Chapter 5 Reference Readings (PDF)

CHAPTER 5 Reference Readings Lesson 7- Could other genes affect cholesterol? What is the effect of mutations in genes related to cholesterol levels? In chapter 4 we learned that mutations in the gene for the LDL receptor protein (LDLR) can disrupt the structure of the protein. This disruption to s...

CHAPTER 5 Reference Readings Lesson 7- Could other genes affect cholesterol? What is the effect of mutations in genes related to cholesterol levels? In chapter 4 we learned that mutations in the gene for the LDL receptor protein (LDLR) can disrupt the structure of the protein. This disruption to structure affects its function in regulating the amount of cholesterol in the blood. We also learned that other proteins are present in cells, and some of these also have functions related to cholesterol processing. Two of these proteins are ApoB and PCSK9. The genes that code for the three proteins are found on different chromosomes. LDLR is on chromosome 19, APOB is located on chromosome 2, and PCSK9 is located on chromosome 1. All three of these genes have multiple alleles. In fact, scientists have discovered nearly 2,000 different mutations in the LDLR gene and close to 100 mutations in PCSK9 and APOB. It helps to decide on a way to refer to each allele. For example, for our purposes we can use LDLR as the name for the typical allele and LDLRdel1 as the name for one of the mutated alleles. The “del” refers to a deletion of nucleotides in the DNA of the gene, which in turn leads to missing amino acids in the protein structure. Proteins involved in moving cholesterol from the blood into the cell. The LDL receptor protein is shown in yellow and “captures” LDL particles in the bloodstream and brings them into a cell. The ApoB protein is depicted as the long light blue strand on the outside of the green LDL particle. ApoB is important for helping the LDL particle bind properly to the LDL receptor. The blue PCSK9 protein can attach to the LDL receptor protein and prevents the recycling of the receptors back to the membrane. Genetic testing can reveal whether someone has one or two copies of a mutation or no mutations. The pair of alleles a person has for a particular gene is called their genotype. Mutated alleles might explain why increased risk of heart disease runs in some families. In chapter 4 we investigated how changes to LDL receptor protein structure can lead to decreased function and high LDL levels in the bloodstream. Scientists have discovered ways in which mutations in other genes can also affect cholesterol homeostasis. In the case of ApoB, mutations are known to change the structure of the protein in ways that interfere with how it binds to LDLR. This change causes fewer LDL particles to be captured and brought into cells. Some mutations in PCSK9 have been found to actually increase the protein’s function. However, this means that LDL receptors are broken down in a cell at an increased rate, reducing the number of receptors on the cell surface. Mutations in the three genes of focus affect different proteins but they all result in similar outcomes: Cholesterol remains in the blood at higher than usual levels, leading to plaque in blood vessels and eventually coronary artery disease. When a single gene mutation leads to disruptions in the body’s normal function or homeostasis, resulting in disease, the cause of the disease is labeled as monogenic. Scientific research has provided evidence that 40-60% of people with clinically high cholesterol and a family history have a mutation in one of the three genes of focus: LDLR, PCSK9, or APOB. What if someone has alleles that affect cholesterol processing in more than one of these three genes? Medical researchers have found several cases of individuals who have alleles associated with high cholesterol levels for both the LDLR and APOB genes, or both the LDLR and PCSK9 genes. What would you expect regarding their LDL levels? If you think their cholesterol levels would be even higher, you are right. The graphs below compare LDL cholesterol levels in individuals who have alleles associated with high cholesterol in one or two genes. In general, there appears to be an additive effect of having mutated alleles in two genes. Most of these individuals have higher cholesterol levels than those with either of the alleles alone. Are there any other genes that affect cholesterol levels? There are many people who have heart disease, or are at high risk, but do not have mutated alleles for any of these genes. In other words, their heart disease does not have a monogenic cause. Could there be additional genes that affect cholesterol levels? Consider all the things that are happening in the cell at any moment. It is a very busy place! The cell’s activities all involve proteins, many of which we have not talked about yet. Some proteins have the function of breaking down molecules like cholesterol. Some help move cholesterol throughout the cell. Others transfer cholesterol from HDL particles to LDL particles. And many more proteins carry out functions that are not related to cholesterol processing. Could mutations in any of the genes coding for these other proteins affect the management of cholesterol? Mutations in the LDLR, APOB, and PCSK9 genes result in changes to their proteins that are directly linked to cholesterol processing. They have a large impact on LDL cholesterol and the risk of developing heart disease, so the genes were relatively easy to identify and connect to monogenic heart disease. However, additional research shows that many other genes may also be associated with heart disease. These genes were harder to identify because they have