User talk:Lich2/sandbox

Background on Biological Mechanisms of Huntington's:

Huntington's disease is a neurodegenerative disorder that destroys basal ganglia cells. Huntington's progressively deteriorates an individual's ability to move, speak, and think properly. Within the United States, it affects approximately 1 out of 30,000 individuals. The disease is caused by an autosomal dominant mutation on chromosome 4 that codes for a normal protein product named Huntingtin. The mutation present in affected individuals produces an elevated amount of "CAG" short tandem repeats that is usually present 10-26 times in non-affected individuals. Affected individuals have 40 or more of these repeats that result in defective protein production. These proteins clump together in the brain of affected individuals and become toxic, resulting in cell death of basal ganglia cells. Huntington's disease presents itself in most individuals at the ages of 30-50 with symptoms such as reduced motor control, poor memory, and twitching. Inevitably the affected individual will succumb to the disease as it is progresses, as there is no treatment able to cure or slow the progression of Huntington's.

The tandem repeats of CAG are found in the IT-15 gene on chromosome four. Higher number of repeated CAG micro-satellites are correlated with earlier age of onset. Because Huntington's disease is an autosomal dominant disorder, natural selection should, in theory, select against it, as the mutated allele would not benefit from heterozygote masking, as would a recessive mutation. However, observations reveal that Huntington's Disease has a higher prevalence value, which led geneticists to believe that there may be evolutionary pressures selecting for Huntington's Disease. One of the most widely accepted reasons for the maintenance of Huntington's disease is its late onset, which allows for affected individuals to pass on the allele to offspring before the onset of symptoms. On top of late onset, increased CAG expansion is predicted to gradually increase, as with disease incidence. This higher than expected prevalence cannot be solely explained by spontaneous mutation. There are many theories behind the fitness payoff of Huntington's. Lich2 (talk) 23:12, 29 February 2016 (UTC)— Preceding unsigned comment added by Lich2 (talk • contribs) 23:02, 29 February 2016 (UTC)[reply]

What is already on the Huntington's Wikipedia page:

Signs and symptons
Genetic mutation of the disease and how it's inherited
Htt gene function and mechanism
Diagnosis of the disease
Managemenet of the disease
Prognosis
Epidemiology of the disease
→→high prevalence in European lineages
→→high prevalence in Maracaibo of Venezula, Tasmania, etc. due to founder effect
History
Ethics
Research directions, primarily in mechanism and preventative medicine

What can be added

Evolutionary Biology
Why is there high prevalence?
Consequences of disease phenotype after reproduction age
potential fitness consequences of Htt mutation
In cancer prevention, etc.

Lich2 (talk) 23:12, 29 February 2016 (UTC)[reply]

Evolutionary Work on Huntington's

Origin of Huntington’s disease:

It is unclear when Huntington's disease first originated, but documentation of these symptoms have been dated back hundreds of years, predominantly in the Middle Ages. During that period, there were limited medical technologies and little known about the disease. Before the disease was able to be characterized, it received several names and labels, one of which was Huntington's Chorea. Chorea refers to "an uncontrollable dance-like motion of twisting and turning", named after the symptomatic spasms of those suffering from HD. In 1993, researchers identified the gene responsible for Huntington's disease, now known as HTT. Since then, there has been evidence to support that the HD allele has emerged multiple times - separate mutations arising in Europe, Japan and Africa. Studies suggest that the Htt protein in all cases made affects the cortical and striatal neurons. In certain populations, the emergence of Huntington's disease may result from the Founder Effect (see section on Founder Effect below). Chh27 (talk) 06:29, 29 February 2016 (UTC)[reply]

Source: Secondary - http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/population-genetics-and-hd/

Evolutionary Forces behind the Increased Prevalence of Huntington’s:

A huge question in evolutionary medicine is to ask why genetic diseases are able to be maintained, or rather, why doesn't natural selection remove these detrimental alleles from a population? It is logical to think that a disease that decreases fitness should decrease in frequency within a population. However, one key characteristic of Huntington’s disease (HD) is that the symptoms and deleterious effects usually do not manifest until after the reproductive years of an individual. This means that an individual may procreate before they are aware that they are affected by Huntington's disease. As a result, the offspring of this individual will have a 50/50 or greater chance of also developing Huntington's disease, depending on whether the parent is heterozygous or homozygous for the deleterious allele. Because of this phenomena, the HD disease allele is not only able to be maintained in a population, but it has the potential to increase in frequency within that same population. In addition, there are other evolutionary forces at play that affect the frequency of HD.

