what is polygenic disorder?
A hereditary issue that is brought about by the joined activity of more than one quality. Instances of polygenic conditions incorporate hypertension, heart disease, and diabetes. Since such scatters rely upon the concurrent nearness of a few qualities, they are not acquired as just as are single-quality sicknesses.
Scientists have been working extensively to understand monogenic and polygenic human diseases. Some monogenic traits (product of a single gene) are cleft chin and face freckles, whereas polygenic traits are the color of eyes and height of a person (product of multiple genes).
The study of the human genome sequence has helped incredibly to understand the widespread markers of genetic variation. It has also helped scientists develop new technologies to determine disease phenotypes with genetic loci. Although polygenic diseases are more common than monogenic diseases, studies of single-gene disorders provide invaluable information about the underlying molecular mechanisms that help understand all forms of genetic diseases.
Monogenic Diseases
The human genome is comprised of around 20,000-25,000 genes that are the backbone of all proteins synthesized. In monogenic diseases, only one of these genes is mutated. Some examples of monogenic diseases are Cystic fibrosis, Sickle cell anemia, Haemophilia, Tay-Sachs disease, and Huntington’s disease. These diseases are rare, more severe, and affect fewer people than polygenic diseases.
Scientists have identified over 4000 genetic diseases caused by a mutation in a single gene. In the USA, approximately 30 million people and globally, 300 million people are affected by different monogenic diseases. Many monogenic diseases are heritable, i.e., passed on from parents to children. A child inherits two copies of each gene from their parents, one from their mother and one from their father. Different combinations of these genes determine if the child will develop a particular disease.
Monogenic diseases can be dominant or recessive and autosomal or sex-linked. For instance, in the case of autosomal dominant inheritance, one copy of the faulty gene from either of the parents can cause the disease. In the case of autosomal recessive inheritance, two copies of faulty genes, one from each parent, are essential to cause the disease. Another method of monogenic disease inheritance is X-linked inheritance, where the faulty gene is only present in the X-chromosome (female chromosome). Irrespective of the method of inheritance, these diseases are easier to detect compared to polygenic diseases.
One of the common monogenic diseases in the European royal family is Hemophilia A. Scientists revealed that this disease occurred due to a sudden mutation in the F8 gene, located on the X-chromosome. The product of this gene is called Factor VIII, which is involved with blood clotting after a wound. Without Factor VIII, blood clotting does not occur, leading to excessive bleeding.
Polygenic Diseases
Various factors influence polygenic or non-Mendelian traits. As stated above, two of the most common polygenic traits are human height and eye color. In the case of human height, researchers found that hundreds of genes are involved in the presentation of this trait. This particular trait also depends on various other factors, such as nutrition.
Polygenic diseases are multifactorial and are more prevalent compared to monogenic diseases. These diseases occur due to various factors, such as genetic variations and environmental factors (e.g., nutrition, exercise, and environmental exposures). Scientists revealed that polygenic diseases, such as type 2 diabetes, coronary artery disease, Alzheimer’s disease, cancer, and schizophrenia, are typically diagnosed in the adult years. This is because of complex assessment processes.
Polygenetic diseases, such as heart disease, arthritis, Type 2 diabetes, and many neurodegenerative diseases, are caused by mutations in several genes, and the contribution of each gene is different. The cumulative effect of gene mutations results in polygenic diseases. Other factors, such as age, sex, nutrition, etc., also play a definitive role in the manifestation of these diseases.
For instance, type 2 diabetes is a disease that is characterized by the presence of a high level of glucose circulating in the blood, and some of the common symptoms of this disease are polyphagia, polyuria, and polydipsia. More than 36 genes (e.g., TCF7L2 allele) are associated with the risk of developing diabetes. Some of these genes are also linked to beta cell functions. Other non-genetic factors also linked with the contraction of diabetes include lifestyle and diet.
Screening for Monogenic and Polygenic Diseases
Individuals who are carriers of monogenic diseases can be determined via carrier screening methods. Even when individuals do not express a monogenic disease, they can be carriers of a faulty gene and pass it on to their children. Some of the methods involved in detecting monogenic diseases are polymerase chain reaction, Southern analysis, allele-specific oligonucleotide screening, linkage analysis, and automated DNA nucleotide sequencing.
