Biology subjects

Myers, S. R.

Publications and source records attributed to Myers, S. R..

7 recordsLinked to original sources

bioRxiv2026

Joint dog and wolf genealogies reveal the evolution of the canine genome

Dogs and their closest extant relative, the grey wolf, diverged around 30k years ago, but have since experienced complex histories of gene flow involving other canids, adaptive pressures due to close association with humans, and changing climates. We infer joint genealogies of dogs, grey wolves, and a coyote using available whole genomes to reconstruct the evolutionary forces shaping the dog genome. These genealogies reveal multiple strong mutation-rate pulses unique to dogs, including signals detectable across ancient dogs from the past 10,000 years. We further detect pervasive genealogical signatures of purifying selection and find that GC-biased gene conversion is a major driver of diversity patterns around gene promoters in dogs. We introduce a new genealogy-based selection scan, TwigScan, that computes time-stratified differentiation, increasing power over traditional FST-based approaches. Applying this framework, alongside a second single-population test for detecting more recent selection within dogs, we identify multiple known and novel loci with signatures of positive selection. Among these, the region surrounding the amylase 2B locus shows evidence of introgression from a deeply divergent, unsampled canid lineage with divergence comparable to that of dholes. AMY2B duplications appear to occur exclusively on this introgressed haplotype which increased in frequency approximately 7,000-8,000 years ago, coinciding with increased reliance on starch-rich diets in human populations. Together, these results show how mutation-rate variation, gene conversion, selection, and inter-species gene flow have jointly shaped the dog genome, highlighting the power of genealogical approaches for resolving complex evolutionary histories.

evolutionary biology↗

bioRxiv2026

Genome-wide genealogies reveal deep admixtures forming modern humans

Over the past decade, genomic modelling has revealed a rich tapestry of admixtures shaping present-day human populations. These have largely focused on the past few thousand years, when ancestral populations are either well characterised by present-day genomic diversity or directly observed through ancient DNA. Genomic modelling and fossil evidence have so far only provided a fragmented picture of the coexistence and mixing of human groups in the deeper past. Here, we propose a new method, GhostBuster, that leverages inferred genome-wide genealogies to detect admixture events of unsampled ghost populations, while simultaneously inferring accurate local ancestry. Local ancestry enables us to identify ancestry-specific genomic signatures that independently corroborate the events. We identify at least three waves of "back-to-Africa" migrations starting [~]14,000 years ago. Applying GhostBuster to deeper timescales reveals that modern humans were shaped by repeated episodes of mixture. Around 50,000 years ago, we identify a human lineage that expanded to form present-day non-Africans, while also expanding within Africa, mixing with the other local African group in varying proportions. These ancient groups help explain polygenic score portability differences within Africa, and exhibit differences in population size and recombination landscapes. Extending our analysis further back to between 300,000 and 1 million years ago reveals two deeply diverged ancestral lineages. These lineages evolved profoundly different recombination landscapes, with different PRDM9 alleles (PRDM9-A and C) and recombination hotspots. We demonstrate that both Neanderthals and ancestral modern humans are formed through a mixture of these two lineages, with no evidence of gene flow from the PRDM9-A-carrying group into Denisovans.

evolutionary biology↗

bioRxiv2023

Leveraging fine-scale population structure reveals conservation in genetic effect sizes between human populations across a range of human phenotypes

An understanding of genetic differences between populations is essential for avoiding confounding in genome-wide association studies (GWAS) and understanding the evolution of human traits. Polygenic risk scores constructed in one group perform poorly in highly genetically-differentiated populations, for reasons which remain controversial. We developed a statistical ancestry inference pipeline able to decompose ancestry both within and between countries, and applied it to the UK Biobank data. This identifies fine-scale patterns of genetic relatedness not captured by standard and widely used principal components (PCs), and allows fine-scale population stratification correction that removes both false positive and false negative associations for traits with geographic correlations. We also develop and apply ANCHOR, an approach leveraging segments of distinct ancestries within individuals to estimate similarity in underlying causal effect sizes between groups, using an existing PGS. Applying ANCHOR to >8000 people of mixed African and European ancestry, we demonstrate that estimated causal effect sizes are highly similar across these ancestries for 26 of 29 quantitative molecular and non-molecular phenotypes (mean correlation 0.98 +/-0.08), providing evidence that gene-environment and gene-gene interactions do not play major roles in the poor prediction of European-ancestry PRS scores in African populations for these traits, contradicting previous findings. Instead our results provide optimism that shared causal mutations operate similarly in different groups, focussing the challenge of improving GWAS "portability" between groups on joint fine-mapping.

genetics↗

bioRxiv2023

The distribution of branch duration and detection of inversions in ancestral recombination graphs

