Biology subjects

Mooney, J. A.

Publications and source records attributed to Mooney, J. A..

11 recordsLinked to original sources

bioRxiv2025

Analytical expectations for ancestry junction accumulation in admixed genomes

Complex demographic events have shaped human history and genetic variation across the genome. Here, we investigate the recent evolutionary history of admixed populations that descend from distinct ancestral sources. We present a discrete, generalizable model of admixture that leverages ancestry switches, which are recombination breakpoints that mark changes in ancestral origin along a chromosome. We derive analytical expectations for the number of ancestry switches within a genomic segment as functions of recombination rate, ancestry heterozygosity, and effective population size. We then extend these expectations to incorporate population-specific recombination maps. Our theoretical predictions are in close agreement with forward-in-time simulations that we use to trace ancestry junction accumulation since an initial admixture event with both constant and variable recombination models. We observe minimal variability in switch counts across ten simulation replicates, underscoring the robustness of the theoretical expectation. Furthermore, model-based switch counts, parameterized using literature-informed demographic values, agree with empirical observations from African American individuals in the 1000 Genomes Project. For example, when modeling human chromosome 1, we found a mean of approximately six switches per haplotype, which aligns with the theoretical expectation under an initial African ancestry proportion of 0.85, and agrees with published estimates from other African-American cohorts. Overall, the model provides a new route for using ancestry switches to understand how recombination and demography jointly shape ancestry patterns in admixed populations without requiring separation into parental sources.

evolutionary biology↗

bioRxiv2025

Neanderthal introgressed ancestry reveals human genomic regions enriched with recessive deleterious mutations

Negative selection on deleterious mutations plays a key role in shaping human genetic variation, yet the dominance effects of these mutations remain poorly understood because existing statistical methods often cannot distinguish dominance effects from the overall selective effects. In this work, we take a fundamentally different approach by leveraging the distribution of Neanderthal ancestry across the human genome. Simulations show that recessive deleterious mutations can increase archaic introgressed ancestry through heterosis in the absence of positive selection, in contrast to the depletion expected under additive effects. We use this signal to develop DominL, a machine learning classifier trained on simulations of human demography with Neanderthal introgression to identify megabase-scale genomic windows enriched with recessive mutations. DominL demonstrates robust accuracy, with particularly high power in exon-dense regions. Applied to 7 non-African populations from the 1000 Genomes Project, DominL identifies approximately 3-9% of the genome as enriched for recessive mutations, with most high-confidence regions shared across populations. Predicted regions show patterns consistent with expected signatures from recessive mutations, including weakened background selection, depletion of runs of homozygosity, and enrichment of non-additive trait-associated variants. These regions also contain genes associated with metabolic and immune-related functions.

evolutionary biology↗

bioRxiv2024

Divergent reference genomes compromise the reconstruction of demographic histories, selection scans, and population genetic summary statistics

Characterizing genetic variation in natural populations is vital to evolutionary biology, however many non-model species lack genomic resources. Here, we demonstrate that reference bias significantly affects population genomic analyses by mapping whole genome sequence data from gray foxes (Urocyon cinereoargenteus) to a conspecific reference and two heterospecific canid genomes (dog and Arctic fox). Mapping to the conspecific genome improved read pairing by [~]5%, detected 26-32% more SNPs, and 33-35% more singletons. Nucleotide diversity estimates increased over 30%, FST increased from 0.189 to 0.197, and effective population size estimates were 30-60% higher with the conspecific reference. Recombination rates varied by up to 3-fold at chromosome ends with heterospecific references. Importantly, FST outlier detection differed markedly, with heterospecific genomes identifying twice as many unique outlier windows. These findings highlight the impact of reference genome choice and the importance of conspecific genomic resources for accurate evolutionary inference. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/625554v2_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@1d717adorg.highwire.dtl.DTLVardef@537c85org.highwire.dtl.DTLVardef@1142d10org.highwire.dtl.DTLVardef@19a9f06_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA species-specific reference genome improves read mapping and variant detection C_LIO_LIReference bias underestimates genetic diversity and differentiation C_LIO_LIDivergent reference genomes distort demographic histories and recombination landscapes C_LIO_LIUnique FST outliers are detected across references, affecting functional interpretations C_LI

evolutionary biology↗

bioRxiv2024

Evolutionary consequences of domestication on the selective effects of new amino acid changing mutations in canids

