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Cite: Wang, Guo-dong, et al. “The genomics of selection in dogs and the parallel evolution between dogs and humans.” Nature Communications 4 (2013): 1860.

To the left is a figure which illustrates the phylogenetic inferences from a new paper in Nature Communications, The genomics of selection in dogs and the parallel evolution between dogs and humans (see Carl Zimmer’s coverage in The New York Times). Why is this paper important? The first thing that jumped out at me is that because they’re using whole genomes (~10X coverage) of a selection of dogs and wolves the results aren’t as subject to the bias of using “chips” of polymorphisms discovered in dogs on wolves (see: Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication). The second aspect is that the coalescence of the dog vs. wolf lineage is pushed further back in time than earlier genetic work, by a factor of three. A standard model for the origin of dogs is that they arose in the Middle East ~10,000-15,000 years ago , possibly as part of the broad shift of lifestyles which culminated in the Neolithic Revolution.

This model is now in serious question. Though there have always been claims of fossils of older domestic canids (adduced as such in terms of morphology) than the ones discovered in the Middle East ~15,000 years ago, this year there has been publication of ancient mtDNA results from ~30,000 years before the present which imply the separation of putative domestic and wolf lineages at least to that date. Over the past few years I have wondered about the specific nature of the emergence of both modern humans and modern dogs, and their co-evolutionary trajectory, over the Pleistocene and into the Holocene, in light of these results.

So the preponderance of data (genomic and archaeological) leans me toward accepting the general shape and >15,000 year B.P. date for the divergence of dog and wolf lineages outlined by the authors. But there is a lot more in terms of the phylogenetics of the paper which I am not willing to agree with as so obvious and clear. In particular, the authors support a Chinese/Southeast Asian origin for the dog, rather than a Middle Eastern one. This position is backed up by the reality that the Southeast Asian dog lineages do seem quite genetically diverse, and basal to other dogs (i.e., they diverge first within the clade of domestic dogs). Additionally, in the paper itself they note that the PCA, which visualizes genetic distance, suggests that the East Asian lineages are somewhat shifted toward the wolf. Model based clustering also implies that East Asian lineages are “more wolf.”

The reason I don’t buy this conjecture is as they say in the paper itself modern distributions and relationships don’t always map onto ancient distributions and relationships. We’ve already gotten into trouble doing this for human populations of similar time depth as the new putative period of dog domestication. Ancient DNA has uncovered a great deal of discordance between the past and present. I don’t expect dogs to be any different. The authors have whole genomes of a dozen animals. When the data set is expanded to hundreds with reasonable geographic coverage let’s talk. They attempt to model some gene flow, but I suspect that this is a major problem when talking about regions of origin of a group of organisms whose divergence from the ancestral outgroup is not quite clear in its nature.

Human directed breeding. Credit: Galabwebdesign.

But, a bigger point which has less to do with the zone of origination of the dog is the mode of the origination “event.” In the paper the authors present a stark model of the classic origination event for dogs, where Ice Age hunter-gatherers adopt some puppies, and this population exhibits a sharp and punctuated divergence from the main line of the wolves. These genetic data don’t indicate that at all. Rather, the “bottleneck” as very mild, if you could call it a bottleneck (see: Vulcans through the eye of the bottleneck). Certainly some inbred modern lineages have gone through bottlenecks, but this was long subsequent to the initial separation of dog and wolf. Rather, the authors put forward an alternative hypothesis where dogs were co-existent with early man, with a subset of wolves who were happy to scavenge on the margins of human settlements. There are variations and flavors of this sort of argument, but you can bracket them as the “self domestication” model. The reality here is that I think our explicit differentiation between forms of selection is wrongheaded, the primary issue isn’t whether dogs were self-domesticated or human-domesticated, but the rate of adaptation and demographic history. It may be that the best way to think about the origin of dogs and humans isn’t that the latter domesticated the former, but that both dogs and humans changed together as their lifestyles and interactions changed. With the rise of agriculture and increased specialization of human lifestyles there occurred a concomitant diversification of dogs.

And that is where I think the second part of the paper, focusing on parallel adaptations on the genomic level, is really interesting.

If you don’t want to click the image above, it seems that genes involved in neurological function, metabolism, and cancer are enriched in terms of signals of selection in domestic dogs. This is not surprising. Dogs exhibit great life history differences from wolves (they breed more, and are not pair bonded), and famously may be able to read human faces despite being less intelligent than wolves. And of course dogs have to eat what we eat, at least to some extent.

