two or three times higher. If there's an affected first degree, relative credibility is approximately 40 percent with prostate cancer, diabetes. So first we'll start talking about type one diabetes. It's an autoimmune disorder t cell infiltration of the pancreas along with antibody formation. It gets pancreas cells and histocompatibility complex zero point three to zero point five percent risk. In the general population, siblings have a six percent risk. If you have a diabetic parent, one to three percent chance if a mother has type one diabetes, four to six percent if the father does, identical twins have a 30 to 50 percent chance that these twins, five to 10 percent, since identical twins are not 100 percent concordant, then genetic factors are not solely responsible for this disorder. There is good evidence that specific viral infections contribute to the cause and at least some individuals, possibly by activating an autoimmune response. Now, Type two diabetes accounts for 90 percent of all diabetic cases. There are several distinguishing factors. It's caused by insulin resistance. Nearly always, some endogenous insulin production can often be treated successfully with dietary modification and or oral drugs typically occurs among people older than 40. And a higher incidence in the obese monozygotic twins concordance rate is about 70 and 90 percent. First degree relative concurrence is 15 to 40 percent. The two most important risk factors for Type two diabetics are positive family history and obesity. Obesity increases insulin resistance. There is a rise in prevalence when populations adopt the diet and exercise pattern typical of the United States and European nations. Exercise can substantially lower one's risk of developing Type two diabetes, even among individuals with family history. Now, that's key for a lot of these genetic disorders. Decrease environmental risk and decrease overall risk despite genetic susceptibility, partially because exercise reduces obesity. But even in the absence of weight loss, exercise increases insulin sensitivity and improves glucose tolerance. Obesity, a body is defined as a body mass index greater than 30. More than one third of American adults are obese and an additional one third are overweight, which is a BMI greater than 25. Obesity itself is not a disease, it is an important risk factor for several diseases, though, including heart disease, stroke, type two diabetes, cancer of the prostate, breast and colon. There's a strong familial correlation of obesity. That is obviously the easiest easily ascribed to common environmental effects, parents of children share similar dietary and exercise habits for dioxins. Studies show that body weight so adopted individuals correlated significantly with the natural parents body weight, but not with those of the adoptive parents. Twin studies showed heredity estimates, irritability estimates between six and eight. Alzheimer's disease is characterized by progressive dementia and memory loss by the formation of amyloid plaques and neurofibrillary tangles in the brain. Alzheimer's disease is a genetically heterogeneous disorder. It's responsible for 60 to 70 percent of the cases of progressive cognitive impairment among older adults. It affects approximately five to 10 percent population older than 65 and 40 percent of the population older than 85. Three to five percent occur before the age of 65 and is considered an early onset either through the early onset is much more likely to be inherited. Death usually occurs within 17 years after the first appearance of symptoms, the risk of developing Alzheimer's disease doubles and the individuals who have been affected first degree relative. Alcoholism is diagnosed in 10 percent of adult males and three to five percent of adult females in the US, the risk of developing alcoholism among individuals with one affected parent is three to five times, three to five times higher than those with unaffected parents. D.G twins have a concordance rate less than 30 percent, and concordance rates for monozygotic twins are in excess of 60 percent. Definitely showing a correlation. Genetics adoption. Studies show that offspring of an alcoholic parent, when raised by non-alcoholic parents, still have a fourfold increase of developing the order. The disorder, the offspring of non-alcoholic parents, when raised by alcoholics, did not have an increased risk of developing alcoholism. Definitely a genetic factor. Alcohol dehydrogenase Janis's ADHD, convert ethanol to see the aldehyde out of high diet drugs and ACS convert, I see how to acetate an illegal of the LDH to gene, which results in excessive accumulation of a lot of hide, which causes facial flushing, nausea, palpitations and lightheadedness through these unpleasant effects. Individuals who have this illegal. Are much less likely to become alcoholics, some genes that encode components of gamma butyric acid GABA are associated with susceptibility to alcohol addiction. Alcohol has been shown to increase Gavrilis and a little allelic variation in Gabber receptor genes may modulate this effect. Genes. Abassi may increase one's susceptibility to alcoholism, but the disease definitely requires an environmental component as well. Schizophrenia is a severe emotional disorder characterized by delusions, hallucinations, retreat from reality and bizarre, withdrawn or inappropriate behavior. The recurrence risk is eight to 10 percent when there's one effective parent. That's 10 times higher than the risk of the general population. Risk increases when more relatives are affected. An individual who has a sibling and a parent with schizophrenia has a risk approaching 20 percent. The risk with two affected parents is nearly 50 percent. The frequency of schizophrenia pro bands who have a schizophrenic parent is only five percent, though that's an interesting statistic. That is because people with schizophrenia are less likely likely to produce children than other individuals. Monozygotic twins have a 40 percent concordance rate, compared to only 12 percent for dizygotic twins. Were the offspring of a schizophrenic parent or adopted by normal parents. The