Some quotations from our Parkinson's disease paper just published in PLoS One

Some quotations from our Parkinson's disease paper just published in PLoS One:

Recent studies have begun to show that a much larger than expected portion of the human genome may be functional [24–29].

An organism can certainly accommodate some limited amounts of random variations within its building parts or DNAs, but too much random errors or mutations may exceed an organism’s maximum level of tolerable disorder or entropy. Thus overall level of randomness or minor allele amounts may be expected to be higher in complex diseases relative to controls.

In fact, while most bench biologists have thought otherwise, nearly all in the population genetics field still believe that most SNPs are neutral or that most minor alleles are minor because of random drift rather than because of disease-association.

The findings of higher MAC in PD cases is consistent with our intuitive hypothesis that a highly complex and ordered system such as the human brain must have an optimum limit on the level of randomness or entropy in its building parts or DNAs. Too much randomness over a critical threshold may trigger complex diseases. There may be only one unique and optimum way to build a complex system but there could be numerous ways to break it.While it may only take one single major effect error in a major pathway to cause diseases, it would require the collective effects of a large number of minor effect errors in many different pathways to achieve a similar outcome.

Application of the MGD theory on complex diseases, first success Parkinson's disease

We have a new research paper on Parkinson's disease in press in PLoS One

It is merely the first success of the MGD theory in solving complex dieseases problems.

Enrichment of Minor Alleles of Common SNPs and Improved Risk Prediction for Parkinson's Disease

Zuobin Zhu, Dejian Yuan, Denghui Luo，Xitong Lu and Shi Huang*

State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China

Abstract

Parkinson disease (PD) is the second most common neurodegenerative disorder in the aged population and thought to involve many genetic loci. While a number of individual single nucleotide polymorphisms (SNPs) have been linked with PD, many remain to be found and no known markers or combinations of them have a useful predictive value for sporadic PD cases. The collective effects of genome wide minor alleles of common SNPs, or the minor allele content (MAC) in an individual, have recently been shown to be linked with quantitative variations of numerous complex traits in model organisms with higher MAC more likely linked with lower fitness. Here we found that PD cases had higher MAC than matched controls. A set of 37564 SNPs with MA (MAF < 0.4) more common in cases (P < 0.05) was found to have the best predictive accuracy. A weighted risk score calculated by using this set can predict 2% of PD cases (100% specificity), which is comparable to using familial PD genes to identify familial PD cases. These results suggest a novel genetic component in PD and provide a useful genetic method to identify a small fraction of PD cases.

Role of genetic polymorphisms in transgenerational inheritance of inherent as well as acquired traits in budding yeast

Zhu, Z., Lu, Q., Yuan, D., Li, Y., Man, X., Zhu, Y., and Huang, S.  (2013)  Role of genetic polymorphisms in transgenerational inheritance of inherent as well as acquired traits in budding yeast.  arXiv:1302.7276 [q-bio.GN]， submitted.  pdf

Role of genetic polymorphisms in transgenerational inheritance of inherent as well as acquired traits in budding yeast

Zuobin Zhu, Qing Lu，Dejian Yuan，Yanke Li，Xian Man，Yueran Zhu， and Shi Huang*

State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, P.R. China

Abstract:

Both inherent and acquired traits can be transmitted through multiple generations with some traits more stable than others.  But the relationship between the stability of such transgenerational inheritance and the genetic variations in an individual or cell has yet to be explored.  We studied the effect of common genetic polymorphisms on transgenerational inheritance of yeast segregants that were derived from a cross between a laboratory strain and a wild strain of Saccharomyces cerevisiae.  For each of 2835 common SNPs analyzed, the parental allele present in less than half of the 124 segregants panel was called the minor allele (MA).  We found a nonrandom distribution of MAs in the segregants, indicating natural selection, as segregants with high MA content or amount (MAC) were not enriched with MAs from the parental strain that contributed significantly more to the whole set of MAs.  We compared segregants with high MAC relative to those with less and found a more dramatic shortening of the lag phase length for the high MAC group in response to 14 days of ethanol training.  Also, the short lag phase as acquired and epigenetically memorized by ethanol training was more dramatically lost after 7 days of recovery in ethanol free medium for the high MAC group. Sodium chloride treatment produced similar observations.  Using public datasets, we found MAC linkage to mRNA expression of hundreds of genes.  Finally, by analyzing a recently published datasets of 1009 yeast segregants that identified numerous additive QTLs for 46 traits, we found by multivariate regression analysis preferential effect of MAC on traits with high number of known additive QTLs (average 16 QTLs for the 5 MAC-linked traits vs 12 for the whole set of 46 traits), consistent with an additive effect of a large number of SNPs or MAs whose individual effect would be too minor to be detectable by existing methods.  These results provide evidence for the slightly deleterious nature of most MAs and a lower capacity to maintain inheritance of traits in individuals or cells with greater MAC, which have implications for disease prevention and treatment.  Individuals with high MAC may be more susceptible to environmental pathogens, but they may also be more treatable if treatment was administered relatively early before the disease has progressed past the threshold of no return, because the acquired disease trait may be less stably maintained in these individuals.  The concept and method of MAC are broadly applicable, and may have solved a large part of the “missing heritability” problem in complex traits by simply relying on a priori truth/intuition that no mutation can be truly neutral or devoid of an entropy generating effect.

