Biology subjects

Ragsdale, A.

Publications and source records attributed to Ragsdale, A..

9 recordsLinked to original sources

bioRxiv2026

Strong correlations between mutation rates and selective constraint in the human genome?

The 21st century has seen repeated challenges to the premise that de novo mutations occur independently from their fitness effects. So far, these attempts have been dismissed as technical artifacts, restoring confidence in the null hypothesis. Yet the development of high-resolution genomic resources enables investigating the relationship between mutation rate variation and selective constraint with unprecedented detail. Here, we use state-of-the art genomic maps to test whether predicted mutation rates differ within and outside putatively constrained sites in humans. Contrary to the hypothesis that is typically put forward, but in agreement with another recent study, we find that protein-coding genes exhibit higher rates of mutation than the neutral genomic background. Conversely, mutation rates are lower in non-coding elements identified through sequence conservation. This can be attributed either to biases in the estimation of mutation rates in sites under selection, biases in scoring constraint in sites with low rates of mutation, or a genuine signal that would merit further investigation. Regardless of the underlying cause, our findings have broad implications for evolutionary genetics. Several studies rely on accurate mutation maps and identification of selection targets across the genome, which inherently confound each other. Caution is therefore warranted when interpreting results from currently available non-coding scores.

evolutionary biology↗

bioRxiv2026

Genetic Basis of Social Structure in the Pastoral Nomads of Central Eurasia

Although the social structure of Central Eurasian pastoral nomads has been described as fluid and ad hoc by historians and anthropologists, its potential genetic basis remains poorly understood. To evaluate whether kinship based social organization has biological foundations, we surveyed Kazak populations in Jetisuu, Kazakstan, for genomic diversity with special reference to their kinship structure. We generated genome-wide SNP data ([~]750K) using GenoChip microarrays for 80 individuals from four Kazak clans in Jetisuu and 10 Kazaks from other regions. Our results reveal substantial concordance between genetic and genealogical data, with [~]64% of Jetisuu Kazaks sharing the same Y-chromosome haplotype, indicating they have a common paternal ancestry aligning with clan genealogies. By contrast, maternal lineages show remarkable heterogeneity, thereby reflecting female exogamy. Despite this sex-biased admixture pattern, autosomal SNPs reveal no pronounced population structure in Kazaks, suggesting genetic homogenization through ancient admixture followed by continuous gene flow between Kazak populations. Notably, Jetisuu Kazaks exhibit significantly reduced levels of runs of homozygosity (ROH) compared to their sedentary neighbors such as Turkmens, Tajiks, Uyghurs, and Uzbeks. This genomic signature likely results from clan exogamy, which functions as a biological mechanism to prevent inbreeding and maintain genetic diversity. Our findings demonstrate that nomadic social organization represents a sophisticated example of gene-culture co-evolution, where cultural practices have systematically shaped genetic patterns over centuries. These data provide new insights into historical pastoral nomadic societies and offer a nuanced perspective on anthropological debates about kinship authenticity in Central Eurasian nomads.

genetics↗

bioRxiv2025

Accessible, realistic genome simulation with selection using stdpopsim

Selection is a fundamental evolutionary force that shapes patterns of genetic variation across species. However, simulations incorporating realistic selection along heterogeneous genomes in complex demographic histories are challenging, limiting our ability to benchmark statistical methods aimed at detecting selection and to explore theoretical predictions. stdpopsim is a community-maintained simulation library that already provides an extensive catalog of species-specific population genetic models. Here we present a major extension to the stdpopsim framework that enables simulation of various modes of selection, including background selection, selective sweeps, and arbitrary distributions of fitness effects (DFE) acting on annotated subsets of the genome (for instance, exons). This extension maintains stdpopsims core principles of reproducibility and accessibility while adding support for species-specific genomic annotations and published DFE estimates. We demonstrate the utility of this framework by comparing methods for demographic inference, DFE estimation, and selective sweep detection across several species and scenarios. Our results demonstrate the robustness of demographic inference methods to selection on linked sites, reveal the sensitivity of DFE-inference methods to model assumptions, and show how genomic features, like recombination rate and functional sequence density, influence power to detect selective sweeps. This extension to stdpopsim provides a powerful new resource for the population genetics community to explore the interplay between selection and other evolutionary forces in a reproducible, user-friendly framework.

evolutionary biology↗

bioRxiv2025

A model for background selection in non-equilibrium populations

In many taxa, levels of genetic diversity are observed to vary along their genome. The framework of background selection models this variation in terms of linkage to constrained sites, and recent applications have been able to explain a large portion of the variation in human genomes. However, these studies have also yielded conflicting results, stemming from two key limitations. First, existing models are inaccurate in a critical region of parameter space (Nes ~ -1), where the local reduction in diversity is sharpest. Second, they assume a constant population size over time. Here, we develop predictions for diversity under background selection based on the Hill-Robertson system of two-locus statistics, which allows for population size changes. We treat the joint effect of multiple selected loci independently, but we show that interference among them is well captured through local rescaling of mutation, recombination and selection in an iterative procedure that converges quickly. We further accommodate existing background selection theory to non-equilibrium demography, bridging the gap between weak and strong selection. Simulations show that our predictions are accurate across the entire range of selection coefficients. We characterize the temporal dynamics of linked selection under population size changes and demonstrate that patterns of diversity can be misinterpreted by other models. Specifically, biases due to the incorrect assumption of equilibrium carry over to downstream inferences of the distribution of fitness effects and deleterious mutation rate. Jointly modeling demography and linked selection therefore improves our understanding of the genomic landscape of diversity, which will help refine inferences of linked selection in humans and other species.

