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  • 1
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    The contribution of historical processes to contemporary extinction risk in placental mammals
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 380, No. 6643 ( 2023-04-28)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6643 ( 2023-04-28)
    Abstract: The Anthropocene is marked by an accelerated loss of biodiversity, widespread population declines, and a global conservation crisis. Given limited resources for conservation intervention, an approach is needed to identify threatened species from among the thousands lacking adequate information for status assessments. Such prioritization for intervention could come from genome sequence data, as genomes contain information about demography, diversity, fitness, and adaptive potential. However, the relevance of genomic data for identifying at-risk species is uncertain, in part because genetic variation may reflect past events and life histories better than contemporary conservation status. RATIONALE The Zoonomia multispecies alignment presents an opportunity to systematically compare neutral and functional genomic diversity and their relationships to contemporary extinction risk across a large sample of diverse mammalian taxa. We surveyed 240 species spanning from the “Least Concern” to “Critically Endangered” categories, as published in the International Union for Conservation of Nature’s Red List of Threatened Species. Using a single genome for each species, we estimated historical effective population sizes ( N e ) and distributions of genome-wide heterozygosity. To estimate genetic load, we identified substitutions relative to reconstructed ancestral sequences, assuming that mutations at evolutionarily conserved sites and in protein-coding sequences, especially in genes essential for viability in mice, are predominantly deleterious. We examined relationships between the conservation status of species and metrics of heterozygosity, demography, and genetic load and used these data to train and test models to distinguish threatened from nonthreatened species. RESULTS Species with smaller historical N e are more likely to be categorized as at risk of extinction, suggesting that demography, even from periods more than 10,000 years in the past, may be informative of contemporary resilience. Species with smaller historical N e also carry proportionally higher burdens of weakly and moderately deleterious alleles, consistent with theoretical expectations of the long-term accumulation and fixation of genetic load under strong genetic drift. We found weak support for a causative link between fixed drift load and extinction risk; however, other types of genetic load not captured in our data, such as rare, highly deleterious alleles, may also play a role. Although ecological (e.g., physiological, life-history, and behavioral) variables were the best predictors of extinction risk, genomic variables nonrandomly distinguished threatened from nonthreatened species in regression and machine learning models. These results suggest that information encoded within even a single genome can provide a risk assessment in the absence of adequate ecological or population census data. CONCLUSION Our analysis highlights the potential for genomic data to rapidly and inexpensively gauge extinction risk by leveraging relationships between contemporary conservation status and genetic variation shaped by the long-term demographic history of species. As more resequencing data and additional reference genomes become available, estimates of genetic load, estimates of recent demographic history, and accuracy of predictive models will improve. We therefore echo calls for including genomic information in assessments of the conservation status of species. Genomic information can help predict extinction risk in diverse mammalian species. Across 240 mammals, species with smaller historical N e had lower genetic diversity, higher genetic load, and were more likely to be threatened with extinction. Genomic data were used to train models that predict whether a species is threatened, which can be valuable for assessing extinction risk in species lacking ecological or census data. [Animal silhouettes are from PhyloPic]
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abn5856
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 2
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    Evolutionary constraint and innovation across hundreds of placental mammals
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 380, No. 6643 ( 2023-04-28)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6643 ( 2023-04-28)