To understand this functional aspect of the evolutionary history of dogs though one does have to nail the phylogenetics down. So there will no doubt be more coming down the pipeline in this domain, and within the next few years the natural history of man’s best friend will be of deep interest. As ancient DNA has revolutionized the understanding of the human past, I suspect there will be attempts to analyze samples from dogs as well (though I assume that the data sets will always be thinner because scholars have always been preoccupied with human remains).

Citation: Wang, Guo-dong, et al. “The genomics of selection in dogs and the parallel evolution between dogs and humans.” Nature Communications 4 (2013): 1860.

(Republished from Discover/GNXP by permission of author or representative)
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The Pith: Wolves and coyotes exhibit geographic population structure. The red wolf may “only” be a coyote with a minor admixture of wolf, instead of a “real species.”

I like dogs. For various structural reasons I am not able to live with a dog right now (not to mention the required investment of time & energy). But the whole military dog storyline associated with the killing of Osama Bin Laden has me thinking a bit more deeply of the co-evolutionary nature of dog-human relationships. Whether dogs have theory-of-mind is controversial, but there’s no doubt that they’re relatively well adapted to operate with humans relatively efficiently as part of a dual-species team. From an evolutionary and genomic perspective dogs are also of interest. Like humans dogs exhibit a huge range of phenotypic variation despite relatively recent common origin. The species which they presumably are derived from, wolves, are intelligent social creatures whose natural range is very expansive indeed. I believe that the general dynamics of evolution and genetics which are operative amongst canids can give us insight into the processes which shape our own species. In part that is due to broad similarities across the two lineages, but in part it is because the story of dogs and the story of humans are not separate, but part of a broader bio-cultural narrative which has played out over the last 50,000 years. So you better be sure that my eyes lit up when I saw this new paper in Genome Research, A genome-wide perspective on the evolutionary history of enigmatic wolf-like canids. It’s a huge sample of canids from across the world, surveyed on ~50,000 single nucelotide polymorphisms (at least at locations which are SNPs in domestic dogs). The whole standard panoply of PCA and model free ancestry inference tools which we are familiar with from human genomics is now applied to canids in this paper. First, let’s hit the abstract:

High-throughput genotyping technologies developed for model species can potentially increase the resolution of demographic history and ancestry in wild relatives. We use a SNP genotyping microarray developed for the domestic dog to assay variation in over 48K loci in wolf-like species worldwide. Despite the high mobility of these large carnivores, we find distinct hierarchical population units within gray wolves and coyotes that correspond with geographic and ecologic differences among populations. Further, we test controversial theories about the ancestry of the Great Lakes wolf and red wolf using an analysis of haplotype blocks across all 38 canid autosomes. We find that these enigmatic canids are highly admixed varieties derived from gray wolves and coyotes, respectively. This divergent genomic history suggests that they do not have a shared recent ancestry as proposed by previous researchers. Interspecific hybridization, as well as the process of evolutionary divergence, may be responsible for the observed phenotypic distinction of both forms. Such admixture complicates decisions regarding endangered species restoration and protection.

The figure to the left shows the distribution of samples within this study. Though eastern Eurasia seems under-sampled they’ve got North America and western Eurasia covered. The primary focus is on North American wolves and coyotes, with domestic dogs and Eurasian wolves as outgroups. Part of the reason that this population mix is necessary is that the SNPs are biased toward those which are informative of population structure in dogs, because these markers vary within dogs. The further you get genetically from dogs (e.g., golden jackal) the less informative these SNPs are going to be. Of the North American canids there is a special focus on the Great Lakes wolf and the red wolf, because there have long been debates about the distinctiveness of these two (sub)species, and there’s a clear public policy ramification in terms of the Endangered Species Act.

Below is a PCA plot which shows the relationship between population clusters along the two largest components of genetic variation in the data. To my surprise the largest dimension separates domestic dogs from all the wild canids:

And to the surprise of the authors, and my own frankly, wolves seem to show a lot of geographically correlated population structure. Look at how cleanly Spanish and Italian wolves separate. The strong distinction between these groups may be a relic of the last Ice Age, when these two peninsular populations were genetically isolated. It’s surprising because if there’s one things wolves can do, it’s disperse. Interestingly the red wolf of the American southeast clusters relatively close to the coyotes! And of the other wolves the Great Lakes wolves are the closest to the coyotes.

