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Dog Genomics

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Citation: Freedman, Adam H., et al. "Genome sequencing highlights the dynamic early history of dogs." PLoS Genetics 10.1 (2014): e1004016.

Citation: Freedman, Adam H., et al. “Genome sequencing highlights the dynamic early history of dogs.” PLoS Genetics 10.1 (2014): e1004016.

The more we scratch beneath the surface with powerful genomic techniques, the more we see that natural history which we had presumed to have a crisp understanding of is quite a bit more muddled. Once the muddle clears what we’ll gain is the gift of accurate complexity, but in many areas right now there is little such clarity. It is a truth that a new discovery or inference does not mean that there are enough points in space to construct a new explanatory constellation when the old does not suffice. Due to the biomedical focus of modern genomics there has been a disproportionate focus on humans, but over time it is clear that this will expand out across the tree of life, and the light shall give way to a temporary fog. First up are organisms of particular human interest and/or model organisms (the latter are species which are useful for elucidating general biological phenomena, and the subjects of study of a large community of researchers). Domestic dogs have the virtue of falling into both categories.


Red Basenji

There are many theories about the origins of our “best friend.” One school of thought (though not necessarily dominant) is that dogs are relatively recent obligate companions of humanity, part of the toolkit of the Neolithic revolution. To be fair this view was rejected by many researchers on the common sense grounds that dogs arrived with the Amerindians 10,000-15,000 years ago. These were clearly hunter-gatherer populations which predated the Neolithic. But there were some genomic research which did imply that even if there were early domestication events, the preponderance of modern domestic dog ancestry dated to the Middle East ~10,000 years before the present. The newest work in genomics seems to falsify that hypothesis rather robustly. These researchers have shown how looking closely and thoroughly at whole genomes (billions of base pairs) organisms, as opposed to a subset of polymorphisms (on the order of tens or hundreds of thousands of base pairs), can yield deeper historical insight.

A new paper out in PLOS GENETICS, Genome Sequencing Highlights the Dynamic Early History of Dogs, has been out as a preprint for a while now, but it seems useful to review what it highlights we now know, and don’t know. As illustrated by the figure above a key element of the revised natural history of the domestic dog must include a minimal level of complexity in the phylogenetic origins of the species. A caricature of the simplest story about the origin of the dog is that it is a tamed wolf. Highly derived from the ancestral state (many characteristics have shifted from the last common ancestor with wolves), but a wolf nonetheless. This idea needs updating because the work in the paper above highlights that extant wolves are not perfect representatives of Pleistocene wolf populations, from which dogs derive. This was already clear with some ancient DNA, but looking at whole genomes of three wolves from disparate regions of Eurasia, a West African Basenji, and an Australian Dingo (along with the Boxer as a reference domestic dog genome and a Golden Jack as an outgroup), a major finding seems to be that modern dogs derive from a population of wolves which are not represented in the populations sampled above. This is important because many inferences about dogs are made simply by assuming that modern wolves are appropriate proxies for the last common ancestor of both lineages.

This substitution seems to be rather shakier than we’d have thought, and this comes to play most obviously in the genetic diversity and bottleneck results we’d take for granted. If modern wolves are the standard for the ancestral population from which dogs derive then the bottleneck is a relatively mild one of a few fold drop in size (wolves are more diverse, but not that much more diverse). But what the authors above found by looking at patterns of genetic diversity across the whole genomes of these wolves is that all three, sampled from Croatia, Israel, and China, also exhibit evidence of a population bottleneck. This makes more sense of the result that it looks as if modern dog lineages underwent a population bottleneck on the order of one magnitude (16 fold). The timing using different methods also definitely predates the Neolithic revolution ~10,000 years ago, and so aligns with the archaeological evidence. Wolves were the companions of hunter-gatherers first before they were associated with farmers. Any possible adaptation of dogs to a starchy diet occurred after the initial bottleneck and separation of the ancestors of this lineage from the ancestors of modern wolves (who seem to have enough variation to have had this trait as part of the ancestral range of the trait in any case). Additionally, there are dog lineages, such as the Dingo, which don’t exhibit any adaptation to starch diets, which makes historical sense as they did not coexist with agricultural populations until recently.

I do want to caution that genomics does not change everything. Many of the broad outlines of what was known before with classical genetic techniques, comparative anatomy, and paleontology, do hold up. For example the domestic dogs do seem to form a monophyletic lineage. By this one simply means that domestic dogs the world over seem to share a small set of common ancestors, rather than being instances of convergent morphological evolution from disparate wolf lineages. What is more surprising though is that these results imply reciprocal monophyly with wolves. This means that domestic dogs are not a specialized branch of a particular population of modern wolves, but a sister lineage to contemporary wolves. Though it is common to say that a dog is just a tamed wolf, one might as easily state that a wolf is a wild dog (yes, I will grant that the dog is likely more derived, but I don’t think we can just substitute modern wolves for ancient ones and call it good). Both are subsets of a wider range of canid ancestors which flourished in the Pleistocene. The tests of admixture of particular lineages suggest that the origins of dogs seem to suggest gene flow with local wolf lineages. This would confound attempts to ascertain a particular zone of domestication or adaptation, as prior genetic affinities or clines in diversity may be due to gene flow rather than patterns of descent (earlier attempts to assert that domestic dogs derive from the Middle East or China may be premised on false assumptions, as well as limitations of less dense marker sets than whole genomes).

The main drawback of this study is obviously the limited sample size. It is freely acknowledged in the paper, but that is why the authors also attempted to select individuals from populations which were highly informative, both geographically and culturally (e.g., Dingoes are outside the range of the wolf, and, not coexistent with ancient agricultural populations). I am more skeptical about assuming that the wolf samples are representative than I am about their selection of three dog lineages (Basenji, Dingo, and the Boxer reference). We know a lot more about the genetics and history of dogs than we do about wolves, and it seems more likely that there are going to be more surprising loose ends in the case of the latter than the former. But if I had to bet I’d say the authors are right, and their inferences are going to hold up (reciprocal monophyly, the bottleneck in wolves, etc.). Yet there’s no doubt going to be a lot of detail added to this model as the sample sizes increase, and ancient DNA is is included in the analysis. Though recent studies seem to establish rather clearly that domestication was a function of the later Pleistocene (and not the Holocene) in the case of dogs, the exact details of where, when, an who, are still quite woolly.

But the ultimate big picture is emphasized by the title above: the Pleistocene is going to seem like a strange country after all is said and done. Many of the organisms which are going to be sequenced in great depth (high coverage) and large sample sizes first are mammals of Palearctic origin which were shaped by the Pleistocene. The importance of this geological period for humans has long been a subject of scholarly attention, but genomics and the light it sheds upon quirks of natural history, might emphasize the ecology-wide reshaping role that Ice Ages had upon the natural history of so many familiar and charismatic species. This is where genomics will open the door to evolutionary ecology of grand scope.

Citation: Freedman, Adam H., et al. “Genome sequencing highlights the dynamic early history of dogs.” PLoS Genetics 10.1 (2014): e1004016.

Related: Please see a post from one of the authors at Haldane’s Sieve.

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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

Razib Khan
About Razib Khan

"I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. If you want to know more, see the links at"