    Abstract: A major challenge in genomics is discerning which bases among billions alter organismal phenotypes and affect health and disease risk. Evidence of past selective pressure on a base, whether highly conserved or fast evolving, is a marker of functional importance. Bases that are unchanged in all mammals may shape phenotypes that are essential for organismal health. Bases that are evolving quickly in some species, or changed only in species that share an adaptive trait, may shape phenotypes that support survival in specific niches. Identifying bases associated with exceptional capacity for cellular recovery, such as in species that hibernate, could inform therapeutic discovery. RATIONALE The power and resolution of evolutionary analyses scale with the number and diversity of species compared. By analyzing genomes for hundreds of placental mammals, we can detect which individual bases in the genome are exceptionally conserved (constrained) and likely to be functionally important in both coding and noncoding regions. By including species that represent all orders of placental mammals and aligning genomes using a method that does not require designating humans as the reference species, we explore unusual traits in other species. RESULTS Zoonomia’s mammalian comparative genomics resources are the most comprehensive and statistically well-powered produced to date, with a protein-coding alignment of 427 mammals and a whole-genome alignment of 240 placental mammals representing all orders. We estimate that at least 10.7% of the human genome is evolutionarily conserved relative to neutrally evolving repeats and identify about 101 million significantly constrained single bases (false discovery rate 〈 0.05). We cataloged 4552 ultraconserved elements at least 20 bases long that are identical in more than 98% of the 240 placental mammals. Many constrained bases have no known function, illustrating the potential for discovery using evolutionary measures. Eighty percent are outside protein-coding exons, and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Constrained bases tend to vary less within human populations, which is consistent with purifying selection. Species threatened with extinction have few substitutions at constrained sites, possibly because severely deleterious alleles have been purged from their small populations. By pairing Zoonomia’s genomic resources with phenotype annotations, we find genomic elements associated with phenotypes that differ between species, including olfaction, hibernation, brain size, and vocal learning. We associate genomic traits, such as the number of olfactory receptor genes, with physical phenotypes, such as the number of olfactory turbinals. By comparing hibernators and nonhibernators, we implicate genes involved in mitochondrial disorders, protection against heat stress, and longevity in this physiologically intriguing phenotype. Using a machine learning–based approach that predicts tissue-specific cis - regulatory activity in hundreds of species using data from just a few, we associate changes in noncoding sequence with traits for which humans are exceptional: brain size and vocal learning. CONCLUSION Large-scale comparative genomics opens new opportunities to explore how genomes evolved as mammals adapted to a wide range of ecological niches and to discover what is shared across species and what is distinctively human. High-quality data for consistently defined phenotypes are necessary to realize this potential. Through partnerships with researchers in other fields, comparative genomics can address questions in human health and basic biology while guiding efforts to protect the biodiversity that is essential to these discoveries. Comparing genomes from 240 species to explore the evolution of placental mammals. Our new phylogeny (black lines) has alternating gray and white shading, which distinguishes mammalian orders (labeled around the perimeter). Rings around the phylogeny annotate species phenotypes. Seven species with diverse traits are illustrated, with black lines marking their branch in the phylogeny. Sequence conservation across species is described at the top left. IMAGE CREDIT: K. MORRILL
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abn3943
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 3
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    Three-dimensional genome rewiring in loci with human accelerated regions
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 380, No. 6643 ( 2023-04-28)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6643 ( 2023-04-28)
    Abstract: Human accelerated regions (HARs) are evolutionarily conserved sequences that acquired an unexpectedly high number of nucleotide substitutions in the human genome since divergence from our common ancestor with chimpanzees. Prior work has established that many HARs are gene regulatory enhancers that function during embryonic development, particularly in neurodevelopment, and that most HARs show signatures of positive selection. However, the events that caused the sudden change in selective pressures on HARs remain a mystery. RATIONALE Because HARs acquired many substitutions in our ancestors after millions of years of extreme constraint across diverse mammals, we reasoned that their conserved roles in regulating development of the brain and other organs must have changed during human evolution. One mechanism that could drive such a functional shift is enhancer hijacking, whereby the target gene repertoire of a noncoding sequence is changed through alterations in three-dimensional genome folding. The regulatory information encoded in a hijacked enhancer would likely need to change to avoid deleterious expression of the altered target gene while also possibly supporting modified expression patterns. Structural variants—large genomic insertions, deletions, and rearrangements—are the greatest sources of sequence differences between the human and