risk of the disease is still about 10 percent. Large scale genetic studies have revealed more than one hundred Lokar that are associated with the risk of schizophrenia. Many of these genes encode components of the dopaminergic, including large signalling pathways and major therapeutic drugs used to treat schizophrenia are dopamine receptor antagonist. Bipolar disorder is a form of psychosis with extreme mood swings and emotional instability, otherwise known as manic depressive disorder. And since the general population is approximately zero point five percent, the risk rises to around five to 10 percent. For those with affected first degree relative twin, studies show that approximately 60 percent of the risk is attributed to genetic factors. Most likely, it's heterogeneous, reflecting the influence of numerous genetic and environmental factors. That makes genetic studies very challenging. Conclusions. The more strongly inherited forms of complex disorders generally have an earlier onset of age with laterality is a component. The bi lateral forms are more likely to cluster strongly in families showing that they're more genetically associated. Although the sex specific threshold model fits some of the complex disorders, it fails to fit others. Most of the diseases discussed in this chapter are both genetic and environmental components, which means that lifestyle modification, diet, exercise, stress reduction can reduce risk significantly. But especially this is especially important for individuals with a family history that may develop disease early in life. So people think just because there's a genetic component that they don't, there's no chance for them to make it better. So why bother trying? But it's obvious with most of these diseases that it's both lifestyle and genetic. And the book stresses the importance of reiterating that to our patients as health care practitioners, the identification of a specific genetic lesion can lead to more effective prevention and treatment of the disease, identification of mutations that this example, identification's of mutations that cause breast cancer may enable early screening and prevention and prevention of metastasis. In this section, we're going to talk about epigenetics and disease. Now, once again, this is module two, which covers in Chapter three, the four or five and six, this is McCance, Chapter six. Epigenetics is modifications that are not included in nucleotide sequence, but are nevertheless transmitted when a somatic cell divides, when gametes are produced or both processed and modulate, modulate how a given set of genomic information gives rise to phenotype. So it's key. It's gene information and phenotype. Three key things. We're going to talk about DNA methylation, histone post translation modifications and RNA based mechanisms. DNA methylation plays a prominent role in human health and disease in females. The inactive X chromosome contains large amounts of methylation. The active X chromosomes are largely devoid of DNA methylation. So its key is showing some key that where there's large amounts of metals methylation, it's inactive. DNA with dense methylation are not actively transcribed. Epigenetic and activation of one of the two X chromosomes occurs during gastrulation, which is a phase of early embryonic development. The determination of which chromosome to be silenced, either the copy from the father or from the mother occurs at random and independently in each cell. Somatic masochism is the difference between the illegals active in two cells can confer two very different traits due to the random inactivation. It can arise for any X encoded trait females who inherit one normally and one disease also an X encoded gene then to have less severe disease phenotypes and males whose loan X chromosome bears a disease Lou. For example, there's a lower severity of colorblindness in females, histone modifications, so histones are positively charged. Proteins around which negatively charged DNA molecules are wound, facilitates compaction of DNA into the cellular nuclei, where all the DNA that comprises the human genome is found around the histones. It is only one of 40000 as well. Hetero chromatic is when a given segment of DNA is bound tightly to its histones. Eukaryotic is when a segment of DNA is only loosely bound to its histones. When it's loosely bound, transcription factors are able to access it and use it as a template for messenger RNA. The states of the individual segments of the genome play a critical role in determining the development potential of a given cell. So we'll continue talking about histone modification, histone acetylation, which tends to diminish the positive charge of histones, reduces the binding street to the DNA, histone methylation can either increase or decrease the bonding between DNA and histones, depending on the specific part of the histones, are added to mutations in genes that code histone modifying proteins have been implicated in various pathological states, including congenital heart disease. Histone modification is critical to normal development. Protamine evolution evolved evolutionarily derived from histones. They enable sperm DNA to achieve compaction even greater than histone bound DNA, improves hydrogenate dynamic features and facilitates movement changes in expression. Apartments have been found to be associated with infertility in males. And I'm going to going to attach an article about that. Epigenetics and human development totipotent. Each cell in the early embryo has the potential to give rise to any somatic cell. All the cells in a given individual contained almost exactly the same genetic information. It is the epigenetic information eventually placed on top of these sequences and enables them to achieve the diverse functions of different things. So that excels housekeeping genes, small percentage of genes that are necessary for function and maintenance of each. So they escape epigenetic silencing and remain transcriptional active and all or nearly all cells. Genomic imprinting violated both the maternal and paternal inherited copies contribute to Offspring phenotype model Lilit, the