Tuesday, May 6, 2025

Phenotypic diversity from dogs to diseases

 



Whether you are trying to keep your neighbor’s German shepherd out of your yard or avoiding that biting Chihuahua on your way to the mail boxes – people have no problem identifying domestic dogs. Most can tell they are not foxes, wolves, or coyotes. There are approximately 400 different domestic dog breeds worldwide – but they all have the same taxonomic classification.

All domestic dogs belong to the same genus and species according to Linnean classification and that is Canis familiarus.  The genus was established in 1758 by Linnaeus to include dogs, wolves (C. rufus, C. lycaon, C. lupus, C. lupaster, C. simnesis) , coyotes (C. latrans), and jackals (C. aureus).  Foxes belong to the genus Vulpes and there are 12 species. This genus forms a clade meaning that they are all descended from a common ancestor.

Domestic dogs can be traced back to 15,000 to 100,000 years ago when they were originally descended from the Gray Wolf in East Asia (1).  Breeding programs have been used to select specific physical and behavioral characteristics of domestic dogs that had led to the observed phenotypic diversity.  The domestication process in general has selected for genetic changes and associated changes at the neurobiological level.  High prevalence illnesses are observed in some dog breeds suggesting that there are heritable loci that could be studied and provide some guidance for human diseases.  Purebred dogs can also have extensive genealogies including family histories and pathology data. 

In terms of comparative genomics (1) there are 4 clades of placental mammals  Afrotheria: ( elephants, manatees, and hyraxes), Xenartha: (sloths, anteaters, and armadillos),  Euarchontoglires: Euarchonta (primates, tree shrews, colugos) + Glires (rodents and lagomorphs), and Laurasiatheria: (shrews, hedgehogs, bats, and other carnivores including dogs).  The most extensively studied mammals at the genetic level all belong to Euarchontoglires (human, chimpanzee, mouse, rat). More detailed information on the dog genome allows for analysis for sections of conserved human DNA, reconstruction of the genetics of a common ancestor between clades, and investigations into the nature of polygenically determined illnesses.

One of the most interesting aspects of reference 1 is the phylogenic tree of the family Canidae showing the relationships between different phyla. This tree was constructed looking at 12 exons (8,080 base pairs (bp) and 4 introns (3029 bp). They were sequences in 30 of the 34 Canid species.  Note where domestic dogs are on the diagram. The boxer photo is used because the boxer genome was the prototypical analysis in this paper because it has some of the longest stretches of homozygosity (62%).  In the diagram clades are color coded (see legend). Each cladogram is constructed with Bayesian analysis generating the respective bootstrap values from Markov chain analysis and posterior probabilities (see legend for location). Indels are insertions-deletions.  Divergence times are in millions of years and are applied to the wolf-like clade discussed in the paper (color coded blue).   

The authors constructed a map of 2,559,519 SNPs (single nucleotide polymorphisms).  They were able to determine the SNP rate for domestic dog breeds and other Canids (wolves and coyotes) and determined it was essentially 1 SNP per 900 (bp) base pairs for all the dog breeds studied except the Alaskan malemute (~1/790 bp).  Wolves and coyotes had greater variation than dogs suggesting a bottleneck during dog domestication.   The authors also demonstrated limited haplotype diversity within dog breeds.  The boxer genome was shown to have homozygosity over 62% of the genome with long blocks having the same haplotype on both chromosomes. The authors looked at the haplotype structure and linkage disequilibrium (LD) across 224 dogs – 10 each from ten breeds and one each from an additional 24 breeds. They used this analysis to construct a population genetics picture of dogs. Among the conclusions is that the dog genome is older (9,000 generations) than the human genome (4,000 generations).   

This is probably a good spot to briefly discuss homozygosity and why that is important.  In terms of experiments. It reduces interindividual variation based on genetics.  Laboratory rats for example have nearly identical genomes after 20 crosses (sib-sib, parent-offspring).  There is a previous post on this blog that discusses stochastics based on behavioral variation in rats with nearly identical genotypes. Dog breeding is a variation on that theme. Dogs do not have the same high degree of homozygosity but they are in the intermediate range.  The majority of dogs in the US are not pure bred but are of mixed heritage.  They can still inherit morphological and behavioral traits as well as genetically based diseases.   The human genome has a lower level of homozygosity due to widespread migration from a common ancestor about 150,000 years ago, a longer life span, as well as cultural constraints such as limits on consanguinity or marriage or a reproductive relationship between two closely related individuals. In the case of marriage by first cousins there is data on consanguinity rates between countries. The medical concern with this practice is that as homozygosity increased the risk of genetically determined autosomal recessive illness increases. Autosomal dominant conditions remain problematic but are not contingent on inheriting identical genes from both parents.   

Species

Homozygosity - same alleles inherited from each biological parent

Norwegian Rat

Rattus norvegicus

1: Considered genetically identical at 20 generations of crossbreeding but some heterozygous alleles can be found out to 40 generations. (7)

2:  Rat breeds (phenotypes) are analogous to dog breeds – as an example the albino lab rat is still Rattus norvegicus.

