Biology subjects

Wu, C.-I.

Publications and source records attributed to Wu, C.-I..

9 recordsLinked to original sources

bioRxiv2018

Skepticism toward adaptive signals in DNA sequence comparisons - Is the neutral theory dead yet?

A recent study suggests that the evidence of adaptive DNA sequence evolution accumulated in the last 20 years may be suspect1. The suspicion thus calls for a re-examination of the reported evidence. The two main lines of evidence are from the McDonald-Kreitman (MK) test, which compares divergence and polymorphism data, and the PAML test, which analyzes multi-species divergence data. Here, we apply these two tests concurrently on the genomic data of Drosophila and Arabidopsis. To our surprise, the >100 genes identified by the two tests do not overlap beyond random expectations. The results could mean i) high false positives by either test or ii) high false-negatives by both tests due to low powers. To rule out the latter, we merge every 20 - 30 genes into a "supergene". At the supergene level, the power of detection is high, with 8% - 56% yielding adaptive signals. Nevertheless, the calls still do not overlap. Since it is unlikely that one test is largely correct and the other is mostly wrong (see Discussion), the total evidence of adaptive DNA sequence evolution should be deemed unreliable. As suggested by Chen et al.1, the reported evidence for positive selection may in fact be signals of fluctuating negative selection, which are handled differently by the two tests. Possible paths forward on this central evolutionary issue are discussed.

evolutionary biology↗

bioRxiv2018

Mechanisms of gene death in the Red Queen race revealed by the analysis of de novo microRNAs

The prevalence of de novo coding genes is controversial due to the length and coding constraints. Non-coding genes, especially small ones, are freer to evolve de novo by comparison. The best examples are microRNAs (miRNAs), a large class of regulatory molecules ~22 nt in length. Here, we study 6 de novo miRNAs in Drosophila which, like most new genes, are testis-specific. We ask how and why de novo genes die because gene death must be sufficiently frequent to balance the many new births. By knocking out each miRNA gene, we could analyze their contributions to each of the 9 components of male fitness (sperm production, length, competitiveness etc.). To our surprise, the knockout mutants often perform better in some components, and slightly worse in others, than the wildtype. When two of the younger miRNAs are assayed in long-term laboratory populations, their total fitness contributions are found to be essentially zero. These results collectively suggest that adaptive de novo genes die regularly, not due to the loss of functionality, but due to the canceling-out of positive and negative fitness effects, which may be characterized as \"quasi-neutrality\". Since de novo genes often emerge adaptively and become lost later, they reveal ongoing period-specific adaptations, reminiscent of the \"Red-Queen\" metaphor for long term evolution.

evolutionary biology↗

bioRxiv2018

Testing the Red Queen hypothesis on de novo new genes - Run or die in the evolution of new microRNAs

The Red Queen hypothesis depicts evolution as the continual struggle to adapt. According to this hypothesis, new genes, especially those originating from non-genic sequences (i.e., de novo genes), are eliminated unless they evolve continually in adaptation to a changing environment. Here, we analyze two Drosophila de novo miRNAs that are expressed in a testis-specific manner with very high rates of evolution in their DNA sequence. We knocked out these miRNAs in two sibling species and investigated their contributions to different fitness components. We observed that the fitness contributions of miR-975 in D. simulans seem positive, in contrast to its neutral contributions in D. melanogaster, while miR-983 appears to have negative contributions in both species, as the fitness of the knockout mutant increases. As predicted by the Red Queen hypothesis, the fitness difference of these de novo miRNAs indicates their different fates.

evolutionary biology↗

bioRxiv2018

Speciation with gene flow via cycles of isolation and migration: Insights from multiple mangrove taxa

Allopatric speciation requiring an unbroken period of geographical isolation has been the standard model of neo-Darwinism. While doubts have been repeatedly raised, strict allopatry without any gene flow remains a plausible mechanism in most cases. To rigorously reject strict allopatry, genomic sequences superimposed on the geological records of a well-delineated geographical barrier will be necessary. The Strait of Malacca, narrowly connecting the Pacific and Indian Ocean coasts, serves at different times either as a geographical barrier or a conduit of gene flow for coastal/marine species. We surveyed 1,700 plants from 29 populations of five common mangrove species by large scale DNA sequencing and added several whole-genome assemblies. Speciation between the two oceans is driven by cycles of isolation and gene flow due to the fluctuations in sea level leading to the opening/closing of the Strait to ocean currents. Because the time required for speciation in mangroves is longer than the isolation phases, speciation in these mangroves has proceeded through many cycles of mixing-isolation-mixing, or MIM cycles. The MIM mechanism, by relaxing the condition of no gene flow, can promote speciation in many more geographical features than strict allopatry can. Finally, the MIM mechanism of speciation is also efficient, potentially yielding mn (m>1) species after n cycles.\n\nSignificance statementMechanisms of species formation have always been a conundrum. Speciation between populations that are fully geographically isolated, or allopatric speciation, has been the standard solution in the last 50 years. Complete geographical isolation with no possibility of gene flow, however, is often untenable and is inefficient in generating the enormous biodiversity. By studying mangroves on the Indo-Malayan coasts, a global hotspot of coastal biodiversity, we were able to combine genomic data with geographical records on the Indo-Pacific barrier that separates Pacific and Indian Ocean coasts. We discovered a novel mechanism of speciation, that we call mixing-isolation-mixing (MIM) cycles. By permitting intermittent gene flow during speciation, MIM can potentially generate species at an exponential rate, thus combining speciation and biodiversity in a unified framework.

evolutionary biology↗

bioRxiv2018

Quasi-neutral molecular evolution -- When positive and negative selection cancel out