chimpanzee genomes, and they have the potential to affect how a region of the genome folds and localizes in the nucleus. We therefore hypothesized that some HARs were generated through enhancer hijacking triggered by nearby human-specific structural variants (hsSVs). RESULTS We leveraged an alignment of hundreds of mammalian genomes plus a Nextflow pipeline that we wrote for automating the detection of lineage-specific accelerated regions to identify 312 high-confidence HARs (zooHARs). Through massively parallel reporter assays and machine learning integration of hundreds of epigenomic datasets, we showed that many zooHARs function as neurodevelopmental enhancers and that their human substitutions alter transcription factor binding sites, consistent with previous studies. We further mapped zooHARs to specific cell types and tissues using single-cell open chromatin and gene expression data, and we found that they represent a more diverse set of neurodevelopmental processes than a parallel set of chimpanzee accelerated regions. To test the enhancer hijacking hypothesis, we first examined the three-dimensional neighborhoods of zooHARs using publicly available chromatin capture (Hi-C) data, finding a significant enrichment of zooHARs in domains with hsSVs. This motivated us to use deep learning to predict how hsSVs changed genome folding in the human versus the chimpanzee genomes. We found that 30% of zooHARs occur within 500 kb of an hsSV that substantially alters local chromatin interactions, and we confirmed this association in Hi-C data that we generated in human and chimpanzee neural progenitor cells. Finally, we showed that chromatin domains containing zooHARs and hsSVs are enriched for genes differentially expressed in human versus chimpanzee neurodevelopment. CONCLUSION The origin of many HARs may be explained by human-specific structural variants that altered three-dimensional genome folding, causing evolutionarily conserved enhancers to adapt to different target genes and regulatory domains. Example of HAR enhancer hijacking. The HAR is nearby and regulates gene A, but not gene B, as the chimpanzee genome folds. An insertion in the human genome brings the HAR closer to gene B, causing expression of gene B. The HAR adapts to being in gene B’s regulatory domain through substitutions to previously conserved nucleotides.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abm1696
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 4
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    A genomic timescale for placental mammal evolution
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 380, No. 6643 ( 2023-04-28)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6643 ( 2023-04-28)
    Abstract: Resolving the role that different environmental forces may have played in the apparent explosive diversification of modern placental mammals is crucial to understanding the evolutionary context of their living and extinct morphological and genomic diversity. RATIONALE Limited access to whole-genome sequence alignments that sample living mammalian biodiversity has hampered phylogenomic inference, which until now has been limited to relatively small, highly constrained sequence matrices often representing 〈 2% of a typical mammalian genome. To eliminate this sampling bias, we used an alignment of 241 whole genomes to comprehensively identify and rigorously analyze noncoding, neutrally evolving sequence variation in coalescent and concatenation-based phylogenetic frameworks. These analyses were followed by validation with multiple classes of phylogenetically informative structural variation. This approach enabled the generation of a robust time tree for placental mammals that evaluated age variation across hundreds of genomic loci that are not restricted by protein coding annotations. RESULTS Coalescent and concatenation phylogenies inferred from multiple treatments of the data were highly congruent, including support for higher-level taxonomic groupings that unite primates+colugos with treeshrews (Euarchonta), bats+cetartiodactyls+perissodactyls+carnivorans+pangolins (Scrotifera), all scrotiferans excluding bats (Fereuungulata), and carnivorans+pangolins with perissodactyls (Zooamata). However, because these approaches infer a single best tree, they mask signatures of phylogenetic conflict that result from incomplete lineage sorting and historical hybridization. Accordingly, we also inferred phylogenies from thousands of noncoding loci distributed across chromosomes with historically contrasting recombination rates. Throughout the radiation of modern orders (such as rodents, primates, bats, and carnivores), we observed notable differences between locus trees inferred from the autosomes and the X chromosome, a pattern typical of speciation with gene flow. We show that in many cases, previously controversial phylogenetic relationships can be reconciled by examining the distribution of conflicting phylogenetic signals along chromosomes with variable historical recombination rates. Lineage divergence time estimates were notably uniform across genomic loci and robust to extensive sensitivity analyses in which the underlying data, fossil constraints, and clock models were varied. The earliest branching events in the placental phylogeny coincide with the breakup of