Biology subjects

Davies, R. W.

Publications and source records attributed to Davies, R. W..

10 recordsLinked to original sources

bioRxiv2024

Rapid and accurate genotype imputation from low coverage short read, long read, and cell free DNA sequence

Inexpensive and accurate genotyping methods are essential to modern genomics and health risk prediction. Here we introduce QUILT2, a scalable read-aware imputation method that can efficiently use biobank scale haplotype reference panels. This allows for fast and accurate imputation using short reads, as well as long reads (e.g. ONT 1X r2 = 0.937 at common SNPs), linked-reads and ancient DNA. In addition, QUILT2 contains a methodological innovation that enables imputation of the maternal and fetal genome using cell free non-invasive prenatal testing (NIPT) data. Using a UK Biobank reference panel, we see accurate imputation of both mother (r2 = 0.966) and fetus (r2 = 0.465) at 0.25X (fetal fraction of 10%, common SNPs). Imputation gets increasingly accurate as coverage increases, with r2 of around 0.90 or above for both mother and fetus at 4.0X (mother r2 = 0.996, fetal r2 = 0.894). We show that this imputation enables powerful GWAS and accurate PRS for both mother and fetus, which creates both clinical opportunities, and if phenotypes can be collected alongside clinical NIPT, the potential for large GWAS.

bioinformatics↗

bioRxiv2023

The temporal recovery of contralateral and ipsilateral knee extensor torque following a bout of unilateral knee extensor resistance exercise in young, healthy resistance-trained men

The present study aimed to characterise the temporal recovery pattern of contralateral-homologous torque following a bout of unilateral resistance exercise (RE). Ten young, healthy, recreationally active, resistance-trained men performed 10 sets of 10 repetitions of knee extensor (KE) contractions at 50 % 1RM with 1 min rest between sets. Isometric maximal voluntary contraction (MVC) peak torque (PT), surface electromyography (sEMG), muscle soreness and serum creatine kinase (CK) levels were assessed immediately before and 5 min after RE cessation, and then +4 h, +24 h, +48 h and +72 h later. Data are presented as mean [95 % CI] % change from pre-exercise values. RE evoked a minor increase in CK and pain in the late recovery period (+24 h to +72 h) (P < 0.034) and decreases in ipsilateral KE PT were observed immediately post-exercise (-26 [-33, -18] %, P < 0.001) and up to +48 h (-12 [-19, -4] %, P = 0.006). Measurable decreases in PT were also observed in the non-exercised contralateral KE immediately post-exercise (-8 [-13, -3] %, P = 0.006) up to +24 h (-8 [-15, 0] %, P = 0.020), but were significantly lower than the ipsilateral KE PT (P < 0.05). These findings suggest the presence of crossover fatigue following RE in young, healthy, active, resistance-trained men, however, the magnitude and temporal recovery are substantially less severe and protracted in the contralateral homologous KE.

physiology↗

bioRxiv2023

Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes

BackgroundUntranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length of UTRs and the composition of regulatory elements within them are known to vary substantially across genes, but little is known about the reasons for this variation in humans. Here, we set out to determine whether this variation, specifically in 5UTRs, correlates with gene dosage sensitivity. ResultsWe investigated 5UTR length, the number of alternative transcription start sites, the potential for alternative splicing, the number and type of upstream open reading frames (uORFs) and the propensity of 5UTRs to form secondary structures. We explored how these elements vary by gene tolerance to loss-of-function (LoF; using the LOEUF metric), and in genes where changes in dosage are known to cause disease. We show that LOEUF correlates with 5UTR length and complexity. Genes that are most intolerant to LoF have longer 5UTRs (P<1x10-15), greater TSS diversity (P<1x 10-15), and more upstream regulatory elements than their LoF tolerant counterparts. We show that these differences are evident in disease gene-sets, but not in recessive developmental disorder genes where LoF of a single allele is tolerated. ConclusionsOur results confirm the importance of post-transcriptional regulation through 5UTRs in tight regulation of mRNA and protein levels, particularly for genes where changes in dosage are deleterious and lead to disease. Finally, to support gene-based investigation we release a web-based browser tool, VuTR (https://vutr.rarediseasegenomics.org/), that supports exploration of the composition of individual 5UTRs and the impact of genetic variation within them.