The domestication of wild canids led to dogs no longer living in the wild but instead residing alongside humans. Extreme changes in behavior and diet associated with domestication may have led to the relaxation of the selective pressure on traits that may be less important in the domesticated context. Thus, here we hypothesize that strongly deleterious mutations may have become less deleterious in domesticated populations. We test this hypothesis by estimating the distribution of fitness effects (DFE) for new amino acid changing mutations using whole-genome sequence data from 24 gray wolves and 61 breed dogs. We find that the DFE is strikingly similar across canids, with 26-28% of new amino acid changing mutations being neutral/nearly neutral (|s| < 1e-5), and 41-48% under strong purifying selection (|s| > 1e-2). Our results are robust to different model assumptions suggesting that the DFE is stable across short evolutionary timescales, even in the face of putative drastic changes in the selective pressure caused by artificial selection during domestication and breed formation. On par with previous works describing DFE evolution, our data indicate that the DFE of amino acid changing mutations depends more strongly on genome structure and organismal characteristics, and less so on shifting selective pressures or environmental factors. Given the constant DFE and previous data showing that genetic variants that differentiate wolf and dog populations are enriched in regulatory elements, we speculate that domestication may have had a larger impact on regulatory variation than on amino acid changing mutations. Significance StatementDomestication of dogs to live alongside humans resulted in a dramatic shift in the pressures of natural selection. Thus, comparing dogs and wolves offers a unique opportunity to assess how these shifts in selective pressures have impacted the fitness effects of individual mutations. In this project, we use patterns of genetic variation in dogs and wolves to estimate the distribution of fitness effects (DFE), or the proportions of amino acid changing mutations with varying fitness effects throughout the genome. Overall, we find that the DFE for amino acid changing mutations is similar between dogs and wolves. Even genes thought to be most affected by domestication show a similar DFE, suggesting that the DFE has remained stable over evolutionary time.

genetics↗

bioRxiv2024

Recommendations for Population and Individual Diagnostic SNP Selection in Non-Model Species

Despite substantial reductions in the cost of sequencing over the last decade, genetic panels remain relevant due to their cost-effectiveness and flexibility across a variety of sample types. In particular, single nucleotide polymorphism (SNP) panels are increasingly favored for conservation applications. SNP panels are often used because of their adaptability, effectiveness with low-quality samples, and cost-efficiency for use in population monitoring and forensics. However, the selection of diagnostic SNPs for population assignment and individual identification can be challenging. The consequences of poor SNP selection are under-powered panels, inaccurate results, and monetary loss. Here, we develop a novel user-friendly SNP selection pipeline for population assignment and individual identification, mPCRselect. mPCRselect allows any researcher, who has sufficient SNP-level data, to design a successful and cost-effective SNP panel for species of conservation concern.

evolutionary biology↗

bioRxiv2024

Genotypic and phenotypic consequences of domestication in dogs

Runs of homozygosity (ROH) are genomic regions that arise when two copies of identical haplotypes are inherited from a shared common ancestor. In this study, we leverage ROH to identify associations between genetic diversity and non-disease phenotypes in Canis lupus familiaris (dogs). We find significant association between the ROH inbreeding coefficient (FROH) and several phenotypic traits. These traits include height, weight, lifespan, muscled, white coloring of the head and chest, furnishings, and fur length. After correcting for population structure, we identified more than 45 genes across the examined quantitative traits that exceed the threshold for suggestive significance. We observe distinct distributions of inbreeding and elevated levels of long ROH in modern breed dogs compared to more ancient breeds, which aligns with breeding practices during Victorian era breed establishment. Our results highlight the impact of non-additive variation and of polygenicity on complex quantitative phenotypes in dogs due to domestication and the breed formation bottleneck.

evolutionary biology↗

bioRxiv2024

Towards Simulation Optimization: An Examination of the Impact of Scaling on Coalescent and Forward Simulations