continental landmasses and rising sea levels in the Late Cretaceous. This signature of allopatric speciation is congruent with the low genomic conflict inferred for most superordinal relationships. By contrast, we observed a second pulse of diversification immediately after the Cretaceous-Paleogene (K-Pg) extinction event superimposed on an episode of rapid land emergence. Greater geographic continuity coupled with tumultuous climatic changes and increased ecological landscape at this time provided enhanced opportunities for mammalian diversification, as depicted in the fossil record. These observations dovetail with increased phylogenetic conflict observed within clades that diversified in the Cenozoic. CONCLUSION Our genome-wide analysis of multiple classes of sequence variation provides the most comprehensive assessment of placental mammal phylogeny, resolves controversial relationships, and clarifies the timing of mammalian diversification. We propose that the combination of Cretaceous continental fragmentation and lineage isolation, followed by the direct and indirect effects of the K-Pg extinction at a time of rapid land emergence, synergistically contributed to the accelerated diversification rate of placental mammals during the early Cenozoic. The timing of placental mammal evolution. Superordinal mammalian diversification took place in the Cretaceous during periods of continental fragmentation and sea level rise with little phylogenomic discordance (pie charts: left, autosomes; right, X chromosome), which is consistent with allopatric speciation. By contrast, the Paleogene hosted intraordinal diversification in the aftermath of the K-Pg mass extinction event, when clades exhibited higher phylogenomic discordance consistent with speciation with gene flow and incomplete lineage sorting.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abl8189
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 5
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    ​Comparative genomics of Balto, a famous historic dog, captures lost diversity of 1920s sled dogs
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 380, No. 6643 ( 2023-04-28)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6643 ( 2023-04-28)
    Abstract: It has been almost 100 years since the sled dog Balto helped save the community of Nome, Alaska, from a diphtheria outbreak. Today, Balto symbolizes the indomitable spirit of the sled dog. He is immortalized in statue and film, and is physically preserved and on display at the Cleveland Museum of Natural History. Balto represents a dog population that was reputed to tolerate harsh conditions at a time when northern communities were reliant on sled dogs. Investigating Balto’s genome sequence using technologies for sequencing degraded DNA offers a new perspective on this historic population. RATIONALE Analyzing high-coverage (40.4-fold) DNA sequencing data from Balto through comparison with large genomic data resources offers an opportunity to investigate genetic diversity and genome function. We leveraged the genome sequence data from 682 dogs, including both working sled dogs and dog breeds, as well as evolutionary constraint scores from the Zoonomia alignment of 240 mammals, to reconstruct Balto’s phenotype and investigate his ancestry and what might distinguish him from modern dogs. RESULTS Balto shares just part of his diverse ancestry with the eponymous Siberian husky breed and was more genetically diverse than both modern breeds and working sled dogs. Both Balto and working sled dogs had a lower burden of rare, potentially damaging variation than modern breeds and fewer potentially damaging variants, suggesting that they represent genetically healthier populations. We inferred Balto’s appearance on the basis of genomic variants known to shape physical characteristics in dogs today. We found that Balto had a combination of coat features atypical for modern sled dog breeds and a slightly smaller stature, inferences that are confirmed by comparison to historical photographs. Balto’s ability to digest starch was enhanced compared to wolves and Greenland sled dogs but reduced compared to modern breeds. He carried a compendium of derived homozygous coding variants at constrained positions in genes connected to bone and skin development, which may have conferred a functional advantage. CONCLUSION Balto belonged to a population of small, fast, and fit sled dogs imported from Siberia. By sequencing his genome from his taxidermied remains and analyzing these data in the context of large comparative and canine datasets, we show that Balto and his working sled dog contemporaries were more genetically diverse than modern breeds and may have carried variants that helped them survive the harsh conditions of 1920s Alaska. Although the era of Balto and his contemporaries has passed, comparative genomics, supported by a growing collection of modern and past genomes, can provide insights into the selective pressures that shaped them. Balto, famed 20th-century Alaskan sled dog, shares common ancestry with modern Asian and Arctic canine lineages. In an unsupervised admixture analysis, Balto’s ancestry, representing 20th-century Alaskan sled dogs, is assigned predominantly to four Arctic lineage dog populations. He had no discernable wolf ancestry. The Alaskan sled dogs (a working population) did not fall into a distinct ancestry cluster but shared about a third of their ancestry with Balto in the supervised admixture analysis. Balto and working sled dogs carried fewer constrained and missense rare variants than modern dog breeds. IMAGE CREDIT: K. MORRILL