smaller effects on cholesterol levels. A few examples of these types of genes are provided in the chart below. Additional genes related to risk of heart disease. By comparing gene sequences in a large number of people with high LDL levels to people with normal cholesterol levels, more than 20 genes were discovered to have mutations that appear to influence heart disease risk. How can we find other genes that affect cholesterol? Researchers use a tool called a “genome-wide association study” (GWAS) to find unknown genes that are associated with particular diseases. A person’s genome is composed of all of their DNA. To perform a GWAS, scientists compare the genomes of many people. They use genetic testing technologies to look for small variations in genome sequence between people who have the disease and those who do not. If many people who have the disease have a variation that people without the disease do not, then that variation may be an allele that contributes to getting the disease. Once additional genes associated with a complex disease are identified, scientists study the proteins the genes code for. Many of the genes they discovered in GWAS research affect cholesterol processing in a small way. Some do not have an obvious link to cholesterol processing and more research is needed to understand their association with heart disease. Researchers are careful to consider whether they have evidence of causation or just correlation when they report ways in which genes may influence risk of disease. Remember that we saw an additive effect of having mutated alleles for more than one of the LDLR, APOB, and PCSK9 genes. Individuals who have high cholesterol, but do not have mutations in any of these genes, may have mutations in several of the many other genes discovered through GWAS. Several genes that have small effects on cholesterol processing may add up to a high cholesterol level. The exact combination of alleles we get seems to be important. Can we explain why someone has a particular trait if it is influenced by more than one gene? Scientists continued their research into the many genes found to be associated with increased risk of heart disease. They determined how important each gene seemed to be in controlling cholesterol levels in the bloodstream. They assigned a score to each gene and then researched whether a higher cumulative risk score correlates to high cholesterol. After studying over 3,000 people, they concluded that the polygenic risk score is predictive of LDL levels. Polygenic risk scores and LDL levels in the blood. Each dot represents a decile. The first dot represents the 10% of people with the lowest scores and their average LDL level. The last dot represents the 10% of people with the highest scores and their average LDL level. Many human traits have a complex genetic story. Rather than simple and clear patterns of inheritance, research shows that often many gene variants are associated with variation in a trait. For example, human height is a polygenic trait. Scientists continue to study which variants have large effects on the trait and which are associated with smaller changes. As we have seen with this lesson, small changes can still add up to a significant effect. Lesson 8- How can two siblings have very different genotypes and outcomes? A pedigree is a diagram that geneticists use to identify patterns of inheritance and make predictions about the likelihood of an individual inheriting a particular trait. A pedigree is used to follow a trait through generations of individuals who are biologically related to each other. They look similar to family trees but the focus of a pedigree is to create a map of the occurrence of particular alleles across generations. How do individuals get and pass on their alleles? Each individual in a pedigree inherited their alleles from two parents. Sexually reproducing organisms create offspring by combining genetic information from two individuals. These organisms make gametes—for example, egg cells and sperm cells—that have half of the genetic information from each parent. Once combined during fertilization, the offspring has a complete genome. Fertilization of a human egg cell. Sperm cells surround an egg cell and both egg and sperm release chemicals to facilitate sperm-egg fusion. Fertilization requires mutual active participation from both gametes; it usually results in only one sperm cell entering the cell membrane of the egg. The cell that results from the joining of the egg and sperm has 46 chromosomes (23 from each parent). The production of gametes explains how a parent passes some of their alleles on to their offspring. Specifically, organisms that reproduce sexually get one copy of each chromosome (and the alleles they carry) from one parent and the other copy from the second parent. Human eggs and sperm have 23 chromosomes, one of each type and thus one allele of each gene. The word we use to describe the genetic makeup of gametes is haploid. Haploid cells have one set of chromosomes. Other body cells have two chromosomes of each type. When two gametes combine, the first diploid body cell is created. So the offspring’s genotype for any gene consists of two alleles. We describe these cells as diploid. Diploid cells have two sets of chromosomes. How are gametes made? Eggs and sperm are made from cells in ovaries and testes that are diploid. So how do we get haploid gametes? The answer to this is a process called meiosis. Meiosis is a type of cell division that precisely distributes one set of chromosomes to cells that become gametes. Before meiosis, chromosomes are duplicated but the copies are still held together. Pair of chromosomes before