3:  Experimental results on one inbred colony cannot be generalized to the next.

Domestic dogs

Canis familiarus

1:  Degree of homozygosity varies with breed and specifics of breeding procedure for pure bred dogs. 

Pure bred dogs – 63% homozygosity (10)

Mixed breed dogs – 53% homozygosity (10)

Humans

Homo sapiens

1: 11% homozygosity in individuals who parents were first cousins (consanguineous) compared with the expected value of 1 out of 16 or 6% (8) applying basic models

2:   Range of homozygosity in humans is wide based on evolutionary factors (bottlenecks, founder effects, inbreeding, outbreeding, background relatedness).  Runs of homozygosity (ROH) are studied more often than whole genome comparisons.  

 

In summary, the genetics of domestic dogs is interesting just considering the phenotypic diversity of Canis familiarus.  It highlights issues of classification and that have been discussed in many places on this blog. Students of biology are familiar with these issues from practically every course they have ever taken.  That does not appear to be the case for people who never studied these problems.  Medicine and psychiatry as branches of biology have similar degrees of freedom on an individual basis and for classification purposes.  Any physician knows that no two persons with the same diagnosis are identical and yet there are scores of critics, administrators, politicians, and healthcare companies operating under that illusion. There are similar illusions about social constructs describing some subpopulations.  All humans are still Homo sapiens.  Further subclassification at the genomic or molecular level may be possible but it does not negate the meaning of the Linnean classification.  

In terms of temperament, personality, and behavioral characteristics correlations exist at the genetic level.  Since most of the behavioral traits are polygenic in nature – they have to be considered very early results.   

 There are probably as many advocates that claim a diagnosis has a simplified meaning that they are either advocating for or against.  Socially constructed classifications like race are more problematic.  The basic observation that hundreds of obviously different looking dogs belonging to the same genus and species may drive the phenotypic diversity point home.  The fact that these dogs breeds are also morphologically and behaviorally diverse as well as the fact that that develop unique diseases – provides a potential opportunity for studying morphology and disease mechanisms in humans. Despite suggestions about dog being potential models for human neuropsychiatric disorders that may be too strong of an association.  The research I did for this post was interesting from an evolutionary and genomic standpoint.  It highlights potential genetic and neurobiological effects of domestication as a selective breeding process.

Considering the application of a similar phenotypical diversity concept to complex diseases – why would we not expect hundreds of phenotypes?  Current analyses seem to suggest very simple phenotyping.  In the case of major depression – a single item from a rating scale – emotional blunting or anhedonia and genetic correlates. Other complex diseases like asthma, systemic lupus erythematosus, and diabetes mellitus have similar problems.  On the other hand, we can look at the combinatorics of the verbal descriptions of depression and how many of those combination exist in a clinical population and find 126 subtypes of depression. The question for me is why a handful of rating scale phenotypes of depression would exist and not 126 or more? The same is true for any psychiatric disorder. And of those 126 or more types – what is happening at the genetic and molecular levels?  The idea of a better classification based on some verbal hierarchy or rearranging the verbal descriptions does not seem promising to me.  The dilemma of trying to classify natural phenomena by words is always a limitation. There is no better example than biological classification.       

 

George Dawson, MD, DFAPA

 

 

Graphics Credit:  From reference 1 with permission - Copyright Clearance Center License Number 6004620929064

 

References:

1:  Lindblad-Toh K, Wade CM, Mikkelsen TS, et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature. 2005 Dec 8;438(7069):803-19. doi: 10.1038/nature04338.

2:  Bergström A, Stanton DWG, Taron UH, et al. Grey wolf genomic history reveals a dual ancestry of dogs. Nature. 2022 Jul;607(7918):313-320. doi: 10.1038/s41586-022-04824-9. Epub 2022 Jun 29. PMID: 35768506; PMCID: PMC9279150.

3:  Spady TC, Ostrander EA. Canine behavioral genetics: pointing out the phenotypes and herding up the genes. Am J Hum Genet. 2008 Jan;82(1):10-8. doi: 10.1016/j.ajhg.2007.12.001.

4:  Parker HG. Genomic analyses of modern dog breeds. Mamm Genome. 2012 Feb;23(1-2):19-27. doi: 10.1007/s00335-011-9387-6. Epub 2012 Jan 10. PMID: 22231497; PMCID: PMC3559126.

5:  Hecht EE, Kukekova AV, Gutman DA, Acland GM, Preuss TM, Trut LN. Neuromorphological Changes following Selection for Tameness and Aggression in the Russian Farm-Fox experiment. J Neurosci. 2021 Jul 14;41(28):6144-6156. doi: 10.1523/JNEUROSCI.3114-20.2021.

6:  Rahim NG, Harismendy O, Topol EJ, Frazer KA. Genetic determinants of phenotypic diversity in humans. Genome Biol. 2008 Apr 24;9(4):215. doi: 10.1186/gb-2008-9-4-215. PMID: 18439327; PMCID: PMC2643926.

