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A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.
A microsatellite is a tract of repetitive DNA in which certain DNA motifs are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organism's genome. They have a higher mutation rate than other areas of DNA leading to high genetic diversity. Microsatellites are often referred to as short tandem repeats (STRs) by forensic geneticists and in genetic genealogy, or as simple sequence repeats (SSRs) by plant geneticists.
Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental/psychiatric abilities. A general lack of coordination and an unsteady gait often follow. It is also a basal ganglia disease causing a hyperkinetic movement disorder known as chorea. As the disease advances, uncoordinated, involuntary body movements of chorea become more apparent. Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk. Mental abilities generally decline into dementia, depression, apathy, and impulsivity at times. The specific symptoms vary somewhat between people. Symptoms usually begin between 30 and 50 years of age, and can start at any age but are usually seen around the age of 40. The disease may develop earlier in each successive generation. About eight percent of cases start before the age of 20 years, and are known as juvenile HD, which typically present with the slow movement symptoms of Parkinson's disease rather than those of chorea.
Genetic linkage is the tendency of DNA sequences that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Two genetic markers that are physically near to each other are unlikely to be separated onto different chromatids during chromosomal crossover, and are therefore said to be more linked than markers that are far apart. In other words, the nearer two genes are on a chromosome, the lower the chance of recombination between them, and the more likely they are to be inherited together. Markers on different chromosomes are perfectly unlinked, although the penetrance of potentially deleterious alleles may be influenced by the presence of other alleles, and these other alleles may be located on other chromosomes than that on which a particular potentially deleterious allele is located.
Repeated sequences are short or long patterns that occur in multiple copies throughout the genome. In many organisms, a significant fraction of the genomic DNA is repetitive, with over two-thirds of the sequence consisting of repetitive elements in humans. Some of these repeated sequences are necessary for maintaining important genome structures such as telomeres or centromeres.
Human genetics is the study of inheritance as it occurs in human beings. Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population genetics, developmental genetics, clinical genetics, and genetic counseling.
Genetics, a discipline of biology, is the science of heredity and variation in living organisms.
In genetics, trinucleotide repeat disorders, a subset of microsatellite expansion diseases, are a set of over 30 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides increase in copy numbers until they cross a threshold above which they cause developmental, neurological or neuromuscular disorders. In addition to the expansions of these trinucleotide repeats, expansions of one tetranucleotide (CCTG), five pentanucleotide, three hexanucleotide, and one dodecanucleotide (CCCCGCCCCGCG) repeat cause 13 other diseases. Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to production of a toxic protein. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.
Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of duplication or deletion event that affects a considerable number of base pairs. Approximately two-thirds of the entire human genome may be composed of repeats and 4.8–9.5% of the human genome can be classified as copy number variations. In mammals, copy number variations play an important role in generating necessary variation in the population as well as disease phenotype.
Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. For example, research on the causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis, management, and counselling people with genetic disorders would be considered part of medical genetics.
Huntingtin(Htt) is the protein coded for in humans by the HTT gene, also known as the IT15 ("interesting transcript 15") gene. Mutated HTT is the cause of Huntington's disease (HD), and has been investigated for this role and also for its involvement in long-term memory storage.
Recombination hotspots are regions in a genome that exhibit elevated rates of recombination relative to a neutral expectation. The recombination rate within hotspots can be hundreds of times that of the surrounding region. Recombination hotspots result from higher DNA break formation in these regions, and apply to both mitotic and meiotic cells. This appellation can refer to recombination events resulting from the uneven distribution of programmed meiotic double-strand breaks.
A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.
Neurogenetics studies the role of genetics in the development and function of the nervous system. It considers neural characteristics as phenotypes, and is mainly based on the observation that the nervous systems of individuals, even of those belonging to the same species, may not be identical. As the name implies, it draws aspects from both the studies of neuroscience and genetics, focusing in particular how the genetic code an organism carries affects its expressed traits. Mutations in this genetic sequence can have a wide range of effects on the quality of life of the individual. Neurological diseases, behavior and personality are all studied in the context of neurogenetics. The field of neurogenetics emerged in the mid to late 20th century with advances closely following advancements made in available technology. Currently, neurogenetics is the center of much research utilizing cutting edge techniques.