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abn5887
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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    A quantitative framework for characterizing the evolutionary history of mammalian gene expression
    Cold Spring Harbor Laboratory ; 2019
    In:  Genome Research Vol. 29, No. 1 ( 2019-01), p. 53-63
    Details
    In: Genome Research, Cold Spring Harbor Laboratory, Vol. 29, No. 1 ( 2019-01), p. 53-63
    Abstract: The evolutionary history of a gene helps predict its function and relationship to phenotypic traits. Although sequence conservation is commonly used to decipher gene function and assess medical relevance, methods for functional inference from comparative expression data are lacking. Here, we use RNA-seq across seven tissues from 17 mammalian species to show that expression evolution across mammals is accurately modeled by the Ornstein–Uhlenbeck process, a commonly proposed model of continuous trait evolution. We apply this model to identify expression pathways under neutral, stabilizing, and directional selection. We further demonstrate novel applications of this model to quantify the extent of stabilizing selection on a gene's expression, parameterize the distribution of each gene's optimal expression level, and detect deleterious expression levels in expression data from individual patients. Our work provides a statistical framework for interpreting expression data across species and in disease.
    Type of Medium: Online Resource
    ISSN: 1088-9051 , 1549-5469
    URL: Article
    DOI: 10.1101/gr.237636.118
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    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2019
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    Using evolutionary constraint to define novel candidate driver genes in medulloblastoma
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 33 ( 2023-08-15)
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    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 33 ( 2023-08-15)
    Abstract: Current knowledge of cancer genomics remains biased against noncoding mutations. To systematically search for regulatory noncoding mutations, we assessed mutations in conserved positions in the genome under the assumption that these are more likely to be functional than mutations in positions with low conservation. To this end, we use whole-genome sequencing data from the International Cancer Genome Consortium and combined it with evolutionary constraint inferred from 240 mammals, to identify genes enriched in noncoding constraint mutations (NCCMs), mutations likely to be regulatory in nature. We compare medulloblastoma (MB), which is malignant, to pilocytic astrocytoma (PA), a primarily benign tumor, and find highly different NCCM frequencies between the two, in agreement with the fact that malignant cancers tend to have more mutations. In PA, a high NCCM frequency only affects the BRAF locus, which is the most commonly mutated gene in PA. In contrast, in MB, 〉 500 genes have high levels of NCCMs. Intriguingly, several loci with NCCMs in MB are associated with different ages of onset, such as the HOXB cluster in young MB patients. In adult patients, NCCMs occurred in, e.g., the WASF-2/AHDC1/FGR locus. One of these NCCMs led to increased expression of the SRC kinase FGR and augmented responsiveness of MB cells to dasatinib, a SRC kinase inhibitor. Our analysis thus points to different molecular pathways in different patient groups. These newly identified putative candidate driver mutations may aid in patient stratification in MB and could be valuable for future selection of personalized treatment options.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2300984120
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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    Chiropterans Are a Hotspot for Horizontal Transfer of DNA Transposons in Mammalia
    Oxford University Press (OUP) ; 2023
    In:  Molecular Biology and Evolution Vol. 40, No. 5 ( 2023-05-02)
    Details
    In: Molecular Biology and Evolution, Oxford University Press (OUP), Vol. 40, No. 5 ( 2023-05-02)
    Abstract: Horizontal transfer of transposable elements (TEs) is an important mechanism contributing to genetic diversity and innovation. Bats (order Chiroptera) have repeatedly been shown to experience horizontal transfer of TEs at what appears to be a high rate compared with other mammals. We investigated the occurrence of horizontally transferred (HT) DNA transposons involving bats. We found over 200 putative HT elements within bats; 16 transposons were shared across distantly related mammalian clades, and 2 other elements were shared with a fish and two lizard species. Our results indicate that bats are a hotspot for horizontal transfer of DNA transposons. These events broadly coincide with the diversification of several bat clades, supporting the hypothesis that DNA transposon invasions have contributed to genetic diversification of bats.