genomics↗

bioRxiv2022

The PREGCARE study: Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Next-generation sequencing has led to a dramatic improvement in molecular diagnoses of serious pediatric disorders caused by apparently de novo mutations (DNMs); by contrast, clinicians ability to counsel the parents about the risk of recurrence in a future child has lagged behind. Owing to the possibility that one of the parents could be mosaic in their germline, a recurrence risk of 1-2% is frequently quoted, but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk stratification, by combining deep-sequencing of multiple tissues in the mother-father-child trio with haplotyping to determine the parental origin of the DNM. In the first 58 couples analysed (total of 59 DNMs in 49 different genes), the risk for 35 (59%) DNMs was decreased below 0.1% but for 6 (10%) couples it was increased owing to parental mosaicism - that could be quantified in semen (recurrence risks of 5.6-12.1%) for the paternal cases. Deep-sequencing of the DNM efficiently identifies couples at greatest risk for recurrence and may qualify them for additional reproductive technologies. Haplotyping can further reassure many other couples that their recurrence risk is very low, but its implementation is more technically challenging and will require better understanding of how couples respond to information that reduces their risks.

genetics↗

bioRxiv2021

Inferring population histories for ancient genomes using genome-wide genealogies

Ancient genomes anchor genealogies in directly observed historical genetic variation, and contextualise ancestral lineages with archaeological insights into their geography and lifestyles. We introduce an extension of the Relate algorithm to incorporate ancient genomes and reconstruct the joint genealogies of 14 previously published high-coverage ancients and 278 present-day individuals of the Simons Genome Diversity Project. As the majority of ancient genomes are of lower coverage and cannot be directly built into genealogies, we additionally present a fast and scalable method, Colate, for inferring coalescence rates between low-coverage genomes without requiring phasing or imputation. Our method leverages sharing patterns of mutations dated using a genealogy to construct a likelihood, which is maximised using an expectation-maximisation algorithm. We apply Colate to 430 ancient human shotgun genomes of >0.5x mean coverage. Using Relate and Colate, we characterise dynamic population structure, such as repeated partial population replacements in Ireland, and gene-flow between early farmer and European hunter-gatherer groups. We further show that the previously reported increase in the TCC/TTC mutation rate, which is strongest in West Eurasians among present-day people, was already widespread across West Eurasia in the Late Glacial Period ~10k - 15k years ago, is strongest in Neolithic and Anatolian farmers, and is remarkably well predicted by the coalescence rates between other genomes and a 10,000-year-old Anatolian individual. This suggests that the driver of this signal originated in ancestors of ancient Anatolia >14k years ago, but was already absent by the Mesolithic and may indicate a genetic link between the Near East and European hunter-gatherer groups in the Late Paleolithic.

genomics↗

bioRxiv2021

Analysis of independent cohorts of outbred CFW mice reveals novel loci for behavioral and physiological traits and identifies factors determining reproducibility

Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3,076 commercially available outbred mice and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6 and GM11545 with bone mineral density, and Psmb9 with weight. However replication at a nominal threshold of 0.05 between the two component studies was surprisingly low, with less than a third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winners Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Available methods to control Winners Curse were contingent on the power of the discovery sample, and depending on the method used, both overestimated and underestimated the true effect. Leveraging these observations we integrated information about replication rates, confounding, and Winners Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility, and demonstrates how to obtain robust results from mapping complex traits in any genome-wide association study.

bioinformatics↗

bioRxiv2020

Haplotype tagging reveals parallel formation of hybrid races in two butterfly species

