Medical genetics is the application of principles of genetics to medical practice. This includes genetic studies, genetic classification of disease, diagnosis and treatment, and genetic counseling; it can also be defined as the branch of medicine that involves the diagnosis and management of hereditary disorders.
Figure 1: double helix structure of the DNA
DNA (deoxyribonucleic acid) is the genetic material of all living organisms, including humans. It is a double-stranded helix with two sides connected by multiple combinations of 4 different bases. 4 bases are displayed in 4 different colors. DNA is a double helix consisting of two complementary strands. The information stored in DNA consists of the instructions for building and maintaining all the cells in an organism. The human genome consists of about 3.2 billion base pairs. Due to the enormous size of DNA, eukaryotes have developed efficient DNA packaging systems. DNA is found in the nucleus, chloroplast, and mitochondria of eukaryotes. In prokaryotes, DNA is not enclosed in a membrane envelope. DNA consists of two strands twisted together, also called a double helix. The left side of figure 1 shows the colored bases of the DNA double helix. From top to bottom, the left strand runs from 3 prime to 5 prime and the right strand runs from 5 prime to 3 prime. The right side of the figure shows an enlargement of 2 nucleotide base combinations. Bases are linked by strands with negatively charged phosphate groups. The 5 prime strands above have a ribose structure drawn with the oxygen atom above and the 3 prime strands above have a ribose structure drawn with the oxygen atom below.
Figure 2: DNA Structure. DNA forms a double helix of two antiparallel strands (left) and a pair of nucleotides composed of thymine-adenine and guanine-cytosine (right).
The double helix is said to be antiparallel because one strand runs in the 5′→ 3′ direction and the other in the 3′→ 5′ direction. 5' and 3' refer to the number of carbon molecules in the sugar backbone (Figure 2). Carbon 5' has a phosphate group and carbon 3' has a hydroxyl group. The strand consists of nucleotides: a sugar molecule (deoxyribose in DNA, ribose in RNA), a phosphate group, and a nitrogenous base. Phosphodiester bonds link nucleotides together. The two chains are linked by weak hydrogen bonds between complementary nucleotides. The nitrogenous bases are “inside” like steps on a ladder.
Read on to know why this can be a distressing topic for teachers and students, five suggestions for fixing it, and thoughts on why virtual labs can make things easier.
There are three reasons in particular why medical genetics can be difficult for even the most intellectually sound students.
We teach students about DNA, and RNA and how these make up the genetic building block of the human body. However, they cannot see it because the process occurs within the cell. It is impossible to see these linkages with the physical eye and this can be imaginary for students.
Figure 3: DNA packaging conditions in a eukaryotic cell. DNA is organized into chromosomes (top), well-organized nucleosome chains (middle), and linear DNA strands (bottom).
Eukaryotic DNA is very long and therefore must be packed tightly to handle (Figure 3). DNA is wrapped around 8 proteins called histones, forming bead-like units called nucleosomes. Nucleosomes form thread-like structures called chromatin. Depending on the phase of the cell cycle, the condensation of chromatin changes from a low-density packing state to a highly condensed state that is thickly structured known as chromosomes. The blue chromosome is X- shaped with a small circular area at the end. An enlargement of this section shows a yellow string wrapped around three loops consisting of a ball string, each ball wrapped twice with a yellow string. A magnification of the yellow wire shows a view of the DNA double helix.
DNA is packed in the nucleus of eukaryotic cells. This means that DNA can be collected from any sample containing eukaryotic cells except pure mature red blood cell samples because red blood cells do not contain a nucleus. When a DNA sample is needed, a blood sample is usually taken and the DNA is extracted from white blood cells. However, when blood sampling is not possible or too risky (children, animals, forensics), small amounts of DNA can also be obtained from oral swabs (which contain epithelial cells) or some hair follicles.
Linkage analysis is very useful for determining the approximate location of a gene of interest, such as a gene suspected of causing a disease or condition. To identify these genes we can use specific DNA markers or sequences with known exact positions. For example, we can use microsatellites or SNPs ( single nucleotide polymorphisms) as markers. By observing which allelic variation is always present in the affected individual, we can narrow down the approximate location of the gene.
