Understanding Mendelian Genetics and Inheritance

Hi guys, welcome back. In this lecture, which is part two of the lectures on Mendelian genetics, we will discuss inheritance modes in particular. We are going to cover sex-linked pedigrees, and remember back to linkage, these are examples of heritage inheritance patterns associated with being linked to sex chromosomes. And this will include X-linked dominant and recessive diseases and Y-linked traits. And then we will cover autosomal recessive and autosomal dominant patterns. We will be looking at a lot of pedigree charts for this. And a pedigree chart is a diagram that shows the occurrence and appearance of phenotypes of a particular gene or organism and its ancestors from one generation to the next. You're probably familiar with the name from hearing about dog or horse pedigrees when talking about those you know best-in-show type animals and pedigree construction is a family history and details about an earlier generation may be uncertain as memories fade so if the sex of a person is unknown a diamond is used someone with a phenotype in question is represented by a filled in darker symbol The symbols you see here on the right side of this slide. Heterozygotes, when identifiable, are indicated by a shade dot inside a symbol or a half-filled symbol. Relationships in a pedigree are shown in a series of lines. So parents are connected by horizontal lines and vertical lines lead to their offspring. And offspring are connected by a horizontal line. sibship line and listed in birth order from left to right. If the offspring are twins, then they are connected by a triangle. If an offspring dies, then its symbol will be crossed by a line. Analyses of the pedigree using the principles of Mendelian inheritance can determine whether a trait has dominant or recessive patterns of inheritance and pedigrees are often constructed after a family member is afflicted with a genetic disorder and they've been identified with that that inheritable heritable disorder and this individual known as the pro band is then indicated on the pedigree generally by an arrow when using pedigrees to make out and predict the inheritance of genetic disorders there are three important terms so there are the unaffected members who do not have the disorder who cannot pass on the disorder There are the affected members who have the disorder and can pass it on. And then there are the carriers. Carrier, they're not affected by the disorder themselves, but they can pass it on. They are the heterozygotes who carry the disorder. So let's start with sex-linked traits and disorders. These impact genes coded on the X or Y chromosome specifically. Most sex-linked disorders are X-linked because the X... chromosome is just larger and when females have Have a our homozygous dominant They can be homozygous dominant homozygous recessive heterozygous for trait or a disorder, but males will be hemizygous for this so there are over a thousand a thousand ninety eight human X linked genes because the biological sex varies in chromosomes type and number, males and females show different patterns of inheritance and severity of the manifestation of X-linked phenotypes. And X-linked genes are never passed from father to son since that only contributes the Y in sons and males are also never carriers. So if there is a mutation of a disorder on the X chromosome, it will always be expressed in males. Okay, so here is a checkpoint question. mom is a carrier um she is blank a homozygous b hemizygous c heterozygous d not affected please pause to answer the answer is e the heterozygous is the unaffected carrier x-linked recessive traits x-linked recessive traits may appear to skip generations because the alleles cause the trait or disorder is often is often masked because it's recessive and only expressed when passed from both parents and these traits are more common in males than females and always expressed in males if the x chromosome from mom has it so none of the offspring of affected males are affected but all of the daughters must be heterozygous carriers because females must receive one of the x chromosomes from their fathers so if the mother is affected her offspring have a 50 chance being affected and a 50% chance of being a carrier with males always being affected and with a carrier mother and unaffected father there is a 50% chance also of the offspring would be unaffected a 25% chance of having an affected son and a 25% chance of having a carrier daughter So perhaps the best known example of hemophilia is hemophilia For an X-Length Recessive Disorder, this is a malady in which a person's blood fails to clot. Many proteins must interact in sequence to make blood clot, and the most common type of hemophilia is caused by the absence or malfunction of one of these proteins, called factor 7, I believe, or 7 or 8. And the most famous cases of hemophilia are found in the pedigree of interrelated royal families of Europe. And the original hemophilia allele of these royal families in Europe in the pedigree arose spontaneously as a mutation in reproductive cells of Queen Victoria's parents or of Queen Victoria herself and Alexis the son of the Tsar of Russia shown here with his family. This is the Tsar of Russia he inherited The allele ultimately from Queen Victoria, who was the grandmother of his mother, Alexandra. Nowadays, hemophilia is treated, but it was formerly really potentially a fatal condition. And this really just shows how interrelated every single monarch in Europe