Genetic Drift: This evolutionary force acts completely by random chance and has profound effects on smaller populations. Since HD is an autosomal dominant disease, it only takes one disease allele to inherit the disease. If someone that is heterozygous for HD mates with someone that doesn’t carry the disease, then there is a 50% chance that their children will inherit the disease. When a disease is present in small populations, it can increase in prevalence or become completely eradicated.

Migration and Founder Effect: If someone with HD moves to another area, they will also carry the disease allele with them. This allows the disease to appear in novel areas, particularly effecting smaller populations. This “founder effect” in combination with genetic drift within a population can explain why HD prevalence has increased worldwide. In modern society, global travel has become increasingly easy increasing the chance that the HD allele is spread to new areas around the world.

Founder Effect in South Africa: Populations of mixed ancestry in South Africa provide an example of the founder effect and Huntington's disease. Supposedly, a Dutch immigrant brought the disease gene to Africa when he immigrated there with the founding population. Data on SNP haplotypes confirm this hypothesis, or that the source of the gene originated from the Netherlands, and that haplotype 1 commonly appears in populations with Huntington’s disease. Chh27 (talk) 06:00, 29 February 2016 (UTC)[reply]

Mutations: A mutation is spontaneous change in a gene that can have deleterious, beneficial or a neutral effect on an organism’s fitness. This evolutionary force is acts on a completely random basis. HD is produced when someone has more than 36 repeats of CAG nucleotides in the HD gene. Short repeating sequence of nucleotides are also called microsatellites. These microsatellite repeats show a mutational bias to increase in length. This can possibly play a role in the increasing prevalence of HD over time.

Source: http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/population-genetics-part-ii-the-future-of-huntingtons-disease/ Source for Founder effect in South Africa: primary is Scholefield J, Greenberg J. A common SNP haplotype provides molecular proof of a founder effect of Huntington disease linking two South African populations. Eur J Hum Genet. 2007;15:590–595; secondary is https://www.blackwellpublishing.com/ridley/a-z/Huntingtons_disease.asp Chh27 (talk) 06:00, 29 February 2016 (UTC)[reply]

Fitness of the Huntington Disease Allele:

There are some aspects of the HD allele that confers increased fitness to the carrier. Although the deleterious effects of HD are transparent to the forces of natural selection because they manifest after reproduction, but there is evidence that the HD allele can increase one’s fitness during the time of reproduction. This suggests that a late onset disease allele like HD may have a positive effect on one’s fitness earlier in life.

Higher Fertility & Promiscuity

Studies have found that HD+ individuals have 1.14-1.34 children for every one that a respective, unaffected sibling has, which led researchers to suggest that the HD+ allele may qualify heightened reproductive function, fertility, or promiscuity. The latter suggestion stems from the psychological instability & risky behavior that many HD+ patients exhibit during neurodegenerative stages. Dwhurst and colleagues suggested that hypersexuality, lack of inhibition, and irresponsible behavior may be leading to increased offspring production.
However, these theories have yet to be supported by significant evidence. This hypothesis hinges on the premise that HD+ patients exhibit promiscuity during asymptomatic stages, before neurodegeneration; however, neurodegeneration is not necessarily a product of HD+ patients but a general side effect of disease progression. Many studies have confirmed that risky behaviors manifest after the onset of disease, not during potential reproductive years. Since the disease phenotype is expressed much later in life, these risky behaviors would be unlikely candidates for increased offsrping.Lich2 (talk) 23:56, 29 February 2016 (UTC)[reply]

Tumor Suppression: Individuals with HD produce higher levels of cancer suppressing p53 than non-carriers.

HD+ patients have lower incidence for almost all cancers compared to normal individuals. This led Eskenzai et al. to propose that the HD+ allele is associated with better health, specifically in cancer suppression. In patients with Huntington's Disease, the gene Huntingtin (htt) has an extra polyglutamine tail, due to the extra CAG trinucleotide mutations in chromosome 4. After this tail has separated from the main protein, it is thought to hazardously interact with other proteins, which may be the cause of neurodegeneration. Other studies have confirmed that the htt mutant protein overall aggregates with intracellular proteins, such as p53.