We have to analyze many individuals in a family over several generations to identify gene locations because we need to find specific alleles that are always present in affected individuals and never present in healthy individuals. There is less genetic variation in a family because they are all genetically related. Therefore, it is best to compare people in the immediate family rather than finding healthy individuals from unrelated families. Healthy people can have the same allele. However, because the person is from an unrelated family, the person does not carry the disease gene. Therefore, we should always compare the immediate family. When analyzed by linkage analysis with gel electrophoresis, homozygous individuals have one band on the gel, while heterozygous individuals have two bands on the gel.
DNA sample type: There are different types of DNA including genomic, mitochondrial, and complementary DNA.
Genomic DNA is the complete DNA sequence, including coding (exons) and non-coding (introns) DNA. Non-coding DNA refers to DNA sequences that do not code for a specific protein. Humans have a high percentage of non-coding DNA in the genome; In fact, almost 98% of our genome consists of non-coding DNA. Although this sequence may not code for a specific protein, research shows that it is important in gene regulation, and more functions of this non-coding DNA are being discovered all the time. All somatic cells in our body have the same genomic DNA sequence unless some somatic mutations or abnormalities occur during life.
Mitochondrial DNA is found in the mitochondria of cells and differs from nuclear DNA in that it comes only from the mother, whereas nuclear DNA comes from the mother and father of the organism.
Complementary DNA (cDNA) is not found in cells but is produced by reverse transcription of RNA in test tubes. RNA is first isolated from cells and then transcribed back into cDNA. RNA isolated from cells includes ribosomal RNA, transfer RNA, and messenger RNA. By analyzing the messenger RNA contained in cells, scientists can tell which genes are active when the cells are isolated. RNA is easily degraded so it is rewritten into cDNA, which is much more stable. cDNA is used in quantitative PCR methods to measure gene expression levels. Since complementary DNA is built on an RNA template, complementary DNA contains only the exons of genes; Introns are spliced during RNA production.
Figure 4: Explanatory chart of family tree symbols
Genealogy (Pedigree) is made to provide an overview of the pattern of inheritance and the frequency with which a trait is (presumed to be) inherited. Each family member is represented by an icon: a circle (female) or square (male), filled or black for affected individuals and blank or white for normal individuals. Marriage is represented by a horizontal line of marriage connecting, offspring are represented under a vertical line of descent, and siblings are attached to a horizontal line of kinship. Each generation is assigned a Roman number (I, II, III, etc.) and each individual of the generation is assigned an Arabic number (1, 2, 3, etc.). Common symbols used to create a family tree: The shape is used to represent a person's gender. Boys are represented as squares and girls as circles. Diamonds are used for people of indeterminate gender. The deceased individual is represented by a slash through their icon. Affected people are represented by filled or shaded shapes rather than blank or light shapes. Trait carriers have their symbols half-filled or shaded. Patients initiating genetic manipulation, or subjects, are indicated by arrows pointing to specific tree shapes. Mating individuals have their shapes connected by horizontal lines. A proband is a person within the family who first sees a doctor for this phenotype (disease). Among the older generations of this family, there may be other affected members; However, a proband usually refers to a member seeking medical assistance or being tested, even if the affected ancestor is known.
Microsatellites are short repeating DNA sequences of two to six base pairs. The number of repetitions may vary individually; they represent different alleles. For example, allele 1 has four repetitions, allele 2 has five repetitions, allele 3 has six repetitions, and so on. SNPs can also be used as markers in linkage analysis; however, there are only two alleles for the SNP. For example, C/T means that allele 1 has C while allele 2 has T. Due to the greater variability in microsatellites than in SNP, it is easier to perform linkage analysis with microsatellites. One of the most common examples of a microsatellite is (CA)n, where n is the number of CA repeats. The number of repetitions can vary from 3 to 100 times, creating a large number of alleles to be present in the population. Remember that a large number of these alleles are present in the population, not individuals. We only have two copies of the chromosome, which means we only have two different alleles in our cells. If an individual has two different alleles, for example (CA)10 and (CA)15, they are said to be heterozygous for the microsatellite. On the other hand, if an individual has only one allele on both chromosomes, they are said to be homozygous for the microsatellite. Microsatellite genotypes can be analyzed by amplification using PCR and length analysis (number of repetitions) using gel electrophoresis.
