User:Jamalehschwartz

Prader-Willi Syndrome

A) Background about the biological mechanisms of your topic

Prader-Willi syndrome is a genetically determined neurodevelopmental syndrome. There are two mechanisms that lead to PWS. The deletion of the Prader-Willi syndrome critical region of paternal origin or maternal uniparental disomy which is when the offspring inherits two maternally derived chromosome, in PWS two chromosome 15s (Howlin 107). PWS causes life-threatening obesity in children. Children can not register whether they are hungry or satiated because of a defect in the hypothalamus. There are three known genetic errors that cause PWS. It is currently unknown how many genes are involved but they are all in the region 15q11-q13, the “long arm” of chromosome 15. The main biological mechanism that causes PWS is the paternal deletion of chromosome 15, affecting up to 70 percent of all cases (PWSA). These patients will then display the classic phenotype of PWS. Common symptoms include underdevelopment of the central nervous system. Mild to moderate intellectual disability is displayed in about 90 percent of all PWS cases (GHR). Hypogonadism (incomplete sexual development) and hypotonia (low muscle tone) are two common traits as well (Mayo Clinic). PWS is mainly considered an autosomal dominant disorder based off of this particular deletion (Kim, 2012). Maternal uniparental disomy (UPD) is the next common cause of PWS. The mechanism of UPD is when the fetus inherits both chromosome 15 copies from the mother and is now in a state of trisomy 15. However, the fetus will then lose the chromosome 15 from the father’s sperm, resulting in a similar situation as a deletion. The baby now has two chromosome 15 from the mother but both are imprinted (Bittel, 2005). This accounts for up to 25% of PWS cases (PWSA). These patients display a milder phenotype and potentially have a better cognitive function than the paternal deletion of PWS (Kim, 2012). The rarest form of genetic cause is the imprinting defect, constituting less than 5 percent of all PWS cases. The imprinting defect is when the paternal chromosome 15 is present but the imprinting mechanism is defective (Lee, 2000). In other words, the genes associated with the father’s chromosome are present but the mother’s imprint is turning the paternal side off, thus, no expression.

Incidence of PWS based on clinical features from 1:8,000 to 1:25,000 genetic confirmation 1:22,000 to 1:25,000 (Howlin 108)

Primary Sources: Bittel DC, Butler MG. Prader-Willi syndrome: clinical genetics, cytogenetics and molecular biology. Expert Rev Mol Med. 2005 Jul 25;7(14):1-20. Review.

Howlin, P., Charman, T., & Ghaziuddin, M. (2011). The SAGE handbook of developmental disorders. Los Angeles, Calif. ; London: SAGE.

Kim, S.-J., Miller, J. L., Kuipers, P. J., German, J. R., Beaudet, A. L., Sahoo, T., Driscoll, D. J. Unique and atypical deletions in Prader-Willi syndrome reveal distinct phenotypes. Europ. J. Hum. Genet. 20: 283-290, 2012.

Lee S, Wevrick R. Identification of novel imprinted transcripts in the Prader-Willi syndrome and Angelman syndrome deletion region: further evidence for regional imprinting control. Am J Hum Genet. 2000 Mar;66(3):848-58.

Secondary Sources: “About Prader-Willi Syndrome.” Prader-Willi Syndrome Association USA. N.p., 2014. Web. 29 Feb. 2016.

National Library of Medicine (US). Genetics Home Reference [Internet]. Prader-Willi syndrome; [reviewed 2014 June; cited 2016 Feb 29]. Available from: https://ghr.nlm.nih.gov/condition/prader-willi-syndrome

“Prader-Willi Syndrome.” Mayo Clinic. N.p., 17 Apr. 2014. Web. 29 Feb. 2016.

B) Evolutionary work that has been done on this topic Haig, David, and Robert Wharton. "Prader-Willi Syndrome and the Evolution of Human Childhood." Am. J. Hum. Biol. American Journal of Human Biology 15.3 (2003): 320-29. Web.

Haig, David, and Stephen Curtis Stearns. “Transfers and Transitions: Parent-offspring Conflict, Genomic Imprinting, and the Evolution of Human Life History”. Proceedings of the National Academy of Sciences of the United States of America 107 (2010): 1731–1735. Web.

SnoRNAs (small nucleolar RNA) direct post-transcriptional modification of rRNA. HBII-85 and HBII-52 are in the imprinted region of chromosome 15 that is associated with PWS. Deletion of HBII-85 results in PWS, while it is unclear what role HBII-52 plays in PWS. SnoRNAs are thought to be conserved in the genome, included in a wide spectrum of organisms from bacteria to mammals. After analysis of the genome sequences between 12 placental mammals. The results gathered implicate that the PWS imprinted snoRNA genes are within a region of high rearrangement.

Zhang, Yi-Jun, Jian-Hua Yang, Qiao-Su Shi, Ling-Ling Zheng, Jun Liu, Hui Zhou, Hui Zhang, and Liang-Hu Qu. "Rapid Birth-and-Death Evolution of Imprinted SnoRNAs in the Prader-Willi Syndrome Locus: Implications for Neural Development in Euarchontoglires." PLoS ONE 9.6 (2014): n. pag. Web.

