Role Of Common Alleles In Complex Traits And Parkinson’s Disease

Single nucleotide polymorphism (SNP) has been widely used to study diseases. However, most common SNPs are thought or assumed to be neutral and hence irrelevant to phenotype variations. Thus, current research on SNPs mostly focuses on identifying a few major effect SNPs in complex diseases or behaviors and has made many important discoveries. However, an alternative view is that most SNPs may be functional. Neither view has direct experimental evidence. Most SNPs have two alleles and the allele with a population frequency of less than0.5is termed the minor allele. Using our own develeped bioinformatics software, we have analyzed large amount of published data as well as our own data. We found that most SNPs are functional. Random enrichment of minor alleles of common SNP was correlated with the stability of the epigenetic programming. Finally, enrichment of minor alleles was linked with Parkinson’s disease. Chapterl:The lower frequency of minor allele is due to natural selectionObjective:to determine whether SNP are functional or whther the frequency of SNP is determined by natural selection.Methods:we used the C.elegans and saccharomyces cerevisiae as model organisms, including237strains of C elegans and109segregants of saccharomyces cerevisiae. We calculated the minor allele content (MAC) of each strains. We analyzed the relationship between brood size and MAC in C.elegans. We also analyzed the published310response to100small-molecule drugs.Results:brood size and living rate of C. elegans all correlated with MAC. Strains of high MAC showed Low reproduction rate (P<0.05), and high LR (P<0.05). In the yeast strains, there were9responses that correlated with MAC in100responses, all the9responses showed that the H-MAC segregants are more sensitive to drugs.Conclusion:The MA are caused by natural selection. too high levels of MAC may weaken the stability of traits. Chapter2:The relationship between SNPs and transgenerational stability of inherent as well as acquired phenotypes as induced by environmental factorsObjective:to study whether the Minor alleles of common SNPs quantitatively affect transgenerational stability of inherent as well as acquired phenotypes as induced by environmental factorsMethods:using SAM software, we danalyzed4482yeast gene expression patterns in glucose as carbon source and also in1%alcohol as carbon source (HMAC and LMAC each20segregants). We determined the lag phase of the yeast (HMAC and LMAC each10segregants) first cultured in the YPD medium(7%alcohol) Yeast were trained for14days in alcohol medium and recovered for8days in alcohol free medium. We also did similar lag phase study in response to0.8M sodium chloride treatment,Results:There were324significant different genes between HMAC and LMAC when using glucose as carbon,17genes are highly expressed in HMAC; With1%alcohol as carbon,there were172significant different genes between HMAC and LMAC,127are highly expressed in HMAC.The lag phase of the HMAC were longer in the YPD medium containing7%alcohol.When they were trained in YPD medium containing7%for14days, the lag phase of the HMAC becomed more shorter than LMAC.And when they restorative training in the normal YPD medium the lag phase of the HMAC also restored greater range than LMAC.It is the similar results when the yeasts were cultured in the YPD containing0.8M sodium chloride.Conclusions:these results show that SNPs affect a large number of gene expression in different growth environment. Strains with high MAC are less able to maintain stability of their inherent traits as well as acquired traits. These results may help understand the role of genetic variation in human trait variation in response to environmental factors.Chapter3:The relationship between SNPs and PDObjective:to study the relationshiop between genome genetic variation and PD.Method:Using C.elegans as model organisms. The larval stage L1C.elegans were incubated for3days with200ug/1MPTPcontrol group without any treatment. Determined the movement frequency and development under microscope.Results:When the larval stage L1C.elegans were incubated for3days with200ug/1MPTP,the development of nematode (Pearson r=0.47, P=0.0365; Spearson r=0.5173, P=0.0195), movement (Pearson r=0.5262, P=0.0172; Spearson r=0.5128, P=0.0208), and all the HMA present developmental delay and movement rate.Conclusion:Enrichment of minor alleles of common SNPs may play a role in PD.