In the absence of both positive and negative selection, DNA sequences evolve at the neutral rate, R = 1. Due to the prevalence of negative selection, R[~]1 is rarely achieved in organismal evolution. However, when R [~] 1 is observed, it does not necessarily indicate neutral evolution because positive and negative selection could be equally strong but in opposite directions - hereby referred to as quasi-neutrality. We now show that somatic-cell evolution could be the paradigm of quasi-neutral evolution for these reasons: 1) Quasi-neutrality is much more likely in small populations (size N < 50) than in large ones; 2) Stem cell population sizes in single niches of normal tissues, from which tumors likely emerges, have small Ns (usually < 50); 3) the genome-wide evolutionary rate across tissue types is close to R = 1; 4) Relative to the average of R [~] 1, many genes evolve at a much higher or lower rate, thus hinting both positive and negative selection; 5) When N < 50, selection efficacy decreases rapidly as N decreases even when the selection intensity stays constant; 6) Notably, N is smaller in the small intestine (SmI) than in the colon (CO); hence, the [~] 70 fold higher rate of phenotypic evolution (observed as cancer risk) in the latter can be explained by the greater efficacy of selection, which then leads to the fixation of more advantageous mutations and fewer deleterious ones in the CO. Under quasineutrality, positive and negative selection can be measured in the same system as the two forces are simultaneously present or absent.

evolutionary biology↗

bioRxiv2017

Gene regulatory network rewiring by an adaptively evolving microRNA cluster in Drosophila

New miRNAs are evolutionarily important but their impact on existing biological networks remains unclear. We report the evolution of a microRNA cluster, mir-972C, that arose de novo and the subsequently rewired gene regulatory networks in Drosophila. Molecular evolution analyses revealed that mir-972C originated in the common ancestor of Drosophila where it comprises five old miRNAs. It subsequently recruited five new members in the melanogaster subgroup after conservative evolution for at least 50 million years. Population genetics analyses reveal that young and old mir-972C miRNAs evolved rapidly under positive selection in both seed and non-seed regions. Combining target prediction and cell transfection experiments, we find that sequence changes in individual mir-972C members resulted in extensive gene regulatory network divergence among D. melanogaster, D. simulans, and D. virilis, whereas the target pool of the cluster as a whole remains relatively conserved. Our results suggest that clustering of young and old miRNAs at the same locus broadens target repertoires, resulting in the gain of new targets without losing many old ones. This may facilitate the establishment of new miRNAs within existing regulatory networks.

evolutionary biology↗

bioRxiv2017

Genetic load and mutational meltdown in cancer cell populations

ABSRACTLarge and non-recombining genomes are prone to accumulating deleterious mutations faster than natural selection can purge (Mullers ratchet). A possible consequence would then be the extinction of small populations. Relative to most single-cell organisms, cancer cells, with large and non-recombining genomes, could be particularly susceptible to such \"mutational meltdown\". Curiously, deleterious mutations in cancer cells are rarely noticed despite the strong signals in cancer genome sequences. Here, by monitoring single-cell clones from HeLa cell lines, we characterize deleterious mutations that retard cell proliferation. The main mutational events are copy number variations (CNVs), which happen at an extraordinarily high rate of 0.29 events per cell division. The average fitness reduction, estimated to be 18% per mutation, is also very high. HeLa cell populations therefore have very substantial genetic load and, at this level, natural population would likely experience mutational meltdown. We suspect that HeLa cell populations may avoid extinction only after the population size becomes large. Because CNVs are common in most cell lines and cancer tissues, the observations hint at cancer cells vulnerability, which could be exploited by therapeutic strategies.

evolutionary biology↗

bioRxiv2017

From foodwebs to gene regulatory networks (GRNs) - weak repressions by microRNAs confer system stability

More than 30% of mRNAs are repressed by microRNAs (miRNAs) but most repressions are too weak to have a phenotypic consequence. The diffuse actions have been a central conundrum in understanding the functions of miRNAs. By applying the May-Wigner theory used in foodweb studies, we show that i) weak repressions cumulatively enhance the stability of gene regulatory network (GRN), and ii) broad and weak repressions confer greater stability than a few strong ones. Transcriptome data show that yeast cells, which do not have miRNAs, use strong and non-specific mRNA degradation to stabilize their GRN; in contrast, human cells use miRNAs to increase degradation more modestly and selectively. Simulations indicate that miRNA repressions should be distributed broadly to >25% of mRNAs, in agreement with observations. As predicted, extremely highly expressed genes are avoided and transcription factors are preferred by miRNAs. In conclusion, the diffuse repression by miRNAs is likely a system-level strategy for enhancing GRN stability. This stability control may be the mechanistic basis of \"canalization\" (i.e., developmental homeostasis within each species), sometimes hypothesized to be a main function of miRNAs.

evolutionary biology↗

bioRxiv2017

Free-living human cells reconfigure their chromosomes in the evolution back to uni-cellularity

Cells of multi-cellular organisms evolve toward uni-cellularity in the form of cancer and, if humans intervene, continue to evolve in cell culture. During this process, gene dosage relationships may evolve in novel ways to cope with the new environment and may regress back to the ancestral unicellular state. In this context, the evolution of sex chromosomes vis-a-vis autosomes is of particular interest. Here, we report the chromosomal evolution in ~600 cancer cell lines. Many of them jettisoned either Y or the inactive X; thus, free-living male and female cells converge by becoming \"de-sexualized\". Surprisingly, the active X often doubled, accompanied by the addition of one haploid complement of autosomes, leading to an X:A ratio of 2:3 from the extant ratio of 1:2. Theoretical modeling of the frequency distribution of X:A karyotypes suggests that the 2:3 ratio confers a higher fitness and may reflect aspects of sex chromosome evolution.

genomics↗