Identification and Management of Loss of Function Alleles

This paper defines some of the scientific terms used when discussing genetic conditions, and reviews the genetic implications and consequences of mating individuals with various genotypes. Many genetic defects are recessive, and the reason for this is that mutant alleles often render the resulting protein nonfunctional. These are called “loss of function” alleles. In many cases if an individual inherits a functional allele from one parent, there is no deleterious phenotype associated with inheriting the loss of function mutant allele from the other parent. As such, a heterozygous “Aa” (A symbolizes the dominant functional allele, a the recessive loss of function allele) animal, or carrier, appears normal. Because carriers appear normal, newly created recessive alleles can increase in frequency in a population more easily than dominant or additive alleles. There is an obvious connection between inbreeding and homozygosity. The main purpose of inbreeding is to make animals more uniform and homozygous for superior genes, however deleterious allelic variants also become homozygous at the same time, unless such variants are lethal in which case there is obvious natural selection against them. With inbreeding, widely used ancestors contribute alleles on both the male and female sides of an animal’s pedigree. It is for this reason that deleterious autosomal recessive alleles are often identified in the descendants of widely used sire lines. It is not because sire’s with excellent genetic merit carry more deleterious alleles, it is because such sires are more likely to be represented on both sides of a pedigree opening up the possibility that an animal will inherit a deleterious allele from both its sire and dam. With the advent of genomic sequencing technologies, our understanding of the prevalence of autosomal recessive conditions has advanced. Given that the average human carries approximately 2,000 deleterious autosomal recessive variants and a similar number is likely to be found in cattle, overtly avoiding the mating of any carrier animals is going to become increasingly unworkable as more deleterious autosomal recessive variants are identified. Management of recessive conditions has to be balanced with other important issues such as the management of trait merit, genetic diversity, other genetic defects, genome-wide inbreeding, logistical constraints and costs. It is likely that decision support software will be required to facilitate the management of this information. Such software will provide an approach to make judicious use of carrier bulls with superior genetic merit while reducing the risk of generating affected calves and strategically working to slowly eradicate the undesirable alleles from the population. While precluding all matings between carrier animals may not be possible, avoiding matings between animals that carry identical alleles is achievable. There is a need to optimize the matings that involve carrier animals in accordance with their genetic merit and actual genotype for undesirable alleles rather than prohibiting their use entirely, and this can best be accomplished using mate selection software. What is a loss of function allele? 1 Research summarized in this manuscript was Competitive Grant no. 2013-68004-20364 (“Identification and management of alleles impairing heifer fertility while optimizing genetic gain in Angus cattle”, PD: Dr. David Patterson, University of Missouri) from the USDA National Institute of Food and Agriculture.