Introduction

Genetic defects comprise single-gene (or monogenic) disorders, chromosomal abnormalities and multifactorial (or complex) disorders. While our understanding of genetic defects has been rapidly increasing in the past decades due to improvements in disease investigations, molecular genetic tools as well as data analysis approaches, we still have far to go.

In humans about 5500 single-gene disorders have been described and for more than 4500 of these, at least one DNA variant (also called an allele or mutation) that causes the disease has been identified (see Online Mendelian Inheritance in Man (OMIM) for details). In animals, which have a similar total number of genes in the genome and where we therefore would expect a similar number of conditions, single-gene disorders are reported less frequently, but disease-causing variants are increasingly identified, particularly for companion animals and livestock (see  Online Mendelian Inheritance in Animals (OMIA) for details).

Information about chromosomal abnormalities is even more limited, as these often affect individual animals, but some examples have been well documented and recent approaches using whole genome sequencing data to detect chromosomal abnormalities in animals will hopefully expand our understanding in this area further.

Many multifactorial disorders (where multiple genes as well as non-genetic factors contribute to development of the disease) have been recognised in animals, hip dysplasia in dogs being just one example.

Repositories of Genetic Defects

With the rapidly increasing information about genetic defects, it can be difficult to stay up to date about recent developments. In humans, an online database of single-gene disorders, Online Mendelian Inheritance in Man (OMIM), has been in place since 1987, and Online Mendelian in Inheritance in Animals (OMIA), modelled on OMIM, has been online since 1995. OMIA is a freely available, online-annotated catalogue of inherited traits (mostly disorders) in any animal species other than human, mouse, rat and zebrafish. While the name suggests that only Mendelian traits are covered, single-gene as well as many multifactorial traits and a small number of chromosomal abnormalities are included in the database.

Single-Gene Disorders

These diseases are most often caused by spontaneous mutations in or near a gene. Most spontaneous mutations have no effect, but some can change the structure or usage of a gene and improve (basis of evolution) or worsen (inherited disease) the function of the encoded protein. It can take several generations (depending on the mode of inheritance and the degree of inbreeding/line breeding) between the occurrence of the mutation and the birth of animals with clinical signs, and it might take even more time before the disease is diagnosed as an inherited disorder. During this time the disease variant can spread worldwide. In some cases when favoured sire lines are involved, where the disease gene lies in close proximity on the DNA to a favourable gene, or where there is a selective advantage of heterozygotes, the frequency of the disease allele can increase quite substantially.

New tools in quantitative and molecular genetics allow us to identify disease genes and mutations, provide us with opportunities for accurate diagnosis and allow us to include the information into existing breeding programs for eradication or management.

Mendelian Modes of Inheritance

Single-gene disorders occur with characteristic frequencies for specific matings. The observed frequencies for any mating are affected by sampling variation, and statistical analysis (chi-squared test) should be performed to assess if the observed frequencies are consistent with predicted frequencies for a specific mode of inheritance. The predicted frequencies of the phenotypes are dependent on how the mutated allele interacts with the wild-type allele. In regard to this interaction, we differentiate between recessive, dominant, co-dominant and incompletely dominant modes of inheritance, and take into consideration if the gene is located on a sex chromosome or an autosome.

The majority of known inherited diseases are caused by recessive alleles – the disease occurs only in animals that inherited the disease allele from both parents, i.e. the disease occurs in animals that are homozygous for the disease allele. With this type of inheritance, animals with one copy of the disease allele and one copy of the normal (so-called wild-type) allele are clinically normal but can pass on the defective allele to the next generation (so-called carriers) – thus the actual occurrence of the disease can jump generations.

The dominant mode of inheritance is less common for inherited diseases. The disease phenotype is evident in all animals that have at least one copy of the disease allele.

A co-dominant mode of inheritance describes a relationship among alleles where both alleles contribute to the phenotype. The heterozygote clearly shows both of the homozygotes’ features as in the blood group phenotype AB in humans.

The term ‘incompletely dominant’ is used when the heterozygous animal displays a phenotype somewhere between the two homozygous phenotypes.

Deviations from Mendelian modes of inheritance

Sometimes the expected ratios for specific matings are not observed in single-gene disorders. Explanations include embryonic lethal traits, sex-linked, sex-limited or sex-influenced traits, and germline mutations.

The relationships between genes and their alleles are not always as simple as described so far. We sometimes observe multiple alleles, incomplete penetrance (some animals in the population have the specific disease genotype but are not affected) or differences in expressivity (variation in allelic expression when the allele is penetrant).

Other traits are influenced by imprinting, a phenomenon in which alleles of specific genes are silenced, depending on the sex of the parent from which the allele was inherited.  

Another form of non-Mendelian inheritance can be found when mutations occur in the mitochondrial genome. Mitochondrial DNA (mtDNA) is transmitted only maternally and codes for genes that are of importance for energy metabolism.

Chromosomal Abnormalities

Many chromosomal abnormalities are due to errors in meiosis, during the formation of individual gametes, and do contribute to embryonic loss but some lead to live-born animals. Individual meiotic events mostly affect individual animals and are therefore usually not a concern at the herd, flock or population level. Chromosomal abnormalities affecting the sex chromosomes are also often reported to result in live-born animals and often impact reproductive ability.