is. Duchenne muscular dystrophy is a fatal X-linked recessive disease as well. And the phenotype is wasting an atrophy of muscles and generally the onset is before the age of 16 with confinement to a wheelchair by 12 and death by 20. And the gene for Duchenne muscular dystrophy has now been isolated and shown to encode a muscle protein, dystrophin. Such insight really holds some hope for better understanding and hopefully therapy for this disease. And a rare x-linked recessive phenotype that is interesting from a point of view of sexual differentiation is a condition called testicular feminization syndrome and This is this has a frequency of about one in 65,000 male births and people Affected afflicted with this X. Well with the testicular feminization syndrome How are cromp chromosomally males? but they develop as females. They have female external genitalia, a blind vagina, no uterus. Testes may be present either in the labia or in the abdomen itself. And although many people are happily married with testicular feminization syndrome, they are, of course, sterile. And the condition is not reversed by treatment with male hormone or androgen. So it is sometimes called androgen insensitivity syndrome. And the reason for this insensitivity is that the causative allele codes for a malfunctioning androgen receptor protein. So male hormones can have no effect on the target organs. Red color blindness is also an example, most commonly in males. And so if you cannot read the number in this image. You might fall into that spectrum. And another is ichthyosis, which is a skin disease depicted in drawing down here. An infant is born with this, having cracked, thin skin, really itchy skin, and ichthyo meaning fish, and so referred to as skin that's scale-like. Which it isn't really exactly. All right. And so X-linked dominant traits occur in every generation, conversely to recessive, because as the dominant gene mass that recessive and affected males only transmit this to daughters since it is an X and not a Y linked and the heterozygous female carrying the trait will transmit it to about half of her children males and females equally both receive an X from her so there are a few examples of excellent dominant disorders such as vitamin D resistant form of rickets that you're born with Fragile X syndrome in which there is an assertion of hundreds of CGG bases. And Fragile X syndrome is genetic that causes a range of developmental problems including learning disabilities, cognitive impairment. Usually males are more severely affected by the disorder than females. Affected individuals with Fragile X usually have delayed development in speech. by the age two and most males with fragile x have mild to moderate intellectual disability they there's some characteristic features as well that become more apparent with age including a long narrow face and large ears a prominent jaw and forehead really flexible fingers things like that and um hypophosphatemic rickets uh previous previously called vitamin D resistant rickets is a disorder where the bones become painfully soft and bend easily due to low levels of phosphate in blood and symptoms usually begin in early childhood and can range in severity and and the severest forms may cause bowing of the legs and bone different deformities and lots of pain joint pain and shorter stature And then amelogenesis imperfecta is another ex-dominant condition. It is a disorder of tooth development, and this condition causes teeth to be unusually small and discolored and have pits or grooves that you can sort of see in this image. And the yellow behind it is the dentin that's underneath enamel, and so that's showing through because the enamel is not growing normally. And this can affect both baby teeth and adult teeth. And there's been like 14 forms of amelogenesis imperfecta and these types are distinguished mostly by the pattern of inheritance. So, and additionally, amelogenesis imperfecta can occur alone or with other signs and symptoms of another syndrome as well that can affect other parts of the body. Okay, so if mom is a carrier for X-linked dominant disorder and dad is an unaffected and not a carrier carrier, how would their kids be affected? A, sons and daughters could be unaffected. B, a son could be affected. C, a daughter could be a carrier. D, all of the above. Please pause to think about the answer. So the answer is... D, all of the above. And you can see in this image, in this pedigree drawn out for this example, you can also solve this through like a Punnett square, but taking into account the differences between the sexes. Y-link disorders are only found in males, and when present, they are always expressed. And one example of a Y-linked disorder is Swire syndrome, in which chromosomally the individual is XY, but they have a female phenotype, but secondary characteristics, secondary sexual characteristics do not form. Those with Swire syndrome actually can become pregnant, kind of like how Arnold is shown here in the movie Junior. Not really the exact way, it's not the same process, but essentially They would require hormones to menstruate, an embryo would be implanted, and then hormones would be required again to maintain the pregnancy. But whoever said that you can't have a baby with a Y chromosome? And sex-linked traits should not be confused with sex-influenced traits. They are not the same thing. Influenced traits may appear in both sexes, but the expression of them differs depending on the sex. So early balding is an