and after duplication. Diploid cells have pairs of chromosomes. One of the 23 pairs that human cells have is shown here. Each chromosome is a long DNA molecule with many genes, two of which are labeled in these chromosome representations. Before meiosis begins, all chromosomes are duplicated, creating two identical DNA molecules, which are held together near their center. Meiosis. Before meiosis begins, chromosomes are duplicated. Notice the separation of chromosomes that occurs when one cell divides into two, and when two cells divide into four. While only one pair is included in the diagram, the same process occurs with all 23 pairs of chromosomes in human cells. Take note of the genetic makeup of the single cell at the beginning and the four resulting cells. Refer to the figure above as you read about the stages of meiosis. During the first stage of meiosis, chromosomes of each type pair up together in the middle of the cell. Then, they are pulled apart to opposite ends of the cell and the cell divides, separating them into two offspring cells. These cells have one copy of each duplicated chromosome. During the second stage of meiosis, the duplicated chromosomes in each cell split and are divided into two more cells. At the end of meiosis, there are four cells, each with one copy of each chromosome. When an egg and a sperm cell merge during fertilization, a new cell is formed. This cell now has two copies of each chromosome, one from each parent. It will grow and divide millions of times to make a unique individual. The alleles on the chromosomes will play an important role in determining the individual’s traits. Why don’t biological siblings always look alike? Offspring of the same two parents all receive half of their chromosomes from each parent. They have the same parents, so why don’t they all look alike? The answer to this question also has to do with meiosis. As we have seen, when gametes are made, the chromosomes line up with their partners during meiosis. But the partnered chromosomes do not line up the same way every time meiosis occurs. There are many possible arrangements if we consider a cell with numerous chromosomes instead of a single pair. Consider a cell with three pairs of chromosomes. If we focus on the first pair and figure out all potential combinations that could assort into a gamete, we find 8 different gametes are possible. Each time meiosis occurs with this diploid cell, four gametes are produced but there are eight possible genetic compositions. Which gamete ends up fusing with another from a different parent in fertilization is usually random. Possible gametes from an individual with three pairs of chromosomes. This individual can make eight different types of gametes. The independent alignment and separation of chromosomes during meiosis that results in a random assortment of chromosome copies in a gamete is called independent assortment. An organism with 3 pairs of chromosomes can make gametes with 23, or 8 different combinations of chromosomes. How many different combinations of chromosomes can be found in human gametes? Humans have 23 pairs of chromosomes in their diploid cells. Thus, humans can make gametes with as many as 223, or 8,388,608 different combinations of their chromosomes. Gametes with any of these potential combinations can be fertilized by the other parent’s gametes, which have just as many potential combinations. This means that there is a possibility of more than 8 million × 8 million, or 64 trillion different combinations of chromosomes for these two individuals’ offspring! (And that’s just for one pair of biological parents!) For reference, only a hundred or so billion people have ever lived on Earth. Given the astounding number of possible chromosome combinations from their parents, siblings may inherit a great variety of allele combinations from their parents. No wonder they don’t all look alike! How does our new understanding help predict the risk of heart disease? Different allele combinations affect not only a person’s physical appearance, but also how their body functions. So far in this unit we have investigated three different genes on three different chromosomes that produce three different proteins that have an impact on the level of cholesterol in the blood. The alleles that individuals carry on chromosomes 1, 2, and 19 for the LDLR, APOB, and PCSK9 genes affect the likelihood that they will develop heart disease. A parent who has two different alleles on the partner chromosomes that carry genes for LDLR, APOB, and PCSK9 can produce gametes with 8 possible combinations of alleles of these genes. If the other parent also has two different alleles for each of these genes, their child could have 1 of 64 possible combinations of the LDLR, APOB, and PCSK9 alleles. Some combinations result in normal cholesterol processing and homeostasis, but others contribute to high levels of LDL in the blood. If two parents each have one or more mutated alleles for these three genes, their children might inherit a genotype that is better, the same, or even worse with regard to cholesterol than their parent. For example, the parents might both have LDLR/LDLRdel1 as their genotypes. The child might then have the genotype LDLRdel1/LDLRdel1, but they also have a chance of not inheriting the mutation at all. If we add in the other genes, there become many more possible combinations, and siblings are very likely to have some shared alleles for these genes but it’s very unlikely for them to have identical genotypes when a number of genes are involved. In summary: Meiosis is the process of cell division to produce the reproductive cells (Gametes) During meiosis, one cell