Genetics: Inheritance, Heredity, and Genetic Variation & Its Relevance In Neurology
By: Rachel Kimball & Tia Joseph
While some neurological disorders may be acquired, such as through injury or disease, many neurological conditions are inherited. Congenital neurological disorders tend to run in families, and while not all members of the family will inherit the disorder, many can be carriers if the disorder is linked to a recessive allele. To name a few, Familial Alzheimers, Huntington’s Disease, and Wilson’s Disease are all inherited genetically.
This post will provide an overview of how genetics works at a molecular level with the hope of providing a foundation for many of the neurological disorders we will dive into in our future posts on Instagram and the website.
DNA as Genetic Material
DNA, or deoxyribonucleic acid, serves as the basis of genetic material in the human body. Most DNA is stored in the nucleus of each cell (with the exception of mitochondrial DNA), and nearly every cell contains the same DNA. Not all DNA is used to eventually code for proteins. If this were the case, your eye color could be seen in your feet! Prokaryotes have circular DNA and Eukaryotes (humans, for example) have linear DNA.
The genetic information stored in DNA is represented in four bases: Adenine (A), Guanine (G), Thymine (T,) and Cytosine (C). According to Chargaff’s rules, Adenine pairs with Thymine and Guanine pairs with Cytosine. The Purines (larger, two rings) are Adenine and Guanine, and the pyrimidines (smaller, two rings) are Thymine and Cytosine. Of the three billion base pairs in the human genome, 99 percent of them are shared among all people! The two long strands that pair up through the bases serve as the rungs of the ladder twist to create a double helix shape. The vertical ends are made up of sugar and phosphate molecules.
DNA replication is a crucial step in creating new cells and synthesizing proteins. The process is semi-conservative, as each daughter DNA has one original strand and one new strand. DNA synthesis occurs at the replication fork which is a Y-shaped area that creates a bubble. Helicases, enzymes that untwist/unwind DNA, flow through the replication fork, separating the two strands that are connected by the attraction between the nitrogenous bases. Single-stranded binding proteins bind to the single strands as they are separated due to the helicase, and this enables DNA polymerase to more easily connect. DNA polymerase is an enzyme that catalyzes DNA synthesis and adds nucleotides to the chain with the help of primers and template strands. DNA is read in the 5’ to 3’ direction and built from the 3’ to 5’ direction. As helicase breaks through the two strands and untwists them, tension is produced upstream, so topoisomerase relieves the tension that results. The leading strand is produced in the same direction that the replication fork is moving in, creating one long strand of DNA, and the lagging strand is produced in the opposite direction as the replication fork, creating short okazaki fragments that bind together by ligase.
A mutation occurs when there is an error in DNA sequencing. Mutations can either be a substitution, deletion or insertion. A substitution has the smallest impact on the amino acid sequence, as it only changes on nucleotides. A deletion/insertion mutation, however, skews all of the nucleotides over by one, hence changing the entire sequence as everything is put into new groups of three nucleotides that eventually code for amino acids.
Telomeres are non coding sections that have a repetitive structure at the end of chromosomes. In human telomeres, this repetitive sequence is TTAGGG. Telomeres serve three main purposes. First, telomeres help organize our 46 chromosomes in the nucleus of our cells. Second, the way that they cap the ends of chromosomes much like aglets on the ends of shoelaces protects the chromosomes from becoming frayed or tangled. Thirdly, they help chromosomes properly divide during cell division. When the chromosome divides during cell division, the telomeres divide as well, and become a little bit shorter with each round of mitosis. As we get older and our cells continue to divide, our telomeres will become so short that they reach a “critical length” that signals the cell to undergo apoptosis, or programmed cell death. While the reduction of telomere length leads to aging cells, which leads to an aging body, telomeres function a little differently in cancer cells. Since cancer cells replicate indefinitely, their telomeres remain long, never reaching that “critical length” signaling apoptosis in cancer cells. This bypassing of apoptosis tricks the human body to continue cell division, resulting in cancer metastasis.
Neurogenetic disorders are conditions caused by changes in genes and chromosomes that can affect the brain, spinal cord, nerves and muscles. Examples of these disorders include Huntington’s disease, Autism spectrum disorder, Charcot-Marie-Tooth disease, Tourette’s syndrome, Familial amyotrophic lateral and sclerosis (familial ALS), just to name a few. For neurogenic disorders such as Huntington’s disease, these conditions can be caused by just a single defective gene on a chromosome. These types of conditions are called “monogenic diseases” for their single-gene mutation. Diseases from this single-gene mutation cause certain neurons in the central or peripheral nervous system to develop abnormally or not function very well. For others, like Tourette’s syndrome, a combination of genetic factors as well as other influences like environment can lead to these conditions. These types of conditions are called “complex diseases”. Neurodegenerative diseases that can have hereditary factors like Alzheimer’s and Parkinson’s disease are also classified as “complex diseases” Neurological disorders affect people of all age ranges, races, and sexes, however symptoms can range. Some symptoms can get worse over time, while others can improve. Family history of neurological disorders, in combination with genetic counseling, testing, and neuro-imaging can help catch these disorders beginning at an early age. Treatment for these diseases can help mitigate symptoms and maximize function.
Genetics and Alzheimer’s Disease
Genetics, in combination with other factors, can also play a role in the development of Alzheimer’s Disease (AD) in an individual. If one or more family members has AD, it is likely that it could run in the family. Scientists have found there to be two groups of genes that can play a role in the inheritance of AD: risk genes and deterministic genes. Risk genes can enhance the likelihood of developing a disease, but do not necessarily cause the development of the disease. Risk genes for AD include the APOE-e4 gene, which 40-65% of people with AD possess. Those that have APOE-e4 also tend to possess symptoms for AD at a younger age. Deterministic genes directly cause a disease to occur, and those possessing these genes are guaranteed to develop the condition. Thankfully, these latter types of genes are extremely rare, accounting for around 1% of AD cases. One subset of AD studied at the MAPP lab is Autosomal Dominant Alzheimer’s Disease (ADAD), ADAD develops in individuals before the age of 65, and is diagnosed in families that have more than one member with Alzheimer’s. Individuals with ADAD inheritance of mutations in the PSEN1 gene, PSEN2 gene, or the APP gene, all in which are inherited in an autosomal dominant fashion, meaning that they only need one copy of the mutated gene to cause the condition.
Understanding genetics and the heredity of disorder is critical to knowing the prevalence of certain diseases in populations, and how they are inherited on a molecular level. By knowing the inheritance patterns of neurogenetic diseases like AD, scientists and medical professionals can better develop treatments and prevention plans to limit the effect and prevalence of these diseases.