example where a heterozygous man will lose most of his hair, but a heterozygous female does not have significant hair loss, but both a male and female who are homozygous will become completely bald. bald and so this trait is dominant in men but recessive in females and even though not completely understood there is some relationship to testosterone production as well all right imprinting imprinting is something else altogether as well so this is where certain genes are expressed depending on the parent of origin so whether a the gene is inherited from mom or dad will result in a different phenotype So Prader-Willi and Engelmann syndrome are examples. Both occur in about one in 15,000 live births in males and females equally and in all ancestry groups. But they both result from a deletion of chromosome 15. But Prader-Willi results from that deletion on the father's chromosome and therefore an imprinting on the mother's allele. while Engelmann syndrome results from a deletion on the mother's chromosome 15 imprinting on the father's allele. So people with Prader-Willi syndrome typically have mild to moderate intellectual impairments. They might have behavioral problems and temper outbursts and stubbornness and some physical features as well as like a narrow forehead, almond shaped eyes, triangular mouth, shorter stature. Sometimes they have fairer skin and fairer lighter hair color. Both affected males and females have underdeveloped genitals generally and puberty. Puberty is generally delayed or incomplete. While Engelmann syndrome also has developmental delay, individuals might have happy or excitable personalities. They're frequently smiling and laughing and flapping their hands in excitement. Sometimes they have difficulty breathing. They usually have an abnormal curve to their spine and microcephaly or a smaller head. Lighter skin and lighter eyes and sometimes deeper set eyes, widely spaced teeth, things like that. Alright, so time for a checkpoint question. Tim questions if he is Pam's baby daddy. Tim is... A homozygous dominant and Pam is heterozygous for the same trait and their baby is homozygous recessive for that trait. What would you tell Tim? Happy Father's Day? Not enough info? Go to Maury. No child support? That kid was switched at birth. Please pause. And the answer is C. He cannot be the biological father. I don't know. If I go out blame in the hospital just yet for that but he is not the biological father. Alright, so in autosomal dominant disorders the normal allele is recessive and the abnormal allele is dominant and these traits are observed in every generation and there is no difference between the sexes and expression. It might seem paradoxical that a rare disorder can be dominant. but remember that dominance and recessiveness are simply reflections of how alleles act and not defined in terms of predominance in the population. And both males and females can be affected and pass this on. Every affected person must have at least one affected parent, but two affected parents could have an unaffected child. And an example of a rare autosomal dominant phenotype is a chondroplasia, a type of dwarfism. And in this case, people with normal stature are genetically small a, small a. And the dwarf phenotype in principle could be big A, little a, or big A, big A. However, it's believed that big A, big A individuals with those two doses of the big A allele produce such a severe effect that the genotype is lethal. So, if true, all achondroplastics are heterozygotes. Huntington's disease is an example of an autosomal dominant disorder too. The phenotype is one of neural degeneration leading to convulsions and premature death. This can start at the age of 30 even or later, sometimes earlier. However it's a... the symptoms generally are not appearing until the person has begun to have children and so each child um so they don't know uh and each child of a carrier of the abnormal allele stands a 50 chance of inherent the allele and the associated disease. So the tragic, this really tragic pattern has led to a drive to find ways to identify people who carry the abnormal allele before they experience onset of the disease, before they even have children, and the discovery of the molecular nature of the mutant allele and then the neutral DNA mutations that act as markers. Close to affected allele in the chromosome might revolutionize this type of diagnosis. And then fibro, fibro neuromatosis, neurofibromatosis, excuse me, is another example. And it's a genetic disorder that causes tumors to form on nerve tissue. And these tumors can develop anywhere in your nervous system, including your brain, spinal cord, any nerve. And neurofibromatosis is usually diagnosed in childhood and early or early adulthood. And these tumors are usually non-cancerous or benign, but sometimes they can become cancerous or malignant. And symptoms are often mild. However, complications of neurofibromatosis can include hearing loss and learning impairment and like heart and blood vessel cardiovascular problems. loss of vision severe pain depending on on where they are so finally autosomal recessive traits since they are recessive you must carry two in order for it to be expressed in the phenotype the heterozygote is a carrier only for the trait and being homozygous for the traits or disease means that an individual has a phenotype um has a phenotype or is affected and most Family members will not express the phenotype, but again, two unaffected parents may have an affected child and two