    Type of Medium: Online Resource
    ISSN: 0737-4038 , 1537-1719
    URL: Article
    DOI: 10.1093/molbev/msad092
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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    Ancestry-inclusive dog genomics challenges popular breed stereotypes
    American Association for the Advancement of Science (AAAS) ; 2022
    In:  Science Vol. 376, No. 6592 ( 2022-04-29)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 376, No. 6592 ( 2022-04-29)
    Abstract: Before the 1800s, dogs were probably primarily selected for functional roles such as hunting, guarding, and herding. Modern dog breeds are a recent invention defined by conformation to a physical ideal and purity of lineage. Breeds are commonly ascribed temperaments and behavioral proclivities based on the purported function of the ancestral source population. By extension, the breed ancestry of individual dogs is assumed to be predictive of temperament and behavior. Through our community science project Darwin’s Ark ( darwinsark.org ), we enrolled a diverse cohort of pet dogs to explore how genetics shapes complex behavioral traits in this exceptional natural model. RATIONALE Dogs are a natural system for investigating the genetics of complex traits. Millions of pet dogs live in human homes, sharing our environment, and receive sophisticated medical care. Behavioral disorders are treated with human psychiatric drugs, achieving similar response rates, and genetic studies suggest shared etiology with some human psychiatric conditions. We developed Darwin’s Ark as an open data resource for collecting owner-reported phenotypes and genetic data and invited any dog owner to enroll their dog. We paired this with low-pass sequencing to capture nearly all common variation in this outbred population. Our inclusive approach achieved the large samples needed to investigate complex traits. RESULTS We surveyed owners of 18,385 dogs (49% purebred) and sequenced the DNA of 2155 dogs. Most behavioral traits are heritable [heritability ( h 2 ) 〉 25%], but behavior only subtly differentiates breeds. Breed offers little predictive value for individuals, explaining just 9% of variation in behavior. For more heritable, more breed-differentiated traits, like biddability (responsiveness to direction and commands), knowing breed ancestry can make behavioral predictions somewhat more accurate (see the figure). For less heritable, less breed-differentiated traits, like agonistic threshold (how easily a dog is provoked by frightening or uncomfortable stimuli), breed is almost uninformative. We used dogs of mixed breed ancestry to test the genetic effect of breed ancestry on behavior and compared that to survey responses from purebred dog owners. For some traits, like biddability and border collie ancestry, we confirm a genetic effect of breed that aligns with survey responses. For others, like human sociability and Labrador retriever ancestry, we found no significant effect. Through genome-wide association, we found 11 regions that are significantly associated with behavior, including howling frequency and human sociability, and 136 suggestive regions. Regions associated with aesthetic traits are unusually differentiated in breeds, consistent with a history of selection, but those associated with behavior are not. CONCLUSION In our ancestrally diverse cohort, we show that behavioral characteristics ascribed to modern breeds are polygenic, environmentally influenced, and found, at varying prevalence, in all breeds. We propose that behaviors perceived as characteristic of modern breeds derive from thousands of years of polygenic adaptation that predates breed formation, with modern breeds distinguished primarily by aesthetic traits. By embracing the full diversity of dogs—including purebred dogs, mixed-breed dogs, purpose-bred working dogs, and village dogs—we can fully realize dogs’ long-recognized potential as a natural model for genetic discovery. Effect of breed on behavior. ( A ) Biddability is among eight behavioral factors defined from surveys. SE, standard error. ( B ) Dogs in some breeds tend to score unusually high or low for this factor compared with dogs overall. ( C and D ) Border collies score lower on average for biddability (vertical line at median) but vary widely (C), including genetically confirmed border collies (D). ( E ) In mixed-breed dogs, border collie ancestry has a small genetic effect on biddability. [Photo credits: K. Wirka (Sprocket); M. Wisniewski (Caboose); B. Hoadley (Molly); M. Logsdon (Hunter); A. Macias (Lily); S. Staples (TWooie)]
