Lack of evolutionary convergence in multiple primary lung cancer suggests insufficient specificity of personalized therapy

Multiple primary lung cancer(MPLC)is an increasingly prevalent subtype of lung cancer.According to recent genomic studies,the different lesions of a single MPLC patient exhibit functional similarities that may reflect evolutionary convergence.We perform whole-exome sequencing for a unique cohort of MPLC patients with multiple samples from each lesion found.Using our own and other relevant public data,evolutionary tree reconstruction reveals that cancer driver gene mutations occurred at the early trunk,indicating evolutionary contingency rather than adaptive convergence.Additionally,tumors from the same MPLC patient are as genetically diverse as those from different patients,while within-tumor genetic heterogeneity is significantly lower.Furthermore,the aberrant molecular functions enriched in mutated genes for a sample show a strong overlap with other samples from the same tumor,but not with samples from other tumors or other patients.Overall,there is no evidence of adaptive convergence during the evolution of MPLC.Most importantly,the similar between-tumor diversity and between-patient diversity suggest that personalized therapies may not adequately account for the genetic diversity among different tumors in an MPLC patient.To fully exploit the strategic value of precision medicine,targeted therapies should be designed and delivered on a per-lesion basis.

The evolution of sex chromosome dosage compensation in animals

The evolution of heteromorphic sex chromosomes shall lead to gene expression dosage problems,as in at least one of the sexes,the sex-linked gene dose has been reduced by half.It has been proposed that the transcriptional output of the whole X or Z chromosome should be doubled for complete dosage compensation in heterogametic sex.However,owing to the variability of the existing methods to determine the transcriptional differences between sex chromosomes and autosomes(S:A ratios)in different studies,we collected more than 500 public RNA-Seq data set from multiple tissues and species in major clades and proposed a unified computational framework for unbiased and comparable measurement of the S:A ratios of multiple species.We also tested the evolution of dosage compensation more directly by assessing changes in the expression levels of the current sex-linked genes relative to those of the ancestral sex-linked genes.We found that in mammals and birds,the S:A ratio is approximately 0.5,whereas in insects,fishes,and flatworms,the S:A ratio is approximately 1.0.Further analysis showed that the fraction of dosage-sensitive housekeeping genes on the X/Z chromosome is significantly correlated with the S:A ratio.In addition,the degree of degeneration of the Y chromosome may be responsible for the change in the S:A ratio in mammals without a dosage compensation mechanism.Our observations offer unequivocal support for the sex chromosome insensitivity hypothesis in animals and suggest that dosage sensitivity states of sex chromosomes are a major factor underlying different evolutionary strategies of dosage compensation.

Specificity of mRNA Folding and Its Association with Evolutionarily Adaptive mRNA Secondary Structures

The secondary structure is a fundamental feature of both non-coding RNAs(ncRNAs)and messenger RNAs(mRNAs).However,our understanding of the secondary structures of mRNAs,especially those of the coding regions,remains elusive,likely due to translation and the lack of RNA-binding proteins that sustain the consensus structure like those binding to ncRNAs.Indeed,mRNAs have recently been found to adopt diverse alternative structures,but the overall functional significance remains untested.We hereby approach this problem by estimating the folding specificity,i.e.,the probability that a fragment of an mRNA folds back to the same partner once refolded.We show that the folding specificity of mRNAs is lower than that of ncRNAs and exhibits moderate evolutionary conservation.Notably,we find that specific rather than alternative folding is likely evolutionarily adaptive since specific folding is frequently associated with functionally important genes or sites within a gene.Additional analysis in combination with ribosome density suggests the ability to modulate ribosome movement as one potential functional advantage provided by specific folding.Our findings reveal a novel facet of the RNA structurome with important functional and evolutionary implications and indicate a potential method for distinguishing the mRNA secondary structures maintained by natural selection from molecular noise.