carrier parents could have about 25% chance of having an affected child or unaffected child and 50% chance of having offspring that carry. There are many autosomal recessive disorders. We talked about cystic fibrosis, the obstructive mucus. lung disease. There is also Tay-Sachs resulting in degeneration of the nervous system. This is typically found in people of Ashkenazi or Eastern European Jewish descent. It's pretty devastating. The child is born with this and they progress to the point where they can't function really at all and die generally quite early. There's nothing you can do. Albinism too is an inability to produce. normal amounts of melanin and then um phenyl ketonuria um or pky sorry pku uh we'll talk more about in a moment but it's also an autosomal recessive disorder so we already had talked about the point mutation causing sickle cell anemia and how these resulting sickle-shaped blood cells do not carry the oxygen needed this point mutation is caused by a recessive allele and must be inherited from each parent to be expressed. The two carrier parents who might not have the disease could have a sickle cell anemia offspring. So there's a one in four chance of having an unaffected child, a 50% chance of having carrier offspring, and one in four 25% chance of having offspring with sickle cell anemia. Phenylketonuria, PKU, is a genetic disorder that is characterized by the inability of the body to utilize the essential amino acid phenylalanine. In the classic form of PKU, the enzyme that breaks down phenylalanine is deficient or not there at all, okay? And this enzyme normally converts phenylalanine to another amino acid, tyrosine, and without the enzyme phenylalanine and its Its breakdown chemicals from other enzyme routes accumulate in the blood and tissues. And chronically high levels of phenylalanine then and some of its breakdown products can cause significant brain problems. So classic PKU is the most common cause of high levels of phenylalanine in the blood and will be the primary focus of what we're talking about here. And so classic PKU has And the other causes of not being able to eliminate fetal alanine affect about one in every 10,000 to 20,000 births. and includes several different populations but males and females pretty much equal and infants with PKU appear normal at birth they may have blue eyes or fairer skin and hair than some of their other family members currently most symptoms of untreated PKU are avoided by newborn screening early and management and about 50% of untreated infants have early symptoms such as vomiting and irritability and like a rash that's like eczema like and sometimes an interesting odor for their urine. Some may also have subtle signs of nervous system dysfunction problems such as in their muscle tone or tendon reflexes and later severe brain problems occur and mental disorders and seizures. So it's something that needs to be picked up right away. In every state, this phenol PKU is screened in the blood, so phenylalanine is screened when you're a newborn, about like three days old or less. And this test is one of several screenings performed before or soon after discharge from the hospital. And usually it's just a few pinpricks of blood to see what the phenylalanine levels are. So if the individual has PKU, essentially... They just need to be on a diet for the rest of their life that involves not eating phenylalanine and the only best way to do this is through like this free government diet that is provided when you have PKU. So why does such high risk genes resulting in disorders that can be lethal in our genome persist instead of being eliminated since they're seemingly disadvantageous? Well, this comes down to what is called balancing selection. And we'll talk more about this actually in a future lecture, but essentially having several alleles ultimately that variation is a survival advantage. So this means that alleles could lead to death of some people, but be an advantage for an overall population that the heterozygote has an advantage. So this disorder or these alleles are not. fully eliminated um but we'll talk more about this um in a week or two might just be next week all right so finally your last checkpoint for this lecture if both mom and dad are carriers for an autosomal recessive disorder then their chance of having an affected child is a 100 b 75 C, 25% D, 50% Please pause to answer. Okay, so the answer is C, 25%. You can see in this pedigree that the heterozygous parents, in all cases for autosomal diseases, will have a 25% chance for every offspring they have being affected. So you may be thinking why this is important. Genetic, in this class, genetic counselors use patterns and things like this to, in Punnett squares, to help families with risks evaluate the risk and prepare them before having children or when they're pregnant. And this is particularly important as some populations have these higher frequencies of some lethal disorders like sickle cell anemia, which sickle cell anemia affects 100,000 Americans and occurs. And one out of 365 African Americans and one out of 16,000, a little bit over 16,000 Hispanic American births, and about one in 13 African American babies is born with the sickle cell trait. So it does matter and it can include therapies that will help them prevent certain consequences of some. disorders, maybe prolong their life in some other disorders. Okay, so in part three of this lecture, next, we will cover the more complex and polygenetic traits and epigenetics.