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abk0639
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
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    Leveraging base-pair mammalian constraint to understand genetic variation and human disease
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 380, No. 6643 ( 2023-04-28)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6643 ( 2023-04-28)
    Abstract: Thousands of genetic variants have been associated with human diseases and traits through genome-wide association studies (GWASs). Translating these discoveries into improved therapeutics requires discerning which variants among hundreds of candidates are causally related to disease risk. To date, only a handful of causal variants have been confirmed. Here, we leverage 100 million years of mammalian evolution to address this major challenge. RATIONALE We compared genomes from hundreds of mammals and identified bases with unusually few variants (evolutionarily constrained). Constraint is a measure of functional importance that is agnostic to cell type or developmental stage. It can be applied to investigate any heritable disease or trait and is complementary to resources using cell type– and time point–specific functional assays like Encyclopedia of DNA Elements (ENCODE) and Genotype-Tissue Expression (GTEx). RESULTS Using constraint calculated across placental mammals, 3.3% of bases in the human genome are significantly constrained, including 57.6% of coding bases. Most constrained bases (80.7%) are noncoding. Common variants (allele frequency ≥ 5%) and low-frequency variants (0.5% ≤ allele frequency 〈 5%) are depleted for constrained bases (1.85 versus 3.26% expected by chance, P 〈 2.2 × 10 −308 ). Pathogenic ClinVar variants are more constrained than benign variants ( P 〈 2.2 × 10 −16 ). The most constrained common variants are more enriched for disease single-nucleotide polymorphism (SNP)–heritability in 63 independent GWASs. The enrichment of SNP-heritability in constrained regions is greater (7.8-fold) than previously reported in mammals and is even higher in primates (11.1-fold). It exceeds the enrichment of SNP-heritability in nonsynonymous coding variants (7.2-fold) and fine-mapped expression quantitative trait loci (eQTL)–SNPs (4.8-fold). The enrichment peaks near constrained bases, with a log-linear decrease of SNP-heritability enrichment as a function of the distance to a constrained base. Zoonomia constraint scores improve functionally informed fine-mapping. Variants at sites constrained in mammals and primates have greater posterior inclusion probabilities and higher per-SNP contributions. In addition, using both constraint and functional annotations improves polygenic risk score accuracy across a range of traits. Finally, incorporating constraint information into the analysis of noncoding somatic variants in medulloblastomas identifies new candidate driver genes. CONCLUSION Genome-wide measures of evolutionary constraint can help discern which variants are functionally important. This information may accelerate the translation of genomic discoveries into the biological, clinical, and therapeutic knowledge that is required to understand and treat human disease. Using evolutionary constraint in genomic studies of human diseases. ( A ) Constraint was calculated across 240 mammal species, including 43 primates (teal line). ( B ) Pathogenic ClinVar variants ( N = 73,885) are more constrained across mammals than benign variants ( N = 231,642; P 〈 2.2 × 10 −16 ). ( C ) More-constrained bases are more enriched for trait-associated variants (63 GWASs). ( D ) Enrichment of heritability is higher in constrained regions than in functional annotations (left), even in a joint model with 106 annotations (right). ( E ) Fine-mapping (PolyFun) using a model that includes constraint scores identifies an experimentally validated association at rs1421085. Error bars represent 95% confidence intervals. BMI, body mass index; LF, low frequency; PIP, posterior inclusion probability.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abn2937
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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    SSG: 11
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