Scaling is a common practice in population genetic simulations to increase computational efficiency. However, there exists a dearth of standardized guidelines for best practices. Few studies have examined the effects of scaling on diversity and whether the results are directly comparable to unscaled and empirical data. We examine the effects of scaling in two model populations, modern humans and Drosophila melanogaster. The reason is twofold: 1) due to the substantial difference in population sizes and generation times, human populations require moderate-to-no scaling, while more dramatic scaling is required for Drosophila; and 2) model populations have empirical data for comparison. We determine whether coalescence, runtime, memory, estimates of diversity, the site frequency spectra, and deleterious variation are affected by scaling. We also explore the effect of varying the simulated segment length and burn-in times. We find that the typical 10N generation burn-in is often not sufficient for full coalescence to occur in human or Drosophila simulations. As expected, memory and runtime increase as the scaling coefficient decreases and the length of the simulated segment increases. We show that simulating larger segments in humans is preferable, as it produces a smaller variance in diversity estimates. Conversely, in Drosophila it is preferable to simulate smaller segments and concatenate them into full genome for achieving comparable levels of diversity to empirical data. We find that aggressive scaling leads to stronger negative selection and ultimately amplifies the strength of background selection on flanking variation. Author SummaryScaling is a common approach to make population genetic simulations more computationally tractable. However, the implications of scaling and best practices for scaling are still unknown. This study highlights the importance of carefully considering scaling practices for forward-in-time population genetics simulations. We provide insights about the trade-offs between computational efficiency and accuracy of scaled simulations relative to empirical data, in human and Drosophila. We achieved this by varying the species demographic model; the method of coalescence; the simulated genomic element length; and the scaling factor. For each combination of parameters genetic diversity was quantified and computational was efficiency tracked. Our findings suggest that when simulating populations, such as humans, where moderate scaling is required, one should simulate larger genomic segments for more accurate measures of diversity. Scaling seems to cause an inflation of diversity in human simulations relative to empirical data. On the other hand, in populations where more aggressive scaling is required, such as Drosophila, simulating smaller segments is advantageous. The scaling factor increases substantially in Drosophila studies, and the simulated data experiences a drastic drop in diversity, relative to empirical data, and an increased effect of purifying selection.

evolutionary biology↗

bioRxiv2024

Developmental hematopoietic stem cell variation explains clonal hematopoiesis later in life

Clonal hematopoiesis becomes increasingly common with age, but its cause is enigmatic because driver mutations are often absent. Serial observations infer weak selection indicating variants are acquired much earlier in life with unexplained initial growth spurts. Here we use fluctuating CpG methylation as a lineage marker to track stem cell clonal dynamics of hematopoiesis. We show, via the shared prenatal circulation of monozygotic twins, that weak selection conferred by stem cell variation created before birth can reliably yield clonal hematopoiesis later in life. Theory indicates weak selection will lead to dominance given enough time and large enough population sizes. Human hematopoiesis satisfies both these conditions. Stochastic loss of weakly selected variants is naturally prevented by the expansion of stem cell lineages during development. The dominance of stem cell clones created before birth is supported by blood fluctuating CpG methylation patterns that exhibit low correlation between unrelated individuals but are highly correlated between many elderly monozygotic twins. Therefore, clonal hematopoiesis driven by weak selection in later life appears to reflect variation created before birth.

systems biology↗

bioRxiv2023

What does the fox (genome) say? A chromosome-level assembly for the gray fox (Urocyon cinereoargenteus)

Reference genome assemblies have been created from multiple lineages within the Canidae family, however, despite its phylogenetic relevance as a basal genus within the clade, there is currently no reference genome for the gray fox (Urocyon cinereoargenteus). Here, we present a chromosome-level assembly for the gray fox (U. cinereoargenteus), which represents the most contiguous, non-domestic canid reference genome available to date, with 90% of the genome contained in just 34 scaffolds and a contig N50 and scaffold N50 of 59.4 and 72.9 Megabases (Mb), respectively. Repeat analyses identified an increased number of simple repeats relative to other canids. Based on mitochondrial DNA, our Vermont sample clusters with other gray fox samples from the northeastern US and contains slightly lower levels of heterozygosity than gray foxes on the west coast of California. This new assembly lays the groundwork for future studies to describe past and present population dynamics, including the delineation of evolutionarily significant units of management relevance. Importantly, the phylogenetic position of Urocyon allows us to verify the loss of PRDM9 functionality in the basal canid lineage, confirming that pseudogenization occurred at least 10 million years ago.

