Biology subjects

Rajaei, M.

Publications and source records attributed to Rajaei, M..

6 recordsLinked to original sources

bioRxiv2025

Deconvolving mutation and selection reveals stage-specific drivers of thyroid cancer

ObjectiveMutational profiles of primary and metastatic thyroid cancer (THCA) have been examined by comparison of somatic mutation prevalences in the two stages, using P values to identify significant differences. However, prevalences and P values for mutations do not directly quantify the cancer effects of somatic variants. MethodsWe calculated cancer effect sizes accounting for substantial gene- and site-specific mutation rates, to quantify somatic selection across stages. This approach provides a direct measure of cancer-driving impact of new mutations and reveals the genes that drive tumorigenesis and progression, and whether mutations have greater effects in primary or metastatic THCA. ResultsTrinucleotide mutation profiles were similar between primary and metastatic THCA. Most canonical driver genes (BRAF, NRAS, TP53, ATM, EIF1AX, KMT2C, NF1, RBM10, ARID1A, PIK3CA, and NKX2-1) exhibited stronger selection during initial tumorigenesis (from organogenesis to primary THCA) than during progression (from primary to metastatic THCA). Notably, TERT mutations have been shown to be at higher prevalence in metastatic tumors, yet their strongest selection occurred earlier, during tumor initiation. In contrast, RET mutations exhibited the opposite trajectory, experiencing weaker selection during tumorigenesis but stronger selection during metastatic progression. ConclusionCancer effect size analysis revealed dynamic shifts in selective pressures across THCA evolution, distinguishing genes that drive initiation from those that promote metastatic progression. This evolutionary framework provides a quantitative basis for understanding THCA pathogenesis and provides guidance for stage-specific precision-medicine therapeutic strategies.

cancer biology↗

bioRxiv2025

Somatic evolution of prostate cancer: mutation, selection, and epistasis across disease stages

BackgroundSomatic mutations involved in prostate cancer tumorigenesis and disease progression have been identified, but their evolutionary dynamics--including differential selective pressures across oncogenesis and metastatic spread--remain poorly understood. No prior study has systematically quantified the adaptive landscape from prostate organogenesis through tumor initiation and progression to metastatic castrate-resistant prostate cancer (mCRPC), nor characterized the selective epistatic interactions that structure this evolutionary trajectory. Methods and FindingsTo address this gap, we analyzed 2,704 low- and high-risk primary tumors and metastatic castration-resistant prostate cancers to quantify the mutation rates, mutational processes, and scaled selection coefficients of somatic mutations across disease stages. Trinucleotide mutational patterns were stable, but both mutation load and mutation rates increased with progression. In parallel, selective pressures on specific somatic mutations changed substantially, revealing a dynamic adaptive landscape. Stage-specific selective effects were associated with significant synergistic and antagonistic selective epistasis among key driver genes. Early selection on SPOP mutations in the BRD3 binding domain were under strong positive selection, and they increased selection for subsequent RHOA mutations while decreasing selection for TP53 mutations. Antagonistic selective epistasis was evident between mutations of CUL3 and both SPOP and PIK3CA. Mutations in KMT2C increased the selection for mutations in TP53, consistent with their frequent co-occurrence. Synergistic epistatic interactions between mutations of PTEN and both PIK3CA and AR support a strong therapeutic rationale for combined inhibition of PI3K/AR pathway in PTEN-deficient prostate cancers. ConclusionsThese findings provide a comprehensive map of the evolving selective and epistatic forces that shape prostate cancer progression across clinical stages. By distinguishing shifts in selection from changes in mutation rate and revealing the extents of cooperative and conflicting relationships among driver mutations, our work identifies critical points of vulnerability and informs that design of therapeutic strategies that anticipate and intercept the somatic evolutionary trajectory of prostate cancer.

cancer biology↗

bioRxiv2025

Evolution of the rate, spectrum, and fitness effects of mutation under minimal selection in Caenorhabditis elegans

The rate, molecular spectrum, and fitness effects of mutations vary at all levels of the biological hierarchy, from within individual genomes to among taxonomic domains. Understanding the evolutionary factors underpinning that variation is of fundamental importance to biology. Accurate quantification of the properties of mutations requires that other evolutionary forces, especially natural selection, be minimized as much as possible. To investigate the evolution of the mutational process in C. elegans, we propagated a set of 100 "first order" mutation accumulation (O1MA) lines under minimal selection for [~]150 generations, divided each O1MA line into two "second order" MA (O2MA) lines and propagated them for another [~]150 generations, at which time the genome of each O2MA line was sequenced, and a subset of 50 O1MA families was assayed for competitive fitness. Over the course of the experiment, the mean nucleotide substitution mutation rate did not change, but the variance increased. In contrast, the indel mutation rate increased significantly. The two types of mutations fulfill the predictions of different theoretical models for the evolution of mutation rate. These results reinforce previous findings that the rate of indels is more sensitive to endogenous stress than the rate of nucleotide substitutions. Several evolutionary quandaries could be resolved if deleterious mutations interact synergistically (negative epistasis). Evidence for synergistic epistasis is famously inconclusive, although there is reason to think it may be more detectable under competitive conditions. However, a model of constant mutational effects on competitive fitness explains the results significantly better than a model including epistasis.

