Industry club: inherited diseases

Results:

The Consortium project has developed a documented approach to manage recessive disease genes. A hand book for use by breeders and breeding organizations has been drafted but is not yet publically available.

The problem:

Inherited diseases have been, and will continue to be, a problem that cattle breeders have to deal with. There are a few examples in the industry which have caused some serious problems. A common feature of the more damaging examples is that the genes causing the disease are recessive, which means the problem can be building up unnoticed. Examples include Hypotrichosis (Hairlessness), Beta-mannosidosis (Beta-man), Syndactyly (Mulefoot) and, in dairy cattle, Bovine Leukocyte Adhesion Deficiency (BLAD)

Cattle, like all animals, have two copies of each gene, one from each parent. In practice one of the copies may be dominant over the other and so the biochemistry or physiology controlled by that gene pair is under the influence of the dominant gene.  An example of this in humans is the inheritance of sickle cell anaemia. When two single recessive copy carriers produce offspring there is a one in four chance that the young will have received two copies of the sickle gene and develop the disease, two of the four offspring will have one copy of each and one will be a non-carrier.

Please refer to 'Diagram 1' link below

So the diseased gene builds up without being noticed. This leads to a flurry of diseased animal when a critical point has been reached which may or may not be recognised early on, partly through ignorance and partly through lack of reporting amongst affected breeders.

By the time the problem has been “outed" the disease causing gene can be spread far and wide. This is especially a problem if a widely used AI sire turns out to be a recessive carrier of a new disease problem. Because of the way random mutation crop up we need to continue to be vigilant and expect the worst! 

The project:

The aim of the project was to develop mapping procedures for routine use which will quickly identify disease and allow plans to be implemented which manage the disease. The latter point is very important in small populations where culling all carriers is not a viable option.

The approach used has been called “homozygocity mapping" which allows the areas of the gene where the disease defect is sited to be identified.

The practice:

The new approach needs animals that are thought to be carriers to supply DNA samples and animals known to be free of diseased genes. The DNA of the animals is compared using SNP markers (single nucleotide polymorphisms).

The “trick" is that all the guaranteed disease free animals will have no copies of the diseased gene and the affected animals will have two copies. When you compare the two sets of animals there is a relatively small area of DNA in the affected animals that is identical in all candidates and this points to the part of the DNA that carries the “offending gene". By identifying the homozygous (same in both copies) bits of the genome you know you will have captured the bit that is causing the disease.

From these small areas you can go on to discover the precise location and nature of the gene that causes disease.

The Problem:

In common with most species, cattle and sheep breeds have significant numbers of inherited diseases. Most of these are due to gene defects that only manifest as disease when an animal inherits the defective gene from both parents. A consequence of this pattern of inheritance is that the frequency of the defective gene can increase to a significant level in the population before the incidence of the disease is noticed as a major issue.

There are now a number of well-documented examples where individual males in a breed have been used to produce very large numbers of grand progeny and at the same time have spread a defective gene widely throughout that breed. The risk of this happening increases with more intensive breeding programmes (with higher inbreeding levels) and with BLUP selection that tends to select families.

Project Aims:

Development of best practice guidelines on:

• Statistical quantitative analysis to check that the disease/condition is consistent with being under genetic control
• Population structure and statistical power as a guide to the numbers of cases and controls that need to be sampled to map the location of the gene with appropriate accuracy
• Setting up the necessary software capability for the mapping of the gene (homozygosity mapping) with dense DNA marker information
• Establishing the flow diagram for the identification of candidate genes within the mapped region and procedures for the selection of genes for sequencing
• Documenting procedures for the comparative genome analysis and bioinformatics to identify the most likely causative mutations from sequence information
• Protocols for the numbers of animals needed to validate the new DNA test as suitable for use in selection to reduce the incidence of the disease
• Demonstration of these processes in practice for a small number of inherited diseases in UK populations
• A workshop to be held at the end of the project to demonstrate the process and possible application to Industry representatives

Approach:

Recent developments in genetics and genomics, including the development of dense DNA marker panels (typically 50,000 DNA SNP markers) and the sequencing of the genomes of a number of species, has transformed the ability of geneticists to identify the genes associated with the disease. It is possible to identify the genetic location of inherited disease and even discover the defect in the gene. One of the key developments is that the defective gene can now be identified using relatively small numbers of affected and normal animals in one or more families where the disease is segregating.