We will be looking at a lot of pedigree charts for this. And a pedigree chart is a diagram that shows the occurrence and appearance of phenotypes of a particular gene or organism and its ancestors from one generation to the next. You're probably familiar with the name from hearing about dog or horse pedigrees when talking about those you know best-in-show type animals and pedigree construction is a family history and details about an earlier generation may be uncertain as memories fade so if the sex of a person is unknown a diamond is used someone with a phenotype in question is represented by a filled in darker symbol The symbols you see here on the right side of this slide.

Heterozygotes, when identifiable, are indicated by a shade dot inside a symbol or a half-filled symbol. Relationships in a pedigree are shown in a series of lines. So parents are connected by horizontal lines and vertical lines lead to their offspring.

And offspring are connected by a horizontal line. sibship line and listed in birth order from left to right. If the offspring are twins, then they are connected by a triangle. If an offspring dies, then its symbol will be crossed by a line.

Analyses of the pedigree using the principles of Mendelian inheritance can determine whether a trait has dominant or recessive patterns of inheritance and pedigrees are often constructed after a family member is afflicted with a genetic disorder and they've been identified with that that inheritable heritable disorder and this individual known as the pro band is then indicated on the pedigree generally by an arrow when using pedigrees to make out and predict the inheritance of genetic disorders there are three important terms so there are the unaffected members who do not have the disorder who cannot pass on the disorder There are the affected members who have the disorder and can pass it on. And then there are the carriers. Carrier, they're not affected by the disorder themselves, but they can pass it on.

They are the heterozygotes who carry the disorder. So let's start with sex-linked traits and disorders. These impact genes coded on the X or Y chromosome specifically. Most sex-linked disorders are X-linked because the X...

chromosome is just larger and when females have Have a our homozygous dominant They can be homozygous dominant homozygous recessive heterozygous for trait or a disorder, but males will be hemizygous for this so there are over a thousand a thousand ninety eight human X linked genes because the biological sex varies in chromosomes type and number, males and females show different patterns of inheritance and severity of the manifestation of X-linked phenotypes. And X-linked genes are never passed from father to son since that only contributes the Y in sons and males are also never carriers. So if there is a mutation of a disorder on the X chromosome, it will always be expressed in males.

Okay, so here is a checkpoint question. mom is a carrier um she is blank a homozygous b hemizygous c heterozygous d not affected please pause to answer the answer is e the heterozygous is the unaffected carrier x-linked recessive traits x-linked recessive traits may appear to skip generations because the alleles cause the trait or disorder is often is often masked because it's recessive and only expressed when passed from both parents and these traits are more common in males than females and always expressed in males if the x chromosome from mom has it so none of the offspring of affected males are affected but all of the daughters must be heterozygous carriers because females must receive one of the x chromosomes from their fathers so if the mother is affected her offspring have a 50 chance being affected and a 50% chance of being a carrier with males always being affected and with a carrier mother and unaffected father there is a 50% chance also of the offspring would be unaffected a 25% chance of having an affected son and a 25% chance of having a carrier daughter So perhaps the best known example of hemophilia is hemophilia For an X-Length Recessive Disorder, this is a malady in which a person's blood fails to clot. Many proteins must interact in sequence to make blood clot, and the most common type of hemophilia is caused by the absence or malfunction of one of these proteins, called factor 7, I believe, or 7 or 8. And the most famous cases of hemophilia are found in the pedigree of interrelated royal families of Europe. And the original hemophilia allele of these royal families in Europe in the pedigree arose spontaneously as a mutation in reproductive cells of Queen Victoria's parents or of Queen Victoria herself and Alexis the son of the Tsar of Russia shown here with his family.

This is the Tsar of Russia he inherited The allele ultimately from Queen Victoria, who was the grandmother of his mother, Alexandra. Nowadays, hemophilia is treated, but it was formerly really potentially a fatal condition. And this really just shows how interrelated every single monarch in Europe is.

Duchenne muscular dystrophy is a fatal X-linked recessive disease as well. And the phenotype is wasting an atrophy of muscles and generally the onset is before the age of 16 with confinement to a wheelchair by 12 and death by 20. And the gene for Duchenne muscular dystrophy has now been isolated and shown to encode a muscle protein, dystrophin. Such insight really holds some hope for better understanding and hopefully therapy for this disease.