Evolutionary significance: Prader-Willi syndrome is due to loss of paternal genes at chromosome 15. This syndrome is characteristic of imprinting, which means that only one parental copy of genes on chromosome 15 are active--and in this case the active genes are maternal. (1) Unlike conditions on the autism spectrum, this syndrome is characterized as a psychotic-affective condition that results in psychosis due to defective neurodevelopment of the hypothalamus (which results from the absence of the paternal copy of these genes). (2) Evolutionarily, the disease is understood to be characterized as decreasing infant demands on the mother—meaning, the child becomes less dependent on the mother earlier than in a typical pregnancy/infancy. (3) This suggests that the genes affected in PWS may be involved in the evolution of children weaning from their mothers earlier--in which case, such genes would be expected to be selected for in the terms of benefiting maternal-offspring relationships. (2) This is significant evolutionarily for the mother because if it means less stress on the mother, this could mean higher reproductive fitness for the mother in future pregnancies (**PERSONAL NOTE: I think this means because she would retain more resources in respect to this particular pregnancy? thats how I understand it too). (3) In turn, this would theoretically give more independence to the child, but at such a young age, this trade-off decreases the child’s fitness. (3) An additional note that is important in this regard is that this evolutionary understanding is based on the assumption that women have more than one reproductive partner. (3) If this were not the case, the costs to both parents would be weighed equally, and there would be no reason for selection on forces that would disproportionately increase the mother’s reproductive fitness next to the father’s. (3)

SOURCES:

Genomic Imprinting. (n.d.). Retrieved February 25, 2016, from http://learn.genetics.utah.edu/content/epigenetics/imprinting/ Crespi, B. J. (2010). The origins and evolution of genetic disease risk in modern humans. Annals of the New York Academy of Sciences, 1206(1), 80-109. Haig, David, and Stephen Curtis Stearns. “Transfers and Transitions: Parent-offspring Conflict, Genomic Imprinting, and the Evolution of Human Life History”. Proceedings of the National Academy of Sciences of the United States of America 107 (2010): 1731–1735. Web.

Secondary source for evolutionary significance of PWS: Keverne E.B. Mammalian viviparity: a complex niche in the evolution of genomic imprinting. Heredity (2014) 113, 138–144; doi:10.1038/hdy.2014.8; published online 26 February 2014. · Imprint control regions (ICRs) are dysregulated in 97% of PWS cases. · This article details the difference between maternal and paternal ICRs · Maternal/fetal co-adaptation in terms of genomic imprinting

WHAT IS “KINSHIP THEORY OF GENOMIC IMPRINTING”?: (1) The Kinship Theory of Genomic Imprinting original encompassed the relationship between mother and child, but it now expands to all kin interactions. This theory defines conditions in which there is a conflict between maternally- and paternally-derived genes (matrigenes and patrigenes, respectively). In addition to conflicts, there may be situations when they have shared interests. Thus, both conflict and cooperation occur between maternally-derived genes and paternally-derived genes. However, conflict between maternal and paternal genes should be interpreted as conflict between mother and father.

(2) Genomic imprinting is thought to have evolved because of the parental conflict surrounding the maternal expenditure of resources on the offspring. Genomic imprinting appeared with the advent of live birth. “Imprinted genes”—one copy of the gene was epigenetically marked (or imprinted) in either the sperm or the egg Paternal genome seeks to obtain more nutrients from mother during pregnancy Maternal genome seeks to limit this. (ex) If the allele inherited by the mother is “imprinted”, it is silenced and only the allele from the father is expressed (3)

Sources: (1) Haig D. Coadaptation and conflict, misconception and muddle, in the evolution of genomic imprinting. Heredity (2014) 113, 96–103; doi:10.1038/hdy.2013.97; published online 16 October 2013. http://www.nature.com.offcampus.lib.washington.edu/hdy/journal/v113/n2/full/hdy201397a.html (2) Jirtle R.L. What is genomic imprinting? (2011) http://www.geneimprint.com/site/what-is-imprinting (3) Genomic imprinting. https://en.wikipedia.org/wiki/Genomic_imprinting

C) Discussions of what is already in Wikipedia and what is not Wikipedia Signs and symptoms across the lifespan Uterus/fetus: lack of developing muscles resulting in difficulties Childhood: physical and mental delay; obesity that persists till adulthood Adulthood: infertility (underdeveloped sexually), obesity, learning disabilities Abnormal physical appearance Strabismus- eyes do not align properly Neuro-cognitive: low average intelligence; strong visual/perception skills but lower communication Behavioral: large appetite leading to obesity; individuals have high ghrelin levels that contribute to appetite Genetics Deletion of paternal region of chromosome 15 Diagnosis 1 in 10,000 to 1 in 25,000 newborns Mild to severe symptoms that change within the individual’s lifetime DNA-based methylation testing to detect the absence of the paternal chromosome Often misdiagnosed as Down syndrome Treatment No cure During infancy, affected individuals undergo therapy to help tone muscles Prescribed growth hormone that aid in linear growth Treat for sleep apnea caused by obesity Greatest problem is obesity Society and culture References to shows that depict the disease Not on Wikipedia PWS in an evolutionary context We are planning on addressing this issue by discussing the potential evolutionary significance of PWS. For the reader, we hope this will help them gain a better understanding of why such a syndrome would evolve. If we are looking at this project in terms of helping patients/families understand their situation more fully, answering this question will hopefully give some clarity to why biology might give rise to such a disorder.