In the case of the determination of polygenic diseases, the advancements in genomics and DNA databases have enormously helped clinicians calculate a polygenic risk score. This score estimates an individual’s risks of developing a complex disease based on their unique genetic variations. Genome-wide association studies (GWAS) are typically used to detect these disorders. Researchers detect genes involved in the development of polygenic diseases predominantly by two strategies, i.e., identifying specific genes that produce protein products associated with the etiopathogenesis of the disease, and sequencing the entire genome using the panel of genetic markers that are almost uniformly distributed across the genome.
Polygenic diseases are caused by the joint contribution of a number of independently acting or interacting polymorphic genes; the individual contribution of each gene may be small or even unnoticeable.
- Single-gene disorders, where a mutation affects one gene. Sickle cell anemia is an example.
- Chromosomal disorders, where chromosomes (or parts of chromosomes) are missing or changed.
- Complex disorders, where there are mutations in two or more genes.
Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with the effects of multiple genes in combination with lifestyles and environmental factors. Multifactorial disorders include heart disease and diabetes.
Polygenic inheritance occurs when one character is controlled by two or more genes. Often the genes are large in quantity but small in effect. Examples of human polygenic inheritance are height, skin color, eye color, and weight.
A “polygene” or “multiple gene inheritance” is a member of a group of non-epistatic genes that interact additively to influence a phenotypic trait. The term monozygous is usually used to refer to a hypothetical gene as it is often difficult to characterize the effect of an individual gene from the effects of other genes and the environment on a particular phenotype. Advances in statistical methodology and high throughput sequencing are, however, allowing researchers to locate candidate genes for the trait. In the case that such a gene is identified, it is referred to as a quantitative trait locus (QTL). These genes are generally pleiotropic as well. The genes that contribute to type 2 diabetes are thought to be mostly polygenes. In July 2016, scientists reported identifying a set of 355 genes from the last universal common ancestor (LUCA) of all organisms living on Earth.
Traits with polygenic determinism correspond to the classical quantitative characters, as opposed to the qualitative characters with monogenic or oligogenic determinism. In essence instead of two options, such as freckles or no freckles, there are many variations, like the color of skin, hair, or even eyes.
A polygenic locus is any individual locus that is included in the system of genes responsible for the genetic component of variation in a quantitative (polygenic) character. Allelic substitutions contribute to the variance in a specified quantitative character. A polygenic locus may be either a single or complex genetic locus in the conventional sense, i.e., either a single gene or closely linked block of functionally related genes.
In a modern sense, the inheritance mode of polygenic patterns is called polygenic inheritance, whose main properties may be summarized as follows:
- Most metric and meristic traits are controlled by a number of genetic loci.
- The main mode of nonallelic genes interaction in corresponding gene series is the addition of mainly small particular allele contributions.
- The effects of allelic substitution at each of the segregating genes are usually relatively small and interchangeable which results that identical phenotype may be displayed by a great variety of genotypes.
- The phenotypic expression of the polygenic characters is undergoing considerable modification by environmental influence.
- Polygenic characters show a continuous rather than discontinuous distribution.
- Balanced systems of polygenic inheritance in a population contain a great deal of potential genetic variability in the heterozygous condition and released by small increments through genetic recombination between linked polygenes.
Mapping polygenes
Example of a genome-wide scan for QTL of osteoporosis
Traditionally, mapping polygenes requires statistical tools available to help measure the effects of polygenes as well as narrow in on single genes. One of these tools is QTL-mapping. QTL-mapping utilizes a phenomenon known as linkage disequilibrium by comparing known marker genes with correlated phenotypes. Often, researchers will find a large region of DNA, called a locus, that accounts for a significant amount of the variation observed in the measured trait. This locus will usually contain a large number of genes that are responsible. A new form of QTL has been described as expression QTL (eQTL). eQTLs regulate the amount of expressed mRNA, which in turn regulates the amount of protein within the organism.
polygenic disorder (diabetes) are of many types
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