And a rare x-linked recessive phenotype that is interesting from a point of view of sexual differentiation is a condition called testicular feminization syndrome and This is this has a frequency of about one in 65,000 male births and people Affected afflicted with this X. Well with the testicular feminization syndrome How are cromp chromosomally males? but they develop as females. They have female external genitalia, a blind vagina, no uterus. Testes may be present either in the labia or in the abdomen itself.

And although many people are happily married with testicular feminization syndrome, they are, of course, sterile. And the condition is not reversed by treatment with male hormone or androgen. So it is sometimes called androgen insensitivity syndrome.

And the reason for this insensitivity is that the causative allele codes for a malfunctioning androgen receptor protein. So male hormones can have no effect on the target organs. Red color blindness is also an example, most commonly in males. And so if you cannot read the number in this image. You might fall into that spectrum.

And another is ichthyosis, which is a skin disease depicted in drawing down here. An infant is born with this, having cracked, thin skin, really itchy skin, and ichthyo meaning fish, and so referred to as skin that's scale-like. Which it isn't really exactly. All right.

And so X-linked dominant traits occur in every generation, conversely to recessive, because as the dominant gene mass that recessive and affected males only transmit this to daughters since it is an X and not a Y linked and the heterozygous female carrying the trait will transmit it to about half of her children males and females equally both receive an X from her so there are a few examples of excellent dominant disorders such as vitamin D resistant form of rickets that you're born with Fragile X syndrome in which there is an assertion of hundreds of CGG bases. And Fragile X syndrome is genetic that causes a range of developmental problems including learning disabilities, cognitive impairment. Usually males are more severely affected by the disorder than females. Affected individuals with Fragile X usually have delayed development in speech. by the age two and most males with fragile x have mild to moderate intellectual disability they there's some characteristic features as well that become more apparent with age including a long narrow face and large ears a prominent jaw and forehead really flexible fingers things like that and um hypophosphatemic rickets uh previous previously called vitamin D resistant rickets is a disorder where the bones become painfully soft and bend easily due to low levels of phosphate in blood and symptoms usually begin in early childhood and can range in severity and and the severest forms may cause bowing of the legs and bone different deformities and lots of pain joint pain and shorter stature And then amelogenesis imperfecta is another ex-dominant condition.

It is a disorder of tooth development, and this condition causes teeth to be unusually small and discolored and have pits or grooves that you can sort of see in this image. And the yellow behind it is the dentin that's underneath enamel, and so that's showing through because the enamel is not growing normally. And this can affect both baby teeth and adult teeth.

And there's been like 14 forms of amelogenesis imperfecta and these types are distinguished mostly by the pattern of inheritance. So, and additionally, amelogenesis imperfecta can occur alone or with other signs and symptoms of another syndrome as well that can affect other parts of the body. Okay, so if mom is a carrier for X-linked dominant disorder and dad is an unaffected and not a carrier carrier, how would their kids be affected?

A, sons and daughters could be unaffected. B, a son could be affected. C, a daughter could be a carrier.

D, all of the above. Please pause to think about the answer. So the answer is...

D, all of the above. And you can see in this image, in this pedigree drawn out for this example, you can also solve this through like a Punnett square, but taking into account the differences between the sexes. Y-link disorders are only found in males, and when present, they are always expressed. And one example of a Y-linked disorder is Swire syndrome, in which chromosomally the individual is XY, but they have a female phenotype, but secondary characteristics, secondary sexual characteristics do not form. Those with Swire syndrome actually can become pregnant, kind of like how Arnold is shown here in the movie Junior.

Not really the exact way, it's not the same process, but essentially They would require hormones to menstruate, an embryo would be implanted, and then hormones would be required again to maintain the pregnancy. But whoever said that you can't have a baby with a Y chromosome? And sex-linked traits should not be confused with sex-influenced traits. They are not the same thing. Influenced traits may appear in both sexes, but the expression of them differs depending on the sex.