Genetic variation segregates as linked sets of variants, or haplotypes. Haplotypes and linkage are central to genetics and underpin virtually all genetic and selection analysis. And yet, genomic data often lack haplotype information, due to constraints in sequencing technologies. Here we present "haplotagging", a simple, low-cost linked-read sequencing technique that allows sequencing of hundreds of individuals while retaining linkage information. We apply haplotagging to construct megabase-size haplotypes for over 600 individual butterflies (Heliconius erato and H. melpomene), which form overlapping hybrid zones across an elevational gradient in Ecuador. Haplotagging identifies loci controlling distinctive high- and lowland wing color patterns. Divergent haplotypes are found at the same major loci in both species, while chromosome rearrangements show no parallelism. Remarkably, in both species the geographic clines for the major wing pattern loci are displaced by 18 km, leading to the rise of a novel hybrid morph in the centre of the hybrid zone. We propose that shared warning signalling (Mullerian mimicry) may couple the cline shifts seen in both species, and facilitate the parallel co-emergence of a novel hybrid morph in both co-mimetic species. Our results show the power of efficient haplotyping methods when combined with large-scale sequencing data from natural populations. One-sentence summaryHaplotagging, a novel linked-read sequencing technique that enables whole genome haplotyping in large populations, reveals the formation of a novel hybrid race in parallel hybrid zones of two co-mimicking Heliconius butterfly species through strikingly parallel divergences in their genomes.

evolutionary biology↗

bioRxiv2020

Private Genomes and Public SNPs: Homomorphic encryption of genotypes and phenotypes for shared quantitative genetics

Sharing human genotype and phenotype data presents a challenge because of privacy concerns, but is essential in order to discover otherwise inaccessible genetic associations. Here we present a method of homomorphic encryption that obscures individuals genotypes and phenotypes and is suited to quantitative genetic association analysis. Encrypted ciphertext and unencrypted plaintext are interchangeable from an analytical perspective. This allows one to store ciphertext on public web services and share data across multiple studies, while maintaining privacy. The encryption method uses as its key a high-dimensional random linear orthogonal transformation that leaves the likelihood of quantitative trait data unchanged under a linear model with normally distributed errors. It also preserves linkage disequilibrium between genetic variants and associations between variants and phenotypes. It scrambles relationships between individuals: encrypted genotype dosages closely resemble Gaussian deviates, and in fact can be replaced by quantiles from a Gaussian with only negligible effects on accuracy. Standard likelihood-based inferences are unaffected by orthogonal encryption. These include the use of mixed linear models to control for unequal relatedness between individuals, the estimation of heritability, and the inclusion of covariates when testing for association. Orthogonal transformations can also be applied in a modular fashion that permits multi-party federated mega-analyses. Under this scheme any number of parties first agree to share a common set of genotype sites and covariates prior to encryption. Each party then privately encrypts and shares their own ciphertext, and analyses the other parties ciphertexts. In the absence of private variants, or knowledge of the key, we show that it is infeasible to decrypt ciphertext using existing brute-force or noise reduction attacks. Therefore, we present the method as a challenge to the community to determine its security.

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↗

bioRxiv2018

Stronger and higher proportion of beneficial amino acid changing mutations in humans compared to mice and flies

Quantifying and comparing the amount of adaptive evolution among different species is key to understanding evolutionary processes. Previous studies have shown differences in adaptive evolution across species; however, their specific causes remain elusive. Here, we use improved modeling of weakly deleterious mutations and the demographic history of the outgroup species and ancestral population and estimate that at least 20% of nonsynonymous substitutions between humans and an outgroup species were fixed by positive selection. This estimate is much higher than previous estimates, which did not correct for the sizes of the outgroup species and ancestral population. Next, we directly estimate the proportion and selection coefficients (p+ and s+, respectively) of newly arising beneficial nonsynonymous mutations in humans, mice, and Drosophila melanogaster by examining patterns of polymorphism and divergence. We develop a novel composite likelihood framework to test whether these parameters differ across species. Overall, we reject a model with the same p+ and s+ of beneficial mutations across species, and estimate that humans have a higher p+s+ compared to D. melanogaster and mice. We demonstrate that this result cannot be caused by biased gene conversion or hypermutable CpG sites. In summary, we find the proportion of beneficial mutations to be higher in humans than in D. melanogaster or mice, suggesting that organismal complexity, which increases the number of steps required in adaptive walks, may be a key predictor of the amount of adaptive evolution within a species.

evolutionary biology↗