P53 is a tumor suppressor that maintains cell growth will stimulating apoptosis in damaged cells. P53 upregulation is critical in heightened immune responses, as it will signal destruction for any cells exhibiting irregular cell cycles, such as tumor cells. When htt and p53 aggregates, the transcription of p53 is altered so that normal rate of cellular apoptosis is increased. Although this destroys the striatal neurons in the body, upregulation of cell destruction also enhances immune responses such that neoplastic lesions are significantly reduced in HD+ patients. The polyglutamine tail interfers with the normal htt gene in regulation cell growth and function, so that cell proliferation is inhibited. This phenotype could be responsible for the lower incidence of cancer in HD+ patients.

It should be noted the cancer suppressing benefits of the mutated htt sits in a specific optimal range of CAG tandem repeats; not enough CAG microsatellites that result in a shorter polyglutamine tail may be benefit the affected individual immunologically, while higher levels of CAG microsatellites result in early onset of neurodegeneration, which harms the respective individual of reproduction fitness.Lich2 (talk) 00:37, 1 March 2016 (UTC)[reply]

Heightened Immune Function:

The study done at Tufts University in 2007 (mentioned in the tumor suppression section) on the presence of the Huntington gene in the human genome suggests the gene provides increased immunity, specifically to cancer. Patients with Huntington’s expressed higher levels of p53, and data from the study indicates a connection between the Huntington protein, p53, and cell apoptosis. While the mechanism remains unclear, the increase in p53 may actually contribute to decreased cancer incidence in these patients, possibly prolong their survival and hence increase their reproductive success (patients live longer, so more time to reproduce). However, scientists struggle to predict the exact amount of Huntington protein and the indicative CAG repeat which allows patients to have increased immunity (see section on tumor suppression). Furthermore, a study done by the University of Washington and University College London in 2008 show that this disease causes the immune systems to overreact, which results in elevated cytokine levels in both the brain and blood, and increased inflammation in the brain. Therefore, Huntington’s disease both enhances and impairs the functionality of the immune system. Chh27 (talk) 07:19, 29 February 2016 (UTC)[reply]

Source: http://ase.tufts.edu/biology/labs/starks/publications/PDF/35.Eskenazietal2007.pdf https://www.sciencedaily.com/releases/2007/09/070925130029.htm

— Preceding unsigned comment added by Brycelacourse (talk • contribs) 03:40, 29 February 2016 (UTC)[reply]

Genetic Factors Affecting Age of Onset:

Although age of onset of Huntington's is mostly placed in middle age, juvenile onset and late onset cases also make up a significant proportion. Late onset (over the age of 50) represent roughly 20% of cases, and juvenile onset (under the age of 20) account for an estimated 5-10% of cases. It can be difficult to be certain of age of onset for individuals, because locomotor symptoms do not always manifest at the same time as mental symptoms, which can include behavioral and psychiatric irregularities. — Preceding unsigned comment added by Jyw062 (talk • contribs) 06:10, 1 March 2016 (UTC)[reply]

PPARGC1A and PCG-1α:

In addition to the CAG tandem repeats on chromosome 4, several other genetic factors influence the demonstrated age of onset in Huntington’s patients. For instance, a study by Weydt et al showed that in particular, the gene PPARGC1A is involved with the age of onset. The authors of the study showed that a particular variation in one nucleotide (also called a SNP, or a single nucleotide polymorphism’) located in the gene was involved with delaying the age onset of locomotor symptoms. An independent study by Terzerdaeh-Fard et al found the same results, strengthening the claims of these authors. Specifically, the change from an A/A to an A/G or a G/G genotype was noticeably associated with the delay of age on onset, and the change to G/G was most pronounced. Compared to other clients in their study that did not possess this SNP, the delay time of patients with this SNP could be up to 3.7 to 4 years.

Additionally, the PPARCG1A gene encodes a protein called PCG-1α, which is involved in the expression of mitochondrial genes. It also appears to be influential in preventing oxidative damage to neurons, which likely contributes to the pathogenesis of Huntington's. In fact, mutant HTT decreases the expression of PCG-1a, and the absence of PCG-1α in mice created Huntington’s-like symptoms and neurodegeneration in rodents. Therefore, Weydt et al and Terzedeh-Fard et al postulate that the presence of PCG-1α has significant implications for Huntington’s disease development in humans, and may influence future treatment targets of the illness.