So early balding is an example where a heterozygous man will lose most of his hair, but a heterozygous female does not have significant hair loss, but both a male and female who are homozygous will become completely bald. bald and so this trait is dominant in men but recessive in females and even though not completely understood there is some relationship to testosterone production as well all right imprinting imprinting is something else altogether as well so this is where certain genes are expressed depending on the parent of origin so whether a the gene is inherited from mom or dad will result in a different phenotype So Prader-Willi and Engelmann syndrome are examples. Both occur in about one in 15,000 live births in males and females equally and in all ancestry groups. But they both result from a deletion of chromosome 15. But Prader-Willi results from that deletion on the father's chromosome and therefore an imprinting on the mother's allele.

while Engelmann syndrome results from a deletion on the mother's chromosome 15 imprinting on the father's allele. So people with Prader-Willi syndrome typically have mild to moderate intellectual impairments. They might have behavioral problems and temper outbursts and stubbornness and some physical features as well as like a narrow forehead, almond shaped eyes, triangular mouth, shorter stature. Sometimes they have fairer skin and fairer lighter hair color. Both affected males and females have underdeveloped genitals generally and puberty.

Puberty is generally delayed or incomplete. While Engelmann syndrome also has developmental delay, individuals might have happy or excitable personalities. They're frequently smiling and laughing and flapping their hands in excitement. Sometimes they have difficulty breathing.

They usually have an abnormal curve to their spine and microcephaly or a smaller head. Lighter skin and lighter eyes and sometimes deeper set eyes, widely spaced teeth, things like that. Alright, so time for a checkpoint question. Tim questions if he is Pam's baby daddy. Tim is...

A homozygous dominant and Pam is heterozygous for the same trait and their baby is homozygous recessive for that trait. What would you tell Tim? Happy Father's Day?

Not enough info? Go to Maury. No child support?

That kid was switched at birth. Please pause. And the answer is C.

He cannot be the biological father. I don't know. If I go out blame in the hospital just yet for that but he is not the biological father.

Alright, so in autosomal dominant disorders the normal allele is recessive and the abnormal allele is dominant and these traits are observed in every generation and there is no difference between the sexes and expression. It might seem paradoxical that a rare disorder can be dominant. but remember that dominance and recessiveness are simply reflections of how alleles act and not defined in terms of predominance in the population. And both males and females can be affected and pass this on. Every affected person must have at least one affected parent, but two affected parents could have an unaffected child.

And an example of a rare autosomal dominant phenotype is a chondroplasia, a type of dwarfism. And in this case, people with normal stature are genetically small a, small a. And the dwarf phenotype in principle could be big A, little a, or big A, big A.

However, it's believed that big A, big A individuals with those two doses of the big A allele produce such a severe effect that the genotype is lethal. So, if true, all achondroplastics are heterozygotes. Huntington's disease is an example of an autosomal dominant disorder too.

The phenotype is one of neural degeneration leading to convulsions and premature death. This can start at the age of 30 even or later, sometimes earlier. However it's a... the symptoms generally are not appearing until the person has begun to have children and so each child um so they don't know uh and each child of a carrier of the abnormal allele stands a 50 chance of inherent the allele and the associated disease.

So the tragic, this really tragic pattern has led to a drive to find ways to identify people who carry the abnormal allele before they experience onset of the disease, before they even have children, and the discovery of the molecular nature of the mutant allele and then the neutral DNA mutations that act as markers. Close to affected allele in the chromosome might revolutionize this type of diagnosis. And then fibro, fibro neuromatosis, neurofibromatosis, excuse me, is another example. And it's a genetic disorder that causes tumors to form on nerve tissue.

And these tumors can develop anywhere in your nervous system, including your brain, spinal cord, any nerve. And neurofibromatosis is usually diagnosed in childhood and early or early adulthood. And these tumors are usually non-cancerous or benign, but sometimes they can become cancerous or malignant.

And symptoms are often mild. However, complications of neurofibromatosis can include hearing loss and learning impairment and like heart and blood vessel cardiovascular problems. loss of vision severe pain depending on on where they are so finally autosomal recessive traits since they are recessive you must carry two in order for it to be expressed in the phenotype the heterozygote is a carrier only for the trait and being homozygous for the traits or disease means that an individual has a phenotype um has a phenotype or is affected and most Family members will not express the phenotype, but again, two unaffected parents may have an affected child and two carrier parents could have about 25% chance of having an affected child or unaffected child and 50% chance of having offspring that carry.

There are many autosomal recessive disorders. We talked about cystic fibrosis, the obstructive mucus. lung disease.

