Genomic Heterozygosity

The best way to determine genomic heterozygosity is to analyse SNP arrays (single nucleotide polymorphism) or whole genome sequencing (WGS), looking at as many individual SNP markers as possible that are evenly distributed across the genome. The percentage is the number of heterozygous SNPs divided by the number of all successfully genotyped SNPs.

Comparability: How high the value turns out depends on which SNPs are genotyped. Arrays preferentially contain SNPs that are highly polymorphic in the breeds used for array design. For breeds that could not be included in the array design, heterozygosity is then systematically underestimated (SNP ascertainment bias, Lachance & Tishkoff 2013). The values are therefore only comparable within the same method and preferably within the same breed, not between different laboratories or arrays.

Terminology: At Generatio, the value is called the genomic HE value, gHE. It indicates the heterozygosity of the individual animal observed with the SNP array. In the population genetics literature, this is usually referred to as observed heterozygosity (Ho); expected heterozygosity (He) there stands for the heterozygosity expected in a population under Hardy-Weinberg equilibrium on the basis of the allele frequencies.

Higher genomic heterozygosity means greater genetic diversity within an animal. For the individual animal, this mainly means that deleterious recessive alleles are less often present in the homozygous state and less often expressed, because they are masked by an intact second allele. For the population, genetic diversity is also the basis for adapting over generations to changing environmental conditions and pathogens.

That inbreeding reduces fitness (inbreeding depression) is well documented in many animal species (Charlesworth & Willis 2009). In dogs, a study of more than 200 breeds showed that breeds with higher genomic inbreeding, and correspondingly lower genomic heterozygosity, had higher morbidity (Bannasch et al. 2021).

The direct association between the heterozygosity of an individual animal and its health or life expectancy (heterozygosity-fitness correlation, HFC), on the other hand, is weak in most studies (Chapman et al. 2009). A single HE value therefore does not allow a prediction for the individual animal. It is meaningful above all in comparison within a breed and together with the genomic inbreeding coefficient and the ROH profile.

Breeds that have been bred as a closed population for a very long time show only low variance in the gHE values of individual animals. The aim here would be to increase heterozygosity through targeted breeding measures. Where geographically separated subpopulations of the breed exist, animals from these subpopulations would be promising candidates. The separated subpopulation may itself show reduced heterozygosity, but if this affects different loci, a mating can directly increase heterozygosity in the offspring (genetic rescue, Whiteley et al. 2015). Mating plans of this kind should, however, always be based on a mating assessment supported by array data that, in addition to heterozygosity, also determines the genomic inbreeding coefficient (GIC) and the ROH profiles.

By monitoring these population genetic parameters, breeders can make informed decisions to avoid inbreeding and promote genetic health.

In scientific research, studies of genomic heterozygosity, alongside the other parameters, provide better insight into the population structure and evolutionary history of a species or breed. They reveal patterns of migration, adaptation and genetic drift, and show, for example, how dog breeds derive from one another. Details can be found in our article Clade and Cladogram. This information is a valuable basis for understanding to what extent populations are (still) able to respond to environmental pressures, and for developing effective conservation strategies.

The HE value is part of the 'Inbreeding & Diversity' assessment. For this purpose, Generatio carries out SNP array genotyping and, in addition to the HE value, determines the genomic inbreeding coefficient and the ROH profile. The assessment is currently available for dogs, horses and camelids.

Single tests:

• Dog:Inbreeding & Diversity (Fitness) Dog
• Horse:Inbreeding & Diversity (Fitness) Horse
• Camelids:Inbreeding & Diversity (Fitness) Camelids

Bundles including inbreeding analysis:

• Dog:SNP Profile Identity & Inbreeding & Fitness Dog: DNA identity and inbreeding analysis
• Dog:ProLine Bundle Dog: DNA identity, inbreeding and diversity analysis and breed analysis
• Horse:Bundle Breed Analysis, Identity, Inbreeding Assessment
• Horse:MIM-6-Var. plus Inbreeding & Fitness: test for the six MIM variants and inbreeding analysis
• Dromedary:Bundle DNA Identity and Inbreeding Analysis Dromedary

Lexicon:

• Genomic Inbreeding Coefficient (GIC)
• ROH Profiles
• Popular Sire Syndrom
• Clade and Cladogram

Literature:

• Charlesworth, D., Willis, J.H.: The genetics of inbreeding depression.Nat Rev Genet 10:783-796, 2009. DOI: 10.1038/nrg2664
• Chapman, J.R., Nakagawa, S., Coltman, D.W., Slate, J., Sheldon, B.C.: A quantitative review of heterozygosity-fitness correlations in animal populations.Mol Ecol 18:2746-2765, 2009. DOI: 10.1111/j.1365-294X.2009.04247.x
• Lachance, J., Tishkoff, S.A.: SNP ascertainment bias in population genetic analyses: why it is important, and how to correct it.BioEssays 35:780-786, 2013. DOI: 10.1002/bies.201300014
• Whiteley, A.R., Fitzpatrick, S.W., Funk, W.C., Tallmon, D.A.: Genetic rescue to the rescue.Trends Ecol Evol 30:42-49, 2015. DOI: 10.1016/j.tree.2014.10.009
• Bannasch, D., Famula, T., Donner, J., Anderson, H. et al.: The effect of inbreeding, body size and morphology on health in dog breeds.Canine Med Genet 8:12, 2021. DOI: 10.1186/s40575-021-00111-4