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.

Recent studies have established that genetic diversities are mostly maintained by selection, therefore rendering the present molecular model of human origins untenable. Using improved methods and public data, we have revisited human evolution and derived an age of 1.91-1.96 million years for the first split in modern human autosomes. We found evidence of modern Y and mtDNA originating in East Asia and dispersing via hybridization with archaic humans. Analyses of autosomes, Y and mtDNA all suggest that Denisovan like humans were archaic Africans with Eurasian admixtures and ancestors of South Asia Negritos and Aboriginal Australians. Verifying our model, we found more ancestry of Southern Chinese from Hunan in Africans relative to other East Asian groups examined. These results suggest multiregional evolution of autosomes and East Asia origin of Y and mtDNA, thereby leading to a coherent account of modern human origins.

a b s t r a c tMicroRNAs (miRNAs) act as key regulators of multiple cancers. miR-329 functions as a tumor suppressor in some malignancies. However, its role in neuroblastoma remains poorly understood. We found that miR-329 was decreased in metastatic tumor tissues compared with matched primary tumor tissues. Forced overexpression of miR-329 substantially suppressed cell proliferation, colony formation, migration, and invasion of neuroblastoma cells. Lysine-specific demethylase 1 (KDM1A) was found to be a target of miR-329. Furthermore, down-regulation of KDM1A by shRNA performed similar effects with overexpression of miR-329. Overexpression of KDM1A partially reversed the tumor suppressive effects of miR-329 in neuroblastoma cells. Collectively, miR-329 may suppress neuroblastoma cell growth and motility partially by targeting KDM1A.

The ancestral origin and genomic history of Chinese Hui people remain to be explored due to the paucity of genome-wide data. Some evidence argues that an eastward migration of Central Asians gave rise to modern Hui people, which is referred to as the demic diffusion hypothesis; other evidence favors the cultural diffusion hypothesis, which posits that East Asians adopted Muslim culture to form the modern culturally distinct populations. However, the extent to which the observed genetic structure of the Huis was mediated by the movement of people or the assimilation of Muslim culture also remains highly contentious. Analyses of over 700 K SNPs in 109 western Chinese individuals (49 Sichuan Huis and 60 geographically close Nanchong Hans) together with the available ancient and modern Eurasian sequences allowed us to fully explore the genomic makeup and origin of Hui and neighboring Han populations. The results from PCA, ADMIXTURE, and allele-sharing-based f-statistics revealed a strong genomic affinity between Sichuan Huis and Neolithic-to-modern Northern East Asians, which suggested a massive gene influx from East Asians into the Sichuan Hui people. Three-way admixture models in the qpWave/qpAdm analyses further revealed a small stream of gene influx from western Eurasians into the Sichuan Hui people, which was further directly confirmed via the admixture event from the temporally distinct Western sources to Sichuan Hui people in the qpGraph-based phylogenetic model, suggesting the key role of the cultural diffusion model in the genetic formation of the Sichuan Huis. ALDER-based admixture date estimation showed that this observed western Eurasian admixture signal was introduced into the Sichuan Huis during the historic periods, which was concordant with the extensive western–eastern communication along the Silk Road and historically documented Huis' migration history. In summary, although significant cultural differentiation exists between Hui people and their neighbors, our genomic analysis showed their strong genetic affinity with modern and ancient Northern East Asians. Our results support the hypothesis that the Sichuan Huis arose from a mixture of minor western Eurasian ancestry and predominant East Asian ancestry.

It has long been assumed that most parts of a genome and most genetic variations or SNPs are non-functional with regard to reproductive fitness. However, the collective effects of SNPs have yet to be examined by experimental science. We here developed a novel approach to examine the relationship between traits and the total amount of SNPs in panels of genetic reference populations. We identified the minor alleles (MAs) in each panel and the MA content (MAC) that each inbred strain carried for a set of SNPs with genotypes determined in these panels. MAC was nearly linearly linked to quantitative variations in numerous traits in model organisms, including life span, tumor susceptibility, learning and memory, sensitivity to alcohol and anti-psychotic drugs, and two correlated traits poor reproductive fitness and strong immunity. These results suggest that the collective effects of SNPs are functional and do affect reproductive fitness. collective effects, complex traits, minor alleles, SNPs, recombinant inbred lines, minor allele content (MAC) Citation:

In 1963, Margoliash discovered the unexpected genetic equidistance result after comparing cytochrome c sequences from different species. This finding, together with the hemoglobin analyses of Zuckerkandl and Pauling in 1962, directly inspired the ad hoc molecular clock hypothesis. Unfortunately, however, many biologists have since mistakenly viewed the molecular clock as a genuine reality, which in turn inspired Kimura, King, and Jukes to propose the neutral theory of molecular evolution. Many years of studies have found numerous contradictions to the theory, and few today believe in a universal constant clock. What is being neglected, however, is that the failure of the molecular clock hypothesis has left the original equidistance result an unsolved mystery. In recent years, we fortuitously rediscovered the equidistance result, which remains unknown to nearly all researchers. Incorporating the proven virtues of existing evolutionary theories and introducing the novel concept of maximum genetic diversity, we proposed a more complete hypothesis of evolutionary genetics and reinterpreted the equidistance result and other major evolutionary phenomena. The hypothesis may rewrite molecular phylogeny and population genetics and solve major biomedical problems that challenge the existing framework of evolutionary biology. genetic equidistance, overlap feature, evolution, molecular clock, neutral theory, maximum genetic diversity hypothesis, microevolution, macroevolution Citation:Hu T B, Long M P, Yuan D J, et al. The genetic equidistance result: misreading by the molecular clock and neutral theory and reinterpretation nearly half of a century later. Sci China Life Sci, 2013Sci, , 56: 254 -261, doi: 10.1007 Among the most interesting phenomena in biology are reproduction, heredity, and evolution. Biological evolution includes both phenotypes and molecules, which are modeled by the theory of natural selection and the neutral theory, respectively. Together, the two make up the modern evolutionary theory (MET). The neutral theory was proposed by Kimura, Jukes, and King to explain the observation that molecules evolved at a steady, clock-like rate [1,2]. But is the molecular clock a genuine universal phenomenon?1 A brief history of the molecular clock hypothesis and the neutral theory: how the molecular clock replaced the genetic equidistance phenomenonGenetic distance is a measure of molecular differences between species and is represented by the percentage differ-

Lung cancer is the leading cause of cancer deaths in both men and women in the US. While most sporadic lung cancer cases are related to environmental factors such as smoking, genetic susceptibility may also play an important role and a number of lung cancer associated single nucleotide polymorphisms (SNPs) have been identified although many remain to be found. The collective effects of genome wide minor alleles of common SNPs, or the minor allele content (MAC) in an individual, have been linked with quantitative variations of complex traits and diseases. Here we studied MAC in lung cancer using previously published SNP datasets and found higher MAC in cases relative to matched controls. A set of 25883 SNPs with MA (MAF < 0.5) more common in cases (P < 0.1) was found to have the best predictive accuracy. A weighted risk score calculated by using this set can predict 2.6% of lung cancer cases (100% specificity). These results identify a novel genetic risk element or higher MAC in lung cancer susceptibility and provide a useful genetic method to identify a small fraction of lung cancer cases.

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