There is also Tay-Sachs resulting in degeneration of the nervous system. This is typically found in people of Ashkenazi or Eastern European Jewish descent. It's pretty devastating. The child is born with this and they progress to the point where they can't function really at all and die generally quite early.

There's nothing you can do. Albinism too is an inability to produce. normal amounts of melanin and then um phenyl ketonuria um or pky sorry pku uh we'll talk more about in a moment but it's also an autosomal recessive disorder so we already had talked about the point mutation causing sickle cell anemia and how these resulting sickle-shaped blood cells do not carry the oxygen needed this point mutation is caused by a recessive allele and must be inherited from each parent to be expressed. The two carrier parents who might not have the disease could have a sickle cell anemia offspring.

So there's a one in four chance of having an unaffected child, a 50% chance of having carrier offspring, and one in four 25% chance of having offspring with sickle cell anemia. Phenylketonuria, PKU, is a genetic disorder that is characterized by the inability of the body to utilize the essential amino acid phenylalanine. In the classic form of PKU, the enzyme that breaks down phenylalanine is deficient or not there at all, okay? And this enzyme normally converts phenylalanine to another amino acid, tyrosine, and without the enzyme phenylalanine and its Its breakdown chemicals from other enzyme routes accumulate in the blood and tissues. And chronically high levels of phenylalanine then and some of its breakdown products can cause significant brain problems.

So classic PKU is the most common cause of high levels of phenylalanine in the blood and will be the primary focus of what we're talking about here. And so classic PKU has And the other causes of not being able to eliminate fetal alanine affect about one in every 10,000 to 20,000 births. and includes several different populations but males and females pretty much equal and infants with PKU appear normal at birth they may have blue eyes or fairer skin and hair than some of their other family members currently most symptoms of untreated PKU are avoided by newborn screening early and management and about 50% of untreated infants have early symptoms such as vomiting and irritability and like a rash that's like eczema like and sometimes an interesting odor for their urine. Some may also have subtle signs of nervous system dysfunction problems such as in their muscle tone or tendon reflexes and later severe brain problems occur and mental disorders and seizures. So it's something that needs to be picked up right away.

In every state, this phenol PKU is screened in the blood, so phenylalanine is screened when you're a newborn, about like three days old or less. And this test is one of several screenings performed before or soon after discharge from the hospital. And usually it's just a few pinpricks of blood to see what the phenylalanine levels are. So if the individual has PKU, essentially... They just need to be on a diet for the rest of their life that involves not eating phenylalanine and the only best way to do this is through like this free government diet that is provided when you have PKU.

So why does such high risk genes resulting in disorders that can be lethal in our genome persist instead of being eliminated since they're seemingly disadvantageous? Well, this comes down to what is called balancing selection. And we'll talk more about this actually in a future lecture, but essentially having several alleles ultimately that variation is a survival advantage. So this means that alleles could lead to death of some people, but be an advantage for an overall population that the heterozygote has an advantage. So this disorder or these alleles are not.

fully eliminated um but we'll talk more about this um in a week or two might just be next week all right so finally your last checkpoint for this lecture if both mom and dad are carriers for an autosomal recessive disorder then their chance of having an affected child is a 100 b 75 C, 25% D, 50% Please pause to answer. Okay, so the answer is C, 25%. You can see in this pedigree that the heterozygous parents, in all cases for autosomal diseases, will have a 25% chance for every offspring they have being affected. So you may be thinking why this is important. Genetic, in this class, genetic counselors use patterns and things like this to, in Punnett squares, to help families with risks evaluate the risk and prepare them before having children or when they're pregnant.

And this is particularly important as some populations have these higher frequencies of some lethal disorders like sickle cell anemia, which sickle cell anemia affects 100,000 Americans and occurs. And one out of 365 African Americans and one out of 16,000, a little bit over 16,000 Hispanic American births, and about one in 13 African American babies is born with the sickle cell trait. So it does matter and it can include therapies that will help them prevent certain consequences of some.

disorders, maybe prolong their life in some other disorders. Okay, so in part three of this lecture, next, we will cover the more complex and polygenetic traits and epigenetics.

Transcript for:Understanding Mendelian Genetics and Inheritance

Transcript for:
Understanding Mendelian Genetics and Inheritance