Nancy Wexler FRCP is an American geneticist and the Higgins Professor of Neuropsychology in the Departments of Neurology and Psychiatry of the Columbia University College of Physicians and Surgeons, best known for her involvement in the discovery of the location of the gene that causes Huntington's disease. She earned a Ph.D. in clinical psychology but instead chose to work in the field of genetics.
Milton Wexler was a Los Angeles psychoanalyst who was responsible for the creation of the Hereditary Disease Foundation.
Rudolph Emile 'Rudy' Tanzi a professor of Neurology at Harvard University, vice-chair of neurology, director of the Genetics and Aging Research Unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH).
Ying-Hui Fu is a Taiwanese-American biologist and human geneticist who has made important contributions to understanding the genetics of many neurological disorders. Her chief discoveries include describing Mendelian sleep phenotypes, identifying causative genes and mutations for circadian rhythm disorders, and characterizing genetic forms of demyelinating degenerative disorders. Fu is currently a professor of neurology at the University of California, San Francisco. She was elected to the US National Academy of Sciences in 2018.
David E. Housman is an American geneticist. He is the Virginia and D.K. Ludwig Professor for Cancer Research in the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology. He is known for his contribution to the discovery of the HTT gene that causes Huntington's disease.
Gerard David Schellenberg is an academic neuropathologist who specializes in the research of Alzheimer's disease. He is the director of Penn Neurodegeneration Genomics Center as well as a professor of Pathology and Laboratory Medicine at the University of Pennsylvania. He is a leading contributor to Alzheimer's disease research.
References
- ↑ "James F. Gusella, PhD". Massachusetts General Hospital. Archived from the original on 2024-04-17. Retrieved 2024-04-17.
- ↑ "Meet Marcy & Jim". Huntington's Disease Society of America. 24 February 2015. Retrieved 2024-04-17.
- ↑ Gusella, James F (1980). Selection and localization of cloned DNA sequences from human chromosome 11 (Thesis).
- ↑ Gusella, James F.; Wexler, Nancy S.; Conneally, P. Michael; Naylor, Susan L.; Anderson, Mary Anne; Tanzi, Rudolph E.; Watkins, Paul C.; Ottina, Kathleen; Wallace, Margaret R.; Sakaguchi, Alan Y.; Young, Anne B.; Shoulson, Ira; Bonilla, Ernesto; Martin, Joseph B. (November 17, 1983). "A Polymorphic DNA Marker Genetically Linked to Huntington's Disease". Nature. 306 (5940): 234–238. doi:10.1038/306234a0. PMID 6316146 . Retrieved 2024-04-17.
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- ↑ MacDonald, Marcy E; Ambrose, Christine M; Duyao, Mabel P; et al. (1993-03-26). "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes". Cell. 72 (6): 971–983. doi:10.1016/0092-8674(93)90585-e. hdl: 2027.42/30901 . PMID 8458085.
- ↑ Rouleau, G. A.; Wertelecki, W.; Haines, J. L.; et al. (1987). "Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22". Nature. 329 (6136): 246–248. doi:10.1038/329246a0. PMID 2888021.
- ↑ Tanzi, R. E.; Gusella, J. F.; Watkins, P. C.; et al. (1987-02-20). "Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus". Science. 235 (4791): 880–884. doi:10.1126/science.2949367. PMID 2949367.
- ↑ Higgins, Anne W; et al. (2008-03-03). "Characterization of Apparently Balanced Chromosomal Rearrangements from the Developmental Genome Anatomy Project". Am. J. Hum. Genet. 82 (3). The American Society of Human Genetics: 712–722. doi:10.1016/j.ajhg.2007.12.011. PMC 2427204 . PMID 18319076.
- 1 2 Nelson, David L. (2017-03-02). "2016 William Allan Award Introduction: James Gusella". American Journal of Human Genetics. 100 (3): 385–386. doi:10.1016/j.ajhg.2017.01.016. PMC 5339081 . PMID 28257684.
- ↑ "Professor James F. Gusella". King Faisal Prize. 10 October 2012. Archived from the original on 2020-03-29. Retrieved 13 August 2018.
- ↑ "AAAS selects 15 Harvard faculty members as fellows". The Harvard Gazette. 2007-11-15. Archived from the original on 2024-04-17. Retrieved 2024-04-17.
- ↑ "Elected Fellows". American Association for the Advancement of Science. Retrieved 2024-04-17.