SLC2A3

For many brain diseases, an abnormal glucose metabolism in the central nervous system (CNS) is a significant indicator. According to Mazziotta et al, positron scanning technology showed minimal glucose uptake in the brains of humans with Huntington’s disease. In humans, glucose metabolism is regulated by multiple glucose transporters, one of which is GLUT 3. GLUT 3 is a protein encoded by the SLC2A3 gene, is one of the main transporters responsible for glucose uptake in the brain, and has undergone several genetic recombination events over time. As a result, both deletion alleles (1 copy of the gene) and duplication alleles (3 copies) exist in humans.

In a study by Vittori et al, the authors postulated that the CNV (copy number variation) of a neuronal GLUT could affect the age of onset in people with Huntington’s. The authors found that the difference in age of onset between people with 3 and 4 copies of the alleles was significant, and in fact people with 4 copies had an later average age of onset by roughly 3 years. It's important to note, however, that this does not affect the overall age of onset of the Huntington's population. Due to low frequency, the deletion (0.25%) and duplication (1.9%) alleles have a more significant impact when comparing individuals.

Vittori et al also found that patients with 3 copies of the alleles had a significantly higher amount of expressed GLUT 3 protein compared to patients with 2 copies of the alleles. Interestingly, the difference of protein expression in patients with 2 copies compared to patients with only 1 copy was not significant. It appears, thus, that having 3 copies of the allele contributes the most to the delay of age of onset in Huntington's patients.

References:

PLEASE CITE YOUR SOURCES CORRECTLY HERE

Higher fertility & cancer suppressionLich2 (talk) 23:59, 29 February 2016 (UTC)[reply]

Primary: Eskenazi, Benjamin R., Noah S. Wilson-Rich, and Philip T. Starks. "A Darwinian Approach to Huntington’s Disease: Subtle Health Benefits of a Neurological Disorder." Medical Hypotheses 69.6 (2007): 1183-189.

Founder Effect in South Africa Chh27 (talk) 06:35, 29 February 2016 (UTC)[reply]

Primary: Scholefield J, Greenberg J. A common SNP haplotype provides molecular proof of a founder effect of Huntington disease linking two South African populations. Eur J Hum Genet. 2007;15:590–595

Secondary: "Evolution - A-Z - Huntington's Disease." Evolution - A-Z - Huntington's Disease. N.p., n.d. Web. 29 Feb. 2016. <https://www.blackwellpublishing.com/ridley/a-z/Huntingtons_disease.asp>.

Origins of Huntington's Disease (some information also already present in Wikipedia) Chh27 (talk) 06:35, 29 February 2016 (UTC)[reply]

Primary: Wang, Nan et al. “Neuronal Targets of Mutant Huntingtin Genetic Reduction to Ameliorate Huntington’s Disease Pathogenesis in Mice.” Nature medicine 20.5 (2014): 536–541. PMC. Web. 29 Feb. 2016.

Secondary: "Huntington's New South Wales." What Is The History Of Huntington's Disease (HD)? N.p., n.d. Web. 29 Feb. 2016. <http://www.huntingtonsnsw.org.au/information/hd-facts/history>.

Secondary: Schmidt, Elaine. "UCLA Scientists Hunt down Origin of Huntington's Disease in the Brain." UCLA Newsroom. N.p., 28 Apr. 2014. Web. 29 Feb. 2016. <http://newsroom.ucla.edu/releases/ucla-scientists-hunt-down-origin-of-huntington-s-disease-in-the-brain>.

Effects on the Immune System Chh27 (talk) 07:28, 29 February 2016 (UTC)[reply]

Primary: Eskenazi B, Wilson-Rich N, Starks P. A Darwinian Approach to Huntington's Disease: Subtle Health Benefits of a Neurological Disorders. Medical Hypotheses. 2007;69:1183–1189.

Secondary: University of Washington. "Huntington's Disease Linked To Overactive Immune Response In The Brain." ScienceDaily. ScienceDaily, 16 July 2008. Web. 29 Feb. 2016. <https://www.sciencedaily.com/releases/2008/07/080714141300.htm>.

Tufts University. "Biologists Link Huntington's Disease To Health Benefits In Young." ScienceDaily. ScienceDaily, 26 September 2007. <www.sciencedaily.com/releases/2007/09/070925130029.htm>.