   

Random enrichment of minor alleles of common SNPs affects complex traits and diseases

We have recently submitted a manuscript for publication as well as an abstract to a human genome variation meeting.  The work represents an application of the MGD hypothesis in solving major real world biomedical problems.  The results confirm the MGD hypothesis and invalidate the neutral theory that has prevailed for nearly half of a century.  The flawed neutral theory has no real world relevance to major biomed problems and no neutral theory experts are known to have contributed anything to research of major biomedical importance (not Kimura, not Ayala, not Nei, not Blair, not Avise, not Felsenstein).  In contrast, the MGD hypothesis can and will survive even without relying on its value to evolution research.  Much of our ongoing research have nothing to do with evolution.  Stay tuned for more of our results on the genetic basis of complex traits and complex diseases about which the neutral paradigm has absolutely no clues. 

Random enrichment of minor alleles of common SNPs affects complex traits and diseases. 

Dejian Yuan^1#, and Zuobin Zhu^1#, Xiaohua Tan¹, Jie Liang¹, Ceng Zeng¹, Jiegen Zhang², Jun Chen², Long Ma¹, Ayca Dogan³, Gudrun Brockmann³, Oliver Goldmann⁴, Eva Medina⁴, Xian Man¹, Ke Yi¹, Yanke Li¹, Qing Lu¹, Yimin Huang¹, Dapeng Wang⁵, Jun Yu⁵, Hui Guo¹, Kun Xia¹, and Shi Huang^1*

¹State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China; ²High Performance Computing Center, Modern Educational Technology Center, New Campus, Central South University, Changsha, Hunan 410083, China. ³Department of Crop and Animal Sciences, Faculty of Agriculture and Horticulture, Humboldt-Universität zu Berlin, Invalidenstraße 42, 10115 Berlin, Germany;  ⁴Infection Immunology Group, HZI – Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany;  ⁵CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, PR China; Graduate University of Chinese Academy of Sciences, Beijing 100049, PR China. 

*Correspondence to:  Shi Huang, huangshi@sklmg.edu.cn  

#These authors contributed equally to this work.

The prevailing null hypothesis in population genetics and molecular evolution posits that most common SNPs are neutral but this has yet to be formally tested by experimental science.  We employed two strategies to determine whether the minor alleles (MAs) of common SNPs are minor because of natural selection.  First, we analyzed multiple panels of genetic reference populations or recombinant inbred lines (RILs) in model organisms (yeast, worm, fly, mouse, and rat), and identified the MAs of common SNPs in each panel and the fraction of MAs that each strain carries.  We measured the brood size of 104 C. elegans RILs and did genotype-phenotype correlation analysis for the brood trait as well as for ~4700 published and unpublished traits for various RIL panels archived at GeneNetwork.  Although beneficial to immunity as is expected, more MAs correlated significantly with poor measurements in many adaptive traits, including reproductive fitness, life span, tumor susceptibility, anxiety, depression, startle response, and learning and memory.   In addition, more MAs were significantly linked with sensitivity to alcohol, methamphetamine, cocaine, pain, and antipsychotic drugs, and levels in glucose, resistin, insulin, IL-17, iron, and dopamine.  Random enrichment of MAs of common SNPs accounted for as much as 49% of total trait variation in some phenotypes in RILs such as transferrin saturation and food intake.  The majority of the ~4700 traits examined did not significantly correlate with MAs, including blood pressure and morphine response.  Different MA-linked traits may or may not share the same set of MAs with related traits sharing more MAs than non-related traits.  Second, we analyzed 21 published GWAS datasets of common diseases and identified the MAs of common SNPs in each control population and the fraction of MAs each control or case carries.  In Europeans or European Americans, more MAs were significantly and repeatedly linked with type 2 diabetes, Parkinson’s disease, psychiatric disorders, autoimmune diseases, alcohol and cocaine addictions, lung cancer, less life span, and lower education level achieved, but not hypertension and opiate and marijuana addictions.  Thus, the effects of excess MAs in humans are remarkably similar to those in model organisms, suggesting that the link between excess MAs and diseases/traits in humans is causal since it can be replicated in model organisms.  These data indicate that most SNPs in any species are functional or under Darwinian natural selection and open a new avenue of inquiry into the genetic basis of complex traits/diseases.  They confirm a self-evident intuition in construction that any system of great order can allow some random errors/noises in building blocks but only to a limit.