Mulifactorial Disease

Many genetic traits have a multifactorial origin – they are influenced by many genes and many non-genetic factors. The phenotypes cannot be classed in distinct groups, but represent a continuously varying trait, e.g. milk production or growth, reflecting the combined effect of many genes and many non-genetic factors. Non-Mendelian defects where a breed disposition has been reported, or where research has quantified the contribution of genetics to the variation in the disease by calculating heritability, is likely to be a multifactorial disease. Many metabolic diseases, conformational faults and susceptibilities to pathogens fall into this category.

Investigating Emerging Disease

If we see occurrence of a disease among related animals or within one breed, and have excluded all obvious non-genetic causes of disease, we can suggest that it is an inherited disease. What can we do to verify this hypothesis?

The easiest way would be to find out if the phenotype (clinical signs and pathology) has been reported before as an inherited disease in the same breed / same species / or other species. This requires a comprehensive description of the phenotype and a repository of all known inherited diseases. The online repositories OMIA and OMIM can supplement time-consuming literature research.

If the disease hasn’t been described as an inherited disorder previously, the diagnosis is more difficult. As first steps, we would have to obtain evidence that it is indeed an inherited disease, and we would like to know how the disease is inherited using pedigree analysis. Pedigree analysis can start with a simple graphical display that allows us to follow the passage of the trait of interest through several generations. These displays can be used to identify common ancestors (potential founder animals) and study the mode of inheritance. If the disorder has a Mendelian inheritance, the pedigree data can be used to deduce or predict the genotypes of some individuals. Caution should be applied to pedigree information that has not been verified by DNA parentage. If possible, parentage verification via blood or DNA testing should be considered.

Software packages are available to keep track of pedigrees, to produce convenient graphical outputs and to perform risk analysis within given pedigrees. For the analysis of complex pedigrees, more sophisticated programs for segregation analysis have been created. Such analysis allows for the identification of common ancestors and some programs allow for the estimation of genotypic probabilities, which can be included in existing breeding programs.

When there is reasonable evidence of single-gene inheritance, identification of disease-causing variants can be attempted often with just a few affected animals and appropriate controls. Well-annotated reference genomes, dense SNP chips and low-cost whole-genome sequencing (WGS) technologies have made this much easier.

For multifactorial diseases, we know that selection on phenotype alone can be beneficial but selection using EBVs or genomic selection is better. So, for multifactorial (complex) traits, identify how to best measure the trait, measure it in appropriate reference populations, estimate its heritability and other parameters, and consider implementing a breeding program based on EBVs. At the same time, breeders should address any identified non-genetic factors that can be varied.

Control of Genetic Conditions

Total prevention of inherited diseases is not possible – almost all animals are carrying several very harmful alleles, and spontaneous mutations will always occur.

Nevertheless, much can be achieved in terms of decreasing the frequency of inherited disorders and in some cases, eliminating inherited disorders.

An essential aspect for the control of inherited disorders is an efficient means of early detection of novel inherited diseases. Currently, most countries are lacking efficient mechanisms for the early detection of inherited diseases. The AHIDA portal has been developed to fill this gap in Australia with the aim to assist with surveillance and reporting of animals with suspected inherited conditions.

Once a disease has been suggested to be an inherited disorder, accurate characterisation of the phenotype is essential. This assists with potential differential diagnosis, with exclusion of phenocopies (clinical signs corresponding to those of a genetic disease but which have a non-genetic cause) and after consultation of the above-mentioned catalogues for inherited diseases, it might be possible to relate the disease to a known inherited disorder.

Pedigree analysis can be used to identify the mode of inheritance. Complex pedigree analysis (including the estimation of genotype probabilities within large populations) can be performed and, especially if the disorder appears to be due to a single gene, the resulting information can be included in existing breeding programs to reduce the frequency of the disorder allele and of the disorder, and (in some cases) to eliminate the disorder.

Dominant diseases are easily excluded from a population unless they are characterised by a late onset of the disease or are closely linked to major desirable genes. The identification of carrier animals for diseases with a recessive mode of inheritance is more difficult but extremely important. If breeders can ensure that at least one parent in every mating is not a carrier, then the disease can be eliminated immediately. Historically, test crosses were used to identify at least some carriers. With a better understanding of some diseases which are caused by inactivity of enzymes, biochemical tests can be developed that can measure a reduced enzyme activity in the heterozygous (clinically normal) animal. The ultimate test is based on the actual causal variant, and such a test can be devised for any disease that has been characterised at the molecular level. However, it is important to note that these DNA tests are only identifying known variants, and genetic heterogeneity and composite heterozygotes need to be considered in the interpretation of these results.

Animal owners and breed societies have developed sound approaches to manage inherited conditions in their populations. The overall aim should be to decrease the occurrence of the genetic defects, and not necessarily attempt to eliminate the deleterious allele, as all animals are likely to carry deleterious alleles. Several factors, such as severity of the impact on welfare and productivity, mode of inheritance, frequency of the deleterious allele and population structure, should be considered in any chosen approach. Testing for known variants, prediction of genotypes of untested animals and public disclosure of such information allows animal owners, breeders and breed societies to make informed decisions.

(Modified from: Tammen, I., Nicholas, F. (2022). Genetic Defects in Cattle. In Paul L.H. McSweeney and John P. McNamara (Eds.), Encyclopedia of Dairy Sciences (3rd edn), (pp. 626-636). USA: Elsevier.)