maternal copy is randomly chosen for inactivation and some somatic cells in the world, and then in others. The paternal copy is randomly chosen for inactivation imprinting, which is only about one percent. Other 99 percent being Balearic of monolithic. Either the maternal copy or the paternal copy is inherited. It's an either. Why is that? So then we have the genetic conflict hypothesis, which is only the hypothesis that remained true and research. Although both mother and father benefit genetically from the birth and survival of offspring, their interests are not entirely aligned. Since mothers make a large physiologic investment in each child, it's in their best interest to limit resources given to any one offspring and maintain capacity of their subsequent children. Except except in cases of lifelong monogamy, it's in the best interest of fathers for their child to exact maximum resources from its mother, and then limit the mother's ability to bear the additional offspring in the future. Imprinting genes from the mother are predicted to limit offspring size, whereas imprinting genes from the father are predicted to result in larger offspring. One important hallmark of imprinting associated diseases is the phenotype is critically dependent on whether the mutation is inherited from the mother or the father. Prader-Willi and Angelman Syndrome are two well known diseases of imprinting, and they're associated with deletion of about four million base pairs on the long arm of the chromosome 15. Prader-Willi syndrome occurs when this deletion is inherited from the father. It results in short stature. Aquitania small hands and feet, obesity, mild to moderate intellectual disability and hypogonadism. Angelman Syndrome is caused by the same deletion on the same chromosome, but it's inherited from the mother. Severe intellectual disability seizures and attacks iGate. Beckwith's Wagman syndrome is another well known imprinting disease, it's identifiable at birth because of the large size or gestational age, neonatal hypoglycemia, a large stone creases on the earlobe and also you have increased risk of developing Wilms tumor or a blastoma 20 30 percent of the cases are caused by inheritance of two copies of chromosome 11 from the father and no copy from the mother. This is called parental. That's only in contrast to the Prater, Willy and Angelman Syndrome. And it's caused in part by overexpression of a gene product sort of under expression Russel's severe syndrome that results in growth retardation, proportionately short stature, likely discrepancy and a small triangular shaped face. One third of the cases are caused by imprinting abnormalities of chromosome 11 15 that five of the 10 percent are caused by maternal parent or that something epigenetics and cognitive development and mental health that in utero ethanol exposure. So neural stem cells exposed to ethanol impair impairs their ability to differentiate to functional neurons. This correlates with this dense medicalisation. At Luchi, they're active in normal neuronal tissue, mental help, children who grow up in poverty, typical and atypical methylation and a serotonin receptor. PTSD causes alterations in gene expression and key neuronal pathways that are associated with atypical methylation in a large set of genes. Autism spectrum disorder is associated with altered DNA methylation at some boakai at the genetics and nutrition. During the winter of nineteen forty three, people in urban areas of the Netherlands suffered starvation as a result of Nazi blockage of food shipments. Individuals in utero during this time are more likely to suffer from obesity and diabetes as adults. The offspring of those children were found to be significantly smaller than children not affected by the blockade. So this is something that was genetically passed to the children. Epigenetics and aging monozygotic twins exhibit differences in methylation patterns of the DNA sequences of their somatic cells that often result in an increase in numbers of phenotypically differences. Twins with significant lifestyle differences tend to accumulate larger numbers of differences in methylation patterns. So as they age the twins, as they kind of diverged from each other and do different things, they get different methylation patterns on their DNA and significant lifestyle differences made that even greater. One of them was smoking versus non non smoking. Twin might have exhibited increases in the genome wide abundance of hydroxy methyl cysteine. So it was seen with time that many have proposed that senescence itself can be characterized as an epigenome phenomenon. As interesting study, metformin is effective in slowing senescence in the East. Studies have suggested that long term use of metformin may extend lifespan beyond non diabetic individuals. I would suggest there's something else happening with metformin, which in studies may modulate epigenetic path, epigenetic pathways with possible opportunities for lifespan, extension, epigenetics and cancer. Tumor cells often exhibit decreased methylation genome wide relative to normal cells of the same type, which can increase. That can increase. The activity of oncogene screening for epigenetic regulation has shown promise as a tool for detecting and characterizing cancer of the colon, breast and prostate. Other genetic based screening approaches have shown promise for bladder, lung and prostate cancer. Treatment of epigenetic disease, epigenetic modifications are potentially reversible. DNA can be methylated, histones can be modified to change the transcriptional state of nearby DNA and micro RNA encoding. Lokar can be up or down regulated DNA reflating agents. So this drug, five citizen known, has been used as a therapeutic drug in the treatment of leukemia. And Miloje dysplastic syndrome, histone diacetyl inhibitors, histone desales increases chromatin compaction causing decreased transcriptional activity treatment with HDFC inhibitors has shown promise in reducing cell division rates of breast, prostate and pancreas cancers. Micro RNA has shown promise for developing drugs that modify only the genes responsible for a specific cancer.