The branch of biology with the most mathematics is also widely known as the most soft! Why?

The field of population genetics and molecular evolution was largely founded by mathematicians/statisticians such as Fisher, Haldene, and Wright. Even pure mathematician like Hardy has contributed a key equation to the field. But contrary to naive expectations, this field of study is more like soft social science than to hard core physics. In the words of Jerry Coyne (an extremely enthusiastic propagator of the Darwinian evolution theory and a professor of evolutionary studies at the University of Chicago): "In science's pecking order, evolutionary biology lurks somewhere near the bottom, far closer to phrenology than to physics".

Why? The reason is simple. Math depends on assumptions or paradigms. The assumptions for hard core sciences are axioms or self evident intuitions. Euclid and Newtons axioms come to mind. They are all a priori true or self evidently true. In contrast, there is not a single assumption in the evolution field that is self evidently true or can qualify as axiom. Nearly all assumptions in that field are in fact self evidently false. Just a few examples, the infinite sites model, the neutral/junk DNA assumption, random mating, and the independent mutations assumptions.

Key figures in the field has also acknowledged this, as Ohta and Gillespie said in 1996: "all current theoretical models suffer either from assumptions that are not quite realistic or from an inability to account readily for all phenomena." (Theoretical Population Biology,1996, 49: 128-142) 

To show a flavor of the amount of math in the field, below are two pages of my notebook from an undergrad evolutionary genetics course taken 32 years ago at my Alma mater Fudan University.

Secrets of the creative brain

There was a recent good article on creativity,Secrets of the creative brain.  A related blog post, The Psycholpathology of Genius.

We are actively working on the genetic basis of complex traits and the most complex is obviously creativity and intelligence. According to the threshold theory, Creativity is not IQ only and a score of 120 is the threshold. Lower or much higher than than that may hurt creativity.

Some quotes from Secrets of the creative brain:

One possible contributory factor is a personality style shared by many of my creative subjects. These subjects are adventuresome and exploratory. They take risks. Particularly in science, the best work tends to occur in new frontiers. (As a popular saying among scientists goes: “When you work at the cutting edge, you are likely to bleed.”) 

I’ve been struck by how many of these people refer to their most creative ideas as “obvious.” Since these ideas are almost always the opposite of obvious to other people, creative luminaries can face doubt and resistance when advocating for them. As one artist told me, “The funny thing about [one’s own] talent is that you are blind to it. You just can’t see what it is when you have it … When you have talent and see things in a particular way, you are amazed that other people can’t see it.” Persisting in the face of doubt or rejection, for artists or for scientists, can be a lonely path—one that may also partially explain why some of these people experience mental illness.

One interesting paradox that has emerged during conversations with subjects about their creative processes is that, though many of them suffer from mood and anxiety disorders, they associate their gifts with strong feelings of joy and excitement. “Doing good science is simply the most pleasurable thing anyone can do,” one scientist told me. “It is like having good sex. It excites you all over and makes you feel as if you are all-powerful and complete.” This is reminiscent of what creative geniuses throughout history have said. 

Many creative people are autodidacts. 

Many creative people are polymaths, as historic geniuses including Michelangelo and Leonardo da Vinci were. 

Creative people tend to be very persistent, even when confronted with skepticism or rejection. 

Some people see things others cannot, and they are right, and we call them creative geniuses. Some people see things others cannot, and they are wrong, and we call them mentally ill. And some people, like John Nash, are both.

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.

   

Kurt Godel: 'I don't believe in empirical science. I only believe in a priori truth'

The great logician Kurt Godel is absolutely brilliant in saying: 'I don't believe in empirical science.  I only believe in a priori truth'. 

As both a bench scientist in an empirical field of science and a theoriest, I would only rephrase that I only believe in emprical science that is consistent with a priori truth or intuition.  Much of biological knowledge today is not based on intuition and the chief theory in biology today, ie the modern evolution theory, is largely based on a negation of intuition.  No wonder you never see truly brilliant minds like a Godel or Einstein to have any admiration for the Darwinian theory of evolution.    

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. 

It is through intuition we discover

Intuition or axiom is the foundation of mathematics and physics, but has been until the first axiom of biology lacking in the science of biology. Darwin philosopher Daniel Dennett is fond of saying how wonderful is Darwin's "strange inversion of reasoning", and he is very proud of the anti-intuitive nonsense that randomness/errors/noises can create complex systems of great order. I would not advise anyone to be a philosopher without being a scientist first if his philosophy depends on scientific discovery. To base one's career on second hand knowledge is being reckless. Dennett is completely fooled by Darwin who not surprisingly is extremely poor with intuition and logic as shown by his difficulty with high school mathematics. Darwinism is based on the negation of intuition or 'strange inversion of intuition', a position no other great minds hold and no true science is based.

I recently found a few great quotes on intuition as listed below:

‘intuition is the source of scientific knowledge.’

— Aristotle

‘The only really valuable thing is intuition.’

— Albert Einstein

‘I believe in intuition and inspiration; at times I feel certain I am right while not knowing the reason.’

— Albert Einstein

‘The intuitive mind is a sacred gift and the rational mind is a faithful servant. We have created a society that honours the servant and has forgotten the gift.’

— Albert Einstein

‘The intellect has little to do on the road to discovery. There comes a leap in consciousness, call it intuition or what you will, and the solution comes to you and you don’t know how or why.’

— Albert Einstein

‘I have had my results for a long time, but I do not yet know how I am to arrive at them.’

— Carl Friedrich Gauss

‘Instinct leads, logic does but follow.’

— William James

‘Intuition does not denote something contrary to reason, but something outside the province of reason.’

—Carl Gustav Jung

‘The disclosure of a new fact, the leap forward, the conquest over yesterday’s ignorance, is an act not of reason but ofimagination, of intuition.’

— Charles Nicolle

‘Knowledge has three degrees—opinion, science, illumination. The means or instrument of the first is sense; of the second, dialectic; of the third, intuition.’

— Plotinus

‘It is through science that we prove, but through intuition that we discover.’

— Henri Poincaré