An allele is one of several alternative forms of the same gene or genetic locus. Sometimes different alleles can result in different observed phenotypic traits, such as B. different pigmentation. However, most genetic variations result in little or no noticeable variation. Most multicellular organisms are diploid. This means they have two alleles for each gene, one inherited from each parent. If the two alleles are the same, the organism is said to be homozygous for the gene. If they differ, we call the organism heterozygous for that gene. If the allele is dominant, one copy of the gene is sufficient to produce the appropriate phenotype. However, to exhibit a recessive phenotype, an individual must have two copies of the gene. The dominant allele is usually denoted by an uppercase letter and the recessive allele is by a lowercase letter. In terms of eye color, for example, "brown" and "blue" where "brown" is the dominant gene. Individuals with two alleles for brown color (AA) have brown eyes. Individuals with one allele for brown and one allele for blue (Aa) also have brown eyes because the brown eye color allele is dominant. A person with blue eyes has two alleles (recessive) for the color blue (aa).
Breast cancer-associated alleles have incomplete penetration. BRCA1/2 is strongly associated with breast cancer. Many people who carry mutations in their BRCA1/2 eventually develop breast cancer; however, not all develop breast cancer. Several people tested positive for the BRCA1/2 mutation and did not develop breast cancer. This is because BRCA1/2 has incomplete penetration. The degree of penetration can be difficult to determine because it can be modified by many factors such as age, environmental factors, other genes (polygenetics), and epigenetic regulation.
Now that you've got an adequate foundation, let's examine five ways you can make embryology lessons more delightful, easier, and fun for you and your learners.
Gregor Mendel, an Austrian monk, conducted extensive experiments on the heredity and genetics of the Pea plant. He described the unit of heredity as an unchanging particle that is passed down to offspring. His work was fundamental to understanding the principles of genetics even today. Therefore, Gregor Mendel is considered the father of genetics.
During this time, Haeckel also correctly predicted that the genetic material was located in the nucleus of the cell. Miescher showed that the matter in the nucleus was nucleic acids. At that time, chromosomes were also discovered as carriers of genetic information.
PCR is a method used to make billions of copies of a particular DNA sequence. For further DNA analysis (e.g. for DNA fingerprinting or genotyping) it is often necessary to have a higher number of copies of a given DNA sequence than would be found in a typical sample. The PCR reaction is very specific, meaning that it only produces a copy of the desired sequence from the DNA template (sample). This specificity is provided by the primers, which are designed to complement each other and bind to a specific region on either side of the desired DNA region ( target region).
Gel electrophoresis is a method for separating charged macromolecules (DNA, RNA, or protein) of different sizes and estimating their length. Since nucleic acids are negatively charged ions at neutral or alkaline pH in aqueous media, this technique is often used to separate DNA or RNA molecules. This is needed, for example, for DNA profiling or for checking RNA integrity. Proteins must be denatured and negatively charged before they can be analyzed by gel electrophoresis. Gel electrophoresis is often used to separate DNA fragments resulting from PCR amplification. This method is also useful for isolating and extracting DNA fragments of a certain size. In the virtual lab, we use an E-Gel machine to perform gel electrophoresis (see image below).
A protein truncation test is a powerful method for evaluating DNA mutations that result in protein cleavage in vitro. Nonsensical mutations produce premature stop codons. This means that the resulting protein will expire earlier than expected and can be detected using a protein truncation assay. These shorter proteins are also called truncated proteins. In protein truncation tests, we don't have to use animals as model systems to synthesize proteins; In contrast, we have an in vitro system in which the resulting protein can be synthesized without the need for live cells.
Next-generation sequencing (NGS) is an advanced sequencing technology that sequences many short DNA molecules at once. This technology is also called massively parallel sequencing. These short DNA sequences are then assembled by aligning their sequences to the reference sequence (reference genome), revealing the complete DNA sequence of the genome. Next-generation sequencing is a very powerful technique that can be used for various applications such as:
whole genome sequencing
Detection of genetic aberrations (e.g. mutations or chromosomal rearrangements)
Discovery of DNA methylation patterns
Next-generation sequencing is a major improvement over the original technique, first-generation sequencing.
Cancer is a genetic disease caused by abnormalities in DNA. It also means that the deviation can be passed from parents to their children, leading to hereditary cancer. These people are born with a defective allele that is inherited from one of their parents. Cancer is not one disease but includes many different diseases. Cancer is caused by abnormal cell growth due to mutations in DNA. These mutations are caused by mutagenic substances such as smoke, ionizing radiation, and pollutants. Viruses are also strong carcinogens as they infect their hosts by inserting DNA into the host genome. DNA mutations and insertions result in altered gene expression. Cancer occurs when a cell acquires a set of these mutations and begins to grow out of control. In healthy cells, the tumor suppressor genes prevent uncontrolled cell growth. If the function of this gene is impaired, abnormal cell growth can develop and result in cancer development. Mutations in this gene are heritable, meaning that some cancers have a strong hereditary component.