One thing to remember is that an individual’s position in these plots can be informative of population wide genetic relationships, or they can be informative of their particular admixture. To get a handle on these particular details the authors looked at two statistics, linkage disequilibrium and runs-of-homozygosity. To be short about it the latter is the best way to check for inbreeding, while the former can give one clues to recent admixture. The figure below shows the results for selected populations. IRNP = Isle Royal National Park in Lake Superior. This is a very isolated population of wolves.

The IRNP is a classic island population which is inbred. It has elevated LD and ROH. The other populations exhibit a variety of results, but the the Mexican and red wolf also exhibit inbreeding or some sort of population bottleneck, though not nearly as much as the IRNP population.

So let’s see what structure tells us. The nice little visualization below shows the relationship of various populations as one ascends up the K’s of structure. On the far left you have coyotes, and far right you have dogs. You see some natural patterns, dogs leaving first, then coyotes, and then Old World wolves. Observe that the red wolf has a strong affinity with coyotes, followed by the Great Lakes wolves.

These sorts of algorithms must be viewed with caution, but this group cross-checked them with PCA. The alignment is impressive. After this they also did a finer-grained chromosomal analysis of admixture patterns. They observed that the Great Lakes wolves exhibited a rather wide range of variation in the extent of their minor coyote component. Some individuals were nearly 100% wolf, while others were nearly 50% coyote. The red wolf seems to be predominantly coyote, while coyotes themselves have wolf and dog ancestry. Time scales of admixture were inferred to be in the range of centuries to nearly 1,000 years, with the assumption that there were earlier admixture events.

This is perhaps problematic. The ESA protects species, so what gets labeled a species is a matter of great contention. The red wolf may be a stabilized hybrid of relatively recent vintage (or perhaps more accurately a back-cross to coyotes from a wolf-coyote hybrid population?). The authors also note that that ironically the red wolf as we know it, on the brink of extinction but brought back through proactive captive breeding, may have been selected for the more wolf-like individuals within the population. So the preconception of the researchers may have changed the nature of the species on a genetic and phenotypic level.

We’re going to get into the thickets really quickly at this rate. I think the big picture is that we shouldn’t fetishize purity of lineage. Another interesting implication of the possibility of long term hybridization is that some of the distinctive alleles of extinct American wolf populations may now only be found in coyotes, since this species was much better at surviving human encroachment. And if wolves went extinct tomorrow, we could reconstruct them from what we find within coyotes I’d think.

Citation: Vonholdt BM, Pollinger JP, Earl DA, Knowles JC, Boyko AR, Parker H, Geffen E, Pilot M, Jedrzejewski W, Jedrzejewska B, Sidorovich V, Greco C, Randi E, Musiani M, Kays R, Bustamante CD, Ostrander EA, Novembre J, & Wayne RK (2011). A genome-wide perspective on the evolutionary history of enigmatic wolf-like canids. Genome research PMID: 21566151

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Dog Genetics, Evolution, Genetics, Genomics 
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Szusza_pekingeseA major issue in human genomics over the past few years has been the case of the “missing heritability“. Roughly, we know that for many traits, such as height, most of the variation in the trait within the population is controlled by variation in the genes of the population. The height of your parents is an extremely good predictor of your height in a developed nation. If you’re adopted, the height of your biological parents is an extremely good predictor of your height in a developed nation, not the height of your adoptive parents. Though a new paper claims to have resolved some of the difficulty, one of the major issues in human height genetics has been the lack of large effect quantitative trait locus. In plain English, a gene which can explain a lot of the variation in the trait. Rather, many have posited that continuous quantitative traits like height are controlled by variation in innumerable common genes of small effect size, or, by innumerable rare genes of large effect size. The same may be an issue with personality genetics, or so is claimed by a recent paper unable to find common variants (though an eminent geneticist pointed out in the comments some problems with the paper itself). One would assume that the same problem would crop up across the tree of life. But a geneticist once told me that he considered biology the science where all rules have exceptions. Many exceptions. A new paper in PLoS Biology paints a fundamentally different picture of the genetic architecture of many morphological traits in the domestic dog, A Simple Genetic Architecture Underlies Morphological Variation in Dogs:

Dogs offer a unique system for the study of genes controlling morphology. DNA from 915 dogs from 80 domestic breeds, as well as a set of feral dogs, was tested at over 60,000 points of variation and the dataset analyzed using novel methods to find loci regulating body size, head shape, leg length, ear position, and a host of other traits. Because each dog breed has undergone strong selection by breeders to have a particular appearance, there is a strong footprint of selection in regions of the genome that are important for controlling traits that define each breed. These analyses identified new regions of the genome, or loci, that are important in controlling body size and shape. Our results, which feature the largest number of domestic dogs studied at such a high level of genetic detail, demonstrate the power of the dog as a model for finding genes that control the body plan of mammals. Further, we show that the remarkable diversity of form in the dog, in contrast to some other species studied to date, appears to have a simple genetic basis dominated by genes of major effect.