Recent breakthroughs have enabled the accurate inference of large-scale genealogies. Through modelling the impact of recombination on the correlation structure between genealogical local trees, we evaluate how this structure is reconstructed by leading approaches. Despite identifying pervasive biases, we show that applying a simple correction recovers the desired distributions for one algorithm, Relate. We develop a statistical test to identify clades spanning unexpectedly long genomic regions, likely reflecting regional suppression of recombination in some individuals. Our approach allows a systematic scan for inter-individual recombination rate variation at an intermediate scale, between genome-wide differences and individual hotspots. Using genealogies reconstructed with Relate for 2 504 human genomes, we identify 50 regions possessing clades with unexpectedly long genomic spans (p < 1 {middle dot} 10-12). The strongest signal corresponds to a known inversion on chromosome 17. The second strongest uncovers a novel 760kb inversion on chromosome 10, common (21%) in S. Asians and correlated with GWAS hits for a range of phenotypes. Other regions indicate additional genomic rearrangements: inversions (8), copy number changes (2), or other variants (12). The remaining regions appear to reflect recombination suppression by previously unevidenced mechanisms. They are enriched for precisely spanning single genes (p = 5 10-10), specifically those expressed in male gametogenesis, and for eQTLs (p = 2 {middle dot}10-3). This suggests an extension of previously hypothesised crossover suppression within meiotic genes, towards a model of suppression varying across individuals with different expression levels. Our methods can be readily applied to other species, showing that genealogies offer previously un-tapped potential to study structural variation and other phenomena impacting evolution.

evolutionary biology↗

bioRxiv2019

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

During meiosis, homologous chromosomes pair (synapse) and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, recombination initiates with double-strand breaks (DSBs) within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have yet been identified.\n\nWe identified Zcwpw1, which possesses H3K4me3 and H3K36me3 recognition domains, as highly co-expressed with Prdm9. Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognizes CpG dinucleotides, including within many Alu transposons.\n\nMale Zcwpw1 homozygous knockout mice show completely normal DSB positioning, but persistent DMC1 foci at many hotspots, particularly those more strongly bound by PRDM9, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest a model where ZCWPW1 recognition of PRDM9-bound sites on either the homologous, or broken, chromosome is critical for synapsis, and hence fertility.\n\nGraphical Abstract LegendIn humans and other species, recombination is initiated by double strand breaks at sites bound by PRDM9. Upon binding, PRDM9 deposits the histone marks H3K4me3 and H3K36me, but the functional importance of these marks has remained unknown. Here, we show that PRDM9 recruits ZCWPW1, a reader of both these marks, to its binding sites genome-wide. ZCWPW1 does not help position the breaks themselves, but is essential for their downstream repair and chromosome pairing, and ultimately meiotic success and fertility in mice.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC=\"FIGDIR/small/821678v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (31K):\norg.highwire.dtl.DTLVardef@141deb9org.highwire.dtl.DTLVardef@18559deorg.highwire.dtl.DTLVardef@1cf380borg.highwire.dtl.DTLVardef@1689072_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2018

A high-resolution map of non-crossover events in mice reveals impacts of genetic diversity on meiotic recombination

During meiotic recombination in most mammals, hundreds of programmed DNA Double-Strand Breaks (DSBs) occur across all chromosomes in each cell at sites bound by the protein PRDM9. Faithful DSB repair using the homologous chromosome is essential for fertility, yielding either non-crossovers, which are frequent but difficult to detect, or crossovers. In certain hybrid mice, high sequence divergence causes PRDM9 to bind each homologue at different sites, \"asymmetrically\", and these mice exhibit meiotic failure and infertility, by unknown mechanisms. To investigate the impact of local sequence divergence on recombination, we intercrossed two mouse subspecies over five generations and deep-sequenced 119 offspring, whose high heterozygosity allowed detection of thousands of crossover and non-crossover events with unprecedented power and spatial resolution. Both crossovers and non-crossovers are strongly depleted at individual asymmetric sites, revealing that PRDM9 not only positions DSBs but also promotes their homologous repair by binding to the unbroken homologue at each site. Unexpectedly, we found that non-crossovers containing multiple mismatches repair by a different mechanism than single-mismatch sites, which undergo GC-biased gene conversion. These results demonstrate that local genetic diversity profoundly alters meiotic repair pathway decisions via at least two distinct mechanisms, impacting genome evolution and Prdm9-related hybrid infertility.

genetics↗

bioRxiv2017

Human PRDM9 Can Bind And Activate Promoters, And Other Zinc-Finger Proteins Associate With Reduced Recombination In cis

Across mammals, PRDM9 binding localizes almost all meiotic recombination hotspots. However, most PRDM9 motif sequence matches are not bound, and most PRDM9-bound loci do not become hotspots. To explore factors that affect binding and subsequent recombination outcomes, we mapped human and chimp PRDM9 binding sites in a human cell line, and measured PRDM9-induced H3K4me3 and gene expression changes. These data revealed varied DNA-binding modalities of PRDM9, and histone modifications that predict binding. At sites where PRDM9 binds, specific cis sequence motifs associated with TRIM28 recruitment, and histone modifications, predict whether recombination subsequently occurs. These results implicate the large family of KRAB-ZNF genes in consistent, localized meiotic recombination suppression. PRDM9 affects gene expression for a small number of genes including CTCFL and VCX, by binding nearby. Finally, we show that PRDM9s DNA-binding zinc finger domain strongly impacts the formation of multimers, with a pair of highly diverged alleles multimerizing less efficiently.

genetics↗