Proto-oncogenes are positive regulators of the cell cycle. When mutated, proto-oncogenes can become oncogenes and cause cancer. Overexpression of oncogenes can lead to uncontrolled cell growth. This is because oncogenes can alter the transcriptional activity, stability, or protein translation of other genes that directly or indirectly control cell growth. More than 100 different types of cancer are known to exist in humans. These tumor cells form clumps and invade other organs. Cancer accounts for about 15% of all human deaths and costs society an estimated $1.2 trillion. The incidence of cancer is on the rise as more people live longer.
Breast cancer is classified as a carcinoma: cancer that originates in epithelial cells. The National Cancer Institute ranks breast cancer as the second most common cancer after prostate cancer, with about 230,000 newly diagnosed cases in 2013 and nearly 40,000 deaths. In the United States, about one in eight women will develop breast cancer at some point in their lives, with a rate of just under 12%. Breast cancer doesn't just happen to women; Men are also prone to breast cancer, although the incidence is much lower. About 5-10% of breast cancers can be attributed to gene mutations inherited from parents. BRCA1 and BRCA2 mutations are the most common. Women with the BRCA1/2 mutation have up to 80% risk of developing breast cancer in their lifetime and are more likely to be diagnosed at a younger age (before menopause). An increased risk of ovarian cancer is also associated with this genetic mutation. Mutations in BRCA1 or BRCA2 can be inherited from either the mother or the father.
Defective tumor suppressors are inherited more frequently than oncogenes. In tumor suppressors, both alleles do not have to function for cancer to develop. It was first described by Alfred G. Knudson in 1971 using Knudson's two-stroke hypothesis. Alfred uses retinoblastoma (cancer that develops in the retina) which occurs in very young children. Later he discovered that these children inherited a defective tumor suppressor gene called RB1 from one of their parents. The first hit is associated with congenital defects, and the second hit is an event that occurs during life. This may be due to random mutations that occur during cell division or external factors such as sun exposure that cause the second allele to become active. Because these people have had the first hit, they will develop cancer much earlier than others born with both healthy alleles, because these people must have both hits during their lifetime.
Two chromosomes with wild-type tumor suppressor genes are shown. With a new mutation in one of the indicated chromosomes, the cell takes the first hit. A second hit was then introduced in the form of deletion of the part of the chromosome that contained the tumor suppressor gene. This leads to tumor formation because there are no tumor suppressor genes. The lower image shows mutations of tumor suppressor genes in cells with germline mutations leading to familial cancers. Two chromosomes are shown, one with a wild-type allele and one with an inherited germline mutation in a tumor suppressor gene. Cell now has the first hit. A second hit was introduced in the form of deletion of the part of the chromosome that harbors the tumor suppressor gene. This leads to tumor formation because there are no tumor suppressor genes. Think of tumor suppressors as brakes that prevent cancer from developing, and oncogenes as accelerators that accelerate cancer progression. BRCA1/2 is a tumor suppressor, along with many other examples such as P53, PTEN, RB, APC, and others. There are several functions of tumor suppressor genes, such as: providing cell cycle and checkpoint control, repairing DNA damage, promoting apoptosis, and preventing epithelial-to-mesenchymal junction (EMT). The inactivation of tumor suppressor genes can lead to tumor formation. Oncogenes are dominant traits; A mutation in just one allele is enough to make a cell avoid apoptosis and continue to proliferate. In cancer, proto-oncogenes can mutate, resulting in increased function. When a proto-oncogene is activated, it is called an oncogene. Oncogenes can be activated in a variety of ways, including mutation, epigenetic regulation, chromosomal translocation, or gene duplication. The result is hyperactive or overexpressed oncogenes that override the function of tumor suppressor genes and promote cancer development. Examples of oncogenes include MYC, RAS, TGF-B, HER2, ERK, and others.
A good mnemonic for the different types of DNA is "Complete Medical Genetics" excluding the lowercase alphabet as shown:
C - Complementary DNA.
M - Mitochondrial DNA.
G - GenomicDNA.
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Knudson AG Jr., 1971, Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. Apr;68(4):820-3.