Biology subjects

Boyko, A. R.

Publications and source records attributed to Boyko, A. R..

6 recordsLinked to original sources

bioRxiv2024

A genotype-first approach identifies variants for orofacial clefts and other phenotypes in dogs

Dog breeding promotes within-group homogeneity through conformation to strict breed standards, and also drives between-group heterogeneity in pursuit of characteristic breed traits. There are over 350 recognized dog breeds that provide the foundation for investigating the genetic basis of phenotypic diversity. Typically, breed standard phenotypes such as stature, fur length, and craniofacial structure are analyzed in genetic association studies. However, such analyses are limited to the assayed phenotypes, leaving difficult to measure phenotypic subtleties potentially overlooked. In this study, the genotype-first approach was adapted to the dog genome to investigate coding variation from over 2000 dogs, leading to discoveries of new mutations related to craniofacial morphology and stature. Breed-enriched variants were prioritized according to gene constraint, which was calculated using a mutation model derived from trinucleotide substitution probabilities in the dog. Among the discovered variants was a splice-acceptor mutation in PDGFRA associated with bifid nose, a characteristic trait of Catalburun dogs, implicating the genes role in midline closure, and a frameshift mutation in LCORL associated with large canine body size, thus highlighting the importance of allelic heterogeneity in selection for breed traits. Most priority variants were not associated with genomic signatures for breed differentiation, as these regions were enriched for constrained genes intolerant to nonsynonymous variation, suggesting a model of breed phenotype diversification based on regulatory changes to essential genes. Identification of trait-associated variants in dogs informs new biological roles for genes. Improved collection of breed disease risk data, along with increased breed representation, will drive further discoveries.

genomics↗

bioRxiv2020

Examination of the efficacy of small genetic panels in genomic conservation of companion animal populations

In many ways dogs are an ideal model for the study of genetic erosion and population recovery, problems of major concern in the field of conservation genetics. Genetic diversity in many dog breeds has been declining systematically since the beginning of the 1800s, when modern breeding practices came into fashion. As such, inbreeding in domestic dog breeds is substantial and widespread and has led to an increase in recessive deleterious mutations of high effect as well as general inbreeding depression. Pedigrees can in theory be used to guide breeding decisions, though are often incomplete and do not reflect the full history of inbreeding. Small microsatellite panels are also used in some cases to choose mating pairs to produce litters with low levels of inbreeding. However, the long-term impact of such practices have not been thoroughly evaluated. Here, we use forward simulation on a model of the dog genome to examine the impact of using limited markers panels to guide pairwise mating decisions on genome-wide population level genetic diversity. Our results suggest that in unsupervised mating schemes, where breeding decisions are made at the pairwise-rather than population-level, such panels can lead to accelerated loss of genetic diversity compared to random mating at regions of the genome unlinked to panel markers and demonstrate the importance of genome-wide genetic panels for managing and conserving genetic diversity in dogs and other companion animals.

evolutionary biology↗

bioRxiv2019

Imputation of canine genotype array data using 365 whole-genome sequences improves power of genome-wide association studies

Genomic resources for the domestic dog have improved with the widespread adoption of a 173k SNP array platform and updated reference genome. SNP arrays of this density are sufficient for detecting genetic associations within breeds but are underpowered for finding associations across multiple breeds or in mixed-breed dogs, where linkage disequilibrium rapidly decays between markers, even though such studies would hold particular promise for mapping complex diseases and traits. Here we introduce an imputation reference panel, consisting of 365 diverse, whole-genome sequenced dogs and wolves, which increases the number of markers that can be queried in genome-wide association studies approximately 130-fold. Using previously genotyped dogs, we show the utility of this reference panel in identifying novel associations and fine-mapping for canine body size and blood phenotypes, even when causal loci are not in strong linkage disequilibrium with any single array marker. This reference panel resource will improve future genome-wide association studies for canine complex diseases and other phenotypes. Author SummaryComplex traits are controlled by more than one gene and as such are difficult to map. For complex trait mapping in the domestic dog, researchers use the current array of 173,000 variants, with only minimal success. Here, we use a method called imputation to increase the number of variants - from 173,000 to 24 million - that can be queried in canine association studies. We use sequence data from the whole genomes of 365 dogs and wolves to accurately predict variants, in a separate cohort of dogs, that are not present on the array. Using dog body size, we show that the increase in variants results in an increase in mapping power, through the identification of new associations and the narrowing of regions of interest. This imputation panel is particularly important because of its usefulness in improving complex trait mapping in the dog, which has significant implications for discovery of variants in humans with similar diseases.

