Thursday, November 26, 2015

Compatibility between mitochondrial and nuclear genomes correlates with the quantitative trait of lifespan in Caenorhabditis elegans.

We just published a new paper in Sci Rep.

Scientific Reports 5, Article number: 17303 (2015)

Compatibility between mitochondrial and nuclear genomes correlates with the quantitative trait of lifespan in Caenorhabditis elegans.

Mutations in mitochondrial genome have epistatic effects on organisms depending on the nuclear background, but a role for the compatibility of mitochondrial-nuclear genomes (mit-n) in the quantitative nature of a complex trait remains unexplored. We studied a panel of recombinant inbred advanced intercrossed lines (RIAILs) of C. elegans that were established from a cross between the N2 and HW strains. We determined the HW nuclear genome content and the mitochondrial type (HW or N2) of each RIAIL strain. We found that the degree of mit-n compatibility was correlated with the lifespans but not the foraging behaviors of RIAILs. Several known aging-associated QTLs individually showed no relationship with mitotypes but collectively a weak trend consistent with a role in mit-n compatibility. By association mapping, we identified 293 SNPs that showed linkage with lifespan and a relationship with mitotypes consistent with a role in mit-n compatibility. We further found an association between mit-n compatibility and several functional characteristics of mitochondria as well as the expressions of genes involved in the respiratory oxidation pathway. The results provide the first evidence implicating mit-n compatibility in the quantitative nature of a complex trait, and may be informative to certain evolutionary puzzles on hybrids.

Saturday, November 21, 2015

Collective effects of common SNPs in foraging decisions in Caenorhabditis elegans and an integrative method of identification of candidate genes

A new paper of ours just published, demonstrating the power of the MGD theory in solving great puzzles of contemporary biology.

 2015 Nov 19;5:16904. doi: 10.1038/srep16904.


Optimal foraging decision is a quantitative flexible behavior, which describes the time at which animals choose to abandon a depleting food supply. The total minor allele content (MAC) in an individual has been shown to correlate with quantitative variations in complex traits. We have studied the role of MAC in the decision to leave a food lawn in recombinant inbred advanced intercross lines (RIAILs) of Caenorhabditis elegans. We found a strong link between MAC and the food lawn leaving rates (Spearman r = 0.4, P = 0.005). We identified 28 genes of unknown functions whose expression levels correlated with both MAC and leaving rates. When examined by RNAi experiments, 8 of 10 tested among the 28 affected leaving rates, whereas only 2 of 9 did among genes that were only associated with leaving rates but not MAC (8/10 vs 2/9, P < 0.05). The results establish a link between MAC and the foraging behavior and identify 8 genes that may play a role in linking MAC with the quantitative nature of the trait. The method of correlations with both MAC and traits may find broad applications in high efficiency identification of target genes for other complex traits in model organisms and humans.

Thursday, October 22, 2015

New thoughts on an old riddle: what determines genetic diversity within and between species?

The abstract and the introduction section of the paper are posted below.


The question of what determines genetic diversity both between and within species has long remained unsolved by the modern evolutionary theory (MET). However, it has not deterred researchers from producing interpretations of genetic diversity by using MET. We here examine the two key experimental observations of genetic diversity made in the 1960s, one between species and the other within a population of a species, that directly contributed to the development of MET. The interpretations of these observations as well as the assumptions by MET are widely known to be inadequate. We review the recent progress of an alternative framework, the maximum genetic diversity (MGD) hypothesis, that uses axioms and natural selection to explain the vast majority of genetic diversity as being at optimum equilibrium that is largely determined by organismal complexity. The MGD hypothesis fully absorbs the proven virtues of MET and considers its assumptions relevant only to a much more limited scope. This new synthesis has accounted for the much overlooked phenomenon of progression towards higher complexity, and more importantly, been instrumental in directing productive research into both evolutionary and biomedical problems.   


The modern evolutionary theory (MET) consists of Darwin’s theory of natural selection and Kimura’s Neutral theory (also Ohta’s Nearly Neutral theory). The theory treats evolution the same as population genetics. The Darwinian theory is much better known than the Neutral theory. However, for molecular evolution and population genetics, the Neutral theory (and the Nearly Neutral theory) has been more useful. Regardless, however, the MET is still incomplete, as acknowledged by Ohta and Gillespie: "..we have yet to find a mechanistic theory of molecular evolution that can readily account for all of the phenomenology. ..we would like to call attention to a looming crisis as theoretical investigations lag behind the phenomenology." [1].

Key puzzles of evolution remain unsolved by the MET. The central problem of the field is and has always been the old riddle of what determines genetic diversity [2-5]. Is it mostly determined by natural selection or neutral drift? Here we critically examine the historical origins and assumptions of the MET. We show that both the neutral and the selection frameworks were largely mistaken right from the beginning. Key observations that directly inspired the neutral theory were nearly half of a century ahead of their time. Selection schemes on the other hand was largely influenced by the one gene one trait genetics of the early 1900s and always treated single locus as the target of selection, which is in fact rarely the case for most of the commonly observed variations as recent studies have shown [6-11]. Finally, we review a candidate for superseding the MET, the maximum genetic diversity (MGD) hypothesis first published in 2008 [12,13], that fully absorbs the proven virtues of the MET and has more explanatory power as well as greater value in directing productive research in a much wider field of biomedical science [6-11,14]. The old riddle of genetic diversity within and between species is solved as mere deductions of the assumptions of the MGD. Only in this case, the assumptions are, for the first time in biology, self-evident intuitions that are no less true or false than any known axioms of hard sciences or mathematics.

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2. Leffler EM, Bullaughey K, Matute DR, Meyer WK, Segurel L, et al. (2012) Revisiting an old riddle: what determines genetic diversity levels within species? PLoS Biol 10: e1001388.
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5. Lewontin RC (1974) The genetic basis of evolutionary change. New York and London: Columbia University Press.
6. Yuan D, Zhu Z, Tan X, Liang J, Zeng C, et al. (2014) Scoring the collective effects of SNPs: association of minor alleles with complex traits in model organisms. Sci China Life Sci 57: 876-888.
7. Zhu Z, Man X, Xia M, Huang Y, Yuan D, et al. (2015) Collective effects of SNPs on transgenerational inheritance in Caenorhabditis elegans and budding yeast. Genomics 106: 23-29.
8. Zhu Z, Yuan D, Luo D, Lu X, Huang S (2015) Enrichment of Minor Alleles of Common SNPs and Improved Risk Prediction for Parkinson's Disease. PLoS ONE 10: e0133421.
9. Yuan D, Zhu Z, Tan X, Liang J, Zeng C, et al. (2012) Minor alleles of common SNPs quantitatively affect traits/diseases and are under both positive and negative selection. arXiv:12092911.
10. Zhu Z, Lu Q, Zeng F, Wang J, Huang S (2015) Compatibility between mitochondrial and nuclear genomes correlates wtih quantitative trait of lifespan in Caenorhabditis elegans. Sci Rep: in press.
11. Zhu Z, Lu Q, Wang J, Huang S (2015) Collective effects of common SNPs in foraging decisions in Caenorhabditis elegans and an integrative method of identification of candidate genes. Sci Rep: in press.
12. Huang S (2009) Inverse relationship between genetic diversity and epigenetic complexity. Preprint available at Nature Precedings <>
13. Huang S (2008) Histone methylation and the initiation of cancer, Cancer Epigenetics; Tollefsbol T, editor. New York: CRC Press.

14. Huang S (2012) Primate phylogeny: molecular evidence for a pongid clade excluding humans and a prosimian clade containing tarsiers. Sci China Life Sci 55: 709-725.