divides twice to form 4 daughter cells.These 4 daughter cells have half the chromosomes of the parent cells (haploid) Lesson 9- How well do our models predict genetic variation? Does anything contribute to variation in offspring other than independent assortment? We have seen that there is a possibility of millions of different combinations of chromosomes that offspring might inherit from their parents. But there is an additional way that meiosis makes even more variations possible. Remember that each chromosome carries up to 2,000 genes. A pair of chromosomes carry the same genes, although they may have the same or different alleles for each gene. Based on what we have learned about meiosis, it would seem that the alleles on a particular chromosome should be inherited together because they are essentially linked together on this chromosome. For example, suppose two genes, A and B, are on the same chromosome. If an individual has alleles A and B on one chromosome and alleles a and b on its partner chromosome, then this individual should pass on either alleles A and B together OR alleles a and b together. Genetic studies, however, have shown that sometimes an individual like this passes on alleles A and b together, or a and B together. This surprising outcome was first discovered in experiments with fruit flies. How does this happen? Crossing over. When chromosomes pair up during meiosis, parts of the DNA strands can overlap. There can be breaks in their DNA strands that result in alleles being swapped. This can result in offspring having an unexpected phenotype. It appears as if the two partner chromosomes have swapped pieces of themselves. In fact, that is exactly what happens, in a process called crossing over. The resulting chromosomes are called recombinant chromosomes because the alleles on them have been recombined in a way that makes a unique chromosome, one that did not exist in the parent. Linked genes. Two genes located close together on the same chromosome are said to be linked, since they will tend to be inherited together. Genes located far apart on the same chromosome are more likely to be separated by crossing over. When genes are close together on the same chromosome they are considered “linked genes” due to the unlikely possibility that a crossing over event occurs between them. Genes located farther apart from each other are more likely to be separated by crossing over. Crossing over events are random and vary each time meiosis occurs. Considering independent assortment and crossing over, two siblings may end up inheriting very different sets of alleles that either contribute to high LDL levels or normal cholesterol processing. Important vocabulary: ​Homologous chromosomes: have the same genes, one from each parents ​Homozygous: two copies of the same allele ​Heterozygous: one copy of two different alleles ​Somatic cells = body cells ​Gametes = sex cells (sperm and eggs) ​Diploid (2N): both sets of homologous chromosomes (Somatic cells) ​Haploid (N): half set of chromosomes (sex cells) ​Genotype: Genetic Code ​Phenotype: Physical Expression ​Nondisjunction: is the failure of chromosomes to separate properly during meiosis, resulting in daughter cells with more or less number of chromosomes (ex.Down syndrome) Study Questions for Chapter 5 – Genetics and Cholesterol Levels Lesson 7: Could Other Genes Affect Cholesterol? ○​ What does the LDL receptor (LDLR) do in the body, and how does it help control cholesterol levels? ○​ How does a mutation in the LDLR gene affect cholesterol in the blood? ○​ What are the roles of the ApoB and PCSK9 proteins in cholesterol processing? ○​ How do mutations in the LDLR, ApoB, and PCSK9 genes lead to higher cholesterol and heart disease? ○​ What is a genotype, and how does it affect cholesterol processing in the body? ○​ What happens to cholesterol levels if a person has mutations in both the LDLR and ApoB genes, or in both the LDLR and PCSK9 genes? ○​ How do mutations in more than one gene add up to higher cholesterol levels? ○​ What does "monogenic" mean? ○​ What is a polygenic risk score, and how does it help predict cholesterol levels and heart disease risk? Lesson 8: How Can Two Siblings Have Very Different Genotypes and Outcomes? ○​ What is a pedigree, and how is it used to study inherited traits like high cholesterol? ○​ How can pedigrees show patterns of inheritance in families? ○​ How do children inherit their genes from their parents? ○​ What is the process that makes gametes (egg and sperm cells), and how does it affect inheritance? ○​ What is meiosis, and why is it important for making gametes (egg and sperm cells)? ○​ How does meiosis help ensure that each child has a mix of genetic material from both parents? ○​ What is independent assortment, and how does it contribute to genetic diversity? ○​ What is crossing over, and how does it increase genetic variation in offspring? ○​ How does crossing over affect genes that are located close to each other on the same chromosome? Lesson 9: How Well Do Our Models Predict Genetic Variation? ○​ Besides independent assortment, what other process during meiosis creates more genetic variation? ○​ How does crossing over increase genetic diversity? ○​ What does it mean for genes to be “linked,” and how does crossing over affect linked genes? ○​ What are recombinant chromosomes, and how do they contribute to genetic diversity? ○​ Give an example of how crossing over creates new combinations of genes. Extras ​ What are Homologous Chromosomes? ​ What is the difference between Homozygous vs. Heterozygous? ​ What is Diploid and Haploid? ​ What is the difference between Genotype vs. Phenotype ​ What is Independent Assortment?