Download Genetic selection programs aimed at increasing the economic value of... preclude selection for disease resistance. Ignoring disease resistance during selection...

Genetic selection programs aimed at increasing the economic value of dairy cattle tend to
preclude selection for disease resistance. Ignoring disease resistance during selection may
result in lower economic returns due to the undesirable correlation between disease and
individual animal performance. One way of bypassing this problem is direct selection of
sires and cows that carry genes related to disease resistance. However, very few genetic
markers related to disease resistance have been identified. Thus, identification of
additional genetic markers that segregate with either disease resistance or susceptibility
may allow improved selection indexes for dairy cattle.
Modern genetic analysis techniques allow rapid screening of individual animals for
structural variation in distinct genes. If variation can be identified in genes that segregate
with disease resistance, it will be possible to use these modern methodologies to select
sires or cows carrying disease resistance and hence this important trait can be included in
selection indexes. Regardless of the mammalian species being considered, genetics of
disease resistance is most closely associated with the major histocompatibility complex
(MHC), a tightly- linked cluster of genes that encode proteins involved in immune
responses. This genetic region in cattle is very similar to other species and has been given
the abbreviated name, BoLA.
Although little is known about genetic variation within the BoLA complex, several
studies have demonstrated association between this genetic region and factors relating to
dairy cattle. For example, the genes encoding prolactin (hormone important for milk
letdown) and butyrophilin (glycoprotein expressed by mammary epithelial cells) have
been located within the MHC complex of several species including BoLA. In addition,
the development of persistent lymphocytosis in cattle infected with bovine leukemia virus
is strongly influenced by the BoLA genotype. Recently, a new family of antigen
processing genes that encode cellular components involved in stimulating the immune
system to recognize and destroy viral- infected cells have been identified in the human
and rodent MHC complexes. We propose that structural variation in these antigen
processing genes may be linked to resistance (or susceptibility) to viral infection.
Accordingly, our research is focused on cloning and characterizing the antigen processing
genes that are likely encoded within BoLA with the ultimate goal of using these genes as
molecular tools for improving cattle genetics.
Viruses, unlike bacteria, are unable to replicate on their own and are thus completely
dependent on machinery within infected host cells to produce infectious particles. In
addition to making complete viral particles, infected mammalian cells place small pieces
of viral proteins within specialized antigen binding proteins as a way of alerting the
immune system that a virus infection has occurred. These specialized antigen binding
proteins (MHC class I proteins), containing small pieces of viral proteins (antigens), are
displayed on the surface of infected cells allowing recognition by a distinct type of
immune effector cell (cytotoxic T lymphocyte) that in turn destroys the infected cell. In
most cases, within time, the host immune system is able to clear a virus infection by
destroying cells that are actively making additional viral particles. However, it is possible
that individual animals differ in their ability to alert the immune system that a virus
infection has occurred. Certainly, those ind ividuals more efficient in this process will be
those that are most quickly able to clear viral infections and perhaps eliminate viruses
before they are able to result in decreases in productive processes.
The antigen processing genes introduced above encode for host proteins that are involved
in producing small pieces of viral proteins (antigens) and transporting them to the
appropriate sub-cellular site where they can bind to the specialized antigen binding
proteins (see Figure 1). Once this process is complete the antigen and binding protein
complexes move to the surface of infected cells where they can be recognized by the host
immune system. To date four antigen processing genes have been identified in the human
and rodent MHC complexes. These include two genes, LMP-2 and LMP-7, that encode
subunits of a large proteolytic complex thought to be responsible for degrading intact
viral proteins into viral antigens. Closely linked to the LMP genes are two additional
genes, TAP-1 and TAP-2, that encode for the two subunits of a peptide transporter
complex (TAP). The so-called TAP complex is thought to provide the viral antigens to
the MHC class I antigen binding protein which subsequently transports them to the
surface of the infected cell.
We suggest that structural variations in the LMP and TAP genes may encode varying
degrees of disease resistance among individual animals. For example, structural variation
in the LMP genes may alter the specificity or efficiency of viral protein breakdown by the
large proteolytic complex (see Figure 1). Likewise, the ability of the peptide transporter
complex to transport the viral antigens that are generated may vary according to the TAP1 and/or TAP-2 allele inherited.
We have begun efforts to characterize and clone these four genes in cattle. Our initial
efforts are focused on identifying genetic variants of the LMP and TAP genes among
different cattle breeds and families so that we can determine if these genes are indeed
present in the BoLA complex as they are in the MHC complexes of other species. Upon
completion of gene mapping and cloning we will proceed with efforts to determine if
structural variation in the antigen processing genes segregates with resistance to some of
the common infectious diseases affecting the dairy industry. A brief summary of the
technical approach we are using in our initial efforts is provided below in Figure 2.
SUMMARY
Genes, that encode proteins with very specific and unique roles in immune responses,
such as the antigen processing genes described in this article, are strong candidates for
genetic markers of disease resistance. Identifying distinct genetic variation in cattle
antigen processing genes will allow us to test the hypothesis that structural variation of
these genes is related to the ability of individual cows to combat viral disease. With
modern molecular techniques being available to genotype individual animals, proof of
this hypothesis will allow the dairy producer to select those animals that carry improved
disease resistance.