evolutionary biology↗

bioRxiv2023

Demographic Modeling of Admixed Latin American Populations from Whole Genomes

Demographic models of Latin American populations often fail to fully capture their complex evolutionary history, which has been shaped by both recent admixture and deeper-in-time demographic events. To address this gap, we used high-coverage whole genome data from Indigenous American ancestries in present-day Mexico and existing genomes from across Latin America to infer multiple demographic models that capture the impact of different timescales on genetic diversity. Our approach, which combines analyses of allele frequencies and ancestry tract length distributions, represents a significant improvement over current models in predicting patterns of genetic variation in admixed Latin American populations. We jointly modeled the contribution of European, African, East Asian, and Indigenous American ancestries into present-day Latin American populations to capture the historical demographic events that have shaped genetic variation. Our inferred demographic histories are consistent across different genomic regions and annotations, suggesting that our inferences are robust to the potential effects of linked selection. In conjunction with published distributions of fitness effects for new nonsynonymous mutations in humans, we show in large-scale simulations that our models recover important features of both neutral and deleterious variation. By providing a more realistic framework for understanding the evolutionary history of Latin American populations, our models can help address the historical under-representation of admixed groups in genomics research, and can be a valuable resource for future studies of populations with complex admixture and demographic histories.

evolutionary biology↗

bioRxiv2022

Nationwide genomic biobank in Mexico unravels demographic history and complex trait architecture from 6,057 individuals

Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories as well as complex trait architectures remain hidden due to the lack of Big Data. To fill this gap, the Mexican Biobank project genotyped 1.8 million markers in 6,057 individuals from 32 states and 898 sampling localities across Mexico with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Through a suite of state-of-the-art methods for ancestry deconvolution and inference of identity-by-descent (IBD) segments, we inferred detailed ancestral histories for the last 200 generations in different Mesoamerican regions, unraveling native and colonial/post-colonial demographic dynamics. We observed large variations in runs of homozygosity (ROH) among genomic regions with different ancestral origins reflecting their demographic histories, which also affect the distribution of rare deleterious variants across Mexico. We analyzed a range of biomedical complex traits and identified significant genetic and environmental factors explaining their variation, such as ROH found to be significant predictors for trait variation in BMI and triglycerides.

genomics↗

bioRxiv2020

Paternal hypoxia exposure primes offspring for increased hypoxia resistance

In a time of rapid environmental change, understanding how the challenges experienced by one generation can influence the fitness of future generations is critically needed. Using tolerance assays, transcriptomic and methylome approaches, we use zebrafish as a model to investigate transgenerational acclimation to hypoxia. We show that short-term paternal exposure to hypoxia endows offspring with greater tolerance to acute hypoxia. We detected two hemoglobin genes that are significantly upregulated by more than 7-fold in the offspring of hypoxia exposed males. Moreover, the offspring which maintained equilibrium the longest showed greatest upregulation in hemoglobin expression. We did not detect differential methylation at any of the differentially expressed genes, suggesting that another epigenetic mechanism is responsible for alterations in gene expression. Overall, our findings suggest that a memory of past hypoxia exposure is maintained and that this environmentally induced information is transferred to subsequent generations, pre-acclimating progeny to cope with hypoxic conditions.

evolutionary biology↗

bioRxiv2019

Coupling Wright-Fisher and coalescent dynamics for realistic simulation of population-scale datasets

1Coalescent simulations are widely used to examine the effects of evolution and demographic history on the genetic makeup of populations. Thanks to recent progress in algorithms and data structures, simulators such as the widely-used msprime [1] now provide genome-wide simulations for millions of individuals. However, this software relies on classic coalescent theory and the corresponding assumptions that sample sizes are small relative to effective population size and that the region being simulated is short. Here we show that coalescent simulations of long regions of the genome exhibit large biases in identity-by-descent (IBD), long-range linkage disequilibrium (LD), and ancestry patterns, particularly when sample size is large. We present a Wright-Fisher extension to msprime, and show that it produces more realistic distributions of IBD, LD, and ancestry proportions, while also addressing more subtle biases of the coalescent. Further, these extensions are more computationally efficient than state-of-the-art coalescent simulations when simulating long regions, including whole-genome data. For shorter regions, efficiency and accuracy can be maintained via a flexible hybrid model which simulates the recent past under the Wright-Fisher model and uses coalescent simulations in the distant past.

evolutionary biology↗

bioRxiv2017

Genomic inferences of domestication events are corroborated by written records in Brassica rapa

Demographic modeling is often used with population genomic data to infer the relationships and ages among populations. However, relatively few analyses are able to validate these inferences with independent data. Here, we leverage written records that describe distinct Brassica rapa crops to corroborate demographic models of domestication. Brassica rapa crops are renowned for their outstanding morphological diversity, but the relationships and order of domestication remains unclear. We generated genome-wide SNPs from 126 accessions collected globally using high-throughput transcriptome data. Analyses of more than 31,000 SNPs across the B. rapa genome revealed evidence for five distinct genetic groups and supported a European-Central Asian origin of B. rapa crops. Our results supported the traditionally recognized South Asian and East Asian B. rapa groups with evidence that pak choi, Chinese cabbage, and yellow sarson are likely monophyletic groups. In contrast, the oil-type B. rapa subsp. oleifera and brown sarson were polyphyletic. We also found no evidence to support the contention that rapini is the wild type or the earliest domesticated subspecies of B. rapa. Demographic analyses suggested that B. rapa was introduced to Asia 2400-4100 years ago, and that Chinese cabbage originated 1200-2100 years ago via admixture of pak choi and European-Central Asian B. rapa. We also inferred significantly different levels of founder effect among the B. rapa subspecies. Written records from antiquity that document these crops are consistent with these inferences. The concordance between our age estimates of domestication events with historical records provides unique support for our demographic inferences.

genetics↗