genomics↗

bioRxiv2018

Fine-scale resolution and analysis of runs of homozygosity in domestic dogs

Abstract/SummaryInbreeding and consanguinity leave distinct genomic traces, most notably long genomic tracts that are identical by descent and completely homozygous. These runs of homozygosity (ROH) can contribute to inbreeding depression if they contain deleterious variants that are fully or partially recessive. Several lines of evidence have been used to show that long (> 5 megabase (Mb)) ROH are disproportionately likely to harbor deleterious variation, but the extent to which long versus short tracts contribute to autozygosity at loci known to be deleterious and recessive has not been studied.\n\nIn domestic dogs, nearly 200 mutations are known to cause recessive diseases, most of which can be efficiently assayed using SNP arrays. By examining genome-wide data from over 200,000 markers, including 150 recessive disease variants, we built high-resolution ROH density maps for nearly 2,500 dogs, recording ROH down to 500 kilobases. We observed over 500 homozygous deleterious recessive genotypes in the panel, 90% of which overlapped with ROH inferred by GERMLINE. Although most of these genotypes were contained in ROH over 5 Mb in length, 14% were contained in short (0.5 - 2.5 Mb) tracts, a significant enrichment compared to the genetic background, suggesting that even short tracts are useful for computing inbreeding metrics like the coefficient of inbreeding estimated from ROH (FROH).\n\nIn our dataset, FROH differed significantly both within and among dog breeds. All breeds harbored some regions of reduced genetic diversity due to drift or selective sweeps, but the degree of inbreeding and the proportion of inbreeding caused by short versus long tracts differed between breeds, reflecting their different population histories. Although only available for a few species, large genome-wide datasets including recessive disease variants hold particular promise not only for disentangling the genetic architecture of inbreeding depression, but also evaluating and improving upon current approaches for detecting ROH.

genomics↗

bioRxiv2018

Direct-To-Consumer DNA testing of 6,000 dogs reveals 98.6-kb duplication causing blue eyes and heterochromia in Siberian Huskies

Consumer genomics enables genetic discovery on an unprecedented scale by linking very large databases of personal genomic data with phenotype information voluntarily submitted via web-based surveys1. These databases are having a transformative effect on human genomic research, yielding insights on increasingly complex traits, behaviors, and disease by including many thousands of individuals in genome-wide association studies (GWAS)2, 3. The promise of consumer genomic data is not limited to human research, however. Genomic tools for dogs are readily available, with hundreds of causal Mendelian variants already characterized4-6, because selection and breeding have led to dramatic phenotypic diversity underlain by a simple genetic structure7, 8. Here, we report the results of the first consumer genomics study ever conducted in a non-human model: a GWAS of blue eyes based on more than 3,000 customer dogs with a validation panel of nearly 3,000 more, the largest canine GWAS to date. We discovered a novel association with blue eyes on chromosome 18 (P = 1x10-65) and used both sequence coverage and microarray probe intensity data to identify the putative causal variant: a 98.6-kb duplication directly upstream of the hox gene ALX4, which plays an important role in mammalian eye development9, 10. This duplication was largely restricted to Siberian Huskies and is highly, but not completely, penetrant. These results underscore the power of consumer-data-driven discovery in nonhuman species, especially dogs, where there is intense owner interest in the personal genomic information of their pets, a high level of engagement with web-based surveys, and an underlying genetic architecture ideal for mapping studies.

bioinformatics↗

bioRxiv2017

Selective sweep analysis using village dogs highlights the pivotal role of the neural crest in dog domestication

BackgroundDogs (Canis lupus familiaris) were domesticated from gray wolves between 10-40 kya in Eurasia, yet details surrounding the process of domestication remain unclear. The vast array of phenotypes exhibited by dogs mirror other domesticated animal species, a phenomenon known as the Domestication Syndrome. Here, we use signatures persisting in the dog genome to identify genes and pathways altered by the intensive selective pressures of domestication.\n\nResultsWe identified 246 candidate domestication regions containing 10.8Mb of genome sequence and 178 genes through whole-genome SNP analysis of 43 globally distributed village dogs and 10 wolves. Comparisons with ancient dog genomes suggest that these regions reflect signatures of domestication rather than breed formation. The strongest hit is located in the Retinoic Acid-Induced 1 (RAI1) gene, mutations of which cause Smith-Magenis syndrome. The identified regions contain a significant enrichment of genes linked to neural crest cell migration, differentiation and development. Read depth analysis suggests that copy number variation played a minor role in dog domestication.\n\nConclusionOur results indicate that phenotypes distinguishing domesticated dogs from wolves, such as tameness, smaller jaws, floppy ears, and diminished craniofacial development, are determined by genes which act early in embryogenesis. These differences are all phenotypes of the Domestication Syndrome, which can be explained by decreases in neural crest cells at these sites. We propose that initial selection during early dog domestication was for behavior, a trait also influenced by genes which act in the neural crest, which secondarily gave rise to the phenotypes of modern dogs.

evolutionary biology↗