evolutionary biology↗

bioRxiv2024

Direct inference of the distribution of fitness effects of spontaneous mutations from recombinant inbred C. elegans mutation accumulation lines

The distribution of fitness effects (DFE) of new mutations plays a central role in evolutionary biology. Estimates of the DFE from experimental Mutation Accumulation (MA) lines are compromised by the complete linkage disequilibrium (LD) between mutations in different lines. To reduce LD, we constructed two sets of recombinant inbred lines from a cross of two C. elegans MA lines. One set of lines ("RIAILs") was intercrossed for ten generations prior to ten generations of selfing; the second set of lines ("RILs") omitted the intercrossing. Residual LD in the RIAILs is much less than in the RILs, which affects the inferred DFE when the sets of lines are analyzed separately. The best-fit model estimated from all lines (RIAILs + RILs) infers a large fraction of mutations with positive effects ([~]40%); models that constrain mutations to have negative effects fit much worse. The conclusion is the same using only the RILs. For the RIAILs, however, models that constrain mutations to have negative effects fit nearly as well as models that allow positive effects. When mutations in high LD are pooled into haplotypes, the inferred DFE becomes increasingly negative-skewed and leptokurtic. We conclude that the conventional wisdom - most mutations have effects near zero, a handful of mutations have effects that are substantially negative and mutations with positive effects are very rare - is likely correct, and that unless it can be shown otherwise, estimates of the DFE that infer a substantial fraction of mutations with positive effects are likely confounded by LD.

evolutionary biology↗

bioRxiv2021

Mutation, selection, and the prevalence of the C. elegans mortal germline phenotype

C. elegans strains with the heat-sensitive mortal germline (Mrt) phenotype become progressively sterile over the course of a few tens of generations when maintained at temperatures near the upper range of C. elegans tolerance. Mrt is transgenerationally-heritable, and proximately under epigenetic control. Previous studies have suggested that Mrt presents a relatively large mutational target, and that Mrt is not uncommon in natural populations of C. elegans. The Mrt phenotype is not monolithic. Some strains exhibit a strong Mrt phenotype, in which individuals invariably become sterile over a few generations, whereas other strains show a weaker (less penetrant) phenotype in which the onset of sterility is slower and more stochastic. We present results in which we (1) quantify the rate of mutation to the Mrt phenotype, and (2) quantify the frequency of Mrt in a collection of 95 wild isolates. Over the course of ~16,000 meioses, we detected one mutation to a strong Mrt phenotype, resulting in a point estimate of the mutation rate UMrt{approx} 6x10-5/genome/generation. We detected no mutations to a weak Mrt phenotype. 6/95 wild isolates have a strong Mrt phenotype, and although quantification of the weak Mrt phenotype is inexact, the weak Mrt phenotype is not rare in nature. We estimate a strength of selection against mutations conferring the strong Mrt phenotype [Formula], similar to selection against mutations affecting competitive fitness. The appreciable frequency of weak Mrt variants in nature combined with the low mutation rate suggests that Mrt may be maintained by balancing selection.

genetics↗

bioRxiv2021

Mutability of mononucleotide repeats, not oxidative stress, explains the discrepancy between laboratory-accumulated mutations and the natural allele-frequency spectrum in C. elegans

Important clues about natural selection can be gleaned from discrepancies between the properties of segregating genetic variants and of mutations accumulated experimentally under minimal selection, provided the mutational process is the same in the lab as in nature. The ratio of transitions to transversions (Ts/Tv) is consistently lower in C. elegans mutation accumulation (MA) experiments than in nature, which has been argued to be in part due to increased oxidative stress in the lab environment. Using whole-genome sequence data from a set of C. elegans MA lines carrying a mutation (mev-1) that increases the cellular titer of reactive oxygen species (ROS), leading to increased endogenous oxidative stress, we find that the base-substitution spectrum is similar between mev-1 lines, its wild-type progenitor (N2), and another set of MA lines derived from a different wild strain (PB306). By contrast, the rate of short insertions is greater in the mev-1 lines, consistent with studies in other organisms in which environmental stress led to an increase in the rate of insertion-deletion mutations. Further, the mutational properties of mononucleotide repeats in all strains are qualitatively different from those of non-mononucleotide sequence, both for indels and base-substitutions, and whereas the non-mononucleotide spectra are fairly similar between MA lines and wild isolates, the mononucleotide spectra are very different. The discrepancy in mutational spectra between lab MA experiments and natural variation is likely due to a consistent (but unknown) effect of the lab environment that manifests itself via different modes of mutability and/or repair at mononucleotide loci.

evolutionary biology↗