7:  National Research Council (US) International Committee of the Institute for Laboratory Animal Research. Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference. Washington (DC): National Academies Press (US); 1999. Genetic and Phenotypic Definition of Laboratory Mice and Rats / What Constitutes an Acceptable Genetic-Phenotypic Definition. Available from: https://www.ncbi.nlm.nih.gov/books/NBK224550/

8:  Woods CG, Cox J, Springell K, Hampshire DJ, Mohamed MD, McKibbin M, Stern R, Raymond FL, Sandford R, Malik Sharif S, Karbani G, Ahmed M, Bond J, Clayton D, Inglehearn CF. Quantification of homozygosity in consanguineous individuals with autosomal recessive disease. Am J Hum Genet. 2006 May;78(5):889-896. doi: 10.1086/503875. Epub 2006 Mar 21. PMID: 16642444; PMCID: PMC1474039.

9:  Bell JS.  Genetic diversity.  Accessed on March 24, 2025 https://www.akcchf.org/assets/files/Genetic-Diversity_Bell-2021.pdf

10:  Pemberton TJ, Absher D, Feldman MW, Myers RM, Rosenberg NA, Li JZ. Genomic patterns of homozygosity in worldwide human populations. Am J Hum Genet. 2012 Aug 10;91(2):275-92. doi: 10.1016/j.ajhg.2012.06.014. PMID: 22883143; PMCID: PMC3415543.

11:  Shearin AL, Ostrander EA. Leading the way: canine models of genomics and disease. Dis Model Mech. 2010 Jan-Feb;3(1-2):27-34. doi: 10.1242/dmm.004358. PMID: 20075379; PMCID: PMC4068608.

12:  Amfim A, Bercea LC, Cucu N. Canine Genetics and Epidemiology of Behavior in Dogs. Epizootics-Outbreaks of Animal Disease: Outbreaks of Animal Disease. 2025 Feb 5:105.

13:  Ilska J, Haskell MJ, Blott SC, Sánchez-Molano E, Polgar Z, Lofgren SE, Clements DN, Wiener P. Genetic Characterization of Dog Personality Traits. Genetics. 2017 Jun;206(2):1101-1111. doi: 10.1534/genetics.116.192674. Epub 2017 Apr 10. PMID: 28396505; PMCID: PMC5487251.

14:  Friedrich J, Strandberg E, Arvelius P, Sánchez-Molano E, Pong-Wong R, Hickey JM, Haskell MJ, Wiener P. Genetic dissection of complex behaviour traits in German Shepherd dogs. Heredity (Edinb). 2019 Dec;123(6):746-758. doi: 10.1038/s41437-019-0275-2. Epub 2019 Oct 14. PMID: 31611599; PMCID: PMC6834583.

15:  Handegård KW, Storengen LM, Joergensen D, Lingaas F. Genomic analysis of firework fear and noise reactivity in standard poodles. Canine Med Genet. 2023 Mar 8;10(1):2. doi: 10.1186/s40575-023-00125-0. PMID: 36890545; PMCID: PMC9996964.

16: Boyko AR, Quignon P, Li L, Schoenebeck JJ, Degenhardt JD, Lohmueller KE, Zhao K, Brisbin A, Parker HG, Vonholdt BM, Cargill M. A simple genetic architecture underlies morphological variation in dogs. PLoS biology. 2010 Aug 10;8(8):e1000451.

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4 comments:

  1. Hi Dr. Dawson! I'm curious what your thoughts are on the HiTOP model of classification.

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    1. Hi Ann - Thanks for the question. HiTOP and RDoC are interesting approaches and are works in progress. I hope to post an update on both in the near future. I hope that I am developing the theme on this blog that the DSM is really underdeveloped relative to its potential. Psychiatry has a long history of shooting itself in the foot for one reason or another. It resulted in an intellectually restricted field relative to the neuropsychiatrists of the late 19th and early 20th centuries. It did not take much originally just the ABPN making a decision that to be board certified in the neurology and psychiatry that most psychiatrists were practicing in the 1930s - you had to take both examinations. The DSM has a lot of unpublished validity data - and the reason for that may be some diagnoses that are more politically motivated than actually exist.

      I have numerous concerns about the underlying assumptions and constructs of all of these systems. It seems they all lack reference points in biology, genetics, and evolution. The problem of biological classification is common across all of those fields, the DSM, RDoC, and HiTOP. I don't think there will be clear improvements in classification until those lessons are learned.

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  2. Maybe this might be of some interest to you, genomic analysis of herding breeds. They found differences between Border Collies from working lines and AKC conformation lines. I've had a Border Collie from AKC Champion parents (Conformation and performance titles such as agility and obedience) and now have a year old puppy from working parents on a goat farm. Only an N of 2, but it's been fun to notice the difference between the dogs' behavior (also first dog was female, new dog is intact male, so that complicates things)

    https://www.science.org/doi/10.1126/sciadv.adp4591

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    1. Yes - thank you - this is an excellent study focused on the genetic correlates of canine behavior. It highlights the authors success in this case as well as the methodological problems inherent in this research. A good example is the behavioral checklists given to dog owners to detect the behavior of interest. Ref 48 by two of these authors also looks interesting.

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