Biology subjects

Wang, R. J.

Publications and source records attributed to Wang, R. J..

11 recordsLinked to original sources

bioRxiv2026

Scaffold Affinity Tunes Biomolecular Condensate Function

Biomolecular condensates (BMCs) organize cellular biochemistry by concentrating selected molecules into dynamic membrane-free compartments. Yet the molecular parameters that determine not only whether condensates form, but also how they behave and what they do, remain poorly defined. Here we show that scaffold binding affinity (Kd) is a quantitative determinant of condensate phase behavior, internal dynamics and biochemical output. Using a modular SUMO-SIM system in which scaffold valency was held constant while binding affinity was systematically varied, we found that affinity governs the phase boundary, resistance to chemical perturbation, and molecular mobility of condensates in vitro and in human cells. In multicomponent mixtures, the highest-affinity scaffold dominated dense-phase composition and dynamics, revealing a hierarchical rule for condensate organization. Finally, affinity-dependent changes in condensate dynamics translated into tunable enzyme activity, establishing binding energetics as an engineerable parameter for programming condensate biochemistry.

biochemistry↗

bioRxiv2024

Unprecedented female mutation bias in aye-ayes

Every mammal studied to date has been found to have a male mutation bias: male parents transmit more de novo mutations to offspring than female parents, contributing increasingly more mutations with age. Although male-biased mutation has been studied for more than 75 years, its causes are still debated. One obstacle to understanding this pattern is its near universality--without variation in mutation bias, it is difficult to find an underlying cause. Here, we present new data on multiple pedigrees from two primate species: aye-ayes (Daubentonia madagascarensis), a member of the strepsirrhine primates, and olive baboons (Papio anubis). In stark contrast to the pattern found across mammals, we find a much larger effect of maternal age than paternal age on mutation rates in the aye-aye. In addition, older aye-aye mothers transmit substantially more mutations than older fathers. We carry out both computational and experimental validation of our results, contrasting them with results from baboons and other primates using the same methodologies. Further, we analyze a set of DNA repair and replication genes to identify candidate mutations that may be responsible for the change in mutation bias observed in aye-ayes. Our results demonstrate that mutation bias is not an immutable trait, but rather one that can evolve between closely related species. Further work on aye-ayes (and possibly other lemuriform primates) should help to explain the molecular basis for sex-biased mutation.

evolutionary biology↗

bioRxiv2023

Robust inference of historical human generation times

Ragsdale and Thornton (2023) raise concerns about our recent estimates of historical human generation times, concluding that our results were "predominantly driven by nonbiological artifacts." While we believe these authors have pointed out several important sources of uncertainty, we show here that their main concerns are either not relevant to our study or support our conclusions as much as they cast doubt on them. In particular, the demographic simulations carried out by Ragsdale and Thornton assume all individuals with recent African ancestry are from West Africa, which is not appropriate for our sample. In contrast to the lack of visual concordance between predictions and data cited by these authors as evidence for a lack of fit, we demonstrate that our model provides a good statistical fit to data on the overall historical mutation spectrum, though one particular mutation type is an outlier. Furthermore, we show that the historical generation times inferred when using alternative methods for estimating the ages of individual alleles are largely in agreement with our results, particularly so when using results from Relate. Importantly, these analyses, as well as recent work from an independent group, confirm the idea that a model built on de novo mutations and applied to polymorphism data provides useful and reliable estimates of generation times in widely distant mammals.

evolutionary biology↗

bioRxiv2022

Hibernation shows no apparent effect on germline mutation rates in grizzly bears

A male mutation bias is observed across vertebrates, and, where data are available, this bias is accompanied by increased per-generation mutation rates with parental age. While continuing mitotic cell division in the male germline post-puberty has been proposed as the major cellular mechanism underlying both patterns, little direct evidence for this role has been found. Understanding the evolution of the per-generation mutation rate among species requires that we identify the molecular mechanisms that change between species. Here, we study the per-generation mutation rate in an extended pedigree of the brown (grizzly) bear, Ursus arctos horribilis. Brown bears hibernate for one-third of the year, a period during which spermatogenesis slows or stops altogether. The cessation of spermatogenesis is predicted to lessen the male mutation bias and to lower the per-generation mutation rate in this species. However, using whole-genome sequencing, we find that both male bias and per-generation mutation rates are the same as expected for a non-hibernating species. We also carry out a phylogenetic comparison of substitution rates along the lineage leading to brown bear and panda (a non-hibernating species) and find no slowing of the substitution rate in the hibernator. Our results contribute to accumulating evidence that suggests that male germline cell division is not the major determinant of mutation rates and mutation biases. The results also provide a quantitative basis for improved estimates of the timing of carnivore evolution.