The paper uses powerful statistical and computational techniques, but the main results are relatively straightforward (assuming you don’t get stressed out by terms such as “random effect in the linear mixed model”). First, they delved a little into the evolutionary history and the general topography of the genomics of various dog breeds, wolves, as well as stray “village dogs” (I assume these are simply these are like the “pariah dogs” of India). Though village dogs had domestic ancestors they’ve gone feral, so they’re an interesting contrast with the new breeds created since the 19th century, as well as the wild ancestors of all dogs, wolves.

Three statistics were used to explore demographic history: linkage disequilibrium (LD), runs of homozygosity (ROH), and haplotype diversity. Inbred individuals have many ROH. They may have one individual show up relatively recently in their ancestry over and over, so it makes sense that they’d have many loci where both copies of the gene are identical by descent and state. Obviously purebred dogs have high ROH. They also have low haplotype diversity. Even the average person on the street is familiar with the freakish inbreeding which goes into the production of many purebred canine lineages, and their lower life expectancy vis a vis the maligned “mutt.” LD decayed much more quickly in wolves than in the dogs, village and purebred. Remember that LD indicates correlations of alleles across loci. It can be caused by selection at a SNP, which rises in frequency so quickly that huge swaths of the adjacent genome of that particular SNP “hitchhike” along before recombination can break up the association to too great an extent. Admixture between very distinctive populations can also produce LD, which again will decay with time due to recombination. Finally, another way LD can occur is through bottlenecks, which like positive selection can increase particular gene frequencies and their associated genomic regions rather rapidly through stochastic processes. It is the last dynamic which probably applies to all dogs: they went through a major population bottleneck during the domestication process, so the genomic pattern spans village and purebred lineages since it is an echo of their common history. Finally haplotype diversity is simply ascertaining the diversity of haplotypes across particular genomic windows. An interesting find in these results is that village dogs actually have lower ROH and higher haplotype diversity than wolves. That suggests that the wolves in this sample went through a major population bottleneck, while village dogs have maintained a larger effective population.

A general finding from the aforementioned examination is that different breeds tended to be genetically rather distinct. This follows naturally from the origin of modern purebreds as tight and distinct inbred lineages. This genome-wide distinctiveness though is a perfect background condition to test for similarities within the genome which correlate with specific morphological similarities across the breeds. And they did find quite a bit:

We searched for the strongest signals of allelic sharing by scanning for extreme values of Wright’s population differentiation statistic FST…cross the breeds. The 11 most extreme FST regions of the dog genome contained SNPs with FST≥0.57 and minor allele frequency (MAF [major allele frequency -Razib])≥0.15 (Table 1). Six of these regions are strongly linked to genetic variants known to affect canine morphology: the 167 bp insertion in RSPO2 associated with the fur growth and texture…an IGF1 haplotype associated with reduced body size…an inserted retrogene (fgf4) associated with short-leggedness…and three genes known to affect coat color in dogs (ASIP, MC1R, and MITF…Two other high FST regions correspond to CFA10.11465975 and CFA1.97045173, which were associated with body weight and snout proportions, respectively, in previous association studies….Two known coat phenotypes (fur length and fur curl…) also exhibited extreme FST values. Only a limited number of high FST regions were not associated with a known morphological trait (Figure 2, black labels). Here, we focus on illuminating the potential targets of selection for these regions as well as identifying genomic regions that associate with skeletal and skull morphology differences among breeds.

Many of these genes are familiar to you in all likelihood because they have the same functional significance in humans. The key difference is effect size. Since the paper is open access I’ll spare you the alphabet soup of genes and their association with canine morphological traits. There are many of them that pop up by examining differences between breeds in morphology (and similarities) and their allele frequencies. The top line is the prediction of trait which can occur via just a few genes. They constructed a regression model where a set of independent variables, genes, can predict the value of a given dependent variable, the trait:

Using forward stepwise regression, we combined potential signals into a multi-SNP predictive model for each trait. In the models of body weight, ear type, and the majority of measured traits, most of the variance across breeds could typically be accounted for with three or fewer loci…Correlated traits (e.g., femur length and humerus length) yielded similar SNP associations. For the 55 traits, the mean proportion of variance explained by the top 1-, 2-, and 3-SNP models was R2 = 0.52, 0.63, and 0.67, respectively….After controlling for body size, mean proportion of variance explained by these models was still appreciable—R2 = 0.21, 0.32, and 0.4, respectively.