Genetic Factors Affecting Age of Onset

Primary: Weydt, Patrick, Selma M. Soyal, Cinzia Gellera, Stefano Didonato, Claus Weidinger, Hannes Oberkofler, G. Bernhard Landwehrmeyer, and Wolfgang Patsch. "The Gene Coding for PGC-1α Modifies Age at Onset in Huntington's Disease." Molecular Neurodegeneration Mol Neurodegeneration 4.1 (2009): 3. Web. 25 Feb. 2016. <http://download.springer.com/static/pdf/450/art%3A10.1186%2F1750-1326-4-3.pdf?originUrl=http://molecularneurodegeneration.biomedcentral.com/article/10.1186/1750-1326-4-3&token2=exp=1456807696~acl=/static/pdf/450/art%253A10.1186%252F1750-1326-4-3.pdf*~hmac=49a88372dcd96da9ba9336df484f3a6ed10e5817c5856caa557b3756070c7415>.

Taherzadeh-Fard, Elahe, Carsten Saft, Jürgen Andrich, Stefan Wieczorek, and Larissa Arning. "PGC-1alpha as Modifier of Onset Age in Huntington Disease." Molecular Neurodegeneration Mol Neurodegeneration 4.1 (2009): 10. Web. 27 Feb. 2016. <http://download.springer.com/static/pdf/338/art%3A10.1186%2F1750-1326-4-10.pdf?originUrl=http://molecularneurodegeneration.biomedcentral.com/article/10.1186/1750-1326-4-10&token2=exp=1456814992~acl=/static/pdf/338/art%253A10.1186%252F1750-1326-4-10.pdf*~hmac=715564ad479aea21bdb05f8adca484b46cd617bd2c4beadcb1057169e5521a8b>.

Vittori, A., C. Breda, M. Repici, M. Orth, R. A. C. Roos, T. F. Outeiro, F. Giorgini, and E. J. Hollox. "Copy-number Variation of the Neuronal Glucose Transporter Gene SLC2A3 and Age of Onset in Huntington's Disease." Human Molecular Genetics 23.12 (2014): 3129-137. Web. 28 Feb. 2016. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030768/pdf/ddu022.pdf>.

Secondary: "Final Diagnosis -- Positive for Huntington Disease at the High End of the Reduced Penetrance Range." Final Diagnosis. Web. 01 Mar. 2016. <http://path.upmc.edu/cases/case669/dx.html>.

(Notes For Each Other):

Notes: It turns out the paper on locomotion is in French (and I don't know enough French to translate it), so I'm researching the Huntington chromosome (specifically the CAG repeat) which seems to correlate with age of onset. More information coming soon! I tried to find more info on locomotion, but was met with a dead end, so we will not be able to include it in the article. Chh27 (talk) 20:07, 26 February 2016 (UTC)[reply]

Notes: After typing your info, please correctly cite your sources in the references section Lich2 (talk) 23:13, 29 February 2016 (UTC)[reply]

Notes: Hi everyone, as we all continually add to this talk page, please write in this box your contributions. That way, it will be easier for us to peer evaluate each other in terms of individual contributions.

Shon: biological background on Huntington's

Bryce: info on some evolutionary forces that increased prevalence of huntington's, introduction on the fitness of huntington's disease allele

Cheng: more biological background on huntington's, higher fertilty/promiscuity, p53 cancer suppression, formatting, what is already on wikipedia and what can be expanded, added reference section

Cathy: Founder Effect in South Africa (I realized Jane might do the same page about the Huntington chromosome since she's researching age of onset, so I researched other evolutionary theories); Origin of Huntington's; Effects on Immune System

Jane: Genetic factors affecting age of onset, including effects of SLC2A3 and PCG-1α

- Hi all, I'm new to the group! Let me know if there is anything specific that you would like me to work on. Otherwise I'll keep editing and adding where I see fit. My email is jjpro94@uw.edu if that helps. (: - Julia — Preceding unsigned comment added by Jproctor94 (talk • contribs) 02:11, 5 March 2016 (UTC)[reply]

Julia: edited origin section, edited evolutionary forces main paragraph, — Preceding unsigned comment added by 73.157.98.14 (talk) 01:05, 3 March 2016 (UTC)[reply]

*Please use both primary and secondary sources*'