evolutionary biology↗

bioRxiv2021

Human generation times across the past 250,000 years

The generation times of our recent ancestors can tell us about both the biology and social organization of prehistoric humans, placing human evolution on an absolute timescale. We present a method for predicting historic male and female generation times based on changes in the mutation spectrum. Our analyses of whole-genome data reveal an average generation time of 26.9 years across the past 250,000 years, with fathers consistently older (30.7 years) than mothers (23.2 years). Shifts in sex-averaged generation times have been driven primarily by changes to the age of paternity rather than maternity, though we report a disproportionate increase in female generation times over the past several thousand years. We also find a large difference in generation times among populations, with samples from current African populations showing longer ancestral generation times than non-Africans for over a hundred thousand years, reaching back to a time when all humans occupied Africa.

evolutionary biology↗

bioRxiv2021

De novo mutations in domestic cat are consistent with an effect of reproductive longevity on both the rate and spectrum of mutations

The mutation rate is a fundamental evolutionary parameter with direct and appreciable effects on the health and function of individuals. Here, we examine this important parameter in the domestic cat, a beloved companion animal as well as a valuable biomedical model. We estimate a mutation rate of 0.86 x 10-8 per bp per generation for the domestic cat (at an average parental age of 3.8 years). We find evidence for a significant paternal age effect, with more mutations transmitted by older sires. Our analyses suggest that the cat and the human have accrued similar numbers of mutations in the germline before reaching sexual maturity. The per-generation mutation rate in the cat is 28% lower than what has been observed in humans, but is consistent with the shorter generation time in the cat. Using a model of reproductive longevity, which takes into account differences in the reproductive age and time to sexual maturity, we are able to explain much of the difference in per-generation rates between species. We further apply our reproductive longevity model in a novel analysis of mutation spectra and find that the spectrum for the cat resembles the human mutation spectrum at a younger age of reproduction. Together, these results implicate changes in life-history as a driver of mutation rate evolution between species. As the first direct observation of the paternal age effect outside of rodents and primates, our results also suggest a phenomenon that may be universal among mammals.

evolutionary biology↗

bioRxiv2020

Distinct error rates for reference and non-reference genotypes estimated by pedigree analysis

Errors in genotype calling can have perverse effects on genetic analyses, confounding association studies and obscuring rare variants. Analyses now routinely incorporate error rates to control for spurious findings. However, reliable estimates of the error rate can be difficult to obtain because of their variance between studies. Most studies also report only a single estimate of the error rate even though genotypes can be miscalled in more than one way. Here, we report a method for estimating the rates at which different types of genotyping errors occur at biallelic loci using pedigree information. Our method identifies potential genotyping errors by exploiting instances where the haplotypic phase has not been faithfully transmitted. The expected frequency of inconsistent phase depends on the combination of genotypes in a pedigree and the probability of miscalling each genotype. We develop a model that uses the differences in these frequencies to estimate rates for different types of genotype error. Simulations show that our method accurately estimates these error rates in a variety of scenarios. We apply this method to a dataset from the whole-genome sequencing of owl monkeys (Aotus nancymaae) in three-generation pedigrees. We find significant differences between estimates for different types of genotyping error, with the most common being homozygous reference sites miscalled as heterozygous and vice versa. The approach we describe is applicable to any set of genotypes where haplotypic phase can reliably be called, and should prove useful in helping to control for false discoveries.

bioinformatics↗

bioRxiv2019

Origins and long-term patterns of copy-number variation in rhesus macaques

Mutations play a key role in the development of disease in an individual and the evolution of traits within species. Recent work in humans and other primates has clarified the origins and patterns of single nucleotide variants, showing that most arise in the fathers germline during spermatogenesis. It remains unknown whether larger mutations, such as deletions and duplications of hundreds or thousands of nucleotides, follow similar patterns. Such mutations lead to copy-number variation (CNV) within and between species, and can have profound effects by deleting or duplicating genes. Here we analyze patterns of CNV mutations in 32 rhesus macaque individuals from 14 parent-offspring trios. We find the rate of CNV mutations per generation is low (less than one per genome) and we observe no correlation between parental age and the number of CNVs that are passed on to offspring. We also examine segregating CNVs within the rhesus macaque sample and compare them to a similar dataset from humans, finding that both species have far more segregating deletions than duplications. We contrast this with long-term patterns of gene copy-number evolution between 17 mammals, where the proportion of deletions that become fixed along the macaque lineage is much smaller than the proportion of segregating deletions. These results suggest purifying selection acting on deletions, such that the majority of them are removed from the population over time. Rhesus macaques are an important biomedical model organism, so these results will aid in our understanding of this species and the disease models it supports.