R2 indicates the proportion of variance in the dependent variable explained by variance in the independent variables. The values for this model are very high. By contrast, a gene for height in humans is a find if it can explain 2% in the trait value variance.

The above found SNPs which could explain variation across breeds which are inbred and highly distinctive in genes and traits. Could the same SNPs explain variance within breeds? Yes:

Most of the variance in body size was explained by the IGF1 locus where we observe a single marker with R2 = 50% and R2 = 17% of variance in breed and village dogs, respectively. The top 3-SNPs explain R2 = 38% of the variance in body weight in village dogs, although the 6-SNP model explains less. The lower R2 in non-breed dogs than breed dogs may be a consequence of lower LD observed in village dogs reducing the strength of association between these markers and the causal body size variants. Alternatively, the lower R2 may also be a consequence of non-genetic factors such as diet or measurement error affecting the observed village dog weights, the smaller range of body sizes observed in the non-breed dog sample, or perhaps to overfitting of the model based on the particular breeds included in the dataset. Nevertheless, R2 = 38% is significantly better than association scans for morphometric traits in humans utilizing denser marker arrays….

Dogs and humans have a long history together. But some of these dogs have a very short history. As noted in the discussion many canine lineages which are purebred are products of Victorian era breeding crazes, and were selected for strange characteristics which were transmitted in a discrete fashion. The recency of the lineages combined with the peculiarities of the breeding programs of this era and dog fanciers generally may explain some of the genetic architecture of canines. The authors note that domestic animals subject to more gradual selection may not, and do not, exhibit the same tendency. Perhaps humans are more like goats or wheat, and less like dogs? The authors note the contrast in loci which exhibit population wide variation:

In humans, high-FST regions are associated with hair and pigmentation phenotypes, disease resistance, and metabolic adaptations…In contrast, the strongest signals of diversifying selection in dogs are all associated with either body size/shape or hair/pigmentation traits, and therefore are unlikely to have been under selection for disease resistance, metabolic adaptations, or behavior. In total, the 11 highest FST regions identified across purebred dogs are all associated with body size/shape or hair phenotypes, including three genomic regions that had not been detected in previous association studies.

The rationale for this study is the utility of dogs as model organisms for humans. They’re taxonomically rather close to us, so their genetics may give us insight into human conditions. The main worry though for me is that the best models here are inbred dogs, where the markers adduced are most valid, but it seems possible they’re the least promising set of models because they have all sorts of genetic peculiarities. But all practicality aside, a fascinating paper.

Image Credit: Jon Radoff and Angela Bull in 2002

Citation: Boyko AR, Quignon P, Li L, Schoenebeck JJ, Degenhardt JD, & et al. (2010). A Simple Genetic Architecture Underlies Morphological Variation in Dogs PLoS Biology : 10.1371/journal.pbio.1000451

(Republished from Discover/GNXP by permission of author or representative)
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Since I see p-ter hasn’t posted on this, in Science, Coat Variation in the Domestic Dog Is Governed by Variants in Three Genes:

Coat color and type are essential characteristics of domestic dog breeds. While the genetic basis of coat color has been well characterized, relatively little is known about the genes influencing coat growth pattern, length, and curl. We performed genome-wide association studies of more than 1000 dogs from 80 domestic breeds to identify genes associated with canine fur phenotypes. Taking advantage of both inter- and intrabreed variability , we identified distinct mutations in three genes, RSPO2, FGF5, and KRT71 (encoding R-spondin-2, fibroblast growth factor-5 and keratin-71, respectively), which together account for the majority of coat phenotypes in purebred dogs in the United States. This work illustrates that an array of varied and seemingly complex phenotypes can be reduced to the combinatorial effects of only a few genes.

See ScienceDaily for summary. This will help us cure cancer! OK, probably not, but hopefully perhaps we might get toward understanding hair form beyond EDAR.

(Republished from by permission of author or representative)
• Category: Science • Tags: Dog Genetics, Genetics 
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Razib Khan
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