genomics↗

bioRxiv2023

Unraveling the Genomic Diversity and Evolutionary History of Captive Tigers in the United States

Genomic studies of rare and endangered species have focused broadly on describing diversity patterns and resolving phylogenetic relationships, with the overarching goal of informing conservation efforts. However, few studies have investigated the genomic diversity potentially housed in captive populations. For tigers (Panthera tigris) in particular, captive individuals vastly outnumber those in the wild, yet the diversity of the captive population remains largely unexplored. Here, we present the first large-scale genetic study of the private (non-zoo) captive tiger population in the United States (U.S.), also known as Generic tigers. We find that the U.S. Generic tiger population has an admixture fingerprint comprising all six extant wild tiger subspecies (P. t. altaica, Amur; P. t. tigris, Bengal; P. t. corbetti, Indochinese; P. t. jacksoni, Malayan; P. t. amoyensis, South China; P. t. sumatrae, Sumatran). We show that the Generic tiger population has a comparable amount of genetic diversity to most wild subspecies, relatively few private variants, and fewer deleterious mutations. We also observe inbreeding coefficients that are similar to wild populations, suggesting that inbreeding in captive populations is not pervasive, although there are some individuals within the Generic population that are substantially inbred. Our results elucidate the admixture history of the Generic tiger population in the U.S. Additionally, we develop a reference panel for tigers and show that it can be used with imputation to accurately distinguish individuals and assign ancestry even with ultra-low coverage (0.25x) data. The study and reference panel will provide a resource to assist in tiger conservation efforts.

evolutionary biology↗

bioRxiv2020

The impact of identity-by-descent on fitness and disease in natural and domesticated Canid populations

Domestic dogs have experienced population bottlenecks, recent inbreeding, and strong artificial selection. These processes have simplified the genetic architecture of complex traits, allowed deleterious variation to persist, and increased both identity-by-descent (IBD) segments and runs of homozygosity (ROH). As such, dogs provide an excellent model for examining how these evolutionary processes influence disease. We assembled a dataset containing 4,414 breed dogs, 327 village dogs, and 380 wolves genotyped at 117,288 markers and phenotype data for clinical and morphological phenotypes. Breed dogs have an enrichment of IBD and ROH, relative to both village dogs and wolves and we use these patterns to show that breed dogs have experienced differing severities of bottlenecks in their recent past. We then found that ROH burden is associated with phenotypes in breed dogs, such as lymphoma. We next test the prediction that breeds with greater ROH have more disease alleles reported in Online Mendelian Inheritance in Animals (OMIA). Surprisingly, the number of causal variants identified correlates with the popularity of that breed rather than the ROH or IBD burden, suggesting an ascertainment bias in OMIA. Lastly, we use the distribution of ROH across the genome to identify genes with depletions of ROH as potential hotspots for inbreeding depression and find multiple exons where ROH are never observed. Our results suggest that inbreeding has played a large role in shaping genetic and phenotypic variation in dogs, and that there remains an excess of understudied breeds that can reveal new disease-causing variation. Significance StatementDogs and humans have coexisted together for thousands of years, but it was not until the Victorian Era that humans practiced selective breeding to produce the modern standards we see today. Strong artificial selection during the breed formation period has simplified the genetic architecture of complex traits and caused an enrichment of identity-by-descent (IBD) segments in the dog genome. This study demonstrates the value of IBD segments and utilizes them to infer the recent demography of canids, predict case-control status for complex traits, locate regions of the genome potentially linked to inbreeding depression, and to identify understudied breeds where there is potential to discover new disease-associated variants.

genetics↗