evolutionary biology↗

bioRxiv2019

Paternal age in rhesus macaques is positively associated with germline mutation accumulation but not with measures of offspring sociability

Mutation is the ultimate source of all genetic novelty and the cause of heritable genetic disorders. Mutational burden has been linked to complex disease, including neurodevelopmental disorders such as schizophrenia and autism. The rate of mutation is a fundamental genomic parameter and direct estimates of this parameter have been enabled by accurate comparisons of whole-genome sequences between parents and offspring. Studies in humans have revealed that the paternal age at conception explains most of the variation in mutation rate: each additional year of paternal age in humans leads to approximately 1.5 additional mutations inherited by the child. Here, we present an estimate of the de novo mutation rate in the rhesus macaque (Macaca mulatta) using whole-genome sequence data from 32 individuals in four large pedigrees. We estimated an average mutation rate of 0.58 x 10-8 per base pair per generation (at an average parental age of 7.5 years), much lower than found in direct estimates from great apes (including human, chimpanzee, and gorilla). As in humans, older macaque fathers transmit more mutations to their offspring, approximately 1.5 extra mutations per year in our probands. Mutations at CpG sites accounted for 24% of all observed point mutations. We found that the rate of mutation accumulation after puberty is similar between macaques and humans, but that a smaller number of mutations accumulate before puberty in macaques. We additionally investigated the role of paternal age on offspring sociability, a proxy for normal neurodevelopment. In 203 male macaques studied in large social groups, we found no relationship between paternal age and multiple measures of social function. Our findings are consistent with the hypothesis that the increased risk of neurodevelopmental disorders with paternal age in primates is not primarily due to de novo mutations.

evolutionary biology↗

bioRxiv2018

Reproductive longevity predicts mutation rates in primates

Mutation rates vary between species across several orders of magnitude, with larger organisms having the highest per-generation mutation rates. Hypotheses for this pattern typically invoke physiological or population-genetic constraints imposed on the molecular machinery preventing mutations1. However, continuing germline cell division in multicellular eukaryotes means that organisms with longer generation times and of larger size will leave more mutations to their offspring simply as a by-product of their increased lifespan2,3. Here, we deeply sequence the genomes of 30 owl monkeys (Aotus nancymaae) from 6 multi-generation pedigrees to demonstrate that paternal age is the major factor determining the number of de novo mutations in this species. We find that owl monkeys have an average mutation rate of 0.81 x 10-8 per site per generation, roughly 32% lower than the estimate in humans. Based on a simple model of reproductive longevity that does not require any changes to the mutational machinery, we show that this is the expected mutation rate in owl monkeys. We further demonstrate that our model predicts species-specific mutation rates in other primates, including study-specific mutation rates in humans based on the average paternal age. Our results suggest that variation in life history traits alone can explain variation in the per-generation mutation rate among primates, and perhaps among a wide range of multicellular organisms.

evolutionary biology↗

bioRxiv2018

Speciation genes are more likely to have discordant gene trees

Speciation genes are responsible for reproductive isolation between species. By directly participating in the process of speciation, the genealogies of isolating loci have been thought to more faithfully represent species trees. The unique properties of speciation genes may provide valuable evolutionary insights and help determine the true history of species divergence. Here, we formally analyze whether genealogies from loci participating in Dobzhansky-Muller (DM) incompatibilities are more likely to be concordant with the species tree under incomplete lineage sorting (ILS). Individual loci differ stochastically from the true history of divergence with a predictable frequency due to ILS, and these expectations--combined with the DM model of intrinsic reproductive isolation from epistatic interactions--can be used to examine the probability of concordance at isolating loci. Contrary to existing verbal models, we find that reproductively isolating loci that follow the DM model are often more likely to have discordant gene trees. These results are dependent on the pattern of isolation observed between three species, the time between speciation events, and the time since the last speciation event. Results supporting a higher probability of discordance are found for both derived-derived and derived-ancestral DM pairs, and regardless of whether incompatibilities are allowed or prohibited from segregating in the same population. Our overall results suggest that DM loci are unlikely to be especially useful for reconstructing species relationships, even in the presence of gene flow between incipient species, and may in fact be positively misleading.

evolutionary biology↗